ACP medicine, 3rd Edition

Cardiovascular Medicine

Valvular Heart Disease

Ronan J. Curtin MD1

Fellow in Advance Cardiac Imaging

Brian P. Griffin MD2

Staff Cardiologist, Section of Imaging, and Director

1Department of Cardiac Medicine, Cleveland Clinic Foundation

2Cardiovascular Training Program, Department of Cardiology, Cleveland Clinic Foundation

Ronan J. Curtin, M.D., has no relationships with manufacturers of products or providers of services discussed in this chapter.

Brian P. Griffin, M.D., has received grants for clinical research from Pfizer, Inc.

June 2006

Valvular heart disease is an important cause of cardiac morbidity in developed countries despite a decline in the prevalence of rheumatic disease in those countries. Valvular heart disease can give rise to stenosis, regurgitation, or a combination of lesions at one or more valves. The more common significant anomalies that are currently encountered are mitral regurgitation, caused by mitral valve prolapse (MVP); aortic stenosis, caused by a congenital bicuspid valve or by senile valvular calcification; and aortic regurgitation, caused by a bicuspid aortic valve or dilatation of the aorta. Valvular lesions can occur as a result of pathologic changes in the valvular leaflets or supporting structures (i.e., the chordae or papillary muscles). Ventricular or aortic enlargement can also produce valvular regurgitation as a result of annular dilatation and inadequate leaflet coaptation in the absence of any specific valve pathology. Valvular heart disease tends to progress over time as degenerative changes are superimposed on the primary pathology. Iatrogenic causes of valvular disease are increasingly recognized. Common causes of major valvular lesions are listed [see Table 1].1

Table 1 Causes of Specific Valvular Lesions

 

Mitral

Aortic

Tricuspid

Pulmonary

Stenosis

Rheumatic disease, calcification, SLE

Calcification, congenital disease, rheumatic disease

Rheumatic disease, carcinoid tumor

Congenital disease, carcinoid tumor

Regurgitation

Myxomatous degeneration, ischemia, secondary causes, rheumatic disease, annular calcification, endocarditis, SLE

Congenital disease, secondary causes, rheumatic disease, endocarditis, SLE

Secondary causes, rheumatic disease, endocarditis

Secondary causes

SLE—systemic lupus erythematosus

Etiology

CONGENITAL DISORDERS

Bicuspid aortic valve, a condition in which the aortic valve has two leaflets instead of three, is the most common congenital cardiac disorder, affecting 1% to 2% of the population [see Figures 1a and 1b].2 Patients with bicuspid aortic valve tend to present with significant aortic stenosis or regurgitation in their fifth or sixth decade of life. The exact cause of bicuspid aortic valve is unknown, but there is a large heritable component and a significant association with other cardiovascular developmental disorders, including coarctation of the aorta, ventricular and atrial septal defect, mitral valvular abnormalities, and hypoplastic left heart.3 Many patients with a bicuspid aortic valve have an associated aortopathy with age-dependent aortic dilatation; by 40 years of age, the majority (77%) of patients have significant dilatation of the ascending aorta and aortic arch.4 A further insight into the complexity of bicuspid aortic valve was provided by the discovery that mutations in the NOTCH1 gene, a signaling and transcriptional regulator, were found to be associated with bicuspid aortic valve and other congenital cardiac disorders in two families.5

 

Figure 1. Pathologic specimen showing degenerative calcification of (a) a tricuspid aortic valve and (b) a congenital bicuspid valve.62

Unlike bicuspid aortic valve, unicuspid aortic valve is rare. The latter typically causes significant aortic stenosis by the third decade of life,6and it is associated with dilatation of the ascending aorta in almost 50% of patients. Pulmonary stenosis, a relatively common disorder, usually presents in childhood. Much less common are the congenital abnormalities of the atrioventricular valves, including cleft mitral valve and tricuspid atresia. Valvular abnormalities can be seen in specific developmental syndromes, such as pulmonary stenosis in rubella syndrome and supravalvular aortic stenosis in Williams syndrome.

MYXOMATOUS DEGENERATION

Myxomatous degeneration most often involves the mitral or tricuspid valve. In this condition, leaflet tissue, particularly chordal tissue, is abnormally extensible and weak. The affected valves are therefore more likely to prolapse, leading to significant regurgitation. On echocardiography, features of myxomatous degeneration include elongated and thickened mitral leaf lets with interchordal hooding and chordal elongation. Chordal rupture is common and may precipitate a rapid clinical deterioration resulting from sudden, severe regurgitation. The precise abnormality in valvular tissue is unknown, but it is thought to involve dysregulation of the extracellular matrix proteins.7 A familial tendency is often noted in this disease.8 Three genetic loci for autosomal dominant inherited myxomatous mitral valve disease have been described, but the precise genes and mutations responsible have not yet been delineated.9,10,11 Inherited connective tissue diseases such as Marfan syndrome produce valvular abnormalities similar to those found in myxomatous degeneration.

RHEUMATIC HEART DISEASE

Rheumatic fever is now rare in the United States, with approximately 100 cases reported each year; however, it remains a major health problem in developing countries, particularly sub-Saharan Africa and Southeast Asia.12 About 60% of people with rheumatic carditis develop chronic rheumatic heart disease. Rheumatic heart disease remains the most common cause of mitral stenosis in the United States; it is also a common cause of aortic regurgitation and multivalvular heart disease.13

Rheumatic fever appears to cause valvular heart disease by an autoimmune phenomenon whereby antibodies against streptococcal antigens cross-react with valvular tissue. Valvular involvement can present acutely as a result of edema of valvular tissue. Chronic rheumatic heart disease is caused by progressive fibrosis, superimposed calcification, and scarring with retraction of leaflet tissue—a process leading to valvular stenosis, incompetence, or both. The mitral and aortic valves are usually involved. The interval between the occurrence of rheumatic fever and occurrence of chronic rheumatic heart disease varies, as does the degree of involvement.

DEGENERATIVE HEART DISEASE

Degenerative calcification is a cause of aortic stenosis in the elderly and in patients with renal dysfunction; it results from calcium deposition on the body of the valvular leaflets rather than on the commissures [see Figures 1a and 1b].2 Factors that have been found to promote degenerative valvular changes are increasing age, a low body mass index, hypertension, and hyperlipidemia. Histologic changes that simulate atheroma and involve lipid deposition and inflammatory cell infiltration of the leaflets have been described in patients with early degenerative changes in the aortic leaflets. Even mild degenerative changes in the aortic valve have been reported to be adverse prognostic factors.14 Calcification of the mitral annulus is common in the elderly; it is more common in women than in men and can produce mitral regurgitation. Occasionally, mitral annular calcification extends onto the valvular leaflets, causing stenosis.

ENDOCARDITIS

Endocarditis usually occurs on previously abnormal valves, although overwhelming sepsis can infect normal valves. The predominant hemodynamic manifestation of endocarditis is valvular regurgitation. Contributory causes of endocarditis-related valvular regurgitation include leaflet prolapse (resulting from a large vegetation), leaflet perforation, and chronic scarring of infected tissue. In rare cases, large vegetations lead to valvular stenosis.

CORONARY ARTERY DISEASE

Mitral regurgitation is common in coronary artery disease (CAD) and has a number of causal mechanisms. Acute ischemia or infarction of a papillary muscle or of the wall to which the papillary muscle is attached leads to impaired leaflet coaptation and mitral regurgitation. Regurgitation can be severe and can vary with the severity of the ischemia. Papillary head rupture or, more rarely, muscle rupture leads to catastrophic regurgitation that is often fatal.

CONNECTIVE TISSUE DISEASE

Libman-Sacks endocarditis consists of noninfected warty vegetations involving predominantly the mitral valve; it is characteristic of systemic lupus erythematosus.15 Significant regurgitation and stenosis rarely occur acutely but are seen with scarring from chronic disease. Valvular involvement in rheumatoid arthritis is common and leads to valvular thickening but is usually not of hemodynamic significance. Aortitis in ankylosing spondylitis may produce significant aortic regurgitation.

IATROGENIC CAUSES OF VALVULAR HEART DISEASE

Iatrogenic causes include radiation therapy, drug therapy, and complications of permanent cardiac pacing devices. Radiation leads to scarring and calcification of valvular leaflets many years after the initiating radiation. This usually follows a typical pattern, affecting predominantly the aortic valve and anterior mitral leaflet. Treatment with serotonin agonists such as methysergide or treatment with anorexiants such as fenfluramine and phentermine in combination (fen-phen) can cause valvular injury [see Anorexiant-Induced Valvular Disorder, below].16,17,18 One report has suggested that implantation of right ventricular pacemaker and implantable cardioverter-defibrillator (ICD) leads can cause an injury to the tricuspid valve that results in severe symptomatic tricuspid regurgitation.19 The incidence of device-induced tricuspid regurgitation is not known and appears to be underestimated by transthoracic echocardiography.

