ACP medicine, 3rd Edition

Cardiovascular Medicine

Cardiomyopathies

  1. William Dec M.D.1

Roman W. DeSanctis M.D.2

1Associate Professor of Medicine, Harvard Medical School, Medical Director, Cardiac Transplantation Program, and Director, Clinical Cardiology, Massachusetts General Hospital

2Evelyn and James Jenks/Paul Dudley White Professor of Medicine, Harvard Medical School, and Physician and Director (Emeritus) of Clinical Cardiology, Massachusetts General Hospital

September 2000

Classification of Cardiomyopathies

The cardiomyopathies are a diverse group of diseases characterized by myocardial dysfunction that is not related to the usual causes of heart disease, notably coronary atherosclerosis, valvular dysfunction, and hypertension. Cardiomyopathies are classified according to hemodynamic characteristics and etiology.

HEMODYNAMIC CLASSIFICATION

The four major hemodynamic categories of cardiomyopathies are dilated, hypertrophic, restrictive, and obliterative [see Table 1]. The major features of dilated cardiomyopathy are ventricular dilatation and systolic dysfunction, which usually involve both ventricles, although some degree of ventricular hypertrophy is often present. Right ventricular dysplasia is a subtype of dilated cardiomyopathy that primarily involves the right ventricle but that may ultimately progress to the left ventricle as well. The hallmark of hypertrophic cardiomyopathy is ventricular hypertrophy, which is usually massive. Often, the thickening of the interventricular septum is disproportionately greater than that of the free wall of the left ventricle. However, concentric hypertrophy, as well as many other patterns of localized hypertrophy, can occur with this disease.1 Restrictive cardiomyopathy is characterized by a rigid, poorly distensible myocardium that causes greatly diminished compliance; restrictive cardiomyopathy may mimic constrictive pericarditis clinically and hemodynamically. Obliterative cardiomyopathy is rarely seen in the Western world. It is endemic in other parts of the world, particularly eastern Africa and India, where it presents as endomyocardial fibrosis. The massive fibrosis of the endocardium encroaches on and diminishes the size of the ventricular cavities and causes a restrictive and obliterative hemodynamic pattern. Space-occupying thrombi associated with eosinophilic endomyocardial disease (also called Löffler endocarditis and fibroplastic endocarditis) may behave similarly.

 

Table 1 Morphologic and Hemodynamic Characteristics of the Cardiomyopathies

Although a single category called restrictive-obliterative has been proposed,2 we believe separate categories for restrictive and obliterative cardiomyopathies are still warranted, because restrictive cardiomyopathies involve only the myocardium, whereas the obliterative cardiomyopathies are characterized by both myocardial and major endocardial abnormalities. In any given case, features of more than one type of cardiomyopathy may be present. For example, the thick, stiff left ventricle of hypertrophic cardiomyopathy causes impaired diastolic relaxation and ventricular filling, which are also features of restrictive cardiomyopathy. Furthermore, the massive hypertrophy that characterizes hypertrophic cardiomyopathy may reduce left ventricular chamber size, which is also a feature of obliterative cardiomyopathy.

ETIOLOGIC CLASSIFICATION

The causes of cardiomyopathies are poorly understood; in many cases, the cause is unknown and the disorder is considered idiopathic. Recognized causes and associations include certain drugs and toxins and several infectious, systemic, infiltrative, nutritional, and ischemic disorders [see Table 2].

Table 2 Etiologic Classification of Cardiomyopathies

Cardiomyopathies of Unknown Etiology

  Idiopathic dilated cardiomyopathy

  Peripartum cardiomyopathy*

  Hypertrophic cardiomyopathy

  Endomyocardial fibrosis

  Subendocardial fibroelastosis

  Eosinophilic endomyocardial disease (also called Löffler endocarditis or fibroplastic endocarditis)

  Right ventricular dysplasia

  Idiopathic restrictive cardiomyopathy

Cardiomyopathies of Known Etiology

  Infectious

    Viral and rickettsial myocarditis (e.g., human immunodeficiency virus, coxsackievirus B,*cytomegalovirus*)

    Septic (bacterial endocarditis*)

    Syphilis

    Parasitic disease (e.g., Chagas disease, trichinosis, toxoplasmosis)*

    Bacterial toxins (e.g., diphtheria toxin) or hypersensitivity (rheumatic fever)

