Current Medical Diagnosis & Treatment 2015

10

Heart Disease

Thomas M. Bashore, MD
Christopher B. Granger, MD
Kevin Jackson, MD
Manesh R. Patel, MD

CONGENITAL HEART DISEASE

In the United States, there are more adults with congenital heart disease than children, with over 1.5 million adults in the United States surviving with congenital heart disease.

Baumgartner H et al; Task Force on the Management of Grown-up Congenital Heart Disease of the European Society of Cardiology (ESC); Association for European Paediatric Cardiology (AEPC); ESC Committee for Practice Guidelines (CPG). ESC Guidelines for the management of grown-up congenital heart disease (new version 2010). Eur Heart J. 2010 Dec;31(23):2915–57. [PMID: 20801927]

Warnes CA et al. ACC/AHA 2008 Guidelines for the Management of Adults With Congenital Heart Disease. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2008 Dec 2;118(23):e714–833. [PMID: 18997169]

PULMONARY VALVE STENOSIS

 ESSENTIALS OF DIAGNOSIS

 Severe cases may present with right-sided heart failure.

 P2 delayed and soft or absent.

 Ejection click often present and decreases with inspiration—the only right heart auscultatory event that decreases with inspiration, all others increase.

 Echocardiography/Doppler is diagnostic.

 Patients with peak pulmonic valve gradients > 60 mm Hg or mean of 40 mm Hg by echocardio-graphy/Doppler should undergo intervention regardless of symptoms.

 General Considerations

Stenosis of the pulmonary valve or right ventricular (RV) infundibulum increases the resistance to RV outflow, raises the RV pressure, and limits pulmonary blood flow. Pulmonic stenosis is often congenital, associated with other cardiac lesions. Pulmonary blood flow preferentially goes to the left lung in valvular pulmonic stenosis. In the absence of associated shunts, arterial saturation is normal. Infundibular stenosis may be so severe that the RV is divided into a low-pressure and high-pressure chamber (double-chambered RV). Peripheral pulmonic stenosis can accompany valvular pulmonic stenosis and may be part of a variety of clinical syndromes, including the congenital rubella syndrome. Patients who have had the Ross procedure for aortic valve disease (transfer of the pulmonary valve to the aortic position with a homograft pulmonary valve placed in the pulmonary position) may experience postoperative (noncongenital) pulmonic stenosis due to an immune response in the homograft. RV outflow obstructions can also occur when there is a conduit from the RV to the pulmonary artery (PA) that becomes stenotic.

 Clinical Findings

  1. Symptoms and Signs

Mild cases of pulmonic stenosis are asymptomatic; moderate to severe pulmonic stenosis may cause symptoms of dyspnea on exertion, syncope, chest pain, and eventually RV failure.

On examination, there is often a palpable parasternal lift due to right ventricular hypertrophy (RVH) and the pulmonary outflow tract may be palpable if it is enlarged. A loud, harsh systolic murmur and occasionally a prominent thrill are present in the left second and third interspaces parasternally. The murmur radiates toward the left shoulder due to the flow pattern and increases with inspiration. In mild to moderate pulmonic stenosis, a loud ejection click can be heard to precede the murmur; this sound decreases with inspiration as the increased RV filling from inspiration prematurely opens the valve during atrial systole. This is the only right-sided auscultatory event that decreases with inspiration. The reason for this is that the valve excursion in systole is less with inspiration than with expiration. This relates to premature opening of the pulmonary valve with the atrial kick into the RV. The click therefore diminishes in intensity when more volume is ejected into the RV with inspiration, raising the RV diastolic pressure. The second sound is obscured by the murmur in severe cases; the pulmonary component may be diminished, delayed, or absent. A right-sided S4 and a prominent a wave in the venous pulse are present when there is RV diastolic dysfunction or a c-v wave if there is tricuspid regurgitation present. Pulmonary valve regurgitation is relatively uncommon in primary pulmonic stenosis and may be very difficult to hear, as the gradient between the reduced PA diastolic pressure and the elevated RV diastolic pressure may be quite small (low-pressure pulmonary valve regurgitation).

  1. ECG and Chest Radiography

Right axis deviation or RVH is noted; peaked P waves provide evidence of right atrial (RA) overload. Heart size may be normal on radiographs, or there may be a prominent RV and RA or gross cardiac enlargement, depending on the severity. There is often poststenotic dilation of the main and left pulmonary arteries. Pulmonary vascularity is usually normal.

  1. Diagnostic Studies

Echocardiography/Doppler is the diagnostic tool of choice, can provide evidence for a doming valve versus a dysplastic valve, can determine the gradient across the valve, and can provide information regarding subvalvular obstruction and the presence or absence of tricuspid or pulmonic valvular regurgitation. Mild pulmonic stenosis is present if the peak gradient by echocardiography/Doppler is < 30 mm Hg, moderate pulmonic stenosis is present if the peak gradient is between 30 mm Hg and 60 mm Hg, and severe pulmonic stenosis is present if the peak gradient is > 60 mm Hg or the mean gradient is > 40 mm Hg. Catheterization is usually unnecessary for the diagnosis; it should be used only if the data are unclear or in preparation for either a percutaneous intervention or surgery.

 Prognosis & Treatment

Patients with mild pulmonic stenosis have a normal life span with no intervention. Moderate stenosis may be asymptomatic in childhood and adolescence, but symptoms often appear as patients grow older. The degree of stenosis does worsen with time in many patients, so serial follow-up is important. Severe stenosis is rarely associated with sudden death but can cause right heart failure in patients as early as in their 20s and 30s. Pregnancy and exercise tends to be well tolerated except in severe stenosis.

Class I indications for intervention include all symptomatic patients and all those with a resting peak gradient > 60 mm Hg or mean > 40 mm Hg, regardless of symptoms. Percutaneous balloon valvuloplasty is highly successful in domed valve patients and is the treatment of choice. Surgical commissurotomy can also be done, or pulmonary valve replacement (with either a bioprosthetic valve or homograft) when pulmonary valve regurgitation is too severe or the valve is dysplastic. Pulmonary outflow tract obstruction due to RV to PA conduit obstruction or to homograft pulmonary valve stenosis can be relieved with a percutaneously implanted pulmonary valve. The applicability of this approach to primary pulmonic valve stenosis remains under investigation.

Endocarditis prophylaxis is unnecessary for native valves even after valvuloplasty unless there has been prior pulmonary valve endocarditis (a very rare entity) (see Table 33–4).

 When to Refer

All symptomatic patients, and all asymptomatic patients whose peak pulmonary valve gradient is > 60 mm Hg or mean gradient > 40 mm Hg, should be referred to a cardiologist with expertise in adult congenital heart disease.

Bashore TM. Adult congenital heart disease: right ventricular outflow tract lesions. Circulation. 2007 Apr 10;115(14):1933–47. [PMID: 17420363]

Odenwald T et al. Pulmonary valve interventions. Expert Rev Cardiovasc Ther. 2011 Nov;9(11):1445–57. [PMID: 22059793]

Warnes CA et al. ACC/AHA 2008 Guidelines for the Management of Adults With Congenital Heart Disease. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2008 Dec 2;118(23):e714–833. [PMID: 18997169]

COARCTATION OF THE AORTA

 ESSENTIALS OF DIAGNOSIS

 Usual presentation is systemic hypertension.

 Echocardiography/Doppler is diagnostic; a gradient of > 20 mm Hg may be significant due to collaterals around the coarctation, reducing gradient despite severe obstruction.

 Associated bicuspid aortic valve (in 50–80% of patients).

 Systolic pressure is higher in upper extremities than in lower extremities; diastolic pressures are similar.

 General Considerations

Coarctation of the aorta consists of localized narrowing of the aortic arch just distal to the origin of the left subclavian artery. Collateral circulation develops around the coarctation through the intercostal arteries and the branches of the subclavian arteries and can result in a lower transcoarctation gradient by enabling blood flow to bypass the obstruction. Coarctation is a cause of secondary hypertension and should be considered in young patients with elevated blood pressure (BP). The renin–angiotensin system is reset, however, and contributes to the hypertension occasionally seen even after coarctation repair. A bicuspid valve is seen in over 50–80% of the cases, and there is an increased incidence of cerebral berry aneurysms.

 Clinical Findings

  1. Symptoms and Signs

If cardiac failure does not occur in infancy, there are usually no symptoms until the hypertension produces left ventricular (LV) failure or cerebral hemorrhage occurs. Strong arterial pulsations are seen in the neck and suprasternal notch. Hypertension is present in the arms, but the pressure is normal or low in the legs. This difference is exaggerated by exercise. Femoral pulsations are weak and are delayed in comparison with the brachial or radial pulse. Patients may have severe coarctation, but with large collateral blood vessels may have relatively small gradients across the coarctation because of high flow through the collaterals to the aorta distal to the coarctation. A continuous murmur heard superiorly and midline in the back or over the left anterior chest may be present when large collaterals are present. The coarctation itself may result in systolic ejection murmurs at the base, often heard posteriorly. There may be an associated aortic regurgitation or stenosis murmur due to the bicuspid aortic valve.

  1. ECG and Chest Radiography

The ECG usually shows LV hypertrophy (LVH). Radiography shows scalloping of the ribs due to enlarged collateral intercostal arteries, dilation of the left subclavian artery and poststenotic aortic dilation, and LV enlargement. The coarctation region and the poststenotic dilation of the descending aorta may result in a “3” sign along aortic shadow on the PA chest radiograph (the notch in the “3” representing the area of coarctation).

  1. Diagnostic Studies

Echocardiography/Doppler is usually diagnostic and may provide additional evidence for a bicuspid aortic valve. Both MRI and CT can also provide excellent images of the coarctation local anatomy and one or the other should be done in all patients to define the coarctation structure. MRI and echocardiography/Doppler can also provide estimates of the gradient across the lesion. A significant peak-to-peak gradient is > 20 mm Hg. Cardiac catheterization provides definitive gradient information and is necessary if percutaneous stenting is to be considered.

 Prognosis & Treatment

Cardiac failure is common in infancy and in older untreated patients; it is uncommon in late childhood and young adulthood. Patients with a demonstrated peak gradient of > 20 mm Hg should be considered for intervention, especially if there is evidence of collateral blood vessels. Most untreated patients with severe coarctation die of hypertension, rupture of the aorta, infective endarteritis, or cerebral hemorrhage before the age of 50. Aortic dissection also occurs with increased frequency. Coarctation of any significance may be poorly tolerated in pregnancy because of the inability to support the placental flow.

Resection of the coarctation site has a surgical mortality rate of 1–4% and includes risk of spinal cord injury. The percutaneous interventional procedure of choice is endovascular stenting when anatomically feasible; self-expanding and balloon-expandable covered stents have been shown to be advantageous over bare metal stents. Otherwise, surgical resection (usually with end-to-end anastomosis) should be performed. About 25% of surgically corrected patients continue to be hypertensive years after surgery because of permanent changes in the renin–angiotensin system, endothelial dysfunction, aortic stiffness, altered arch morphology, and increased ventricular stiffness. Recurrence of the coarctation stenosis following intervention requires long-term follow-up.

 When to Refer

All patients with coarctation and a detectable gradient should be referred to a cardiologist with expertise in adult congenital heart disease.

Brown ML et al. Coarctation of the aorta: lifelong surveillance is mandatory following surgical repair. J Am Coll Cardiol. 2013 Sep 10;62(11):1020–5. [PMID: 23850909]

Vergales JE et al. Coarctation of the aorta—the current state of surgical and transcatheter therapies. Curr Cardiol Rev. 2013 Aug;9(3):211–9. [PMID: 23909637]

Warnes CA et al. ACC/AHA 2008 Guidelines for the Management of Adults With Congenital Heart Disease. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2008 Dec 2;118(23):e714–833. [PMID: 18997169]

ATRIAL SEPTAL DEFECT & PATENTFORAMEN OVALE

 ESSENTIALS OF DIAGNOSIS

 Often asymptomatic and discovered on routine physical examination.

 Echocardiography/Doppler is diagnostic.

 All atrial septal defects (ASD) should be closed either by a percutaneous device or by surgery if there is any evidence of an RV volume overload regardless of symptoms.

 A patent foramen ovale (PFO), present in 25% of the population, rarely can lead to paradoxic emboli. Suspicion should be highest in patients who have cryptogenic stroke before age 55 years.

 General Considerations

The most common form of ASD (80% of cases) is persistence of the ostium secundum in the mid septum. A less common abnormality is persistence of the ostium primum (low in the septum). In many patients with an ostium primum defect, there are mitral or tricuspid valve “clefts” as well as a ventricular septal defect (VSD) as part of the atrioventricular (AV) septal defect. A third form of ASD is thesinus venosus defect, a hole usually at of the upper or (rarely) the lower part of the atrial septum due to failure of the embryonic superior vena cava or the inferior vena cava to merge with the atria properly. The inferior vena cava sinus venosus defect is uncommon. The superior vena cava sinus venosus defect is usually associated with an anomalous connection of the right upper pulmonary vein into the superior vena cava. The coronary sinus ASD is also rare and basically an unroofed coronary sinus. In all cases, normally oxygenated blood from the higher-pressure LA passes into the RA, increasing RV output and pulmonary blood flow. In children, the degree of shunting across these defects may be quite large (pulmonary to systemic blood flow ratios of 3:1 or so). As the RV diastolic pressure rises from the chronic volume overload, the RA pressure may rise and the degree of left-to-right shunting may decrease. Eventually, if the RA pressure exceeds the LA, the shunt may reverse and be primarily right-to-left and systemic cyanosis appears. The major factor in the direction of shunt flow is thus the compliance of the respective atrial chambers.

The pulmonary pressures are modestly elevated in most patients with an ASD due to the high pulmonary blood flow, but severe pulmonary hypertension with cyanosis (Eisenmenger physiology) is actually unusual, occurring in only about 15% of the patients with an ASD alone. Eventual RV failure may occur though, and most shunts should be corrected unless they are quite small (< 1.5:1 left-to-right shunt). In adults, a large left-to-right shunt may have begun to reverse, so the absolute left-to-right shunt measurement (Qp/Qs, where Qp = pulmonary flow and Qs = systemic flow) at the time the patient is studied may underestimate the original shunt size. In addition, in most patients the LV and LA compliance normally declines more over time than the RV and RA, and the natural history of small atrial septal shunts is to increase the left-to-right shunt as the patient ages.

ASDs predispose to atrial fibrillation due to RA enlargement, and paradoxic right-to-left emboli do occur. Interestingly, paradoxic emboli may be more common in patients with a PFO than a true ASD. An aneurysm of the atrial septum is not a true aneurysm but rather simply redundancy of the atrial septum. When present with a PFO, the back and forth swinging of the redundant atrial septum (“jump rope septum”) tends to pull open the PFO. This helps explain why more right-to-left shunting occurs in patients with an atrial septal aneurysm and PFO than in those with a PFO alone and creates the anatomic substrate for the occurrence of paradoxical emboli. Other factors may distort the atrial septum (such as an enlarged aorta) and increase shunting in patients with a PFO. Right to left PFO shunting may be more prominent upright, creating orthostatic hypoxemia (platypnea orthodeoxia).

 Clinical Findings

  1. Symptoms and Signs

Patients with a small or moderate ASD or with a PFO are asymptomatic unless a complication occurs. There is only trivial shunting in a PFO unless the RA pressure increases for some other reason or the atrial septum is distorted. Shunting in a PFO is more common if an atrial septal aneurysm is present. With larger ASD shunts, exertional dyspnea or heart failure may develop, most commonly in the fourth decade of life or later. Prominent RV and PA pulsations are then readily visible and palpable. A moderately loud systolic ejection murmur can be heard in the second and third interspaces parasternally as a result of increased flow through the pulmonary valve. S2 is widely split and does not vary with breathing due to the fact that the left-to-right shunt decreases as the RA pressure increases with inspiration and the RV stroke volume is held relatively constant in inspiration and expiration (“fixed” splitting of the second sound results). In very large left-to-right shunts, a tricuspid rumble may be heard due to the high flow across the tricuspid valve.

  1. ECG and Chest Radiography

Right axis deviation or RVH may be present depending on the size of the RV volume overload. Incomplete or complete right bundle branch block is present in nearly all cases of ASD, and superior axis deviation is noted in the complete AV septal defect, where complete heart block is often seen as well. With sinus venosus defects, the P axis is leftward of +15° due to abnormal atrial activation with loss of the upper RA tissue from around the sinus node. In some patients with a secundum defect, there is notching in the inferior QRS leads (sometimes referred to as crochetage since the negative spike within the QRS resembles a crochet needle). The chest radiograph shows large pulmonary arteries, increased pulmonary vascularity, an enlarged RA and RV, and a small aortic knob as with all pre-tricuspid valve cardiac left-to-right shunts.

  1. Diagnostic Studies

Echocardiography demonstrates evidence of RA and RV volume overload. The atrial defect is usually observed, although sinus venosus defects may be elusive. Many patients with a PFO also have an atrial septal aneurysm (defined as > 10 mm excursion of the septum from the static position). Echocardiography with agitated saline bubble contrast can demonstrate a right-to-left shunt, and both pulsed and color flow Doppler flow studies can demonstrate shunting in either direction. In platypnea orthodeoxia, the shunt may primarily result from inferior vena cava blood, and a femoral vein saline injection may be required to demonstrate the shunt. Transesophageal echocardiography (TEE) is helpful when transthoracic echocardiography quality is not optimal because it improves the sensitivity for detection of small shunts and provides a better assessment of PFO anatomy. Both CT and MRI can elucidate the atrial septal anatomy and demonstrate associated lesions, such as anomalous pulmonary venous connections. Atrial septal anatomy can be complex, and MRI can both define multiple fenestrations and reveal whether there is an adequate rim around the defect to allow for safe positioning of an atrial septal device. Cardiac catheterization can define the size and location of the shunt and determine the pulmonary pressure and pulmonary vascular resistance (PVR).

 Prognosis & Treatment

Patients with small atrial shunts live a normal life span with no intervention. Large shunts usually cause disability by age 40 years. Because left-to-right shunts tend to increase with age-related changes in LV (and subsequently LA) compliance, guidelines suggest that closure of all left-to-right shunts over 1.5:1 should be accomplished. This situation always results in RV volume overload. Increased PVR and pulmonary hypertension secondary to pulmonary vascular disease rarely occur in childhood or young adult life in secundum defects but are more common in primum defects. If the pulmonary systolic pressure is > two-thirds the systemic pressure, the pulmonary hypertension may preclude ASD closure. After age 40 years, cardiac arrhythmias (especially atrial fibrillation) and heart failure occur with increased frequency due to the chronic right heart volume overload. Paradoxical systemic arterial embolization also becomes more of a concern as RV compliance is lost and the left-to-right shunt begins to reverse.

PFOs are usually not associated with significant shunting, and therefore the patients are asymptomatic and the heart size is normal. However, PFOs are responsible for most paradoxical emboli and are one of the most frequent causes of cryptogenic strokes in patients under age 55 years. An associated atrial septal aneurysm increases the risk of right-to-left shunting.

Occasionally, a PFO may be responsible for cyanosis, especially if the RA pressure is elevated from pulmonary or RV hypertension or from severe tricuspid regurgitation.

Surgery involves anything from simple stitching of the foramen closed to patching of the hole with Dacron or a pericardial patch. For ostium secundum ASDs, percutaneous closure by use of a variety of devices is preferred over surgery when the anatomy is appropriate.

Patients with a PFO who have symptoms related to stroke or transient ischemic attack (especially if the age is under 55) or who have hypoxemia (especially upon standing) should have the PFO closed if no other cause for symptoms is evident. For patients with cryptogenic stroke or transient ischemic attack, it remains uncertain whether closure of the PFO, either by open surgical or percutaneous techniques, has any advantage over anticoagulation with either warfarin or aspirin. RESPECT (Randomized Evaluation of recurrent Stroke comparing PFO Closure to current standard Treatment) randomized 980 patients, and PCTRIAL (Percutaneous Closure of patent foramen ovale versus medical treatment in patients with cryptogenic stroke TRIAL) randomized 414 patients. Neither trial met the superiority composite end point (death, nonfatal stroke, transient ischemic attack, or peripheral embolism), but both trials had much fewer events in the medical arms than prior studies had suggested. Practically, young patients (< 55 years of age) with cryptogenic stroke and no other identifiable cause except for the presence of a PFO may still be considered for PFO closure in many centers, but the data suggest medical therapy remains an equally viable option.

When cyanosis might be improved by PFO closure, it is appropriate to consider it. PFO closure is also occasionally recommended for deep sea divers to help prevent the “bends” due to nitrous oxide shunting. A case-control study did not confirm the relationship between migraine plus aura and a PFO.

 When to Refer

  • All patients with an ASD should be evaluated by a cardiologist with expertise in adult congenital disease to ensure no other structural disease is present and to investigate whether the RV is enlarged.
  • If the RA and RV sizes remain normal, serial echocardiography should be performed.
  • If the RA and RV volumes increase, then referral to a cardiologist who performs percutaneous closure is warranted.
  • Patients < 55 years of age with an apparent paradoxical embolus and a PFO should be referred for possible closure of the defect, although studies have yet to prove the effectiveness of percutaneous closure and medical therapy appears equally effective.
  • Patients with cyanosis and a PFO with evidence for a right-to-left shunt by agitated saline bubble contrast on echocardiography.

Carroll JD et al; RESPECT Investigators. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med. 2013 Mar 21;368(12):1092–100. [PMID: 23514286]

Di Tullio MR et al. Patent foramen ovale, subclinical cerebrovascular disease, and ischemic stroke in a population-based cohort. J Am Coll Cardiol. 2013 Jul 2;62(1):35–41. [PMID: 23644084]

Garg P et al. Lack of association between migraine headache and patent foramen ovale: results of a case-control study. Circulation. 2010 Mar 30;121(12):1406–12. [PMID: 20231534]

Hoffmann A et al. Cerebrovascular accidents in adult patients with congenital heart disease. Heart. 2010 Aug;96(15):1223–6. [PMID: 20639238]

Landzberg MJ et al. Patent foramen ovale: when is intervention warranted? Can J Cardiol. 2013 Jul;29(7):890–2. [PMID: 23790552]

Tobis J et al. Percutaneous treatment of patent foramen ovale and atrial septal defects. J Am Coll Cardiol. 2012 Oct 30;60 (18): 1722–32. [PMID: 23040567]

Warnes CA et al. ACC/AHA 2008 Guidelines for the Management of Adults With Congenital Heart Disease. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2008 Dec 2;118(23):e714–833. [PMID: 18997169]

VENTRICULAR SEPTAL DEFECT

 ESSENTIALS OF DIAGNOSIS

 A restrictive VSD is small and makes a louder murmur than an unrestricted one. The higher the gradient across the septum, the smaller the left-to- right shunt.

 Small defects may be asymptomatic.

 Larger defects may result in pulmonary hypertension (Eisenmenger physiology) if not repaired.

 Echocardiography/Doppler is diagnostic.

 General Considerations

De novo VSDs are uncommon in adults. Congenital VSDs occur in various parts of the ventricular septum. Four types are often described: in type A, the VSD lies underneath the semilunar valves; in type B, the VSD is membranous with three variations; in type C, the inlet VSD is present below the tricuspid valve and often part of the AV canal defect; and type D is the muscular VSD. Membranous and muscular septal defects may spontaneously close in childhood as the septum grows and hypertrophies. A left-to-right shunt is present unless there is associated RV hypertension. The smaller the defect, the greater the gradient from the LV to the RV and the louder the murmur. The presentation in adults depends on the size of the shunt and whether there is associated pulmonic or subpulmonic stenosis that has protected the lung from the systemic pressure and volume. Unprotected lungs with large shunts invariably lead to pulmonary vascular disease and severe pulmonary hypertension (Eisenmenger physiology).

 Clinical Findings

  1. Symptoms and Signs

The clinical features depend on the size of the defect and the presence or absence of RV outflow obstruction or increased PVR. Small shunts are associated with loud, harsh holosystolic murmurs in the left third and fourth interspaces along the sternum. A systolic thrill is common. Larger shunts may create RV volume and pressure overload. If pulmonary hypertension occurs, high-pressure pulmonary valve regurgitation may result. Right heart failure may gradually become evident late in the course, and the shunt will begin to balance or reverse as RV and LV systolic pressures equalize with the advent of pulmonary hypertension. Cyanosis from right-to-left shunting may then occur.

  1. ECG and Chest Radiography

The ECG may be normal or may show right, left, or biventricular hypertrophy, depending on the size of the defect and the PVR. With large shunts, the RV, the LV, the LA, and the pulmonary arteries are enlarged and pulmonary vascularity is increased on chest radiographs. The RV is often normal until late in the process. If an increased PVR (pulmonary hypertension) evolves, an enlarged PA with pruning of the distal pulmonary vascular bed is seen. In rare cases of a VSD high in the ventricular septum, an aortic cusp may prolapse into the VSD and reduce the VSD shunt but result in acute aortic regurgitation.

  1. Diagnostic Studies

Echocardiography can demonstrate the size of the overloaded chambers and can usually define the defect anatomy. Doppler can qualitatively assess the magnitude of shunting by noting the gradient from LV to RV and, if some tricuspid regurgitation is present, the RV systolic pressure can be estimated. The septal leaflet of the tricuspid valve may be part of the VSD anatomy and the complex appears as a ventricular septal “aneurysm.” These membranous septal aneurysms may fenestrate and result in a VSD shunt or may remain intact. Color flow Doppler helps delineate the shunt severity and the presence of valvular regurgitation. MRI and cardiac CT can often visualize the defect and describe any other anatomic abnormalities. MRI can provide quantitative shunt data as well. Cardiac catheterization is usually reserved for those with at least moderate shunting to determine the PVR and the degree of pulmonary hypertension. A PVR of > 7.0 absolute units or a PVR/systemic vascular resistance ratio of > 0.67 (two-thirds systemic) usually implies inoperability. The vasoreactivity of the pulmonary circuit may be tested at catheterization using agents such as inhaled nitric oxide.

 Prognosis & Treatment

Patients with a small VSD as the only abnormality have a normal life expectancy except for the small threat of infective endocarditis. Antibiotic prophylaxis after dental work is only recommended when the VSD is residual from a prior patch closure or when there is associated pulmonary hypertension and cyanosis (see Tables 33–433–5, and 33–6). With large shunts, heart failure may develop early in life, and survival beyond age 40 years is unusual without intervention.

The 2008 ACC/AHA guidelines for the management of patients with VSD include the following:

  1. Medical management (class 2b recommendation): Pulmonary vasodilatory therapy is appropriate for adults with a VSD and severe pulmonary hypertension. The response to inhaled nitric oxide is used to guide which agent would be the best option.
  2. Surgical management (class 1 recommendation): Closure is indicated when the left-to-right shunt ratio is > 2.0 or there is clinical LV volume overload. In addition, closure is recommended if there has been a history of infective endocarditis.
  3. Surgical management (class 2b recommendation): Closure is reasonable if the left-to-right shunt is > 1.5 and pulmonary pressure and PVR are less than two-thirds systemic pressure and systemic vascular resistance. Closure is also reasonable if the shunt ratio is > 1.5 and there is evidence of heart failure.

Small shunts (pulmonary-to-systemic flow ratio < 1.5) in asymptomatic patients do not require surgery or other intervention. The presence of RV infundibular stenosis or pulmonary valve stenosis may protect the pulmonary circuit such that some patients even with a large VSD may still be operable as adults.

Surgical repair of a VSD is generally a low-risk procedure unless there is significant Eisenmenger physiology. Devices for nonsurgical closure of muscular VSDs are approved and those for membranous VSDs are being implanted with promising results; however, conduction disturbance is a major complication. The percutaneous devices are also approved for closure of a VSD related to acute myocardial infarction, although the results in this very high-risk patient population have not been encouraging. The drugs used to treat pulmonary hypertension secondary to VSD are similar to those used to treat idiopathic (“primary”) pulmonary hypertension (see below).

 When to Refer

All patients with a VSD should be referred to a cardiologist with expertise in adult congenital disease to decide if long-term follow-up is warranted.

Anderson BR et al. Contemporary outcomes of surgical ventricular septal defect closure. J Thorac Cardiovasc Surg. 2013 Mar;145(3):641–7. [PMID: 23414985]

Penny DJ et al. Ventricular septal defect. Lancet. 2011 Mar 26;377(9771):1103–12. [PMID: 21349577]

Warnes CA et al. ACC/AHA 2008 Guidelines for the Management of Adults With Congenital Heart Disease. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2008 Dec 2;118(23):e714–833. [PMID: 18997169]

TETRALOGY OF FALLOT

 ESSENTIALS OF DIAGNOSIS

 Five features are characteristic:

– VSD.

– RVH.

– RV outflow obstruction from infundibular stenosis.

– Overriding aorta in half (< 50% of the aorta over the septum).

– A right-sided aortic arch is seen in 25%.

 Echocardiography/Doppler and the examination may underestimate significant pulmonary valve regurgitation. Be wary if the RV is enlarged.

 Arrhythmias are common; periodic Holter monitoring is recommended.

 Serious arrhythmias and sudden death may occur if the QRS width is > 180 msec.

 General Considerations

Patients with tetralogy of Fallot have a VSD, RV infundibular stenosis, RVH, and a dilated aorta (in about 50% of patients it overrides the septum). If there is an associated ASD, the complex is referred to as pentalogy of Fallot. There may or may not be pulmonary valve stenosis as well, usually due to a bicuspid pulmonary valve. The aorta can be quite enlarged and aortic regurgitation may occur. If more than 50% of the aorta overrides into the RV outflow tract, the anatomy is considered as double outlet RV. Two vascular abnormalities are common: a right-sided aortic arch (in 25%) and anomalous left anterior descending coronary artery from the right cusp (7–9%). The latter is important in that surgical correction must avoid injuring the coronary artery when repairing the RV outflow obstruction.

Most adult patients have undergone prior surgery. If significant RV outflow obstruction is present in infancy, a systemic arterial to pulmonary artery shunt is often the initial surgical procedure to improve pulmonary blood flow. This procedure enables blood to reach the underperfused lung either by directly attaching one of the subclavian arteries to the PA (classic Blalock shunt) or by creating a conduit between the two (modified Blalock shunt). Other types of systemic to pulmonary shunts no longer in use include a window between the right PA and the aorta (Waterston-Cooley shunt) or a window between the left PA and the descending aorta (Potts shunt). In the adult, there may be a reduced upper extremity pulse on the side used for the classic Blalock procedure. Total repair of the tetralogy of Fallot generally includes a VSD patch and usually an enlarging RV outflow tract patch, as well as a take-down of the arterial-pulmonary artery shunt. Often the RV outflow tract patch extends through the pulmonary valve into the PA (trans-annular patch), and the patient is left with varying degrees of pulmonary valve regurgitation. Over the years, the volume overload from severe pulmonary valve regurgitation becomes the major hemodynamic problem seen in adults. Ventricular arrhythmias can also originate from the edge of the patch, and tend to increase with the size of the RV.

 Clinical Findings

Most adult patients in whom tetralogy of Fallot has been repaired are relatively asymptomatic unless right heart failure occurs or arrhythmias become an issue. Patients can be active and generally require no specific therapy except endocarditis prophylaxis.

  1. Symptoms and Signs

Physical examination should include checking both arms for any loss of pulse from a prior shunt procedure in infancy. The jugular venous pulsations (JVP) may reveal an increased a wave from poor RV compliance or rarely a c-v wave due to tricuspid regurgitation. The right-sided arch has no consequence. The precordium may be active, often with a persistent pulmonary outflow murmur. P2 may or may not be audible. A right-sided gallop may be heard. A residual VSD or aortic regurgitation murmur may be present. At times, the insertion site of a prior Blalock or other shunt may create a stenotic area in the branch PA and a continuous murmur occurs as a result.

  1. ECG and Chest Radiography

The ECG reveals RVH and right axis deviation; in repaired tetralogy, there is often a right bundle branch block pattern. The chest radiograph shows a classic boot-shaped heart with prominence of the RV and a concavity in the RV outflow tract. This may be less impressive following repair. The aorta may be enlarged and right-sided. Importantly, the width of the QRS should be examined yearly. There are data that persons at greatest risk for sudden death are those with a QRS width of > 180 msec. Most experts recommend Holter monitoring as well, especially if patients experience palpitations. The width of the QRS corresponds to the RV size, and in some patients, the QRS width actually decreases following relief of the pulmonary valve regurgitation with use of a prosthetic pulmonary valve.

  1. Diagnostic Studies

Echocardiography/Doppler usually establishes the diagnosis by noting the unrestricted (large) VSD, the RV infundibular stenosis, and the enlarged aorta. In patients who have had tetralogy of Fallot repaired, echocardiography/Doppler also provides data regarding the amount of pulmonary valve regurgitation, RV and LV function, and the presence of aortic regurgitation.

Cardiac MRI and CT can quantitate both the pulmonary insufficiency and the RV volumes. In addition, cardiac MRI and CT can identify whether there is either a native pulmonary arterial branch stenosis or a stenosis at the distal site of a prior arterial-to-PA shunt or other anomalies such as an ASD. Cardiac catheterization is occasionally required to document the degree of pulmonary valve regurgitation because noninvasive studies depend on velocity gradients. Pulmonary angiography demonstrates the degree of pulmonary valve regurgitation, and RV angiography helps assess any postoperative outflow tract aneurysm.

 Prognosis & Treatment

A few patients with “just the right amount” of subpulmonic stenosis enter adulthood without having had surgery. However, most adult patients have had surgical repair of tetralogy of Fallot, including VSD closure, resection of infundibular muscle, and insertion of an outflow tract patch to relieve the subpulmonic obstruction. Many have a transannular patch resulting in pulmonary valve regurgitation. Patients should be monitored to ensure the RV volume does not increase. Low-pressure pulmonary valve regurgitation is difficult to diagnose due to the fact that the RV diastolic pressures tend to be high and the pulmonary arterial diastolic pressure is low. This means there is little gradient between the PA and the RV in diastole, so that there may be little murmur or evidence for turbulence on color flow Doppler. If the RV begins to enlarge, it must be assumed that this is due to pulmonary valve regurgitation until proven otherwise. Early surgical pulmonary valve replacement is increasingly being favored. A percutaneous approach is not approved at this point.

If an anomalous coronary artery is present, then an extracardiac conduit around it from the RV to the PA may be necessary. By 20-year follow-up, reoperation is needed in about 10–15%, not only for severe pulmonary valve regurgitation but also for residual infundibular stenosis. Usually the pulmonary valve is replaced with a pulmonary homograft, although a porcine bioprosthetic valve is also suitable. Cryoablation of tissue giving rise to arrhythmias is sometimes performed at the time of reoperation. Branch pulmonary stenosis may be percutaneously opened by stenting. If a conduit has been used already for repair of the RV outflow obstruction, a percutaneous approach with a stented pulmonary valve may be possible. All patients require endocarditis prophylaxis (see Tables 33–433–5, and 33–6). Most adults with stable hemodynamics can be quite active, and most women can carry a pregnancy adequately.

Arrhythmias are not uncommon with both atrial fibrillation and ventricular ectopy noted especially after the age of 45. Left heart disease appears to cause these arrhythmias more often than right heart disease. Biventricular dysfunction is not an uncommon consequence as the patient ages. The cause of associated LV dysfunction is often multifactorial and frequently unclear.

 When to Refer

All patients with tetralogy of Fallot should be referred to a cardiologist with expertise in adult congenital heart disease.

Aboulhosn JA et al; Alliance for Adult Research in Congenital Cardiology (AARCC). Left and right ventricular diastolic function in adults with surgically repaired tetralogy of Fallot: a multi-institutional study. Can J Cardiol. 2013 Jul;29(7): 866–72. [PMID: 23369488]

Apitz C et al. Tetralogy of Fallot. Lancet. 2009 Oct 24;374(9699): 1462–71. [PMID: 19683809]

Bashore TM. Adult congenital heart disease: right ventricular outflow tract lesions. Circulation. 2007 Apr 10;115(14):1933–47. [PMID: 17420363]

Khairy P et al; Alliance for Adult Research in Congenital Cardiology (AARCC). Arrhythmia burden in adults with surgically repaired tetralogy of Fallot: a multi-institutional study. Circulation. 2010 Aug 31;122(9):868–75. [PMID: 20713900]

Scherptong RW et al. Follow-up after pulmonary valve replacement in adults with tetralogy of Fallot: association between QRS duration and outcome. J Am Coll Cardiol. 2010 Oct 26;56:1486–92. [PMID: 20951325]

PATENT DUCTUS ARTERIOSUS

 ESSENTIALS OF DIAGNOSIS

 Rare in adults.

 Adults with a small or moderate size patent ductus arteriosus are usually asymptomatic, at least until middle age.

 The lesion is best visualized by MRI, CT, or contrast angiography.

 General Considerations

The embryonic ductus arteriosus allows shunting of blood from the PA to the aorta in utero. The ductus arteriosus normally closes immediately after birth so that right heart blood flows only to the pulmonary arteries. Failure to close results in a persistent shunt connecting the left PA and aorta, usually near the origin of the left subclavian artery. Prior to birth, the ductus is kept patent by the effect of circulating prostaglandins; in the neonate, a patent ductus can often be closed by administration of a prostaglandin inhibitor such as indomethacin. The effect of the persistent left-to-right shunt on the pulmonary circuit is dependent on the size of the ductus. If large enough, pulmonary hypertension (Eisenmenger physiology) may occur. A small ductus may be well tolerated until adulthood.

 Clinical Findings

  1. Symptoms and Signs

There are no symptoms unless LV failure or pulmonary hypertension develops. The heart is of normal size or slightly enlarged, with a hyperdynamic apical impulse. The pulse pressure is wide, and diastolic pressure is low. A continuous rough “machinery” murmur, accentuated in late systole at the time of S2, is heard best in the left first and second interspaces at the left sternal border. Thrills are common. If pulmonary hypertension is present (Eisenmenger physiology), the shunt may reverse and the lower body receives desaturated blood, while the upper body receives saturated blood. Thus, the hands appear normal while the toes are cyanotic and clubbed (differential cyanosis).

  1. ECG and Chest Radiography

A normal ECG tracing or LVH is found, depending on the magnitude of shunting. On chest radiographs, the heart is normal in size and contour, or there may be LV and LA enlargement. The PA, aorta, and LA are prominent because they all are in the shunt pathway.

  1. Diagnostic Studies

Echocardiography/Doppler can determine LV, RV, and atrial dimensions. Color flow Doppler allows visualization of the high velocity shunt jet into the proximal left PA. Cardiac MRI and CT, however, are the best noninvasive modalities to demonstrate the abnormality and its shape and to assess the size of the pulmonary arteries. Cardiac catheterization can establish the shunt size and direction, and define the size and anatomic features of the ductus. It can also help determine whether pulmonary hypertension has occurred and vasodilatory testing can be performed to see if some of the pulmonary hypertension is reactive.

 Prognosis & Treatment

Large shunts cause a high mortality rate from cardiac failure early in life. Smaller shunts are compatible with long survival, heart failure being the most common late complication. Infective endocarditis or endarteritis may rarely occur, and antibiotic prophylaxis for dental procedures continues to be recommended by some clinicians (see Tables 33–433–5, and 33–6).

Surgical ligation of the patent ductus can be accomplished with excellent results. If the ductus has a “neck” and is of small enough size, percutaneous approaches using either coils or occluder devices are the preferred therapy. Newer duct occluder devices have a high success rate at a very low risk and are preferred. Patients with Eisenmenger physiology who have not undergone surgical ligation may benefit from pulmonary vasodilator therapy. To monitor these latter patients, serial assessment of toe oxygen saturation as a marker of improvement in the right-to-left shunt is important because of the reversal in flow in the ductus. On rare occasions the ductus may become aneurysmal and require repair.

Table 10–1 outlines the current recommendations for intervention in adult patients with a patent ductus arteriosus. Note it is the only lesion that depends on auscultation; if the murmur is audible, it should be repaired.

Table 10–1. Recommendations for interventions in patients with patent ductus arteriosus.1

 When to Refer

All patients with patent ductus arteriosus should be referred to a cardiologist with expertise in adult congenital disease.

Laughon M et al. Patent ductus arteriosus management: what are the next steps? J Pediatr. 2010 Sep;157(3):355–7. [PMID: 20580017]

Song S et al. Hybrid approach for aneurysm of patent ductus arteriosus in an adult. Ann Thorac Surg. 2013 Jan;95(1):e15–7. [PMID: 23272885]

Warnes CA et al. ACC/AHA 2008 Guidelines for the Management of Adults With Congenital Heart Disease. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2008 Dec 2;118(23):e714–833. [PMID: 18997169]

VALVULAR HEART DISEASE

A 2014 update of the ACCF/AHA valvular guidelines suggests all lesions may be best classified clinically into one of six categories:

   

Nishimura RA et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Mar 3. [Epub ahead of print] [PMID: 24589853]

MITRAL STENOSIS

 ESSENTIALS OF DIAGNOSIS

 Fatigue, exertional dyspnea, orthopnea, and paroxysmal nocturnal dyspnea when the stenosis becomes severe.

 Symptoms often precipitated by onset of atrial fibrillation or pregnancy.

 Two syndromes occur; one with moderate mitral stenosis and dyspnea and one with severe mitral stenosis, pulmonary hypertension, and low cardiac output.

 Echocardiography/Doppler is diagnostic.

 Intervention indicated for symptoms or evidence of pulmonary hypertension. Most symptomatic patients have a valve area < 1.5 cm2.

 General Considerations

Most patients with mitral stenosis are usually presumed to have underlying rheumatic heart disease, though a history of rheumatic fever is usually noted in only about one-third. Rheumatic mitral stenosis results in thickening of the leaflets, fusion of the mitral commissures, retraction, thickening and fusion of the chordae, and calcium deposition in the valve. Mitral stenosis can also occur due to congenital disease with chordal fusion or papillary muscle malposition. The papillary muscles may be abnormally close together, sometimes so close they merge into a single papillary muscle (the parachute mitral valve). In these patients, the chordae or valvular tissue (or both) may also be fused. In other patients, mitral annular calcification may stiffen the mitral valve and reduce its motion to the point where a mitral gradient is present, most often in the elderly or patients with end-stage renal disease. Calcium in the mitral annulus virtually invades the mitral leaflet from the annulus inward as opposed to the calcium buildup from rheumatic heart disease, where it is commonly in the commissures and leaflet edges. Mitral valve obstruction may also develop in patients who have had mitral valve repair with a mitral annular ring that is too small, or in patients who have had a surgical valve replacement (prosthetic valve-patient mismatch).

 Clinical Findings

  1. Symptoms and Signs

Two clinical syndromes occur with mitral stenosis. In mild to moderate mitral stenosis, LA pressure and cardiac output may be essentially normal, and the patient is either asymptomatic or symptomatic only with extreme exertion. The measured valve area is usually between 1.5 cm2 and 1.0 cm2. In severe mitral stenosis (valve area < 1.0 cm2), severe pulmonary hypertension develops due to a “secondary stenosis” of the pulmonary vasculature. In this condition, pulmonary edema is uncommon, but symptoms of low cardiac output and right heart failure predominate.

A characteristic finding of rheumatic mitral stenosis is an opening snap following A2 due to the stiff mitral valve. The interval between the opening snap and aortic closure sound is long when the LA pressure is low but shortens as the LA pressure rises and approaches the aortic diastolic pressure. As mitral stenosis worsens, there is a localized diastolic murmur low in pitch whose duration increases with the severity of the stenosis. The heart murmur is best heard at the apex with the patient in the left lateral position (Table 10–2).

Table 10–2. Differential diagnosis of valvular heart disease.

Paroxysmal or chronic atrial fibrillation eventually develops in 50–80% of patients. Any increase in the heart rate reduces diastolic filling time and increases the mitral gradient. A sudden increase in heart rate may precipitate pulmonary edema. Therefore, heart rate control is important to maintain, with slow heart rates allowing for more diastolic filling of the LV.

  1. Diagnostic Studies

Echocardiography is the most valuable technique for assessing mitral stenosis (Table 10–2). A scoring system is helpful in defining which patients are eligible for percutaneous valvuloplasty. One to four points are assigned to each of four observed parameters, with one being the least involvement and four the greatest: mitral leaflet thickening, mitral leaflet mobility, submitral scarring, and commissural calcium. Patients with a total valve score of 8 or less respond best to balloon valvuloplasty. LA size can also be determined by echocardiography: increased size denotes an increased likelihood of atrial fibrillation and thrombus formation. The effective mitral valve area can be determined by planimetering the smallest mitral orifice or by using the continuous-wave Doppler gradient. Some determination of the pulmonary pressure can also be quantitated by measuring the peak RV pressure from the tricuspid velocity jet signal.

Because echocardiography and careful symptom evaluation provide most of the needed information, cardiac catheterization is used primarily to detect associated coronary or myocardial disease—usually after the decision to intervene has been made.

 Treatment & Prognosis

In most cases, there is a long asymptomatic phase after the initial rheumatic infection, followed by subtle limitation of activity. Pregnancy and its associated increase in cardiac output, which results in an increased transmitral pressure gradient, often precipitate symptoms. Toward the end of pregnancy, the cardiac output is also maintained by an increase in heart rate, further increasing the mitral gradient by shortening diastolic time. Patients with moderate to severe mitral stenosis should have the condition corrected prior to becoming pregnant if possible. Pregnant patients who become symptomatic can undergo successful surgery, preferably in the third trimester, although balloon valvuloplasty is the treatment of choice if the echo score is low enough.

The onset of atrial fibrillation often precipitates symptoms, which usually initially improve with control of the ventricular rate or restoration of sinus rhythm. Conversion to and subsequent maintenance of sinus rhythm are most commonly successful when the duration of atrial fibrillation is brief (< 6–12 months) and the LA is not severely dilated (diameter < 4.5 cm). Once atrial fibrillation occurs, the patient should receive warfarin anticoagulation therapy even if sinus rhythm is restored, since atrial fibrillation often recurs even with antiarrhythmic therapy and 20–30% of these patients will have systemic embolization if untreated. Systemic embolization in the presence of only mild to moderate disease is not an indication for surgery but should be treated with warfarin anticoagulation. Newer target specific anticoagulants (dabigatran, apixaban, and rivaroxaban) have not been studied for the prevention of stroke and non–central nervous system embolism in patients with moderate or severe mitral stenosis and atrial fibrillation, and they are not approved for these patients.

Indications for intervention focus on symptoms such as an episode of pulmonary edema, a decline in exercise capacity, or any evidence for pulmonary hypertension (peak systolic pulmonary pressure > 50 mm Hg). Some experts believe that the presence of atrial fibrillation should be a consideration for an intervention. Most interventions are not pursued until the patient is symptomatic (stage D) (Figure 10–1). In some patients, symptoms develop with calculated mitral valve areas between 1.5 cm2 and 1.0 cm2. Symptoms should drive the decision to intervene in these patients, not the estimated valve area.

 Figure 10–1. The 2014 AHA/ACC guidelines for intervention in mitral stenosis. (Reproduced with permission from Nishimura RA et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Mar 3. [Epub ahead of print] [PMID: 24589853])

Open mitral commissurotomy is now rarely performed and has given way to percutaneous balloon valvuloplasty. Ten-year follow-up data comparing surgery to balloon valvuloplasty suggest no real difference in outcome between the two modalities. Replacement of the valve is indicated when combined stenosis and regurgitation are present or when the mitral valve echo score is > 8–10. Percutaneous mitral valvuloplasty has a very low mortality rate (< 0.5%) and low morbidity rate (3–5%). Operative mortality rates are also low: 1–3% in most institutions. Repeat balloon valvuloplasty can be done if the morphology of the valve is suitable. At surgery, a Maze procedure may be done at the same time to reduce recurrent atrial arrhythmias. It involves a number of endocardial incisions across the right and left atria to disrupt the electrical activity that sustains atrial arrhythmias.

Mechanical mitral prosthetic valves are more prone to thrombosis than aortic prosthetic valves. Bioprosthetic valves degenerate after about 10–15 years and percutaneous balloon valvuloplasty procedures are not effective on bioprosthetic valves when stenosis occurs, although the emergence of improved percutaneous stented valve technology suggests this may be used to relieve bioprosthetic mitral stenosis in high-risk patients. Younger patients and those with end-stage renal disease are generally felt to do least well with bioprosthetic heart valves, although recent data have questioned the role of chronic kidney disease as a major risk factor. Endocarditis prophylaxis is always indicated for prosthetic valves but is not indicated in native valve disease (see Tables 33–433–5, and 33–6).

 When to Refer

  • Patients with mitral stenosis should be monitored with yearly examinations and echocardiograms.
  • All patients should initially be seen by a cardiologist, who can then decide how often the patient needs cardiology follow-up.

Chandrashekhar Y et al. Mitral stenosis. Lancet. 2009 Oct 10;374 (9697):271–83. [PMID: 19747723]

Nishimura RA et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Mar 3. [Epub ahead of print] [PMID: 24589853]

Vahanian A et al; Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS). Guidelines on the management of valvular heart disease (version 2012). Eur Heart J. 2012 Oct;33(19):2451–96. [PMID: 22922415]

MITRAL REGURGITATION (Mitral Insufficiency)

 ESSENTIALS OF DIAGNOSIS

 May be asymptomatic for years (or for life) or may cause left-sided heart failure.

 Echocardiographic findings can help decide when to operate.

 For chronic primary mitral regurgitation, surgery is indicated for symptoms or when the LV ejection fraction (LVEF) is < 60% or the echocardiographic LV end-systolic dimension is > 4.0 cm.

 In patients with mitral prolapse and severe mitral regurgitation, earlier surgery is indicated if mitral repair can be performed.

 General Considerations

Mitral regurgitation places a volume load on the heart (increases preload) but reduces afterload. The result is an enlarged LV with an increased EF. Over time, the stress of the volume overload reduces myocardial contractile function; when this occurs, there is a drop in EF and a rise in end-systolic volume.

 Clinical Findings

  1. Symptoms and Signs

In acute mitral regurgitation, the LA size is not large, and LA pressure rises abruptly, leading to pulmonary edema if severe. When chronic, the LA enlarges progressively and the increased volume can be handled without a major rise in the LA pressure; the pressure in pulmonary veins and capillaries may rise only transiently during exertion. Exertional dyspnea and fatigue progress gradually over many years.

Mitral regurgitation leads to chronic LA and LV enlargement and may result in subsequent atrial fibrillation and LV dysfunction. Clinically, mitral regurgitation is characterized by a pansystolic murmur maximal at the apex, radiating to the axilla and occasionally to the base; a hyperdynamic LV impulse and a brisk carotid upstroke; and a prominent third heart sound due to the increased volume returning to the LV in early diastole (Tables 10–2 and 2–3). The mitral regurgitation murmur due to mitral valve prolapse tends to radiate anteriorly in the presence of posterior leaflet prolapse and posteriorly when the prolapse is primarily of the anterior leaflet.

Table 10–3. Effect of various interventions on systolic murmurs.

  1. Diagnostic Studies

Echocardiographic information demonstrating the underlying pathologic process (rheumatic, prolapse, flail leaflet, cardiomyopathy), LV size and function, LA size, PA pressure, and RV function can be invaluable in planning treatment as well as in recognizing associated lesions. The 2014 guidelines for VHD from the ACCF/AHA provide details of the classification of primary and secondary mitral valve regurgitation. Doppler techniques provide qualitative and semiquantitative estimates of the severity of mitral regurgitation. TEE may help reveal the cause of regurgitation and is especially useful in patients who have had mitral valve replacement, in suspected endocarditis, and in identifying candidates for valvular repair. Echocardiographic dimensions and measures of systolic function are critical in deciding the timing of surgery. In patients with severe mitral regurgitation (stage C1) but preserved LV dimensions should undergo at least yearly echocardiography. Exercise hemodynamics with either Doppler echocardiography or cardiac catheterization may be useful when the symptoms do not fit the anatomic severity of mitral regurgitation. B-type natriuretic peptide (BNP) is useful in the early identification of LV dysfunction in the presence of mitral regurgitation, and asymptomatic patients with BNP values > 105 pg/mL are at higher risk for developing heart failure. Conversely, low values of BNP appear to have a negative predictive value.

Cardiac MRI is occasionally useful, if specific myocardial causes are being sought (such as amyloid or myocarditis) or if myocardial viability assessment is needed prior to deciding whether to add coronary artery bypass grafting to mitral repair in patients with chronic ischemic mitral regurgitation.

Cardiac catheterization provides a further assessment of regurgitation and its hemodynamic impact along with LV function, resting cardiac output, and PA pressure. The 2014 ACCF/AHA guidelines recommend coronary angiography to determine the presence of CAD prior to valve surgery in all men over age 40 years and in menopausal women with coronary risk factors. In younger patients (< 50 years of age), cardiac multidetector CT may be adequate to screen patients with VHD for asymptomatic CAD. A normal CT angiogram identifies normal or insignificant disease in a very high percentage of patients.

 Treatment & Prognosis

  1. Primary Mitral Regurgitation

The degree of LV enlargement usually reflects the severity and chronicity of regurgitation. LV volume overload may ultimately lead to LV failure and reduced cardiac output. LA enlargement may be considerable in chronic mitral regurgitation and considerable mitral regurgitation regurgitant volume may be tolerated. Patients with chronic lesions may remain asymptomatic for many years. Surgery is necessary when symptoms develop. However, because progressive and irreversible deterioration of LV function may occur prior to the onset of symptoms, early surgery is indicated even in asymptomatic patients with a reduced EF (< 60%) or marked LV dilation (end-systolic dimension > 4.0 cm on echocardiography) (Figure 10–2). Pulmonary hypertension development suggests the mitral regurgitation is severe as well and should prompt intervention.

 Figure 10–2. The 2014 AHA/ACC guidelines for intervention in mitral regurgitation. (Reproduced with permission from Nishimura RA et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Mar 3. [Epub ahead of print] [PMID: 24589853]

Nonrheumatic mitral regurgitation may develop abruptly, such as with papillary muscle dysfunction following myocardial infarction, valve perforation in infective endocarditis, in patients with hypertrophic cardiomyopathy, or when there are ruptured chordae tendineae in mitral valve prolapse. Emergency surgery may be required for acute nonrheumatic mitral regurgitation.

Some patients may become hemodynamically unstable and can be initially treated with vasodilators or intra-aortic balloon counterpulsation, which reduce the amount of retrograde regurgitant flow by lowering systemic vascular resistance. There is controversy regarding the role of afterload reduction in chronic mitral regurgitation, since the lesion inherently results in a reduction in afterload, and there are no data that chronic afterload reduction is effective. A heightened sympathetic state has led some experts to suggest that beta-blockade be considered routinely. Cardiomyopathy and mitral regurgitation due to persistent tachycardia may also improve with normalization of the heart rate.

  1. Myocardial Disease and Mitral Regurgitation

When mitral regurgitation is due to papillary dysfunction, it may subside as the infarction heals or LV dilation diminishes. The cause of the regurgitation in most situations is displacement of the papillary muscles and an enlarged mitral annulus rather than true papillary muscle ischemia. The fundamental problem is the lack of leaflet coaptation during systole. In acute infarction, rupture of the papillary muscle may occur with catastrophic results. Transient—but sometimes severe—mitral regurgitation may occur during episodes of myocardial ischemia and contribute to flash pulmonary edema. Patients with dilated cardiomyopathies of any origin may have secondary mitral regurgitation due to papillary muscle displacement or dilation of the mitral annulus. In patients with ischemic cardiomyopathy, ventricular reconstructive surgery to restore the mitral apparatus anatomy and reshape the ventricle (Dor procedure) has had limited success and is now rarely performed. If mitral valve replacement is performed, preservation of the chordae to the native valve helps prevent further ventricular dilation following surgery. Several groups have reported good results with mitral valve repair in patients with LVEF < 30% and secondary mitral regurgitation. The 2014 ACCF/AHA guidelines (Figure 10–2) advise that mitral valve repair/replacement can be attempted in patients with an EF < 30% or an LV end-systolic dimension > 5.5 cm, or both, as long as repair and preservation of the chordae are possible. Recent data suggest that mitral valve replacement with chordal preservation may be as effective as mitral valve repair. There may also be a role for cardiac resynchronization therapy with biventricular pacemaker insertion, which has been found to reduce mitral regurgitation due to cardiomyopathy in many patients.