OTHER CAUSES OF VALVULAR HEART DISEASE

Amyloid disease causes valvular thickening but rarely causes significant stenosis. The carcinoid syndrome most often involves the valves on the right side of the heart and leads to stenosis or incompetence of the tricuspid or pulmonary valve.

SECONDARY INVOLVEMENT

Left ventricular dilatation can cause dilatation of the mitral annulus and, thereby, mitral regurgitation. Common secondary causes of mitral regurgitation include CAD, aortic valvular disease, and dilated cardiomyopathy. Similarly, tricuspid regurgitation results from right ventricular enlargement secondary to pulmonary hypertension or an atrial septal defect. Dilatation of the ascending aorta, especially involving the annulus of the aortic valve, can lead to aortic regurgitation. This condition is seen in hypertension and in aneurysms of the ascending aorta.

Assessment and Management

Valvular heart disease often remains asymptomatic for many years, but once symptoms develop, survival is reduced if the lesion is not corrected. The assessment of patients with valvular heart disease can be summarized [see Table 2]. Patients should be carefully questioned regarding any limitation of physical activity. The evaluation of exercise capacity may require a stress test in some cases. The physical examination, which includes cardiac auscultation [see Table 3], is important in characterizing the lesion and its hemodynamic severity; however, all significant murmurs should be further assessed by echocardiography.20 Valvular stenosis is readily quantified by continuous wave Doppler echocardiography using the modified Bernoulli equation (P = 4v2, where P is the pressure gradient measured in mm Hg and v is the flow velocity measured in m/sec). For example, if the peak velocity recorded across the aortic valve by Doppler echocardiography is 4 m/sec, then the peak pressure gradient will be estimated as 4(42), or 64 mm Hg. Valvular regurgitation can be more difficult to assess and requires an integrated approach that includes color flow Doppler, continuous wave Doppler, pulsed wave Doppler, and two-dimensional echocardiographic measurements.21 The effects of valvular heart disease on chamber size and function are best assessed serially by echocardiography or, at the time of cardiac catheterization, by ventriculography. In cases of stenotic lesions, intervention is rarely required until symptoms occur. Indications for intervention in regurgitant lesions are more complex; such indications include significant symptoms or, in the absence of symptoms, increasing ventricular size, overt ventricular contractile dysfunction, or both.20 All patients with even mild valvular heart disease require prophylaxis against endocarditis at the time of dental procedures or other procedures that can produce significant bacteremia. The American Heart Association has recommended several prophylactic regimens [see Table 4].22

Table 2 Assessment of Patients with Valvular Heart Disease

Parameters

Tools

Symptom severity

History, stress testing

Nature of valve lesion

Auscultation, Doppler echochardiography

Hemodynamic severity of lesion

Physical examination, Doppler echocardiography, cardiac catheterization

Effects of lesion on cardiac chamber size and function

Echocardiography, cardiac catheterization, stress echocardiography

Determination of the optimal time for intervention

Echocardiography, stress echocardiography

Selection of appropriate procedure/prosthesis

Echocardiography

Table 3 Auscultatory Findings Associated with Common Valve Problems

Lesion

Cardiac Cycle

Quality

Location

Other Sounds

Aortic stenosis

Systolic, mid-peaking to late peaking

Harsh

Aortic area, left sternal border, apex

Soft S2, S4

Aortic regurgitation

Diastolic, early decrescendo

Blowing

Left sternal border, aortic area

Mitral stenosis

Diastolic, mid-peaking to late peaking, increases with atrial contraction if rhythm is normal

Rumble

Apex

Opening snap, loud S1

Mitral regurgitation

Systolic, holosystolic, late systolic with MVP, papillary muscle dysfunction

Blowing

Apex, axilla

Click, soft S1, S3

Tricuspid regurgitation

Systolic, increase with inspiration

Blowing

Lower left sternal border, xiphisternum

Pulmonary stenosis

Systolic, mid-peaking

Harsh

Pulmonary area, left sternal border

MVP—mitral valve prolapse

Table 4 Summary of American Heart Association Recommendations for Endocarditis Prophylaxis9

Procedure

Patient Condition

Drug

Regimen*

Dental, oral, respiratory tract, or esophageal

At risk

Amoxicillin

Adults, 2.0 g; children, 50 mg/kg; orally 1 hr before procedure

At risk and unable to take oral medications

Ampicillin

Adults, 2.0 g; children, 50 mg/kg. I.M. or I.V. within 30 min before procedure

At risk and allergic to amoxicillin, ampicillin, and penicillin

Clindamycin
      or
Cephalaxinor cefadroxil
      or
Azithromycin or clarithromycin

Adults, 600 mg; children, 20 mg/kg; orally 1 hr before procedure
Adults, 2.0 g; children, 50 mg/kg.; orally 1 hr before procedure
Adults, 500 mg; children, 15 mg/kg; orally 1 hr before procedure

At risk and allergic to amoxicillin, ampicillin, and penicillin and unable to take oral medications

Clindamycin
      or
Cefazolin

Adults, 600 mg; children, 20 mg/kg.I.V. within 30 min before procedure
Adults, 1.0 mg; children, 25 mg/kg. I.M. or I.V. within 30 min before procedure

Genitourinary/gastrointestinal

High risk

Ampicillin plus gentamicin

Ampicillin: adults, 2.0 g; children, 50 mg/kg
      plus
Gentamicin: 1.5 mg/kg (for both adults and children, not to exceed 120 mg) I.M. or I.V. within 30 min before starting procedure
   Then, 6 hr later,
Ampicillin: adults, 1 g; children, 25 mg/kg.I.M. or I.V.
      or
Amoxicillin, orally: adults, 1.0 g; children, 25 mg/kg

High risk and allergic to ampicillin and amoxicillin

Vancomycin plus gentamicin

Vancomycin: adults, 1.0 g; children, 20 mg/kg I.V.; over 1–2 hr
      plus
Gentamicin: 1.5 mg/kg (for both adults and children, not to exceed 120 mg) I.M. or I.V.
Complete injection/infusion within 30 min before starting procedure

Moderate risk

Amoxicillin
          or
Ampicillin

Adults, 2.0 g; children, 50 mg/kg; orally 1 hr before procedure
Adults, 2.0 g; children, 50 mg/kg. I.M. or I.V. within 30 min before starting the procedure

Moderate risk and allergic to ampicillin and amoxicillin

Vancomycin

Adults, 1.0 g; children, 20 mg/kg; over 1–2 hr; complete infusion within 30 min of starting the procedure

Note: For patients already taking an antibiotic or for other special situations, see reference 9.
*Total children's dose should not exceed adult dose.
Follow-up dose no longer recommended.
Cephalosporins should not be used in patients with immediate-type hypersensitivity reaction to penicillins.

Despite the increase in intravascular volume that occurs during pregnancy, pregnancy is usually well tolerated in previously asymptomatic patients with valvular heart disease.23 During pregnancy, regurgitant lesions are better tolerated than stenosis. Prophylactic intervention to increase the valvular area is recommended in patients with hemodynamically severe stenosis before pregnancy.

Patients with hemodynamically significant valvular heart disease should generally avoid participation in competitive sports. Reference should be made to the recommendations of the American College of Cardiology for more information about specific lesions.20 Valvular heart disease is a chronic disease requiring periodic examination and follow-up, even in asymptomatic patients and in those who have had corrective surgical or other procedures. Patients with prosthetic valves should be seen at least yearly.

Specific Valvular Lesions

MITRAL STENOSIS

Normally, the cross-sectional area of the mitral valve is at least 4 cm2. Mitral stenosis leads to a reduction in valvular area; stenosis is considered severe when the valvular area is less than 1 cm2. To maintain flow through the valve, left atrial pressure rises, leading to an increase in the pressure gradient across the valve and increased pulmonary venous and capillary pressures, with resultant dyspnea. Flow through the stenotic valve is dependent on the duration of diastole. Tachycardia shortens diastole disproportionately and causes a further elevation in left atrial pressure and can precipitate symptoms even in patients with relatively mild stenosis. Elevated left atrial pressure contributes to left atrial enlargement, which in turn predisposes the patient to atrial fibrillation, atrial thrombus formation, and thromboembolism, all of which are common complications of mitral stenosis. Severe mitral stenosis is often associated with an increase in pulmonary arterial pressure, leading to right-sided heart failure and secondary tricuspid and pulmonary incompetence. In patients with severe pulmonary hypertension, cardiac output at rest is reduced; this output reduction can cause a relatively low pressure gradient across the mitral valve even in patients with severe stenosis.