  Toxic

    Alcohol*

    Cobalt*

    Carbon tetrachloride

    Carbon monoxide*

    Thioridazine drugs

    Anticancer agents (e.g., daunorubicin, doxorubicin, cyclophosphamide)

    Antimonials

    Cocaine*

    Antiretroviral agents (e.g., zidovudine,* dideoxyinosine*)

    Interferon alfa

  Systemic

    Neuromuscular and muscular degenerative syndromes: muscular dystrophies (e.g., progressive muscular dystrophy, myotonic dystrophy), Friedreich ataxia

    Collagen vascular disease

    Sarcoidosis*

    Endocrine diseases* (e.g., thyrotoxicosis, myxedema, pheochromocytoma, acromegaly)

  Infiltrative

    Amyloidosis

    Hemochromatosis

    Glycogen storage disease

    Fabry disease

    Hurler syndrome

    Primary or metastatic tumors (e.g., lymphoma, melanoma)

  Nutritional

    Beriberi*

    Selenium deficiency*

    Kwashiorkor

  Ischemic

 

* Is potentially reversible.
 Usually causes a restrictive hemodynamic picture.

Dilated cardiomyopathy can either be idiopathic or have a known etiology. It can be associated with pregnancy, excessive alcohol consumption, or several disease processes or can occur as a toxic effect of drugs. Although the cause of obliterative cardiomyopathies remains unknown, the vast majority of cases of hypertrophic cardiomyopathy result from specific defects in the genes regulating the formation of cardiac muscle. Restrictive cardiomyopathies usually result from diseases that infiltrate the myocardium, such as amyloidosis, hemochromatosis, and glycogen storage diseases; however, many cases of restrictive cardiomyopathy are idiopathic.

When cardiomyopathy has a definite etiology—for example, when it is secondary to another disease (e.g., sarcoidosis or scleroderma)—signs of that process are usually evident. On rare occasions, however, cardiac involvement may precede other systemic manifestations.

Dilated Cardiomyopathy

ETIOLOGY

Pregnancy

Peripartum cardiomyopathy is an idiopathic dilated cardiomyopathy that usually develops in the last month of pregnancy or 3 to 4 months after parturition. It is unlikely that the stress of pregnancy exacerbates an underlying subclinical cardiomyopathy, because the disease typically develops well after the period of maximum physiologic stress has passed. A small minority of cases of peripartum cardiomyopathy have been shown by endomyocardial biopsy to result from acute inflammatory myocarditis.3

Drugs and Toxins

Dilated cardiomyopathy is associated with excessive alcohol intake. There is ample evidence that alcohol depresses cardiac function, and it appears that alcohol can damage the heart in some heavy drinkers.4 The typical patient with alcoholic cardiomyopathy is a middle-aged man who has consumed at least 80 g of alcohol daily for 10 or more years. Another drug that has been implicated in the development of dilated cardiomyopathy is cocaine.

Serious myocardial damage can result from certain drugs used in anticancer chemotherapy, especially the anthracycline drugs doxorubicin and daunorubicin. The incidence and, to some extent, the severity of these reactions are directly related to the cumulative dose. The incidence is 3.5% in patients who receive a cumulative dose of doxorubicin of 400 mg/m2, 7% in patients who receive 550 mg/m2, and 15% in patients who receive 700 mg/m2.5,6 There is evidence that cardiotoxicity is reduced if doxorubicin is administered in smaller doses (20 mg/m2) on a weekly basis rather than in larger doses (60 mg/m2) every 3 weeks. Patients with preexisting cardiac disease, those 70 years of age or older, and those treated with concomitant mediastinal irradiation are more vulnerable.7 Combinations of doxorubicin with other antineoplastic drugs, such as dactinomycin, dacarbazine, cyclophosphamide, and mitomycin, also appear to increase the risk. There is evidence that the bispiperazinedione dexrazoxane can protect against cardiac toxicity when given simultaneously with doxorubicin to women with breast cancer, but this may also partially reduce the beneficial chemotherapeutic effects of doxorubicin.8

Congestive heart failure associated with anthracycline administration may develop within 2 months after the last dose of the drug, although latent periods of several months or years have been reported.9 Among 201 pediatric cancer patients who had received anthracycline therapy and were followed for 4 to 20 years, 23% showed evidence of late cardiac abnormalities.9 Mortality can be as high as 60%.