Currently, there are several ongoing trials of percutaneous approaches to reducing mitral regurgitation. These approaches include the use of a mitral clip device to create a double orifice mitral valve, various coronary catheter devices to reduce the mitral annular area, and devices to reduce the septal-lateral ventricular size and consequent mitral orifice size. Some success has been noted with the mitral clip device. A complete understanding about when this may be useful is still under investigation. The device is reserved for patients in whom surgical risk is considered excessive. In addition, vascular plugging and occluder devices are being used in selected patients to occlude perivalvular leaks around prosthetic mitral valves.

 When to Refer

All patients with more than mild mitral regurgitation should be referred to a cardiologist for an evaluation. Serial examinations and echocardiograms (usually yearly) should be obtained, and referral made if there is any increase in the LV end-systolic dimensions, a fall in the EF to < 60%, or symptoms.

Ahmed MI et al. A randomized controlled phase IIb trial of beta(1)-receptor blockade for chronic degenerative mitral regurgitation. J Am Coll Cardiol. 2012 Aug 28;60(9):833–8. [PMID: 22818065]

Mauri L et al; EVEREST II Investigators. 4-year results of a randomized controlled trial of percutaneous repair versus surgery for mitral regurgitation. J Am Coll Cardiol. 2013 Jul 23;62(4):317–28. [PMID: 23665364]

Nishimura RA et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Mar 3. [Epub ahead of print] [PMID: 24589853]

Suri RM et al. Association between early surgical intervention vs watchful waiting and outcomes for mitral regurgitation due to flail mitral valve leaflets. JAMA. 2013 Aug 14;310(6):609–16. [PMID: 23942679]

Vahanian A et al; Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS). Guidelines on the management of valvular heart disease (version 2012). Eur Heart J. 2012 Oct;33(19):2451–96. [PMID: 22922415]

Whitlow PL et al; EVEREST II Investigators. Acute and 12-month results with catheter-based mitral valve leaflet repair: The EVEREST II (Endovascular Valve Edge-to-Edge Repair) High Risk Study. J Am Coll Cardiol. 2012 Jan 10;59(2):130–9. [PMID: 22222076]

MITRAL VALVE PROLAPSE SYNDROME

 ESSENTIALS OF DIAGNOSIS

 Single or multiple mid-systolic clicks often heard on auscultation.

 Murmur may be pansystolic or only late in systole.

 Often associated with skeletal changes (straight back, pectus excavatum, and scoliosis) or hyperflexibility of joints.

 Echocardiography is confirmatory with prolapse of mitral leaflets in systole into the LA.

 Chest pain and palpitations common symptoms in the young adult.

 General Considerations

The significance of mild mitral valve prolapse (“floppy” or myxomatous mitral valve), also commonly referred to as “degenerative” mitral valve disease, has been in dispute because of the frequency with which it is diagnosed by echocardiography even in healthy young women (up to 10%). A controversial hyperadrenergic syndrome has also been described (especially in young females) that may be responsible for some of the noncardiac symptoms observed. Fortunately, this hyperadrenergic component attenuates with age. Some patients with mitral prolapse have findings of a systemic collagen abnormality (Marfan or Ehlers-Danlos syndrome). In these conditions, a dilated aortic root and aortic regurgitation may coexist. In many persons, the “degenerative” myxomatous mitral valve clearly leads to long-term sequelae and is the most common cause of mitral regurgitation in developing countries.

Patients who have only a mid-systolic click usually have no immediate clinical issues, but significant mitral regurgitation may develop, occasionally suddenly due to rupture of chordae tendineae (flail leaflet) or gradually due to progressive annular dilation. The need for valve repair or replacement increases with age, so that approximately 2% per year of patients with clinically significant regurgitation over age 60 years will eventually require surgery.

 Clinical Findings

  1. Symptoms and Signs

Mitral valve prolapse is usually asymptomatic but may be associated with nonspecific chest pain, dyspnea, fatigue, or palpitations. Most patients are female, many are thin, and some have skeletal deformities such as pectus excavatum or scoliosis. On auscultation, there are characteristic mid-systolic clicks that may be multiple and emanate from the chordae or redundant valve tissue. If leaflets fail to come together properly, the clicks will be followed by a late systolic murmur. As the mitral regurgitation worsens, the murmur is heard more and more throughout systole. The smaller the LV chamber, the greater the degree of prolapse, and thus auscultatory findings are often accentuated in the standing position or during the Valsalva maneuver.

  1. Diagnostic Studies

The diagnosis is primarily clinical and confirmed echocardiographically. Mitral prolapse is often associated with aortic root disease, and any evidence for a dilated aorta by chest radiography should prompt either CT or MRI angiography. If palpitations are an issue, an ambulatory monitor is often helpful to distinguish atrial from ventricular tachyarrhythmias.

 Treatment

Beta-blockers in low doses are used to treat the hyperadrenergic state when present and are usually satisfactory for treatment of arrhythmias (see Table 11–6). Selective serotonin reuptake inhibitors have also been used, especially if orthostatic hypotension or anxiety is associated with mitral valve prolapse; results have been mixed. Afterload reduction has not been shown to be effective when mitral regurgitation is present.

Mitral valve repair is strongly favored over valve replacement, and its efficacy has led many to recommend intervention earlier and earlier in the course of the disease process. Mitral repair may include shortening of chordae, chordae transfers, wedge resection of redundant valve tissue, or the insertion of a mitral annular ring to reduce the annular size, or some combination of these techniques. Stitching of the leaflets together to create a double orifice mitral valve is also used at times (Alfieri procedure) and can be performed percutaneously. Mitral repair or replacement can be achieved through a right minithoracotomy with or without the use of a robotic device. Endocarditis prophylaxis is no longer recommended for most patients with mitral valve prolapse regardless of the degree of mitral regurgitation. A variety of percutaneous techniques and devices have been tried with some success (notably in the mitral clip trials), although results suggest that surgical repair may be more durable.

 When to Refer

  • All patients with mitral valve prolapse and audible mitral regurgitation should be seen at least once by a cardiologist.
  • Periodic echocardiography is warranted to assess LV size (especially end-systolic dimensions) and EF when mitral regurgitation is present. If only mitral clicks are audible, then serial echocardiography is not warranted.

Filho AS et al. Mitral valve prolapse and anxiety disorders. Br J Psychiatry. 2011 Sep;199(3):247–8. [PMID: 21881100]

Mauri L et al; EVEREST II Investigators. 4-year results of a randomized controlled trial of percutaneous repair versus surgery for mitral regurgitation. J Am Coll Cardiol. 2013 Jul 23;62(4):317–28. [PMID: 23665364]

Whitlow PL et al; EVEREST II Investigators. Acute and 12-month results with catheter-based mitral valve leaflet repair: The EVEREST II (Endovascular Valve Edge-to-Edge Repair) High Risk Study. J Am Coll Cardiol. 2012 Jan 10;59(2):130–9. [PMID: 22222076]

AORTIC STENOSIS

 ESSENTIALS OF DIAGNOSIS

 Congenital bicuspid aortic valve, usually asymptomatic until middle or old age.

 “Degenerative” or calcific aortic stenosis; same risk factors as atherosclerosis.

 Symptoms likely once the mean gradient is > 40 mm Hg.

 Echocardiography/Doppler is diagnostic.

 Surgery indicated for symptoms.

 Surgery considered for asymptomatic patients with severe aortic stenosis (mean gradient > 50 mm Hg).

 Emerging role for BNP as marker of early LV myocardial failure.

 General Considerations

There are two common clinical scenarios in which aortic stenosis is prevalent. The first is due to a congenitally abnormal unicuspid or bicuspid valve, rather than tricuspid. Symptoms occur in young or adolescent individuals if the stenosis is severe, but more often emerge at age 50–65 years when calcification and degeneration of the valve becomes manifest. A dilated ascending aorta, primarily due to an intrinsic defect in the aortic root media, may accompany the bicuspid valve in about half of these patients. Coarctation of the aorta is also seen in a number of patients with congenital aortic stenosis. Offspring of patients with a bicuspid valve have a much higher incidence of the disease as well (up to 30% in some series).

A second group develops what has traditionally been called degenerative or calcific aortic stenosis, which is thought to be related to calcium deposition due to processes similar to what occurs in atherosclerotic vascular disease. Approximately 25% of patients over age 65 years and 35% of those over age 70 years have echocardiographic evidence of aortic valve thickening (sclerosis). About 10–20% of these will progress to hemodynamically significant aortic stenosis over a period of 10–15 years. Certain genetic markers are now being discovered that are associated with aortic stenosis (most notably Notch 1), so a genetic component appears a likely contributor, at least in some patients. Other associated genetic markers have also been described.

Aortic stenosis has become the most common surgical valve lesion in developed countries, and many patients are elderly. The risk factors include hypertension, hypercholesterolemia, and smoking. Hypertrophic obstructive cardiomyopathy (HOCM) may also coexist with valvular aortic stenosis.

 Clinical Findings

  1. Symptoms and Signs

Slightly narrowed, thickened, or roughened valves (aortic sclerosis) or aortic dilation may produce the typical ejection murmur of aortic stenosis. In mild or moderate cases where the valve is still pliable, an ejection click may precede the murmur. The characteristic systolic ejection murmur is heard at the aortic area and is usually transmitted to the neck and apex. In some cases, only the high-pitched components of the murmur are heard at the apex, and the murmur may sound like mitral regurgitation (so-called Gallaverdin phenomenon). In severe aortic stenosis, a palpable LV heave or thrill, a weak to absent aortic second sound, or reversed splitting of the second sound is present (see Table 10–2). When the valve area is < 0.8–1.0 cm2 (normal, 3–4 cm2), ventricular systole becomes prolonged and the typical carotid pulse pattern of delayed upstroke and low amplitude is present. This may be an unreliable finding in older patients with extensive arteriosclerotic vascular disease and a stiff aorta. LVH increases progressively due to the pressure overload, eventually resulting in elevation in ventricular end-diastolic pressure. Cardiac output is maintained until the stenosis is severe (with a valve area < 0.8 cm2). LV failure, angina pectoris, or syncope may be presenting symptoms and signs of significant aortic stenosis; importantly, all symptoms tend to occur with exertion.

In a few patients, there appears to be a mismatch among the typical aortic stenosis assessments: the aortic valve gradient severity (low), the aortic valve area (severe), the degree of the LVH (severe), and the EF (normal). These “paradoxical” low flow aortic stenosis patients may have significant LV afterload due to increased aortic vascular impedance as well as the valvular stenosis resistance. The 2014 ACCF/AHA and the European valvular guidelines acknowledge the possible inclusion of these patients in the treatment algorithms for aortic stenosis (Table 10–4).

Table 10–4. 2014 ACCF/ACC guidelines for surgical indications in aortic stenosis.

Symptoms of LV failure may be sudden in onset or may progress gradually. Angina pectoris frequently occurs in aortic stenosis due to underperfusion of the endocardium. Of patients with calcific aortic stenosis and angina, 50% have significant associated CAD. Syncope, a late finding, occurs with exertion as the LV pressures rises, stimulating the LV baroreceptors to cause peripheral vasodilation. This vasodilation results in the need for an increase in stroke volume, which increases the LV systolic pressure again, creating a cycle of vasodilation and stimulation of the baroreceptors that eventually results in a drop in BP, as the stenotic valve prevents further increase in stroke volume. Less commonly, syncope may be due to arrhythmias (usually ventricular tachycardia but sometimes AV block as calcific invasion of the conduction system from the aortic valve may occur).

  1. Diagnostic Studies

The ECG reveals LVH or secondary repolarization changes in most patients but can be normal in up to 10%. The chest radiograph may show a normal or enlarged cardiac silhouette, calcification of the aortic valve, and dilation and calcification of the ascending aorta. The echocardiogram provides useful data about aortic valve calcification and opening and the severity of LV wall thickness and overall ventricular function, while Doppler can provide an excellent estimate of the aortic valve gradient. The 2014 ACCF/AHA guidelines provide echo/Doppler criteria for identifying aortic stenosis severity. Valve area estimation by echocardiography is less reliable but a critical component to the diagnosis of paradoxical low flow aortic stenosis (low gradient, low flow, normal LVEF patients). Cardiac catheterization mostly provides an assessment of the hemodynamic consequence of the aortic stenosis, and the anatomy of the coronary arteries. In younger patients, and in patients with high aortic gradients the aortic valve need not be crossed at catheterization. If the valve is crossed, the valve gradient can be measured at catheterization and an estimated valve area calculated; a valve area < 1.0 cm2 indicates significant stenosis. Aortic regurgitation can be semiquantified by aortic root angiography.

In patients with a low LVEF and both low output and a low valve gradient (< 40 mm Hg), it may be unclear if an increased afterload is responsible for the low EF or if there is an associated cardiomyopathy. To sort this out, the patient should be studied at baseline and then during an intervention that increases cardiac output (eg, dobutamine or nitroprusside infusion). If the valve area increases, then the flow-limiting problem is not the valve, but rather a cardiomyopathy with low cardiac output, and surgery is generally not warranted. If the valve area remains unchanged at the higher induced outputs and there remains contractile reserve (an increase in the stroke volume > 20%), then the valve is generally considered flow limiting and surgery is indicated. Recent data have suggested the use of BNP may provide prognostic data in the setting of poor LV function and aortic stenosis. A BNP > 550 pg/mL has been associated with a poor outcome in these patients regardless of the results of dobutamine testing.

 Prognosis & Treatment

Valve replacement is usually not indicated in asymptomatic individuals, though a class II indication is to operate once the peak valve gradient by Doppler exceeds 64 mm Hg or the mean gradient exceeds 60 mm Hg. Stress testing and perhaps the use of BNP may help identify patients who deny symptoms but have compromised ventricular function. Following the onset of heart failure, angina, or syncope, the prognosis without surgery is poor (50% 3-year mortality rate). Medical treatment may stabilize patients in heart failure, but surgery is indicated for all symptomatic patients with evidence of significant aortic stenosis.

The surgical mortality rate for valve replacement is low, even in the elderly, and ranges from 2% to 5%. This low risk is due to the dramatic hemodynamic improvement that occurs with relief of the increased afterload. Mortality rates are substantially higher when there is an associated ischemic cardiomyopathy. Severe coronary lesions are usually bypassed at the same time, although there are little data to suggest this practice affects outcome. Around one-third to one-half of all patients with aortic stenosis has significant CAD.

Statins have not been shown to be beneficial in preventing the progression of aortic stenosis but longer-term studies in patients with early disease are still pending. If patients with aortic stenosis have concomitant CAD, the guidelines for use of statins should be followed. Control of systemic hypertension is also an important adjunct, and inadequate systemic BP control is common due to unreasonable concerns about providing too much afterload reduction in patients with aortic stenosis.

The interventional options in patients with aortic stenosis are variable and dependent on the patient’s lifestyle and age. The algorithm to decide when an intervention is appropriate in various situations is outlined in Figure 10–3.

 Figure 10–3. Algorithm for the management of aortic valve stenosis. (Reproduc ed, with permission from Nishimura RA et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Mar 3. [Epub ahead of print] [PMID: 24589853])

In the young and adolescent patient, percutaneous balloon valvuloplasty still has a role but is associated with early restenosis in the elderly, and thus is rarely used except as a temporizing measure in calcific aortic stenosis. Data suggest aortic balloon valvuloplasty in the elderly has an advantage only in those with preserved LV function, and such patients are usually excellent candidates for surgical aortic valve replacement (AVR). Middle-aged adults generally can tolerate the anticoagulation therapy necessary for the use of mechanical AVR, so most undergo AVR with a bileaflet mechanical valve. If the aortic root is severely dilated as well (> 4.5 cm), then the valve may be housed in a Dacron sheath (Bentall procedure) and the root replaced. Alternatively, a human homograft root and valve replacement can be used. In the elderly, bioprosthetic (either porcine or bovine pericardial) valves with a life expectancy of about 10–15 years are routinely used instead of mechanical valves to avoid need for anticoagulation. Data favor the bovine pericardial valve over the porcine aortic valve. If the aortic annulus is small, a bioprosthetic valve with a short sheath can be sewn to the aortic wall (the stentless AVR) rather than sewing the prosthetic annulus to the aortic annulus. (Annulus is a relative term when speaking of the aortic valve, since there is no true annulus.) Another popular surgical option is the Wheat procedure; it involves aortic root replacement above the coronary arteries and AVR. The coronary arteries thus remain attached to the native aorta between the new graft and prosthetic valve rather than being reimplanted onto an artificial sheath or homograft.

In patients with a bicuspid aortic valve, there is often an associated ascending aortic aneurysm. If the maximal dimension of the aortic root exceeds 5.5 cm, it is recommended to proceed with root replacement regardless of the severity of the aortic valve disease. The aortic valve may be replaced at the same time or may be left alone (valve sparing operation).

Anticoagulation is required with the use of mechanical valves, and the international normalized ratio (INR) should be maintained between 2.0 and 3.0 or between 2.5 and 3.5, depending on type and position of valve and patient risk factors. In general, mechanical aortic valves are less subject to thrombosis than mechanical mitral valves. Some newer bileaflet mechanical valves (On-X) that require either no or a reduced dose of warfarin therapy are being evaluated, although the final data regarding the safety of this particular design are not available. The Prospective Randomized On-X valve AntiCoagulation Trial (PROACT) was begun in 2006 and is ongoing. Preliminary results have been reported and are very promising.

The use of transcutaneous aortic valve replacement (TAVR) has grown dramatically, with over 60,000 implants reported. In the United States, the Food and Drug Administration (FDA) has granted limited approval for one device (Edwards SAPIENTM), and trials of a second device (CoreValveTM) have been reported in high-risk patients. The devices use either a stent with a trileaflet bovine pericardial valve constructed in it or a stent with a large valve from a cow’s jugular vein mounted inside. There are a variety of approaches, though most valves are placed via a femoral artery approach. Other options include an antegrade approach via transseptal across the atrial septum, via the LV apex with a small surgical incision, via the subclavian arteries, or via a minithoracotomy. The Edwards SAPIEN valve is a balloon-expandable valvular stent, while the CoreValve is a valvular stent that self-expands when pushed out of the catheter sheath. Multiple other devices are in trials; these allow for repositioning and may result in less paravalvular regurgitation.

Table 10–5 outlines the suggested indications for TAVR. TAVR has also been used in “valve-in-valve” procedures to reduce the gradient in patients with prosthetic valve stenosis. A high incidence of heart block has been noted after CoreValve and many require permanent pacing. After placement of the SAPIEN device, residual aortic regurgitation remains a concern and has impact on its long-term success. TAVR has been remarkably successful in very high-risk and very elderly patients, and ongoing studies are addressing its usefulness in lower-risk patients compared to surgical AVR.

Table 10–5. Recommendations for use of TAVR.

 When to Refer

  • All patients with echocardiographic evidence for mild-to-moderate aortic stenosis (estimated peak valve gradient > 30 mm Hg by echocardiography/Doppler) should be referred to a cardiologist for evaluation and to determine the frequency of follow-up.
  • Any patients with symptoms suggestive of aortic stenosis should be seen by a cardiologist.

Chan KL et al; ASTRONOMER Investigators. Effect of lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation. 2010 Jan 19;121(2):306–14. [PMID: 20048204]

Goel SS et al. Severe aortic stenosis and coronary artery disease—implications for management in the transcatheter aortic valve replacement era: a comprehensive review. J Am Coll Cardiol. 2013 Jul 2;62(1):1–10. [PMID: 23644089]

Herrmann HC et al. Predictors of mortality and outcomes of therapy in low-flow severe aortic stenosis: a Placement of Aortic Transcatheter Valves (PARTNER) trial analysis. Circulation. 2013 Jun 11;127(23):2316–26. [PMID: 23661722]

Holmes DR Jret al. 2012 ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement. J Am Coll Cardiol. 2012 Mar 27;59(13):1200–54. [PMID: 22300974]

Jander N et al. Outcome of patients with low-gradient “severe” aortic stenosis and preserved ejection fraction. Circulation. 2011 Mar 1;123(8):887–95. [PMID: 21321152]

Leon MB et al; PARTNER Trial Investigators. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med. 2010 Oct 21;363(17): 1597–607. [PMID: 20961243]

Lindman BR et al. Current management of calcific aortic stenosis. Circ Res. 2013 Jul 5;113(2):223–37. [PMID: 23833296]

Nishimura RA et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Mar 3. [Epub ahead of print] [PMID: 24589853]

Vahanian A et al; Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS). Guidelines on the management of valvular heart disease (version 2012). Eur Heart J. 2012 Oct;33(19):2451–96. [PMID: 22922415]

AORTIC REGURGITATION

 ESSENTIALS OF DIAGNOSIS

 Usually asymptomatic until middle age; presents with left-sided failure or chest pain.

 Echocardiography/Doppler is diagnostic.

 Surgery indicated for symptoms, EF < 55%, or LV end-systolic dimension > 5.0–5.5 cm.

 General Considerations

Rheumatic aortic regurgitation has become much less common than in the preantibiotic era, and nonrheumatic causes now predominate. These include congenitally bicuspid valves, infective endocarditis, and hypertension. Many patients have aortic regurgitation secondary to aortic root diseases such as that associated with Marfan syndrome or to aortic dissection. Rarely, inflammatory diseases, such as ankylosing spondylitis or reactive arthritis, may be causative.

 Clinical Findings

  1. Symptoms and Signs

The clinical presentation is determined by the rapidity with which regurgitation develops. In chronic aortic regurgitation, the only sign for many years may be a soft aortic diastolic murmur. As the severity of the aortic regurgitation increases, diastolic BP falls, and the LV progressively enlarges. Most patients remain asymptomatic even at this point. LV failure is a late event and may be sudden in onset. Exertional dyspnea and fatigue are the most frequent symptoms, but paroxysmal nocturnal dyspnea and pulmonary edema may also occur. Angina pectoris or atypical chest pain may occasionally be present. Associated CAD and presyncope or syncope are less common than in aortic stenosis.

Hemodynamically, because of compensatory LV dilation, patients eject a large stroke volume, which is adequate to maintain forward cardiac output until late in the course of the disease. LV diastolic pressure may rise when heart failure occurs. Abnormal LV systolic function, as manifested by reduced EF < 55%) and increasing end-systolic LV volume (>5.0 cm), is a sign that surgical intervention is warranted.

The major physical findings in chronic aortic regurgitation relate to the high stroke volume being ejected into the systemic vascular system with rapid runoff as the regurgitation takes place (see Table 10–2). This results in a wide arterial pulse pressure. The pulse has a rapid rise and fall (water-hammer pulse or Corrigan pulse), with an elevated systolic and low diastolic pressure. The large stroke volume is also responsible for characteristic findings such as Quincke pulses (nailbed capillary pulsations), Duroziez sign (to and fro murmur over a partially compressed peripheral artery, commonly the femoral), and Musset sign (head bob with each pulse). In younger patients, the increased stroke volume may summate with the pressure wave reflected from the periphery and create a higher than expected systolic pressure in the lower extremities compared with the central aorta. Since the peripheral bed is much larger in the leg than the arm, the BP in the leg may be over 40 mm Hg higher than in the arm (Hill sign) in severe aortic regurgitation. The apical impulse is prominent, laterally displaced, usually hyperdynamic, and may be sustained. A systolic murmur is usually present and may be quite soft and localized; the aortic diastolic murmur is usually high-pitched and decrescendo. A mid or late diastolic low-pitched mitral murmur (Austin Flint murmur) may be heard in advanced aortic regurgitation, owing to relative obstruction of mitral inflow produced by partial closure of the mitral valve by the rapidly rising LV diastolic pressure due to the aortic regurgitation.

In acute aortic regurgitation (usually from aortic dissection or infective endocarditis), LV failure is manifested primarily as pulmonary edema and may develop rapidly; surgery is urgently required in such cases. Patients with acute aortic regurgitation do not have the dilated LV of chronic aortic regurgitation and the extra LV volume is handled poorly. For the same reason, the diastolic murmur is shorter, may be minimal in intensity, and the pulse pressure may not be widened—making clinical diagnosis difficult. The mitral valve may close prematurely even before LV systole has been initiated (pre-closure) due to the rapid rise in the LV diastolic pressure, and the first heart sound is thus diminished or inaudible. Pre-closure of the mitral valve can be readily detected on echocardiography and is considered an indication for surgical intervention.

  1. Diagnostic Studies

The ECG usually shows moderate to severe LVH. Radiographs show cardiomegaly with LV prominence and sometimes a dilated aorta.

Echocardiography demonstrates the major diagnostic features, including whether the lesion involves the proximal aortic root and what valvular pathology is present. Annual assessments of LV size and function are critical in determining the timing for valve replacement. The 2014 ACCF/ACC valvular guidelines provides criteria for assessing the severity of aortic regurgitation. Cardiac MRI and CT can estimate aortic root size, particularly when there is concern for an ascending aneurysm. MRI can provide a regurgitant fraction to help confirm severity. Cardiac catheterization may be unnecessary in younger patients, particularly those with acute aortic regurgitation, but can help define hemodynamics, aortic root abnormalities, and associated CAD preoperatively in older patients. Increasing data are emerging that serum BNP or pro-NT BNP may be an early sign of LV dysfunction, and it is possible that these data will be added to recommendations for surgical intervention in the future.

 Treatment & Prognosis

Aortic regurgitation that appears or worsens during or after an episode of infective endocarditis or aortic dissection may lead to acute severe LV failure or subacute progression over weeks or months. The former usually presents as pulmonary edema; surgical replacement of the valve is indicated even during active infection. These patients may be transiently improved or stabilized by vasodilators.

Chronic aortic regurgitation may be tolerated for many years, but the prognosis without surgery becomes poor when symptoms occur. Since aortic regurgitation places both a preload (volume) and afterload increase on the LV, medications that decrease afterload can reduce regurgitation severity. Current recommendations advocate afterload reduction in aortic regurgitation when there is associated systolic hypertension (systolic BP > 140 mm Hg). Afterload reduction in normotensive patients remains controversial. Angiotensin receptor blockers (ARBs), rather than beta-blockers, are the preferred additions to the medical therapy in patients with Marfan disease because of the ARBs ability to reduce aortic stiffness (by blocking TGF-beta) and to slow the rate of aortic dilation. The role of beta-blockers continues to be explored in aortic regurgitation in an attempt to reduce adverse neuroendocrine activation.

Surgery is indicated once symptoms emerge or for any evidence of LV dysfunction. Figure 10–4 outlines the recommendations for intervention in chronic aortic regurgitation.

 Figure 10–4. Algorithm for the management of chronic aortic regurgitation. (Reproduced with permission from Nishimura RA et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Mar 3. [Epub ahead of print] [PMID: 24589853]

LV dysfunction in this situation can be defined by echocardiography if the EF is < 55% or if the LV end-systolic dimension is > 5.0 cm (class 2b indication), even in the asymptomatic patient. In addition, aortic root diameters of > 4.5 cm in Marfan or > 5.0 cm in non-Marfan patients are indications for surgery to avoid the rapid expansion that occurs when the root diameter exceeds 6.0 cm. Although the operative mortality rate is higher when LV function is severely impaired, valve replacement or repair is still likely indicated, since LV function often improves and the long-term prognosis is thereby enhanced even in this situation. The issues with AVR covered in the above section concerning aortic stenosis pertain here. Currently, however, there are no percutaneous approaches to aortic regurgitation. Aortic regurgitation due to a paravalvular prosthetic valve defect can occasionally be occluded with percutaneous occluder devices. The choice of prosthetic valve for AVR depends on the patient’s age and compatibility with warfarin anticoagulation. Table 10–6 summarizes the recommendations for aortic regurgitation intervention.

Table 10–6. Summary of recommendations for aortic regurgitation: intervention.

The operative mortality for AVR is usually in the 3–5% range. Aortic regurgitation due to aortic root disease requires repair or replacement of the root. Though valve-sparing operations have improved recently, most patients with root replacement undergo valve replacement at the same time. Root replacement in association with valve replacement may require reanastomosis of the coronary arteries, and thus the procedure is more complex than valve replacement alone. The Wheat procedure replaces the aortic root but spares the area where the coronaries attach to avoid the necessity for their reimplantation. Following surgery, LV size usually decreases and LV function generally improves even when the baseline EF is depressed.

Guidelines vary regarding when intervention on the aortic root in patients with bicuspid aortic valve disease is appropriate. The ACCF/AHA guidelines suggest the “cutoff” diameter value for repair should be 5.5 cm, while the ESC recommendation is still 5.0 cm. There are data that the root expands more rapidly or dissection is much more prevalent when the aortic root diameter exceeds 6.0 cm, and the general sense is not to let it approach that diameter. The following classifications outline when to operate on the aortic root in patients with a bicuspid aortic valve based on the former and more recent guidelines:

Class 1 indication (LOE C): aortic root diameter of sinuses or ascending aorta > 5.5 cm.

Class 2a indication (LOE C): aortic root diameter of sinuses or ascending aorta > 5.0 cn with associated risk factors (family history of dissection or increase in size.0.5 cm per year).

Cla ss 2a indication (LOE C): aortic root diameter > 4.5 cm if patient undergoing AVR for clinical reasons.

 When to Refer

  • Patients with audible aortic regurgitation should be seen, at least initially, by a cardiologist who can determine whether the patient needs follow-up.
  • Patients with a dilated aortic root should be monitored by a cardiologist, since imaging studies other than the chest radiograph or echocardiogram may be required to decide surgical timing.

Bonow RO. Chronic mitral regurgitation and aortic regurgitation: have indications for surgery changed? J Am Coll Cardiol. 2013 Feb 19;61(7):693–701. [PMID: 23265342]

Elder DH et al. The impact of renin-angiotensin-aldosterone system blockade on heart failure outcomes and mortality in patients identified to have aortic regurgitation: a large population study. J Am Coll Cardiol. 2011 Nov 8;58(20):2084–91. [PMID: 22051330]

Nishimura RA et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Mar 3. [Epub ahead of print] [PMID: 24589853]

Vahanian A et al; Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS). Guidelines on the management of valvular heart disease (version 2012). Eur Heart J. 2012 Oct;33(19):2451–96. [PMID: 22922415]

TRICUSPID STENOSIS

 ESSENTIALS OF DIAGNOSIS

 Female predominance.

 History of rheumatic heart disease. Carcinoid disease or prosthetic valve degeneration are the most common etiologies in the United States.

 Echocardiography/Doppler is diagnostic; mean valve gradient > 5 mm Hg indicates severe tricuspid stenosis.

 General Considerations

Tricuspid valve stenosis is usually rheumatic in origin, although in the United States, tricuspid stenosis is more commonly due to tricuspid valve repair or replacement or to the carcinoid syndrome. Tricuspid regurgitation frequently accompanies the lesion. It should be suspected when “right heart failure” appears in the course of mitral valve disease or in the postoperative period after tricuspid valve repair or replacement. Congenital forms of tricuspid stenosis may also be rarely observed, as have case reports of multiple pacemaker leads creating RV inflow obstruction at the tricuspid valve.

 Clinical Findings

  1. Symptoms and Signs

Tricuspid stenosis is characterized by right heart failure with hepatomegaly, ascites, and dependent edema. In sinus rhythm, giant a wave is seen in the JVP, which is elevated (see Table 10–2). The typical diastolic rumble along the lower left sternal border mimics mitral stenosis, though in tricuspid stenosis the rumble increases with inspiration. In sinus rhythm, a presystolic liver pulsation may be found.

  1. Diagnostic Studies

In the absence of atrial fibrillation, the ECG reveals RA enlargement. The chest radiograph may show marked cardiomegaly with a normal PA size. A dilated superior vena cava and azygous vein may be evident.

The normal valve area of the tricuspid valve is 10 cm2, so significant stenosis must be present to produce a gradient. Hemodynamically, a mean diastolic pressure gradient of > 5 mm Hg is considered significant, although even a 2 mm Hg gradient can be considered abnormal. This can be demonstrated by echocardiography or cardiac catheterization.

 Treatment & Prognosis

Tricuspid stenosis may be progressive, eventually causing severe right-sided heart failure. Initialtherapy is directed at reducing the fluid congestion, with diuretics the mainstay (see Treatment, Heart Failure, below). When there is considerable bowel edema, torsemide may have an advantage over other loop diuretics, such as furosemide, because it is better absorbed from the gut. Aldosterone inhibitors also help, particularly if there is liver engorgement or ascites. Neither surgical nor percutaneous valvuloplasty is particularly effective for relief of tricuspid stenosis, as residual tricuspid regurgitation is common. Tricuspid valve replacement is clearly the preferred surgical approach. Mechanical tricuspid valve replacement is rarely done because the low flow predisposes to thrombosis and because the mechanical valve cannot be crossed should the need arise for right heart catheterization or pacemaker implantation. Therefore, bioprosthetic valves are almost always preferred. Often tricuspid valve replacement is done in conjunction with mitral valve replacement for mitral stenosis. The indications for valve replacement in severe tricuspid stenosis are straightforward:

Class 1 indication (LOE C); at time of operation for left-sided valve disease.

Class 1 indication (LOE C); if symptomatic.

Class 2b indication (LOE C): rarely percutaneous balloon commissurotomy for isolated tricuspid stenosis in high-risk patients with no significant tricuspid regurgitation.

Hong SN. Carcinoid heart disease. J Am Coll Cardiol. 2010 May 4;55(18):1996. [PMID: 20430272]

Nishimura RA et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Mar 3. [Epub ahead of print] [PMID: 24589853]

Yeter E et al. Tricuspid balloon valvuloplasty to treat tricuspid stenosis. J Heart Valve Dis. 2010 Jan;19(1):159–60. [PMID: 20329507]

TRICUSPID REGURGITATION

 ESSENTIALS OF DIAGNOSIS

 Frequently occurs in patients with pulmonary or cardiac disease with pressure or volume overload on the right ventricle.

 Tricuspid valve regurgitation from pacemaker lead placement is becoming more common.

 Echocardiography useful in determining cause (low- or high-pressure tricuspid regurgitation).

 General Considerations

Tricuspid valvular regurgitation often occurs whenever there is RV dilation from any cause. As tricuspid regurgitation increases, the RV size increases further, and this in turn worsens the severity of the tricuspid regurgitation. The causes of tricuspid regurgitation thus relate to anatomic issues with either the valve itself or to the RV geometry. In most cases, the cause is the RV geometry and not primary tricuspid valve disease. An enlarged, dilated RV may be present if there is pulmonary hypertension for any reason, in severe pulmonary valve regurgitation, or in cardiomyopathy. The RV may be injured from myocardial infarction or may be inherently dilated due to infiltrative diseases (RV dysplasia or sarcoidosis). RV dilation is often secondary to left heart failure. Inherent abnormalities of the tricuspid valve include Ebstein anomaly (displacement of the septal and posterior, but not the anterior, leaflets into the RV), tricuspid valve prolapse, carcinoid plaque formation, collagen disease inflammation, valvular tumors, or tricuspid endocarditis. In addition, pacemaker lead valvular injury is becoming an increasingly recognized iatrogenic cause.

 Clinical Findings

  1. Symptoms and Signs

The symptoms and signs of tricuspid regurgitation are identical to those resulting from RV failure due to any cause. As a generality, the diagnosis can be made by careful inspection of the JVP (see Table 10–2). The JVP waveform should decline during ventricular systole (the x descent). The timing of this decline can be observed by palpating the opposite carotid artery. As tricuspid regurgitation worsens, more and more of this x descent valley in the JVP is filled with the regurgitant wave until all of the x descent is obliterated and a positive systolic waveform will be noted in the JVP. An associated tricuspid regurgitation murmur may or may not be audible and can be distinguished from mitral regurgitation by the left parasternal location and increase with inspiration. An S3 may accompany the murmur and is related to the high flow returning from the RA. Cyanosis may be present if the increased RA pressure stretches the atrial septum and opens a PFO or there is a true ASD (eg, in about 50% of patients with Ebstein anomaly). Severe tricuspid regurgitation results in hepatomegaly, edema, and ascites.

  1. Diagnostic Studies

The ECG is usually nonspecific, though atrial fibrillation is not uncommon. The chest radiograph may reveal evidence of an enlarged RA or dilated azygous vein and pleural effusion. The echocardiogram helps assess severity of tricuspid regurgitation, RV systolic pressure, and RV size and function. A paradoxically moving interventricular septum may be present due to the volume overload on the RV. Catheterization confirms the presence of the regurgitant wave in the RA and elevated RA pressures. If the PA or RV systolic pressure is < 40 mm Hg, primary valvular tricuspid regurgitation should be suspected.

 Treatment & Prognosis

Mild tricuspid regurgitation is common and generally can be well managed with diuretics. When present, bowel edema may reduce the effectiveness of diuretics such as furosemide, and intravenous diuretics should initially be used. Torsemide is better absorbed in this situation when oral diuretics are added. Aldosterone antagonists have a role as well, particularly if ascites is present. At times, the efficacy of loop diuretics can be enhanced by adding a thiazide diuretic (see Treatment, Heart Failure, below). Aquapheresis has also been proven helpful to reduce the edema in marked right heart failure.

Definitive treatment usually requires elimination of the cause of the tricuspid regurgitation. If the problem is left heart disease, then treatment of the left heart issues may lower pulmonary pressures, reduce RV size, and resolve the tricuspid regurgitation. Treatment for primary and secondary causes of pulmonary hypertension will generally reduce the tricuspid regurgitation. It is a class I recommendation that tricuspid annuloplasty be performed when tricuspid regurgitation is present and mitral valve replacement or repair is being performed for mitral regurgitation. Annuloplasty without insertion of a prosthetic ring (DeVega annuloplasty) may also be effective in reducing the tricuspid annular dilation. The valve leaflet itself can occasionally be repaired in tricuspid valve endocarditis. In years past, tricuspid regurgitation due to endocarditis in substance abuse patients was treated temporarily with removal of the valve, although it had to be replaced eventually (usually by 3–6 months); this practice is rarely done now. If there is an inherent defect in the tricuspid valve apparatus that cannot be repaired, then replacement of the tricuspid valve is warranted. Almost always, a bioprosthetic valve, and not a mechanical valve, is used. Anticoagulation is not required for bioprosthetic valves unless there is associated atrial fibrillation. The indications for surgical intervention are summarized in Figure 10–5.

 Figure 10–5. The 2014 AHA/ACC guidelines on the indications for surgical intervention in tricuspid regurgitation. (Reproduced with permission from Nishimura RA et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Mar 3. [Epub ahead of print] [PMID: 24589853])

 When to Refer

  • Anyone with moderate or severe tricuspid regurgitation should be seen at least once by a cardiologist to determine whether studies and intervention are needed.
  • Severe tricuspid regurgitation requires regular follow-up by a cardiologist.

Kim JB et al. Surgical outcomes of severe tricuspid regurgitation: predictors of adverse clinical outcomes. Heart. 2013 Feb;99(3): 181–7. [PMID: 23038792]

Nishimura RA et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Mar 3. [Epub ahead of print] [PMID: 24589853]

Vahanian A et al; Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS). Guidelines on the management of valvular heart disease (version 2012). Eur Heart J. 2012 Oct;33(19):2451–96. [PMID: 22922415]

PULMONARY VALVE REGURGITATION

 ESSENTIALS OF DIAGNOSIS

 Most cases are due to pulmonary hypertension.

 Echocardiogram is definitive in high-pressure, but may be less definitive in low-pressure, pulmonary valve regurgitation.

 Low-pressure pulmonary valve regurgitation is well tolerated.

 General Considerations

Pulmonary valve regurgitation can be divided into high-pressure causes (due to pulmonary hypertension) and low-pressure causes (usually due to a dilated pulmonary annulus, to a congenitally abnormal [bicuspid or dysplastic] pulmonary valve, or to plaque from carcinoid disease). It may also follow surgical repair, eg, frequently occurring after repair of tetralogy of Fallot with a transannular patch. Because the RV tolerates a volume load better than a pressure load, it tends to tolerate low pressure pulmonary valve regurgitation for long periods of time without dysfunction.

 Clinical Findings

Most patients are asymptomatic. Others show symptoms of right heart volume overload. On examination, a hyperdynamic RV can usually be palpated (RV lift). If the PA is enlarged, it may be palpated along the left sternal border. P2 will be palpable in pulmonary hypertension and both systolic and diastolic thrills are occasionally noted. On auscultation, the second heart sound may be widely split due to prolonged RV systole. A pulmonary valve systolic click may be noted as well as a right-sided gallop. If pulmonic stenosis is also present, the ejection click may decline with inspiration while any associated systolic murmur will increase. In high-pressure pulmonary valve regurgitation, the pulmonary diastolic (Graham Steell) murmur is readily audible. It is often due to a dilated pulmonary annulus. The murmur increases with inspiration and diminishes with the Valsalva maneuver. In low-pressure pulmonary valve regurgitation, the PA diastolic pressure may be only a few mm Hg higher than the RV diastolic pressure, and there is little diastolic gradient to produce a murmur or characteristic echocardiography/Doppler findings. At times, only contrast angiography or MRI of the main PA will show the free flowing pulmonary valve regurgitation in low-pressure pulmonary valve regurgitation. This situation is common in following patients with repair of tetralogy of Fallot where, despite little murmur, there may be free flowing pulmonary valve regurgitation. This can be suspected by noting an enlarging right ventricle.

The ECG is generally of little value, although right bundle branch block is common, and there may be ECG criteria for RVH. The chest radiograph may show only the enlarged RV and PA. Echocardiography may demonstrate evidence of RV volume overload (paradoxic septal motion and an enlarged RV), and Doppler can determine peak systolic RV pressure and reveal any associated tricuspid regurgitation. The interventricular septum may appear flattened if there is pulmonary hypertension. The size of the main PA can be determined and color flow Doppler can demonstrate the pulmonary valve regurgitation, particularly in the high-pressure situation. Cardiac MRI and CT can be useful for assessing the size of the PA, for imaging the jet lesion, for excluding other causes of pulmonary hypertension (eg, thromboembolic disease, peripheral PA stenosis), and for evaluating RV function. MRI provides a regurgitant fraction to help quantitate the degree of pulmonary valve regurgitation. Cardiac catheterization is confirmatory.

 Treatment & Prognosis

Pulmonary valve regurgitation rarely needs specific therapy other than treatment of the primary cause. In low-pressure pulmonary valve regurgitation due to surgical patch repair of tetralogy of Fallot, pulmonary valve replacement may be indicated if RV enlargement or dysfunction is present. In tetralogy of Fallot, the QRS will widen as RV function declines and the ECG is helpful here (a QRS > 180 msec suggests a higher risk for sudden death) and increasing RV volumes should trigger an evaluation for potential pulmonary valve regurgitation. In carcinoid heart disease, pulmonary valve replacement with a porcine bioprosthesis may be undertaken, though the plaque from this disorder eventually covers the prosthetic pulmonary valve, and this tends to limit the lifespan of these valves. In high-pressure pulmonary valve regurgitation, treatment to control the cause of the pulmonary hypertension is key. Low-pressure pulmonary valve regurgitation is well tolerated over many years; exercise and pregnancy are well tolerated. High-pressure pulmonary valve regurgitation is poorly tolerated and is a serious condition that needs a thorough evaluation for cause and therapy. High pulmonary pressures require a thorough evaluation to distinguish a primary pulmonary cause versus one due to left-sided heart disease. Pulmonary valve replacement requires a bioprosthetic valve in most cases. Pulmonary regurgitation due to an RV to PA conduit or due to a pulmonary autograft replacement as part of the Ross procedure can be repaired with a percutaneous pulmonary valve (Melody valve).

 When to Refer

  • Patients with pulmonary valve regurgitation that results in RV enlargement should be referred to a cardiologist regardless of the estimated pulmonary pressures.

McElhinney DB et al. Short- and medium-term outcomes after transcatheter pulmonary valve replacement in the expanded multicenter US Melody valve trial. Circulation. 2010 Aug 3;122(5):507–16. [PMID: 20644013]

Warnes CA et al. ACC/AHA 2008 Guidelines for the Management of Adults With Congenital Heart Disease. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2008 Dec 2;118(23):e714–833. [PMID: 18997169]

MANAGEMENT OF ANTICOAGULATION FOR PROSTHETIC HEART VALVES DURING PREGNANCY & NONCARDIAC SURGERY OR PROCEDURES

The risk of thromboembolism is much lower with bioprosthetic valves than mechanical prosthetic valves. Mechanical mitral valve prostheses pose a greater risk for thrombosis than mechanical aortic valves. For that reason, the INR should be kept between 2.5 and 3.5 for mechanical mitral prosthetic valves but can be kept between 2.0 and 2.5 for mechanical aortic prosthetic valves. Recent data suggest that with some bileaflet AVRs, an INR as low as 1.5 may be considered safely. Most guidelines recommend that anticoagulation with a vitamin K antagonist is reasonable for the first 3 months after a bioprosthetic mitral valve replacement or repair, though many surgical programs do not feel that is necessary without atrial fibrillation. Enteric-coated aspirin (81 mg once daily) is concomitantly given to patients with both types of mechanical valves but appears to be more important for mitral valve prostheses and for both types of valves when other high-risk factors for thrombosis are present. Clopidogrel is recommended for the first 6 months after TAVR in addition to lifelong aspirin.

The use of vitamin K antagonists, unfractionated heparin, low-molecular-weight heparin and antifibrinolytics in various clinical situations in patients with VHD is summarized in Table 10–7 and the issues are covered in depth in both the 2102 ESC and the 2014 ACCF/AHA VHD guidelines.

Table 10–7. Recommendations for administering vitamin K antagonist (VKA) therapy in patients undergoingprocedures or patients with certain clinical conditions.

Warfarin causes fetal skeletal abnormalities in up to 2% of women who become pregnant while taking it, so every effort is made to defer valve replacement in women until after childbearing age. However, if a woman with a mechanical valve becomes pregnant while taking warfarin, the risk of stopping warfarin may be higher for the mother than the risk of continuing warfarin for the fetus. The risk of warfarin to the fetal skeleton is greatest during the first trimester. Current guidelines suggest warfarin and low-dose asprin are safe during the second and third trimester and should be stopped at time of delivery. At time of vaginal delivery, unfractionated heparin with activated partial thromboplastin time (aPTT) at least two times control is desirable. The risk of warfarin embryopathy has been related to the dose, and guidelines suggest it is reasonable to continue warfarin for the first trimester if the dose is ≤ 5 mg/d. If the dose is > 5 mg/d, it is appropriate to consider either low-molecular-weight heparin as long as the anti-Xa is being monitored (range 0.8 units/mL to 1.2 units/mL) or unfractionated heparin if the aPTT can be monitored and is at least two times control. Target specific oral anticoagulants (antithrombin or Xa inhibitors) should not be used in place of warfarin for mechanical prosthetic valves. This is based on the RE-ALIGN trial that showed that carefully-dosed dabigatran had both more thrombotic complications and more bleeding than warfarin.

Eikelboom JW et al; RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013 Sep 26;369(13):1206–14. [PMID: 23991661]

Holbrook A et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e152S–84S. [PMID: 22315259]

Nishimura RA et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Mar 3. [Epub ahead of print] [PMID: 24589853]

Vahanian A et al; Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS). Guidelines on the management of valvular heart disease (version 2012). Eur Heart J. 2012 Oct;33(19):2451–96. [PMID: 22922415]

CORONARY HEART DISEASE(ATHEROSCLEROTIC CAD, ISCHEMIC HEART DISEASE)

Coronary heart disease, or atherosclerotic CAD, is the number one killer in the United States and worldwide. Every minute, an American dies of coronary heart disease. About 37% of people who experience an acute coronary event, either angina or myocardial infarction, will die of it in the same year. Death rates of coronary heart disease have declined every year since 1968, with about half of the decline from 1980 to 2000 due to treatments and half due to improved risk factors. Coronary heart disease is still responsible for approximately one of five deaths and over 600,000 deaths per year in the United States. Coronary heart disease afflicts nearly 16 million Americans and the prevalence rises steadily with age; thus, the aging of the US population promises to increase the overall burden of coronary heart disease.

 Risk Factors for CAD

Most patients with coronary heart disease have some identifiable risk factor. These include a positive family history (the younger the onset in a first-degree relative, the greater the risk), male sex, blood lipid abnormalities, diabetes mellitus, hypertension, physical inactivity, abdominal obesity, and cigarette smoking, psychosocial factors, consumption of too few fruits and vegetables, and too much alcohol. Smoking remains the number one preventable cause of death and illness in the United States. Although smoking rates have declined in the United States in recent decades, 18% of women and 21% of men still smoke. According to the World Health Organization, 1 year after quitting, the risk of coronary heart disease decreases by 50%. Various interventions have been shown to increase the likelihood of successful smoking cessation (see Chapter 1).

Hypercholesterolemia provides an important modifiable risk factor for coronary heart disease. Risk increases progressively with higher levels of low-density lipoprotein (LDL) cholesterol and declines with higher levels of high-density lipoprotein (HDL) cholesterol. Composite risk scores, such as the Framingham score (see Table 28–2) and the 10-year atherosclerotic cardiovascular disease risk calculator (http://my.americanheart.org/cvriskcalculator), provide estimates of 10-year probability of development of coronary heart disease that can guide primary prevention strategies. The 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults suggests statin therapy in four populations: patients with (1) clinical atherosclerotic disease, (2) LDL cholesterol ≥ 190 mg/dL, (3) diabetes who are aged 40–75 years, and (4) an estimated 10-year atherosclotic risk of ≥ 7.5% aged 40–75 years (Figure 10–6). Importantly, the updated guidelines no longer recommend treating to a target LDL cholesterol, an approach that has never been shown to be effective in randomized trials. Patients in these categories should be treated with moderate or high intensity statin, with high intensity statin for the higher risk populations (Table 10–8).

 Figure 10–6. Major recommendation for statin therapy for ASCVD prevention. (Reproduced, with permission, from Stone NJ et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2013 Nov 12. [Epub ahead of print])

Table 10–8. High-, moderate-, and low-intensity statin therapy (used in the RCTs reviewed by the expert panel).1,2

 Myocardial Hibernation & Stunning

Areas of myocardium that are persistently underperfused but still viable may develop sustained contractile dysfunction. This phenomenon, which is termed “myocardial hibernation,” appears to represent an adaptive response that maybe associated with depressed LV function. It is important to recognize this phenomenon, since this form of dysfunction is reversible following coronary revascularization. Hibernating myocardium can be identified by radionuclide testing, positron emission tomography (PET), contrast-enhanced MRI, or its retained response to inotropic stimulation with dobutamine. A related phenomenon, termed “myocardial stunning,” is the occurrence of persistent contractile dysfunction following prolonged or repetitive episodes of myocardial ischemia. Clinically, myocardial stunning is often seen after reperfusion of acute myocardial infarction and is defined with improvement following revascularization.

Stone NJ et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2013 Nov 12. [Epub ahead of print] [PMID: 24222016]

CHRONIC STABLE ANGINA PECTORIS

 ESSENTIALS OF DIAGNOSIS

 Precordial chest pain, usually precipitated by stress or exertion, relieved rapidly by rest or nitrates.

 ECG or scintigraphic evidence of ischemia during pain or stress testing.

 Angiographic demonstration of significant obstruction of major coronary vessels.

 General Considerations

Angina pectoris is usually due to atherosclerotic heart disease. Coronary vasospasm may occur at the site of a lesion or, less frequently, in apparently normal vessels. Other unusual causes of coronary artery obstruction such as congenital anomalies, emboli, arteritis, or dissection may cause ischemia or infarction. Angina may also occur in the absence of coronary artery obstruction as a result of severe myocardial hypertrophy, severe aortic stenosis or regurgitation, or in response to increased metabolic demands, as in hyperthyroidism, marked anemia, or paroxysmal tachycardias with rapid ventricular rates. Rarely, angina occurs with angiographically normal coronary arteries and without other identifiable causes. This presentation has been labeled syndrome X and is most likely due to inadequate flow reserve in the resistance vessels (microvasculature). Syndrome X remains difficult to diagnose. Although treatment is often not very successful in relieving symptoms, the prognosis of syndrome X is good.

 Clinical Findings

  1. Symptoms

The diagnosis of angina pectoris depends principally upon the history, which should specifically include the following information: circumstances that precipitate and relieve angina, characteristics of the discomfort, location and radiation, duration of attacks, and effect of nitroglycerin.

Circumstances that precipitate and relieve angina—Angina occurs most commonly during activity and is relieved by resting. Patients may prefer to remain upright rather than lie down, as increased preload in recumbency increases myocardial work. The amount of activity required to produce angina may be relatively consistent under comparable physical and emotional circumstances or may vary from day to day. The threshold for angina is usually less after meals, during excitement, or on exposure to cold. It is often lower in the morning or after strong emotion; the latter can provoke attacks in the absence of exertion. In addition, discomfort may occur during sexual activity, at rest, or at night as a result of coronary spasm.

  1. Characteristics of the discomfort—Patients often do not refer to angina as “pain” but as a sensation of tightness, squeezing, burning, pressing, choking, aching, bursting, “gas,” indigestion, or an ill-characterized discomfort. It is often characterized by clenching a fist over the mid chest. The distress of angina is rarely sharply localized and is not spasmodic.
  2. Location and radiation—The distribution of the distress may vary widely in different patients but is usually the same for each patient unless unstable angina or myocardial infarction supervenes. In most cases, the discomfort is felt behind or slightly to the left of the mid sternum. When it begins farther to the left or, uncommonly, on the right, it characteristically moves centrally substernally. Although angina may radiate to any dermatome from C8 to T4, it radiates most often to the left shoulder and upper arm, frequently moving down the inner volar aspect of the arm to the elbow, forearm, wrist, or fourth and fifth fingers. It may also radiate to the right shoulder or arm, the lower jaw, the neck, or even the back.
  3. Duration of attacks—Angina is generally of short duration and subsides completely without residual discomfort. If the attack is precipitated by exertion and the patient promptly stops to rest, it usually lasts < 3 minutes. Attacks following a heavy meal or brought on by anger often last 15–20 minutes. Attacks lasting more than 30 minutes are unusual and suggest the development of an acute coronary syndrome with unstable angina, myocardial infarction, or an alternative diagnosis.
  4. Effect of nitroglycerin—The diagnosis of angina pectoris is supported if sublingual nitroglycerin promptly and invariably shortens an attack and if prophylactic nitrates permit greater exertion or prevent angina entirely.
  5. Signs

Examination during angina frequently reveals a significant elevation in systolic and diastolic BP, although hypotension may also occur, and may reflect more severe ischemia or inferior ischemia (especially with bradycardia) due to a Bezold–Jarisch reflex. Occasionally, a gallop rhythm and an apical systolic murmur due to transient mitral regurgitation from papillary muscle dysfunction are present during pain only. Supraventricular or ventricular arrhythmias may be present, either as the precipitating factor or as a result of ischemia.

It is important to detect signs of diseases that may contribute to or accompany atherosclerotic heart disease, eg, diabetes mellitus (retinopathy or neuropathy), xanthelasma tendinous xanthomas,, hypertension, thyrotoxicosis, myxedema, or peripheral artery disease. Aortic stenosis or regurgitation, hypertrophic cardiomyopathy, and mitral valve prolapse should be sought, since they may produce angina or other forms of chest pain.