Diagnosis

Clinical manifestations

Mitral stenosis is often asymptomatic at presentation and for many years thereafter. Symptomatic patients often present with dyspnea, but they can also present with angina, right-sided heart failure, atrial arrhythmia, or embolism. The physical findings in mitral stenosis depend on the severity of the stenosis, the mobility of the valve, and the cardiac rhythm. The principal sign is a rumbling diastolic murmur that is best heard at the apex with the stethoscope bell. Such a murmur is accentuated by having the patient lie on the left side and by using provocative maneuvers, such as exercise, to increase the heart rate. In sinus rhythm, the murmur increases in intensity with atrial contraction (presystolic accentuation). Increased severity of stenosis is associated with a longer murmur and a thrill. With a pliable valve, an opening sound (the opening snap) is heard and the sudden closure of the stenotic valve at end diastole gives rise to a loud first heart sound that lends a tapping quality to the apex beat. When the valve calcifies and becomes less mobile, the opening snap and loud first heart sound disappear. A loud pulmonary component of the second heart sound is heard with pulmonary hypertension. The signs and symptoms of mitral stenosis are simulated by left atrial myxoma. In this condition, functional mitral stenosis results from a mobile tumor arising from the interatrial septum and prolapsing into the mitral valve opening.

Imaging studies

Electrocardiography can reveal left atrial enlargement if the patient is in sinus rhythm. Left atrial enlargement, mitral valve calcification, and signs of pulmonary congestion can all be present on chest x-ray. Echocardiography is the test of choice in confirming the diagnosis, establishing the severity of stenosis, detecting complications, and determining the most appropriate treatment. Echocardiography also allows accurate differentiation of mitral stenosis from a left atrial myxoma.

Typically, the stenotic mitral valve leaflets are thicker and less mobile than normal, and they are fused at the commissures. The severity of stenosis is determined by measuring the pressure gradient across the valve with Doppler echocardiography and by calculating the valvular area. Mitral stenosis should be suspected if the mean gradient exceeds 5 mm Hg; the pressure can exceed 20 mm Hg in severe stenosis. Valvular area is measured by tracing the smallest opening of the valve in cross section [see Figure 2]. This method is the most accurate way of defining the severity of stenosis, although it is technically demanding and sometimes impossible to perform by two-dimensional echocardiography.24 Three-dimensional echocardiography is better at identifying the true mitral valve orifice, and it allows very accurate measurement of mitral valve area; however, its availability is limited.25 Mitral valve area is most readily estimated by Doppler echocardiography. Such evaluation is made on the basis of an empirical formula that calculates the time it takes for the pressure gradient to fall to half its initial value (the pressure half-time). Valvular area is estimated as 220 divided by the pressure half-time. Pulmonary arterial systolic pressure (PAP) can be determined from the tricuspid regurgitant velocity (TRv) and the estimated right atrial pressure (RAP) (usually estimated as 5 mm Hg) by the following equation:

PAP = 4(TRv2) + RAP

If the tricuspid regurgitant velocity is 3 m/sec and if RAP is estimated to be 5 mm Hg, then the estimated PAP is 4(32) + 5 = 41 mm Hg. The likelihood that the valve may be successfully dilated, either with percutaneous balloon valvuloplasty or open surgical procedure, is estimated by use of a scoring system based on the echocardiographic appearance of the valvular leaflets and supporting structures.26

 

Figure 2. Two-dimensional echocardiographic parasternal short-axis image of a mitral valve before (left) and after (right) percutaneous balloon mitral valvuloplasty. The valve area is estimated by planimetry and increases from 0.7 cm2 before valvuloplasty to 2.4 cm2 after valvuloplasty.

Transesophageal echocardiography is more useful than trans thoracic echocardiography in excluding atrial thrombus and determining the severity of mitral regurgitation and is usually performed if balloon valvuloplasty is being considered. Cardiac catheterization is rarely needed to establish the diagnosis but is used to confirm the severity of stenosis. The valvular gradient is the difference between the left atrial pressure or the pulmonary arterial wedge pressure and the left ventricular diastolic pressure. Valvular area can be calculated from the pressure gradient and the cardiac output.

Stress echocardiography can be very helpful when there is a discrepancy between symptoms and baseline hemodynamic data. It provides an objective assessment of symptoms and functional capacity, as well as transmitral and pulmonary pressures at rest and with exercise. An exercise mean transmitral gradient of 15 mm Hg or higher and a peak right ventricular systolic pressure greater than 60 mm Hg indicate hemodynamically significant mitral stenosis.20

Treatment

Once symptoms develop in mitral stenosis, the chance of survival decreases without surgical or balloon dilatation or replacement of the valve. In the absence of symptoms, management is directed at preventing recurrence of rheumatic fever.27

Medical therapy

Patients in atrial fibrillation require heart-rate control with a beta blocker (e.g., atenolol, 50 mg daily), a calcium channel blocker (e.g., diltiazem CD, 100 mg daily), digoxin (0.125 to 0.25 mg daily), or a combination of these therapies. Systemic anticoagulation with warfarin is indicated to prevent thromboembolism when (1) atrial fibrillation is present, (2) there is a history of embolism, or (3) a thrombus is detected in the atrium. Anticoagulation should be considered for patients with paroxysmal atrial fibrillation, a dilated left atrium (> 50 to 55 mm in diameter on echocardiography), or severe atrial stasis (as evidenced by swirling echoes or smoke in the left atrium on echocardiography).28,29 In symptomatic patients for whom surgical intervention poses a relatively high risk, the judicious use of diuretics and drugs to control heart rate (i.e., digoxin, calcium channel blockers, or beta blockers) may allow symptomatic relief without the need for surgical intervention.

Surgical intervention

Intervention to increase valvular area is indicated before the onset of symptoms of dyspnea in the following patients: (1) women with severe stenosis who wish to become pregnant but are unlikely to tolerate the volume load of pregnancy, (2) patients who experience recurrent thromboembolic events, and (3) patients who have severe pulmonary hypertension. A number of interventions are currently available to increase the valvular area in mitral stenosis. These interventions include percutaneous balloon valvuloplasty, which is performed in the cardiac catheterization laboratory; surgical commissurotomy; and replacement of the mitral valve with a prosthesis.

Balloon valvuloplasty, which is performed by inflating a specially designed balloon catheter in the mitral orifice to split the fused commissures,30 provides excellent symptomatic relief in suitable patients31; it is currently the intervention of choice in mitral stenosis. Balloon valvuloplasty typically doubles the mitral valve area, from 1.0 cm2 to 2.0 cm2, and provides a concomitant reduction in the pressure gradient [see Figure 3]. Complications of mitral balloon valvuloplasty include severe mitral regurgitation (3%), thromboembolism (3%), and residual atrial septal defect with significant shunting (10% to 20%). Mortality associated with the procedure is less than 1%.32,33Contraindications to mitral balloon valvuloplasty include significant mitral regurgitation, which is likely to increase after balloon inflation; the presence of a left atrial thrombus, which can be dislodged at the time of the procedure; and significant subvalvular involvement or leaflet calcification, each of which increases the risk of complications and limits the degree of dilatation produced.34 In pregnant patients with symptomatically severe mitral stenosis that is not responsive to conservative measures (e.g., bed rest and heart-rate control), balloon valvuloplasty is the intervention of choice.35

 

Figure 3. Simultaneous left atrial pressure (LA, black line) and left ventricular pressure (LV, blue line) are shown before (a) and after (b) percutaneous mitral valvuloplasty. The shaded area shows the pressure gradient across the mitral valve; the pressure falls after valvuloplasty.

Surgical commissurotomy is usually performed under direct vision after cardiopulmonary bypass. Surgical commissurotomy may be feasible when balloon valvuloplasty is impossible (e.g., in patients with significant mitral regurgitation, subvalvular stenosis, or atrial thrombus). A number of studies comparing surgical commissurotomy with balloon commissurotomy have shown equivalent immediate, medium-term (3- to 4-year), and long-term (7-year) results with regard to increase in valvular area, improvement in symptoms, and freedom from repeat intervention in appropriately selected patients.34,36 At 7 years after balloon commissurotomy, 50% to 69% of patients remain free of major cardiovascular events, and up to 90% of patients remain free of reintervention.36,37,38 However, commissurotomy, whether effected by a balloon or surgically, is a palliative procedure; in most cases, further intervention is eventually required. Repeat commissurotomy is sometimes feasible; most often, mitral valve replacement is necessary.39

A prosthetic replacement is indicated if the valve is heavily scarred or calcified or if severe mitral regurgitation is present. Morbidity and mortality are higher with prosthetic replacement than with either surgical or balloon commissurotomy.