Infectious and Autoimmune Processes

Some cases of cardiomyopathy that are classified as idiopathic may be sequelae of viral infections, such as infection with coxsackievirus B,10or autoimmune processes.11 Although enteroviral RNA sequences have been detected in explanted myocardium or in endomyocardial biopsy samples of 25% to 30% of patients with idiopathic dilated cardiomyopathy, the significance of those sequences is uncertain.12,13 Some investigators have reported that patients with dilated cardiomyopathy demonstrate a significantly higher incidence of the histocompatibility antigens HLA-B27 and HLA-DR4 and reduced suppressor cell activity, but other researchers have found no evidence of an abnormal cellular immune response. In addition, beta1 receptor antibodies have been reported to occur in up to 45% of cases of dilated cardiomyopathy.14Transvenous endomyocardial biopsy has revealed that a significant number of these patients also have active myocarditis. The precise implications of these findings remain unclear.

There is a high incidence of cardiac dysfunction in patients with AIDS. Evidence of clinically reduced myocardial function, usually determined by cardiac echocardiography, has been noted in 10% to 20% of patients with AIDS,15 and autopsy evidence of myocarditis has been found in approximately 50% of patients who have died of AIDS.16 It is unclear how much of the myocardial dysfunction results from HIV infection itself, but substantial evidence suggests that HIV plays an important role. Additionally, opportunistic infections—viral, protozoal, fungal, and bacterial—have all been implicated. Furthermore, reversible cardiac toxicity has been ascribed to certain drugs, such as zidovudine (AZT) and interferon alfa-2b, that are used to treat AIDS and its complications.17 As the lives of HIV-infected patients are prolonged, it is likely that more of these patients will have cardiac complications.

Genetic Mutations

A familial form of dilated cardiomyopathy may be present in 10% to 30% of cases of previously disguised idiopathic cardiomyopathy.18Specific genetic mutations in dystrophin (X-linked inheritance), actin (autosomal dominant inheritance), and nuclear envelope proteins such as lamin A/C (autosomal dominant) have been characterized.19 Nearly one third of asymptomatic relatives will have echocardiographic abnormalities, and over 25% of these individuals will develop overt dilated cardiomyopathy.20

Coronary Artery Disease

It is not known whether ischemia related to coronary artery disease can cause dilated cardiomyopathy. If coronary ischemia does cause cardiomyopathy, then by inference, coronary revascularization may reverse the process. There is no doubt that recurrent and extensive myocardial infarction can lead to cardiomyopathy (typically, left ventricular failure). Moreover, there have been reports of patients with severe coronary artery disease and dilated cardiomyopathy who had no history of angina or of known myocardial infarction.21

Despite these findings, there is little direct evidence that significant disease of the major coronary arteries results in cardiomyopathy. In fact, left ventricular function usually remains normal despite severe obstructive coronary artery disease, as long as myocardial infarction has not occurred. It has been shown that the cardiomyopathic syndrome in coronary artery disease is directly related to the extent and severity of proximal coronary artery disease and hence to the previous occurrence of multiple myocardial infarctions.21 However, recurring severe ischemia can contribute to congestive heart failure in some individuals who already have significant impairment of resting left ventricular function. It is important to detect these patients because surgical revascularization may lead to improved left ventricular function.

In a group of patients with intimal obliterative disease of the small coronary arteries (100 to 200 mm in diameter), the presenting symptoms suggested cardiomyopathy. Such abnormalities have been described in Marfan syndrome, primary pulmonary hypertension, and neuromuscular degenerative syndromes.22 Small vessel disease is also seen in some cases of hypertrophic cardiomyopathy.

PATHOPHYSIOLOGY

Dilated cardiomyopathy is characterized by diminished myocardial contractility. Frequently, the cardiomyopathic process involves both ventricles. Apoptosis, or programmed cell death, has been reported in clinical and experimental dilated cardiomyopathy.23,24 Cardiocyte dropout may contribute to impaired contractility. Impaired contractility is reflected in diminished systolic performance of the heart—that is, reduced ejection fraction, increased end—diastolic and residual volumes, biventricular failure, and reduced ventricular stroke work. The myocardium is frequently hypertrophied, but ventricular dilatation and failure, not hypertrophy, are the fundamental problems.