  1. Laboratory Findings

Other than standard laboratory tests to evaluate for acute coronary syndrome (troponin and CK-MB), factors contributing to ischemia (such as anemia), and to screen for risk factors that may increase the probability of true coronary heart disease (such as hyperlipidemia and diabetes mellitus), blood tests are not helpful to diagnose chronic angina.

  1. ECG

The resting ECG is often normal in patients with angina. In the remainder, abnormalities include old myocardial infarction, nonspecific ST–T changes, and changes of LVH. During anginal episodes, as well as during asymptomatic ischemia, the characteristic ECG change is horizontal or downsloping ST-segment depression that reverses after the ischemia disappears. T wave flattening or inversion may also occur. Less frequently, transient ST-segment elevation is observed; this finding suggests severe (transmural) ischemia from coronary occlusion, and it can occur with coronary spasm.

  1. Pretest Probability

The history as detailed above, the physical examination findings, and laboratory and ECG findings are used to develop a pretest probability of CAD as the cause of the clinical symptoms. Other important factors to include in calculating the pretest probability of CAD are patient age, sex, and clinical symptoms. Patients with low to intermediate pretest probability for CAD should undergo noninvasive stress testing whereas patients with high pretest probability are generally referred for cardiac catheterization.

  1. Exercise ECG

Exercise testing is the most commonly used noninvasive procedure for evaluating for inducible ischemia in the patient with angina. Exercise testing is often combined with imaging studies (nuclear, echocardiography, or MRI [see below]), but in low-risk patients without baseline ST segment abnormalities or in whom anatomic localization is not necessary, the exercise ECG remains the recommended initial procedure because of considerations of cost and convenience.

Exercise testing can be done on a motorized treadmill or with a bicycle ergometer. A variety of exercise protocols are utilized, the most common being the Bruce protocol, which increases the treadmill speed and elevation every 3 minutes until limited by symptoms. At least two ECG leads should be monitored continuously.

  1. Precautions and risks—The risk of exercise testing is about one infarction or death per 1000 tests, but individuals who have pain at rest or minimal activity are at higher risk and should not be tested. Many of the traditional exclusions, such as recent myocardial infarction or heart failure, are no longer usedif the patient is stable and ambulatory, but symptomatic aortic stenosis remains a contraindication.
  2. Indications—Exercise testing is used (1) to confirm the diagnosis of angina; (2) to determine the severity of limitation of activity due to angina; (3) to assess prognosis in patients with known coronary disease, including those recovering from myocardial infarction, by detecting groups at high or low risk; and (4) to evaluate responses to therapy. Because false-positive tests often exceed true positives, leading to much patient anxiety and self-imposed or mandated disability, exercise testing of asymptomatic individuals should be done only for those whose occupations place them or others at special risk (eg, airline pilots), and older individuals commencing strenuous activity.
  3. Interpretation—The usual ECG criterion for a positive test is 1 mm (0.1 mV) horizontal or downsloping ST-segment depression (beyond baseline) measured 80 milliseconds after the J point. By this criterion, 60–80% of patients with anatomically significant coronary disease will have a positive test, but 10–30% of those without significant disease will also be positive. False positives are uncommon when a 2-mm depression is present. Additional information is inferred from the time of onset and duration of the ECG changes, their magnitude and configuration, BP and heart rate changes, the duration of exercise, and the presence of associated symptoms. In general, patients exhibiting more severe ST-segment depression (> 2 mm) at low workloads (< 6 minutes on the Bruce protocol) or heart rates (< 70% of age-predicted maximum)—especially when the duration of exercise and rise in BP are limited or when hypotension occurs during the test—have more severe disease and a poorer prognosis. Depending on symptom status, age, and other factors, such patients should be referred for coronary arteriography and possible revascularization. On the other hand, less impressive positive tests in asymptomatic patients are often “false positives.” Therefore, exercise testing results that do not conform to the clinical picture should be confirmed by stress imaging.
  4. Myocardial Stress Imaging

Myocardial stress imaging (scintigraphy, echocardiography, or MRI) is indicated (1) when the resting ECG makes an exercise ECG difficult to interpret (eg, left bundle branch block, baseline ST–T changes, low voltage); (2) for confirmation of the results of the exercise ECG when they are contrary to the clinical impression (eg, a positive test in an asymptomatic patient); (3) to localize the region of ischemia; (4) to distinguish ischemic from infarcted myocardium; (5) to assess the completeness of revascularization following bypass surgery or coronary angioplasty; or (6) as a prognostic indicator in patients with known coronary disease. Published criteria summarize these indications for stress testing.

  1. Myocardial perfusion scintigraphy—This test, also known as radionuclide imaging, provides images in which radionuclide uptake is proportionate to blood flow at the time of injection.

Stress imaging is positive in about 75–90% of patients with anatomically significant coronary disease and in 20–30% of those without it. Occasionally, other conditions, including infiltrative diseases (sarcoidosis, amyloidosis), left bundle branch block, and dilated cardiomyopathy, may produce resting or persistent perfusion defects. False-positive radionuclide tests may occur as a result of diaphragmatic attenuation or, in women, attenuation through breast tissue. Tomographic imaging (single-photon emission computed tomography, SPECT) can reduce the severity of artifacts.

  1. Radionuclide angiography—This procedure, also known as Multi Gated Acquisition Scan, or MUGA scan, uses radionuclide tracers to image the LV and measures its EF and wall motion. In coronary disease, resting abnormalities usually represent infarction, and those that occur only with exercise usually indicate stress-induced ischemia. Exercise radionuclide angiography has approximately the same sensitivity as myocardial perfusion scintigraphy, but it is less specific in older individuals and those with other forms of heart disease. In addition, because of the precision around LVEF, the test is also used for monitoring patients exposed to cardiotoxic therapies (such as chemotherapeutic agents).
  2. Stress echocardiography—Echocardiograms performed during supine exercise or immediately following upright exercise may demonstrate exercise-induced segmental wall motion abnormalities as an indicator of ischemia. In experienced laboratories, the test accuracy is comparable to that obtained with scintigraphy—though a higher proportion of tests is technically inadequate. While exercise is the preferred stress because of other information derived, pharmacologic stress with high-dose dobutamine (20–40 mcg/kg/min) can be used as an alternative to exercise.
  3. Other Imaging
  4. Positron emission tomography—PET and SPECT scanning can accurately distinguish transiently dysfunctional (“stunned”) myocardium from scar tissue.
  5. CT and MRI scanningCT scanningcan image the heart and, with contrast medium and multislice technology, the coronary arteries. Multislice CT angiography may be useful in evaluating patients with low likelihood of significant CAD to rule out disease. CT angiography may also be useful for evaluating chest pain and suspected acute coronary syndrome. However, the role of CT angiography in routine practice is yet to be established, since it currently requires both radiation exposure and contrast load. Radionuclide SPECT imaging also has similar radiation exposure. CT angiography with noninvasive functional assessment of coronary stenosis (Fractional flow reserve) termed “CT-FFR” is also being evaluated in patients with low-intermediate likelihood of CAD.

Electron beam CT (EBCT) can quantify coronary artery calcification, which is highly correlated with atheromatous plaque and has high sensitivity, but low specificity, for obstructive coronary disease. Thus, although this test can stratify patients into lower and higher risk groups, the appropriate management of individual patients with asymptomatic coronary artery calcification—beyond aggressive risk factors modification—is unclear. This test has not traditionally been used in symptomatic patients. According to the American Heart Association, persons who are at low risk (< 10% 10-year risk) or at high risk (>20% 10-year risk) do not benefit from coronary calcium assessment (class III, level of evidence: B) (see Tables 28–1 and 28–2). However, in clinically selected, intermediate-risk patients, it may be reasonable to determine the atherosclerosis burden using EBCT in order to refine clinical risk prediction and to select patients for more aggressive target values for lipid-lowering therapies (class IIb, level of evidence: B).

Cardiac M RI using gadolinium provides high-resolution images of the heart and great vessels without radiation exposure or use of iodinated contrast media. Gadolinium has been associated with a rare but fatal complication in patients with severe kidney disease, called necrotizing systemic fibrosis. Gadolinium can demonstrate perfusion using dobutamine or adenosine to produce pharmacologic stress. Advances have been made in imaging the proximal coronary arteries, but this application remains investigational.

  1. Ambulatory ECG Monitoring

Ambulatory ECG recorders can monitor for ischemic ST-segment depression but this modality is rarely used for ischemia detection.

  1. Coronary Angiography

Selective coronary arteriography is the definitive diagnostic procedure for CAD. It can be performed with low mortality (about 0.1%) and morbidity (1–5%), but due to the invasive nature and cost, it is currently only recommended in patients with a high pretest probability of CAD.

Coronary arteriography should be performed in the following circumstances if percutaneous transluminal coronary angioplasty or bypass surgery is a consideration:

  1. Limiting stable angina despite an adequate medical regimen.
  2. Clinical presentation (unstable angina, postinfarction angina, etc) or noninvasive testing suggests high-risk disease (see Indications for Revascularization).
  3. Concomitant aortic valve disease and angina pectoris, to determine whether the angina is due to accompanying coronary disease.
  4. Asymptomatic older patients undergoing valve surgery so that concomitant bypass may be done if the anatomy is propitious.
  5. Recurrence of symptoms after coronary revascularization to determine whether bypass grafts or native vessels are occluded.
  6. Cardiac failure where a surgically correctable lesion, such as LV aneurysm, mitral regurgitation, or reversible ischemic dysfunction, is suspected.
  7. Survivors of sudden death or symptomatic or life-threatening arrhythmias when CAD may be a correctable cause.
  8. Chest pain of uncertain cause or cardiomyopathy of unknown cause.
  9. Emergently performed cardiac catheterization with intention to perform primary PCI in patients with suspected acute myocardial infarction.

Appropriate use criteria for the use of diagnostic heart catheterization and coronary angiography were developed by the ACC/AHA in 2012.

A narrowing > 50% of the luminal diameter is considered hemodynamically (and clinically) significant, although most lesions producing ischemia are associated with narrowing in excess of 70%. In those with strongly positive exercise ECGs or scintigraphic studies, three-vessel or left main disease may be present in 75–95% depending on the criteria used. Intravascular ultrasound (IVUS) is useful when the angiogram is equivocal as well as for assessing the results of angioplasty or stenting. In addition, IVUS is the invasive diagnostic method of choice for ostial left main lesions and coronary dissections. In fractional flow reserve (FFR), a pressure wire is used to measure the relative change in pressure across a coronary lesion after the administration of adenosine. Revascularization based on abnormal FFR improves clinical outcomes compared to revascularization of all angiographically stenotic lesions. FFR is an important invasive tool to aid with ischemia driven revascularization and has become the standard tool to evaluate borderline lesions in cases in which the clinical team is evaluating the clinical and hemodynamic significance of a coronary stenosis.

LV angiography is usually performed at the same time as coronary arteriography. Global and regional LV function are visualized, as well as mitral regurgitation if present. LV function is a major determinant of prognosis in coronary heart disease.

 Differential Diagnosis

When atypical features are present—such as prolonged duration (hours or days) or darting, knifelike pains at the apex or over the precordium—ischemia is less likely.

Anterior chest wall syndrome is characterized by sharply localized tenderness of intercostal muscles. Inflammation of the chondrocostal junctions may result in diffuse chest pain that is also reproduced by local pressure (Tietze syndrome). Intercostal neuritis (due to herpes zoster, diabetes mellitus, for example) also mimics angina.

Cervical or thoracic spine disease involving the dorsal roots produces sudden sharp, severe chest pain suggesting angina in location and “radiation” but related to specific movements of the neck or spine, recumbency, and straining or lifting. Pain due to cervical or thoracic disk disease involves the outer or dorsal aspect of the arm and the thumb and index fingers rather than the ring and little fingers.

Reflux esophagitis, peptic ulcer, chronic cholecystitis, esophageal spasm, and functional gastrointestinal disease may produce pain suggestive of angina pectoris. The picture may be especially confusing because ischemic pain may also be associated with upper gastrointestinal symptoms, and esophageal motility disorders may be improved by nitrates and calcium channel blockers. Assessment of esophageal motility may be helpful.

Degenerative and inflammatory lesions of the left shoulder and thoracic outlet syndromes may cause chest pain due to nerve irritation or muscular compression; the symptoms are usually precipitated by movement of the arm and shoulder and are associated with paresthesias.

Pneumonia, pulmonary embolism, and spontaneous pneumothorax may cause chest pain as well as dyspnea. Dissection of the thoracic aorta can cause severe chest pain that is commonly felt in the back; it is sudden in onset, reaches maximum intensity immediately, and may be associated with changes in pulses. Other cardiac disorders such as mitral valve prolapse, hypertrophic cardiomyopathy, myocarditis, pericarditis, aortic valve disease, or RVH may cause atypical chest pain or even myocardial ischemia.

 Treatment

Sublingual nitroglycerin is the drug of choice for acute management; it acts in about 1–2 minutes. As soon as the attack begins, one fresh tablet is placed under the tongue. This may be repeated at 3- to 5-minute intervals, but current recommendations are that if pain is not relieved or improving after 5 minutes, that the patient call 9-1-1; pain not responding to three tablets or lasting more than 20 minutes may represent evolving infarction. The dosage (0.3, 0.4, or 0.6 mg) and the number of tablets to be used before seeking further medical attention must be individualized. Nitroglycerin buccal spray is also available as a metered (0.4 mg) delivery system. It has the advantage of being more convenient for patients who have difficulty handling the pills and of being more stable.

 Prevention of Further Attacks

  1. Aggravating Factors

Angina may be aggravated by hypertension, LV failure, arrhythmia (usually tachycardias), strenuous activity, cold temperatures, and emotional states. These factors should be identified and treated when possible.

  1. Nitroglycerin

Nitroglycerin, 0.3–0.6 mg sublingually or 0.4–0.8 mg translingually by spray, should be taken 5 minutes before any activity likely to precipitate angina. Sublingual isosorbide dinitrate (2.5–10 mg) is only slightly longer-acting than sublingual nitroglycerin.

  1. Long-Acting Nitrates

Longer-acting nitrate preparations include isosorbide dinitrate, 10–40 mg orally three times daily; isosorbide mononitrate, 10–40 mg orally twice daily or 60–120 mg once daily in a sustained-release preparation; oral sustained-release nitroglycerin preparations, 6.25–12.5 mg two to four times daily; nitroglycerin ointment, 6.25–25 mg applied two to four times daily; and transdermal nitroglycerin patches that deliver nitroglycerin at a predetermined rate (usually 5–20 mg/24 h). The main limitation to long-term nitrate therapy is tolerance, which can be limited by using a regimen that includes a minimum 8- to 10-hour period per day without nitrates. Isosorbide dinitrate can be given three times daily, with the last dose after dinner, or longer-acting isosorbide mononitrate once daily. Transdermal nitrate preparations should be removed overnight in most patients.

Nitrate therapy is often limited by headache. Other side effects include nausea, light-headedness, and hypotension.

  1. Beta-Blockers

Beta-blockers are the only antianginal agents that have been demonstrated to prolong life in patients with coronary disease (post-myocardial infarction). Beta-blockers should be considered for first-line therapy in most patients with chronic angina and are recommened as such by the Stable Ischemic Heart disease guidelines (Figure 10–7).

 Figure 10–7. Algorithm for guideline-directed medical therapy for patients with stable ischemic heart disease. The use of bile acid sequestrant is relatively contraindicated when triglycerides are ≥ 200 mg/dl and contraindicated when triglycerides are ≥ 500 mg/dl. Dietary supplement niacin must not be used as a substitute for prescription niacin. (Reproduced, with permission, from Fihn SD et al; American College of Cardiology Foundation/American Heart Association Task Force. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease. Circulation. 2012 Dec 18;126(25):e354-471.)

Beta-blockers with intrinsic sympathomimetic activity, such as pindolol, are less desirable because they may exacerbate angina in some individuals and have not been effective in secondary prevention trials. The pharmacology and side effects of the beta-blockers are discussed in Chapter 11 (see Table 11–6). The dosages of all these drugs when given for angina are similar. The major contraindications are severe bronchospastic disease, bradyarrhythmias, and decompensated heart failure.

  1. Ranolazine

Ranolazine is indicated as first-line use for chronic angina. Ranolazine has no effect on heart rate and BP, and it has been shown in clinical trials to prolong exercise duration and time to angina, both as monotherapy and when administered with conventional antianginal therapy. It is safe to use with erectile dysfunction drugs. The usual dose is 500 mg orally twice a day. Because it can cause QT prolongation, it is contraindicated in patients with existing QT prolongation; in patients taking QT prolonging drugs, such as class I or III antiarrhythmics (eg, quinidine, dofetilide, sotalol); and in those taking potent and moderate CYP450 3A inhibitors (eg, clarithromycin and rifampin). Of interest, in spite of the QT prolongation, there is a significantly lower rate of ventricular arrhythmias with its use following acute coronary syndromes, as shown in the MERLIN trial. It also decreases occurrence of atrial fibrillation and results in a small decrease in HbA1c. It is contraindicated in patients with significant liver and kidney disease. Ranolazine is not to be used for treatment of acute anginal episodes.

  1. Calcium Channel Blocking Agents

Unlike the beta-blockers, calcium channel blockers have not been shown to reduce mortality postinfarction and in some cases have increased ischemia and mortality rates. This appears to be the case with some dihydropyridines (eg, nifedipine) and with diltiazem and verapamil in patients with clinical heart failure or moderate to severe LV dysfunction. Meta-analyses have suggested that short-acting nifedipine in moderate to high doses causes an increase in mortality. It is uncertain whether these findings are relevant to longer-acting dihydropyridines. Nevertheless, considering the uncertainties and the lack of demonstrated favorable effect on outcomes, calcium channel blockers should be considered third-line anti-ischemic drugs in the postinfarction patient. Similarly, these agents, with the exception of amlodipine (which proved safe in patients with heart failure in the PRAISE-2 trial), should be avoided in patients with heart failure or low EFs.

The pharmacologic effects and side effects of the calcium channel blockers are discussed in Chapter 11 and summarized in Table 11–8. Diltiazem, amlodipine, and verapamil are preferable because they produce less reflex tachycardia and because the former, at least, may cause fewer side effects. Nifedipine, nicardipine, and amlodipine are also approved agents for angina. Isradipine, felodipine, and nisoldipine are not approved for angina but probably are as effective as the other dihydropyridines.

  1. Alternative and Combination Therapies

Patients who do not respond to one class of antianginal medication often respond to another. It may, therefore, be worthwhile to use an alternative agent before progressing to combinations. The stable ischemic heart disease guidelines recommend starting with a beta-blocker as initial therapy, followed by calcium channel blockers, long-acting nitrates, or ranolazine. A few patients will have further response to a regimen including all four agents.

  1. Platelet-Inhibiting Agents

Several studies have demonstrated the benefit of antiplatelet drugs for patients with stable and unstable vascular disease. Therefore, unless contraindicated, aspirin (81–325 mg orally daily) should be prescribed for all patients with angina. Clopidogrel, 75 mg orally daily, reduces vascular events in patients with stable vascular disease (as an alternative to aspirin) and in patients with acute coronary syndromes (in addition to aspirin). Thus, it is also a good alternative in aspirin-intolerant patients. Clopidogrel did not reduce myocardial infarction, stroke, or cardiovascular death in the CHARISMA trial of patients with cardiovascular disease or multiple risk factors, with about a 50% increase in bleeding. However, it might be reasonable to use combination clopidogrel and aspirin for certain high-risk patients with established coronary disease.

  1. Risk Reduction

Patients with coronary disease should undergo aggressive risk factor modification. This approach, with a particular focus on statin treatment, treating hypertension, stopping smoking, and exercise and weight control (especially for patients with metabolic syndrome or at risk for diabetes), may markedly improve outcome. For patients with diabetes and cardiovascular disease, there is uncertainty about the optimal target blood sugar control. The ADVANCE trial suggested some benefit for tight blood sugar control with target HbA1C ≤ 6.5% but the ACCORD trial found that routine aggressive targeting for blood sugar control to HbA1C to < 6.0% in patients with diabetes and coronary disease was associated with increased mortality. Therefore, tight blood sugar control should be avoided particularly in patients with history of severe hypoglycemia, long-standing diabetes, and advanced vascular disease. Aggressive BP control (target systolic BP < 120 mm Hg) in the ACCORD trial was not associated with reduction in coronary heart disease events, although stroke was reduced.

  1. Revascularization
  2. Indications—There is general agreement that otherwise healthy patients in the following groups should undergo revascularization: (1) Patients with unacceptable symptoms despite medical therapy to its tolerable limits. (2) Patients with left main coronary artery stenosis > 50% with or without symptoms. (3) Patients with three-vessel disease with LV dysfunction (EF < 50% or previous transmural infarction). (4) Patients with unstable angina who after symptom control by medical therapy continue to exhibit ischemia on exercise testing or monitoring. (5) Post-myocardial infarction patients with continuing angina or severe ischemia on noninvasive testing. The use of revascularization for patients with acute coronary syndromes and acute ST elevation myocardial infarction is discussed below.

Data from the COURAGE trial have shown that for patients with chronic angina and disease suitable for percutaneous coronary intervention (PCI), PCI in addition to stringent guideline-directed medical therapy aimed at both risk reduction and anti-anginal care offers no mortality benefit beyond excellent medical therapy alone, and relatively moderate long-term symptomatic improvement. Also, drug-eluting stents, widely used because of their benefits in preventing restenosis, have been associated with higher rates of late stent thrombosis. Therefore, for patients with mild to moderate CAD and limited symptoms, revascularization may not provide significant functional status quality of life benefit. For patients with moderate to significant coronary stenosis, such as those who have two-vessel disease associated with underlying LV dysfunction, anatomically critical lesions (> 90% proximal stenoses, especially of the proximal left anterior descending artery), or physiologic evidence of severe ischemia (early positive exercise tests, large exercise-induced thallium scintigraphic defects, or frequent episodes of ischemia on ambulatory monitoring), a heart team consisting of revascularization physicians (interventional cardiologists and surgeons) may be required to review and provide patients with best revascularization options.

  1. Type of procedure
  2. PERCUTANEOUS CORONARY INTERVENTION INCLUDING STENTING—PCI, including balloon angioplasty and coronary stenting, can effectively open stenotic coronary arteries. Coronary stenting, with either bare metal stents or drug-eluting stents, has substantially reduced restenosis. Stenting can also be used selectively for left main coronary stenosis, particularly when coronary artery bypass grafting (CABG) is contraindicated.

PCI is possible but often less successful in bypass graft stenoses. Experienced operators are able to successfully dilate > 90% of lesions attempted. The major early complication is intimal dissection with vessel occlusion, although this is rare with coronary stenting. The use of intravenous platelet glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban) substantially reduce the rate of periprocedural myocardial infarction, and placement of intracoronary stents markedly improve initial and long-term angiographic results, especially with complex and long lesions. After percutaneous coronary intervention, all patients should have CK-MB and troponin measured. The definition of a periprocedural infarction is still under debate with many experts advocating for a clinical definition that incorporates enzymes, angiographic findings, and electrocardiographic evidence. Acute thrombosis after stent placement can largely be prevented by aggressive antithrombotic therapy (long-term aspirin, 81–325 mg, plus clopidogrel, 300–600 mg loading dose followed by 75 mg daily, for between 30 days and 1 year, and with acute use of platelet glycoprotein IIb/IIIa inhibitors).

A major limitation with PCI has been restenosis, which occurs in the first 6 months in < 10% of vessels treated with drug-eluting stents, 15–30% of vessels treated with bare metal stents, and 30–40% of vessels without stenting. Factors associated with higher restenosis rates include diabetes, small luminal diameter, longer and more complex lesions, and lesions at coronary ostia or in the left anterior descending coronary artery. Drug-eluting stents that elute antiproliferative agents such as sirolimus, everolimus, zotarolimus, or paclitaxel have substantially reduced restenosis. In-stent restenosis is often treated with restenting with drug-eluting stents, and rarely with brachytherapy. The nearly 2 million PCIs performed worldwide per year far exceeds the number of CABG operations, but the rationale for many of the procedures performed in patients with stable angina should be for angina symptom reduction. The COURAGE trial has confirmed earlier studies in showing that even for patients with moderate anginal symptoms and positive stress tests PCI provides no benefit over medical therapy with respect to death or myocardial infarction. PCI was more effective at relieving angina, although most patients in the medical group had improvement in symptoms. Thus, in patients with mild or moderate stable symptoms, aggressive lipid-lowering and antianginal therapy may be a preferable initial strategy, reserving PCI for patients with significant and refractory symptoms or for those who are unable to take the prescribed medicines.

Several studies of PCI, including those with drug-eluting stents, versus CABG in patients with multivessel disease have been reported. The SYNTAX trial as well as previously performed trials with drug-eluting stent use in PCI patients show comparable mortality and infarction rates over follow-up periods of 1–3 years but a high rate (approximately 40%) of repeat procedures following PCI. Stroke rates are higher with CABG. As a result, the choice of revascularization procedure may depend on details of coronary anatomy and is often a matter of patient preference. However, it should be noted that < 20% of patients with multivessel disease meet the entry criteria for the clinical trials, so these results cannot be generalized to all multivessel disease patients. Outcomes with percutaneous revascularization in diabetics have generally been inferior to those with CABG. The FREEDOM trial demonstrated that CABG surgery was superior to PCI with regards to death, myocardial infarction, and stroke for patients with diabetes and multivessel coronary disease at 5 years across all subgroups of SYNTAX score anatomy.

  1. CORONARY ARTERY BYPASS GRAFTING—CABG can be accomplished with a very low mortality rate (1–3%) in otherwise healthy patients with preserved cardiac function. However, the mortality rate of this procedure rises to 4–8% in older individuals and in patients who have had a prior CABG.

Grafts using one or both internal mammary arteries (usually to the left anterior descending artery or its branches) provide the best long-term results in terms of patency and flow. Segments of the saphenous vein (or, less optimally, other veins) or the radial artery interposed between the aorta and the coronary arteries distal to the obstructions are also used. One to five distal anastomoses are commonly performed.

Minimally invasive surgical techniques may involve a limited sternotomy, lateral thoracotomy (MIDCAB), or thoracoscopy (port-access). They are more technically demanding, usually not suitable for more than two grafts, and do not have established durability. Bypass surgery can be performed both on circulatory support (on pump) and without direct circulatory support (off-pump). Randomized trial data have not shown a benefit with off-pump bypass surgery but minimally invasive surgical techniques allow earlier postoperative mobilization and discharge.

The operative mortality rate is increased in patients with poor LV function (LVEF < 35%) or those requiring additional procedures (valve replacement or ventricular aneurysmectomy). Patients over 70 years of age, patients undergoing repeat procedures, or those with important noncardiac disease (especially chronic kidney disease and diabetes) or poor general health also have higher operative mortality and morbidity rates, and full recovery is slow. Thus, CABG should be reserved for more severely symptomatic patients in this group. Early (1–6 months) graft patency rates average 85–90% (higher for internal mammary grafts), and subsequent graft closure rates are about 4% annually. Early graft failure is common in vessels with poor distal flow, while late closure is more frequent in patients who continue smoking and those with untreated hyperlipidemia. Antiplatelet therapy with aspirin improves graft patency rates. Smoking cessation and vigorous treatment of blood lipid abnormalities (particularly with statins) are necessary. Repeat revascularization (see below) may be necessitated because of recurrent symptoms due to progressive native vessel disease and graft occlusions. Reoperation is technically demanding and less often fully successful than the initial operation.

  1. Mechanical Extracorporeal Counterpulsation

Extracorporeal counterpulsation entails repetitive inflation of a high-pressure chamber surrounding the lower half of the body during the diastolic phase of the cardiac cycle for daily 1-hour sessions over a period of 7 weeks. Randomized trials have shown that extracorporeal counterpulsation reduces angina thus it may be considered for relief of refractory angina in patients with stable coronary disease.

  1. Neuromodulation

Spinal cord stimulation can be used to relieve chronic refractory angina. Spinal cord stimulators are subcutaneously implantable via a minimally invasive procedure under local anesthesia.

 Prognosis

The prognosis of angina pectoris has improved with development of therapies aimed at secondary prevention. Mortality rates vary depending on the number of vessels diseased, the severity of obstruction, the status of LV function, and the presence of complex arrhythmias. Mortality rates are progressively higher in patients with one-, two-, and three-vessel disease and those with left main coronary artery obstruction (ranging from 1% per year to 25% per year). The outlook in individual patients is unpredictable, and nearly half of the deaths are sudden. Therefore, risk stratification is attempted. Patients with accelerating symptoms have a poorer outlook. Among stable patients, those whose exercise tolerance is severely limited by ischemia (< 6 minutes on the Bruce treadmill protocol) and those with extensive ischemia by exercise ECG or scintigraphy have more severe anatomic disease and a poorer prognosis. The Duke Treadmill Score, based on a standard Bruce protocol exercise treadmill test, provides an estimate of risk of death at 1 year. The score uses time on the treadmill, amount of ST-segment depression, and presence of angina (Table 10–9).

Table 10–9. Duke treadmill score: Calculation and interpretation.

 When to Refer

All patients with new or worsening symptoms believed to represent progressive angina or a positive stress test for myocardial ischemia with continued angina despite medical therapy (or both) should be referred to a cardiologist.

 When to Admit

  • Patients with elevated cardiac biomarkers, ischemic ECG findings, or hemodynamic instability.
  • Patients with new or worsened symptoms possibly thought to be ischemic but who lack high-risk features can be observed with serial ECGs and biomarkers, and discharged if stress testing shows low-risk findings.

Boden WE et al; COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007 Apr 12;356(15):1503–16. [PMID: 17387127]

Cassar A et al. Chronic coronary artery disease: diagnosis and management. Mayo Clin Proc. 2009 Dec;84(12):1130–46. [PMID: 19955250]

Fihn SD et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2012 Dec 18;126(25):e354–471. [PMID: 23166211]

Grines CL et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Circulation. 2007 Feb 13;115(6):813–8. [PMID: 17224480]

Levine GN et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011 Dec 6;124(23):e574–651. [PMID: 22064601]

Min JK et al. Diagnostic accuracy of fractional flow reserve from anatomic CT angiography. JAMA. 2012 Sep 26;308(12):1237–45. [PMID: 22922562]

Moussa ID et al. Consideration of a new definition of clinically relevant myocardial infarction after coronary revascularization: an expert consensus document from the Society for Cardiovascular Angiography and Interventions (SCAI). J Am Coll Cardiol. 2013 Oct 22;62(17):1563–70. [PMID: 24135581]

Patel MR et al. ACCF/SCAI/STS/AATS/AHA/ASNC 2009 Appropriateness Criteria for Coronary Revascularization: a report by the American College of Cardiology Foundation Appropriateness Criteria Task Force, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, American Association for Thoracic Surgery, American Heart Association, and the American Society of Nuclear Cardiology Endorsed by the American Society of Echocardiography, the Heart Failure Society of America, and the Society of Cardiovascular Computed Tomography. J Am Coll Cardiol. 2009 Feb 10;53(6):530–53. [PMID: 19195618]

Patel MR et al. ACCF/SCAI/AATS/AHA/ASE/ASNC/HFSA/HRS/SCCM/SCCT/SCMR/STS 2012 appropriate use criteria for diagnostic catheterization: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, Society for Cardiovascular Angiography and Interventions, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society of Critical Care Medicine, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2012 May 29;59(22):1995–2027. [PMID: 22578925]

Patel MR et al. Low diagnostic yield of elective coronary angiography. N Engl J Med. 2010 Mar 11;362(10):886–95. [PMID: 20220183]

Skyler JS et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA Diabetes Trials: a position statement of the American Diabetes Association and a Scientific Statement of the American College of Cardiology Foundation and the American Heart Association. J Am Coll Cardiol. 2009 Jan 20;53(3):298–304. [PMID: 19147051]

Torpy JM et al. JAMA patient page. Cardiac stress testing. JAMA. 2008 Oct 15;300(15):1836. [PMID: 18854548]

CORONARY VASOSPASM & ANGINA WITH NORMAL CORONARY ARTERIOGRAMS

 ESSENTIALS OF DIAGNOSIS

 Precordial chest pain, often occurring at rest during stress or without known precipitant, relieved rapidly by nitrates.

 ECG evidence of ischemia during pain, sometime with ST-segment elevation.

 Angiographic demonstration of:

– No significant obstruction of major coronary vessels.

– Coronary spasm that responds to intra-coronary nitroglycerin or calcium channel blockers.

 General Considerations

Although most symptoms of myocardial ischemia result from fixed stenosis of the coronary arteries or intraplaque hemorrhage or thrombosis at the site of lesions, some ischemic events may be precipitated or exacerbated by coronary vasoconstriction.

Spasm of the large coronary arteries with resulting decreased coronary blood flow may occur spontaneously or may be induced by exposure to cold, emotional stress, or vasoconstricting medications, such as ergot derivative drugs. Spasm may occur both in normal and in stenosed coronary arteries. Even myocardial infarction may occur as a result of spasm in the absence of visible obstructive coronary heart disease, although most instances of such coronary spasm occur in the presence of coronary stenosis.

Cocaine can induce myocardial ischemia and infarction by causing coronary artery vasoconstriction or by increasing myocardial energy requirements. It also may contribute to accelerated atherosclerosis and thrombosis. The ischemia in Prinzmetal (variant) angina usually results from coronary vasoconstriction. It tends to involve the right coronary artery and there may be no fixed stenoses. Myocardial ischemia may also occur in patients with normal coronary arteries as a result of disease of the coronary microcirculation or abnormal vascular reactivity. This has been termed “syndrome X.”

 Clinical Findings

Ischemia may be silent or result in angina pectoris.

Prinzmetal (variant) angina is a clinical syndrome in which chest pain occurs without the usual precipitating factors and is associated with ST-segment elevation rather than depression. It often affects women under 50 years of age. It characteristically occurs in the early morning, awakening patients from sleep, and is apt to be associated with arrhythmias or conduction defects. It may be diagnosed by challenge with ergonovine (a vasoconstrictor), although the results of such provocation are not specific and it entails risk.

 Treatment

Patients with chest pain associated with ST-segment elevation should undergo coronary arteriography to determine whether fixed stenotic lesions are present. If they are, aggressive medical therapy or revascularization is indicated, since this may represent an unstable phase of the disease. If significant lesions are not seen and spasm is suspected, avoidance of precipitants such as cigarette smoking and cocaine is the top priority. Episodes of coronary spasm generally respond well to nitrates, and both nitrates and calcium channel blockers (including long-acting nifedipine, diltiazem, or amlopidine, [seeTable 11–8]) are effective prophylactically. By allowing unopposed alpha-1-mediated vasoconstriction, beta-blockers have exacerbated coronary vasospasm, but they may have a role in management of patients in whom spasm is associated with fixed stenoses.

 When to Refer

All patients with persistent symptoms of chest pain that may represent spasm should be referred to a cardiologist.

Agarwal M et al. Nonacute coronary syndrome anginal chest pain. Med Clin North Am. 2010 Mar;94(2):201–16. [PMID: 20380951]

ACUTE CORONARY SYNDROMES WITHOUT ST-SEGMENT ELEVATION

 ESSENTIALS OF DIAGNOSIS

 Distinction in acute coronary syndrome between patients with and without ST-segment elevation at presentation is essential to determine need for reperfusion therapy.

 Fibrinolytic therapy is harmful in acute coronary syndrome without ST-segment elevation, unlike with ST-segment elevation where acute reperfusion saves lives.

 Antiplatelet and anticoagulation therapies and coronary intervention are mainstays of treatment.

 General Considerations

Acute coronary syndromes comprise the spectrum of unstable cardiac ischemia from unstable angina to acute myocardial infarction. Acute coronary syndromes are classified based on the presenting ECG as either “ST-segment elevation” (STEMI) or “non–ST-segment elevation” (NSTEMI). This allows for immediate classification and guides determination of whether patients should be considered for acute reperfusion therapy. The evolution of cardiac biomarkers then allows determination of whether myocardial infarction has occurred.

Acute coronary syndromes represent a dynamic state in which patients frequently shift from one category to another, as new ST elevation can develop after presentation and cardiac biomarkers can become abnormal with recurrent ischemic episodes.

 Clinical Findings

  1. Symptoms and Signs

Patients with acute coronary syndromes generally have symptoms and signs of myocardial ischemia either at rest or with minimal exertion. These symptoms and signs are similar to chronic angina symptoms described above, consisting of substernal chest pain or discomfort that may radiate to the jaw, left shoulder or arm. Dyspnea, nausea, diaphoresis, or syncope may either accompany the chest discomfort or may be the only symptom of acute coronary syndrome. About one-third of patients with myocardial infarction have no chest pain per se—these patients tend to be older, female, have diabetes, and be at higher risk for subsequent mortality. Patients with acute coronary syndromes have signs of heart failure in about 10% of cases, and this is also associated with higher risk of death.

Many hospitals have developed chest pain observation units to provide a systematic approach toward serial risk stratification to improve the triage process. In many cases, those who have not experienced new chest pain and have insignificant ECG changes and no cardiac biomarker elevation undergo treadmill exercise tests or imaging procedures to exclude ischemia at the end of an 8- to 24-hour period and are discharged directly from the emergency department if these tests are negative.

  1. Laboratory Findings

Depending on the time from symptom onset to presentation, initial laboratory findings may be normal. The markers of cardiac myocyte necrosis, myoglobin, CK-MB, and troponin I and T may all be used to identify acute myocardial infarction. These markers have a well-described pattern of release over time in patients with myocardial infarction (see Laboratory Findings, Acute Myocardial Infarction with ST-Segment Elevation, below). In patients with STEMI, these initial markers are often within normal limits as the patient is being rushed to immediate reperfusion. In patients without ST-segment elevation, it is the presence of abnormal CK-MB or troponin values that are associated with myocyte necrosis and the diagnosis of myocardial infarction. The universal definition of myocardial infarction is a rise of cardiac biomarkers with at least one value above the 99th percentile of the upper reference limit together with evidence of myocardial ischemia with at least one of the following: symptoms of ischemia, ECG changes of new ischemia, new Q waves, or imaging evidence of new loss of viable myocardium or new wall motion abnormality.

Serum creatinine is an important determinant of risk, and estimated creatinine clearance is important to guide dosing of certain antithrombotics, including eptifibatide and enoxaparin.

  1. ECG

Many patients with acute coronary syndromes will exhibit ECG changes during pain—either ST-segment elevation, ST-segment depression, or T wave flattening or inversion. Dynamic ST segment shift is the most specific for acute coronary syndrome. ST segment elevation in lead aVR suggests left main or three vessel disease.

 Treatment

  1. General Measures

Treatment of acute coronary syndromes without ST elevation should be multifaceted. Patients who are at medium or high risk should be hospitalized, maintained at bed rest or at very limited activity for the first 24 hours, monitored, and given supplemental oxygen. Sedation with a benzodiazepine agent may help if anxiety is present.

  1. Specific Measures

Figure 10–8 provides an algorithm for initial management of non-ST segment myocardial infarction.

 Figure 10–8. Flowchart for class 1 and class II a recommendations for initial management of unstable angina/non– ST-segment elevation myocardial infarction (UA/NS TEMI). ASA, aspirin; CABG, coronary artery bypass grafting; GP IIb/IIIa, glycoprotein IIb/IIIa; LOE, level of evidence; UFH, unfractionated heparin. (Reproduced, with permission, from Wright RS et al. 2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011 May 10;123(18):2022–60. Erratum in: Circulation. 2011 Sep 20;124(12):e337–40; Circulation. 2011 Jun 7;123(22):e625–6. [PMID: 21444889])

  1. Antiplatelet and Anticoagulation Therapy

Patients should receive a combination of antiplatelet and anticoagulant agents on presentation. Fibrinolytic therapy should be avoided in patients without ST-segment elevation since they generally do not have an acute coronary occlusion, and the risk of such therapy appears to outweigh the benefit.

  1. Antiplatelet therapy
  2. ASPIRIN—Aspirin, 81–325 mg daily, should be commenced immediately and continued for the first month. The 2012 ACC/AHA guidelines for longer-term aspirin treatment recommend aspirin 75–162 mg/d as preferable to higher doses with or without coronary stenting.
  3. P2Y12INHIBITORS—ACC/AHA guidelines call for either a P2Y12inhibitor (clopidogrel, prasugrel [at the time of PCI], or ticagrelor) or a glycoprotein IIb/IIIa inhibitor “up-front” (prior to coronary angiography) as a class I recommendation. The European Society of Cardiology guidelines provide a stronger recommendation for a P2Y12inhibitor up-front, as a class IA recommendation for all patients. Both sets of guidelines recommend postponing elective CABG surgery for at least 5 days after the last dose of clopidogrel or ticagrelor and at least 7 days after the last dose of prasugrel due to risk of bleeding.

The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial demonstrated a 20% reduction in the composite end point of cardiovascular death, myocardial infarction, and stroke with the addition of clopidogrel (300 mg loading dose, 75 mg/d for 9–12 months) to aspirin in patients with non–ST-segment elevation acute coronary syndromes. The large CURRENT trial showed that “double-dose” clopidogrel (600 mg initial oral loading dose, followed by 150 mg orally daily) for 7 days reduced stent thrombosis with a modest increase in major (but not fatal) bleeding and, therefore, it is an option for patients with acute coronary syndrome undergoing PCI.

The European Society of Cardiology guidelines recommend ticagrelor for all patients at moderate to high risk for acute coronary syndrome (class 1 recommendation). Prasugrel is recommended for patients who have not yet received another P2Y12 inhibitor, for whom a PCI is planned, and who are not at high risk for life-threatening bleeding. Clopidogrel is reserved for patients who cannot receive either ticagrelor or prasugrel. Some studies have shown an association between assays of residual platelet function and thrombotic risk during P2Y12 inhibitor therapy, and both the European and the US guidelines recommend only selective use of platelet function testing to guide therapy (class IIb recommendation).

Prasugrel is both more potent and has a faster onset of action than clopidogrel. The TRITON trial compared prasugrel with clopidogrel in patients with STEMI or NSTEMI in whom PCI was planned; prasugrel resulted in a 19% relative reduction in death from cardiovascular causes, myocardial infarction, or stroke, at the expense of an increase in serious bleeding (including fatal bleeding). Stent thrombosis was reduced by half. Because patients with prior stroke or transient ischemic attack had higher risk of intracranial hemorrhage, prasugrel is contraindicated in such patients. Bleeding was also higher in patients with low body weight (< 60 kg) and older age (≥ 75 years), and caution should be used in these populations. For patients with STEMI treated with PCI, prasugrel appears to be especially effective without a substantial increase in bleeding. For patients who will not receive revascularization, prasugrel, when compared to clopidogrel, had no overall benefit in the TRILOGY trial (the dose of prasugrel was lowered for the elderly).

Ticagrelor has a faster onset of action than clopidogrel and a more consistent and potent effect. The PLATO trial showed that when ticagrelor was started at the time of presentation in acute coronary syndrome patients (UA/NSTEMI and STEMI), it reduced cardiovascular death, myocardial infarction, and stroke by 16% when compared with clopidogrel. In addition, there was a 22% relative riskreduction in mortality with ticagrelor. The overall rates of bleeding were similar between ticagrelor and clopidogrel, although non-CABG related bleeding was modestly higher. The finding of a lesser treatment effect in the United States may have been related to use of higher-dose aspirin, and thus when using ticagrelor, low-dose aspirin (81 mg/d) is recommended.

  1. GLYCOPROTEIN IIB/IIIA INHIBITORS—Small molecule inhibitors of the platelet glycoprotein IIb/IIIa receptor are useful adjuncts in high-risk patients (usually defined by fluctuating ST-segment depression or positive biomarkers) with acute coronary syndromes, particularly when they are undergoing PCI.Tirofiban,0.4 mcg/kg/min for 30 minutes followed by 0.1 mcg/kg/min, and eptifibatide, 180 mcg/kg bolus followed by a continuous infusion of 2 mcg/kg/min, have both been shown to be effective. Downward dose adjustments (1 mcg/kg/min) are required in patients with reduced kidney function. For example, if the estimated creatinine clearance is below 50 mL/min, the eptifibatide infusion should be cut in half to 1 mcg/kg/min. The ISAR-REACT 2 trial showed that for patients undergoing PCI with high-risk acute coronary syndrome, especially with elevated troponin, intravenous abciximab (added to clopidogrel 600 mg loading dose) reduces ischemic events by about 25%. The EARLY-ACS trial in over 10,000 patients with high-risk acute coronary syndrome found no benefit from eptifibatide started at the time of admission and higher rates of bleeding compared with eptifibatide treatment started at the time of invasive coronary angiography.
  2. Anticoagulant therapy
  3. HEPARIN—Several trials have shown thatlow-molecular-weight heparin(enoxaparin 1 mg/kg subcutaneously every 12 hours) is somewhat more effective than unfractionated heparin in preventing recurrent ischemic events in the setting of acute coronary syndromes. However, the SYNERGY trial showed that unfractionated heparin and enoxaparin had similar rates of death or (re)infarction in the setting of frequent early coronary intervention.
  4. FONDAPARINUX—Fondaparinux, a specific factor Xa inhibitor given in a dose of 2.5 mg subcutaneously once a day, was found in the OASIS-5 trial to be equally effective as enoxaparin among 20,000 patients at preventing early death, myocardial infarction, and refractory ischemia, and resulted in a 50% reduction in major bleeding. This reduction in major bleeding translated into a significant reduction in mortality (and in death or myocardial infarction) at 30 days. While catheter-related thrombosis was more common during coronary intervention procedures with fondaparinux, the FUTURA trial found that it can be controlled by adding unfractionated heparin (in a dose of 85 units/kg without glycoprotein IIb/IIIa inhibitors, and 60 units/kg with glycoprotein IIb/IIIa inhibitors) during the procedure. Guidelines recommend fondaparinux, describing it as especially favorable for patients who are initially treated medically and who are at high risk for bleeding, such as the elderly.
  5. DIRECT THROMBIN INHIBITORS—The ACUITY trial showed thatbivalirudinappears to be a reasonable alternative to heparin (unfractionated heparin or enoxaparin) plus a glycoprotein IIb/IIIa antagonist for many patients with acute coronary syndromes who are undergoing early coronary intervention. Bivalirudin (without routine glycoprotein IIb/IIIa inhibitor) is associated with substantially less bleeding than heparin plus glycoprotein IIb/IIIa inhibitor. The ISAR REACT-4 trial showed that bivalirudin has similar efficacy compared to abciximab but better bleeding outcomes in NSTEMI patients.
  6. Temporary Discontinuation of Antiplatelet Therapy for Procedures

Patients who have had recent coronary stents are at risk for thrombotic events, including stent thrombosis, if P2Y12 inhibitors are discontinued for procedures (eg, dental procedures or colonoscopy). If possible, these procedures should be delayed until the end of the necessary treatment period with P2Y12 inhibitors, which generally is at least 1 month with bare metal stents and 3–6 months with drug-eluting stents. Before that time, if a procedure is necessary, risk and benefit of continuing the antiplatelet therapy through the time of the procedure should be assessed. Aspirin should generally be continued throughout the period of the procedure. The cardiologist should be consulted before temporary discontinuation of these agents.

  1. Nitroglycerin

Nitrates are first-line therapy for patients with acute coronary syndromes presenting with chest pain. Nonparenteral therapy with sublingual or oral agents or nitroglycerin ointment is usually sufficient. If pain persists or recurs, intravenous nitroglycerin should be started. The usual initial dosage is 10 mcg/min. The dosage should be titrated upward by 10–20 mcg/min (to a maximum of 200 mcg/min) until angina disappears or mean arterial pressure drops by 10%. Careful—usually continuous—BP monitoring is required when intravenous nitroglycerin is used. Avoid hypotension (systolic BP < 100 mm Hg). Tolerance to continuous nitrate infusion is common.

  1. Beta-Blockers

Beta-blockers are an important part of the initial treatment of unstable angina unless otherwise contraindicated. The pharmacology of these agents is discussed in Chapter 11 and summarized in Table 11–6. Use of agents with intrinsic sympathomimetic activity should be avoided in this setting. Oral medication is adequate in most patients, but intravenous treatment with metoprolol, given as three 5-mg doses 5 minutes apart as tolerated and in the absence of heart failure, achieves a more rapid effect. Oral therapy should be titrated upward as BP permits.

  1. Calcium Channel Blockers

Calcium channel blockers have not been shown to favorably affect outcome in unstable angina, and they should be used primarily as third-line therapy in patients with continuing symptoms on nitrates and beta-blockers or those who are not candidates for these drugs. In the presence of nitrates and without accompanying beta-blockers, diltiazem or verapamil is preferred, since nifedipine and the other dihydropyridines are more likely to cause reflex tachycardia or hypotension. The initial dosage should be low, but upward titration should proceed steadily (see Table 11–8).

  1. Statins

The PROVE-IT trial provides evidence for starting a statin in the days immediately following an acute coronary syndrome. In this trial, more intensive therapy with atorvastatin 80 mg/d, regardless of total or LDL cholesterol level, improved outcome compared to pravastatin 40 mg/d, with the curves of death or major cardiovascular event separating as early as 3 months after starting therapy. High-dose statins are recommended for all patients with acute coronary syndromes (Table 10–8).

 Indications for Coronary Angiography

For patients with acute coronary syndrome, including non–ST-segment elevation myocardial infarction, risk stratification is important for determining intensity of care. Several therapies, including glycoprotein IIb/IIIa inhibitors, low-molecular-weight heparin, and early invasive catheterization, have been shown to have the greatest benefit in higher-risk patients with acute coronary syndrome. As outlined in the ACC/AHA guidelines, patients with any high-risk feature (Table 10–10) generally warrant an early invasive strategy with catheterization and revascularization. For patients without these high-risk features, either an invasive or noninvasive approach, using exercise (or pharmacologic stress for patients unable to exercise) stress testing to identify patients who have residual ischemia and/or high risk, can be used. Moreover, based on the ICTUS trial, a strategy based on selective coronary angiography and revascularization for instability or inducible ischemia, or both, even for patients with positive troponin, is acceptable (ACC/AHA class IIb recommendation).

Two risk-stratification tools are available that can be used at the bedside, the GRACE Risk Score (http://www.outcomes-umassmed.org/grace) and the TIMI Risk Score (available for PDA download athttp://www.timi.org). The GRACE risk score, which applies to patients with or without ST elevation, was developed in a more generalizable registry population and includes Killip class, BP, ST-segment deviation, cardiac arrest at presentation, serum creatinine, elevated creatine kinase (CK)-MB or troponin, and heart rate. The TIMI Risk Score includes seven variables: age ≥ 65, three or more cardiac risk factors, prior coronary stenosis ≥ 50%, ST-segment deviation, two anginal events in prior 24 hours, aspirin in prior 7 days, and elevated cardiac markers.

 When to Refer

  • All patients with acute myocardial infarction should be referred to a cardiologist.
  • Patients who are taking a P2Y12inhibitor following coronary stenting should consult a cardiologist before discontinuing treatment for nonemergency procedures.

Gurbel PA et al. Platelet function during extended prasugrel and clopidogrel therapy for patients with ACS treated without revascularization: the TRILOGY ACS Platelet Function Substudy. JAMA. 2012 Nov 7;308(17):1785–94. [PMID: 23124119]

Hamm CW et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2011 Dec;32(23):2999–3054. [PMID: 21873419]

Jneid H et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non–ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2012 Aug 14;126(7):875–910. [PMID: 22800849]

Levine GN et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011 Dec 6;124(23):e574–651. [PMID: 22064601]

Thygesen K et al. Third universal definition of myocardial infarction. Circulation. 2012 Oct 16;126(16):2020–35. [PMID: 22923432]

Wallentin L et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009 Sep 10;361(11):1045–57. [PMID: 19717846]

ACUTE MYOCARDIAL INFARCTION WITH ST-SEGMENT ELEVATION

 ESSENTIALS OF DIAGNOSIS

 Sudden but not instantaneous development of prolonged (> 30 minutes) anterior chest discomfort (sometimes felt as “gas” or pressure).

 Sometimes painless, masquerading as acute heart failure, syncope, stroke, or shock.

 ECG: ST-segment elevation or left bundle branch block.

 Immediate reperfusion treatment is warranted.

 Primary PCI within 90 minutes of first medical contact is the goal and is superior to fibrinolytic therapy.

 Fibrinolytic therapy within 30 minutes of hospital presentation is the goal, and if given within 12 hours of onset of symptoms reduces mortality.

 General Considerations

STEMI results, in most cases, from an occlusive coronary thrombus at the site of a preexisting (though not necessarily severe) atherosclerotic plaque. More rarely, infarction may result from prolonged vasospasm, inadequate myocardial blood flow (eg, hypotension), or excessive metabolic demand. Very rarely, myocardial infarction may be caused by embolic occlusion, vasculitis, aortic root or coronary artery dissection, or aortitis. Cocaine is a cause of infarction, which should be considered in young individuals without risk factors. A condition that may mimic STEMI is stress cardiomyopathy (also referred to as Tako-Tsubo or apical ballooning syndrome) (see below).

ST elevation connotes an acute coronary occlusion and thus warrants immediate reperfusion therapy.

 Clinical Findings

  1. Symptoms
  2. Premonitory pain—There is usually a worsening in the pattern of angina preceding the onset of symptoms of myocardial infarction; classically the onset of angina occurs with minimal exertion or at rest.
  3. Pain of infarction—Unlike anginal episodes, most infarctions occur at rest, and more commonly in the early morning. The pain is similar to angina in location and radiation but it may be more severe, and it builds up rapidly or in waves to maximum intensity over a few minutes or longer. Nitroglycerin has little effect; even opioids may not relieve the pain.
  4. Associated symptoms—Patients may break out in a cold sweat, feel weak and apprehensive, and move about, seeking a position of comfort. They prefer not to lie quietly. Light-headedness, syncope, dyspnea, orthopnea, cough, wheezing, nausea and vomiting, or abdominal bloating may be present singly or in any combination.
  5. Painless infarction—One-third of patients with acute myocardial infarction present without chest pain, and these patients tend to be undertreated and have poor outcomes. Older patients, women, and patients with diabetes mellitus are more likely to present without classic chest pain. As many as 25% of infarctions are detected on routine ECG without any recallable acute episode.
  6. Sudden death and early arrhythmias—Of all deaths from myocardial infarction, about 50% occur before the patients arrive at the hospital, with death presumably caused by ventricular fibrillation.
  7. Signs
  8. General—Patients may appear anxious and sometimes are sweating profusely. The heart rate may range from marked bradycardia (most commonly in inferior infarction) to tachycardia, low cardiac output, or arrhythmia. The BP may be high, especially in former hypertensive patients, or low in patients with shock. Respiratory distress usually indicates heart failure. Fever, usually low grade, may appear after 12 hours and persist for several days.
  9. Chest—TheKillip classificationis the standard way to classify heart failure in patients with acute myocardial infarction and has powerful prognostic value. Killip class I is absence of rales and S3, class II is rales that do not clear with coughing over one-third or less of the lung fields or presence of an S3, class III is rales that do not clear with coughing over more than one-third of the lung fields, and class IV is cardiogenic shock (rales, hypotension, and signs of hypoperfusion).
  10. Heart—The cardiac examination may be unimpressive or very abnormal. Jugular venous distention reflects RA hypertension, and a Kussmaul sign (failure of decrease of jugular venous pressure with inspiration) is suggestive of RV infarction. Soft heart sounds may indicate LV dysfunction. Atrial gallops (S4) are the rule, whereas ventricular gallops (S3) are less common and indicate significant LV dysfunction. Mitral regurgitation murmurs are not uncommon and may indicate papillary muscle dysfunction or, rarely, rupture. Pericardial friction rubs are uncommon in the first 24 hours but may appear later.
  11. Extremities—Edema is usually not present. Cyanosis and cold temperature indicate low output. The peripheral pulses should be noted, since later shock or emboli may alter the examination.
  12. Laboratory Findings

Cardiac-specific markers of myocardial damage include quantitative determinations of CK-MB, highly sensitive and conventional troponin I, and troponin T. Each of these tests may become positive as early as 4–6 hours after the onset of a myocardial infarction and should be abnormal by 8–12 hours. Troponins are more sensitive and specific than CK-MB. “Highly sensitive” or “fourth-generation” troponin assays, which are not yet approved in the United States but are the standard assays in most of Europe, have a 10- to 100-fold lower limit of detection with high analytic precision, enabling quantification of levels even in most normal individuals and allowing myocardial infarction to be detected earlier, using the change in value over 3 hours.