MITRAL REGURGITATION

Mitral regurgitation leads to volume overload of the left ventricle, which must increase in size to achieve a normal stroke output to accommodate the leakage of blood back into the left atrium. Progressive left ventricular dilatation eventually leads to an increase in afterload, contractile impairment, reduction of cardiac output, and heart failure. In acute mitral regurgitation (such as that which can occur with chordal rupture, ischemia, or endocarditis), left atrial and pulmonary venous and arterial pressures increase quickly, giving rise to dyspnea and, often, acute pulmonary edema. In more chronic forms of mitral regurgitation, an increase in left atrial pressure is often offset by a concomitant increase in atrial compliance; hence, symptoms appear late in the course of the disease. Left atrial enlargement predisposes the patient to atrial fibrillation and atrial thromboembolism. In long-standing mitral regurgitation, pulmonary hypertension can develop, which in turn leads to tricuspid regurgitation and right-sided heart failure.

Diagnosis

Clinical manifestations

In most patients, mitral regurgitation remains asymptomatic for many years. Dyspnea, fatigue from low cardiac output, and edema occur late in the course of the disease. Mitral regurgitation is recognized clinically by a systolic murmur at the apex, radiating to the axilla and increasing on expiration. In patients with a posteriorly directed jet of mitral regurgitation, the murmur is heard well at the back. In more severe cases, the murmur lasts throughout systole, the first and second heart sounds are soft or difficult to hear, and a third heart sound is present. A midsystolic click can be present in myxomatous disease; in less severe cases, this click can precede the murmur. The murmur can also be confined to late systole with papillary muscle dysfunction. Mitral regurgitant murmurs caused by ischemia can be variable in duration and intensity, depending on the degree of ischemia and the loading conditions.

Imaging studies

Doppler echocardiography is the noninvasive method of choice in confirming the presence of mitral regurgitation. Doppler echocardiography is used both to diagnose the mechanism of the regurgitation (e.g., prolapse or annular dilatation) and to provide a measure of its severity [see Assessment of Regurgitation Severity, below]. Transesophageal echocardiography is very sensitive in the detection of mitral regurgitation; it is used mainly in patients who are difficult to evaluate by the transthoracic approach or when the valvular morphology and regurgitant severity are still in question after transthoracic echocardiography. Contrast ventriculography is used to determine the severity of mitral regurgitation in patients undergoing cardiac catheterization. This procedure involves injecting radiopaque contrast medium into the left ventricle and assessing the extent and duration of opacification of the left atrium. In patients undergoing hemodynamic monitoring, large systolic V waves on the pulmonary arterial wedge tracing raise the suspicion of acute severe mitral regurgitation, as can occur in acute ischemia; however, such systolic V waves can occur in the absence of severe regurgitation.

Assessment of regurgitation severity

Measuring the severity of regurgitation by echocardiography requires an integrated assessment of several parameters. These include color flow Doppler to assess the regurgitant jet; continuous wave Doppler to assess jet density; pulsed wave Doppler to assess transmitral and pulmonary venous flow; and two-dimensional echocardiography to assess structural features (e.g., left atrial size, left ventricle size, and contractile function).21 Quantitative measurements of regurgitation—such as the regurgitant volume, regurgitant fraction (i.e., regurgitant volume divided by [regurgitant volume plus stroke volume]), and regurgitant orifice area (ROA) (i.e., the area through which the valve leaks)—are now possible with newer Doppler techniques. An accurate measurement of ROA and regurgitant volume can be achieved in most patients by the flow convergence (also called the proximal isovelocity surface area (PISA]) method of calculation. This method is based on the principle that as blood approaches the regurgitant orifice, its velocity increases and its volume remains constant. This can be represented graphically as a series of hemispheres of increasing velocity and decreasing surface area on the ventricular aspect of the mitral regurgitant orifice [see Figure 4]. Knowing the velocity of one of these hemispheres (Nyquist limit) and its radius allows us to calculate the ROA by using the following formula:

ROA = 2πr2 × Va/Pk Vreg

where r is the radius, Va is the Nyquist limit of blood flow in the direction of the regurgitant jet, and Pk Vreg is the maximal velocity of the regurgitant jet on continuous wave Doppler. This method of calculation, when properly applied, is useful in determining the true severity of the lesion; repeated calculations can be used to evaluate the changes of the lesion over time.40

 

Figure 4. Transesophageal echocardiogram of a patient with severe, posteriorly directed mitral regurgitation (MR). An aliasing radius of 1.2 cm was measured at a Nyquist limit of 60 cm/sec. Peak MR velocity by color flow Doppler measured 540 cm/sec (not shown). Using the formula ROA = 2πr2 × Va/Pk Vreg, the ROA was calculated at 1 cm2 (6.28 × (1.2)2 × 60/540). (ROA—regurgitant orifice area; r—radius; Va—Nyquist limit; Pk Vreg—maximal velocity of regurgitant jet on continuous wave Doppler)

Calculation of ROA may prove useful in determining the appropriate timing of surgery in asymptomatic patients [see Indications for Surgery in Asymptomatic Patients, below]. However, size and volume of the left ventricle and contractile function, as assessed by the ejection fraction, are the standard parameters used to determine the need for surgical intervention.

Treatment

Indications for surgery in asymptomatic patients

Asymptomatic mitral regurgitation is more difficult to assess than other valvular lesions because in this condition, the true contractile function of the left ventricle is difficult to determine with conventional measures such as the ejection fraction. Left ventricular dysfunction is often latent, and once present, the dysfunction may not be corrected by operative intervention.41 Conventional measurements of contractility are confounded by the increase in ventricular preload caused by the extra volume of blood in the left atrium and the variable effect on afterload. Afterload is increased by left ventricular dilatation, but this effect is offset as the ventricle ejects much of its blood into a relatively low pressure system (the left atrium). The left ventricular ejection fraction can appear falsely elevated in mitral regurgitation and usually falls after surgical correction. An ejection fraction of less than 60% should be considered abnormally low in patients with mitral regurgitation. The American Heart Association/American College of Cardiology (AHA/ACC) guidelines recommend referral for mitral valve repair or replacement when the left ventricular end-systolic dimension is greater than 4.5 cm and resting ejection fraction is less than 60%.20 There is evidence, however, suggesting that a left ventricular end-systolic dimension greater than 4.0 cm is more sensitive to contractile reserve and that its use as an indication for surgery leads to improved postoperative outcomes.42,43 Stress echocardiography is useful in detecting latent left ventricular dysfunction not evident on a resting study. Failure of the left ventricular ejection fraction to increase or failure of the left ventricular end-systolic volume to decrease on exercise is predictive of incipient left ventricular dysfunction, but this finding is not a well-established indication for early surgery.44,45 Recent data indicate that quantitative measurements of mitral regurgitation are also important in making a decision on the appropriate timing of surgery for patients with asymptomatic mitral regurgitation. An ROA greater than 0.4 cm2 indicates severe mitral regurgitation and, in asymptomatic patients, is associated with a high risk of cardiovascular events, including death.46 Serial echocardiographic evaluation should be performed at least yearly and should be performed more frequently as ventricular dilatation progresses in patients with severe asymptomatic mitral regurgitation. Studies indicate a better long-term survival rate in patients with severe mitral regurgitation when surgery is performed early.47,48

Indications for surgery in symptomatic patients

Symptomatic severe mitral regurgitation is considered an indication for surgical intervention if the valve is primarily involved. Symptom atic patients with ischemic mitral regurgitation often require mitral valve surgery in addition to revascularization [see Surgical Intervention,below]. Mitral regurgitation secondary to left ventricular dilatation often improves with afterload reduction, and surgical intervention is not usually indicated.

Patients with moderately severe or severe left ventricular dysfunction (ejection fraction < 35%) and significant mitral regurgitation were once thought to be poor surgical candidates because of high operative risk; however, studies have shown that there is acceptable risk associated with operations in these patients.49,50 Surgery usually improves symptoms in these patients, but a survival benefit has not yet been demonstrated.51,52

Nonsurgical intervention

Patients who are not considered suitable for surgery because of left ventricular dysfunction often benefit from afterload reduction and diuretics.53 However, in patients who have primary asymptomatic mitral regurgitation with preserved left ventricular function, afterload reduction has not been shown to delay surgery or improve left ventricular function in the few small studies that have addressed this issue; afterload reduction is not currently recommended to treat such patients.54 Afterload reduction is beneficial for stabilizing patients with hemodynamically significant acute mitral regurgitation in preparation for surgery.

Surgical intervention

Mitral valve repair is currently the technique of choice in the surgical management of mitral regurgitation caused by degenerative mitral valve disease, bacterial endocarditis, and, in select patients, ischemic mitral regurgitation [see Figures 5a and 5b]. Mitral valve repair is less useful for patients with rheumatic mitral disease because of the limited durability of valve repair in this patient group.55

 

Figure 5. Transesophageal echocardiogram of a patient with severe myxomatous mitral regurgitation (MR) before (a) and after (b) mitral valve repair.