Circulating levels of troponins may remain elevated for 5–7 days or longer and therefore are generally not useful for evaluating suspected early reinfarction. Elevated CK-MB generally normalizes within 24 hours, thus being more helpful for evaluation of reinfarction. Low level elevations of troponin in patients with severe chronic kidney disease may not be related to acute coronary disease but rather a function of the physiologic washout of the marker. While many conditions including chronic heart failure are associated with elevated levels of the high-sensitivity troponin assays, these assays may be especially useful when negative to exclude myocardial infarction in patients complaining of chest pain.

  1. ECG

The extent of the ECG abnormalities, especially the sum of the total amount of ST-segment deviation, is a good indicator of extent of acute infarction and risk of subsequent adverse events. The classic evolution of changes is from peaked (“hyperacute”) T waves, to ST-segment elevation, to Q wave development, to T-wave inversion. This may occur over a few hours to several days. The evolution of new Q waves (> 30 milliseconds in duration and 25% of the R wave amplitude) is diagnostic, but Q waves do not occur in 30–50% of acute infarctions (non-Q wave infarctions). Left bundle branch block, especially when new (or not known to be old), in a patient with symptoms of an acute myocardial infarction, is considered to be a “STEMI equivalent”; reperfusion therapy is indicated for the affected patient. Concordant ST elevation (ie, ST elevation in leads with an overall positive QRS complex) with left bundle branch block is a specific finding indicating STEMI.

  1. Chest Radiography

The chest radiograph may demonstrate signs of heart failure, but these changes often lag behind the clinical findings. Signs of aortic dissection, including mediastinal widening, should be sought as a possible alternative diagnosis.

  1. Echocardiography

Echocardiography provides convenient bedside assessment of LV global and regional function. This can help with the diagnosis and management of infarction; echocardiography has been used successfully to make judgments about admission and management of patients with suspected infarction, including in patients with ST-segment elevation or left bundle branch block of uncertain significance, since normal wall motion makes an infarction unlikely. Doppler echocardiography is generally the most convenient procedure for diagnosing postinfarction mitral regurgitation or VSD.

  1. Other Noninvasive Studies

Diagnosis of myocardial infarction and extent of myocardial infarction can be assessed by various imaging studies in addition to echocardiography. MRI with gadolinium contrast enhancement is the most sensitive test to detect and quantitate extent of infarction, with the ability to detect as little as 2 g of myocardial infarction. Technetium-99m pyrophosphate scintigraphy, when injected at least 18 hours postinfarction, complexes with calcium in necrotic myocardium to provide a “hot spot” image of the infarction. This test is insensitive to small infarctions, and false-positive studies occur, so its use is limited to patients in whom the diagnosis by ECG and enzymes is not possible—principally those who present several days after the event or have intraoperative infarctions. Scintigraphy with thallium-201 or technetium-based perfusion tracers will demonstrate “cold spots” in regions of diminished perfusion, which usually represent infarction when the radiotracer is administered at rest, but abnormalities do not distinguish recent from old damage. All of these tests may be considered after the patient has had revascularization.

  1. Hemodynamic Measurements

These can be helpful in managing the patient with suspected cardiogenic shock. Use of PA catheters, however, has generally not been associated with better outcomes and should be limited to patients with severe hemodynamic compromise for whom the information would be anticipated to change management.

 Treatment

  1. Aspirin, P2Y12Inhibitors (Prasugrel, Ticagrelor, and Clopidogrel)

All patients with definite or suspected myocardial infarction should receive aspirin at a dose of 162 mg or 325 mg at once regardless of whether fibrinolytic therapy is being considered or the patient has been taking aspirin. Chewable aspirin provides more rapid blood levels. Patients with a definite aspirin allergy should be treated with a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor). Clopidogrel at a loading dose of 600 mg orally (or 300 mg) will result in faster onset of action than the standard 75 mg maintenance dose.

P2Y12 inhibitors, in combination with aspirin, have also been shown to provide important benefits in patients with acute STEMI. Thus, guidelines call for a P2Y12 inhibitor to be added to aspirin to all patients with STEMI, regardless of whether or not reperfusion is given, and continued for at least 14 days, and generally for 1 year. The preferred P2Y12 inhibitors are prasugrel (60 mg orally on day 1, then 10 mg daily) or ticagrelor (150 mg orally on day 1, then 90 mg twice daily). Both of these drugs demonstrated superior outcomes to clopidogrel in clinical studies of primary PCI. With fibrinolytic therapy, there are no randomized trial data regarding when the early use of prasugrel or ticagrelor and clopidogrel is indicated (at the dose of 300-mg loading dose for patients < 75 years of age and no loading dose for patients > 75 years of age). Prasugrel is contraindicated in patients with history of stroke or who are older than 75 years.

  1. Reperfusion Therapy

The current recommendation is to treat patients with STEMI who seek medical attention within 12 hours of the onset of symptoms with reperfusion therapy, either primary PCI or fibrinolytic therapy. Patients without ST-segment elevation (previously labeled “non-Q wave” infarctions) do not benefit, and may derive harm, from thrombolysis.

  1. Primary percutaneous coronary intervention—Immediate coronary angiography and primary PCI (including stenting) of the infarct-related artery have been shown to be superior to thrombolysis when done by experienced operators in high-volume centers with rapid time from first medical contact to intervention (“door-to-balloon”). US and European guidelines call for first medical contact or “door-to-balloon” times of ≤ 90 minutes. Several trials have shown that if efficient transfer systems are in place, transfer of patients with acute myocardial infarction from hospitals without primary PCI capability to hospitals with primary PCI capability with first door-to-device times of ≤ 120 minutes can improve outcome compared with fibrinolytic therapy at the presenting hospital, although this requires sophisticated systems to ensure rapid identification, transfer, and expertise in PCI. Because PCI also carries a lower risk of hemorrhagic complications including intracranial hemorrhage, it may be the preferred strategy in many older patients and others with contraindications to fibrinolytic therapy (seeTable 10–10for factors to consider in choosing fibrinolytic therapy or primary PCI).

Table 10–10. Indications for catheterization and percutaneous coronary intervention.1

In general, stenting is standard for patients with acute myocardial infarction. Primary PCI stenting is done with bivalirudin or unfractionated heparin with glycoprotein IIb/IIIa inhibitors. Although randomized trials have shown a benefit with regards to fewer repeat interventions for restenosis with use of drug-eluting stents in STEMI patients, bare metal stents are used more commonly since the patient’s ability to obtain and comply with P2Y12 inhibitor therapy is often not known at the time of PCI. In the subgroup of patients with cardiogenic shock, early catheterization and percutaneous or surgical revascularization are the preferred management and have been shown to reduce mortality.

There was a signal of early (< 24 hours) increased stent thrombosis with bivalirudin in HORIZONS that was also seen in the EUROMAX trial despite prolongation of the bivalirudin infusion.

“Facilitated” PCI, whereby a combination of medications (full- or reduced-dose fibrinolytic agents with or without glycoprotein IIb/IIIa inhibitors) is given followed by immediate PCI is not recommended. Patients should be treated either with primary PCI or with fibrinolytic agents (and immediate rescue PCI for reperfusion failure), if it can be done promptly as outlined in the ACC/AHA and European guidelines. Timely access to most appropriate reperfusion, including primary PCI, can be expanded with development of regional systems of care, including emergency medical systems and networks of hospitals. Patients treated with fibrinolytic therapy appear to have improved outcomes if transferred for routine coronary angiography and PCI within 24 hours. The American Heart Association has a program called Mission: Lifeline to support development of regional systems of care (see http://www.heart.org/missionlifeline).

  1. Fibrinolytic therapy
  2. BENEFIT—Fibrinolytic therapy reduces mortality and limits infarct size in patients with acute myocardial infarction associated with ST-segment elevation (defined as ≥ 0.1 mV in two inferior or lateral leads or two contiguous precordial leads), or with left bundle branch block (not known to be old). The greatest benefit occurs if treatment is initiated within the first 3 hours, when up to a 50% reduction in mortality rate can be achieved. The magnitude of benefit declines rapidly thereafter, but a 10% relative mortality reduction can be achieved up to 12 hours after the onset of chest pain. The survival benefit is greatest in patients with large—usually anterior—infarctions. Primary PCI (including stenting) of the infarct-related artery, however, is superior to thrombolysis when done by experienced operators with rapid time from first medical contact to intervention (“door-to-balloon”) (see above).
  3. CONTRAINDICATIONS—Major bleeding complications occur in 0.5–5% of patients, the most serious of which is intracranial hemorrhage. The major risk factors for intracranial bleeding are older age (≥ 75 years), hypertension at presentation (especially over 180/110 mm Hg), low body weight (< 70 kg), and the use of fibrin-specific fibrinolytic agents (alteplase, reteplase, tenecteplase). Although patients over age 75 years have a much higher mortality rate with acute myocardial infarction and therefore may derive greater benefit, the risk of severe bleeding is also higher, particularly among patients with risk factors for intracranial hemorrhage, such as severe hypertension or recent stroke. Patients presenting more than 12 hours after the onset of chest pain may also derive a small benefit, particularly if pain and ST-segment elevation persist, but rarely does this benefit outweigh the attendant risk.

Contraindications to fibrinolytic therapy include previous hemorrhagic stroke, other strokes or cerebrovascular events within 1 year, known intracranial neoplasm, recent head trauma (including minor trauma), active internal bleeding (excluding menstruation), or suspected aortic dissection. Relative contraindications are BP > 180/110 mm Hg at presentation, other intracerebral pathology not listed above as a contraindication, known bleeding diathesis, trauma (including minor head trauma) within 2–4 weeks, major surgery within 3 weeks, prolonged > 10 minutes) or traumatic cardiopulmonary resuscitation, recent (within 2–4 weeks) internal bleeding, noncompressible vascular punctures, active diabetic retinopathy, pregnancy, active peptic ulcer disease, a history of severe hypertension, current use of anticoagulants (INR > 2.0–3.0), and (for streptokinase) prior allergic reaction or exposure to streptokinase or anistreplase within 2 years.

  1. FIBRINOLYTIC AGENTS—The following fibrinolytic agents are available for acute myocardial infarction and are characterized inTable 10–11.

Table 10–11. Fibrinolytic therapy for acute myocardial infarction.

Alteplase (recombinant tissue plasminogen activator; t-PA) results in about a 50% reduction in circulating fibrinogen. In the first GUSTO trial, which compared a 90-minute dosing of t-PA (with unfractionated heparin) with streptokinase, the 30-day mortality rate with t-PA was one absolute percentage point lower (one additional life saved per 100 patients treated), though there was also a smallincrease in the rate of intracranial hemorrhage. An angiographic substudy confirmed a higher 90-minute patency rate and a higher rate of normal (TIMI grade 3) flow in patients.

Reteplase is a recombinant deletion mutant of t-PA that is slightly less fibrin specific. In comparative trials, it appears to have efficacy similar to that of alteplase, but it has a longer duration of action and can be administered as two boluses 30 minutes apart.

Tenecteplase (TNK-t-PA) is a genetically engineered substitution mutant of native t-PA that has reduced plasma clearance, increased fibrin sensitivity, and increased resistance to plasminogen activator inhibitor-1. It can be given as a single weight-adjusted bolus. In a large comparative trial, this agent was equivalent to t-PA with regard to efficacy and resulted in significantly less noncerebral bleeding. In the STREAM trial, as part of pharmacoinvasive therapy with use of clopidogrel, aspirin, and enoxaparin and routine catheterization within 24 hours, the tenecteplase dose was reduced in half for patients ≥ age 75 with an apparent reduction in intracranial hemorrhage. Streptokinase, commonly used outside of the United States, is somewhat less effective at opening occluded arteries and less effective at reducing mortality. It is non–fibrin-specific, causes depletion of circulating fibrinogen, and has a tendency to induce hypotension, particularly if infused rapidly. This can be managed by slowing or interrupting the infusion and administering fluids. There is controversy as to whether adjunctive heparin is beneficial in patients given streptokinase, unlike its administration with the more clot-specific agents. Allergic reactions, including anaphylaxis, occur in 1–2% of patients, and this agent should generally not be administered to patients with prior exposure.

(1) Selection of a fibrinolytic agent—In the United States, most patients are treated with alteplase, reteplase, or tenecteplase. The differences in efficacy between them are small compared with the potential benefit of treating a greater proportion of appropriate candidates in a more prompt manner. The principal objective should be to administer a thrombolytic agent within 30 minutes of presentation—or even during transport. The ability to administer tenecteplase as a single bolus is an attractive feature that may facilitate earlier treatment. The combination of a reduced-dose thrombolytic given with a platelet glycoprotein IIb/IIIa inhibitor does not reduce mortality but does cause a modest increase in bleeding complications.

(2) Postfibrinolytic management—After completion of the fibrinolytic infusion, aspirin (81–325 mg/d) and anticoagulation should be continued until revascularization or for the duration of the hospital stay (or up to 8 days) with some anticoagulant, with advantages favoring either enoxaparin or fondaparinux.

(A) LOW-MOLECULAR-WEIGHT HEPARIN—In the EXTRACT trial, enoxaparin significantly reduced death and myocardial infarction at day 30 (compared with unfractionated heparin), at the expense of a modest increase in bleeding. In patients younger than age 75, enoxaparin was given as a 30-mg intravenous bolus and 1 mg/kg every 12 hours; in patients age 75 years and older, it was given with no bolus and 0.75 mg/kg intravenously every 12 hours. This appeared to attenuate the risk of intracranial hemorrhage in the elderly that had been seen with full-dose enoxaparin. Another antithrombotic option is fondaparinux, given at a dose of 2.5 mg subcutaneously once a day. There is no benefit of fondaparinux among patients undergoing primary PCI, and fondaparinux is not recommended as a sole anticoagulant during PCI due to risk of catheter thrombosis.

(B) UNFRACTIONATED HEPARIN—Anticoagulation with intravenous heparin (initial dose of 60 units/kg bolus to a maximum of 4000 units, followed by an infusion of 12 units/kg/min to a maximum of 1000 units, then adjusted to maintain an aPTT of 50–75 seconds beginning with an aPTT drawn 3 hours after thrombolytic) is continued for at least 48 hours after alteplase, reteplase, or tenecteplase, and with continuation of an anticoagulant until revascularization (if performed) or until hospital discharge (or day 8).

For all patients with acute myocardial infarction treated with intensive antithrombotic therapy, prophylactic treatment with proton pump inhibitors or antacids and an H2-blocker is advisable, although certain proton pump inhibitors, such as omeprazole and esomeprazole, decrease the effect of clopidogrel.

  1. Assessment of myocardial reperfusion, recurrent ischemic pain, reinfarction—Myocardial reperfusion can be recognized clinically by the early cessation of pain and the resolution of ST-segment elevation. Although at least 50% resolution of ST-segment elevation by 90 minutes may occur without coronary reperfusion, ST resolution is a strong predictor of better outcome. Even with anticoagulation, 10–20% of reperfused vessels will reocclude during hospitalization, although reocclusion and reinfarction appear to be reduced following intervention. Reinfarction, indicated by recurrence of pain and ST-segment elevation, can be treated by readministration of a thrombolytic agent or immediate angiography and PCI.
  2. General Measures

Cardiac care unit monitoring should be instituted as soon as possible. Patients without complications can be transferred to a telemetry unit after 24 hours. Activity should initially be limited to bed rest but can be advanced within 24 hours. Progressive ambulation should be started after 24–72 hours if tolerated. For patients without complications, discharge by day 4 appears to be appropriate. Low-flow oxygen therapy (2–4 L/min) should be given if oxygen saturation is reduced.

  1. Analgesia

An initial attempt should be made to relieve pain with sublingual nitroglycerin. However, if no response occurs after two or three tablets, intravenous opioids provide the most rapid and effective analgesia and may also reduce pulmonary congestion. Morphine sulfate, 4–8 mg, or meperidine, 50–75 mg, should be given. Subsequent small doses can be given every 15 minutes until pain abates.

Nonsteroidal anti-inflammatory agents, other than aspirin, should be avoided during hospitalization for STEMI due to increased risk of mortality, myocardial rupture, hypertension, heart failure, and kidney injury with their use.

  1. Beta-Adrenergic Blocking Agents

Trials have shown modest short-term benefit from beta-blockers started during the first 24 hours after acute myocardial infarction if there are no contraindications (metoprolol 25–50 mg orally twice daily). Aggressive beta-blockade can increase shock, with overall harm in patients with heart failure. Thus, early beta-blockade should be avoided in patients with any degree of heart failure, evidence of low output state, increased risk of cardiogenic shock, or other relative contraindications to beta-blockade. Carvedilol (beginning at 6.25 mg twice a day, titrated to 25 mg twice a day) was shown to be beneficial in the CAPRICORN trial following the acute phase of large myocardial infarction.

  1. Nitrates

Nitroglycerin is the agent of choice for continued or recurrent ischemic pain and is useful in lowering BP or relieving pulmonary congestion. However, routine nitrate administration is not recommended, since no improvement in outcome has been observed in the ISIS-4 or GISSI-3 trials. Nitrates should be avoided in patients who received phosphodiesterase inhibitors (sildenafil, vardenafil, and tadalafil) in the prior 24 hours.

  1. Angiotensin-Converting Enzyme (ACE) Inhibitors

A series of trials (SAVE, AIRE, SMILE, TRACE, GISSI-III, and ISIS-4) have shown both short- and long-term improvement in survival with ACE inhibitor therapy. The benefits are greatest in patients with EF ≤ 40%, large infarctions, or clinical evidence of heart failure. Because substantial amounts of the survival benefit occur on the first day, ACE inhibitor treatment should be commenced early in patients without hypotension, especially patients with large or anterior myocardial infarction. Given the benefits of ACE inhibitors for patients with vascular disease, it is reasonable to use ACE inhibitors for all patients following STEMI who do not have contraindications (see Table 11–4).

  1. Angiotensin Receptor Blockers

Although there has been inconsistency in the effects of different ARBs on mortality for patients post-myocardial infarction with heart failure and/or LV dysfunction, the VALIANT trial showed that valsartan 160 mg orally twice a day is equivalent to captopril in reducing mortality. Thus, valsartan should be used for all patients with ACE inhibitor intolerance, and is a reasonable, albeit more expensive, alternative to captopril. The combination of captopril and valsartan (at reduced dose) was no better than either agent alone and resulted in more side effects.

  1. Aldosterone Antagonists

The RALES trial showed that 25 mg spironolactone can reduce the mortality rate of patients with advanced heart failure, and the EPHESUS trial showed a 15% relative risk reduction in mortality with eplerenone 25 mg daily for patients post-myocardial infarction with LV dysfunction and either clinical heart failure or diabetes. Kidney dysfunction or hyperkalemia are contraindications, and patients must be monitored carefully for development of hyperkalemia.

  1. Calcium Channel Blockers

There are no studies to support the routine use of calcium channel blockers in most patients with acute myocardial infarction—and indeed, they have the potential to exacerbate ischemia and cause death from reflex tachycardia or myocardial depression. Long-acting calcium channel blockers should generally be reserved for management of hypertension or ischemia as second- or third-line drugs after beta-blockers and nitrates.

  1. Long-Term Antithrombotic Therapy

Discharge on aspirin, 81–325 mg/d, since it is highly effective, inexpensive, and well tolerated, is a key quality indicator of myocardial infarction care. In the CURE trial, clopidogrel, 75 mg/d, (in addition to aspirin) for 3–12 months for non-ST elevation acute coronary syndromes resulted in a similar 20% relative risk reduction in cardiovascular death, myocardial infarction, and stroke, and continuing clopidogrel for 1 year for patients with STEMI is reasonable, regardless of whether they underwent reperfusion therapy. The TRITON trial showed that prasugrel was more beneficial than clopidogrel in reducing ischemic events in patients undergoing PCI, but it resulted in more bleeding. The PLATO trial showed that long-term therapy with ticagrelor and low-dose aspirin was superior to clopidogrel and aspirin. In the WARIS-II trial, long-term anticoagulation with warfarin post-myocardial infarction was associated with a reduction in the composite of death, reinfarction, and stroke, with substantially higher rates of bleeding.

Patients who have received a coronary stent and who require warfarin anticoagulation present a particular challenge, since “triple therapy” with aspirin, clopidogrel, and warfarin has a high risk of bleeding. Triple therapy should be (1) limited to patients with a clear indication for warfarin (such as CHADS2 score of 2 or more or a mechanical prosthetic valve), (2) used for the shortest period of time (such as 1 month after placement of bare metal stent; drug-eluting stents that would require longer clopidogrel duration should be avoided if possible), (3) used with low-dose aspirin and with strategies to reduce risk of bleeding (eg, proton pump inhibitors for patients with history of gastrointestinal bleeding), and (4) used with consideration of a lower target anticoagulation intensity (INR 2.0 to 2.5, at least for the indication of atrial fibrillation) during the period of concomitant treatment with aspirin and P2Y12 therapy. Several ongoing studies will evaluate the target specific oral anticoagulants in this area.

  1. Coronary Angiography

For patients who do not reperfuse based on lack of at least 50% resolution of ST elevation, rescue angioplasty should be performed and has been shown to reduce the composite of death, reinfarction, stroke, or severe heart failure. According to the evidence in the 2012 European and ACC/AHA guidelines, patients treated with coronary angiography and PCI 3–24 hours after fibrinolytic therapy showed improved outcomes. Patients with recurrent ischemic pain prior to discharge should undergo catheterization and, if indicated, revascularization. PCI of a totally occluded infarct-related artery > 24 hours after STEMI should generally not be performed in asymptomatic patients with one or two vessel disease without evidence of severe ischemia.

 When to Refer

All patients with acute myocardial infarction should be referred to a cardiologist.

Armstrong PW et al; STREAM Investigative Team. Fibrinolysis or primary PCI in ST-segment elevation myocardial infarction. N Engl J Med. 2013 Apr 11;368(15):1379–87. [PMID: 23473396]

Fox KA et al; FIR Collaboration. Long-term outcome of a routine versus selective invasive strategy in patients with non-ST-segment elevation acute coronary syndrome a meta-analysis of individual patient data. J Am Coll Cardiol. 2010 Jun 1;55(22):2435–45. [PMID: 20359842]

Kushner FG et al. 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2009 Dec 1;120(22):2271–306. Erratum in: Circulation. 2010 Mar 30;121(12):e257. Dosage error in article text. [PMID: 19923169]

Levine GN et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011 Dec 6;124(23):e574–651. [PMID: 22064601]

Mehta S et al. Adjunct therapy in STEMI intervention. Cardiol Clin. 2010 Feb;28(1):107–25. [PMID: 19962053]

Steg PG et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Eur Heart J. 2012 Oct;33(20):2569–619. [PMID: 22922416]

Torpy JM et al. JAMA patient page. Myocardial infarction. JAMA. 2008 Jan 30;299(4):476. [PMID: 18230786]

Wijns W et al. Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2010 Oct;31(20):2501–55. [PMID: 20802248]

 Complications

A variety of complications can occur after myocardial infarction even when treatment is initiated promptly.

  1. Postinfarction Ischemia

In clinical trials of thrombolysis, recurrent ischemia occurred in about one-third of patients, was more common following non–ST elevation myocardial infarction than after STEMI, and had important short- and long-term prognostic implications. Vigorous medical therapy should be instituted, including nitrates and beta-blockers as well as aspirin 81–325 mg/d, anticoagulant therapy (unfractionated heparin, enoxaparin, or fondaparinux) and clopidogrel. Most patients with postinfarction angina—and all who are refractory to medical therapy—should undergo early catheterization and revascularization by PCI or CABG.

  1. Arrhythmias

Abnormalities of rhythm and conduction are common.

  1. Sinus bradycardia—This is most common in inferior infarctions or may be precipitated by medications. Observation or withdrawal of the offending agent is usually sufficient. If accompanied by signs of low cardiac output, atropine, 0.5–1 mg intravenously, is usually effective. Temporary pacing is rarely required.
  2. Supraventricular tachyarrhythmias—Sinus tachycardia is common and may reflect either increased adrenergic stimulation or hemodynamic compromise due to hypovolemia or pump failure. In the latter, beta-blockade is contraindicated. Supraventricular premature beats are common and may be premonitory for atrial fibrillation. Electrolyte abnormalities and hypoxia should be corrected and causative agents (especially aminophylline) stopped. Atrial fibrillation should be rapidly controlled or converted to sinus rhythm. Intravenous beta-blockers such as metoprolol (2.5–5 mg/h) or short-acting esmolol (50–200 mcg/kg/min) are the agents of choice if cardiac function is adequate. Intravenous diltiazem (5–15 mg/h) may be used if beta-blockers are contraindicated or ineffective. Digoxin (0.5 mg as initial dose, then 0.25 mg every 90–120 minutes [up to 1–1.25 mg] for a loading dose, followed by 0.25 mg daily if kidney function is normal) is preferable if heart failure is present with atrial fibrillation, but the onset of action is delayed. Electrical cardioversion (commencing with 100 J) may be necessary if atrial fibrillation is complicated by hypotension, heart failure, or ischemia, but the arrhythmia often recurs. Amiodarone (150 mg intravenous bolus and then 15–30 mg/h intravenously, or rapid oral loading with 400 mg three times daily) may be helpful to restore or maintain sinus rhythm.
  3. Ventricular arrhythmias—Ventricular arrhythmias are most common in the first few hours after infarction and are a marker of high risk. Ventricular premature beats may be premonitory for ventricular tachycardia or fibrillation but generally should not be treated in the absence of frequent or sustained ventricular tachycardia. Lidocaine isnotrecommended as a prophylactic measure.

Sustained ventricular tachycardia should be treated with a 1 mg/kg bolus of lidocaine if the patient is stable or by electrical cardioversion (100–200 J) if not. If the arrhythmia cannot be suppressed with lidocaine, procainamide (100 mg boluses over 1–2 minutes every 5 minutes to a cumulative dose of 750–1000 mg) or intravenous amiodarone (150 mg over 10 minutes, which may be repeated as needed, followed by 360 mg over 6 hours and then 540 mg over 18 hours) should be initiated, followed by an infusion of 0.5 mg/min (720 mg/24 hours). Ventricular fibrillation is treated electrically (300–400 J). Unresponsive ventricular fibrillation should be treated with additional amiodarone and repeat cardioversion while cardiopulmonary resuscitation (CPR) is administered.

Accelerated idioventricular rhythm is a regular, wide-complex rhythm at a rate of 70–100/min. It may occur with or without reperfusion and should not be treated with antiarrhythmics, which could cause asystole.

  1. Conduction disturbances—All degrees of AV block may occur in the course of acute myocardial infarction. Block at the level of the AV node is more common than infranodal block and occurs in approximately 20% of inferior myocardial infarctions. First-degree block is the most common and requires no treatment. Second-degree block is usually of the Mobitz type I form (Wenckebach), is often transient, and requires treatment only if associated with a heart rate slow enough to cause symptoms. Complete AV block occurs in up to 5% of acute inferior infarctions, usually is preceded by Mobitz I second-degree block, and generally resolves spontaneously, though it may persist for hours to several weeks. The escape rhythm originates in the distal AV node or AV junction and hence has a narrow QRS complex and is reliable, albeit often slow (30–50 beats/min). Treatment is often necessary because of resulting hypotension and low cardiac output. Intravenous atropine (1 mg) usually restores AV conduction temporarily, but if the escape complex is wide or if repeated atropine treatments are needed, temporary ventricular pacing isindicated. The prognosis for these patients is only slightly worse than for patients in whom AV block did not develop.

In anterior infarctions, the site of block is distal, below the AV node, and usually a result of extensive damage of the His-Purkinje system and bundle branches. New first-degree block (prolongation of the PR interval) is unusual in anterior infarction; Mobitz type II AV block or complete heart block may be preceded by intraventricular conduction defects or may occur abruptly. The escape rhythm, if present, is an unreliable wide-complex idioventricular rhythm. Urgent ventricular pacing is mandatory, but even with successful pacing, morbidity and mortality are high because of the extensive myocardial damage. New conduction abnormalities such as right or left bundle branch block or fascicular blocks may presage progression, often sudden, to second- or third-degree AV block. Temporary ventricular pacing is recommended for new-onset alternating bilateral bundle branch block, bifascicular block, or bundle branch block with worsening first-degree AV block. Patients with anterior infarction who progress to second- or third-degree block even transiently should be considered for insertion of a prophylactic permanent ventricular pacemaker before discharge.

  1. Myocardial Dysfunction

Persons with hypotension not responsive to fluid resuscitation or refractory heart failure or cardiogenic shock should be considered for urgent echocardiography to assess left and right ventricular function and for mechanical complications, right heart catheterization, and continuous measurements of arterial pressure. These measurements permit the accurate assessment of volume status and may facilitate decisions about volume resuscitation, selective use of pressors and inotropes, and mechanical support.

  1. Acute LV failure—Dyspnea, diffuse rales, and arterial hypoxemia usually indicate LV failure. General measures include supplemental oxygen to increase arterial saturation to above 95% and elevation of the trunk. Diuretics are usually the initial therapy unless RV infarction is present. Intravenous furosemide (10–40 mg) or bumetanide (0.5–1 mg) is preferred because of the reliably rapid onset and short duration of action of these drugs. Higher dosages can be given if an inadequate response occurs. Morphine sulfate (4 mg intravenously followed by increments of 2 mg) is valuable in acute pulmonary edema.

Diuretics are usually effective; however, because most patients with acute infarction are not volume overloaded, the hemodynamic response may be limited and may be associated with hypotension. In mild heart failure, sublingual isosorbide dinitrate (2.5–10 mg every 2 hours) or nitroglycerin ointment (6.25–25 mg every 4 hours) may be adequate to lower PCWP. In more severe failure, especially if cardiac output is reduced and BP is normal or high, sodium nitroprusside may be the preferred agent. It should be initiated only with arterial pressure monitoring; the initial dosage should be low (0.25 mcg/kg/min) to avoid excessive hypotension, but the dosage can be increased by increments of 0.5 mcg/kg/min every 5–10 minutes up to 5–10 mcg/kg/min until the desired hemodynamic response is obtained. Excessive hypotension (mean BP < 65–75 mm Hg) or tachycardia (> 10/min increase) should be avoided.

Intravenous nitroglycerin (starting at 10 mcg/min) also may be effective but may lower PCWP with less hypotension. Oral or transdermal vasodilator therapy with nitrates or ACE inhibitors is often necessary after the initial 24–48 hours (see below).

Inotropic agents should be avoided if possible, because they often increase heart rate and myocardial oxygen requirements and worsen clinical outcomes. Dobutamine has the best hemodynamic profile, increasing cardiac output and modestly lowering PCWP, usually without excessive tachycardia, hypotension, or arrhythmias. The initial dosage is 2.5 mcg/kg/min, and it may be increased by similar increments up to 15–20 mcg/kg/min at intervals of 5–10 minutes. Dopamine is more useful in the presence of hypotension (see below), since it produces peripheral vasoconstriction, but it has a less beneficial effect on PCWP. Digoxin has not been helpful in acute infarction except to control the ventricular response in atrial fibrillation, but it may be beneficial if chronic heart failure persists.

  1. Hypotension and shock—Patients with hypotension (systolic BP < 90 mm Hg, individualized depending on prior BP) and signs of diminished perfusion (low urinary output, confusion, cold extremities) that does not respond to fluid resuscitation should be presumed to have cardiogenic shock and should be considered for urgent catheterization and revascularization as well as selective use of intra-aortic balloon pump (IABP) support and hemodynamic monitoring with a PA catheter, although these later measures have not been shown to improve outcome. Up to 20% will have findings indicative of intravascular hypovolemia (due to diaphoresis, vomiting, decreased venous tone, medications—such as diuretics, nitrates, morphine, beta-blockers, calcium channel blockers, and thrombolytic agents—and lack of oral intake). These should be treated with successive boluses of 100 mL of normal saline until PCWP reaches 15–18 mm Hg to determine whether cardiac output and BP respond.Pericardial tamponadedue to hemorrhagic pericarditis (especially after thrombolytic therapy or cardiopulmonary resuscitation) or ventricular rupture should be considered and excluded by echocardiography if clinically indicated. RV infarction, characterized by a normal PCWP but elevated RA pressure, can produce hypotension. This is discussed below.

Most patients with cardiogenic shock will have moderate to severe LV systolic dysfunction, with a mean EF of 30% in the SHOCK trial. If hypotension is only modest (systolic pressure > 90 mm Hg) and the PCWP is elevated, diuretics should be administered. If the BP falls, inotropic support will need to be added. A large randomized trial showed no benefit of IABP support in cardiogenic shock.

Dopamine is generally considered to be the most appropriate pressor for cardiogenic hypotension. It should be initiated at a rate of 2–4 mcg/kg/min and increased at 5-minute intervals to the appropriate hemodynamic end point. At low dosages (< 5 mcg/kg/min), it improves renal blood flow; at intermediate dosages (2.5–10 mcg/kg/min), it stimulates myocardial contractility; at higher dosages (> 8 mcg/kg/min), it is a potent alpha-1-adrenergic agonist. In general, BP and cardiac index rise, but PCWP does not fall. Dopamine may be combined with nitroprusside or dobutamine (see above for dosing), or the latter may be used in its place if hypotension is not severe. Norepinephrine (0.1–0.5 mcg/kg/min) is generally reserved for failure of other vasopressors, since epinephrine produces less vasoconstriction and does not increase coronary perfusion pressure (aortic diastolic pressure), but it does tend to worsen the balance between myocardial oxygen delivery and utilization.

Patients with cardiogenic shock not due to hypovolemia have a poor prognosis, with 30-day mortality rates of 40–80%. If they do not respond rapidly, IABP may be considered to both reduce myocardial energy requirements (systolic unloading) and improve diastolic coronary blood flow. However, the SHOCK II trial did not find a difference in all-cause mortality at 30-days between patients randomized to IABP versus routine care with rapid revascularization. Longer term outcomes from this trial failed to identify any situation in which IABP use was helpful. Surgically implanted (or percutaneous) ventricular assist devices may be used in refractory cases. Emergent cardiac catheterization and coronary angiography followed by percutaneous or surgical revascularization offer the best chance of survival.

  1. RV Infarction

RV infarction is present in one-third of patients with inferior wall infarction but is clinically significant in < 50% of these. It presents as hypotension with relatively preserved LV function and should be considered whenever patients with inferior infarction exhibit low BP, raised venous pressure, and clear lungs. Hypotension is often exacerbated by medications that decrease intravascular volume or produce venodilation, such as diuretics, nitrates, and opioids. RA pressure and JVP are high, while PCWP is normal or low and the lungs are clear. The diagnosis is suggested by ST-segment elevation in right-sided anterior chest leads, particularly RV4. The diagnosis can be confirmed by echocardiography or hemodynamic measurements. Treatment consists of fluid loading beginning with 500 mL of 0.9% saline over 2 hours to improve LV filling, and inotropic agents only if necessary.

  1. Mechanical Defects

Partial or complete rupture of a papillary muscle or of the interventricular septum occurs in < 1% of acute myocardial infarctions and carries a poor prognosis. These complications occur in both anterior and inferior infarctions, usually 3–7 days after the acute event. They are detected by the appearance of a new systolic murmur and clinical deterioration, often with pulmonary edema. The two lesions are distinguished by the location of the murmur (apical versus parasternal) and by Doppler echocardiography. Hemodynamic monitoring is essential for appropriate management and demonstrates an increase in oxygen saturation between the RA and PA in VSD and, often, a large v wave with mitral regurgitation. Treatment by nitroprusside and, preferably, intra-aortic balloon counterpulsation (IABC) reduces the regurgitation or shunt, but surgical correction is mandatory. In patients remaining hemodynamically unstable or requiring continuous parenteral pharmacologic treatment or counterpulsation, early surgery is recommended, though mortality rates are high (15% to nearly 100%, depending on residual ventricular function and clinical status). Patients who are stabilized medically can have delayed surgery with lower risks (10–25%), although this may be due to the death of sicker patients, some of whom may have been saved by earlier surgery.

  1. Myocardial Rupture

Complete rupture of the LV free wall occurs in < 1% of patients and usually results in immediate death. It occurs 2–7 days postinfarction, usually involves the anterior wall, and is more frequent in older women. Incomplete or gradual rupture may be sealed off by the pericardium, creating a pseudoaneurysm. This may be recognized by echocardiography, radionuclide angiography, or LV angiography, often as an incidental finding. It demonstrates a narrow-neck connection to the LV. Early surgical repair is indicated, since delayed rupture is common.

  1. LV Aneurysm

An LV aneurysm, a sharply delineated area of scar that bulges paradoxically during systole, develops in 10–20% of patients surviving an acute infarction. This usually follows anterior Q wave infarctions. Aneurysms are recognized by persistent ST-segment elevation (beyond 4–8 weeks), and a wide neck from the LV can be demonstrated by echocardiography, scintigraphy, or contrast angiography. They rarely rupture but may be associated with arterial emboli, ventricular arrhythmias, and heart failure. Surgical resection may be performed for these indications if other measures fail. The best results (mortality rates of 10–20%) are obtained when the residual myocardium contracts well and when significant coronary lesions supplying adjacent regions are bypassed.

  1. Pericarditis

The pericardium is involved in approximately 50% of infarctions, but pericarditis is often not clinically significant. Twenty percent of patients with Q wave infarctions will have an audible friction rub if examined repetitively. Pericardial pain occurs in approximately the same proportion after 2–7 days and is recognized by its variation with respiration and position (improved by sitting). Often, no treatment is required, but aspirin (650 mg every 4–6 hours) will usually relieve the pain. Indomethacin and corticosteroids can cause impaired infarct healing and predispose to myocardial rupture, and therefore should generally be avoided in the early post-myocardial infarction period. Likewise, anticoagulation should be used cautiously, since hemorrhagic pericarditis may result.

One week to 12 weeks after infarction, Dressler syndrome (post-myocardial infarction syndrome) occurs in < 5% of patients. This is an autoimmune phenomenon and presents as pericarditis with associated fever, leukocytosis and, occasionally, pericardial or pleural effusion. It may recur over months. Treatment is the same as for other forms of pericarditis. A short course of nonsteroidal agents or corticosteroids may help relieve symptoms.

  1. Mural Thrombus

Mural thrombi are common in large anterior infarctions but not in infarctions at other locations. Arterial emboli occur in approximately 2% of patients with known infarction, usually within 6 weeks. Anticoagulation with heparin followed by short-term (3-month) warfarin therapy prevents most emboli and should be considered in all patients with large anterior infarctions. Mural thrombi can be detected by echocardiography or cardiac MRI, but these procedures should not be relied upon for determining the need for anticoagulation.

Thiele H et al; IABP-SHOCK II Trial Investigators. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med. 2012 Oct 4;367(14):1287–96. [PMID: 22920912]

 Postinfarction Management

After the first 24 hours, the focus of patient management is to prevent recurrent ischemia, improve infarct healing and prevent remodeling, and prevent recurrent vascular events. Patients with hemodynamic compromise, who are at high risk for death, need careful monitoring and management of volume status.

  1. Risk Stratification

Risk stratification is important for management of STEMI. GRACE and TIMI risk scores can be helpful tools. The GRACE risk score is available for web access and/or PDA download athttp://www.outcomes-umassmed.org/grace, and the TIMI Risk Score is available at http://www.timi.org. Patients with recurrent ischemia (spontaneous or provoked), hemodynamic instability, impaired LV function, heart failure, or serious ventricular arrhythmias should undergo cardiac catheterization (Table 10–10). ACE inhibitor (or ARB) therapy is indicated in patients with clinical heart failure or LVEF ≤ 40%. Aldosterone blockade is indicated for patients with an LVEF ≤ 40% and either heart failure or diabetes mellitus.

For patients not undergoing cardiac catheterization, submaximal exercise (or pharmacologic stress testing for patients unable to exercise) before discharge or a maximal test after 3–6 weeks (the latter being more sensitive for ischemia) helps patients and clinicians plan the return to normal activity. Imaging in conjunction with stress testing adds additional sensitivity for ischemia and provides localizing information. Both exercise and pharmacologic stress imaging have successfully predicted subsequent outcome. One of these tests should be used prior to discharge in patients who have received thrombolytic therapy as a means of selecting appropriate candidates for coronary angiography.

  1. Secondary Prevention

Postinfarction management should begin with identification and modification of risk factors. Treatment of hyperlipidemia and smoking cessation both prevent recurrent infarction and death. Statin therapy should be started before the patient is discharged from the hospital to reduce recurrent atherothrombotic events. BP control and cardiac rehabilitation or exercise are also recommended.

Beta-blockers improve survival rates, primarily by reducing the incidence of sudden death in high-risk subsets of patients, though their value may be less in patients without complications with small infarctions and normal exercise tests. While a variety of beta-blockers have been shown to be beneficial, for patients with LV dysfunction managed with contemporary treatment, carvedilol titrated to 25 mg orally twice a day has been shown to reduce mortality. Beta-blockers with intrinsic sympathomimetic activity have not proved beneficial in postinfarction patients.

Antiplatelet agents are beneficial; aspirin (81–325 mg daily, with 81 mg daily the preferred long-term dose) is recommended, and adding clopidogrel (75 mg daily) has been shown to provide additional benefit short term after STEMI. Prasugrel provides further reduction in thrombotic outcomes compared with clopidogrel, at the cost of more bleeding. Likewise, ticagrelor provides benefit over clopidogrel but should be used with low-dose aspirin (81 mg/d). Warfarin anticoagulation for 3 months reduces the incidence of arterial emboli after large anterior infarctions, and according to the results of at least one study it improves long-term prognosis, but these studies were before routine use of aspirin and clopidogrel. An advantage to combining low-dose aspirin and warfarin has not been demonstrated, except perhaps in patients with atrial fibrillation.

Calcium channel blockers have not been shown to improve prognoses overall and should not be prescribed purely for secondary prevention. Antiarrhythmic therapy other than with beta-blockers has not been shown to be effective except in patients with symptomatic arrhythmias. Amiodarone has been studied in several trials of postinfarct patients with either LV dysfunction or frequent ventricular ectopy. Although survival was not improved, amiodarone was not harmful—unlike other agents in this setting. Therefore, it is the agent of choice for individuals with symptomatic postinfarction supraventricular arrhythmias. While implantable defibrillators improve survival for patients with postinfarction LV dysfunction and heart failure, the DINAMIT trial found no benefit to implantable defibrillators implanted in the 40 days following acute myocardial infarction.

Cardiac rehabilitation programs and exercise training can be of considerable psychological benefit and appear to improve prognosis.

  1. ACE Inhibitors and ARBs in Patients with LV Dysfunction

Patients who sustain substantial myocardial damage often experience subsequent progressive LV dilation and dysfunction, leading to clinical heart failure and reduced long-term survival. In patients with EFs < 40%, long-term ACE inhibitor (or ARB) therapy prevents LV dilation and the onset of heart failure and prolongs survival. The HOPE trial, as well as an overview of trials of ACE inhibitors for secondary prevention, also demonstrated a reduction of approximately 20% in mortality rates and the occurrence of nonfatal myocardial infarction and stroke with ramipril treatment of patients with coronary or peripheral vascular disease and without confirmed LV systolic dysfunction. Therefore, ACE inhibitor therapy should be strongly considered in this broader group of patients—and especially in patients with diabetes and those with even mild systolic hypertension, in whom the greatest benefit was observed (see Table 11–7).

  1. Revascularization

Postinfarction patients not treated with primary PCI who appear likely to benefit from early revascularization if the anatomy is appropriate are (1) those who have undergone fibrinolytic therapy, especially if they have high-risk features (including systolic BP of < 100 mm Hg, heart rate of > 100 bpm, Killip class II or III, ST-segment depression of 2 mm or more in the anterior leads); (2) patients with LV dysfunction (EF < 30–40%); (3) patients with non–ST elevation MI and high-risk features; and (4) patients with markedly positive exercise tests and multi-vessel disease. The value of revascularization in patients not treated with acute reperfusion therapy with preserved LV function who have mild ischemia and are not symptom limited is less clear. In general, patients without high-risk features who survive infarctions without complications, have preserved LV function (EF > 50%), and have no exercise-induced ischemia have an excellent prognosis and do not require invasive evaluation.

O’Gara PT et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013 Jan 29;127(4):e362–425. Erratum in: Circulation. 2013 Dec 24;128(25):e481. [PMID: 23247304]

DISORDERS OF RATE & RHYTHM

Abnormalities of cardiac rhythm and conduction can be symptomatic (syncope, near syncope, dizziness, fatigue, or palpitations), or asymptomatic. In addition, they can be lethal (sudden cardiac death) or dangerous to the extent that they reduce cardiac output, so that perfusion of the brain and myocardium is impaired. Stable supraventricular tachycardia is generally well tolerated in patients without underlying heart disease but may lead to myocardial ischemia or heart failure in patients with coronary disease, valvular abnormalities, and systolic or diastolic myocardial dysfunction. Ventricular tachycardia, if prolonged (lasting more than 10–30 seconds), often results in hemodynamic compromise and may deteriorate into ventricular fibrillation if left untreated.

Whether slow heart rates produce symptoms at rest or with exertion depends on whether cerebral and peripheral perfusion can be maintained, which is generally a function of whether the patient is upright or supine and whether LV function is adequate to maintain stroke volume. If the heart rate abruptly slows, as with the onset of complete heart block or sinus arrest, syncope or convulsions (or both) may result.

Arrhythmias are detected either because they produce symptoms or because they are detected during the course of monitoring. Arrhythmias causing sudden death, syncope, or near syncope require further evaluation and treatment unless they are related to conditions that are reversible or immediately treatable (eg, electrolyte abnormalities or acute myocardial infarction). In contrast, there is controversy over when and how to evaluate and treat rhythm disturbances that are not symptomatic but are possible markers for more serious abnormalities (eg, nonsustained ventricular tachycardia [NSVT]). This uncertainty reflects two issues: (1) the difficulty of reliably stratifying patients into high-risk and low-risk groups; and (2) the lack of treatments that are both effective and safe. Thus, screening patients for these so-called “premonitory” abnormalities is often not productive.

A number of procedures are used to evaluate patients with symptoms who are believed to be at risk for life-threatening arrhythmias, including in-hospital and ambulatory ECG monitoring, event recorders (instruments that can be used for prolonged periods to record or transmit rhythm tracings when infrequent episodes occur), exercise testing, catheter-based electrophysiologic studies (to assess sinus node function, AV conduction, and inducibility of arrhythmias), and tests of autonomic nervous system function (tilt-table testing).

Treatment of arrhythmias varies and can include modalities such as antiarrhythmic drugs (see Table 10–12) and more invasive techniques such as catheter ablation.

Table 10–12. Antiarrhythmic drugs.

 Antiarrhythmic Drugs (Table 10–12)

Antiarrhythmic drugs are frequently used to treat arrhythmias, but have variable efficacy and produce frequent side effects. They are often divided into classes based on their electropharmacologic actions and many of these drugs have multiple actions. The most frequently used classification scheme is the Vaughan-Williams, which consists of four classes.

Class I agents block membrane sodium channels. Three subclasses are further defined by the effect of the agents on the Purkinje fiber action potential. Class Ia drugs (ie, quinidine, procainamide, disopyramide) slow the rate of rise of the action potential (Vmax) and prolong its duration, thus slowing conduction and increasing refractoriness (moderate depression of phase 0 upstroke of the action potential). Class Ib agents (ie, lidocaine, mexiletine) shorten action potential duration; they do not affect conduction or refractoriness (minimal depression of phase 0 upstroke of the action potential). Class Ic agents (ie, flecainide, propafenone) prolong Vmax and slow repolarization, thus slowing conduction and prolonging refractoriness, but more so than class Ia drugs (maximal depression of phase 0 upstroke of the action potential).

Class II agents are the beta-blockers, which decrease automaticity, prolong AV conduction, and prolong refractoriness.

Class III agents (ie, amiodarone, dronedarone, sotalol, dofetilide, ibutilide) block potassium channels and prolong repolarization, widening the QRS and prolonging the QT interval. They decrease automaticity and conduction and prolong refractoriness. Dronedarone has been shown to reduce cardiovascular hospitalizations when used in patients with paroxysmal atrial fibrillation in the absence of heart failure; however, the PALLAS trial found an increase in cardiovascular events when dronedarone was used in patients with permanent atrial fibrillation.

Class IV agents are the calcium channel blockers, which decrease automaticity and AV conduction.

There are some antiarrhythmic agents that do not fall into one of these categories. The most frequently used are digoxin and adenosine. Digoxin inhibits the Na+, K+-ATPase pump. Digoxin prolongs AV nodal conduction and the AV nodal refractory period, but it shortens the action potential and decreases the refractoriness of the ventricular myocardium and Purkinje fibers. Adenosine can block AV nodal conduction and shortens atrial refractoriness.

Although the in vitro electrophysiologic effects of most of these agents have been defined, their use remains largely empiric. All can exacerbate arrhythmias (proarrhythmic effect), and many depress LV function.

The risk of antiarrhythmic agents has been highlighted by many studies, most notably the Coronary Arrhythmia Suppression Trial (CAST), in which two class Ic agents (flecainide, encainide) and a class Ia agent (moricizine) increased mortality rates in patients with asymptomatic ventricular ectopy after myocardial infarction. A similar result has been reported in the Mortality in the Survival With Oral D-sotalol (SWORD) study with d-sotalol, a class III agent without the beta-blocking activity of the currently marketed formulation d,l-sotalol. Class 1c antiarrhythmic agents should therefore not be used in patients with prior myocardial infarction or structural heart disease.

The use of antiarrhythmic agents for specific arrhythmias is discussed below.

Connolly SJ et al; PALLAS Investigators. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med. 2011 Dec 15;365(24):2268–76. [PMID: 22082198]

Ganjehei L et al. Pharmacologic management of arrhythmias. Tex Heart Inst J. 2011;38(4):344–9. [PMID: 21841856]

Li EC et al. Drug-induced QT-interval prolongation: considerations for clinicians. Pharmacotherapy. 2010 Jul;30(7): 684–701. [PMID: 20575633]

Shu J et al. Pharmacotherapy of cardiac arrhythmias—basic science for clinicians. Pacing Clin Electrophysiol. 2009 Nov;32(11):1454–65. [PMID: 19744278]

Thireau J et al. New drugs vs. old concepts: a fresh look at antiarrhythmics. Pharmacol Ther. 2011 Nov;132(2):125–45. [PMID: 21420430]

Torp-Pedersen C et al. Antiarrhythmic drugs: safety first. J Am Coll Cardiol. 2010 April 13;55(15):1569–76. [PMID: 20378074]

 Catheter Ablation for Cardiac Arrhythmias

Catheter ablation has become the primary modality of therapy for many symptomatic supraventricular arrhythmias, including AV nodal reentrant tachycardia, tachycardias involving accessory pathways, paroxysmal atrial tachycardia, and atrial flutter. Catheter ablation of atrial fibrillation is more complex and usually involves complete electrical isolation of the pulmonary veins (which are often the sites of initiation of atrial fibrillation) or placing linear lesions within the atria to prevent propagation throughout the atrial chamber. This technique is currently considered a reasonable second-line therapy (after pharmacologic treatment) for certain patients with symptomatic drug-refractory atrial fibrillation. Catheter ablation of ventricular arrhythmias has proved more difficult, but experienced centers have demonstrated reasonable success with all types of ventricular tachycardias including bundle-branch reentry, tachycardia originating in the ventricular outflow tract or papillary muscles, tachycardias originating in the left side of the interventricular septum (fascicular ventricular tachycardia), and ventricular tachycardias occurring in patients with ischemic or dilated cardiomyopathy. Ablation of many of these arrhythmias can be performed from the epicardial surface of the heart via a percutaneous subxiphoid approach.

Catheter ablation has also been successfully performed for the treatment of ventricular fibrillation when a uniform premature ventricular contraction (PVC) can be identified. In addition, patients with symptomatic PVCs or PVCs occurring at a high enough burden to result in a cardiomyopathy (usually > 10,000/day) are often referred for catheter ablation as well.

Catheter ablation procedures are generally safe, with an overall major complication rate ranging from 2% to 8%. Major vascular damage during catheter insertion occurs in < 2% of patients. There is a low incidence of perforation of the myocardial wall resulting in pericardial tamponade. Sufficient damage to the AV node to require permanent cardiac pacing occurs in < 1% of patients. When transseptal access through the interatrial septum or retrograde LV catheterization is required, additional potential complications include damage to the heart valves, damage to a coronary artery, or systemic emboli. A rare but potentially fatal complication after catheter ablation of atrial fibrillation is the development of an atrio-esophageal fistula resulting from ablation on the posterior wall of the LA just overlying the esophagus.

Aliot EM et al. EHRA/HRS Expert Consensus on Catheter Ablation of Ventricular Arrhythmias: developed in a partnership with the European Heart Rhythm Association (EHRA), a Registered Branch of the European Society of Cardiology (ESC), and the Heart Rhythm Society (HRS); in collaboration with the American College of Cardiology (ACC) and the American Heart Association (AHA). Heart Rhythm. 2009 Jun;6(6):886–933. [PMID: 19467519]

Bohnen M et al. Incidence and predictors of major complications from contemporary catheter ablation to treat cardiac arrhythmias. Heart Rhythm. 2011 Nov;8(11):1661–6. [PMID: 21699857]

Calkins H et al. HRS/HERA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, end-points and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Heart Rhythm. 2012 Apr;9(4):632–96.e21. [PMID: 22386883]

Wazni O et al. Catheter ablation for atrial fibrillation. N Engl J Med. 2011 Dec 15;365(24):2296–304. [PMID: 22168644]

SINUS ARRHYTHMIA, BRADYCARDIA, & TACHYCARDIA

Sinus arrhythmia is a cyclic increase in normal heart rate with inspiration and decrease with expiration. It results from reflex changes in vagal influence on the normal pacemaker and disappears with breath holding or increase of heart rate. It is common in both the young and the elderly and is not a pathologic arrhythmia.

Sinus bradycardia is a heart rate slower than 60 beats/min due to increased vagal influence on the normal pacemaker or organic disease of the sinus node. The rate usually increases during exercise or administration of atropine. In healthy individuals, and especially in patients who are in excellent physical condition, sinus bradycardia to rates of 50 beats/min or even lower is a normal finding. However, severe sinus bradycardia (< 45 beats/min) may be an indication of sinus node pathology (see below), especially in elderly patients and individuals with heart disease. It may cause weakness, confusion, or syncope if cerebral perfusion is impaired. Atrial, junctional and ventricular ectopic rhythms are more apt to occur with slow sinus rates. Pacing may be required if symptoms correlate with the bradycardia.

Sinus tachycardia is defined as a heart rate faster than 100 beats/min that is caused by rapid impulse formation from the sinoatrial node; it occurs with fever, exercise, emotion, pain, anemia, heart failure, shock, thyrotoxicosis, or in response to many drugs. Alcohol and alcohol withdrawal are common causes of sinus tachycardia and other supraventricular arrhythmias. The onset and termination are usually gradual, in contrast to paroxysmal supraventricular tachycardia due to reentry. The rate infrequently exceeds 160 beats/min but may reach 180 beats/min in young persons. The rhythm is generally regular, but serial 1-minute counts of the heart rate indicate that it varies five or more beats per minute with changes in position, with breath holding, or with sedation. In rare instances, otherwise healthy individuals may present with “inappropriate” sinus tachycardia where persistently elevated basal heart rates are not in-line with physiologic demands. Long-term consequences of this disorder are few. While the exact mechanism underlying “inappropriate” sinus tachycardia are unclear, pharmacologic agents, such as beta-blockers or ivabradine (which selectively blocks the If current within the sinus node), have been shown to have varying success in improving symptoms. Catheter ablation aimed at modifying the sinus node to lower mean heart rate has been reported, however recurrence rates are high.

 When to Refer

Patients with symptoms related to bradycardia or tachycardia when reversible etiologies have been excluded.

 When to Admit

Patients with bradycardia and recent or recurrent syncope.

ATRIAL PREMATURE BEATS (Atrial Extrasystoles)

 ESSENTIALS OF DIAGNOSIS

 Usually asymptomatic.

 Isolated interruption in regular rhythm.

 P-wave morphology on ECG usually differs from sinus P-wave morphology.

 Can be harbinger of future development of atrial fibrillation.

Atrial premature beats occur when an ectopic focus in the atria fires before the next sinus node impulse. The contour of the P wave usually differs from the patient’s normal complex, unless the ectopic focus is near the sinus node. Such premature beats occur frequently in normal hearts. Acceleration of the heart rate by any means usually abolishes most premature beats. Early atrial premature beats may cause aberrant QRS complexes (left or right bundle branch block) or may not be conducted to the ventricles because the AV node or ventricles are still refractory.

Differentiation of Aberrantly Conducted Supraventricular Beats from Ventricular Beats

This distinction can be very difficult in patients with a wide QRS complex; it is important because of the differing prognostic and therapeutic implications of each type. Findings favoring a ventricular origin include (1) AV dissociation; (2) a QRS duration exceeding 0.14 second; (3) capture or fusion beats (infrequent); (4) left axis deviation with right bundle branch block morphology; (5) monophasic (R) or biphasic (qR, QR, or RS) complexes in V1; and (6) a qR or QS complex in V6. Supraventricular origin is favored by (1) a triphasic QRS complex, especially with initial negativity in leads I and V6; (2) ventricular rates exceeding 170 beats/min; (3) QRS duration longer than 0.12 second but not longer than 0.14 second; and (4) the presence of preexcitation syndrome.

The relationship of the P waves to the tachycardia complex is helpful. A 1:1 relationship usually means a supraventricular origin, except in the case of ventricular tachycardia with retrograde atrial activation.

Treatment of this arrhythmia is rarely indicated.

PAROXYSMAL SUPRAVENTRICULAR TACHYCARDIA

 ESSENTIALS OF DIAGNOSIS

 Frequently associated with palpitations.

 Abrupt onset/offset.

 Rapid, regular rhythm.

 Most commonly seen in young adults.

 Rarely causes syncope.

 Usually have a narrow QRS complex on ECG.

 Often responsive to vagal maneuvers, AV nodal blockers, or adenosine.

 General Considerations

This is a common paroxysmal tachycardia and often occurs in patients without structural heart disease. The most common mechanism for paroxysmal supraventricular tachycardia is reentry, which may be initiated or terminated by a fortuitously timed atrial or ventricular premature beat. The reentrant circuit most commonly involves dual pathways (a slow and a fast pathway) within the AV node. This is referred to as AV nodal reentrant tachycardia (AVNRT). Less commonly, reentry is due to an accessory pathway between the atria and ventricles, referred to as atrioventricular reciprocating tachycardia (AVRT). Approximately one-third of patients with supraventricular tachycardia have accessory pathways to the ventricles. The pathophysiology and management of arrhythmias due to accessory pathways differ in important ways and are discussed separately below.

 Clinical Findings

  1. Symptoms and Signs

Patients may be asymptomatic except for awareness of rapid heart action, but some experience mild chest pain or shortness of breath, especially when episodes are prolonged, even in the absence of associated cardiac abnormalities. Episodes begin and end abruptly and may last a few seconds to several hours or longer.

  1. ECG

The heart rate may be 140–240 beats/min (usually 160–220 beats/min) and is regular (despite exercise or change in position). The P wave usually differs in contour from sinus beats and is often buried in the QRS complex.

 Treatment

In the absence of structural heart disease, serious effects are rare, and most episodes resolve spontaneously. Particular effort should be made to terminate the episode quickly if cardiac failure, syncope, or anginal pain develops or if there is underlying cardiac or (particularly) coronary disease. Because reentry is the most common mechanism for paroxysmal supraventricular tachycardia, effective therapy requires that conduction be interrupted at some point in the reentry circuit and the vast majority of these circuits involve the AV node.

  1. Mechanical Measures

A variety of maneuvers have been used to interrupt episodes, and patients may learn to perform these themselves. These maneuvers result in an acute increase in vagal tone and include the Valsalva maneuver, stretching the arms and body, lowering the head between the knees, coughing, splashing cold water on the face, and breath holding. Carotid sinus massage is often performed by physicians but should be avoided if the patient has carotid bruits or a history of transient cerebral ischemic attacks. Firm but gentle pressure and massage are applied first over the right carotid sinus for 10–20 seconds and, if unsuccessful, then over the left carotid sinus. Pressure should not be exerted on both sides at the same time. Continuous ECG or auscultatory monitoring of the heart rate is essential so that pressure can be relieved as soon as the rhythm is broken or if excessive bradycardia occurs. Carotid sinus pressure will interrupt up to half of the attacks, especially if the patient has received a digitalis glycoside or other agent (such as a calcium channel blocker) that delays AV conduction. These maneuvers stimulate a vagal outpouring, delay AV conduction, and block the reentry mechanism at the level of the AV node, terminating the arrhythmia.

  1. Drug Therapy

If mechanical measures fail, two rapidly acting intravenous agents will terminate more than 90% of episodes. Intravenous adenosine has a very brief duration of action and minimal negative inotropic activity (Table 10–12). Because the half-life of adenosine is < 10 seconds, the drug must be given rapidly (in 1–2 seconds from a peripheral intravenous line); use half the dose if given through a central line. Adenosine causes block of electrical conduction through the AV node. Adenosine is very well tolerated, but nearly 20% of patients will experience transient flushing, and some patients experience severe chest discomfort. Caution must be taken when adenosine is given to elderly patients because the resulting pause can be prolonged. Adenosine must also be used with caution in patients with reactive airways disease because it can promote bronchospasm.

Calcium channel blockers also rapidly induce AV block and break many episodes of reentrant supraventricular tachycardia (Table 10–12). These agents should be used with caution in patients with heart failure due to their negative inotropic effects. These agents include verapamil and diltiazem. Diltiazem may cause less hypotension and myocardial depression than verapamil.

Intravenous beta-blockers include esmolol (a very short-acting beta-blocker), propranolol, and metoprolol. All may be effective for virtually any type of supraventricular tachycardia and cause less myocardial depression than the calcium channel blockers. If the tachycardia is believed to be mediated by an accessory pathway, intravenous procainamide may terminate the tachycardia by prolonging refractoriness in the accessory pathway; however, because it facilitates AV conduction and an initial increase in rate may occur, it is usually not given until after a calcium channel blocker or a beta-blocker has been administered. Although intravenous amiodarone is safe, it is usually not required and often ineffective for treatment of these arrhythmias.

  1. Cardioversion

If the patient is hemodynamically unstable or if adenosine, beta-blockers, and calcium channel blockers are contraindicated or ineffective, synchronized electrical cardioversion (beginning at 100 J) is almost universally successful. If digitalis toxicity is present or strongly suspected, as in the case of paroxysmal tachycardia with block, electrical cardioversion should be avoided.

 Prevention

  1. Catheter Ablation

Because of concerns about the safety and the intolerability of antiarrhythmic medications, radiofrequency ablation is the preferred approach to patients with recurrent symptomatic reentrant supraventricular tachycardia, whether it is due to dual pathways within the AV node or to accessory pathways.

  1. Drugs

AV nodal blocking agents are the drugs of choice as first-line medical therapy (Table 10–12). Beta-blockers or non-dihydropyridine calcium channel blockers, such as diltiazem and verapamil, are typically used first. Patients who do not respond to agents that increase refractoriness of the AV node may be treated with antiarrhythmics. The class Ic agents (flecainide, propafenone) can be used in patients without underlying structural heart disease. In patients with evidence of structural heart disease, class III agents, such as sotalol or amiodarone, are probably a better choice because of the lower incidence of ventricular proarrhythmia during long-term therapy.

Colucci RA et al. Common types of supraventricular tachycardia: diagnosis and management. Am Fam Physician. 2010 Oct 15;82(8):942–52. [PMID: 20949888]

Link MS. Clinical practice. Evaluation and initial treatment of supraventricular tachycardia. N Engl J Med. 2012 Oct 11;367(15): 1438–48. [PMID: 23050527]

Linton NW et al. Narrow complex (supraventricular) tachycardias. Postgrad Med J. 2009 Oct;85(1008):546–51. [PMID: 19789194]

Marill KA et al. Adenosine for wide-complex tachycardia: efficacy and safety. Crit Care Med. 2009 Sep;37(9):2512–8. [PMID: 19623049]

Rosso R et al. Focal atrial tachycardia. Heart. 2010 Feb;96(3): 181–5. [PMID: 19443472]

Tabatabaei N et al. Supravalvular arrhythmia: identifying and ablating the substrate. Circ Arrhythm Electrophysiol. 2009 Jun;2(3):316–26. [PMID: 19808482]

SUPRAVENTRICULAR TACHYCARDIAS DUE TO ACCESSORY AV PATHWAYS (Preexcitation Syndromes)

 ESSENTIALS OF DIAGNOSIS

 Frequently associated with palpitations.

 Can be associated with syncope.

 Rapid, regular rhythm.

 May have narrow or wide QRS complex on ECG.

 Often have preexcitation (delta wave) on baseline ECG.

 General Considerations

Accessory pathways or bypass tracts between the atrium and the ventricle bypass the compact AV node and can predispose to reentrant arrhythmias, such as AV reciprocating tachycardia (AVRT) and atrial fibrillation. These may be wholly or partly within the node (eg, Mahaim fibers), yielding a short PR interval and normal QRS morphology. More commonly, they make direct connections between the atrium and ventricle through Kent bundles (Wolff-Parkinson-White syndrome). This often produces a short PR interval with a delta wave (preexcitation) at the onset of the wide, slurred QRS complex owing to early ventricular depolarization of the region adjacent to the pathway. Although the morphology and polarity of the delta wave can suggest the location of the pathway, mapping by intracardiac recordings is required for precise anatomic localization.

Accessory pathways occur in 0.1–0.3% of the population and facilitate reentrant arrhythmias owing to the disparity in refractory periods of the AV node and accessory pathway. Whether the tachycardia is associated with a narrow or wide QRS complex is frequently determined by whether antegrade conduction is through the node (narrow) or the bypass tract (wide). Some bypass tracts only conduct in a retrograde direction. In these cases, the bypass tract is termed “concealed” because it is not readily apparent on a baseline (sinus) ECG. Orthodromic reentrant tachycardia is a reentrant rhythm that conducts antegrade down the AV node and retrograde up the accessory pathway, resulting in a narrow QRS complex unless an underlying bundle branch block or interventricular conduction delay is present. Antidromic reentrant tachycardia conducts antegrade down the accessory pathway and retrograde through the AV node, resulting in a wide and often bizarre appearing QRS complex. Accessory pathways are often less refractory than specialized conduction tissue and thus tachycardias involving accessory pathways have the potential to be more rapid. Up to 30% of patients with Wolff-Parkinson-White syndrome will develop atrial fibrillation or flutter with antegrade conduction down the accessory pathway and a rapid ventricular response. If this conduction is very rapid, it can potentially degenerate to ventricular fibrillation.

 Clinical Findings & Treatment

Some patients have a delta wave found incidentally on ECG (Wolff-Parkinson-White pattern). Even in the absence of palpitations, light-headedness, or syncope, these patients are at higher risk for sudden cardiac death than the general population. Risk factors include younger age (< 30), male sex, history of atrial fibrillation and associated congenital heart disease. Multiple risk stratification strategies have been proposed to identify asymptomatic patients with Wolff-Parkinson-White pattern ECG who may be at higher risk for lethal cardiac arrhythmias. A sudden loss of preexcitation during exercise testing likely indicates an accessory pathway with poor conduction properties and therefore low risk for rapid anterograde conduction. In the absence of this finding or other signs of weak anterograde properties (intermittent preexcitation on resting ECG or Holter monitoring), patients may be referred for invasive electrophysiology testing. During the study, patients found to have the shortest preexcited R-R interval (SPERRI) during atrial fibrillation of ≤ 250 msec or inducible supraventricular tachycardia are at increased risk for sudden cardiac death and should undergo catheter ablation.

  1. Catheter Ablation

As with AVNRT, radiofrequency catheter ablation has become the procedure of choice in patients with accessory pathways and recurrent symptoms or asymptomatic patients with Wolff-Parkinson-White pattern ECG and high risk features at baseline or during electrophysiology study. Success rates for ablation of accessory pathways with radiofrequency catheters exceed 95% in appropriate patients. Major complications from catheter ablation are rare but include AV block, cardiac tamponade, and thromboembolic events. Minor complications, including hematoma at the catheter access site, occurs in 1–2% of procedures.

  1. Pharmacologic Therapy

Narrow-complex reentrant rhythms involving a bypass tract can be managed as discussed for AVNRT. Atrial fibrillation and flutter with a concomitant antegrade conducting bypass tract must be managed differently, since agents such as digoxin, calcium channel blockers, and even beta-blockers may increase the refractoriness of the AV node with minimal or no effect on the accessory pathway, often leading to faster ventricular rates. Therefore, these agents should be avoided. The class Ia, class Ic, and class III antiarrhythmic agents will increase the refractoriness of the bypass tract and are the drugs of choice for wide-complex tachycardias involving accessory pathways. If hemodynamic compromise is present, electrical cardioversion is warranted.

Long-term therapy often involves a combination of agents that increase refractoriness in the bypass tract (class Ia or Ic agents) and in the AV node (calcium channel blockers and beta-blockers), provided that atrial fibrillation or flutter with short RR cycle lengths is not present (see above). The class III agent, amiodarone, can be effective in refractory cases. Patients who are difficult to manage should undergo electrophysiologic evaluation.

 When to Refer

  • Patients with an incidental finding of Wolff-Parkinson-White pattern on ECG without evidence of loss of preexcitation spontaneously or during exercise testing.
  • Patients with recurrent symptoms or episodes despite treatment with AV nodal blocking agents.
  • Patients with preexcitation and a history of atrial fibrillation.

 When to Admit

  • Patients with paroxysmal supraventricular tachycardia and syncope.
  • Patients with a history of syncope and preexcitation identified on an ECG.

Cohen MI et al. PACES/HRS expert consensus statement on the management of the asymptomatic young patient with a Wolff-Parkinson-White (WPW, ventricular preexcitation) electrocardiographic pattern: developed in partnership between the Pediatric and Congenital Electrophysiology Society (PACES) and the Heart Rhythm Society (HRS). Endorsed by the governing bodies of PACES, HRS, the American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), the American Academy of Pediatrics (AAP), and the Canadian Heart Rhythm Society (CHRS). Heart Rhythm. 2012 Jun;9(6):1006–24. [PMID: 22579340]

Czosek RJ et al. Cost-effectiveness of various risk stratification methods for asymptomatic ventricular pre-excitation. Am J Cardiol. 2013 Jul 15;112(2):245–50. [PMID: 23587276]

Mark DG et al. Preexcitation syndromes: diagnostic consideration in the ED. Am J Emerg Med. 2009 Sep;27(7):878–88. [PMID: 19683122]

Obeyesekere MN et al. Risk of arrhythmia and sudden death in patients with asymptomatic preexcitation: a meta-analysis. Circulation. 2012 May 15;125(19):2308–15. [PMID: 22532593]

ATRIAL FIBRILLATION

 ESSENTIALS OF DIAGNOSIS

 Irregularly irregular heart rhythm.

 Usually tachycardic.

 Often associated with palpitations (acute onset) or fatigue (chronic).

 ECG shows erratic atrial activity with irregular ventricular response.

 High risk for thromboembolism: common cause of stroke.

 High incidence and prevalence in the elderly population.

 General Considerations

Atrial fibrillation is the most common chronic arrhythmia, with an incidence and prevalence that rise with age, so that it affects approximately 9% of individuals over age 80 years. It occurs in rheumatic and other forms of VHD, dilated cardiomyopathy, ASD, hypertension, and coronary heart disease as well as in patients with no apparent cardiac disease; it may be the initial presenting sign in thyrotoxicosis, and this condition should be excluded with the initial episode. The atrial activity may be very fine and difficult to detect on the ECG, or quite coarse and often mistaken for atrial flutter. Atrial fibrillation often appears in a paroxysmal fashion before becoming the established rhythm. Pericarditis, chest trauma, thoracic or cardiac surgery, thyroid disorders, obstructive sleep apnea, or pulmonary disease (as well as medications such as theophylline and beta-adrenergic agonists) may cause attacks in patients with normal hearts. Acute alcohol excess and alcohol withdrawal—and, in predisposed individuals, even consumption of small amounts of alcohol—may precipitate atrial fibrillation. This latter presentation, which is often termed “holiday heart,” is usually transient and self-limited. Short-term rate control usually suffices as treatment. Perhaps the most serious consequence of atrial fibrillation is the propensity for thrombus formation due to stasis in the atria (particularly the left atrial appendage) and consequent embolization, most devastatingly to the cerebral circulation. Overall, the rate of stroke is approximately 5% per year. However, patients with significant obstructive valvular disease, chronic heart failure or LV dysfunction, diabetes mellitus, hypertension, or age over 75 years and those with a history of prior stroke or other embolic events are at substantially higher risk (up to nearly 20% per year in patients with multiple risk factors) (Table 10–13). A substantial portion of the aging population with hypertension has asymptomatic or “subclinical” atrial fibrillation that is also associated with increased risk of stroke.

Table 10–13. CHADS2 Risk Score for assessing risk of stroke and for selecting antithrombotic therapy for patients with atrial fibrillation.

 Clinical Findings

  1. Symptoms and Signs

Atrial fibrillation itself is rarely life-threatening; however, it can have serious consequences if the ventricular rate is sufficiently rapid to precipitate hypotension, myocardial ischemia, or tachycardia-induced myocardial dysfunction. Moreover, particularly in patients with risk factors, atrial fibrillation is a major preventable cause of stroke. Although many patients—particularly older or inactive individuals—have relatively few symptoms if the rate is controlled, some patients are aware of the irregular rhythm and may find it very uncomfortable. Most patients will complain of fatigue whether they experience other symptoms or not. The heart rate may range from quite slow to extremely rapid, but is uniformly irregular unless underlying complete heart block with junctional escape rhythm or a permanent ventricular pacemaker is in place. Atrial fibrillation is the only common arrhythmia in which the ventricular rate is rapid and the rhythm very irregular. Because of the varying stroke volumes resulting from fluctuating periods of diastolic filling, not all ventricular beats produce a palpable peripheral pulse. The difference between the apical rate and the pulse rate is the “pulse deficit”; this deficit is greater when the ventricular rate is high.

  1. ECG

The surface ECG typically demonstrates erratic, disorganized atrial activity between discrete QRS complexes occurring in an irregular pattern. The atrial activity may be very fine and difficult to detect on the ECG, or quite coarse and often mistaken for atrial flutter.

 Treatment

  1. Newly Diagnosed Atrial Fibrillation
  2. Initial management
  3. HEMODYANMICALIY UNSTABLE PATIENT—If the patient is hemodynamically unstable—usually as a result of a rapid ventricular rate or associated cardiac or noncardiac conditions—hospitalization and immediate treatment of atrial fibrillation are required. Urgent cardioversion is usually indicated in patients with shock or severe hypotension, pulmonary edema, or ongoing myocardial infarction or ischemia. There is a potential risk of thromboembolism in patients undergoing cardioversion who have not received anticoagulation therapy if atrial fibrillation has been present for >48 hours; however, in hemodynamically unstable patients the need for immediate rate control outweighs that risk. Electrical cardioversion is usually preferred in unstable patients. An initial shock with 100–200 J is administered in synchrony with the R wave. If sinus rhythm is not restored, an additional attempt with 360 J is indicated. If this fails, cardioversion may be successful after loadingwith intravenous ibutilide (1 mg over 10 minutes, repeated in 10 minutes if necessary).
  4. HEMODYNAMICALIY STABLE PATIENT—If, as is often the case—particularly in older individuals—the patient has no symptoms, hemodynamic instability, or evidence of important precipitating conditions (such as silent myocardial infarction or ischemia, decompensated heart failure, pulmonary embolism, or hemodynamically significant valvular disease), hospitalization is usually not necessary. In most of these cases, atrial fibrillation is an unrecognized chronic or paroxysmal condition and should be managed accordingly (see Subsequent Management, below). For new onset atrial fibrillation, thyroid function tests and assessment for occult valvular or myocardial disease should be performed.

In more stable patients or those at particularly high risk for embolism (ie, underlying mitral stenosis, a history of prior embolism, or severe heart failure), a strategy of rate control and anticoagulation is appropriate. This is also true when the conditions that precipitated atrial fibrillation are likely to persist (such as following cardiac or noncardiac surgery, with respiratory failure, or with pericarditis). Rate control and anticoagulation is also appropriate even when the conditions causing the atrial fibrillation might resolve spontaneously over a period of hours to days (such as atrial fibrillation due to excessive alcohol intake, electrolyte imbalance or atrial fibrillation due to exposure to excessive theophylline or sympathomimetic agents). The choice of agent is guided by the hemodynamic status of the patient, associated conditions, and the urgency of achieving rate control. Although both hypotension and heart failure may improve when the ventricular rate is slowed, calcium channel blockers and beta-blockers may themselves precipitate hemodynamic deterioration. Digoxin is less risky, but even when used aggressively (0.5 mg intravenously over 30 minutes, followed by increments of 0.25 mg every 1–2 hours to a total dose of 1–1.5 mg over 24 hours in patients not previously receiving this agent), rate control is rather slow and may be inadequate, particularly in patients with sympathetic activation.

In the setting of myocardial infarction or ischemia, beta-blockers are the preferred agent. The most frequently used agents are either metoprolol (administered as a 5 mg intravenous bolus, repeated twice at intervals of 5 minutes and then given as needed by repeat boluses or orally at total daily doses of 50–400 mg) or, in very unstable patients, esmolol (0.5 mg/kg intravenously, repeated once if necessary, followed by a titrated infusion of 0.05–0.2 mg/kg/min). If beta-blockers are contraindicated, calcium channel blockers are immediately effective. Diltiazem (20 mg bolus, repeated after 15 minutes if necessary, followed by a maintenance infusion of 5–15 mg/h) is the preferred calcium blocker if hypotension or LV dysfunction is present. Otherwise, verapamil (5–10 mg intravenously over 2–3 minutes, repeated after 30 minutes if necessary) may be used. Amiodarone, even when administered intravenously, has a relatively slow onset but is often a useful adjunct when rate control with the previously cited agents is incomplete or contraindicated or when cardioversion is planned in the near future. However, amiodarone should not be used in this setting if long-term therapy is planned with other antiarrhythmic agents.

If the onset of atrial fibrillation was > 48 hours prior to presentation (or unknown) and early cardioversion is considered necessary due to inability to adequately rate control, a transesophageal echocardiogram should be performed prior to cardioversion to exclude left atrial thrombus. If thrombus is present, the cardioversion is delayed until after a 4-week period of therapeutic anticoagulation. In any case, because atrial contractile activity may not recover for several weeks after restoration of sinus rhythm in patients who have been in atrial fibrillation for more than several days, cardioversion should be followed by anticoagulation for at least 1 month unless there is a strong contraindication.

  1. Subsequent management—Up to two-thirds of patients experiencing a first episode of atrial fibrillation will spontaneously revert to sinus rhythm within 24 hours. In the absence of VHD, diabetes, hypertension or other risk factors for stroke, these patients may not require long-term anticoagulation beyond aspirin. If atrial fibrillation persists or has been present for more than a week, spontaneous conversion is unlikely. In most cases immediate cardioversion is not required and management consists of rate control and anticoagulation whether or not the patient has been admitted to the hospital. Rate control is usually relatively easy to achieve with beta-blockers, rate-slowing calcium blockers and, occasionally, digoxin, used as single agents or more often in combination. In older patients, who often have diminished AV nodal function and relatively limited activity, modest rate control can often be achieved with a single agent. Many younger or more active individuals require a combination of two agents. Choice of the initial medication is best based on the presence of accompanying conditions: Hypertensive patients should be given beta-blockers or calcium blockers (seeTables 11–6and 11–8); coronary patients should usually receive a beta-blocker; and patients with heart failure should be given a beta-blocker with consideration of adding digoxin. Adequacy of rate control should be evaluated by recording the apical pulse rate both at rest and with an appropriate level of activity (such as after brisk walking around the corridor or climbing stairs).
  2. ANTICOAGULATION—For patients with atrial fibrillation, even when it is paroxysmal or occurs rarely, the need for oral anticoagulation should be evaluated and treatment initiated for those without strong contraindication. Patients with “lone atrial fibrillation” (eg, no evidence of associated heart disease, hypertension, atherosclerotic vascular disease, diabetes mellitus, or history of stroke or TIA) under age 65 years need no antithrombotic treatment. Patients withtransient atrial fibrillation, such as in the setting of acute myocardial infarction or pneumonia, but no prior history of arrhythmia, are at high risk for future development of atrial fibrillation and appropriate anticoagulation should be initiated based on risk factors (seeTable 10–13). If the cause is reversible, such as after coronary artery bypass surgery or associated with hyperthyroidism, then long term anticoagulation is not necessary.

In addition to the traditional five risk factors that comprise the CHADS2 score (heart failure, hypertension, age ≥ 75 years, diabetes mellitus, and [2 points for] history of stroke or transient ischemic attack), the European and American guidelines recommend that three additional factors included in the CHA2DS2-VASc score be considered: age 65–74 years, female gender, and presence of vascular disease (Table 10–14). The CHA2DSv-VASc score is especially relevant for patients who have a CHADS2 score of 0 or 1; if the CHA2DS2-VASc score is ≥ 2, oral anticoagulation is recommended, and if CHA2DS2-VASc score is 1, oral anticoagulation, aspirin, or no anticoagulation can be used, with a preference for oral anticoagulation, taking into account risk, benefit, and patient preferences. The use of warfarin is discussed in the section on Selecting Appropriate Anticoagulant Therapy in Chapter 14. Unfortunately, studies show that only about half of patients with atrial fibrillation and an indication for oral anticoagulation are receiving it, and even when treated with warfarin, they are out of the target INR range nearly half the time. Cardioversion, if planned, should be performed after at least 3–4 weeks of anticoagulation at a therapeutic level (or after exclusion of left atrial appendage thrombus by transesophageal echocardiogram as discussed above). Anticoagulation clinics with systematic management of warfarin dosing and adjustment have been shown to result in better maintenance of target anticoagulation.

Table 10–14. CHA2DS2-VASc Risk Score for assessing risk of stroke and for selecting antithrombotic therapy for patients with atrial fibrillation.

Three target specific (or direct acting) oral anticoagulants—dabigatran, rivaroxaban, and apixaban—have been shown to be at least as effective as warfarin for stroke prevention in patients with nonvalvular atrial fibrillation (Table 10–15).

Table 10–15. Target specific oral anticoagulants for stroke prevention in patients with nonvalvular atrial fibrillation.

Dabigatran was compared with warfarin (in the RELY trial) for prevention of stroke and systemic embolism for patients with atrial fibrillation and at least one additional risk factor for stroke. The lower dabigatran dose (110 mg orally twice daily) was noninferior to warfarin in stroke prevention and caused significantly less bleeding, and a second higher (150 mg orally twice daily) dose, which has been approved by the FDA, resulted in significantly fewer strokes with similar bleeding rates. Both doses of dabigatran caused substantially less intracerebral hemorrhage than warfarin. There is higher incidence of gastrointestinal bleeding with dabigatran, and there is no readily available direct reversal agent. In spite of this, when oral anticoagulation with either dabigatran or warfarin was stopped for elective or emergency procedures or surgery in the RELY trial, the risk of bleeding was numerically lower with dabigatran than with warfarin. Dabigatran is 80% renally metabolized. In the United States, the 110 mg dose is not approved, and creatinine clearance should be calculated before initiating therapy. The lower dose of 75 mg twice a day is recommended for patients with creatinine clearances 15–30 mL/min, although clinical practice guidelines recommend avoiding any of the target specific oral anticoagulants in patients with an estimated creatine clearance < 30 mL/min since these patients were excluded from the clinical trials. There is no widely available test to accurately measure the effect of dabigatran, although the aPTT is affected by dabigatran and a normal aPTT suggests little if any dabigatran effect. Patients may be converted from warfarin to dabigatran by stopping the warfarin and beginning dabigatran once the INR is ≤ 2.0, and this is a reasonable approach for transition from warfarin to any of the target specific oral anticoagulants. Neither dabigatran nor any of the target specific oral anticoagulants should be used in patients with mechanical prosthetic heart valves.

Rivaroxaban is approved by the FDA for stroke prevention in nonvalvular atrial fibrillation. In the ROCKET-AF trial, rivaroxaban proved noninferior to warfarin for stroke prevention for patients with high-risk features of thromboembolism, with half of the patients in the ROCKET-AF trial having a history of stroke. Rivaroxaban is dosed at 20 mg once daily, with a reduced dose (15 mg/d) for patients with creatinine clearances < 50 mL/min. Similar to dabigatran, there was substantially less intracranial hemorrhage with rivaroxaban than warfarin.

Apixaban is more effective than warfarin at stroke prevention while having a substantially lower risk of major bleeding (in the ARISOTLE trial) and a lower risk of all-cause mortality. Apixaban is approved by the FDA and its dosage is 5 mg twice daily or 2.5 mg twice daily for patients with two of three high-risk criteria (age ≥ 80 years, body weight ≤ 60 kg, and serum creatinine ≥ 1.5 mg/dL). Apixaban is associated with less intracranial hemorrhage and is well tolerated. Apixaban was also shown to be superior to aspirin (and better tolerated) in the AVERROES trial of patients deemed not suitable for warfarin. These target specific oral anticoagulants have important advantages over warfarin, and therefore they are recommended preferentially over vitamin K antagonists in the European Guidelines (Figure 10–9).

 Figure 10–9. Choice of anticoagulant. (Reproduced, with permission, from Camm AJ et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J. 2012 Nov;33(21):2719-47.)

There are some patients with atrial fibrillation, however, who should be treated with vitamin K antagonists. These patients include those who have mechanical prosthetic valves, advanced kidney disease (creatinine clearance < 30 mL/min), moderate or severe mitral stenosis, and those who cannot afford the newer drugs. Patients who have been stable on warfarin for a long period of time, with a high time in target INR range, and who are at lower risk for intracranial hemorrhage will have relatively less benefit to switch to a newer drug.

There are some important practical issues with using the newer drugs. It is important to monitor kidney function at baseline and at least once a year, or more often for those with impaired kidney function. Each of the drugs interacts with other drugs affecting the P-glycoprotein pathway, like oral ketoconazole, verapamil, and dronederone. To transition patients from warfarin to a direct-acting drug, wait until the INR decreases to about 2.0. Each of the drugs has a half-life of about 10 hours for patients with normal kidney function. For elective procedures, stop the drugs two to three half-lives before procedures with low to moderate bleeding risk (ie, colonoscopy, dental extraction, cardiac catheterization), and five half-lives before procedures like major surgery. There are no practical tests to immediately measure the effect of the drugs, although a normal aPTT suggests little effect with dabigatran, and a normal prothrombin suggests little effect with rivaroxaban. For rivaroxaban and apixaban, chromogenic Xa assays will measure the effect, but may not be readily available. For bleeding, standard measures (eg, diagnosing and controlling the source, stopping antithrombotic agents, and replacing blood products) should be taken. If the direct-acting drug was taken in the prior 2–4 hours, use activated oral charcoal to reduce absorption. If the patient is taking aspirin, consider platelet transfusion. For life-threatening bleeding, prothrombin complex concentrate may have an effect, but this should generally be used in consultation with hematology. For cardioversion, the target specific drugs appear to have similar rates of subsequent stroke as warfarin, as long as patients have been taking the drugs and adherent for at least several weeks. Like with warfarin, there appears to be a 1.5- to 2-fold increased rate of bleeding associated with the use of aspirin, which therefore should not be used with the oral anticoagulants unless there is a clear indication, like acute coronary syndrome within the prior year.

The management of serious bleeding events for patients on target specific oral anticoagulants is under investigation, however preliminary data suggest that administration of coagulation factors (activated or four-factor prothrombin complex concentrate) may quickly reverse the effects of these agents. Due to the short half-life of the target specific oral anticoagulants (9–12 hours with normal kidney function), supportive measures (packed red blood cells, FFP, platelets) may suffice until the drug has cleared.

The safety of electrical cardioversion has not been specifically studied for any of the three target specific agents, although there is experience with several hundred patients in each of the clinical trials comparing the new agents to warfarin. While the experience is limited, stroke risk following cardioversion was reported to be low and similar to the risk in patients treated with warfarin. Most patients had been taking anticoagulants for at least several weeks prior to cardioversion and therefore the strategy of 3–4 weeks of stable anticoagulation or transesophageal echocardiogram to exclude left atrial thrombus prior to cardioversion applies.

  1. RATE CONTROL OR ELECTIVE CARDIOVERSION—Two large randomized controlled trials (the 4060-patient Atrial Fibrillation Follow-up Investigation of Rhythm Management, or AFFIRM trial; and the Rate Control Versus Electrical Cardioversion for Persistent Atrial Fibrillation, or RACE trial) compared strategies of rate control and rhythm control. In both, a strategy of rate control and long-term anticoagulation was associated with no higher rates of death or stroke—both, if anything, favored rate control—and only a modestly increased risk of hemorrhagic events than a strategy of restoring sinus rhythm and maintaining it with antiarrhythmic drug therapy. Of note is that exercise tolerance and quality of life were not significantly better in the rhythm control group. Nonetheless, the decision of whether to attempt to restore sinus rhythm following the initial episode remains controversial. Elective cardioversion following an appropriate period of anticoagulation is generally recommended for the initial episode in patients in whom atrial fibrillation is thought to be of recent onset and when there is an identifiable precipitating factor. Similarly, cardioversion is appropriate in patients who remain symptomatic from the rhythm despite aggressive efforts to achieve rate control.

In cases in which elective cardioversion is required, it may be accomplished electrically or pharmacologically. Intravenous ibutilide may be used as described above in a setting in which the patient can undergo continuous ECG monitoring for at least 4–6 hours following administration. In patients in whom a decision has been made to continue antiarrhythmic therapy to maintain sinus rhythm (see next paragraph), cardioversion can be attempted with an agent that is being considered for long-term use. For instance, after therapeutic anticoagulation has been established, amiodarone can be initiated on an outpatient basis (400 mg twice daily for 2 weeks, followed by 200 mg twice daily for at least 2–4 weeks and then a maintenance dose of 200 mg daily). Because amiodarone increases the prothrombin time in patients taking warfarin and increases digoxin levels, careful monitoring of anticoagulation and drug levels is required.

Other agents that may be used for both cardioversion and maintenance therapy include dofetilide, propafenone, flecainide, and sotalol. Dofetilide (125–500 mcg twice daily orally) must be initiated in hospital due to the potential risk of torsades de pointes and the downward dose adjustment that is required for patients with renal impairment. Propafenone (150–300 mg orally every 8 hours) should be avoided in patients with structural heart disease (CAD, systolic dysfunction, or significant LVH). Flecainide (50–150 mg twice daily orally) should be used in conjunction with an AV nodal blocking drug if there is a history of atrial flutter and should be avoided in patients with structural heart disease. Sotalol (80–160 mg orally twice daily) should be initiated in the hospital in patients with structural heart disease due to a risk of torsades de pointes; it is not very effective for converting atrial fibrillation but can be used to maintain sinus rhythm following cardioversion.

In patients treated long-term with an antiarrhythmic agent, sinus rhythm will persist in approximately 50%. The most commonly used medications are amiodarone, dronedarone, sotalol, propafenone, flecainide, and dofetilide, but the latter four agents are associated with a clear risk of proarrhythmia in certain populations; dronedarone has less efficacy than amiodarone, and amiodarone frequently causes other adverse effects. Therefore, after an initial presentation of atrial fibrillation, it may be prudent to determine whether atrial fibrillation recurs during a period of 6 months without antiarrhythmic drugs (during which anticoagulation is maintained). If it does recur, the decision to restore sinus rhythm and initiate long-term antiarrhythmic therapy can be based on how well the patient tolerates atrial fibrillation. The decision to maintain long-term anticoagulation should be based on risk factors (CHADS2 or CHA2DSv-VASc score) and not on the perceived presence or absence of atrial fibrillation as future episodes may be asymptomatic.

  1. Paroxysmal and Refractory Atrial Fibrillation
  2. Recurrent paroxysmal atrial fibrillation—Patients with recurrent paroxysmal atrial fibrillation are at similar stroke risk as those who are in atrial fibrillation chronically. Although these episodes may be apparent to the patient, many are not recognized and may be totally asymptomatic. Thus, ambulatory ECG monitoring or event recorders are indicated in those in whom paroxysmal atrial fibrillation is suspected. Antiarrhythmic agents are usually not successful in preventing all paroxysmal atrial fibrillation episodes. However, dofetilide has been shown to be as effective as amiodarone in maintaining sinus rhythm in certain patients and does not have as many untoward long-term effects. Long-term anticoagulation should be considered for all patients except in those who are under 65 years of age and have no additional stroke risk factors (see above).
  3. Refractory atrial fibrillation—Because of trial results indicating that important adverse clinical outcomes (death, stroke, hemorrhage, heart failure) are no more common with rate control than rhythm control, atrial fibrillation should generally be considered refractory if it causes persistent symptoms or limits activity. This is much more likely in younger individuals and those who are active or engage in strenuous exercise. Even in such individuals, two-drug or three-drug combinations of a beta-blocker, rate-slowing calcium blocker, and digoxin usually can prevent excessive ventricular rates, though in some cases they are associated with excessive bradycardia during sedentary periods.

If antiarrhythmic or rate-control medications fail to improve the symptoms of atrial fibrillation, catheter ablation of foci in and around the pulmonary veins that initiate atrial fibrillation may be considered. Pulmonary vein isolation is a reasonable second-line therapy for individuals with symptomatic atrial fibrillation that is refractory to pharmacologic therapy. Ablation is successful about 70% of the time but more than one procedure may be required. The procedure is routinely performed in the electrophysiology laboratory using a catheter-based approach and can also be performed via a subxiphoid approach thorascopically, via thoracotomy, or via median sternotomy in the operating room by experienced surgeons. In patients deemed inappropriate for pulmonary vein isolation, radiofrequency ablation of the AV node and permanent pacing ensure rate control and may facilitate a more physiologic rate response to activity, but this is used only as a last resort.

 When to Refer

  • Symptomatic atrial fibrillation with or without rate control.
  • Asymptomatic atrial fibrillation with poor rate control despite AV nodal blockers.

 When to Admit

  • Atrial fibrillation with rapid ventricular response resulting in hemodynamic compromise.
  • Atrial fibrillation resulting in acute heart failure.

Bishara R et al. Transient atrial fibrillation and risk of stroke after acute myocardial infarction. Thromb Haemost. 2011 Nov; 106(5): 877–84. [PMID: 21866303]

Calkins H et al. HRS/HERA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, end-points and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Heart Rhythm. 2012 Apr;9(4):632–96, e21 [PMID: 22386883]

Connolly SJ et al; RELY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009 Sep 17;361(12):1139–51. Erratum in: N Engl J Med. 2010 Nov 4;363(19):1877. [PMID: 19717844]

Durrant J et al. Stroke risk stratification scores in atrial fibrillation: current recommendations for clinical practice and future perspectives. Expert Rev Cardiovasc Ther. 2013 Jan;11(1): 77–90. [PMID: 23259448]

Granger CB et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011 Sep 15;365(11):981–92. [PMID: 21870978]

Healey JS et al; ASSERT Investigators. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med. 2012 Jan 12;366(2): 120–9. [PMID: 22236222]

January CT et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation. 2014 Apr 10. [Epub ahead of print] No abstract available. [PMD: 24682347]

Nagarakanti R et al. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation. 2011 Jan 18;123(2):131–6. [PMID: 21200007]

Patel MR et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8;365(10):883–91. [PMID: 21830957]

Van Gelder IC et al; RACE II Investigators. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med. 2010 Apr 15;362(15):1363–73. [PMID: 20231232]

ATRIAL FLUTTER

 ESSENTIALS OF DIAGNOSIS

 Usually regular heart rhythm.

 Often tachycardic (100–150 beats/min).

 Often associated with palpitations (acute onset) or fatigue (chronic).

 ECG shows “sawtooth” pattern of atrial activity in leads II, III, and AVF.

 Often seen in conjunction with structural heart disease or chronic obstructive pulmonary disease (COPD).

Atrial flutter is less common than fibrillation. It occurs most often in patients with COPD but may be seen also in those with rheumatic or coronary heart disease, heart failure, ASD, or surgically repaired congenital heart disease. The reentrant circuit generates atrial rates of 250–350 beats/min, usually with transmission of every second, third, or fourth impulse through the AV node to the ventricles. The ECG typically demonstrates a “sawtooth” pattern of atrial activity in the inferior leads (II, III, and AVF).

 Treatment

Ventricular rate control is accomplished using the same agents used in atrial fibrillation, but it is much more difficult with atrial flutter than with atrial fibrillation. Conversion of atrial flutter to sinus rhythm with class I antiarrhythmic agents is also difficult to achieve, and administration of these drugs has been associated with slowing of the atrial flutter rate to the point at which 1:1 AV conduction can occur at rates in excess of 200 beats/min, with subsequent hemodynamic collapse. The intravenous class III antiarrhythmic agent ibutilide has been significantly more successful in converting atrial flutter (Table 10–12). About 50–70% of patients return to sinus rhythm within 60–90 minutes following the infusion of 1–2 mg of this agent. Electrical cardioversion is also very effective for atrial flutter, with approximately 90% of patients converting following synchronized shocks of as little as 25–50 J.

The persistence of atrial contractile function in this arrhythmia provides some protection against thrombus formation, though the risk of systemic embolization remains increased. Precardioversion anticoagulation is not necessary for atrial flutter of < 48 hours duration except in the setting of mitral valve disease. However, anticoagulation with warfarin or the newer anticoagulants (dabigatran, rivaroxaban, or apixaban) is necessary in chronic atrial flutter, given that the stroke risk is the same as with chronic atrial fibrillation, perhaps because transient periods of atrial fibrillation are common in these patients.

Chronic atrial flutter is often a difficult management problem, as rate control is difficult. If pharmacologic therapy is chosen, amiodarone and dofetilide are the antiarrhythmics of choice (Table 10–12). Dofetilide is often given in conjunction with an AV nodal blocker (other than verapamil). Atrial flutter can follow a typical or atypical reentry circuit around the atrium. The anatomy of the typical circuit has been well defined and allows for catheter ablation within the atrium to interrupt the circuit and eliminate atrial flutter. Catheter ablation is a highly successful treatment that has become the preferred approach for recurrent typical atrial flutter.

 When to Refer

  • Symptomatic atrial flutter with or without rate control.
  • Asymptomatic atrial flutter with poor rate control despite AV nodal blockers.

 When to Admit

  • Atrial flutter with 1:1 conduction resulting in hemodynamic compromise.
  • Atrial flutter resulting in acute heart failure.

Parikh MG et al. Usefulness of transesophageal echocardiography to confirm clinical utility of CHA2DS2-VASc and CHADS2 scores in atrial flutter. Am J Cardiol. 2012 Feb 15;109(4):550–5. [PMID: 22133753]

Scheuermeyer FX et al. Emergency department management and 1-year outcomes of patients with atrial flutter. Ann Emerg Med. 2011 Jun;57(6):564–71. [PMID: 21257230]

Spector P et al. Meta-analysis of ablation of atrial flutter and supraventricular tachycardia. Am J Cardiol. 2009 Sep 1;104(5): 671–7. [PMID: 19699343]

MULTIFOCAL ATRIAL TACHYCARDIA

 ESSENTIALS OF DIAGNOSIS

 ECG reveals three or more distinct P-wave morphologies.

 Often associated with palpitations.

 Associated with severe COPD.

 Treatment of the underlying lung disease is the most effective therapy.

This is a rhythm characterized by varying P wave morphology (by definition, three or more foci) and markedly irregular PP intervals. The rate is usually between 100 and 140 beats/min, and AV block is unusual. Most patients have concomitant severe COPD. Treatment of the underlying condition is the most effective approach; verapamil, 240–480 mg orally daily in divided doses, is also of value in some patients, but this particular arrhythmia is very difficult to manage.

Spodick DH. Multifocal atrial arrhythmia. Am J Geriatr Cardiol. 2005 May–Jun;14(3):162. [PMID: 15886545]

AV JUNCTIONAL RHYTHM

 ESSENTIALS OF DIAGNOSIS

 Regular heart rhythm.

 Can have wide or narrow QRS complex.

 Often seen in digitalis toxicity.

The atrial-nodal junction or the nodal-His bundle junction may assume pacemaker activity for the heart, usually at a rate of 35–60 beats/min. This may occur in patients with myocarditis, CAD, and digitalis toxicity as well as in individuals with normal hearts. The rate responds normally to exercise, and the diagnosis is often an incidental finding on ECG monitoring, but it can be suspected if the jugular venous pulse shows cannon a waves. Junctional rhythm is often an escape rhythm because of depressed sinus node function with sinoatrial block or delayed conduction in the AV node. Nonparoxysmal junctional tachycardia results from increased automaticity of the junctional tissues in digitalis toxicity or ischemia and is associated with a narrow QRS complex and a rate usually < 120–130 beats/min. It is usually considered benign when it occurs in acute myocardial infarction, but the ischemia that induces it may also cause ventricular tachycardia and ventricular fibrillation.

VENTRICULAR PREMATURE BEATS (Ventricular Extrasystoles)

Ventricular premature beats, also called PVCs, are typically isolated beats originating from ventricular tissue. Sudden death occurs more frequently (presumably as a result of ventricular fibrillation) when ventricular premature beats occur in the presence of organic heart disease but not in individuals with no known cardiac disease.

 Clinical Findings

The patient may or may not sense the irregular beat, usually as a skipped beat. Exercise generally abolishes premature beats in normal hearts, and the rhythm becomes regular. Ventricular premature beats are characterized by wide QRS complexes that differ in morphology from the patient’s normal beats. They are usually not preceded by a P wave, although retrograde ventriculoatrial conduction may occur. Unless the latter is present, there is a fully compensatory pause (ie, without change in the PP interval). Bigeminy and trigeminy are arrhythmias in which every second or third beat is premature; these patterns confirm a reentry mechanism for the ectopic beat. Ambulatory ECG monitoring or monitoring during graded exercise may reveal more frequent and complex ventricular premature beats than occur in a single routine ECG. An increased frequency of ventricular premature beats during exercise is associated with a higher risk of cardiovascular mortality, though there is no evidence that specific therapy has a role.

 Treatment

If no associated cardiac disease is present and if the ectopic beats are asymptomatic, no therapy is indicated. If they are frequent, electrolyte abnormalities (especially hypokalemia or hyperkalemia and hypomagnesemia), hyperthyroidism, and occult heart disease should be excluded. Pharmacologic treatment is indicated only for patients who are symptomatic. If the underlying condition is mitral prolapse, hypertrophic cardiomyopathy, LVH, or coronary disease—or if the QT interval is prolonged—beta-blocker therapy is appropriate. The class I and III agents (see Table 10–12) are all effective in reducing ventricular premature beats but may exacerbate serious arrhythmias in 5–20% of patients; sudden death may occur. Therefore, every attempt should be made to avoid using class I or III antiarrhythmic agents in patients without symptoms. Catheter ablation is a well-established therapy for symptomatic individuals who do not respond to antiarrhythmic drugs or for those patients whose burden of ectopic beats has resulted in a tachycardia-induced cardiomyopathy.

Chen T et al. Ventricular ectopy in patients with left ventricular dysfunction: should it be treated? J Card Fail. 2013 Jan;19(1): 40–9. [PMID: 23273593]

Yokokawa M et al. Recovery from left ventricular dysfunction after ablation of frequent premature ventricular complexes. Heart Rhythm. 2013 Feb;10(2):172–5. [PMID: 23099051]

VENTRICULAR TACHYCARDIA

 ESSENTIALS OF DIAGNOSIS

 Fast, wide QRS complex on ECG.

 Often associated with structural heart disease.

 Frequently associated with syncope.

 In the absence of reversible cause, implantable cardioverter defibrillator (ICD) is recommended.

 General Considerations

Ventricular tachycardia is defined as three or more consecutive ventricular premature beats. The usual rate is 160–240 beats/min and is moderately regular but less so than atrial tachycardia. The usual mechanism is reentry, but abnormally triggered rhythms occur.

Ventricular tachycardia is a frequent complication of acute myocardial infarction and dilated cardiomyopathy but may occur in chronic coronary disease, hypertrophic cardiomyopathy, mitral valve prolapse, myocarditis, and in most other forms of myocardial disease. It can also be a consequence of atypical forms of cardiomyopathies, such as arrhythmogenic right ventricular cardiomyopathy. However, ventricular tachycardia can also occur in patients with structurally normal hearts. Torsades de pointes, a form of ventricular tachycardia in which QRS morphology twists around the baseline, may occur in the setting of severe hypokalemia, hypomagnesemia, or after administration of a drug that prolongs the QT interval. In nonacute settings, most patients with ventricular tachycardia have known or easily detectable cardiac disease, and the finding of ventricular tachycardia is an unfavorable prognostic sign.

 Clinical Findings

  1. Symptoms and Signs

Patients may be asymptomatic or experience syncope or milder symptoms of impaired cerebral perfusion.

  1. Laboratory Findings

Ventricular tachycardia can occur in the setting of hypokalemia and hypomagnesemia. Cardiac markers may be elevated when ventricular tachycardia presents in the setting of acute myocardial infarction or as a consequence of underlying coronary disease and demand ischemia.

  1. Differentiation of Aberrantly Conducted Supraventricular Beats from Ventricular Beats

Ventricular tachycardia is either nonsustained (three or more consecutive beats lasting < 30 seconds and terminating spontaneously) or sustained. The distinction from aberrant conduction of supraventricular tachycardia may be difficult in patients with a wide QRS complex; it is important because of the differing prognostic and therapeutic implications of each type. Findings favoring a ventricular origin include (1) AV dissociation; (2) a QRS duration exceeding 0.14 second; (3) capture or fusion beats (infrequent); (4) left axis deviation with right bundle branch block morphology; (5) monophasic (R) or biphasic (qR, QR, or RS) complexes in V1; and (6) a qR or QS complex in V6. Supraventricular origin is favored by (1) a triphasic QRS complex, especially if there was initial negativity in leads I and V6; (2) ventricular rates exceeding 170 beats/min; (3) QRS duration longer than 0.12 second but not longer than 0.14 second; and (4) the presence of preexcitation syndrome.

The relationship of the P waves to the tachycardia complex is helpful. A 1:1 relationship usually means a supraventricular origin, except in the case of ventricular tachycardia with retrograde P waves.

 Treatment

  1. Acute Ventricular Tachycardia

The treatment of acute ventricular tachycardia is determined by the degree of hemodynamic compromise and the duration of the arrhythmia. The management of ventricular tachycardia in acute myocardial infarction is discussed in the Complications section of Acute Myocardial Infarction with ST-Segment Elevation, above. In other patients, if ventricular tachycardia causes hypotension, heart failure, or myocardial ischemia, synchronized DC cardioversion with 100–360 J should be performed immediately. If the patient is tolerating the rhythm, amiodarone 150 mg as a slow intravenous bolus over 10 minutes, followed by an infusion of 1 mg/min for 6 hours and then a maintenance infusion of 0.5 mg/min for an additional 18–42 hours can be used. Lidocaine, 1 mg/kg as an intravenous bolus injection, can also be used. If the ventricular tachycardia recurs, supplemental amiodarone infusions of 150 mg over 10 minutes can be given. If the patient is stable, intravenous procainamide, 20 mg/min intravenously (up to 1000 mg), followed by an infusion of 20–80 mcg/kg/min could also be tried. Empiric magnesium replacement (1–2 g intravenously) may help. Ventricular tachycardia can also be terminated by ventricular overdrive pacing (through a pacemaker or ICD), and this approach is useful when the rhythm is recurrent.

  1. Chronic Recurrent Ventricular Tachycardia
  2. Sustained ventricular tachycardia—Patients with symptomatic or sustained ventricular tachycardia in the absence of a reversible precipitating cause (acute myocardial infarction or ischemia, electrolyte imbalance, drug toxicity, etc) are at high risk for recurrence. In those with significant LV dysfunction, subsequent sudden death is common. Several trials, including the Antiarrhythmics Versus Implantable Defibrillator (AVID) and the Canadian Implantable Defibrillator trials, strongly suggest that these patients should be managed with ICDs. In those with preserved LV function, the mortality rate is lower and the etiology is often different than in those with depressed ventricular function. Treatment with amiodarone, optimally in combination with a beta-blocker, may be adequate. Sotalol may be an alternative, though there is less supporting evidence. However, many times if ventricular tachycardia occurs in a patient with preserved ventricular function, it is either an outflow tract tachycardia or a fascicular ventricular tachycardia, and these arrhythmias will often respond to AV nodal blockers or can be effectively treated with catheter ablation. The role of electrophysiologic study in this group may help identify patients who are candidates for radiofrequency ablation of a ventricular tachycardia focus. This is particularly the case for arrhythmias that originate in the ventricular outflow tract (often appearing as left bundle branch block with inferior axis on the surface ECG), the left posterior fascicle (right bundle branch block, superior axis morphology), or sustained bundle branch reentry. Catheter ablation can be used as a palliative therapy for those patients with recurrent tachycardia who receive ICD shocks despite antiarrhythmic therapy.
  3. Nonsustained ventricular tachycardia (NSVT)—NSVT is defined as runs of three or more ventricular beats lasting < 30 seconds and terminating spontaneously. These may besymptomatic (usually experienced as light-headedness) or asymptomatic. In individuals without heart disease, NSVT is not clearly associated with a poor prognosis. However, in patients with structural heart disease, particularly when they have reduced LVEF, there is an increased risk of subsequent symptomatic ventricular tachycardia or sudden death. Beta-blockers reduce these risks in patients who have coronary disease with significant LV systolic dysfunction (EF < 40%), but if sustained ventricular tachycardia has been induced during electrophysiologic testing, an implantable defibrillator may be indicated. In patients with chronic heart failure and reduced EF—whether due to coronary disease or primary cardiomyopathy and regardless of the presence of asymptomatic ventricular arrhythmias—beta-blockers reduce the incidence of sudden death by 40–50% and should be routine therapy (see section on Heart Failure).

Although there are no definitive data with amiodarone in this group, trends from a number of studies suggest that it may be beneficial. Other antiarrhythmic agents should generally be avoided because their proarrhythmic risk appears to outweigh any benefit, even in patients with inducible arrhythmias that are successfully suppressed in the electrophysiology laboratory.

 When to Admit

Any sustained ventricular tachycardia.