Valve repair is accomplished by use of a variety of techniques, depending on the mechanism and etiology of the regurgitation. Such techniques include partial leaflet resection, chordal shortening or transfer, and insertion of an annuloplasty ring to reduce the size of the annulus. In patients with degenerative valve disease, the benefits of valve repair over valve replacement include lower operative and long-term mortality, better preservation of ventricular function, reduced need for warfarin therapy, and a lower risk of serious hemorrhage.56,57Reoperation rates for valve repair and valve replacement are similar (1% to 2% a year). Valve repair is most successful in patients who have degenerative mitral valve disease with severe mitral regurgitation caused by segmental posterior leaflet prolapse; in these patients, valve repair is enhanced by intraoperative echocardiography.58

Mitral valve repair for anterior leaflet prolapse is more challenging for the surgeon, and the risk of reoperation is higher than that associated with surgery for posterior leaflet prolapse.57 Nevertheless, the results remain more favorable for anterior leaflet repair than for mitral valve replacement. Long-term success with mitral valve repair for bacterial endocarditis is excellent, and evidence supports early consideration of surgery if indications are present.59

Mitral valve repair for ischemic mitral regurgitation remains controversial, but it may be successful in select patients.60,61 In patients with ischemic mitral regurgitation, valve repair generally consists of insertion of an undersized annuloplasty ring. Survival has increased dramatically for combined coronary artery and mitral valve surgery, and some of this improvement may be attributable to increasing rates of valve repair versus valve replacement.61,62 Some observational studies have shown that the addition of mitral annuloplasty to coronary artery bypass surgery in patients with ischemic mitral regurgitation results in an improvement in functional class and survival; however, other studies have not supported this finding.60,63

The decision whether to proceed with mitral valve repair or with mitral valve replacement should ideally include consultation with a surgeon who is skilled in mitral valve repair. If mitral valve repair is not possible, a mitral prosthesis is implanted.64 Prosthetic implantation procedures increasingly include preservation of chordal and papillary muscles, because evidence indicates that preservation of these muscles conserves left ventricular function after surgery.65 Percutaneous catheter repair of degenerative and ischemic mitral regurgitation is currently under investigation; various technologies have been used, including a clip that is deployed to improve coaptation of the valvular leaflets at their midpoint and an annuloplasty ring that is placed around the mitral valve annulus by way of the coronary sinus.66,67

MITRAL VALVE PROLAPSE

MVP is a common condition in which the mitral valve leaflets are displaced in systole into the left atrium.8 MVP has a highly variable natural history and can occur in some form in up to 2.4% of the general population.68,69 In the majority of cases, MVP represents a benign abnormality; in patients who develop significant mitral regurgitation, the disorder is associated with increased cardiovascular morbidity and mortality and requires surgical intervention.68 A variety of symptoms (e.g., atypical chest pain, palpitations, anxiety, and syncope) and clinical findings (e.g., low body weight, low blood pressure, pectus excavatum, and electrocardiographic abnormalities)—the so-called MVP syndrome—were attributed to MVP in the past.70 However, the association between MVP and most of these clinical findings is erroneous; most likely, the presumed association was drawn on the basis of selection bias and overdiagnosis of MVP in older studies. Only the association of MVP with low body weight was reproduced in the Framingham community-based study.71

Diagnosis

A midsystolic click at the mitral area during cardiac auscultation is often the finding that first brings MVP to the attention of the examiner. The click has been attributed to tensing of the redundant valvular tissue with cardiac contraction. A late systolic murmur can follow the click. Maneuvers that reduce intracardiac volume, such as having the patient stand or perform the Valsalva maneuver, cause the click to occur earlier in systole and cause an increase in the duration of the murmur. The typical auscultatory findings and their response to these maneuvers are sufficient to make a diagnosis of MVP. Two-dimensional echocardiography is the method of choice to confirm the diagnosis. Overdiagnosis of MVP by M-mode and two-dimensional echo cardiography was common before the realization that the mitral valve annulus is nonplanar and saddle shaped. True MVP is diagnosed on two-dimensional echocardiography by leaflet prolapse beyond the annular plane, as seen in a long-axis view.72 Two-dimensional echocardiography can also be used to determine whether the valvular leaflets are thickened and redundant, which indicates the presence of myxomatous mitral valve disease. Color flow Doppler echocardiography can establish the presence of associated mitral regurgitation.71 Patients with prolapse but with otherwise anatomically normal leaflets and no mitral regurgitation are at low risk for complications.

Treatment

Asymptomatic mitral valve prolapse requires no specific treatment. Periodic examination is indicated to detect any progression in the severity of mitral regurgitation. Prophylaxis for endocarditis is indicated if both a click and a murmur are present, but it is not indicated in the absence of mitral regurgitation.22 Treatment of mitral regurgitation is discussed elsewhere [see Mitral Regurgitation, above].

AORTIC STENOSIS

The normal aortic valve area (AVA) is 3 to 4 cm2 in area when the valve is fully open. Aortic stenosis is considered severe when the AVA is 1 cm2 or less and is considered critical when the AVA is less than 0.75 cm2. Aortic stenosis causes concentric left ventricular hypertrophy as a compensatory mechanism that maintains cardiac output at rest despite the increased pressure gradient across the valve. Eventually, this compensatory mechanism is overcome, causing the left ventricle to fail and dilate and the resting cardiac output to decline.

Diagnosis

Clinical manifestations

There is a variable relation between the severity of stenosis and symptoms. Many patients with critical aortic stenosis are asymptomatic, whereas patients in states of volume overload, such as pregnancy, may have symptoms with stenosis of lesser severity. Dyspnea is often the presenting feature; it reflects increased left atrial pressure and pulmonary venous hypertension from the increased left ventricular pressure in systole and the diastolic ventricular dysfunction imposed by left ventricular hypertrophy. Angina is common even in the absence of significant obstruction in the epicardial coronary blood vessels because of impaired supply of blood to the subendocardium in the hypertrophied left ventricle. Exertional syncope also occurs with stenosis and can result from the inability to increase cardiac output sufficiently to supply both skeletal muscle and the cerebral vasculature, resulting in impaired cerebral blood supply, or from abnormal baroreceptor reflexes. Serious arrhythmia can also cause syncope and, in severe aortic stenosis, even sudden death. Fatigue is common because of low cardiac output.

In severe aortic stenosis, the carotid pulse typically is reduced in intensity and has a slow delayed upstroke. Aortic stenosis gives rise to a systolic murmur that is heard over the aortic area and that can radiate to the carotid arteries and to the apex. In severe stenosis, the murmur peaks later in systole and can be associated with a thrill. A fourth heart sound is usually present. In mobile congenitally abnormal valves, an ejection click can precede the murmur. Severe calcific aortic stenosis is often associated with a diminished intensity of the aortic component of the second heart sound. Although the physical findings are important in alerting the clinician to the presence of aortic valve disease, the degree of hemodynamic severity is more reliably determined with Doppler echocardiography.

Imaging studies

The presence of left ventricular hypertrophy on electrocardiography provides useful supporting evidence for significant aortic stenosis. Doppler echocardiography is used to determine the mechanism and the hemodynamic severity of the stenosis and the effects of disease on left ventricular size and function. In aortic stenosis, the opening of the aortic valve is reduced, as seen on the echocardiogram.

Assessment of stenosis severity

Using two-dimensional and Doppler echocardiography, the modified Bernoulli equation can be used to measure the aortic pressure gradient, and the AVA can be calculated by using the continuity equation. In patients with severe aortic stenosis, the mean pressure gradient across the valve is usually more than 50 mm Hg, and the AVA is less than 1.0 cm2. The transvalvular gradients are typically overestimated in patients with coexisting aortic regurgitation and underestimated in patients with reduced cardiac output. The measurement of the AVA by use of the continuity equation is relatively unaffected by either of these scenarios; therefore, measurement of AVA by this method is a useful complement to the measurement of peak and mean gradients. However, in two patient groups—namely, patients with very severe left ventricular dysfunction and patients with very low flow rates—the AVA measured by the continuity equation tends to underestimate the true AVA.73,74 In patients with low cardiac output, dobutamine stress echocardiography can help differentiate true aortic stenosis from pseudoaortic stenosis.75 Truly severe aortic stenosis is suggested by an AVA that does not increase with dobutamine infusion. In addition, low-dose dobutamine stress echocardiography can detect contractile reserve—a feature that is associated with a lower operative risk and better long-term prognosis after aortic valve replacement in patients with severe left ventricular dysfunction.76,77

Invasive evaluation

Because of the accuracy of echocardiography, invasive assessment of aortic stenosis by right and left heart catheterization using the Gorlin equation is necessary only when there is a discrepancy between the clinical and the echocardiographic findings [see Figure 6].78 It should be noted that in patients with low cardiac output, the AVA calculated by echocardiography is more accurate than invasive assessment using the Gorlin equation.79 Because there is a high incidence of CAD in patients with aortic valve stenosis, cardiac catheterization is frequently performed before aortic valve replacement to assess for CAD.80

 

Figure 6. Simultaneous left ventricular (broken blue line) and aortic (solid blue line) pressure tracings and continuous wave Doppler tracing in a patient with severe aortic stenosis. The pressure gradient (P-P; 30 mm Hg) is the area between the aortic and left ventricular (LV) tracings. Maximal pressure gradient (Max) by cardiac catheterization (60 mm Hg) is similar to that measured by Doppler echocardiography (64 mm Hg).78

Treatment

Medical treatment

Currently, there is no specific medical treatment for aortic stenosis. Because degenerative aortic stenosis has many features in common with atherosclerosis, including similar risk factors, statin therapy has been postulated as a possible treatment. Initial retrospective studies suggested a clinical benefit of statin therapy in slowing aortic stenosis progression, but this finding has not been reproduced in one relatively small randomized, controlled trial.81,82,83 Larger clinical trials are currently under way.