Chen J et al. Rapid-rate nonsustained ventricular tachycardia found on implantable cardioverter-defibrillator interrogation: relationship to outcomes in the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial). J Am Coll Cardiol. 2013 May 28;61(21):2161–8. [PMID: 23541974]

Kuck KH et al; VTACH study group. Catheter ablation of stable ventricular tachycardia before defibrillator implantation in patients with coronary heart disease (VTACH): a multicentre randomised controlled trial. Lancet. 2010 Jan 2;375(9708): 31–40. [PMID: 20109864]

VENTRICULAR FIBRILLATION & DEATH

Sudden cardiac death is defined as unexpected nontraumatic death in clinically well or stable patients who die within 1 hour after onset of symptoms. The causative rhythm in most cases is ventricular fibrillation, which is usually preceded by ventricular tachycardia except in the setting of acute ischemia or infarction. Complete heart block and sinus node arrest may also cause sudden death. A disproportionate number of sudden deaths occur in the early morning hours and this suggests that there is a strong interplay with the autonomic nervous system. Over 75% of victims of sudden cardiac death have severe CAD. Many have old myocardial infarctions. Sudden death may be the initial manifestation of coronary disease in up to 20% of patients and accounts for approximately 50% of deaths from coronary disease. Other conditions that predispose to sudden death include severe LVH, hypertrophic cardiomyopathy, congestive cardiomyopathy, aortic stenosis, pulmonic stenosis, primary pulmonary hypertension, cyanotic congenital heart disease, atrial myxoma, mitral valve prolapse, hypoxia, electrolyte abnormalities, prolonged QT interval syndrome, the Brugada syndrome, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia, and conduction system disease.

 Treatment

Unless ventricular fibrillation occurs shortly after myocardial infarction, is associated with ischemia, or is seen with an unusual correctable process (such as an electrolyte abnormality, drug toxicity, or aortic stenosis), surviving patients require evaluation and intervention since recurrences are frequent. Coronary arteriography should be performed to exclude coronary disease as the underlying cause, since revascularization may prevent recurrence. When ventricular fibrillation occurs in the initial 24 hours after infarction, long-term management is no different from that of other patients with acute infarction. Conduction disturbances should be managed as described in the next section. Survivors of ventricular fibrillation or cardiac arrest have improved long-term outcomes if a hypothermia protocol is rapidly initiated and continued for 24–36 hours after cardiac arrest.

The current consensus is that if myocardial infarction or ischemia, bradyarrhythmias and conduction disturbances or other identifiable and correctable precipitating causes of ventricular fibrillation are not found to be the cause of the sudden death episode, an ICD is the treatment of choice. In addition, evidence from the MADIT II study and Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) suggest that patients with severe LV dysfunction—whether due to an ischemic cause such as a remote myocardial infarction or a nonischemic cause of advanced heart failure—have a reduced risk of death with the prophylactic implantation of an ICD. However, the DINAMIT study demonstrated that implanting prophylactic ICDs in patients early after myocardial infarction is associated with a trend toward worse outcomes. These patients may be managed with a wearable defibrillator vest until recovery of ventricular function can be assessed at a later date.

Brodine WN et al; MADIT-II Research Group. Effects of beta-blockers on implantable cardioverter defibrillator therapy and survival in the patients with ischemic cardiomyopathy (from the Multicenter Automatic Defibrillator Implantation Trial-II). Am J Cardiol. 2005 Sep 1;96(5):691–5. [PMID: 16125497]

Hohnloser SH et al; DINAMIT Investigators. Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction. N Engl J Med. 2004 Dec 9;351(24):2481–8. [PMID: 15590950]

Kadish A et al; Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) Investigators. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med. 2004 May 20;350(21): 2151–8. [PMID: 15152060]

Nielsen N et al; TTM Trial Investigators. Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest. N Engl J Med. 2013 Dec 5;369(23):2197–206. [PMID: 24237006]

Olasveengen TM et al. Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial. JAMA. 2009 Nov 25;302(20):2222–9. [PMID: 19934423]

Sasson C et al. Predictors of survival from out-of-hospital cardiac arrest: a systematic review and meta-analysis. Circulation. 2010 Jan 1;3(1):63–81. [PMID: 20123673]

ACCELERATED IDIOVENTRICULAR RHYTHM

Accelerated idioventricular rhythm is a regular wide complex rhythm with a rate of 60–120 beats/min, usually with a gradual onset. Because the rate is often similar to the sinus rate, fusion beats and alternating rhythms are common. Two mechanisms have been invoked: (1) an escape rhythm due to suppression of higher pacemakers resulting from sinoatrial and AV block or from depressed sinus node function; and (2) slow ventricular tachycardia due to increased automaticity or, less frequently, reentry. It occurs commonly in acute infarction and following reperfusion with thrombolytic drugs. The incidence of associated ventricular fibrillation is much less than that of ventricular tachycardia with a rapid rate, and treatment is not indicated unless there is hemodynamic compromise or more serious arrhythmias. This rhythm also is common in digitalis toxicity.

Accelerated idioventricular rhythm must be distinguished from the idioventricular or junctional rhythm with rates < 40–45 beats/min that occurs in the presence of complete AV block. AV dissociation—where ventricular rate exceeds sinus—but not AV block occurs in most cases of accelerated idioventricular rhythm.

LONG QT SYNDROME

Congenital long QT syndrome is an uncommon disease that is characterized by recurrent syncope, a long QT interval (usually 0.5–0.7 second), documented ventricular arrhythmias, and sudden death. It may occur in the presence (Jervell-Lange-Nielsen syndrome) or absence (Romano-Ward syndrome) of congenital deafness. Inheritance may be autosomal recessive or autosomal dominant (Romano-Ward). Specific genetic mutations affecting membrane potassium and sodium channels have been identified and help delineate the mechanisms and susceptibility to arrhythmia.

Because this is a primary electrical disorder usually with no evidence of structural heart disease or LV dysfunction, the long-term prognosis is excellent if arrhythmia is controlled. Long-term treatment with beta-blockers or permanent pacing has been shown to be effective. ICD implantation is recommended for patients in whom recurrent syncope, sustained ventricular arrhythmias, or sudden cardiac death occurs despite drug therapy. An ICD should be considered as primary therapy in certain patients, such as those in whom aborted sudden cardiac death is the initial presentation of the long-QT syndrome, when there is a strong family history of sudden cardiac death, or when compliance or intolerance to drugs is a concern.

Acquired long QT interval secondary to use of antiarrhythmic agents, methadone, antidepressant drugs, or certain antibiotics; electrolyte abnormalities; myocardial ischemia; or significant bradycardia may result in ventricular tachycardia (particularly torsades de pointes). Notably, many antiarrhythmic drugs that are effective for the treatment of atrial and ventricular arrhythmias may significantly prolong the QT interval (sotalol, dofetilide). If a drug therapy is found to prolong the QT interval beyond 500 ms or 15% longer than the baseline QT, it should be discontinued.

The management of torsades de pointes differs from that of other forms of ventricular tachycardia. Class Ia, Ic, or III antiarrhythmics, which prolong the QT interval, should be avoided—or withdrawn immediately if being used. Intravenous beta-blockers may be effective, especially in congenital forms of long-QT syndrome; intravenous magnesium should be given acutely. Increasing the heart rate, whether by infusion of beta-agonist (dopamine or isoproterenol) or temporary atrial or ventricular pacing, is an effective approach that can both break and prevent the rhythm.

Moskovitz JB et al. Electrocardiographic implications of the prolonged QT interval. Am J Emerg Med. 2013 May;31(5): 866–71. [PMID: 23602761]

Roden DM. Clinical practice. Long-QT syndrome. N Engl J Med. 2008 Jan 10;358(2):169–76. [PMID: 18184962]

Schwartz P et al. Who are the long-QT syndrome patients who receive an implantable cardioverter-defibrillator and what happens to them?: data from the European Long-QT Syndrome Implantable Cardioverter-Defibrillator (LQTS ICD) Registry. Circulation. 2010 Sep 28;122(13):1272–82. [PMID: 20837891]

BRADYCARDIAS & CONDUCTION DISTURBANCES

SICK SINUS SYNDROME

 ESSENTIALS OF DIAGNOSIS

 Most patients are asymptomatic.

 More common in elderly population.

 May have recurrent supraventricular arrhythmia and bradyarrhythmia.

 Frequently seen in patients with concomitant atrial fibrillation.

 Often chronotropically incompetent.

 May be caused by drug therapy.

 General Considerations

This imprecise diagnosis is applied to patients with sinus arrest, sinoatrial exit block (recognized by a pause equal to a multiple of the underlying PP interval or progressive shortening of the PP interval prior to a pause), or persistent sinus bradycardia. These rhythms are often caused or exacerbated by drug therapy (digitalis, calcium channel blockers, beta-blockers, sympatholytic agents, antiarrhythmics), and agents that may be responsible should be withdrawn prior to making the diagnosis. Another presentation is of recurrent supraventricular tachycardias (paroxysmal reentry tachycardias, atrial flutter, and atrial fibrillation), associated with bradyarrhythmias (“tachy-brady syndrome”). The long pauses that often follow the termination of tachycardia cause the associated symptoms.

Sick sinus syndrome occurs most commonly in elderly patients and is frequently seen in patients with concomitant atrial fibrillation. The pathologic changes are usually nonspecific, characterized by patchy fibrosis of the sinus node and cardiac conduction system. Sick sinus syndrome may be caused by other conditions, including sarcoidosis, amyloidosis, Chagas disease, and various cardiomyopathies. Coronary disease is an uncommon cause.

 Clinical Findings

Most patients with ECG evidence of sick sinus syndrome are asymptomatic, but rare individuals may experience syncope, dizziness, confusion, palpitations, heart failure, or angina. Because these symptoms are either nonspecific or are due to other causes, it is essential that they be demonstrated to coincide temporally with arrhythmias. This may require prolonged ambulatory monitoring or the use of an event recorder.

 Treatment

Most symptomatic patients will require permanent pacing (see AV block, below). Dual-chamber pacing is preferred because ventricular pacing is associated with a higher incidence of subsequent atrial fibrillation, and subsequent AV block occurs at a rate of 2% per year. In addition, resultant “pacemaker syndrome” can result from loss of AV synchrony. Treatment of associated tachyarrhythmias is often difficult without first instituting pacing, since beta-blockers, calcium-channel blockers, digoxin, and other antiarrhythmic agents may exacerbate the bradycardia. Unfortunately, symptomatic relief following pacing has not been consistent, largely because of inadequate documentation of the etiologic role of bradyarrhythmias in producing the symptom. Furthermore, many of these patients may have associated ventricular arrhythmias that may require treatment. Permanent pacing may alleviate symptoms in carefully selected patients.

Alboni P et al. Treatment of persistent sinus bradycardia with intermittent symptoms: are guidelines clear? Europace. 2009 May;11(5):562–4. [PMID: 19213798]

Riahi S et al; DANPACE Investigators. Heart failure in patients with sick sinus syndrome treated with single lead atrial or dual-chamber pacing: no association with pacing mode or right ventricular pacing site. Europace. 2012 Oct;14(10):1475–82. [PMID: 22447958]

AV BLOCK

AV block is categorized as first-degree (PR interval > 0.21 second with all atrial impulses conducted), second-degree (intermittent blocked beats), or third-degree (complete heart block, in which no supraventricular impulses are conducted to the ventricles).

Second-degree block is further subclassified. In Mobitz type I (Wenckebach) AV block, the AV conduction time (PR interval) progressively lengthens, with the RR interval shortening before the blocked beat; this phenomenon is almost always due to abnormal conduction within the AV node. In Mobitz type II AV block, there are intermittently nonconducted atrial beats not preceded by lengthening AV conduction. It is usually due to block within the His bundle system. The classification as Mobitz type I or Mobitz type II is only partially reliable because patients may appear to have both types on the surface ECG, and the site of origin of 2:1 AV block cannot be predicted from the ECG. The width of the QRS complexes assists in determining whether the block is nodal or infranodal. When they are narrow, the block is usually nodal; when they are wide, the block is usually infranodal. Electrophysiologic studies may be necessary for accurate localization. Management of AV block in acute myocardial infarction has already been discussed.

First-degree and Mobitz type I block may occur in normal individuals with heightened vagal tone. They may also occur as a drug effect (especially digitalis, calcium channel blockers, beta-blockers, or other sympatholytic agents), often superimposed on organic disease. These disturbances also occur transiently or chronically due to ischemia, infarction, inflammatory processes (including Lyme disease), fibrosis, calcification, or infiltration. The prognosis is usually good, since reliable alternative pacemakers arise from the AV junction below the level of block if higher degrees of block occur.

Mobitz type II block is almost always due to organic disease involving the infranodal conduction system. In the event of progression to complete heart block, alternative pacemakers are not reliable. Thus, prophylactic ventricular pacing is required.

Complete (third-degree) heart block is a more advanced form of block often due to a lesion distal to the His bundle and associated with bilateral bundle branch block. The QRS is wide and the ventricular rate is slower, usually < 50 beats/min. Transmission of atrial impulses through the AV node is completely blocked, and a ventricular pacemaker maintains a slow, regular ventricular rate, usually < 45 beats/min. Exercise does not increase the rate. The first heart sound varies in intensity; wide pulse pressure, a changing systolic BP level, and cannon venous pulsations in the neck are also present. Patients may be asymptomatic or may complain of weakness or dyspnea if the rate is < 35 beats/min; symptoms may occur at higher rates if the left ventricle cannot increase its stroke output. During periods of transition from partial to complete heart block, some patients have ventricular asystole that lasts several seconds to minutes. Syncope occurs abruptly.

Patients with episodic or chronic infranodal complete heart block require permanent pacing, and temporary pacing is indicated if implantation of a permanent pacemaker is delayed.

 Treatment

The indications for permanent pacing have been discussed: symptomatic bradyarrhythmias, asymptomatic Mobitz II AV block, or complete heart block. A standardized nomenclature for pacemaker generators is used, usually consisting of four letters. The first letter refers to the chamber that is stimulated (A = atrium, V = ventricle, D = dual, for both). The second letter refers to the chamber in which sensing occurs (also A, V, or D). The third letter refers to the sensory mode (I = inhibition by a sensed impulse, T = triggering by a sensed impulse, D = dual modes of response). The fourth letter refers to the programmability or rate modulation capacity (usually P for programming for two functions, M for programming more than two, and R for rate modulation).

A dual-chamber multiple programmable pacemaker that senses and paces in both chambers is the most physiologic approach to pacing patients who remain in sinus rhythm. AV synchrony is particularly important in patients in whom atrial contraction produces a substantial increment in stroke volume and in those in whom sensing the atrial rate to provide rate-responsive ventricular pacing is useful. Dual-chamber pacing is most useful for individuals with LV systolic or—perhaps more importantly—diastolic dysfunction and for physically active individuals. In patients with single-chamber ventricular pacemakers, the lack of an atrial kick may lead to the so-called pacemaker syndrome, in which the patient experiences signs of low cardiac output while upright.

Pulse generators are also available that can increase their rate in response to motion or respiratory rate when the intrinsic atrial rate is inappropriately low. These are most useful in active individuals. Follow-up after pacemaker implantation, usually by telephonic monitoring, is essential. All pulse generators and lead systems have an early failure rate that is now below 1% and an expected battery life varying from 4 years to 10 years.

Epstein AE et al. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation. 2013 Jan 22;127(3):e283–352. [PMID: 23255456]

AV DISSOCIATION

When a ventricular pacemaker is firing at a rate faster than or close to the sinus rate (accelerated idioventricular rhythm, ventricular premature beats, or ventricular tachycardia), atrial impulses arriving at the AV node when it is refractory may not be conducted. This phenomenon is AV dissociation but does not necessarily indicate AV block. No treatment is required aside from management of the causative arrhythmia.

INTRAVENTRICULAR CONDUCTION DEFECTS

Intraventricular conduction defects, including bundle branch block, are common in individuals with otherwise normal hearts and in many disease processes, including ischemic heart disease, inflammatory disease, infiltrative disease, cardiomyopathy, and postcardiotomy. Bifascicular block is present when two of these—right bundle, left anterior, and left posterior fascicle—are involved. Trifascicular block is defined as right bundle branch block with alternating left hemiblock, alternating right and left bundle branch block, or bifascicular block with documented prolonged infranodal conduction (long His-ventricular interval).

The prognosis of intraventricular block is generally related to the underlying myocardial process. Patients with no apparent heart disease have an overall survival rate similar to that of matched controls. However, left bundle branch block—but not right—is associated with a higher risk of development of overt cardiac disease and cardiac mortality. With bifascicular block, the incidence of occult complete heart block or progression to it is low, and pacing is not usually warranted in asymptomatic patients. However, in patients with bifascicular block that presents with syncope where no other readily identifiable cause is found, early pacemaker implantation has been shown to reduce further episodes.

Garcia D et al. Intraventricular conduction abnormality—an electrocardiographic algorithm for rapid detection and diagnosis. Am J Emerg Med. 2009 May;27(4):492–502. [PMID: 19555622]

Santini M et al. Prevention of syncope through permanent cardiac pacing in patients with bifascicular block and syncope of unexplained origin: the PRESS study. Circ Arrhythm Electrophysiol. 2013 Feb;6(1):101–7. [PMID: 23390123]

SYNCOPE

 ESSENTIALS OF DIAGNOSIS

 Transient loss of consciousness and postural tone from vasodepressor or cardiogenic causes.

 Prompt recovery without resuscitative measures.

 Common clinical problem.

 General Considerations

Syncope is a symptom defined as a transient, self-limited loss of consciousness, usually leading to a fall. Thirty percent of the adult population will experience at least one episode of syncope. It accounts for approximately 3% of emergency department visits. A specific cause of syncope is identified in about 50% of cases during the initial evaluation. The prognosis is relatively favorable except when accompanying cardiac disease is present. In many patients with recurrent syncope or near syncope, arrhythmias are not the cause. This is particularly true when the patient has no evidence of associated heart disease by history, examination, standard ECG, or noninvasive testing. The history is the most important of the evaluation to identify the cause of syncope.

Vasodepressor syncope may be due to excessive vagal tone or impaired reflex control of the peripheral circulation. The most frequent type of vasodepressor syncope is vasovagal hypotension or the “common faint,” which is often initiated by a stressful, painful, or claustrophobic experience, especially in young women. Enhanced vagal tone with resulting hypotension is the cause of syncope in carotid sinus hypersensitivity and postmicturition syncope; vagal-induced sinus bradycardia, sinus arrest, and AV block are common accompaniments and may themselves be the cause of syncope.

Orthostatic (postural) hypotension is another common cause of vasodepressor syncope, especially in the elderly; in diabetic patients or others with autonomic neuropathy; in patients with blood loss or hypovolemia; and in patients taking vasodilators, diuretics, and adrenergic-blocking drugs. In addition, a syndrome of chronic idiopathic orthostatic hypotension exists primarily in older men. In most of these conditions, the normal vasoconstrictive response to assuming upright posture, which compensates for the abrupt decrease in venous return, is impaired.

Cardiogenic syncope can occur on a mechanical or arrhythmic basis. There is usually no prodrome; thus, injury secondary to falling is common. Mechanical problems that can cause syncope include aortic stenosis (where syncope may occur from autonomic reflex abnormalities or ventricular tachycardia), pulmonary stenosis, HOCM, congenital lesions associated with pulmonary hypertension or right-to-left shunting, and LA myxoma obstructing the mitral valve. Episodes are commonly exertional or postexertional. More commonly, cardiac syncope is due to disorders of automaticity (sick sinus syndrome), conduction disorders (AV block), or tachyarrhythmias (especially ventricular tachycardia and supraventricular tachycardia with rapid ventricular rate).

 Clinical Findings

  1. Symptoms and Signs

Syncope is characteristically abrupt in onset, often resulting in injury, transient (lasting for seconds to a few minutes), and followed by prompt recovery of full consciousness.

Vasodepressor premonitory symptoms, such as nausea, diaphoresis, tachycardia, and pallor, are usual in the “common faint.” Episodes can be aborted by lying down or removing the inciting stimulus. Inorthostatic (postural) hypotension, a greater than normal decline (20 mm Hg) in BP immediately upon arising from the supine to the standing position is observed, with or without tachycardia depending on the status of autonomic (baroreceptor) function.

  1. Diagnostic Tests

The evaluation for syncope depends on findings from the history and physical examination (especially orthostatic BP evaluation, examination of carotid and other arteries, and cardiac examination).

  1. ECG—The resting ECG may reveal arrhythmias, evidence of accessory pathways, prolonged QT interval, and other signs of heart disease (such as infarction or hypertrophy). If the history is consistent with syncope, ambulatory ECG monitoring is essential. This may need to be repeated several times, since yields increase with longer periods of monitoring, at least up to 3 days. Event recorder and transtelephone ECG monitoring may be helpful in patients with intermittent presyncopal episodes. Caution is required before attributing a patient’s symptom to rhythm or conduction abnormalities observed during monitoring without concomitant symptoms. In many cases, the symptoms are due to a different arrhythmia or to noncardiac causes. For instance, dizziness or syncope in older patients may be unrelated to concomitantly observed bradycardia, sinus node abnormalities, and ventricular ectopy.
  2. Autonomic testing—Orthostatic hypotension from autonomic function can be diagnosed with more certainty by observing BP and heart rate responses to Valsalva maneuver and by tilt testing.

Carotid sinus massage in patients who do not have carotid bruits or a history of cerebral vascular disease can precipitate sinus node arrest or AV block in patients with carotid sinus hypersensitivity.Head-up tilt-table testing can identify patients whose syncope may be on a vasovagal basis. In older patients, vasoconstrictor abnormalities and autonomic insufficiency are perhaps the most common causes of syncope. Thus, tilt testing should be done before proceeding to invasive studies unless clinical and ambulatory ECG evaluation suggests a cardiac abnormality. Although different testing protocols are used, passive tilting to at least 70 degrees for 10–40 minutes—in conjunction with isoproterenol infusion or sublingual nitroglycerin, if necessary—is typical. Syncope due to bradycardia, hypotension, or both will occur in approximately one-third of patients with recurrent syncope. Some studies have suggested that, at least with some of the more extreme protocols, false-positive responses may occur.

  1. Electrophysiologic studies—Electrophysiologic studies to assess sinus node function and AV conduction and to induce supraventricular or ventricular tachycardia are indicated in patients with recurrent episodes, nondiagnostic ambulatory ECGs, and negative autonomic testing if vasomotor syncope is a consideration. Electrophysiologic studies reveal an arrhythmic cause in 20–50% of patients, depending on the study criteria, and are most often diagnostic when the patient has had multiple episodes and has identifiable cardiac abnormalities.
  2. Exercise testing—When the symptoms are associated with exertion or stress, exercise testing may be helpful.

 Treatment

Treatment consists largely of counseling patients to avoid predisposing situations. Paradoxically, beta-blockers have been used in patients with altered autonomic function uncovered by head-up tilt testing but they have provided only minimal benefit. If symptomatic bradyarrhythmias or supraventricular tachyarrhythmias are detected, therapy can usually be initiated without additional diagnostic studies. Permanent pacing has little benefit except in patients with documented severe pauses and bradycardiac responses.

Volume expanders, such as fludrocortisone, or vasoconstrictors, such as midodrine, have also been tried but with minimal benefit. Selective serotonin reuptake inhibitors have shown some benefit in select patients.

See Recommendations for Resumption of Driving, below.

 When to Admit

  • Patients with syncope and concomitant structural heart disease or when a primary cardiac etiology is suspected.
  • Patients with recent or recurrent syncope are often monitored in the hospital.
  • Those with less ominous symptoms may be monitored as outpatients.

Benditt DG. Syncope risk assessment in the emergency department and clinic. Prog Cardiovasc Dis. 2013 Jan–Feb;55(4): 376–81. [PMID: 23472774]

Kessler C et al. The emergency department approach to syncope: evidence-based guidelines and prediction rules. Emerg Med Clin North Am. 2010 Aug;28(3):487–500. [PMID: 20709240]

Krahn AD et al. Selecting appropriate diagnostic tools for evaluating the patient with syncope/collapse. Prog Cardiovasc Dis. 2013 Jan–Feb;55(4):402–9. [PMID: 23472778]

RECOMMENDATIONS FOR RESUMPTION OF DRIVING

An important management problem in patients who have experienced syncope, symptomatic ventricular tachycardia, or aborted sudden death is to provide recommendations concerning automobile driving. Patients with syncope or aborted sudden death thought to have been due to temporary factors (acute myocardial infarction, bradyarrhythmias subsequently treated with permanent pacing, drug effect, electrolyte imbalance) should be strongly advised after recovery not to drive for at least 1 month. Other patients with symptomatic ventricular tachycardia or aborted sudden death, whether treated pharmacologically, with antitachycardia devices, or with ablation therapy, should not drive for at least 6 months. Longer restrictions are warranted in these patients if spontaneous arrhythmias persist. The clinician should comply with local reporting and driving restriction regulations and consult local authorities concerning individual cases where required.

Sakaguchi S et al. Syncope and driving, flying and vocational concerns. Prog Cardiovasc Dis. 2013 Jan–Feb;55(4):454–63. [PMID: 23472784]

HEART FAILURE

 ESSENTIALS OF DIAGNOSIS

 LV failure: Either due to systolic or diastolic dysfunction. Predominant symptoms are those of low cardiac output and congestion, including dyspnea.

 RV failure: Symptoms of fluid overload predominate; usually RV failure is secondary to LV failure.

 Assessment of LV function is a crucial part of diagnosis and management.

 Optimal management of chronic heart failure includes combination medical therapies, such as ACE inhibitors, aldosterone antagonists, and beta-blockers.

 General Considerations

Heart failure is a common syndrome that is increasing in incidence and prevalence. Approximately 5 million patients in the United States have heart failure, and there are nearly 500,000 new cases each year. Each year in the United States, over 1 million patients are discharged from the hospital with a diagnosis of heart failure. It is primarily a disease of aging, with over 75% of existing and new cases occurring in individuals over 65 years of age. The prevalence of heart failure rises from < 1% in individuals below 60 years to nearly 10% in those over 80 years of age.

Heart failure may be right sided or left sided (or both). Patients with left heart failure may have symptoms of low cardiac output and elevated pulmonary venous pressure; dyspnea is the predominant feature. Signs of fluid retention predominate in right heart failure. Most patients exhibit symptoms or signs of both right- and left-sided failure, and LV dysfunction is the primary cause of RV failure. Approximately half of patients with heart failure have preserved LV systolic function and usually have some degree of diastolic dysfunction. Patients with reduced or preserved systolic function may have similar symptoms and it may be difficult to distinguish clinically between the two based on signs and symptoms. In developed countries, CAD with resulting myocardial infarction and loss of functioning myocardium (ischemic cardiomyopathy) is the most common cause of systolic heart failure. Systemic hypertension remains an important cause of heart failure and, even more commonly in the United States, an exacerbating factor in patients with cardiac dysfunction due to other causes such as CAD. Several processes may present with dilated or congestive cardiomyopathy, which is characterized by LV or biventricular dilation and generalized systolic dysfunction. These are discussed elsewhere in this chapter, but the most common are alcoholic cardiomyopathy, viral myocarditis (including infections by HIV), and dilated cardiomyopathies with no obvious underlying cause (idiopathic cardiomyopathy). Rare causes of dilated cardiomyopathy include infiltrative diseases (hemochromatosis, sarcoidosis, amyloidosis, etc), other infectious agents, metabolic disorders, cardiotoxins, and drug toxicity. VHDs—particularly degenerative aortic stenosis and chronic aortic or mitral regurgitation—are not infrequent causes of heart failure. The most frequent cause of diastolic cardiac dysfunction is LVH, commonly resulting from hypertension, but conditions such as hypertrophic or restrictive cardiomyopathy, diabetes, and pericardial disease can produce the same clinical picture. Atrial fibrillation with or without rapid ventricular response may contribute to impaired left ventricular filling, and aging itself contributes to impaired left ventricular relaxation.

Heart failure is often preventable by early detection of patients at risk and by early intervention. The importance of these approaches is emphasized by US guidelines that have incorporated a classification of heart failure that includes four stages. Stage A includes patients at risk for developing heart failure (such as patients with hypertension or CAD without current or previous symptoms or identifiable structural abnormalities of the myocardium). In the majority of these patients, development of heart failure can be prevented with interventions such as the aggressive treatment of hypertension, modification of coronary risk factors, and reduction of excessive alcohol intake. Stage B includes patients who have structural heart disease but no current or previously recognized symptoms of heart failure. Examples include patients with previous myocardial infarction, other causes of reduced systolic function, LVH, or asymptomatic valvular disease. Both ACE inhibitors and beta-blockers prevent heart failure in the first two of these conditions, and more aggressive treatment of hypertension and early surgical intervention are effective in the latter two. Stages C and D include patients with clinical heart failure and the relatively small group of patients that has become refractory to the usual therapies, respectively. These are discussed below.

 Clinical Findings

  1. Symptoms

The most common symptom of patients with left heart failure is shortness of breath, chiefly exertional dyspnea at first and then progressing to orthopnea, paroxysmal nocturnal dyspnea, and rest dyspnea. Chronic nonproductive cough, which is often worse in the recumbent position, may occur. Nocturia due to excretion of fluid retained during the day and increased renal perfusion in the recumbent position is a common nonspecific symptom of heart failure, as is fatigue and exercise intolerance. These symptoms correlate poorly with the degree of cardiac dysfunction. Patients with right heart failure have predominate signs of fluid retention, with the patient exhibiting edema, hepatic congestion and, on occasion, loss of appetite and nausea due to edema of the gut or impaired gastrointestinal perfusion and ascites. Surprisingly, some individuals with severe LV dysfunction will display few signs of left heart failure and appear to have isolated right heart failure. Indeed, they may be clinically indistinguishable from patients with cor pulmonale, who have right heart failure secondary to pulmonary disease.

Patients with acute heart failure from myocardial infarction, myocarditis, and acute valvular regurgitation due to endocarditis or other conditions usually present with pulmonary edema. Patients with episodic symptoms may be having LV dysfunction due to intermittent ischemia. Patients may also present with acute exacerbations of chronic, stable heart failure. Exacerbations are usually caused by alterations in therapy (or patient noncompliance), excessive salt and fluid intake, arrhythmias, excessive activity, pulmonary emboli, intercurrent infection, or progression of the underlying disease.

Patients with heart failure are often categorized by the NYHA classification as class I (asymptomatic), class II (symptomatic with moderate activity), class III (symptomatic with mild activity), or class IV (symptomatic at rest). This classification is important since some of the treatments are indicated based on NYHA classification.

  1. Signs

Many patients with heart failure, including some with severe symptoms, appear comfortable at rest. Others will be dyspneic during conversation or minor activity, and those with long-standing severe heart failure may appear cachectic or cyanotic. The vital signs may be normal, but tachycardia, hypotension, and reduced pulse pressure may be present. Patients often show signs of increased sympathetic nervous system activity, including cold extremities and diaphoresis. Important peripheral signs of heart failure can be detected by examination of the neck, the lungs, the abdomen, and the extremities. RA pressure may be estimated through the height of the pulsations in the jugular venous system. In addition to the height of the venous pressure, abnormal pulsations such as regurgitant v waves should be sought. Examination of the carotid pulse may allow estimation of pulse pressure as well as detection of aortic stenosis. Thyroid examination may reveal occult hyperthyroidism or hypothyroidism, which are readily treatable causes of heart failure. Crackles at the lung bases reflect transudation of fluid into the alveoli. Pleural effusions may cause bibasilar dullness to percussion. Expiratory wheezing and rhonchi may be signs of heart failure. Patients with severe right heart failure may have hepatic enlargement—tender or nontender—due to passive congestion. Systolic pulsations may be felt in tricuspid regurgitation. Sustained moderate pressure on the liver may increase jugular venous pressure (a positive hepatojugular reflux is an increase of > 1 cm). Ascites may also be present. Peripheral pitting edema is a common sign in patients with right heart failure and may extend into the thighs and abdominal wall.

Cardinal cardiac examination signs are a parasternal lift, indicating pulmonary hypertension; an enlarged and sustained LV impulse, indicating LV dilation and hypertrophy; a diminished first heart sound, suggesting impaired contractility; and an S3 gallop originating in the LV and sometimes the RV. An S4 is usually present in diastolic heart failure. Murmurs should be sought to exclude primary valvular disease; secondary mitral regurgitation and tricuspid regurgitation murmurs are common in patients with dilated ventricles. In chronic heart failure, many of the expected signs of heart failure may be absent despite markedly abnormal cardiac function and hemodynamic measurements.

  1. Laboratory Findings

A blood count may reveal anemia and a high red-cell distribution width (RDW), both of which are associated with poor prognosis in chronic heart failure through poorly understood mechanisms. Renal function tests can determine whether cardiac failure is associated with impaired renal function that may reflect poor renal perfusion. Chronic kidney disease is another poor prognostic factor in heart failure and may limit certain treatment options. Serum electrolytes may disclose hypokalemia, which increases the risk of arrhythmias; hyperkalemia, which may limit the use of inhibitors of the renin–angiotensin system; or hyponatremia, an indicator of marked activation of the renin–angiotensin system and a poor prognostic sign. Thyroid function should be assessed to detect occult thyrotoxicosis or myxedema and iron studies test should be checked to test for hemochromatosis. In unexplained cases, appropriate biopsies may lead to a diagnosis of amyloidosis. Myocardial biopsy may exclude specific causes of dilated cardiomyopathy but rarely reveals specific reversible diagnoses.

Serum BNP is a powerful prognostic marker that adds to clinical assessment in differentiating dyspnea due to heart failure from noncardiac causes. Two markers—BNP and N-terminal pro-BNP—provide similar diagnostic and prognostic information. BNP is expressed primarily in the ventricles and is elevated when ventricular filling pressures are high. It is quite sensitive in patients with symptomatic heart failure—whether due to systolic or to diastolic dysfunction—but less specific in older patients, women, and patients with COPD. Studies have shown that BNP can help in emergency department triage in diagnosis of acute decompensated heart failure, such that a NT-proBNP < 300 pg/mL or BNP < 100 pg/mL, combined with a normal ECG, makes heart failure unlikely. BNP is less sensitive and specific to diagnose heart failure in the chronic setting. BNP may be helpful in guiding intensity of diuretic and other therapies for monitoring and management of chronic heart failure. Worsening breathlessness or weight associated with a rising BNP (or both) might prompt increasing the dose of diuretics. However, to date, the routine use of BNP to guide therapy has not been shown to be beneficial in randomized trials. Elevation of serum troponin, and especially of high-sensitivity troponin, is common in both chronic and acute heart failure, and it is associated with higher risk of adverse outcomes.

  1. ECG and Chest Radiography

ECG may indicate an underlying or secondary arrhythmia, myocardial infarction, or nonspecific changes that often include low voltage, intraventricular conduction defects, LVH, and nonspecific repolarization changes. Chest radiographs provide information about the size and shape of the cardiac silhouette. Cardiomegaly is an important finding and is a poor prognostic sign. Evidence of pulmonary venous hypertension includes relative dilation of the upper lobe veins, perivascular edema (haziness of vessel outlines), interstitial edema, and alveolar fluid. In acute heart failure, these findings correlate moderately well with pulmonary venous pressure. However, patients with chronic heart failure may show relatively normal pulmonary vasculature despite markedly elevated pressures. Pleural effusions are common and tend to be bilateral or right-sided.

  1. Additional Studies

Many studies have indicated that the clinical diagnosis of systolic myocardial dysfunction is often inaccurate. The primary confounding conditions are diastolic dysfunction of the heart with decreased relaxation and filling of the LV (particularly in hypertension and in hypertrophic states) and pulmonary disease. Because patients with heart failure usually have significant resting ECG abnormalities, stress imaging procedures such as perfusion scintigraphy or dobutamine echocardiography are often indicated.

The most useful test is the echocardiogram because it can differentiate heart failure with and without preserved LV systolic function. The echocardiogram can define the size and function of both ventricles and of the atria. It will also allow detection of pericardial effusion, valvular abnormalities, intracardiac shunts, and segmental wall motion abnormalities suggestive of old myocardial infarction as opposed to more generalized forms of dilated cardiomyopathy.

Radionuclide angiography as well as cardiac MRI also measure LVEF and permit analysis of regional wall motion. These tests are especially useful when echocardiography is technically suboptimal, such as in patients with severe pulmonary disease. When myocardial ischemia is suspected as a cause of LV dysfunction, stress testing should be performed.

  1. Cardiac Catheterization

In most patients with heart failure, clinical examination and noninvasive tests can determine LV size and function and valve function to confirm the diagnosis. Left heart catheterization may be helpful to define the presence and extent of CAD, although CT angiography may also be appropriate, especially when the likelihood of coronary disease is low. Evaluation for coronary disease is particularly important when LV dysfunction may be partially reversible by revascularization. The combination of angina or noninvasive evidence of significant myocardial ischemia with symptomatic heart failure is often an indication for coronary angiography if the patient is a potential candidate for revascularization. Right heart catheterization may be useful to select and monitor therapy in patients refractory to standard therapy.

 Treatment

The treatment of heart failure is aimed at relieving symptoms, improving functional status, and preventing death and hospitalizations. Figure 10–10 outlines the role of the major pharmacologic and device therapies for chronic heart failure. The evidence of clinical benefit, including reducing death and hospitalization, of most therapies is limited to patients with heart failure with reduced LVEF. Treatment of heart failure with preserved LV ejection is aimed at improving symptoms and treating comorbidities.

 Figure 10–10. Treatment options for patients with chronic symptomatic systolic heart failure. ACE, angiotensinconverting enzyme; ARB, angiotensin receptor blocker; CRT-D, cardiac resynchronization therapy defibrillator; CRT-P, cardiac resynchronization therapy pacemaker; H-ISDN, hydralazine and isosorbide dinitrate; HR, heart rate; ICD, implantable cardioverter defibrillator; LBBB, left bundle branch block; LVAD, left ventricular assist device; LVEF, left ventricular ejection fraction; MR antagonist, mineralocorticoid receptor antagonist; NYHA, New York Heart Association. (Modified, with permission, from McMurray JJ et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Eur J Heart Fail. 2012 Aug;14(8):803–69. [PMID: 22828712])

  1. Correction of Reversible Causes

The major reversible causes of chronic heart failure include valvular lesions, myocardial ischemia, uncontrolled hypertension, arrhythmias (especially persistent tachycardias), alcohol- or drug-induced myocardial depression, intracardiac shunts, and high-output states. Calcium channel blockers (specifically verapamil or diltiazem), antiarrhythmic drugs, thiazolidinediones, and nonsteroidal anti-inflammatory agents may be important contributors to worsening heart failure. Some metabolic and infiltrative cardiomyopathies may be partially reversible, or their progression may be slowed; these include hemochromatosis, sarcoidosis, and amyloidosis. Reversible causes of diastolic dysfunction include pericardial disease and LVH due to hypertension. Once possible reversible components are being addressed, the measures outlined below are appropriate.

  1. Pharmacologic

See also the following section on Acute Heart Failure & Pulmonary Edema.

  1. Diuretic therapy—Diuretics are the most effective means of providing symptomatic relief to patients with moderate to severe heart failure with dyspnea and fluid overload. Few patients with symptoms or signs of fluid retention can be optimally managed without a diuretic. However, excessive diuresis can lead to electrolyte imbalance and neurohormonal activation.A combination of a diuretic and an ACE inhibitor should be the initial treatment in most symptomatic patients with heart failure and reduced LVEF, with the early addition of a beta-blocker.

When fluid retention is mild, thiazide diuretics or a similar type of agent (hydrochlorothiazide, 25–100 mg; metolazone, 2.5–5 mg; chlorthalidone, 25–50 mg; etc) may be sufficient. Thiazide or related diuretics often provide better control of hypertension than short-acting loop agents. The thiazides are generally ineffective when the glomerular filtration rate falls below 30–40 mL/min, a not infrequent occurrence in patients with severe heart failure. Metolazone maintains its efficacy down to a glomerular filtration rate of approximately 20–30 mL/min. Adverse reactions include hypokalemia and intravascular volume depletion with resulting prerenal azotemia, skin rashes, neutropenia and thrombocytopenia, hyperglycemia, hyperuricemia, and hepatic dysfunction.

Patients with more severe heart failure should be treated with one of the oral loop diuretics. These include furosemide (20–320 mg daily), bumetanide (1–8 mg daily), and torsemide (20–200 mg daily). These agents have a rapid onset and a relatively short duration of action. In patients with preserved kidney function, two or more daily doses are preferable to a single larger dose. In acute situations or when gastrointestinal absorption is in doubt, they should be given intravenously. Torsemide may be effective when furosemide is not, including related to better absorption and a longer half life. Larger doses (up to 500 mg of furosemide or equivalent) may be required with severe renal impairment. The major adverse reactions include intravascular volume depletion, prerenal azotemia, and hypotension. Hypokalemia, particularly with accompanying digitalis therapy, is a major problem. Less common side effects include skin rashes, gastrointestinal distress, and ototoxicity (the latter more common with ethacrynic acid and possibly less common with bumetanide).

The oral potassium-sparing agents are often useful in combination with the loop diuretics and thiazides. Triamterene (37.5–75 mg daily) and amiloride (5–10 mg daily) act on the distal tubule to reduce potassium secretion. Their diuretic potency is only mild and not adequate for most patients with heart failure, but they may minimize the hypokalemia induced by more potent agents. Side effects include hyperkalemia, gastrointestinal symptoms, and kidney dysfunction.

Spironolactone (12.5–100 mg daily) and eplerenone (25–100 mg daily) are specific inhibitors of aldosterone, which is often increased in heart failure and has important effects beyond potassium retention (see below). Their onsets of action are slower than the other potassium-sparing agents, and spironolactone’s side effects include gynecomastia. Combinations of potassium supplements or ACE inhibitors and potassium-sparing drugs can produce hyperkalemia but have been used with success in patients with persistent hypokalemia.

Patients with refractory edema may respond to combinations of a loop diuretic and thiazide-like agents. Metolazone, because of its maintained activity with chronic kidney disease, is the most useful agent for such a combination. Extreme caution must be observed with this approach, since massive diuresis and electrolyte imbalances often occur; 2.5 mg of metolazone orally should be added to the previous dosage of loop diuretic. In many cases this is necessary only once or twice a week, but dosages up to 10 mg daily have been used in some patients.

  1. Inhibitors of the renin–angiotensin–aldosterone system—Inhibition of renin–angiotensin–aldosterone system with ACE inhibitors should be part of the initial therapy of this syndrome based on their life-saving benefits.
  2. ACEINHIBITORS—Many ACE inhibitors are available, and at least seven have been shown to be effective for the treatment of heart failure or the related indication of postinfarction LV dysfunction (seeTable 11–7). ACE inhibitors reduce mortality by approximately 20% in patients with symptomatic heart failure and have been shown also to prevent hospitalizations, increase exercise tolerance, and reduce symptoms in these patients. As a result, ACE inhibitors should be part of first-line treatment of patients with symptomatic LV systolic dysfunction (EF < 40%), usually in combination with a diuretic. They are also indicated for the management of patients with reduced EFs without symptoms because they prevent the progression to clinical heart failure.

Because ACE inhibitors may induce significant hypotension, particularly following the initial doses, they must be started with caution. Hypotension is most prominent in patients with already low BPs (systolic pressure < 100 mm Hg), hypovolemia, prerenal azotemia (especially if it is diuretic induced), and hyponatremia (an indicator of activation of the renin–angiotensin system). These patients should generally be started at low dosages (captopril 6.25 mg orally three times daily, enalapril 2.5 mg orally daily, or the equivalent), but other patients may be started at twice these dosages. Within several days (for those with the markers of higher risk) or at most 2 weeks, patients should be questioned about symptoms of hypotension, and both kidney function and K+ levels should be monitored.

ACE inhibitors should be titrated to the dosages proved effective in clinical trials (captopril 50 mg three times daily, enalapril 10 mg twice daily, ramipril 10 mg daily, lisinopril 20 mg daily, or the equivalent) over a period of 1–3 months. Most patients will tolerate these doses. Asymptomatic hypotension is not a contraindication to up-titrating or continuing ACE inhibitors. Some patients exhibit increases in serum creatinine or K+, but they do not require discontinuation if the levels stabilize—even at values as high as 3 mg/dL and 5.5 mEq/L, respectively. Kidney dysfunction is more frequent in diabetic patients, older patients, and those with low systolic pressures, and these groups should be monitored more closely. The most common side effects of ACE inhibitors in heart failure patients are dizziness (often not related to the level of BP) and cough, though the latter is often due as much to heart failure or intercurrent pulmonary conditions as to the ACE inhibitor.

  1. ANGIOTENSIN II RECEPTOR BLOCKERS—Another approach to inhibiting the renin–angiotensin–aldosterone system is the use of specific ARBs (seeTable 11–7), which will decrease adverse effects of angiotensin II by blocking the AT1receptor. In addition, because there are alternative pathways of angiotensin II production in many tissues, the receptor blockers may provide more complete blockade of the AT1 receptor.

However, these agents do not share the effects of ACE inhibitors on other potentially important pathways that produce increases in bradykinin, prostaglandins, and nitric oxide in the heart, blood vessels, and other tissues. The Valsartan in Heart Failure Trial (Val-HeFT) examined the efficacy of adding valsartan (titrated to a dose of 160 mg orally twice a day) to ACE inhibitor therapy. While the addition of valsartan did not reduce mortality, the composite of death or hospitalization for heart failure was significantly reduced. The CHARM trial randomized 7601 patients with chronic heart failure with or without LV systolic dysfunction and with or without background ACE inhibitor therapy to candesartan (titrated to 32 mg orally daily) or placebo. Among patients with an LVEF of < 40%, there was an 18% reduction in cardiovascular death or heart failure hospitalization and a statistically significant 12% reduction in all-cause mortality. The benefits were similar among patients on ACE inhibitors, including among patients on full-dose ACE inhibitors. Thus, ARBs, specifically candesartan or valsartan, provide important benefits as an alternative to, and in addition to, ACE inhibitors in chronic heart failure with reduced LVEF. A large trial of patients with chronic heart failure and preserved LVEF found no benefit from the ARB irbesartan.

  1. SPIRONOLACTIONE AND EPLERENONE—Inhibiting aldosterone has become a mainstay of management of symptomatic heart failure with reduced LVEF. The RALES trial compared spironolactone 25 mg daily with placebo in patients with advanced heart failure (current or recent class IV) already receiving ACE inhibitors and diuretics and showed a 29% reduction in mortality as well as similar decreases in other clinical end points. Hyperkalemia was uncommon in this severe heart failure clinical trial population, which was maintained on high doses of diuretic, but hyperkalemia with spironolactone appears to be common in general practice. Potassium levels should be monitored closely during initiation of spironolactone (after 1 and 4 weeks of therapy), particularly for patients with even mild degrees of kidney injury, and in patients receiving ACE inhibitors. Based on the EMPHASIS-HF trial, the efficacy and safety of aldosterone antagonism—in the form of eplerenone, 25–50 mg orally daily—is established for patients with mild or moderate heart failure. This trial showed a significant reduction in cardiovascular death as well as in hospitalization for heart failure among patients with NYHA class II heart failure and LVEF< 30%. Most experts believe that spironolactone is likely to provide similar benefit.Careful monitoring of serum potassium levels, in particular for patients with any degree of kidney insufficiency, is important to avoid life-threatening hyperkalemia.Serum potassium should be checked within 1 week of initiating an aldosterone blocker and periodically thereafter.

While the TOPCAT trial failed to show that spironolactone improved cardiovascular mortality and morbidity in a population of patients with heart failure and preserved LVEF (≥ 45%), there appeared to be a reduction in heart failure hospitalization, but at the cost of increased hyperkalemia and renal dysfunction.

  1. Beta-blockers—Beta-blockers are part of the foundation of care of chronic heart failure based on their life-saving benefits. The mechanism of this benefit remains unclear, but it is likely that chronic elevations of catecholamines and sympathetic nervous system activity cause progressive myocardial damage, leading to worsening LV function and dilation. The primary evidence for this hypothesis is that over a period of 3–6 months, beta-blockers produce consistent substantial rises in EF (averaging 10% absolute increase) and reductions in LV size and mass.

Three drugs have strong evidence of reducing mortality: carvedilol (a nonselective beta-1- and beta-2-receptor blocker), the beta-1-selective extended-release agent metoprolol succinate, (but not short-acting metoprolol tartrate), and bisoprolol (beta-1-selective agent).

This has led to a strong recommendation that stable patients (defined as having no recent deterioration or evidence of volume overload) with mild, moderate, and even severe heart failure should be treated with a beta-blocker unless there is a noncardiac contraindication. In the COPERNICUS trial, carvedilol was both well tolerated and highly effective in reducing both mortality and heart failure hospitalizations in a group of patients with severe (NYHA class III or IV) symptoms, but care was taken to ensure that they were free of fluid retention at the time of initiation. In this study, one death was prevented for every 13 patients treated for 1 year—as dramatic an effect as has been seen with a pharmacologic therapy in the history of cardiovascular medicine. One trial comparing carvedilol and (short-acting) metoprolol tartrate (COMET) found significant reductions in all-cause mortality and cardiovascular mortality with carvedilol. Thus, patients with chronic heart failure should be treated with extended-release metoprolol succinate, bisoprolol, or carvedilol, but not short-acting metoprolol tartrate.

Because even apparently stable patients may deteriorate when beta-blockers are initiated, initiation must be done gradually and with great care. Carvedilol is initiated at a dosage of 3.125 mg orally twice daily and may be increased to 6.25, 12.5, and 25 mg twice daily at intervals of approximately 2 weeks. The protocols for sustained-release metoprolol use were started at 12.5 or 25 mg orally daily and doubled at intervals of 2 weeks to a target dose of 200 mg daily (using the Toprol XL sustained-release preparation). Bisoprolol was administered at a dosage of 1.25, 2.5, 3.75, 5, 7.5, and 10 mg orally daily, with increments at 1- to 4-week intervals. More gradual up-titration is often more convenient and may be better tolerated. The SENIORS trial of 2135 patients found that nebivolol was effective in elderly patients (70 years and older) with chronic heart failure, although the evidence of degree of benefit was not as strong as with the three proven beta-blockers carvedilol, metoprolol succinate, or bisoprolol.

Patients should be instructed to monitor their weights at home as an indicator of fluid retention and to report any increase or change in symptoms immediately. Before each dose increase, the patient should be seen and examined to ensure that there has not been fluid retention or worsening of symptoms. If heart failure worsens, this can usually be managed by increasing diuretic doses and delaying further increases in beta-blocker doses, though downward adjustments or discontinuation is sometimes required. Carvedilol, because of its beta-blocking activity, may cause dizziness or hypotension. This can usually be managed by reducing the doses of other vasodilators and by slowing the pace of dose increases.

  1. Digitalis glycosides—The efficacy of digitalis glycosides in reducing the symptoms of heart failure has been established in at least four multicenter trials that have demonstrated that digoxin withdrawal is associated with worsening symptoms and signs of heart failure, more frequent hospitalizations for decompensation, and reduced exercise tolerance. This was also seen in the 6800-patient Digitalis Investigators Group (DIG) trial, though that study found no benefit (or harm) with regard to survival. A reduction in deaths due to progressive heart failure was balanced by an increase in deaths due to ischemic and arrhythmic events. Based on these results, digoxin should be used for patients who remain symptomatic when taking diuretics and ACE inhibitors as well as for patients with heart failure who are in atrial fibrillation and require rate control.

Digoxin has a half-life of 24–36 hours and is eliminated almost entirely by the kidneys. The oral maintenance dose may range from 0.125 mg three times weekly to 0.5 mg daily. It is lower in patients with kidney dysfunction, in older patients, and in those with smaller lean body mass. Although an oral loading dose of 0.75–1.25 mg (depending primarily on lean body size) over 24–48 hours may be given if an early effect is desired, in most patients with chronic heart failure it is sufficient to begin with the expected maintenance dose (usually 0.125–0.25 mg daily). Amiodarone, quinidine, propafenone, and verapamil are among the drugs that may increase digoxin levels up to 100%. It is prudent to measure a blood level after 7–14 days (and at least 6 hours after the last dose was administered). Optimum serum digoxin levels are 0.7–1.2 ng/mL, though clinically evident toxicity is rare with levels < 1.8 ng/mL. Digoxin may induce ventricular arrhythmias, especially when hypokalemia or myocardial ischemia is present. Once an appropriate maintenance dose is established, subsequent levels are usually not indicated unless there is a change in kidney function or medications that affects digoxin levels or a significant deterioration in cardiac status that may be associated with reduced clearance. Digoxin toxicity is discussed in Chapter 38.

  1. Vasodilators—Although ACE inhibitors, which have vasodilating properties, improve prognosis, such a benefit is not established with the direct-acting vasodilators. The combination of hydralazine and isosorbide dinitrate has been shown to improve outcome in African Americans, but the effect is less clear than the well-established benefits of ACE inhibitors. The 2012 European guidelines give hydralazine and isosorbide dinitrate a modest class IIb recommendation for patients with reduced LVEF who are unable to tolerate ACE inhibitor and ARB therapy, or who have persistent symptoms despite treatment with a beta-blocker, ACE inhibitor, and aldosterone antagonist.

See section on Acute Myocardial Infarction earlier in this chapter for a discussion on the intravenous vasodilating drugs and their dosages.

  1. NITRATES—Intravenous vasodilators (sodium nitroprusside or nitroglycerin) are used primarily for acute or severely decompensated chronic heart failure, especially when accompanied by hypertension or myocardial ischemia. If neither of the latter is present, therapy is best initiated and adjusted based on hemodynamic measurements. The starting dosage for nitroglycerin is generally about 10 mcg/min, which is titrated upward by 10–20 mcg/min (to a maximum of 200 mcg/min) until mean arterial pressure drops by 10%. Hypotension (BP < 100 mm Hg systolic) should be avoided. For sodium nitroprusside, the starting dosage is 0.3–0.5 mcg/kg/min with upward titration to a maximum dose of 10 mcg/kg/min.

Isosorbide dinitrate, 20–80 mg orally three times daily, and nitroglycerin ointment, 12.5–50 mg (1–4 inches) every 6–8 hours, appears to be equally effective although the ointment is somewhat inconvenient for long-term therapy. The nitrates are moderately effective in relieving shortness of breath, especially in patients with mild to moderate symptoms, but less successful—probably because they have little effect on cardiac output—in advanced heart failure. Nitrate therapy is generally well tolerated, but headaches and hypotension may limit the dose of all agents. The development of tolerance to long-term nitrate therapy occurs. This is minimized by intermittent therapy, especially if a daily 8- to 12-hour nitrate-free interval is used, but probably develops to some extent in most patients receiving these agents. Transdermal nitroglycerin patches have no sustained effect in patients with heart failure and should not be used for this indication.

  1. HYDRALAZINE—Oral hydralazine is a potent arteriolar dilator; when used as a single agent, it has not been shown to improve symptoms or exercise tolerance during long-term treatment. The combination of nitrates and oral hydralazine produces greater hemodynamic effects.

Hydralazine therapy is frequently limited by side effects. Approximately 30% of patients are unable to tolerate the relatively high doses required to produce hemodynamic improvement in heart failure (200–400 mg daily in divided doses). The major side effect is gastrointestinal distress, but headaches, tachycardia, and hypotension are relatively common. ARBs have largely supplanted the use of the hydralazine–isosorbide dinitrate combination in ACE-intolerant patients.

  1. Ivabradine—Ivabradine inhibits the If channel in the sinus node and has the specific effect of slowing sinus rate. The SHIFT trial enrolled 6588 patients with symptomatic heart failure, LVEF ≤ 35%, and sinus rhythm with rate ≥ 70 beats per minute. Most patients were receiving an ACE inhibitor, a beta-blocker, and an aldosterone antagonist, although a minority were on full-dose beta-blocker. Cardiovascular death and hospitalizaiton for heart failure were reduced by 18%, with an absolute reduction of 4.2% over 23 months, mainly driven by less heart failure hospitalization. Ivabradine is not approved for use in the United States; it is approved by the European Medicines Agency for use in patients with a heart rate ≥ 75 beats per minute. The European guidelines give it a class IIa recommendation for patients in sinus rhythm with heart rate ≥ 70 beats per minute with an EF ≤ 35%, and persisting symptoms despite treatment with an evidence-based dose of beta-blocker (or maximum tolerated dose below that), ACE inhibitor (or ARB), and an aldosterone antagonist (or ARB).
  2. Combination of medical therapies—Optimal management of chronic heart failure involves using combinations of proven life-saving therapies. In addition to ACE inhibitors and beta-blockers, patients who remain symptomatic should be considered for additional therapy, in the form of ARBs (best proven in class II–III heart failure), mineralocorticoid (aldosterone) receptor antagonists, or hydralazine and isosorbide dinitrate (with some evidence of benefit in African Americans).
  3. Treatments that may cause harm in heart failure with reduced LVEF—Several therapies should be avoided, when possible, in patients with systolic heart failure, and therefore are listed as class III recommendations in the European guidelines. These include thiazoladinediones (glitazones) that cause worsening heart failure, most calcium channel blockers (with the exception of amlodipine and felodipine), nonsteroidal anti-inflammatory drugs, and cyclooxygenase-2 inhibitors that cause sodium and water retention and renal impairment, and the combination of an ACE inhibitor, ARB, and aldosterone blocker that increases the risk of hyperkalemia.
  4. Anticoagulation—Patients with LV failure and reduced EF are at somewhat increased risk for developing intracardiac thrombi and systemic arterial emboli. However, this risk appears to be primarily in patients who are in atrial fibrillation, who have had thromboemboli, or who have large recent anterior myocardial infarction. In general, these patients should receive warfarin for 3 months following the myocardial infarction. Other patients with heart failure have embolic rates of approximately two per 100 patient-years of follow-up, which approximates the rate of major bleeding, and routine anticoagulation does not appear warranted except in patients with prior embolic events or mobile LV thrombi.
  5. Antiarrhythmic therapy—Patients with moderate to severe heart failure have a high incidence of both symptomatic and asymptomatic arrhythmias. Although < 10% of patients have syncope or presyncope resulting from ventricular tachycardia, ambulatory monitoring reveals that up to 70% of patients have asymptomatic episodes of NSVT. These arrhythmias indicate a poor prognosis independent of the severity of LV dysfunction, but many of the deaths are probably not arrhythmia related. Beta-blockers, because of their marked favorable effect on prognosis in general and on the incidence of sudden death specifically, should be initiated in these as well as all other patients with heart failure (see Beta-Blockers, above). Empiric antiarrhythmic therapy with amiodarone did not improve outcome in the SCD-HeFT trial, and most other agents are contraindicated because of their proarrhythmic effects in this population and their adverse effect on cardiac function. For patients with systolic heart failure and atrial fibrillation, a rhythm control strategy has not been shown to improve outcome compared to a rate control strategy and thus should be reserved for patients with a reversible cause of atrial fibrillation or refractory symptoms. Then, amiodarone is the drug of choice.
  6. Statin therapy—Even though vascular disease is present in many patients with chronic heart failure, the role of statins has not been well defined in the heart failure population. Two trials—the CORONA and the GISSI-HF trials—have failed to show benefits of statins in the chronic heart failure population.
  7. Nonpharmacologic Treatment
  8. Implantable cardioverter defibrillators—Randomized clinical trials have extended the indications for ICDs beyond patients with symptomatic or asymptomatic arrhythmias to the broad population of patients with chronic heart failure and LV systolic dysfunction who are receiving contemporary heart failure treatments, including beta-blockers. In the second Multicenter Automatic Defibrillator Implantation Trial (MADIT II), 1232 patients with prior myocardial infarction and an EF < 30% were randomized to an ICD or a control group. Mortality was 31% lower in the ICD group, which translated into nine lives saved for each 100 patients who received a device and were monitored for 3 years. The United States Centers for Medicare and Medicaid Services providesreimbursement coverage to include patients with chronic heart failure and ischemic or nonischemic cardiomyopathy with an EF ≤ 35%.
  9. Biventricular pacing (resynchronization)—Many patients with heart failure due to systolic dysfunction have abnormal intraventricular conduction that results in dyssynchronous and hence inefficient contractions. Several studies have evaluated the efficacy of “multisite” pacing, using leads that stimulate the RV from the apex and the LV from the lateral wall via the coronary sinus. Patients with wide QRS complexes (generally ≥ 120 milliseconds), reduced EFs, and moderate to severe symptoms have been evaluated. Results from trials with up to 2 years of follow-up have shown an increase in EF, improvement in symptoms and exercise tolerance, and reduction in death and hospitalization. The best responders to cardiac resynchronization therapy are patients with wider QRS, left bundle branch block, and nonischemic cardiomyopathy, and the lowest responders are those with narrow QRS and non–left bundle branch block pattern. Thus, as recommended in the 2013 European guidelines, resynchronization therapy is indicated for patients with class II, III, and ambulatory class IV heart failure, EF ≤ 35%, and left bundle branch blockpattern with QRS duration of ≥ 120 msec. Patients with non–left bundle branch block pattern and prolonged QRS duration may be considered for treatment.
  10. Case management, diet, and exercise training—Thirty to 50 percent of heart failure patients who are hospitalized will be readmitted within 3–6 months. Strategies to prevent clinical deterioration, such as case management, home monitoring of weight and clinical status, and patient adjustment of diuretics, can prevent rehospitalizations and should be part of the treatment regimen of advanced heart failure. Involvement of a multidisciplinary team (rather than a single physician) and in-person (rather than telephonic) communication appear to be important features of successful programs.

Patients should routinely practice moderate salt restriction (2–2.5 g sodium or 5–6 g salt per day). More severe sodium restriction is usually difficult to achieve and unnecessary because of the availability of potent diuretic agents.

Exercise training improves activity tolerance in significant part by reversing the peripheral abnormalities associated with heart failure and deconditioning. In severe heart failure, restriction of activity may facilitate temporary recompensation. A large trial (HF ACTION, 2331 patients) showed no significant benefit (nor harm) from a structured exercise training program on death or hospitalization, although functional status and symptoms were improved. Thus, in stable patients, a prudent increase in activity or a regular exercise regimen can be encouraged. Indeed, a gradual exercise program is associated with diminished symptoms and substantial increases in exercise capacity.

  1. Coronary revascularization—Since underlying CAD is the cause of heart failure in the majority of patients, coronary revascularization has been thought to be able to both improve symptoms and prevent progression. However, the STITCH trial failed to show an overall survival benefit from CABG among patients with multivessel coronary disease who were candidates for CABG but who had heart failure and a LVEF of ≤ 35%. Revascularization does appear warranted for some patients with heart failure, including those with more severe angina or left main coronary disease (excluded from the STITCH trial), or selected patients with less severe symptoms.
  2. Cardiac transplantation—Because of the poor prognosis of patients with advanced heart failure, cardiac transplantation is widely used. Many centers have 1-year survival rates exceeding 80–90%, and 5-year survival rates above 70%. Infections, hypertension and kidney dysfunction caused by cyclosporine, rapidly progressive coronary atherosclerosis, and immunosuppressant-related cancers have been the major complications. The high cost and limited number of donor organs require careful patient selection early in the course.
  3. Other surgical treatment options—Externally powered and implantable ventricular assist devices can be used in patients who require ventricular support either to allow the heart to recover or as a bridge to transplantation. The latest generation devices are small enough to allow patients unrestricted mobility and even discharge from the hospital. Continuous flow devices appear to be more effective than pulsatile flow devices. However, complications are frequent, including bleeding, thromboembolism, and infection, and the cost is very high, exceeding $200,000 in the initial 1–3 months.

Although 1-year survival was improved in the REMATCH randomized trial, all 129 patients died by 26 months.

  1. Palliative care—Despite the technologic advances of recent years, it should be remembered that many patients with chronic heart failure are elderly and have multiple comorbidities. Many of them will not experience meaningful improvements in survival with aggressive therapy, and the goal of management should be symptomatic improvement and palliation (seeChapter 5).

 Prognosis

Once manifest, heart failure carries a poor prognosis. Even with modern treatment, the 5-year mortality is approximately 50%. Mortality rates vary from < 5% per year in those with no or few symptoms to > 30% per year in those with severe and refractory symptoms. These figures emphasize the critical importance of early detection and intervention. Higher mortality is related to older age, lower LVEF, more severe symptoms, chronic kidney disease, and diabetes. The prognosis of heart failure has improved in the past two decades, probably at least in part because of the more widespread use of ACE inhibitors and beta-blockers, which markedly improve survival.

 When to Refer

Patients with new symptoms of heart failure not explained by an obvious cause should be referred to a cardiologist. Patients with continued symptoms of heart failure and reduced LVEF (≤ 35%) should be referred to a cardiologist for consideration of placement of an ICD or cardiac resynchronization therapy (if QRS duration is ≥ 120 msec especially with left bundle branch block pattern).

 When to Admit

  • Patients with unexplained new or worsened symptoms, or positive cardiac biomarkers concerning for acute myocardial necrosis.
  • Patients with hypoxia, fluid overload, or pulmonary edema not readily resolved in outpatient setting.

Brignole M et al. 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Eur Heart J. 2013 Aug;34(29):2281–329. [PMID: 23801822]

Davies EJ et al. Exercise based rehabilitation for heart failure. Cochrane Database Syst Rev. 2010 Apr 14;4: CD003331. [PMID: 20393935]

Ezekowitz JA et al. Standardizing care for acute decompensated heart failure in a large megatrial: the approach for the Acute Studies of Clinical Effectiveness of Nesiritide in Subjects with Decompensated Heart Failure (ASCEND-HF). Am Heart J. 2009 Feb;157(2):219–28. [PMID: 19185628]

Hunt SA et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation. 2009 Apr 14;119(14):e391–479. [PMID: 19324966]

McMurray JJ et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Eur J Heart Fail. 2012 Aug;14(8):803–69. [PMID: 22828712]

Moss AJ et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med. 2009 Oct 1;361(14): 1329–38. [PMID: 19723701]

Shah AM et al; TOPCAT Investigators. Cardiac structure and function in heart failure with preserved ejection fraction: baseline findings from the echocardiographic study of the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial. Circ Heart Fail. 2014 Jan 1;7(1): 104–15. [PMID: 24249049]

Swedberg K et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010 Sep 11;376(9744):875–85. [PMID: 20801500]

Tang AS et al; Resynchronization-Defibrillation for Ambulatory Heart Failure Trial Investigators. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med. 2010 Dec 16;363(25):2385–95. [PMID: 21073365]

Torpy JM et al. JAMA patient page. Heart failure. JAMA. 2009 May 13;301(18):1950. [PMID: 19436025]

Velazquez EJ et al; STICH Investigators. Coronary-artery bypass surgery in patients with left ventricular dysfunction. N Engl J Med. 2011 Apr 28;364(17):1607–16. [PMID: 21463150]

Zannad F et al; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011 Jan 6;364(1):11–21. [PMID: 21073363]

ACUTE HEART FAILURE & PULMONARY EDEMA

 ESSENTIALS OF DIAGNOSIS

 Acute onset or worsening of dyspnea at rest.

 Tachycardia, diaphoresis, cyanosis.

 Pulmonary rales, rhonchi; expiratory wheezing.

 Radiograph shows interstitial and alveolar edema with or without cardiomegaly.

 Arterial hypoxemia.

 General Considerations

Typical causes of acute cardiogenic pulmonary edema include acute myocardial infarction or severe ischemia, exacerbation of chronic heart failure, acute severe hypertension, acute kidney injury, acute volume overload of the LV (valvular regurgitation), and mitral stenosis. By far the most common presentation in developed countries is one of acute or subacute deterioration of chronic heart failure, precipitated by discontinuation of medications, excessive salt intake, myocardial ischemia, tachyarrhythmias (especially rapid atrial fibrillation), or intercurrent infection. Often in the latter group, there is preceding volume overload with worsening edema and progressive shortness of breath for which earlier intervention can usually avoid the need for hospital admission.

 Clinical Findings

Acute pulmonary edema presents with a characteristic clinical picture of severe dyspnea, the production of pink, frothy sputum, and diaphoresis and cyanosis. Rales are present in all lung fields, as are generalized wheezing and rhonchi. Pulmonary edema may appear acutely or sub-acutely in the setting of chronic heart failure or may be the first manifestation of cardiac disease, usually acute myocardial infarction, which may be painful or silent. Less severe decompensations usually present with dyspnea at rest and rales and other evidence of fluid retention but without severe hypoxia.

Noncardiac causes of pulmonary edema include intravenous opioids, increased intracerebral pressure, high altitude, sepsis, several medications, inhaled toxins, transfusion reactions, shock, and disseminated intravascular coagulation. These are distinguished from cardiogenic pulmonary edema by the clinical setting, the history, and the physical examination. Conversely, in most patients with cardiogenic pulmonary edema, an underlying cardiac abnormality can usually be detected clinically or by the ECG, chest radiograph, or echocardiogram.

The chest radiograph reveals signs of pulmonary vascular redistribution, blurriness of vascular outlines, increased interstitial markings, and, characteristically, the butterfly pattern of distribution of alveolar edema. The heart may be enlarged or normal in size depending on whether heart failure was previously present. Assessment of cardiac function by echocardiography is important, since a substantial proportion of patients has normal EFs with elevated atrial pressures due to diastolic dysfunction. In cardiogenic pulmonary edema, BNP is elevated, and the PCWP is invariably elevated, usually over 25 mm Hg. In noncardiogenic pulmonary edema, the wedge pressure may be normal or even low.

 Treatment

In full-blown pulmonary edema, the patient should be placed in a sitting position with legs dangling over the side of the bed; this facilitates respiration and reduces venous return. Oxygen is delivered by mask to obtain an arterial Po2 > 60 mm Hg. Noninvasive pressure support ventilation may improve oxygenation and prevent severe CO2 retention while pharmacologic interventions take effect. However, if respiratory distress remains severe, endotracheal intubation and mechanical ventilation may be necessary.

Morphine is highly effective in pulmonary edema and may be helpful in less severe decompensations when the patient is uncomfortable. The initial dosage is 2–8 mg intravenously (subcutaneous administration is effective in milder cases) and may be repeated after 2–4 hours. Morphine increases venous capacitance, lowering LA pressure, and relieves anxiety, which can reduce the efficiency of ventilation. However, morphine may lead to CO2 retention by reducing the ventilatory drive. It should be avoided in patients with opioid-induced pulmonary edema, who may improve with opioid-antagonists, and in those with neurogenic pulmonary edema.

Intravenous diuretic therapy (furosemide, 40 mg, or bumetanide, 1 mg—or higher doses if the patient has been receiving long-term diuretic therapy) is usually indicated even if the patient has not exhibited prior fluid retention. These agents produce venodilation prior to the onset of diuresis. The DOSE trial has shown that, for acute decompensated heart failure, bolus doses of furosemide are of similar efficacy as continuous intravenous infusion, and that higher dose furosemide (2.5 times the prior daily dose) resulted in more rapid fluid removal without a substantially higher risk of kidney impairment.

Nitrate the rapy accelerates clinical improvement by reducing both BP and LV filling pressures. Sublingual nitroglycerin or isosorbide dinitrate, topical nitroglycerin, or intravenous nitrates will ameliorate dyspnea rapidly prior to the onset of diuresis, and these agents are particularly valuable in patients with accompanying hypertension.

Intravenous nesiritide, a recombinant form of human BNP, is a potent vasodilator that reduces ventricular filling pressures and improves cardiac output. Its hemodynamic effects resemble those of intravenous nitroglycerin with a more predictable dose–response curve and a longer duration of action. In clinical studies, nesiritide (administered as 2 mcg/kg by intravenous bolus injection followed by an infusion of 0.01 mcg/kg/min, which may be up-titrated if needed) produced a rapid improvement in both dyspnea and hemodynamics. The primary adverse effect is hypotension, which may be symptomatic and sustained. The ASCEND trial randomized nearly 7000 patients with acute decompensated heart failure to receive either nesiritide or placebo; results showed a reduction in dyspnea, worsening in kidney function, and no effect on death or heart failure rehospitalization. Because most patients with acute heart failure respond well to conventional therapy, the role of nesiritide may be primarily in patients who continue to be symptomatic after initial treatment with diuretics and nitrates.

A randomized placebo-controlled trial of 950 patients evaluating intravenous milrinone in patients admitted for decompensated heart failure who had no definite indications for inotropic therapy showed no benefit in increasing survival, decreasing length of admission, or preventing readmission. In addition, rates of sustained hypotension and atrial fibrillation were significantly increased. Thus, the role of positive inotropic agents appears to be limited in patients with refractory symptoms and signs of low cardiac output, particularly if life-threatening vital organ hypoperfusion (such as deteriorating kidney function) is present. In some cases, dobutamine or milrinone may help maintain patients who are awaiting cardiac transplantation.

Bronchospasm may occur in response to pulmonary edema and may itself exacerbate hypoxemia and dyspnea. Treatment with inhaled beta-adrenergic agonists or intravenous aminophylline may be helpful, but both may also provoke tachycardia and supraventricular arrhythmias.

In most cases, pulmonary edema responds rapidly to therapy. When the patient has improved, the cause or precipitating factor should be ascertained. In patients without prior heart failure, evaluation should include echocardiography and in many cases cardiac catheterization and coronary angiography. Patients with acute decompensation of chronic heart failure should be treated to achieve a euvolemic state and have their medical regimen optimized. Generally, an oral diuretic and an ACE inhibitor should be initiated, with efficacy and tolerability confirmed prior to discharge. In selected patients, early but careful initiation of beta-blockers in low doses should be considered.

Felker GM et al; NHLBI Heart Failure Clinical Research Network. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011 Mar 3;364(9):797–805. [PMID: 21366472]

Gray AJ et al; 3CPO Study Investigators. A multicentre randomised controlled trial of the use of continuous positive airway pressure and non-invasive positive pressure ventilation in the early treatment of patients presenting to the emergency department with severe acute cardiogenic pulmonary oedema: the 3CPO trial. Health Technol Assess. 2009 Jul;13(33): 1–106. [PMID: 19615296]

Weng CL et al. Meta-analysis: noninvasive ventilation in acute cardiogenic pulmonary edema. Ann Intern Med. 2010 May 4;152(9):590–600. [PMID: 20439577]

West RL et al. A review of dyspnea in acute heart failure syndromes. Am Heart J. 2010 Aug;160(2):209–14. [PMID: 20691823]

MYOCARDITIS & THE CARDIOMYOPATHIES

INFECTIOUS MYOCARDITIS

 ESSENTIALS OF DIAGNOSIS

 Often follows an upper respiratory infection.

 May present with chest pain (pleuritic or nonspecific) or signs of heart failure.

 Echocardiogram documents cardiomegaly and contractile dysfunction.

 Myocardial biopsy, though not sensitive, may reveal a characteristic inflammatory pattern. MRI may now have a role in diagnosis.

 General Considerations

Cardiac dysfunction due to primary myocarditis is presumed generally to be caused by either an acute viral infection or a postviral immune response. Secondary myocarditis is the result of inflammation caused by nonviral pathogens, drugs, chemicals, physical agents, or inflammatory diseases such as systemic lupus erythematosus. The list of both infectious and noninfectious causes of myocarditis is extensive (Table 10–16).

Table 10–16. Causes of myocarditis.

Early phase myocarditis is initiated by infection of cardiac tissue. Both cellular and humoral inflammatory processes contribute to the progression to chronic injury, and there are subgroups that might benefit from immunosuppression.

Genetic predisposition is a likely factor in some cases. Autoimmune myocarditis (eg, giant cell myocarditis) may occur with no identifiable viral infection.

 Clinical Findings

  1. Symptoms and Signs

Patients may present several days to a few weeks after the onset of an acute febrile illness or a respiratory infection or with heart failure without antecedent symptoms. The onset of heart failure may be gradual or may be abrupt and fulminant. Emboli may occur. Pleural-pericardial chest pain is common. Examination reveals tachycardia, a gallop rhythm, and other evidence of heart failure or conduction defect. Many acute infections are subclinical, though they may present later as idiopathic cardiomyopathy or with ventricular arrhythmias. At times, the presentation may mimic an acute myocardial infarction with ST changes, positive cardiac markers, and regional wall motion abnormalities despite normal coronaries. Microaneurysms may also occur and may be associated with serious ventricular arrhythmias. Patients may present in a variety of ways with fulminant, subacute, or chronic myocarditis. In the European Study of Epidemiology and Treatment of Inflammatory Heart Disease, 72% had dyspnea, 32% had chest pain, and 18% had arrhythmias.

  1. ECG and Chest Radiography

ECG may show sinus tachycardia, other arrhythmias, nonspecific repolarization changes, and intraventricular conduction abnormalities. The presence of Q waves or left bundle branch block portends a higher rate of death or cardiac transplantation. Ventricular ectopy may be the initial and only clinical finding. Chest radiograph is nonspecific, but cardiomegaly is frequent, though not universal. Evidence for pulmonary venous hypertension is common and frank pulmonary edema may be present.

  1. Diagnostic Studies

There is no specific laboratory study that is consistently present, though the white blood cell count is usually elevated and the sedimentation rate and CRP may be increased. Troponin I levels are elevated in about one-third of patients, but CK-MB is elevated in only 10%. Echocardiography provides the most convenient way of evaluating cardiac function and can exclude many other processes. MRI with gadolinium enhancement reveals spotty areas of injury throughout the myocardium, but both T2 and T1-weighted images are needed to achieve optimal results; correlation with endomyocardial biopsy results has been poor.

  1. Endomyocardial Biopsy

Confirmation of myocarditis still requires histologic evidence. An AHA/ACCF/ESC joint statement in 2007 made a class 1 recommendation for biopsy under the following situations: (1) in patients with heart failure, a normal-sized or dilated LV < 2 weeks after onset of symptoms, and hemodynamic compromise; or (2) in patients with a dilated LV 2 weeks to 3 months after onset of symptoms, new ventricular arrhythmias or AV nodal block (Mobitz II or complete heart block) or who do not respond to usual care after 1–2 weeks. In some cases, the identification of inflammation without viral genomes by PCR suggests that immunosuppression might be useful.

 Treatment & Prognosis

Patients with fulminant myocarditis may present with acute cardiogenic shock. The ventricles are usually not dilated, but thickened (possibly due to myoedema). There is a high death rate, but if the patients recover, they are often left with no residual cardiomyopathy. Patients with subacute disease have a dilated cardiomyopathy and generally make an incomplete recovery. Those who present with chronic disease tend to have only mild dilation of the LV and eventually present with a more restrictive cardiomyopathy. Treatment is directed toward the clinical scenario with ACE inhibitors and beta-blockers if LVEF is < 40%. Nonsteroidal anti-inflammatory drugs should be used if myopericarditis-related chest pain occurs. Colchicine has been suggested if pericarditis predominates. Arrhythmias should be suppressed.

Specific antimicrobial therapy is indicated when an infecting agent is identified. Exercise should be limited during the recovery phase. Some experts believe digoxin should be avoided, and it likely has little value in this setting. Immunosuppressive therapy with corticosteroids and intravenous immunoglobulin (IVIG) has been used in the hopes of improving the outcome when the process is acute (< 6 months) and if the biopsy suggests ongoing inflammation. However, controlled trials have not suggested a benefit. Uncontrolled trials suggest that interferon might have a role. Studies are lacking as to when to discontinue the chosen therapy if the patient improves. Patients with fulminant myocarditis require aggressive short-term support including an IABP or an LV assist device. If severe pulmonary infiltrates accompany the fulminant myocarditis, extracorporeal membrane oxygenation (ECMO) support may be temporarily required and has had notable success. Ongoing studies are addressing whether patients with giant cell myocarditis may be responsive to immunosuppressive agents, as a special case. Overall, if improvement does not occur, many patients may be eventual candidates for cardiac transplantation or long-term use of the newer LV assist devices.

 When to Refer

Patients in whom myocarditis is suspected should be seen by a cardiologist at a tertiary care center where facilities are available for diagnosis and therapies available should a fulminant course ensue. The facility should have ventricular support devices and transplantation options available.

Cooper LT et al. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. J Am Coll Cardiol. 2007 Nov 6;50(19):1914–31. [PMID: 17980265]

Schultheiss HP et al. The management of myocarditis. Eur Heart J. 2011 Nov;32(21):2616–25. [PMID: 21705357]

DRUG-INDUCED & TOXIC MYOCARDITIS

A variety of medications, illicit drugs, and toxic substances can produce acute or chronic myocardial injury; the clinical presentation varies widely. The phenothiazines, lithium, chloroquine, disopyramide, antimony-containing compounds, and arsenicals can also cause ECG changes, arrhythmias, or heart failure. Hypersensitivity reactions to sulfonamides, penicillins, and aminosalicylic acid as well as other drugs can result in cardiac dysfunction. Radiation can cause an acute inflammatory reaction as well as a chronic fibrosis of heart muscle, usually in conjunction with pericarditis.

The incidence of cocaine cardiotoxicity has increased markedly. Cocaine can result in coronary artery spasm, myocardial infarction, arrhythmias, and myocarditis. Because many of these processes are believed to be mediated by cocaine’s inhibitory effect on norepinephrine reuptake by sympathetic nerves, beta-blockers have been used in patients with fixed stenosis. In documented coronary spasm, calcium channel blockers and nitrates may be effective. Usual therapy for heart failure or conduction system disease is warranted when symptoms occur. Other illicit drug use has been associated with myocarditis in various case reports.

The problem of cardiovascular side effects from cancer chemotherapy agents is a growing one. Anthracyclines remain the cornerstone of treatment of many malignancies. Heart failure can be expected in 5% of patients treated with a cumulative dose of 400–450 mg/m2, and this rate is doubled if the patient is over age 65. The major mechanism of cardiotoxicity is thought to be due to oxidative stress inducing both apoptosis and necrosis of myocytes. There is also disruption of the sarcomere. This is the rationale behind the superoxide dismutase mimetic and iron-chelating agent, dexrazoxane, to protect from the injury. The use of trastuzumab in combination with anthracyclines increases the risk of cardiac dysfunction to up to 28%; this has been an issue since combined use of these agents is particularly effective in HER2-positive breast cancer.

In patients receiving chemotherapy, it is important to look for subtle signs of cardiovascular compromise. Echocardiography, cardiac MRI, and serial multigated acquisition (MUGA) studies can provide concrete data regarding LV function. Serum troponin and BNP levels as markers of cardiac injury, and the neutrophil glucosamine-associated lipocalcin as a marker of renal injury, are often elevated in patients with significant cardiotoxicity.

 When to Refer

Many patients with myocardial injury from toxic agents can be monitored safely if ventricular function remains relatively preserved (EF > 40%) and no heart failure symptoms occur. Diastolic dysfunction may be subtle.

Once heart failure becomes evident or significant conduction system disease becomes manifest, the patient should be evaluated and monitored by a cardiologist in case myocardial dysfunction worsens and further intervention becomes warranted.

Eschenhagen T et al. Cardiovascular side effects of cancer therapies: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2011 Jan;13(1):1–10. [PMID: 21169385]

Riezzo I et al. Side effects of cocaine abuse: multiorgan toxicity and pathological consequences. Curr Med Chem. 2012;19 (33):5624–46. [PMID: 22934772]

DILATED CARDIOMYOPATHY

 ESSENTIALS OF DIAGNOSIS

 Symptoms and signs of heart failure.

 Echocardiogram confirms LV dilation, thinning, and global dysfunction.

 Severity of RV dysfunction critical in long-term prognosis.

 General Considerations

The cardiomyopathies are a heterogeneous group of entities primarily affecting the myocardium and not associated with other major causes of cardiac disease, such as ischemic heart disease, hypertension, pericardial disease, valvular disease, or congenital defects. Although some have specific causes, many cases are idiopathic. The classification of cardiomyopathies is based on features of presentation and pathophysiology (Table 10–17).

Table 10–17. Classification of the cardiomyopathies.

Dilated cardiomyopathies cause about 25% of all cases of heart failure. They usually present with symptoms and signs of heart failure (most commonly dyspnea). Occasionally, symptomatic ventricular arrhythmias are the presenting event. LV dilation and systolic dysfunction (EF < 50%) are essential for diagnosis. Dilated cardiomyopathy occurs more often in blacks than whites and in men more than women. A growing number of cardiomyopathies due to genetic abnormalities are being recognized, and it is estimated these may represent up to 30–48% of cases. Often no cause can be identified, but chronic alcohol abuse and unrecognized myocarditis are probably frequent causes. Chronic tachycardia may also precipitate a dilated cardiomyopathy that may improve over time if rate control can be achieved. Amyloidosis, sarcoidosis, hemochromatosis, and diabetes may rarely present as dilated cardiomyopathies, as well as the more classic restrictive picture. The RV may be primarily involved in arrhythmogenic RV dysplasia, an unusual cardiomyopathy with displacement of myocardial cells by adipose tissue, or in Uhl disease, in which there is extreme thinning of the RV walls. The function of the RV often determines how well patients do over the long term since RV dysfunction may or may not be present in patients with severe LV dysfunction. An embryologic defect can result in massive trabeculation in the LV (ventricular noncompaction). Intraventricular thrombus is not uncommon in dilated cardiomyopathy.

 Clinical Findings

  1. Symptoms and Signs

In most patients, symptoms of heart failure develop gradually. The physical examination reveals rales, an elevated JVP, cardiomegaly, S3 gallop rhythm, often the murmurs of functional mitral or tricuspid regurgitation, peripheral edema, or ascites. In severe heart failure, Cheyne-Stokes breathing, pulsus alternans, pallor, and cyanosis may be present.

  1. ECG and Chest Radiography

The major findings are listed in Table 10–17. Sinus tachycardia is common. Other common abnormalities include left bundle branch block and ventricular or atrial arrhythmias. The chest radiograph reveals cardiomegaly, evidence for left and/or right heart failure, and pleural effusions (right > left).

  1. Diagnostic Studies

An echocardiogram is indicated to exclude unsuspected valvular or other lesions and confirm the presence of dilated cardiomyopathy and the reduced systolic function (as opposed to pure diastolic heart failure). Mitral Doppler inflow patterns also help in the diagnosis of associated diastolic dysfunction. Color flow Doppler can reveal tricuspid or mitral regurgitation, and continuous Doppler can help define PA pressures. Exercise or pharmacologic stress myocardial perfusion imaging may suggest the possibility of underlying coronary disease. Radionuclide ventriculography provides a noninvasive measure of the EF and both RV and LV wall motion, though its use is now being supplanted by cardiac MRI in many institutions. Cardiac MRI is particularly helpful in inflammatory or infiltrative processes, such as sarcoidosis or hemochromatosis, and is the diagnostic study of choice for RV dysplasia where there is fatty infiltration. MRI can also help define an ischemic etiology by noting gadolinium hyperenhancement consistent with myocardial scar. Cardiac catheterization is seldom of specific value unless myocardial ischemia or LV aneurysm is suspected. The serum ferritin is an adequate screening study for hemochromatosis. The erythrocyte sedimentation rate may be low due to liver congestion if right heart failure is present. The serum level of BNP or pro-BNP can be used to help quantitate the severity of heart failure. Intracavitary thrombosis is not uncommon. Myocardial biopsy is rarely useful in establishing the diagnosis, though occasionally the underlying cause (eg, sarcoidosis, hemochromatosis) can be discerned. Biopsy is most useful in transplant rejection.

 Treatment

Standard therapy for heart failure should include ACE inhibitors or ARBs, beta-blockers, diuretics, and an aldosterone antagonist. Systemic BP control is important. Digoxin is a second-line drug but remains favored as an adjunct by some clinicians. Calcium channel blockers should generally be avoided unless absolutely necessary for rate control in atrial fibrillation. Sodium restriction is helpful, especially in acute heart failure. When atrial fibrillation is present, heart rate control is vital if sinus rhythm cannot be established or maintained. There are little data to suggest an advantage of sinus rhythm over atrial fibrillation on long-term outcomes. Many patients may be candidates for cardiac synchronization therapy with biventricular pacing and an implantable defibrillator. Few cases of cardiomyopathy are amenable to specific therapy for the underlying cause. Alcohol use should be discontinued, since there is often marked recovery of cardiac function following a period of abstinence in alcoholic cardiomyopathy. Endocrine causes (hyperthyroidism or hypothyroidism, acromegaly, and pheochromocytoma) should be treated. Immunosuppressive therapy is not indicated in chronic dilated cardiomyopathy. The management of heart failure is outlined in the section on heart failure. There are some patients who may benefit from implantable LV assist devices either as a bridge to transplantation or to temporize while cardiac function returns. LV assist devices are also being considered as destination therapy in patients who are not candidates for cardiac transplantation. Arterial and pulmonary emboli are more common in dilated cardiomyopathy than in ischemic cardiomyopathy. Suitable candidates may benefit from long-term anticoagulation, and all patients with atrial fibrillation should be so treated. Some clinicians use warfarin to prevent or treat an LV thrombus when discovered on an echocardiogram.

 Prognosis

The prognosis of dilated cardiomyopathy without clinical heart failure is variable, with some patients remaining stable, some deteriorating gradually, and others declining rapidly. Once heart failure is manifest, the natural history is similar to that of other causes of heart failure, with an annual mortality around 11–13%.

 When to Refer

Patients with new or worsened symptoms of heart failure with dilated cardiomyopathy should be referred to a cardiologist. Patients with continued symptoms of heart failure and reduced LVEF (≤ 35%) should be referred to a cardiologist for consideration of placement of an ICD or cardiac resynchronization therapy (if QRS duration is ≥ 120 msec especially with left bundle branch block pattern). Patients with advanced refractory symptoms should be referred for consideration of heart transplant or LV assist device therapy.

 When to Admit

Patients with hypoxia, fluid overload, or pulmonary edema not readily resolved in outpatient setting should be admitted.

Anderson L et al. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Eur Heart J. 2008 Dec;29(13):1696–97. [PMID: 18456711]

Jefferies JL et al. Dilated cardiomyopathy. Lancet. 2010 Feb 27;375(9716):752–62. [PMID: 20189027]

McNally EM et al. Genetic mutations and mechanisms in dilated cardiomyopathy. J Clin Invest. 2013 Jan 2;123(1): 19–26. [PMID: 23281406]

TAKO-TSUBO CARDIOMYOPATHY

 ESSENTIALS OF DIAGNOSIS

 Occurs after a major catecholamine discharge.

 Acute chest pain or shortness of breath.

 Predominately affects postmenopausal women.

 Presents as an acute anterior myocardial infarction, but coronaries normal at cardiac catheterization.

 Imaging reveals apical left ventricular ballooning due to anteroapical stunning of the myocardium.

 Most patients recover completely.

 General Considerations

LV apical ballooning (Tako-Tsubo syndrome) follows a high catecholamine surge. The resulting shape of the LV suggests a rounded ampulla form similar to a Japanese octopus pot (tako-tsubo pot). Mid-ventricular ballooning has also been described. The key feature is that the myocardial stunning that occurs does not follow the pattern suggestive of coronary ischemia. The acute myocardial injury is more common in postmenopausal women. It has been described following some stressful event, such as hypoglycemia, lightning strikes, earthquakes, postventricular tachycardia, during alcohol withdrawal, following surgery, during hyperthyroidism, after stroke, and following emotional stress (“broken-heart syndrome”). Virtually any event that triggers excess catecholamines may be implicated. Pericarditis and even tamponade has been described in isolated cases.

 Clinical Findings

  1. Symptoms and Signs

The symptoms are similar to any acute coronary syndrome. Typical angina and dyspnea are usually present. Syncope is rare, although arrhythmias are not uncommon.

  1. ECG and Chest Radiography

The ECG reveals ST-segment elevation as well as deep anterior T wave inversion. The chest radiograph is either normal or reveals pulmonary congestion. The dramatic T wave inversions gradually resolve over time.

  1. Diagnostic Studies

The echocardiogram reveals LV apical dyskinesia usually not consistent with any particular coronary distribution. The urgent cardiac catheterization reveals the LV apical ballooning in association with normal coronaries. Initial cardiac enzymes are positive but often taper quickly. In almost all cases, MRI hyperenhancement studies reveal no long-term scarring.

 Treatment

Immediate therapy is similar to any acute myocardial infarction. Initiation of long-term therapy depends on whether LV dysfunction persists. Most patients receive aspirin, beta-blockers, and ACE inhibitors until the LV fully recovers. See Treatment of Heart Failure, above.

 Prognosis

Prognosis is good unless there is a serious complication (such as mitral regurgitation, ventricular rupture, ventricular tachycardia). Recovery is expected in most cases after a period of weeks to months. At times, the LV function recovers in days. Rarely, repeat episodes have been reported.

Eitel I et al. Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy. JAMA. 2011 Jul 20;306(3):277–86. [PMID: 21771988]

Milinis K et al. Takotsubo cardiomyopathy: pathophysiology and treatment. Postgrad Med J. 2012 Sep;88(1043):530–8. [PMID: 22647668]

HYPERTROPHIC CARDIOMYOPATHY

 ESSENTIALS OF DIAGNOSIS

 May present with dyspnea, chest pain, syncope.

 Though LV outflow gradient is classic, symptoms are primarily related to diastolic dysfunction.

 Echocardiogram is diagnostic.

 Increased risk of sudden death.

 General Considerations

Hypertrophic cardiomyopathy is noted when there is LV hypertrophy unrelated to any pressure or volume overload. The increased wall thickness reduces LV systolic stress, increases the EF, and can result in an “empty ventricle” at end-systole. The interventricular septum may be disproportionately involved (asymmetric septal hypertrophy), but in some cases the hypertrophy is localized to the mid ventricle or to the apex. The LV outflow tract is narrowed during systole due to the hypertrophied septum and systolic anterior motion of the mitral valve. The obstruction is worsened by factors that increase myocardial contractility (sympathetic stimulation, digoxin, and postextrasystolic beat) or that decrease LV filling (Valsalva maneuver, peripheral vasodilators). The amount of obstruction is preload and afterload dependent and can vary from day to day. The consequence of the hypertrophy is elevated LV diastolic pressures rather than systolic dysfunction. Rarely, systolic dysfunction develops late in the disease. The LV is usually more involved than the RV and the atria are frequently significantly enlarged.

HOCM is inherited as an autosomal dominant trait with variable penetrance and is caused by mutations of one of a large number of genes, most of which code for myosin heavy chains or proteins regulating calcium handling. The prognosis is related to the specific gene mutation. Patients usually present in early adulthood. Elite athletes may demonstrate considerable hypertrophy that can be confused with HOCM, but generally diastolic dysfunction is not present in the athlete. The apical variety is particularly common in those of Asian descent. A mid-ventricular obstructive form is also known where there is contact between the septum and papillary muscles. A hypertrophic cardiomyopathy in the elderly (usually in association with hypertension) has also been defined as a distinct entity. Mitral annular calcification is often present. Mitral regurgitation is variable and often dynamic, depending on the degree of outflow tract obstruction.

 Clinical Findings

  1. Symptoms and Signs

The most frequent symptoms are dyspnea and chest pain (Table 10–17). Syncope is also common and is typically postexertional, when diastolic filling diminishes and outflow obstruction increases due to residual circulating catecholamines. Arrhythmias are an important problem. Atrial fibrillation is a long-term consequence of chronically elevated LA pressures and is a poor prognostic sign. Ventricular arrhythmias are also common, and sudden death may occur, often in athletes after extraordinary exertion.

Features on physical examination include a bisferiens carotid pulse, triple apical impulse (due to the prominent atrial filling wave and early and late systolic impulses), and a loud S4. The JVP may reveal a prominent a wave due to reduced RV compliance. In cases with outflow obstruction, a loud systolic murmur is present along the left sternal border that increases with upright posture or Valsalva maneuver and decreases with squatting. These maneuvers help differentiate the murmur of HOCM from that of aortic stenosis, since in HOCM, reducing the LV volume increases obstruction and the murmur intensity; whereas in valvular aortic stenosis, reducing the stroke volume across the valve decreases the murmur. Mitral regurgitation is frequently present as well.

  1. ECG and Chest Radiography

LVH is nearly universal in symptomatic patients, though entirely normal ECGs are present in up to 25%, usually in those with localized hypertrophy. Exaggerated septal Q waves inferolaterally may mimic myocardial infarction. The chest radiograph is often unimpressive. Unlike aortic stenosis, the ascending aorta is not dilated.

  1. Diagnostic Studies

The echocardiogram is diagnostic, revealing asymmetric LVH, systolic anterior motion of the mitral valve, early closing followed by reopening of the aortic valve, a small and hypercontractile LV, and delayed relaxation and filling of the LV during diastole. The septum is usually 1.3–1.5 times the thickness of the posterior wall. Septal motion tends to be reduced. Doppler ultrasound reveals turbulent flow and a dynamic gradient in the LV outflow tract and, commonly, mitral regurgitation. Abnormalities in the diastolic filling pattern are present in 80% of patients. Echocardiography can usually differentiate the disease from ventricular noncompaction. Myocardial perfusion imaging may suggest septal ischemia in the presence of normal coronary arteries. Cardiac MRI confirms the hypertrophy and contrast enhancement frequently reveals evidence for scar at the junction of the RV attachment to the septum. Cardiac catheterization confirms the diagnosis and defines the presence or absence of CAD. Frequently, coronary arterial bridging (squeezing in systole) occurs, especially of the septal arteries. Exercise studies are recommended to assess for ventricular arrhythmias and to document the BP response. Holter monitoring is recommended for determination of ventricular ectopy.

 Treatment

Beta-blockers should be the initial drug in symptomatic individuals, especially when dynamic outflow obstruction is noted on the echocardiogram. The resulting slower heart rates assist with diastolic filling of the stiff LV. Dyspnea, angina, and arrhythmias respond in about 50% of patients. Calcium channel blockers, especially verapamil, have also been effective in symptomatic patients. Their effect is due primarily to improved diastolic function; however, their vasodilating actions can also increase outflow obstruction and cause hypotension. Disopyramide is also used because of its negative inotropic effects; it is usually used in addition to the medical regimen rather than as primary therapy or to help control atrial arrhythmias. Diuretics are frequently necessary due to the high diastolic pressure and PCWP. Patients do best in sinus rhythm, and atrial fibrillation should be aggressively treated with antiarrhythmics or radiofrequency ablation. Dual-chamber pacing may prevent the progression of hypertrophy and obstruction. There appears to be an advantage to the use of short-AV delay biventricular pacing. Nonsurgical septal ablation has been performed by injection of alcohol into septal branches of the left coronary artery with good results in small series of patients. Patients with malignant ventricular arrhythmias and unexplained syncope in the presence of a positive family history for sudden death with or without an abnormal BP response to exercise are probably best managed with an implantable defibrillator. Excision of part of the outflow myocardial septum (myotomy–myomectomy) by experienced surgeons has been successful in patients with severe symptoms unresponsive to medical therapy. A few surgeons advocate mitral valve replacement, as this results in resolution of the gradient as well, and prevents associated mitral regurgitation. In some cases, myomectomy has been combined with an Alfieri stitch on the mitral valve with success. Rare cases with progression to dilation or with intractable symptoms can be considered for cardiac transplantation. Figure 10–11 provides an algorithm for the treatment of HOCM.

 Figure 10–11. Recommended therapeutic approach to the patient with hypertrophic obstructive cardiomyopathy (HOCM). ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blockers; HF, heart failure; LVEF, left ventricular ejection fraction. (Reproduced, with permission, from Gersh BJ et al. 2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2011 Dec 13;58(25):e212–60.)

Pregnancy results in an increased risk in patients with symptoms or outflow tract gradients of > 50 mm Hg. Genetic counseling is indicated before planned conception. In pregnant patients with HOCM, continuation of beta-blocker therapy is recommended.

 Prognosis

The natural history of HOCM is highly variable. Several specific mutations are associated with a higher incidence of early malignant arrhythmias and sudden death, and definition of the genetic abnormality provides the best estimate of prognosis. Some patients remain asymptomatic for many years or for life. Sudden death, especially during exercise, may be the initial event. The highest risk patients are those with (1) a personal history of serious ventricular arrhythmias or survival of a sudden death episode; (2) a family history of sudden death; (3) unexplained syncope; (4) documented NSVT, defined as three or more beats of ventricular tachycardia at ≥ 120 beats per minute on ambulatory Holter monitoring; and (5) maximal LV wall thickness ≥ 30 mm. In addition, patients whose BP does not increase during treadmill stress testing are also at risk, as are those with double and compound genetic mutations and those with marked LV outflow tract obstruction. MRI data suggest that the extent of scarring on hyperenhancement may also be predictive of adverse events. HOCM is the pathologic feature most frequently associated with sudden death in athletes. Pregnancy is generally well tolerated. Endocarditis prophylaxis is no longer indicated. A final stage may be a transition into dilated cardiomyopathy in 5–10% of patients due to the long-term effects of LV remodeling; treatment at that stage is similar to that for dilated cardiomyopathy.

 When to Refer

Patients should be referred to a cardiologist when symptoms are difficult to control, syncope has occurred, or there are any of the high-risk features present as noted above.

Gersh BJ et al. 2011 ACCF/AHA guideline for the treatment of hypertrophic cardiomyopathy. J Am Coll Cardiol. 2011 Dec 13;58(25):e212–60. [PMID: 22075469]

Maron BJ et al. Hypertrophic cardiomyopathy. Lancet. 2013 Jan 19;381(9862):242–55. [PMID: 22874472]

RESTRICTIVE CARDIOMYOPATHY

 ESSENTIALS OF DIAGNOSIS

 Right heart failure tends to dominate over left heart failure.

 Pulmonary hypertension is present.

 Amyloidosis is the most common cause.

 Echocardiography is key to diagnosis.

 Myocardial biopsy or cardiac MRI can confirm amyloid.

 General Considerations

Restrictive cardiomyopathy is characterized by impaired diastolic filling with reasonably preserved contractile function. The condition is relatively uncommon, with the most frequent cause being amyloidosis. Cardiac amyloidosis is more common in men than in women and rarely manifests before the age of 40. The AL type is the most common. In the elderly, secondary amyloidosis can occur (AA type). It may manifest secondarily to multiple myeloma. A familiar type (most often seen in elderly blacks) occurs due to a build-up of transthyretin.

In Africa, endomyocardial fibrosis, a specific entity in which there is severe fibrosis of the endocardium, often with eosinophilia (Löffler syndrome), is seen. Other causes of restrictive cardiomyopathy are infiltrative cardiomyopathies (eg, hemochromatosis, sarcoidosis) and connective tissue diseases (eg, scleroderma).

 Clinical Findings

  1. Symptoms and Signs

Restrictive cardiomyopathy must be distinguished from constrictive pericarditis (Table 10–17). The key feature is that ventricular interaction is accentuated with respiration in constrictive pericarditis and that interaction is absent in restrictive cardiomyopathy. In addition, the pulmonary arterial pressure is invariably elevated in restrictive cardiomyopathy due to the high pulmonary capillary wedge pressure (PCWP) and is normal in uncomplicated constrictive pericarditis.

  1. Diagnostic Studies

Conduction disturbances are frequently present. Low voltage on the ECG combined with ventricular hypertrophy on the echocardiogram is suggestive of disease. Cardiac MRI presents a distinctive pattern of diffuse hyperenhancement of the gadolinium image in amyloidosis and is a useful screening test. The echocardiogram reveals a small thickened LV with bright myocardium (speckled), rapid early diastolic filling revealed by the mitral inflow Doppler, and biatrial enlargement. The LV chamber size is usually normal with a reduced LVEF. Atrial septal thickening may be evident. Rectal, abdominal fat, or gingival biopsies can confirm systemic involvement, but myocardial involvement may still be present if these are negative, and requires endomyocardial biopsy for the confirmation of cardiac amyloid. Demonstration of tissue infiltration on biopsy specimens using special stains followed by immunohistochemical studies and genetic testing is essential to define which specific protein is involved.

 Treatment

Unfortunately, little useful therapy is available for either the causative conditions or the restrictive cardiomyopathy itself. Diuretics can help, but excessive diuresis can produce worsening kidney dysfunction. As with most patients with severe right heart failure, loop diuretics, thiazides, and aldosterone antagonists are all useful. Recently, the use of ultrafiltration devices have allowed for improved diuresis, although it is not clear if prognosis is improved. Digoxin may precipitate arrhythmias and generally should not be used. Beta-blockers help slow heart rates and improve filling. Corticosteroids may be helpful in sarcoidosis but they are more effective for the conduction abnormalities than heart failure. In amyloidosis, the therapeutic strategy depends on the characterization of the type of amyloid protein and extent of disease and may include chemotherapy or bone marrow transplantation. In familial amyloidosis, liver transplantation may be an option. Cardiac transplantation has also been used in patients with primary cardiac amyloidosis and no evidence of systemic involvement.

 When to Refer

All patients with the diagnosis of a restrictive cardiomyopathy should be referred to a cardiologist to decide etiology and plan appropriate treatment. This is especially true if amyloidosis is suspected because the prognosis is poor.

Kapoor P et al. Cardiac amyloidosis: a practical approach to diagnosis and management. Am J Med. 2011 Nov;124(11): 1006–15. [PMID: 22017778]

Quarta CC et al. Amyloidosis. Circulation. 2012 Sep18;126(12): e178–82. [PMID: 22988049]

Sharma N et al. Current state of cardiac amyloidosis. Curr Opin Cardiol. 2013 Mar;28(2):242–8. [PMID: 23324855]

RHEUMATIC FEVER

 ESSENTIALS OF DIAGNOSIS

 More common in developing countries (100 cases/100,000 population) than in the United States (˜2 cases/100,000 population).

 Peak incidence ages 5–15 years.

 Diagnosis based on Jones criteria and confirmation of streptococcal infection.

 May involve mitral and other valves acutely, rarely leading to heart failure.

 General Considerations

Rheumatic fever is a systemic immune process that is a sequela of a beta-hemolytic streptococcal infection of the pharynx. It is a major scourge in developing countries and responsible for 250,000 deaths in young people worldwide each year. Signs of rheumatic fever usually commence 2–3 weeks after infection but may appear as early as 1 week or as late as 5 weeks. The disease has become quite uncommon in the United States, except in immigrants; however, there have been reports of new outbreaks in several regions of the United States. The peak incidence is between ages 5 and 15 years; rheumatic fever is rare before age 4 years or after age 40 years. Rheumatic carditis and valvulitis may be self-limited or may lead to slowly progressive valvular deformity. The characteristic lesion is a perivascular granulomatous reaction with vasculitis. The mitral valve is acutely attacked in 75–80% of cases, the aortic valve in 30% (but rarely as the sole valve involved), and the tricuspid and pulmonary valves in under 5% of. Overall, carditis is thought to occur in about 30–45% of cases of acute rheumatic fever.

Chronic rheumatic heart disease results from single or repeated attacks of rheumatic fever that produce rigidity and deformity of valve cusps, fusion of the commissures, or shortening and fusion of the chordae tendineae. Valvular stenosis or regurgitation results, and the two often coexist. In chronic rheumatic heart disease, the mitral valve alone is affected in 50–60% of cases; combined lesions of the aortic and mitral valves occur in 20%; pure aortic lesions are less common. Tricuspid involvement occurs in about 10% of cases but only in association with mitral or aortic disease and is thought to be more common when recurrent infections have occurred. The pulmonary valve is rarely affected long term. A history of rheumatic fever is obtainable in only 60% of patients with rheumatic heart disease.

 Clinical Findings

The presence of two major criteria—or one major and two minor criteria—establishes the diagnosis. Echocardiographic studies revealing valvular abnormalities have suggested that subclinical cardiac involvement may be missed using the strict Jones criteria. India, New Zealand, and Australia have all published revised guidelines.

  1. Major Criteria
  2. Carditis—Carditis is most likely to be evident in children and adolescents. Any of the following suggests the presence of carditis: (1) pericarditis; (2) cardiomegaly, detected by physical signs, radiography, or echocardiography; (3) heart failure, right- or left-sided—the former perhaps more prominent in children, with painful liver engorgement due to tricuspid regurgitation; and (4) mitral or aortic regurgitation murmurs, indicative of dilation of a valve ring with or without associated valvulitis The Carey–Coombs short mid-diastolic mitral murmur may be present due to inflammation of the mitral valve.

In the absence of any of the above definitive signs, the diagnosis of carditis depends on the following less specific abnormalities: (1) ECG changes, including changing contour of P waves or inversion of T waves; (2) changing quality of heart sounds; and (3) sinus tachycardia, arrhythmia, or ectopic beats.

  1. Erythema marginatum and subcutaneous nodules—Erythema marginatum begins as rapidly enlarging macules that assume the shape of rings or crescents with clear centers. They may be raised, confluent, and either transient or persistent.

Subcutaneous nodules are uncommon except in children. They are small (≤ 2 cm in diameter), firm, and nontender and are attached to fascia or tendon sheaths over bony prominences. They persist for days or weeks, are recurrent, and are indistinguishable from rheumatoid nodules.

  1. Sydenham chorea—This is the least common (3% of cases) but most diagnostic manifestation of acute rheumatic fever. Defined as involuntary choreoathetoid movements primarily of the face, tongue, and upper extremities, sydenham chorea may be the sole manifestation of rheumatic fever; only 50% of cases have other overt signs. Girls are more frequently affected, and occurrence in adults is rare.
  2. Polyarthritis—This is a migratory polyarthritis that involves the large joints sequentially. In adults, only a single joint may be affected. The arthritis lasts 1–5 weeks and subsides without residual deformity. Prompt response of arthritis to therapeutic doses of salicylates or nonsteroidal agents is characteristic.
  3. Minor Criteria

These include fever, polyarthralgias, reversible prolongation of the PR interval, and an elevated erythrocyte sedimentation rate or CRP. Supporting evidence includes positive throat culture or rapid streptococcal antigen test and elevated or rising streptococcal antibody titer.

  1. Laboratory Findings

There is nonspecific evidence of inflammatory disease, as shown by a rapid sedimentation rate. High or increasing titers of antistreptococcal antibodies (antistreptolysin O and anti-DNase B) are used to confirm recent infection; 10% of cases lack this serologic evidence.

 Treatment

  1. General Measures

The patient should be kept at strict bed rest until the temperature returns to normal (without the use of antipyretic medications) and the sedimentation rate, plus the resting pulse rate, and the ECG have all returned to baseline.

  1. Medical Measures
  2. Salicylates—The salicylates markedly reduce fever and relieve joint pain and swelling. They have no effect on the natural course of the disease. Adults may require large doses of aspirin, 0.6–0.9 g every 4 hours; children are treated with lower doses.
  3. Penicillin—Penicillin (benzathine penicillin, 1.2 million units intramuscularly once, or procaine penicillin, 600,000 units intramuscularly daily for 10 days) is used to eradicate streptococcal infection if present. Erythromycin may be substituted (40 mg/kg/d).
  4. Corticosteroids—There is no proof that cardiac damage is prevented or minimized by corticosteroids. A short course of corticosteroids (prednisone, 40–60 mg orally daily, with tapering over 2 weeks) usually causes rapid improvement of the joint symptoms and is indicated when response to salicylates has been inadequate.

 Prevention of Recurrent Rheumatic Fever

Improvement in socioeconomic conditions and public health are critical to reducing bouts of rheumatic fever. The initial episode of rheumatic fever can usually be prevented by early treatment of streptococcal pharyngitis. (See Chapter 33.) Prevention of recurrent episodes of rheumatic fever is critical. Recurrences of rheumatic fever are most common in patients who have had carditis during their initial episode and in children, 20% of whom will have a second episode within 5 years. The preferred method of prophylaxis is with benzathine penicillin G, 1.2 million units intramuscularly every 4 weeks. Oral penicillin (200,000–250,000 units twice daily) is less reliable.