Indications for surgery

Aortic stenosis is a progressive disease, and patients with the disease can remain asymptomatic for many years. The rate of progression varies greatly but increases with age, associated CAD, and the severity of the stenosis.84 Progression to symptoms is more likely when the AVA is relatively small or when left ventricular hypertrophy is present.85 Once symptoms become manifest, the survival rate without surgical treatment is reduced; mean survival is 5 years in patients with angina, 3 years in patients with syncope, and 2 years or less in patients with heart failure.84 Operative mortality increases with severe symptoms, advanced age, and the presence of left ventricular dysfunction. The onset of symptoms, therefore, is the major indication for surgical intervention. Left ventricular dysfunction attributable to aortic stenosis is another indication for intervention, because it demonstrates the failure of compensatory mechanisms and the presence of incipient symptoms. Sudden death occurs without symptoms in about 4% of patients who have an initial peak systolic velocity of 4 m/sec or greater, as detected by Doppler echocardiography, and who are followed for 5 years. Patients should be instructed to report the onset of any symptoms and should undergo regular follow-up evaluations with physical examination and Doppler echocardiography. Doppler examination should be performed at least yearly in patients with moderate or severe aortic stenosis. Asymptomatic patients with severe aortic stenosis who have moderate or severe calcification, left ventricular systolic dysfunction, hypotension on exercise, ventricular tachycardia, excessive left ventricular hypertrophy, or an AVA less than 0.6 cm2 are at higher risk for adverse outcomes and should either be monitored more closely until symptoms supervene or be considered for elective surgery.20,86 Brain natriuretic peptide (BNP) measurement appears to be an independent predictor of mortality in patients with severe aortic stenosis; in asymptomatic patients, regular BNP measurement may supplement assessment of symptoms in determining the timing of aortic valve replacement.87,88 More experience with measurement of BNP in aortic stenosis is required before any firm recommendations can be made.

The decision whether to perform prophylactic aortic valve replacement in a patient with mild to moderate asymptomatic aortic stenosis who is undergoing coronary bypass surgery is a difficult one; it is dependent on the characteristics of the individual patient, including age, the grade of severity of aortic stenosis on echocardiography, and the rate of disease progression. In general, for patients younger than 70 years, concomitant aortic valve replacement should be recommended if the peak aortic gradient is greater than 25 to 30 mm Hg.89 Aortic valve surgery in the very elderly is associated with increased mortality, but it provides excellent palliation of symptoms; surgery should be considered for such patients provided they are otherwise good candidates.85 Patients with severe left ventricular dysfunction resulting from aortic stenosis should also be considered for surgery, because significant improvement in ventricular function and symptoms is often achieved by surgery and because the survival rate in these patients is poor without surgery.

Surgical intervention

Surgical intervention for patients with aortic stenosis usually involves insertion of a prosthesis or a human valve. In congenital aortic stenosis, valve repair or commissurotomy can be feasible, although significant aortic regurgitation can result. Balloon valvuloplasty has proved to be disappointing in the long-term treatment of adult calcific aortic stenosis. Balloon valvuloplasty typically increases AVA from 0.5 cm2 to 0.8 cm2 and is associated with improvement of symptoms in the majority of cases30; however, stenosis recurs in as many as 50% of patients within 6 months, and fewer than 25% survive more than 3 years.90 Balloon valvuloplasty is now indicated in the palliative treatment of adult patients with aortic stenosis who are not surgical candidates because of significant comorbidity; it is also used to stabilize critically ill patients for whom surgery is planned at a later stage. Balloon dilatation is effective in young patients with congenital aortic stenosis and is an alternative to surgery in symptomatic aortic stenosis during pregnancy. Successful percutaneous deployment of an aortic valve prosthesis has been reported in humans and is currently under clinical investigation.91

AORTIC REGURGITATION

Aortic regurgitation causes volume overload of the left ventricle. In chronic aortic regurgitation, the volume overload is well tolerated for years. The left ventricle dilates to accommodate the increased volume load and thereby maintains a normal resting cardiac output. In aortic regurgitation, unlike in mitral regurgitation, the left ventricle must expel all of the increased volume of blood into the systemic circulation; severe enlargement of the left ventricle is common. Because of a compensatory increase in ventricular compliance, left ventricular diastolic pressure often remains in the normal range despite the increase in ventricular size. The ventricle hypertrophies to maintain normal wall stress. Eventually, compensatory mechanisms fail, and contractile impairment and increased diastolic pressure result in elevated left atrial and pulmonary venous pressures and symptoms. Acute aortic regurgitation can develop as a result of sudden disruption of the valve apparatus with endocarditis or aortic dissection. This condition is poorly tolerated because the left ventricle is unable to dilate fast enough to compensate for the volume load. Left ventricular diastolic pressure rises rapidly and leads to pulmonary congestion and edema. Cardiac output falls, and shock and even death can follow.

Diagnosis

Clinical manifestations

In chronic aortic regurgitation, symptomatic presentation occurs late in the course of disease; dyspnea and fatigue are the usual findings. Angina can occur in the absence of CAD because of the increased demand for oxygen caused by severe left ventricular enlargement and hypertrophy together with the reduced supply of oxygen resulting from the underperfusion of the coronary arteries. Such underperfusion is caused by the low diastolic pressure that is characteristic of this condition.

The cardinal physical sign of aortic regurgitation is a diastolic murmur that is high pitched and best heard with the diaphragm of the stethoscope with respiration suspended in expiration. The murmur is loudest immediately after aortic valve closure; it progressively diminishes in intensity throughout diastole, paralleling the decline in the pressure gradient between the aorta and the left ventricle. The murmur is best heard on the left of the sternal border in disease of the aortic cusps and on the right of the sternal border in disease of the aortic root. Even in the absence of significant stenosis, an aortic systolic murmur is audible, reflecting the increased flow through the valve. Severe chronic aortic regurgitation is characterized by a wide pulse pressure and an elevated systolic pressure caused by the increased stroke output; also characteristic is a reduction in the diastolic pressure, which occurs as blood leaks back into the left ventricle throughout diastole. If the aortic regurgitant jet hits the mitral valve leaflet, it can cause partial closure of the valve, creating an apical diastolic murmur that simulates mitral stenosis (Austin Flint murmur). The ejection of a large volume of blood into the systemic circulation and its rapid leak backward into the heart cause many peripheral circulatory manifestations that confirm rather than establish the diagnosis. Acute aortic regurgitation can be more difficult to recognize because the murmur is often short, and the reduced cardiac output leads to reduced intensity of the murmur.

Imaging studies

Marked cardiomegaly and prominence of the ascending aorta are often present on chest x-ray in patients with chronic severe aortic regurgitation. Doppler echocardiography confirms the mechanism and severity of aortic regurgitation and its effect on left ventricular size and function. Regurgitant volume and fraction can be quantified by echocardiographic Doppler techniques. More often, the severity of regurgitation is graded on the basis of several qualitative and semiquantitative measures, including the dimensions of the regurgitant jet in the left ventricular outflow tract, as determined by color flow Doppler mapping, and the presence of diastolic flow reversal in the descending thoracic aorta, as determined by pulsed wave Doppler echocardiography [see Figures 7a and 7b].21 In severe aortic regurgitation, early closure of the mitral valve and diastolic mitral regurgitation can occur as a result of the increased pressure in the left ventricle in diastole [see Figures 7a and 7b]. Confirmation of the severity of aortic regurgitation is obtained by aortography, a process in which contrast medium is injected into the aortic root and the retrograde filling and clearing of contrast dye from the left ventricle are examined. Aortography should be performed if there is any discrepancy between the clinical findings and the findings on Doppler echocardiography. Stress ventriculography and echocardiography have both been used to determine the response of the left ventricle to the effects of exercise. A significant fall in left ventricular ejection fraction or an increase in end-systolic volume suggests incipient contractile dysfunction; however, this is not a well-established indication for early surgical intervention.