If the patient is allergic to penicillin, sulfadiazine (or sulfisoxazole), 1 g daily, or erythromycin, 250 mg orally twice daily, may be substituted. The macrolide azithromycin is similarly effective against group A streptococcal infection. If the patient has not had an immediate hypersensitivity (anaphylactic-type) reaction to penicillin, then cephalosporin may also be used.

Recurrences are uncommon after 5 years following the first episode and in patients over 25 years of age. Prophylaxis is usually discontinued after these times except in groups with a high risk of streptococcal infection—parents or teachers of young children, nurses, military recruits, etc. Secondary prevention of rheumatic fever depends on whether carditis has occurred. If there is no evidence for carditis, preventive therapy can be stopped at age 21 years. If carditis has occurred but there is no residual valvular disease, it can be stopped at 10 years after the episode. If carditis has occurred with residual valvular involvement, it should be continued for 10 years after the last episode or until age 40 years if the patient is in a situation in which reexposure would be expected.

 Prognosis

Initial episodes of rheumatic fever may last months in children and weeks in adults. The immediate mortality rate is 1–2%. Persistent rheumatic carditis with cardiomegaly, heart failure, and pericarditis implies a poor prognosis; 30% of children thus affected die within 10 years after the initial attack. After 10 years, two-thirds of patients will have detectable valvular abnormalities (usually thickened valves with limited mobility), but significant symptomatic VHD or persistent cardiomyopathy occurs in < 10% of patients with a single episode. In developing countries, acute rheumatic fever occurs earlier in life, recurs more frequently, and the evolution to chronic valvular disease is both accelerated and more severe.

Lee JL et al. Acute rheumatic fever and its consequences: a persistent threat to developing nations in the 21st century. Autoimmun Rev. 2009 Dec;9(2):117–23. [PMID: 19386288]

Marijon E et al. Rheumatic heart disease. Lancet. 2012 Mar 10;379(9819):953–64. [PMID: 22405798]

Roberts K et al. Screening for rheumatic heart disease: current approaches and controversies. Nat Rev Cardiol. 2013 Jan; 10(1): 49–58. [PMID: 23149830]

DISEASES OF THE PERICARDIUM

ACUTE INFLAMMATORY PERICARDITIS

 ESSENTIALS OF DIAGNOSIS

 Anterior pleuritic chest pain that is worse supine than upright.

 Pericardial rub.

 Fever common.

 Erythrocyte sedimentation rate usually elevated.

 ECG reveals diffuse ST-segment elevation with associated PR depression.

 General Considerations

Acute (< 2 weeks) inflammation of the pericardium may be infectious in origin or may be due to systemic diseases (autoimmune syndromes, uremia), neoplasm, radiation, drug toxicity, hemopericardium, postcardiac surgery, or contiguous inflammatory processes in the myocardium or lung. In many of these conditions, the pathologic process involves both the pericardium and the myocardium.

Viral infections (especially infections with coxsackieviruses and echoviruses but also influenza, Epstein–Barr, varicella, hepatitis, mumps, and HIV viruses) are the most common cause of acute pericarditis and probably are responsible for many cases classified as idiopathic. Males—usually under age 50 years—are most commonly affected. The differential diagnosis primarily requires exclusion of acute myocardial infarction. Tuberculous pericarditis has become rare in developed countries but remains common in certain areas of the world. It results from direct lymphatic or hematogenous spread; clinical pulmonary involvement may be absent or minor, although associated pleural effusions are common. Bacterial pericarditis is rare and usually results from direct extension from pulmonary infections. Pneumococci can cause a primary pericardial infection. Borrelia burgdorferi, the organism responsible for Lyme disease, can also cause myopericarditis. Uremic pericarditis is a common complication of chronic kidney disease. The pathogenesis is uncertain; it occurs both with untreated uremia and in otherwise stable dialysis patients. Spread of adjacent lung cancer as well as invasion by breast cancer, renal cell carcinoma, Hodgkin disease, and lymphomas are the most common neoplastic processes involving the pericardium and have become the most frequent causes of pericardial tamponade in many countries. Pericarditis may occur 2–5 days after infarction due to an inflammatory reaction to transmural myocardial necrosis [postmyocardial infarction or postcardiotomy pericarditis (Dressler syndrome)]. Radiation can initiate a fibrinous and fibrotic process in the pericardium, presenting as subacute pericarditis or constriction. Radiation pericarditis usually follows treatments of more than 4000 cGy delivered to ports including more than 30% of the heart.

Other causes of pericarditis include connective tissue diseases, such as lupus erythematosus and rheumatoid arthritis, drug-induced pericarditis (minoxidil, penicillins, clozapine), and myxedema.

 Clinical Findings

  1. Symptoms and Signs

The presentation and course of inflammatory pericarditis depend on its cause, but most syndromes have associated chest pain, which is usually pleuritic and postural (relieved by sitting). The pain is substernal but may radiate to the neck, shoulders, back, or epigastrium. Dyspnea may also be present and the patient is often febrile. A pericardial friction rub is characteristic, with or without evidence of fluid accumulation or constriction (see below). The presentation of tuberculous pericarditis tends to be subacute, but nonspecific symptoms (fever, night sweats, fatigue) may be present for days to months. Pericardial involvement develops in 1–8% of patients with pulmonary tuberculosis. Symptoms and signs of bacterial pericarditis are similar to those of other types of inflammatory pericarditides, but patients appear toxic and are often critically ill. Uremic pericarditis can present with or without symptoms; fever is absent. Often neoplastic pericarditis is painless, and the presenting symptoms relate to hemodynamic compromise or the primary disease. At times the pericardial effusion is very large, consistent with its chronic nature. Postmyocardial infarction or postcardiotomy pericarditis (Dressler syndrome) usually presents as a recurrence of pain with pleural-pericardial features. A rub is often audible, and repolarization changes on the ECG may be confused with ischemia. Large effusions are uncommon, and spontaneous resolution usually occurs in a few days. Dressler syndrome occurs days to weeks to several months after myocardial infarction or open heart surgery, may be recurrent, and probably represents an autoimmune syndrome. Patients present with typical pain, fever, malaise, and leukocytosis. Rarely, other symptoms of an autoimmune disorder, such as joint pain and fever, may occur. Tamponade is rare with Dressler syndrome after myocardial infarction but not when it occurs postoperatively. The clinical onset of radiation pericarditis is usually within the first year but may be delayed for many years; often a full decade or more may pass before constriction becomes evident.

  1. Laboratory Findings and Diagnostic Studies

The diagnosis of viral pericarditis is usually clinical, and leukocytosis is often present. Rising viral titers in paired sera may be obtained for confirmation but are rarely done. Cardiac enzymes may be slightly elevated, reflecting an epicardial myocarditis component. The echocardiogram is often normal or reveals only a trivial amount of extra fluid during the acute inflammatory process. The diagnosis oftuberculous pericarditis can be inferred if acid-fast bacilli are found elsewhere. The tuberculous pericardial effusions are usually small or moderate but may be large when chronic. The yield of organisms by pericardiocentesis is low; pericardial biopsy has a higher yield but may also be negative, and pericardiectomy may be required. If bacterial pericarditis is suspected on clinical grounds, diagnostic pericardiocentesis can be confirmatory. In uremic patients not on dialysis, the incidence of pericarditis correlates roughly with the level of blood urea nitrogen (BUN) and creatinine. The pericardium is characteristically “shaggy” in uremic pericarditis, and the effusion is hemorrhagic and exudative. The diagnosis of neoplastic pericarditis can occasionally be made by cytologic examination of the effusion or by pericardial biopsy, but it may be difficult to establish clinically if the patient has received mediastinal radiation within the previous year. Neoplastic pericardial effusions develop over a long period of time and may become quite huge (> 2 L). The sedimentation rate is high in postmyocardial infarction or postcardiotomy pericarditis and can help confirm the diagnosis. Large pericardial effusions and accompanying pleural effusions are frequent. Myxedema pericardial effusions due to hypothyroidism usually are characterized by the presence of cholesterol crystals within the fluid.

  1. Other Studies

The ECG usually shows generalized ST and T wave changes and may manifest a characteristic progression beginning with diffuse ST elevation, followed by a return to baseline and then to T wave inversion. Atrial injury is often present and manifested by PR depression especially in the limb leads. The chest radiograph is frequently normal, but may show cardiac enlargement if pericardial fluid is present, as well as signs of related pulmonary disease. Mass lesions and enlarged lymph nodes may suggest a neoplastic process. MRI and CT scan can visualize neighboring tumor in neoplastic pericarditis. A screening chest CT or MRI is often recommended to ensure there are no extracardiac diseases contiguous to the pericardium.

 Treatment

Most experts suggest a restriction in activity until symptom resolution. Nonsteroidal anti-inflammatory drugs are generally effective. Studies also suggest that the initial treatment of the acute episode with colchicine helps prevent recurrences. Current recommendations include ibuprofen 600–800 mg three times daily for 1–2 weeks or indomethacin 50 mg three times daily for 1–2 weeks. Doses can be decreased once symptoms resolve. Colchicine should be added to the nonsteroidal anti-inflammatory drug at 0.5–0.6 mg twice daily and continued for 3 months. Colchicine should also be the initial therapy in all refractory cases and in recurrent pericarditis. Its use should be for 6 months in such cases. Aspirin and colchicine should be used instead of nonsteroidal anti-inflammatory drugs in postmyocardial infarction pericarditis (Dressler syndrome) since nonsteriodal anti-inflammatory drugs may have an adverse effect on myocardial healing. Aspirin in doses of 650–1000 mg three times daily for 1–2 weeks plus 3 months of colchicine is the recommended treatment. Systemic corticosteroids can be used in patients with severe symptoms, in refractory cases, or in patients with immune-mediated etiologies, but such therapy may entail a higher risk of recurrence and colchicine is recommended in addition, again for 3 months, to help prevent recurrences. Prednisone in doses of 0.25–0.5 mg/kg/d is suggested. In general, symptoms subside in several days to weeks. The major early complication is tamponade, which occurs in < 5% of patients. There may be recurrences in the first few weeks or months. Rarely, when colchicine therapy alone fails, recurrent pericarditis may require more significant immunosuppression, such as cyclophosphamide or methotrexate. If colchicine plus more significant immunosuppression fails, surgical pericardial stripping may be required in recurrent cases even without clinical evidence for constrictive pericarditis.

Standard antituberculous drug therapy is usually successful for tuberculous pericarditis (see Chapter 9), but constrictive pericarditis can occur. Uremic pericarditis usually resolves with the institution of—or with more aggressive—dialysis. Tamponade is fairly common, and partial pericardiectomy (pericardial window) may be necessary. Whereas anti-inflammatory agents may relieve the pain and fever associated with uremic pericarditis, indomethacin and systemic corticosteroids do not affect its natural history. The prognosis with neoplastic effusion is poor, with only a small minority surviving 1 year. If it is compromising the clinical comfort of the patient, the effusion is initially drained percutaneously. A pericardial window, either by a subxiphoid approach or via video-assisted thoracic surgery, allows for partial pericardiectomy. Instillation of chemotherapeutic agents or tetracycline may be used to reduce the recurrence rate. Symptomatic therapy is the initial approach to radiation pericarditis, but recurrent effusions and constriction often require surgery.

 When to Refer

Patients who do not respond initially to conservative management, who have recurrences, or who appear to be developing constrictive pericarditis should be referred to a cardiologist for further assessment.

Lotrionte M et al. International collaborative systematic review of controlled clinical trials on the pharmacologic treatment of acute pericarditis and its recurrences. Am Heart J. 2010 Oct;160(4):662–70. [PMID: 20934560]

Markel G et al. Prevention of recurrent pericarditis with colchicine in 2012. Clin Cardiol. 2013 Mar;36(3):125–8. [PMID: 23404655]

Sparano DM et al. Pericarditis and pericardial effusion: management update. Curr Treat Options Cardiovasc Med. 2011 Dec; 13(6):543–55. [PMID: 21989746]

Spodick DH. Colchicine effectively and safely treats acute pericarditis and prevents and treats recurrent pericarditides. Heart. 2012 Jul;98(14):1035–6. [PMID: 22634168]

PERICARDIAL EFFUSION & TAMPONADE

Pericardial effusion can develop during any of the pericarditis processes. The speed of accumulation determines the physiologic importance of the effusion. Because the pericardium stretches, large effusions (> 1000 mL) that develop slowly may produce no hemodynamic effects. Conversely, smaller effusions that appear rapidly can cause tamponade due to the curvilinear relationship between the volume of fluid and the intrapericardial pressure. Tamponade is characterized by elevated intrapericardial pressure (> 15 mm Hg), which restricts venous return and ventricular filling. As a result, the stroke volume and arterial pulse pressure fall, and the heart rate and venous pressure rise. Shock and death may result.

 Clinical Findings

  1. Symptoms and Signs

Pericardial effusions may be associated with pain if they occur as part of an acute inflammatory process or may be painless, as is often the case with neoplastic or uremic effusion. Dyspnea and cough are common, especially with tamponade. Other symptoms may result from the primary disease.

A pericardial friction rub may be present even with large effusions. In cardiac tamponade, tachycardia, tachypnea, a narrow pulse pressure, and a relatively preserved systolic pressure are characteristic. Pulsus paradoxus is defined as a > 10 mm Hg decline in systolic pressure during inspiration. Since the RV and LV share the same pericardium, when there is significant pericardial effusion, as the RV enlarges with inspiratory filling, septal motion toward the LV reduces LV filling and results in an accentuated drop in the stroke volume and BP with inspiration. Central venous pressure is elevated and since the intrapericardial, and thus intracardiac, pressures are high even at the initiation of diastole, there is no evident y descent in the RA, RV, or LV hemodynamic tracings. This differs from constriction where most of the initial filling of the RV and LV occurs during early diastole (the Y descent), and it is only in mid to late diastole that the ventricles can no longer fill. Edema or ascites are rarely present in tamponade; these signs favor a more chronic process.

  1. Laboratory Findings

Laboratory tests tend to reflect the underlying processes (see causes of pericarditis above).

  1. Diagnostic Studies

Chest radiograph can suggest chronic effusion by an enlarged cardiac silhouette with a globular configuration but may appear normal in acute situations. The ECG often reveals nonspecific T wave changes and reduced QRS voltage. Electrical alternans is present occasionally but is pathognomonic due to the heart swinging within the large effusion. Echocardiography is the primary method for demonstrating pericardial effusion and is quite sensitive. If tamponade is present, the high intrapericardial pressure may collapse lower pressure cardiac structures, such as the RA and RV. In tamponade, the normal inspiratory reduction in LV filling is accentuated due to RV/LV interaction and there is a > 25% reduction in maximal mitral inflow velocities. RV collapse is particularly evident in diastole as the enlarging diastolic LV crowds out the RV within the fixed space provided by the ventricles and pericardium. The apparent RV diastolic “collapse” is due to the thinner RV being unable to fill appropriately during diastole at the same time that the thicker and more powerful LV enters diastole. Cardiac CT and MRI also demonstrate pericardial fluid, pericardial thickening, and any associated contiguous lesions. Diagnostic pericardiocentesis or biopsy is often indicated for microbiologic and cytologic studies; a pericardial biopsy may be performed relatively simply through a small subxiphoid incision or by use of a video-assisted thoracoscopic surgical procedure. Unfortunately, the quality of the pericardial fluid itself rarely leads to a diagnosis, and any type of fluid (serous, serosanguinous, bloody, etc) can be seen in most diseases. Pericardial fluid analysis is most useful in excluding a bacterial cause. Effusions due to hypothyroidism or lymphatic obstruction may contain cholesterol or be chylous in nature, respectively.

 Treatment

Small effusions can be followed clinically by careful observations of the JVP and by testing for a change in the paradoxical pulse. Serial echocardiograms are indicated if no intervention is immediately contemplated. When tamponade is present, urgent pericardiocentesis is required. Because the pressure–volume relationship in the pericardial fluid is curvilinear and upsloping, removal of a small amount of fluid often produces a dramatic fall in the intrapericardial pressure and immediate hemodynamic benefit; but complete drainage with a catheter is preferable. Continued or repeat drainage may be indicated, especially in malignant effusions. Pericardial windows via video-assisted thorascopy have been particularly effective in preventing recurrences. Effusions related to recurrent inflammatory pericarditis can be treated as noted above (see Acute Inflammatory Pericarditis).

Additional therapy is determined by the nature of the primary process. Recurrent effusion in neoplastic disease and uremia, in particular, may require partial pericardiectomy.

 When to Refer

  • Any unexplained pericardial effusion should be referred to a cardiologist.
  • Trivial pericardial effusions are common, especially in heart failure, and need not be referred unless symptoms of pericarditis are evident.
  • Hypotension or a paradoxical pulse suggesting the pericardial effusion is hemodynamically compromising the patient should prompt an immediate referral.
  • Echocardiographic signs of tamponade should always trigger referral.

Bodson L et al. Cardiac tamponade. Curr Opin Crit Care. 2011 Oct;17(5):416–24. [PMID: 21716107]

Imazio M et al. Medical therapy of pericardial diseases: part II: noninfectious pericarditis, pericardial effusions and constrictive pericarditis. J Cardiovasc Med (Hagerstown). 2010 Nov;11(11): 785–94. [PMID: 20925146]

Refaat MM et al. Neoplastic pericardial effusion. Clin Cardiol. 2011 Oct;34(10):593–8. [PMID: 21928406]

CONSTRICTIVE PERICARDITIS

 ESSENTIALS OF DIAGNOSIS

 Evidence of right heart failure.

 No fall or an elevation of the JVP with inspiration (Kussmaul sign).

 Echocardiographic evidence for septal bounce and reduced mitral inflow velocities with inspiration.

 May be difficult to differentiate from restrictive cardiomyopathy.

 Cardiac catheterization may be necessary.

 General Considerations

Inflammation can lead to a thickened, fibrotic, adherent pericardium that restricts diastolic filling and produces chronically elevated venous pressures. In the past, tuberculosis was the most common cause of constrictive pericarditis, but the process now more often occurs after radiation therapy, cardiac surgery, or viral pericarditis; histoplasmosis is another uncommon cause, occurring mainly in individuals who live in the Ohio River Valley.

At times, both pericardial tamponade and constrictive pericarditis may coexist, a condition referred to as effusive-constrictive pericarditis. The only definitive way to diagnose this condition is to reveal the underlying constrictive physiology once the pericardial fluid is drained.

 Clinical Findings

  1. Symptoms and Signs

The principal symptoms are slowly progressive dyspnea, fatigue, and weakness. Chronic edema, hepatic congestion, and ascites are usually present. Ascites often seems out of proportion to the degree of peripheral edema. The examination reveals these signs and a characteristically elevated jugular venous pressure with a rapid y descent. This can be detected at bedside by careful observation of the jugular pulse and noting an apparent increased pulse wave at the end of ventricular systole (due to an apparent accentuation of the v wave by the rapid y descent). Kussmaul sign—a failure of the JVP to fall with inspiration—is also a frequent finding. The apex may actually retract with systole and a pericardial “knock” may be heard in early diastole. Pulsus paradoxus is unusual. Atrial fibrillation is common.

  1. Diagnostic Studies

At times constrictive pericarditis is extremely difficult to differentiate from restrictive cardiomyopathy. When unclear, the use of both noninvasive testing and cardiac catheterization is required to sort out the difference.

  1. Radiographic findings—The chest radiograph may show normal heart size or cardiomegaly. Pericardial calcification is best seen on the lateral view and is uncommon. It rarely involves the LV apex, and finding of calcification at the LV apex is more consistent with LV aneurysm.
  2. Echocardiography—Echocardiography rarely demonstrates a thickened pericardium. A septal “bounce” reflecting the rapid early filling is common, though. RV/LV interaction may be demonstrated by a reduction in the mitral inflow Doppler pattern of > 25%, much as in tamponade. The Doppler mitral inflow pattern should demonstrate at least a 25% fall with inspiration. Usually the initial inflow into the LV is very rapid and this can be demonstrated as well by the Doppler inflow (E wave) pattern.
  3. Cardiac CT and MRI—These imaging tests are only occasionally helpful. Pericardial thickening of > 4 mm must be present to establish the diagnosis, and no pericardial thickening is demonstrable in 20–25% of patients with constrictive pericarditis. Some MRI techniques demonstrate the septal bounce and can provide evidence for ventricular interaction.
  4. Cardiac catheterization—This procedure is often confirmatory or can be diagnostic in difficult cases where the echocardiographic features are unclear or mixed. As a generality, the pulmonary pressure is low in constriction (as opposed to restrictive cardiomyopathy). In constrictive pericarditis, because of the need to demonstrate RV/LV interaction, cardiac catheterization should include simultaneous measurement of both the LV and RV pressure tracings with inspiration and expiration. Hemodynamically, patients with constriction have equalization of end-diastolic pressures throughout their cardiac chambers, there is rapid early filling then an abrupt increase in diastolic pressure (“square-root” sign), the RV end-diastolic pressure is more than one-third the systolic pressure, simultaneous measurements of RV and LV systolic pressure reveal a discordance with inspiration (the RV rises as the LV falls), and there is usually a Kussmaul sign (failure of the RA pressure to fall with inspiration). The area of the RV pressure tracing may also be less in expiration and greater during inspiration, reflecting the variability in filling of the RV with respiration. The ratio of the RV tracing area to the LV tracing area should increase with inspiration if constriction is present; this is due to the increased RV filling and higher RV systolic pressure with inspiration while the LV systolic pressure falls and the LV tracing area becomes less. These findings differ from restrictive cardiomyopathy in which the LV diastolic pressure is usually greater than the RV diastolic pressure by 5 mm Hg, there is pulmonary hypertension, and simultaneous measurements of the RV and LV systolic pressure reveal a concordant drop in the peak systolic ventricular pressures during inspiration with no change in the RV/LV tracing area ratio with inspiration.

 Treatment

Initial treatment consists of diuresis. As in other disorders of right heart failure, the diuresis should be aggressive, using loop diuretics (torsemide if bowel edema is suspected), thiazides, and aldosterone antagonists (especially if ascites is present). At times, aquaphoresis may be of value. Surgical pericardiectomy should be done when diuretics are unable to control symptoms. Pericardiectomy removes only the pericardium between the phrenic nerve pathways, however, and most patients still require diuretics after the procedure, though symptoms are usually dramatically improved. Morbidity and mortality after pericardiectomy are high (up to 15%) and are greatest in those with the most disability prior to the procedure.

 When to Refer

If the diagnosis of constrictive pericarditis is unclear or the symptoms resist medical therapy, then referral to a cardiologist is warranted to both establish the diagnosis and recommend therapy.

Imazio M. Contemporary management of pericardial diseases. Curr Opin Cardiol. 2012 May;27(3):308–17. [PMID: 22450720]

Talreja DR et al. Constrictive pericarditis in the modern era: novel criteria for diagnosis in the cardiac catheterization laboratory. J Am Coll Cardiol. 2008 Jan22;51(3):315–9. [PMID: 18206742]

PULMONARY HYPERTENSION & PULMONARY HEART DISEASE

PULMONARY HYPERTENSION

 ESSENTIALS OF DIAGNOSIS

 Mean PA pressure ≥ 25 mm Hg with normal PCWP.

 Dyspnea, and often cyanosis, with no evidence of left heart disease.

 Enlarged pulmonary arteries on chest radiograph.

 Elevated JVP and RV heave.

 Echocardiography is often diagnostic.

 General Considerations

The normal pulmonary bed offers about one-tenth as much resistance to blood flow as the systemic arterial system. Experts recommend that a diagnosis of idiopathic pulmonary hypertension should be firmly based on a mean PA pressure of ≥ 25 mm Hg in association with a PCWP of < 16 mm Hg at rest.

The clinical classification of pulmonary hypertension by the Fourth World Symposium on Pulmonary Hypertension is outlined in Table 10–18.

Table 10–18. Clinical classification of pulmonary hypertension.

Group 1 includes pulmonary arterial hypertension related to an underlying pulmonary vasculopathy. It includes the former “primary” pulmonary hypertension under the term “idiopathic pulmonary hypertension” and is defined as pulmonary hypertension and elevated PVR in the absence of other disease of the lungs or heart. Its cause is unknown. Drug and toxic pulmonary hypertension has been described associated with the use of anorexigenic agents that increase serotonin release and block its uptake. These include aminorex fumarate, fenfluramine, and dexfenfluramine. In some cases, there is epidemiologic linkage to ingestion of rapeseed oil or L-tryptophan and use of illicit drugs, such as amphetamines. Pulmonary hypertension associated with connective tissue disease includes cases associated with scleroderma—up to 8–12% of patients with scleroderma may be affected.

Group 2 includes all cases related to left heart disease. Group 3 includes cases due to parenchymal lung disease, impaired control of breathing, or living at high altitude. This group encompasses those with idiopathic pulmonary fibrosis and COPD. Group 4 represents patients with chronic thromboemboli. Group 5 includes multifactorial cases.

 Clinical Findings

  1. Symptoms and Signs

The clinical picture is similar to that of pulmonary hypertension from other causes. Dyspnea, chest pain, fatigue, and lightheadedness are early symptoms; later symptoms include syncope, abdominal distention, ascites, and peripheral edema. Chronic lung disease, especially sleep apnea, often is overlooked as a cause for pulmonary hypertension as is chronic thromboembolic disease. Patients with idiopathic pulmonary hypertension are characteristically young women who have evidence of right heart failure that is usually progressive, leading to death in 2–8 years without therapy. This is a decidedly different prognosis than patients with Eisenmenger physiology due to a left-to-right shunt; 40% of patients with Eisenmenger physiology are alive 25 years after the diagnosis has been made. Patients have manifestations of low cardiac output, with weakness and fatigue, as well as edema and ascites as right heart failure advances. Peripheral cyanosis is present, and syncope on effort may occur.

  1. Diagnostic Studies

The laboratory evaluation of idiopathic pulmonary hypertension must exclude a secondary cause. A hypercoagulable state should be sought by measuring proteins C and S levels, the presence of a lupus anticoagulant, the level of factor V Leiden, prothrombin gene mutations, and D-dimer. Chronic pulmonary emboli must be excluded (usually by ventilation-perfusion lung scan or contrast spiral CT); the ventilation-perfusion scan is the more sensitive test. The chest radiograph helps exclude a primary pulmonary etiology—evidence for patchy pulmonary edema may raise the suspicion of pulmonary veno-occlusive disease due to obstruction in pulmonary venous drainage. A sleep study may be warranted if sleep apnea is suspected. The ECG is generally consistent with RVH and RA enlargement. Echocardiography with Doppler helps exclude an intracardiac shunt and usually demonstrates an enlarged RV and RA—at times they may be huge and hypocontractile. Severe pulmonic or tricuspid regurgitation may be present. Septal flattening is consistent with pulmonary hypertension. Doppler interrogation of the tricuspid regurgitation jet helps provide an estimate of RV systolic pressure. Pulmonary function tests help exclude other disorders, though primary pulmonary hypertension may present with a reduced carbon monoxide diffusing capacity of the lung (DlCO) and severe desaturation (particularly if a PFO has been stretched open and a right-to-left shunt is present). A declining DlCO in a scleroderma patient may precede the development of pulmonary hypertension. Chest CT demonstrates enlarged pulmonary arteries and excludes other causes (such as emphysema or interstitial lung disease). Pulmonary angiography (or MR angiography or CT angiography) reveals loss of the smaller acinar pulmonary vessels and tapering of the larger ones. Catheterization allows measurement of pulmonary pressures and testing for vasoreactivity using a variety of agents, including 100% oxygen, adenosine, epoprostenol, and nitric oxide. Nitric oxide is preferred due to its ease of use and short half-life. A positive response is defined as one that decreases the pulmonary mean pressure by 10 mm Hg with the final mean PA pressure < 40 mm Hg.

 Treatment & Prognosis

General measures include the use of warfarin in all patients with idiopathic pulmonary hypertension who have no contraindication to its use, diuretics in patients with right-sided heart failure, oxygen (especially during sleep) with a goal of maintaining an oxygen saturation of> 90%, and occasionally, digoxin. Patients are advised against heavy physical exertion. A sodium restricted diet (< 2400 mg/d) is advised. The therapeutic algorithm is based on the response to an intravenous vasodilator trial and the clinical risk assessment (Figure 10–12). Patients with a positive response to the intravenous vasodilator should first be tried on oral calcium channel blockers or sildenafil, or both. Patients who do not have a positive response are then divided into those of lower risk (no RV failure, > 400 meters on a 6-minute walk test, peak VO2 max > 10.4 mL/kg/min, minimal RV dysfunction, normal right heart hemodynamics and minimally elevated BNP) and those of highest risk (RV failure, rapidly progressive symptoms, < 300 meters on a 6-minute walk, peak VO2 max < 10.4 mL/kg/min, abnormal echocardiographic findings (pericardial effusion, severe RV enlargement and dysfunction, RA pressure > 20 mm Hg, cardiac index < 2.0 L/min/m2, or significantly elevated BNP). A negative response to vasodilators in a low-risk patient suggests the next line of therapy be endothelin receptor blockers or phosphodiesterase-5 inhibitors as initial oral treatment. If the patient does not respond, then the use of epoprostenol (intravenously) or treprostinil (intravenously), iloprost (inhaled), or treprostinil (subcutaneously) may be tried. For those high-risk patients who do not respond, then therapy consists of use of an intravenous prostacyclin (epoprostenil or treprostinil). Failure of all of these therapies suggests that lung transplantation should be considered. Palliation of patients who are not too cyanotic can be achieved by atrial septostomy to increase forward cardiac output.

 Figure 10–12. Pulmonary hypertension treatment algorithm. ERB, endothelin receptor blockers; PDE-5, phosphodiesterase- 5. (Modified, with permission, from McLaughlin VV et al; American College of Cardiology Foundation Task Force on Expert Consensus Documents; American Heart Association; American College of Chest Physicians; American Thoracic Society, Inc; Pulmonary Hypertension Association. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009 Apr 28;53(17):1573–619.)

In a few patients with acute or chronic pulmonary emboli or both, pulmonary thrombectomy may be effective. In chronic thromboembolic disease, a new soluble guanylate cyclase stimulator, riociguat, has also been found to be of value in patients who cannot undergo thrombectomy or who have undergone the procedure but still experience symptoms.

Most patients die of RV failure; a severely dilated RV with poor contractile function (cor pulmonale) has been shown to predict early mortality. Pregnancy is potentially life-threatening and must be avoided or terminated early to save the mother’s life if the pulmonary hypertension is severe. Survival has improved with idiopathic pulmonary hypertension, though it still remains a dread disease. One, 2- and 3-year survival rates of 85.7%, 69.5%, and 54.9% are still reported. Men fare worse than women, and etiology, functional class, exercise tolerance, and RV hemodynamics all adversely affect outcome.

 When to Refer

All patients with suspected pulmonary hypertension should be referred to either a cardiologist or pulmonologist who specializes in the evaluation and treatment of patients with unexplained pulmonary hypertension.

Benza RL et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation. 2010 Jul 13;122(2):164–72. [PMID: 20585012]

Ghofrani HA et al; PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013 Jul 25;369(4):330–40. [PMID: 23883378]

Hoeper MM et al. Diagnosis, assessment and treatment of non-pulmonary arterial pulmonary hypertension. J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S85–96. [PMID: 19555862]

McLaughlin VV et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009 Apr 28;53(17):1573–619. [PMID: 19389575]

Pulido T et al; SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013 Aug 29;369(9):809–18. [PMID: 23984728]

PULMONARY HEART DISEASE (Cor Pulmonale)

 ESSENTIALS OF DIAGNOSIS

 Associated with chronic bronchitis or emphysema or pulmonary hypertension.

 Elevated jugular venous pressure, parasternal lift, edema, hepatomegaly, ascites.

 ECG shows tall, peaked P waves (P pulmonale), right axis deviation, and RVH.

 Echocardiogram excludes primary LV dysfunction.

 General Considerations

The term “cor pulmonale” denotes RV systolic and diastolic failure resulting from pulmonary disease and the attendant hypoxia or from pulmonary vascular disease (pulmonary hypertension). Its clinical features depend on both the primary underlying disease and its effects on the heart.

Cor pulmonale is most commonly caused by pulmonary hypertension from any cause (see above), COPD or idiopathic pulmonary fibrosis. Less frequent causes include pneumoconiosis and kyphoscoliosis.

 Clinical Findings

  1. Symptoms and Signs

The predominant symptoms of compensated cor pulmonale are related to the pulmonary disorder and include chronic productive cough, exertional dyspnea, wheezing respirations, easy fatigability, and weakness. When the pulmonary disease causes RV failure, these symptoms may be intensified. Dependent edema and right upper quadrant pain may also appear. The signs of cor pulmonale include cyanosis, clubbing, distended neck veins, RV heave or gallop (or both), prominent lower sternal or epigastric pulsations, an enlarged and tender liver, dependent edema, and ascites. Severe lung disease can be a cause of low cardiac output by reducing LV filling and subsequently LV preload and stroke volume.

  1. Laboratory Findings

Polycythemia is often present in cor pulmonale secondary to chronic hypoxemia. The arterial oxygen saturation is often below 85% and frequently falls with exertion; PCO2 may or may not be elevated. Cyanosis is more prevalent if there is right to left shunting via a PFO.

  1. ECG and Chest Radiography

The ECG may show right axis deviation and peaked P waves. Deep S waves are present in lead V6. Right axis deviation and low voltage may be noted in patients with pulmonary emphysema. Frank RVH is uncommon except in pulmonary hypertension. The ECG often mimics myocardial infarction; Q waves may be present in leads II, III, and aVF because of the vertically placed heart, but they are rarely deep or wide, as in inferior myocardial infarction. Supraventricular arrhythmias are frequent and nonspecific.

The chest radiograph discloses the presence or absence of parenchymal disease and a prominent or enlarged RV and PA.

  1. Diagnostic Studies

Pulmonary function tests usually confirm the underlying lung disease. The echocardiogram should show normal LV size and function but RV and RA dilation and RV dysfunction. Perfusion lung scans are rarely of value, but, if negative, they help exclude chronic pulmonary emboli. Multislice CT has replaced pulmonary angiography as the most specific method of diagnosis for the pulmonary emboli. The serum BNP level may be elevated from RV dysfunction.

 Differential Diagnosis

In its early stages, cor pulmonale can be diagnosed on the basis of the clinical examination and radiologic, echocardiographic or ECG evidence. Catheterization of the right heart will establish a definitive diagnosis but is more often performed to exclude left-sided heart failure or pulmonary venous disease, which can be an unrecognized cause of right-sided failure in some patients. Differential diagnostic considerations relate primarily to the specific pulmonary disease that has produced RV failure (see above).

 Treatment

The details of the treatment of chronic pulmonary disease (chronic respiratory failure) are discussed in Chapter 9. Otherwise, therapy is directed at the pulmonary process responsible for right heart failure. Oxygen, salt and fluid restriction, and diuretics are mainstays, with combination diuretic therapy (loop diuretics, thiazides and spironolactone) often useful, as described above for other causes of right heart failure. Inotropic agents are useful when acute decompensation occurs.

Patients with systolic heart failure and COPD are more likely to be older, have more comorbidities, reduced exercise capacity, and increased cardiovascular mortality and heart failure hospitalization, but they do not have a differential response to exercise training. The use of beta-blockers is not associated with differences in outcome for patients with or without COPD.

 Prognosis

Compensated cor pulmonale has the same prognosis as the underlying pulmonary disease. Once signs of heart failure appear, the average life expectancy is 2–5 years, but survival is significantly longer when uncomplicated emphysema is the cause.

 When to Refer

Patients with unexplained or difficult to manage right heart failure should be referred to a cardiologist or a pulmonologist in an effort to uncover correctable causes and to address therapeutic options.

Barr RG et al. Percent emphysema, airflow obstruction and impaired left ventricular filling. N Engl J Med. 2010 Jan 21; 362(3):217–27. [PMID: 20089972]

Hoeper MM et al. Diagnosis, assessment and treatment of non-pulmonary arterial pulmonary hypertension. J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S85–96. [PMID: 19555862]

Mentz RJ et al. Clinical characteristics, response to exercise training, and outcomes in patients with heart failure and chronic obstructive pulmonary disease: findings from Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION). Am Heart J. 2013 Feb;165(2):193–9. [PMID: 23351822]

Stone IS et al. Chronic obstructive pulmonary disease: a modifiable risk factor for cardiovascular disease? Heart. 2012 Jul;98(14):1055–62. [PMID: 22739636]

NEOPLASTIC DISEASES OF THE HEART

Primary cardiac tumors are rare and constitute only a small fraction of all tumors that involve the heart or pericardium. The most common primary tumor is atrial myxoma; it comprises about 50% of all tumors in adult case series. It is generally attached to the atrial septum and is more likely to affect the LA than the RA. Patients with myxoma can present with the characteristics of a systemic illness, with obstruction of blood flow through the heart, or with signs of peripheral embolization. The characteristics include fever, malaise, weight loss, leukocytosis, elevated sedimentation rate, and emboli (peripheral or pulmonary, depending on the location of the tumor). This is often confused with infective endocarditis, lymphoma, other cancers, or autoimmune diseases. In other cases, the tumor may grow to considerable size and produce symptoms by obstructing mitral inflow. Episodic pulmonary edema (classically occurring when an upright posture is assumed) and signs of low output may result. Physical examination may reveal a diastolic sound related to motion of the tumor (“tumor plop”) or a diastolic murmur similar to that of mitral stenosis. Right-sided myxomas may cause symptoms of right-sided failure. Familial myxomas occur as part of the Carney complex—that consists of myxomas, pigmented skin lesions, and endocrine neoplasia.

The diagnosis is established by echocardiography or by pathologic study of embolic material. Cardiac MRI is useful as an adjunct. Contrast angiography is frequently unnecessary. Surgical excision is usually curative, though recurrences do occur and serial echocardiographic follow-up, on at least a yearly basis, is recommended.

The second most common primary cardiac tumors are valvular papillary fibroelastomas and atrial septal lipomas. These tend to be benign and usually require no therapy, although large ones may embolize or cause valvular dysfunction. Other primary cardiac tumors include rhabdomyomas (that often appear multiple in both the RV and LV), fibrous histiocytomas, hemangiomas, and a variety of unusual sarcomas. The diagnosis may be supported by an abnormal cardiac contour on radiograph. Echocardiography is usually helpful but may miss tumors infiltrating the ventricular wall. Cardiac MRI is emerging as the diagnostic procedure of choice.

Metastases from malignant tumors can also affect the heart. Most often this occurs in malignant melanoma, but other tumors involving the heart include bronchogenic carcinoma, carcinoma of the breast, the lymphomas, renal cell carcinoma, and, in patients with AIDS, Kaposi sarcoma. These are often clinically silent but may lead to pericardial tamponade, arrhythmias and conduction disturbances, heart failure, and peripheral emboli. ECG may reveal regional Q waves. The diagnosis is often made by echocardiography, but cardiac MRI and CT scanning can often better delineate the extent of involvement. The prognosis is poor for secondary cardiac tumors; effective treatment is not available. On rare occasions, surgical resection for debulking or removal and chemotherapy is warranted. Primary pericardial tumors, such as mesotheliomas related to asbestos exposure, may also occur.

Many primary tumors may be resectable. Atrial myxomas should be removed surgically due to the high incidence of embolization from these friable tumors. Papillary fibroelastomas are usually benign but may embolize and large ones should be considered for surgical excision. Large pericardial effusions from metastatic tumors may be drained for comfort, but the fluid invariably recurs. Rhabdomyomas may be surgically cured if the tumor is accessible and can be removed while still leaving enough functioning myocardium intact.

 When to Refer

All patients with suspected cardiac tumors should be referred to a cardiologist or cardiac surgeon for evaluation and possible therapy.

Burnside N et al. Malignant primary cardiac tumours. Interact Cardiovasc Thorac Surg. 2012 Dec;15(6):1004–6. [PMID: 22922450]

Michael RJ. Cardiac tumor issue overview. Methodist DeBakey Cardiovasc J. 2010 Jul–Sep;6(3):2–3. [PMID: 20834204]

Motwani M et al. MR imaging of cardiac tumors and masses: a review of methods and clinical applications. Radiology. 2013 Jul;268(1):26–43. [PMID: 23793590]

TRAUMATIC HEART DISEASE

Trauma is the leading cause of death in patients aged 1–44 years of age; cardiac and vascular trauma is second only to neurologic injury as the reason for these deaths. Penetrating wounds to the heart are usually lethal unless surgically repaired. Stab wounds to the RV occasionally lead to hemopericardium without progressing to tamponade.

Blunt trauma is a more frequent cause of cardiac injuries, particularly outside of the emergency department setting. This type of injury is quite frequent in motor vehicle accidents and may occur with any form of chest trauma, including CPR efforts. The most common injuries are myocardial contusions or hematomas. Other forms of nonischemic cardiac injury include metabolic injury due to burns, electrical current, or sepsis. These may be asymptomatic (particularly in the setting of more severe injuries) or may present with chest pain of a nonspecific nature or, not uncommonly, with a pericardial component. Elevations of cardiac enzymes are frequent but the levels do not correlate with prognosis. Echocardiography may reveal an akinetic segment or pericardial effusion. Pericardiocentesis is warranted if tamponade is evident. Heart failure is uncommon if there are no associated cardiac or pericardial injuries, and conservative management is usually sufficient.

Severe trauma may also cause myocardial or valvular rupture. Cardiac rupture may involve any chamber, but survival is most likely if injury is to one of the atria or the RV. Hemopericardium or pericardial tamponade is the usual clinical presentation, and surgery is almost always necessary. Mitral and aortic valve rupture may occur during severe blunt trauma—the former presumably if the impact occurs during systole and the latter if during diastole. Patients reach the hospital in shock or severe heart failure. Immediate surgical repair is essential. The same types of injuries may result in transection of the aorta, either at the level of the arch or distal to the takeoff of the left subclavian artery. Transthoracic echocardiography and TEE are the most helpful and immediately available diagnostic techniques.

Blunt trauma may also result in damage to the coronary arteries. Acute or subacute coronary thrombosis is the most common presentation. The clinical syndrome is one of acute myocardial infarction with attendant ECG, enzymatic, and contractile abnormalities. Emergent revascularization is sometimes feasible, either by the percutaneous route or by coronary artery bypass surgery. LV aneurysms are common outcomes of traumatic coronary occlusions, likely due to sudden occlusion with no collateral vascular support. Coronary artery dissection or rupture may also occur in the setting of blunt cardiac trauma.

As expected, patients with severe preexisting conditions fare the least well after cardiac trauma. Data from ReCONECT, a trauma consortium, reveals that mortality is linked to volume of cases seen at various centers, preexisting coronary disease or heart failure, intubation, age, and a severity scoring index.

Bock JS et al. Blunt cardiac injury. Cardiol Clin. 2012 Nov; 30(4):545–55. [PMID: 23102031]

Clancy K et al. Screening for blunt cardiac injury: an Eastern Association for the Surgery of Trauma practice management guideline. J Trauma Acute Care Surg. 2012 Nov;73(5 Suppl 4): S301–6. [PMID: 23114485]

Harrington DL et al; Research Consortium of New England Centers for Trauma (ReCONECT). Factors associated with survival following blunt chest trauma in older patients: results from a large regional trauma cooperative. Arch Surg. 2010 May;145(5):432–7. [PMID: 20479340]

Restrepo CS et al. Imaging patients with cardiac trauma. Radiographics. 2012 May–Jun;32(3):633–49. [PMID: 22582351]

RISK OF SURGERY IN THE CARDIAC PATIENT

See Chapter 3.

HEART DISEASE & PREGNANCY

The management of cardiac disease in pregnancy is discussed in the references listed below, including the available scoring systems to assess risk. Only a few major points can be covered in this brief section. Fundamentally, the highest risk patients are those with pulmonary hypertension, severe valvular stenosis, cyanosis, and heart failure. Regurgitant valve disease patients tolerate pregnancy better than stenotic valve disease patients due to the afterload reducing effect of pregnancy.

A comprehensive review of the safety of drugs in pregnancy and during breast-feeding can be found at www.perinatology.com/exposures/druglist.htm.

CARDIOVASCULAR COMPLICATIONS OF PREGNANCY

Pregnancy-related hypertension (eclampsia and preeclampsia) is discussed in Chapter 19.

  1. Cardiomyopathy of Pregnancy (Peripartum Cardiomyopathy)

In approximately 1 in 3000 to 4000 live births, dilated cardiomyopathy develops in the mother in the final month of pregnancy or within 6 months after delivery. The disease may be related to a cathepsin-D cleavage product of the hormone prolactin, suggesting blockage of prolactin may be a potential therapeutic strategy if proven in clinical trials using bromocriptine. Immune and viral causes have also been postulated. Small studies have suggested some improvement with the use of intravenous immunoglobulin and pentoxifylline. The disease occurs more frequently in women over age 30 years, is usually related to the first or second pregnancy, and there has been some association with gestational hypertension and drugs used to stop uterine contractions. Risk factors include obesity, a history of cardiac disorders such as myocarditis, use of certain medications, smoking, alcoholism, multiple pregnancies, being African American, and being malnourished.

The course of the disease is variable; most cases improve or resolve completely over several months, but others progress to refractory heart failure. About 60% of patients make a complete recovery. Serum BNP levels are routinely elevated in pregnancy, but serial values may be useful in predicting who may be at increased risk for a worse outcome. Beta-blockers have been administered judiciously to these patients, with at least anecdotal success. Diuretics, hydralazine, and nitrates help treat the heart failure with minimal risk to the fetus. Some experts advocate anticoagulation because of an increased risk of thrombotic events, and both warfarin and heparin have their proponents. In severe cases, transient use of extracorporeal oxygenation (ECMO) has been lifesaving. Recurrence in subsequent pregnancies is common, particularly if cardiac function has not completely recovered, and subsequent pregnancies are to be discouraged if the EF remains < 55%. The risk of recurrent heart failure in a subsequent pregnancy has been estimated to be about 1 in 5 (21%).

Biteker M et al. Role of bromocriptine in peripartum cardiomyopathy. Am J Obstet Gynecol. 2009 Aug;201(2):e13. [PMID: 19306960]

Elkayam U et al. Peripartum cardiomyopathy. Cardiol Clin. 2012 Aug;30(3):435–40. [PMID: 22813368]

Johnson-Coyle L et al; American College of Cardiology Foundation; American Heart Association. Peripartum cardiomyopathy: review and practice guidelines. Am J Crit Care. 2012 Mar;21(2):89–98. Erratum in: Am J Crit Care. 2012 May;21 (3):155. Dosage error in article text. [PMID: 22381985]

Rutherford JD. Heart failure in pregnancy. Curr Heart Fail Rep. 2012 Dec;9(4):277–81. [PMID: 22821089]

Shah T et al. Peripartum cardiomyopathy: a contemporary review. Methodist Debakey Cardiovasc J. 2013 Jan–Mar;9(1): 38–43. [PMID: 23519269]

  1. Coronary Artery & Other Vascular Abnormalities During Pregnancy

There have been a number of reports of myocardial infarction during pregnancy. It is known that pregnancy predisposes to dissection of the aorta and other arteries, perhaps because of the accompanying connective tissue changes. The risk may be particularly high in patients with Marfan, Ehlers-Danlos, or Loeys-Dietz syndromes. However, coronary artery dissection is responsible for only a minority of the infarctions; most are caused by atherosclerotic CAD or coronary emboli. The majority of the events occur near term or shortly following delivery, and paradoxical emboli through a PFO has been implicated in a few instances. Clinical management is essentially similar to that of other patients with acute infarction, unless there is a connective tissue disorder. If nonatherosclerotic dissection is present, coronary intervention may be risky as further dissection can be aggravated. In most instances, conservative management is warranted. At times, extensive aortic dissection requires surgical intervention. Recent studies suggest Marfan patients are particularly susceptible to further aortic expansion during pregnancy when the aortic diameter is > 4.5 cm and guidelines suggest pregnancy be discouraged in these situations.

Donnelly RT et al. The immediate and long-term impact of pregnancy on aortic growth rate and mortality in women with Marfan syndrome. J Am Coll Cardiol. 2012 Jul 17;60(3):224–9. [PMID: 22789886]

El-Deeb M et al. Acute coronary syndrome in pregnant women. Expert Rev Cardiovasc Ther. 2011 Apr;9(4):505–15. [PMID: 21517733]

Goland S et al. Pregnancy in Marfan syndrome: maternal and fetal risks and recommendations for patient assessment and management. Cardiol Rev. 2009 Nov–Dec;17(6):253–62. [PMID: 19829173]

Kealey A. Coronary artery disease and myocardial infarction in pregnancy: a review of epidemiology, diagnosis, medical and surgical management. Can J Cardiol. 2010 Jun;26(6):185–9. [PMID: 20548979]

  1. Prophylaxis for Infective Endocarditis During Pregnancy & Delivery

The 2007 ACC/AHA Task Force addressing adults with congenital heart disease has formulated guidelines outlining recommendations for pregnant women during labor and delivery. Pregnancy itself is not considered a risk for endocarditis. Since vaginal delivery might include bacteremia, the guidelines advocated endocarditis prophylaxis to cover the same high-risk groups as in the traditional endocarditis recommendations from the ACC/AHA, acknowledging the data are lacking to support this approach. It is reasonable (Class 2a, LOE C) to consider antibiotic prophylaxis against infective endocarditis before vaginal delivery at the time of membrane rupture in select patients with the highest risk of adverse outcomes, which include those with the following indications: (1) prosthetic cardiac valve or prosthetic material used for cardiac valve repair, and (2) unrepaired and palliated cyanotic congenital heart disease, including surgically constructed palliative shunts conduits.

Duval X et al; AEPEI Study Group. Temporal trends in infective endocarditis in the context of prophylaxis guideline modifications: three successive population-based surveys. J Am Coll Cardiol. 2012 May 29;59(22):1968–76. [PMID: 22624837]

Warnes CA et al. ACC/AHA 2008 Guidelines for the Management of Adults With Congenital Heart Disease. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2008 Dec 2;118(23):e714–833. [PMID: 18997169]

 Management of Labor

Although vaginal delivery is usually well tolerated, unstable patients (including patients with severe hypertension and worsening heart failure) should have planned cesarean section. An increased risk of aortic rupture has been noted during delivery in patients with coarctation of the aorta and severe aortic root dilation with Marfan syndrome, and vaginal delivery should be avoided in these conditions. For most patients, even those with congenital heart disease, vaginal delivery is preferred.

CARDIOVASCULAR SCREENING OF ATHLETES

The sudden death of a competitive athlete inevitably becomes an occasion for local if not national publicity. On each occasion, the public and the medical community ask whether such events could be prevented by more careful or complete screening. Although each event is tragic, it must be appreciated that there are approximately 5 million competitive athletes at the high school level or above in any given year in the United States. The number of cardiac deaths occurring during athletic participation is unknown, but estimates at the high school level range from one in 300,000 to one in 100,000 participants. Death rates among more mature athletes increase as the prevalence of CAD rises. These numbers highlight the problem of how to screen individual participants. Even an inexpensive test such as an ECG would generate an enormous cost if required of all athletes, and it is likely that few at-risk individuals would be detected. Echocardiography, either as a routine test or as a follow-up examination for abnormal ECGs, would be prohibitively expensive except for the elite professional athlete. Thus, the most feasible approach is that of a careful medical history and cardiac examination performed by personnel aware of the conditions responsible for most sudden deaths in competitive athletes. In a series of 158 athletic deaths in the United States between 1985 and 1995, hypertrophic cardiomyopathy (36%) and coronary anomalies (19%) were by far the most frequent underlying conditions. LV hypertrophy was present in another 10%, ruptured aorta (presumably due to Marfan syndrome or cystic medial necrosis) in 6%, myocarditis or dilated cardiomyopathy in 6%, aortic stenosis in 4%, and arrhythmogenic RV dysplasia in 3%. In addition, commotio cordis, or sudden death due to direct myocardial injury, may occur. More common in children, ventricular tachycardia or ventricular fibrillation may occur even after a minor direct blow to the heart; it is thought to be due to the precipitation of a PVC just prior to the peak of the T wave on ECG.

It is likely that a careful family and medical history and cardiovascular examination will identify some individuals at risk. A family history of premature sudden death or cardiovascular disease or of any of these predisposing conditions should mandate further workup, including an ECG and echocardiogram. Symptoms of unexplained fatigue or dyspnea, exertional chest pain, syncope, or near-syncope also warrant further evaluation. A Marfan-like appearance, significant elevation of BP or abnormalities of heart rate or rhythm, and pathologic heart murmurs or heart sounds should also be investigated before clearance for athletic participation is given. Such an evaluation is recommended before participation at the high school and college levels and every 2 years during athletic competition.

Stress-induced syncope or chest pressure may be the first clue to an anomalous origin of a coronary artery. Anatomically, this lesion occurs most often when the left anterior descending artery or left main coronary arises from the right coronary cusp and traverses between the aorta and pulmonary trunks. The “slit-like” orifice that results from the angulation at the vessel origin is thought to cause ischemia when the aorta and pulmonary arteries enlarge during rigorous exercise.

The toughest distinction may be in sorting out the healthy athlete with LVH from the athlete with hypertrophic cardiomyopathy. In general, the healthy athlete’s heart is less likely to have an unusual pattern of LVH, or to have LA enlargement, an abnormal ECG, an LV cavity < 45 mm in diameter at end-diastole, an abnormal diastolic filling pattern, or a family history of hypertrophic cardiomyopathy. In addition, the athlete is more likely to be male than the individual with hypertrophic cardiomyopathy. Increased risk is also evident in patients with the Wolff-Parkinson-White syndrome, a prolonged QTc interval, or the Brugada syndrome on their ECG.

Selective use of routine ECG and stress testing is recommended in men above age 40 years and women above age 50 years who continue to participate in vigorous exercise and at earlier ages when there is a positive family history for premature CAD, hypertrophic cardiomyopathy, or multiple risk factors. Because at least some of the risk features (long QT, LVH, Brugada syndrome, Wolff-Parkinson-White syndrome) may be evident on routine ECG screening, several cost-effectiveness studies have been done. Most suggest that pre-participation ECGs are of potential value, though what to do when the QTc is mildly increased is unclear. Many experts feel the high incidence of false-positive ECG studies make it very ineffective as a screening tool. With the low prevalence of cardiac anomalies in the general public, it has been estimated that 200,000 individual athletes would need to be screened to identify the single individual who would die suddenly. The issue of routine screening, therefore, remains controversial.

Once a high-risk individual has been identified, guidelines from the Bethesda conference and the ESC have been provided to help determine whether the athlete may continue to participate in sporting events. Table 10–19 summarizes these recommendations.

Table 10–19. Recommendations for competitive sports participation among athletes with potential causes of SCD.

Chandra N et al. Sudden cardiac death in young athletes: practical challenges and diagnostic dilemmas. J Am Coll Cardiol. 2013 Mar 12;61(10):1027–40. [PMID: 23473408]

Higgins JP et al. Sudden cardiac death in young athletes: preparticipation screening for underlying cardiovascular abnormalities and approaches to prevention. Phys Sportsmed. 2013 Feb;41(1):81–93. [PMID: 23445863]

Paterick TE et al. March Madness 2011: for whom the bell tolls? Am J Med. 2012 Mar;125(3):231–5. [PMID: 22340916]

Schoenbaum M et al. Economic evaluation of strategies to reduce sudden cardiac death in young athletes. Pediatrics. 2012 Aug;130(2):e380–9. [PMID: 22753553]