 

Figure 7. Parasternal long-axis view (a) and short-axis view (b) of a severely regurgitant aortic allograft. Aortic regurgitation (AR) is seen circumferentially around the insertion site. Diastolic mitral regurgitation (MR) is also seen.

Treatment

Chronic aortic regurgitation is well tolerated for many years.92 Operative mortality is increased and long-term survival reduced if the left ventricle is greatly enlarged or if left ventricular dysfunction has been present for more than 1 year. Left ventricular dysfunction that is present for a shorter period is likely to improve and even resolve after surgery. Several studies have shown that asymptomatic patients with normal left ventricular function can be safely followed for a long period (up to 11 years in one study) when serial physical examination and Doppler echocardiographic examination are performed at least yearly and then performed more frequently as left ventricular dilatation progresses.93 Surgery is indicated when symptoms develop. In asymptomatic patients, surgery is indicated when resting left ventricular function declines or if severe left ventricular dilatation (end-systolic dimension > 5 cm; end-diastolic dimension > 7 cm) occurs.20,94Evidence suggests that these dimensions should be normalized for body size and that surgery should be considered at an earlier stage, especially in women. Afterload reduction with vasodilators such as hydralazine, captopril, and nifedipine has been shown to reduce left ventricular volume and mass and increase ejection fraction in aortic regurgitation.54 However, vasodilator treatment for aortic regurgitation has yielded variable results in clinical trials.

Whereas one series has suggested that treatment with nifedipine delays the need for surgical intervention and improves recovery of myocardial contractility postoperatively, another showed no benefit with either nifedipine or enalapril in asymptomatic aortic regurgitation.95,96,97 Acute severe aortic regurgitation necessitates urgent surgery. Intravenous vasodilatation with sodium nitroprusside or another vasodilator can reduce the regurgitant volume and help stabilize the patient awaiting surgery.

Surgical intervention for aortic regurgitation usually leads to improvement in symptoms and left ventricular size. Although the operative risk is increased when severe left ventricular dilatation or dysfunction is present, significant improvement in symptoms and ventricular function often occurs after surgery; the prognosis without surgery is very poor.94 Aortic regurgitation usually requires insertion of a prosthesis or a human valve. Occasionally, repair is feasible, especially in cases of a prolapsing bicuspid valve or a dilated aortic ring.

TRICUSPID AND PULMONARY DISEASE

Specific Lesions

Tricuspid regurgitation

Tricuspid regurgitation is most often secondary to right ventricular dilatation and is the most common valvular problem of the right heart. Tricuspid regurgitation may be caused by damage to or disruption of the valvular apparatus resulting from transvenous permanent pacing and ICD leads. Tricuspid regurgitation is recognized on physical examination by the characteristic large V waves in the jugular venous pulse and by a systolic murmur heard at the base of the xiphisternum that increases on inspiration. In severe cases, pulsatile hepatomegaly is present. Doppler echocardiography allows rapid detection and assessment of the severity of the regurgitation. Presentation often includes fatigue from reduced forward output and peripheral edema. Severe tricuspid regurgitation is usually treated with surgical repair. If a repair is not possible, a biologic prosthesis is usually implanted because of the increased risk of thrombosis of a mechanical prosthesis at this position. Secondary tricuspid regurgitation can improve if the primary condition causing pulmonary hypertension is treated and leads to a decrease in right heart size.

Tricuspid stenosis

Tricuspid stenosis occurs in approximately 5% to 10% of patients with severe mitral stenosis. The characteristic physical findings are a large A wave in the jugular venous pressures and a diastolic murmur over the tricuspid area. Doppler echocardiography and right heart catheterization are both used to assess severity. The mean gradient across the tricuspid valve is typically greater than 5 mm Hg. In patients with significant stenosis, either balloon dilatation, surgical repair, or valve replacement is indicated.

Pulmonary disease

Congenital pulmonary stenosis occurs in isolation or as part of various syndromes and is usually detected before adulthood. Significant pulmonary stenosis is treated with balloon dilatation or surgery. Significant pulmonary insufficiency is rare but can occur with a carcinoid tumor or endocarditis or secondary to pulmonary hypertension. Pulmonary allograft implantation is indicated for severe cases.

Valve Replacement

Prosthestic valves can be classified into two groups—mechanical and biologic—each having different properties, problems, and indications.98

Mechanical prostheses

Mechanical prostheses are of two main types: ball-in-cage and tilting-disk [see Figures 8a and 8b]. The Starr-Edwards valve is the prototypical ball-in-cage valve that has been implanted with various modifications since the 1960s. Tilting-disk valves can consist of one or two leaflets. Single-leaflet models include the Björk-Shiley and Medtronic-Hall valves. The most commonly implanted bileaflet models are the St. Jude valve and the CarboMedics valve. The major advantage of mechanical prostheses is durability. Mechanical prostheses can remain functional for decades and are used especially in young or middle-aged patients to reduce the need for reoperation.99 Their chief disadvantage is the associated risk of thromboembolism, which necessitates long-term anticoagulation and carries a risk of hemorrhage. An increased incidence of subsequent infection, hemolysis, thrombosis of the valve, and mechanical failure is another problem associated with mechanical prostheses.

 

Figure 8. Two aortic mechanical prostheses. (a) Starr-Edwards ball-in-cage prosthesis and (b) St. Jude bileaflet tilting-disk prosthesis.

Biologic prostheses

Three classes of biologic valves are currently available: xenografts, allografts, and autografts. A xeno graft is a prosthesis fashioned from animal tissue [see Figures 9a and 9b]. Most xenografts consist of modified porcine valves that are preserved in glutaraldehyde and mounted on a stent.100 Prostheses have also been constructed of pericardium and other biologic materials.101 Stentless biologic prostheses are postulated to improve the effective size of the prosthetic valve opening and enhance regression of left ventricular hypertrophyr102; however, not all studies have confirmed this.103,104 Allografts (homografts) are human valves that have been harvested post mortem and either cryopreserved or treated with antibiotics.105 An autograft is a valve from the patient's own body that is removed from its original position and inserted at a different anatomic site.106,107 The most common autograft is the pulmonary valve inserted at the aortic position. A pulmonary allograft is inserted in its place.

 

Figure 9. (a) Top view of an aortic porcine xenograft that has been preserved in glutaraldehyde and mounted on a flexible plastic stent. (b) Bottom view of the same valve.

Patients with biologic valves have a lower risk of thromboembolism than those with mechanical prostheses, and they do not usually require long-term anticoagulation. Biologic valves are indicated for patients in whom anticoagulation is inappropriate. Xenografts are less durable than mechanical prostheses. Xenograft durability is greatest in patients older than 60 years and improves with age.108 Xenografts are not usually inserted in patients younger than 60 years because of the poor survival record of such grafts in this patient group. Allografts and autografts are alternatives to mechanical prosthetic implantation at the aortic or pulmonary positions in younger patients. Insertion of these valves is technically more demanding and is not widely done. No long-term survival benefit has been demonstrated for allografts over xenografts. Autografts have proved to be durable and have the potential to grow in situ.106,107 They are used in the management of pediatric and adolescent patients with aortic valve disease.109 Both allografts and autografts result in a low reinfection rate when used in the treatment of prosthetic aortic endocarditis; they are considered the valve replacement of choice for this condition.105

Problems and Complications of Valvular Prostheses

Thromboembolism

Systemic anticoagulation with warfarin or dicumarol decreases the incidence of, but does not eliminate the occurrence of, thromboembolism with mechanical valves.110 The incidence of thromboembolic events is lowest in patients younger than 50 years, lower with aortic prostheses than with mitral or multiple prostheses, and lower with bileaflet disk valves than with single-leaflet valves.111 Hemorrhagic events are more common in older patients. Anticoagulation is generally monitored using the international normalized ratio (INR). Studies have indicated that the level of anticoagulation required to prevent thromboembolism is less than was previously thought. A large study of anticoagulation in patients with mechanical prostheses has suggested that an INR of between 2.5 and 4.0 is desirable in most instances and minimizes hemorrhagic and thromboembolic complications.111 The appropriate INR for an individual patient will vary depending on the history of embolic or bleeding events; age; and type, position, and number of prostheses. Antiplatelet agents such as aspirin (81 mg q.d.) or clopidogrel (75 mg once daily) may be added to the anticoagulation regimen in patients who have sustained recurrent thromboembolic events despite adequate anticoagulation. Thromboembolic risk with xenografts is greatest in the first 3 months after surgery.112 During this period, oral anticoagulation medications are recommended for high-risk patients (e.g., those with mitral prostheses or paroxysmal atrial fibrillation); for patients who are not at high risk, aspirin, 325 mg/day, is recommended.

Valvular thrombosis

Acute thrombosis of a mechanical valve is more common with a single tilting-disk valve. The incidence is highest at the tricuspid position, followed by the mitral position and then the aortic position. Thrombosis of left-sided valves can lead to acute pulmonary edema and systemic thromboembolism. Reduced motion of the disk or ball is characteristic of valvular thrombosis and can be demonstrated with transesophageal echocardiography or fluoroscopy.113,114 There is usually an increased pressure gradient across the valve. Acute thrombosis of a mechanical valve is an indication for emergency surgery to remove the thrombus and to implant another prosthesis. In patients who are not surgical candidates or who are considered at high operative risk, thrombolysis has been used successfully to increase the valvular opening and motion and to reduce the valvular gradient. Success rates greater than 70% have been reported in a number of series.114Thromboembolism is the most common complication of thrombolysis in this setting and occurs in 12% to 22% of patients. Further episodes of valvular thrombosis after initial successful thrombolysis have been reported.114

Valvular failure

In mechanical prostheses, failure of one of the mechanical parts is rare but can have catastrophic consequences. Failure is most common with tilting-disk valves, particularly with the Björk-Shiley single-leaflet tilting-disk valve, which is no longer available commercially in the United States.115 Failure of the outlet strut in several of these models led to embolization of the disk and acute valvular failure, with high morbidity and mortality. Because even advanced imaging techniques have poor sensitivity to detect strut fracture, prophylactic repeat surgery was recommended for certain groups of patients in whom the failure rate was highest.115,116 These predictive models based on patient and implantation characteristics appear to have been successful.117 Valvular failure is expected with bioprostheses and allografts. Fortunately, degeneration is a slow process with biologic prostheses; significant hemodynamic consequences do not occur for years after implantation. Leaflet calcification can give rise to stenosis, whereas cusp degeneration can lead to perforation with resultant regurgitation. Degeneration of a biologic prosthesis is managed in the same way as stenosis or regurgitation of a native valve. Repeat surgery is indicated for significant symptoms or progressive ventricular enlargement or dysfunction.

Failure of either a mechanical or a biologic prosthesis can occur because of problems with the sutures holding the valve in place. Suture-related failures can occur spontaneously or because of associated infection. A St. Jude valve in which the sewing ring was impregnated with silver nitrate to reduce the likelihood of infection was recalled because of a high incidence of paravalvular leak. The paravalvular leak resulting from suture failure can begin as a relatively mild lesion, but progression is common. In severe instances, partial or complete dehiscence can result in a characteristic rocking motion of the valve, as revealed by echocardiography. Paravalvular leaks are often accompanied by significant hemolysis as red blood cells are destroyed at the site of increased shear stress.118 Hemodynamically significant paravalvular leaks are considered an indication for reoperation.

Infection

There is a greater risk of endocarditis with mechanical prostheses and xenografts than with native valves or allografts. Prosthetic valve endocarditis is often associated with abscess formation. Prosthetic vegetation and abscess formation are best evaluated by using transesophageal echocardiography, which should be performed if prosthetic valve endocarditis is being considered as a diagnosis. Prosthetic valve endocarditis is extremely difficult to eradicate with medical treatment alone; operative intervention is usually required.

Inherent or acquired prosthetic stenosis

All prosthetic valves are inherently stenotic, but in an appropriately selected prosthesis, the degree of stenosis is mild and not of clinical significance. Occasionally, a smaller-than-desirable prosthesis is implanted because the native valve annulus is small; a so-called patient-prosthesis mismatch has been described for both mitral and aortic valve replacements.119,120 In such cases, patients can manifest symptoms and signs of valvular stenosis; severely increased pressure gradients across the valve can also be present in these patients, especially during exercise. In severe cases, explantation of the prosthesis and annular reconstruction may be necessary to accommodate a prosthesis of sufficient size. Where possible, care should be taken to insert an appropriately sized prosthesis at the time of initial surgery.121 In some patients with mechanical prostheses, prosthetic stenosis is acquired because of ingrowth of a fibrous pannus that can impede blood flow and may require reoperation.

Problems associated with pregnancy

Pregnancy is contraindicated in women with mechanical prostheses because of considerable risk to mother and fetus. The risk to the mother is associated with difficulty in maintaining effective anticoagulation; the risk to the fetus is associated with potential teratogenic effects of warfarin.122 If possible, valve repair or insertion of an allograft or autograft should be attempted in a woman of childbearing age who wishes to become pregnant. Xenografts are less durable in young patients, especially during pregnancy, and are best avoided.123

The management of patients with mechanical prostheses who become pregnant or desire pregnancy is controversial. None of the three available anticoagulants have been adequately studied in pregnancy. Warfarin is associated with embryopathy and increases the risk of fetal wastage. Optimal anticoagulation is also difficult with unfractionated heparin, especially when given subcutaneously, and is associated with increased maternal risk of thromboembolism and hemorrhage.23 High rates of thromboembolism have been reported with use of low-molecular-weight heparin in pregnant women, which prompted the Food and Drug Administration to issue a black-box warning—the FDA's most serious warning in the labeling of a prescription medication. However, thromboembolism associated with use of low-molecular-weight heparin in pregnancy seems to be related to inadequate dosing and inadequate monitoring.124 Self-administration of either unfractionated or low-molecular-weight heparin subcutaneously throughout pregnancy (ideally, from the time of conception) is one approach to the management of pregnant patients with mechanical prostheses.23 Unfractionated or low-molecular-weight heparin is administered every 8 to 12 hours, and patients are monitored by their physician at least every 2 weeks. For patients treated with unfractionated heparin, the recommended level of the activated partial thromboplastin time is 2.0 to 3.0 times the control value 6 hours after administration. Because of an increased and changing dose requirement in pregnancy, weight-based dose calculation of low-molecular-weight heparin is inadequate. It is recommended that the patient's plasma level of low-molecular-weight heparin be measured before administration of each dose; the anti-Xa assay is used for this purpose. A predose anti-Xa level of 0.6 to 0.7 U/ml is recommended. Peak levels of anti-Xa (4 hours after dosing) should also be measured to detect excessive anticoagulation (> 1.5 U/ml). Subcutaneous heparin should be replaced by intravenous unfractionated heparin 18 to 24 hours before elective delivery. Low-dose aspirin may be considered for additional prophylaxis of thromboembolism in high-risk patients.125

ANOREXIANT-INDUCED VALVULAR DISORDER

Drugs that suppress appetite (anorexiants) have been reported to cause a valvular disorder similar to that caused by ergot derivatives and carcinoid syndrome. This finding was first reported in 1997, and a number of large studies since then have confirmed an increased prevalence of valvular disorders in populations treated with fenfluramine, dexfenfluramine, phentermine, or a combination of these drugs.16,17,18 Over 18 million prescriptions were filled for these drugs in 1996 alone. The precise pathophysiology of the valvular disorder is still unclear. All of these anorexiants affect central serotoninergic receptors. A causal relation of serotonin in this disorder is also suggested by the disorder's similarity to carcinoid disease, in which serotonin is also implicated as a causative factor. Initial reports suggested a high prevalence of valvular disease in patients treated with these anorexiants, and they were withdrawn from the market in September 1997. The prevalence of clinically symptomatic valve-related disease in patients receiving these drugs has been reported to be 1 in 1,000.126Anorexiant-drug valvulopathy affects mainly the aortic and mitral valve. Leaflet thickening, restricted leaflet motion, chordal thickening, and valvular regurgitation without stenosis are the most common abnormalities seen.127 Although valvular disease severe enough to warrant surgery has been reported, the valvular lesion, in many instances, has appeared to be mild or moderate in severity. Factors thought to increase the likelihood of more severe disease are longer duration of treatment with anorexiant therapy, use of drug combinations, and higher dosages of drugs. Patients receiving less than 3 months of treatment appear to have a relatively low likelihood of significant valvular disease.126 Studies also suggest that the valvular lesions may not progress and may even regress after discontinuance of the drug.128Patients exposed to anorexiants should undergo a thorough cardiovascular examination for signs of mitral or aortic regurgitation. Echocardiography is indicated if the physical findings suggest valvular disease or if the duration of treatment has been more than 3 months. Patients with evidence of valvular disease on echocardiography should be followed serially and receive prophylactic antibiotics for dental and other procedures associated with significant bacteremia.

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Editors: Dale, David C.; Federman, Daniel D.