Cardiac output is usually reduced in patients with dilated cardiomyopathy; it is almost invariably decreased when congestive heart failure is advanced. During exercise, filling pressures rise abnormally, but cardiac output remains fixed or may even fall. In rare instances, as in beriberi or thyrotoxicosis, dilated cardiomyopathy is associated with a high cardiac output.

Occasionally, the cardiomyopathic process can involve predominantly the right ventricle. This condition, termed right ventricular dysplasia, is characterized by clinical evidence of right ventricular dysfunction and often by coexistent ventricular tachycardia of right ventricular origin.25 Noninvasive studies of cardiac function in a series of patients with right ventricular dysplasia revealed subtle abnormalities of left ventricular function that were especially evident during exercise. Hence, the cardiomyopathic process is not always confined to the right ventricle; in particular, as the disease progresses, the left ventricle may ultimately become involved. Familial right ventricular dysplasia has also been reported.26

DIAGNOSIS

Clinical Features

The most common symptoms of dilated cardiomyopathy are dyspnea and fatigue. Although pulmonary congestion is frequent, acute pulmonary edema is less common. This has been ascribed to the fact that the coincidence of right ventricular failure with left ventricular failure protects the pulmonary vascular bed from pulmonary edema. However, acute pulmonary edema can occur, especially in response to a respiratory infection, heart rhythm change, or worsening of mitral regurgitation.

Palpitations are common and reflect the occurrence of ectopic beats and arrhythmias; occasionally, arrhythmias cause syncope. Although systemic and pulmonary emboli are an infrequent initial presentation, they occur in approximately 1% to 4% of patients each year and are more common in those with advanced heart failure and cardiomegaly. Chest pain is present in over one third of patients, but it usually does not have the typical qualities of angina unless coronary artery disease is present. Ischemiclike chest pain in some patients with dilated cardiomyopathy has been ascribed to inadequate coronary vasodilator reserve.27 Pleuritic chest pain may indicate the occurrence of pulmonary infarction. Asymptomatic cardiomegaly is detected in fewer than 10% of patients.

Physical Findings

Physical findings in patients with dilated cardiomyopathy reflect the severity of left ventricular dysfunction and range from asymptomatic cardiomegaly to overt heart failure. In congestive heart failure, the blood pressure is often slightly elevated: the systolic pressure may be raised to 150 to 170 mm Hg and the diastolic pressure to 100 to 110 mm Hg. As congestive heart failure clears, blood pressure returns to normal. Systemic venous pressure is frequently increased, and the liver may be enlarged and tender; both of these abnormalities are signs of right ventricular failure. Prominent venous A waves, reflecting reduced right ventricular compliance, may be seen. Prominent V waves, if present, result from tricuspid incompetence. Cardiac enlargement is the rule, and an abnormally displaced, heaving cardiac impulse—particularly of the left ventricle but often of the right ventricle as well—may be palpable. Presystolic impulses may be generated by vigorous atrial contraction.

The most prevalent auscultatory findings in dilated cardiomyopathy are gallops. A fourth heart sound (S4, or atrial gallop) is almost universal, and a third heart sound (S3 gallop) is heard in about 75% of decompensated cases. It is sometimes possible to differentiate right from left ventricular S3 gallops that are simultaneously present. Right ventricular S3 gallops, best heard at the lower left sternal border, may be accentuated on inspiration and diminish or disappear on expiration.

Although the loudness of S3 gallops fluctuates with the severity of congestive heart failure, the third heart sounds may persist even when compensation is restored. Furthermore, if they do disappear, they can often be elicited with gentle exercise. When the heart rate is rapid, summation gallops, which represent fusion of S3 and S4 gallops, are sometimes heard.

Murmurs in dilated cardiomyopathy are generally functional and are usually associated with relative mitral insufficiency. The murmurs arise from misalignment of the papillary muscles as they are displaced by the enlarging ventricles, a misalignment that causes mitral incompetence. Cardiomyopathic involvement of the papillary muscles may contribute to mitral regurgitation. Tricuspid regurgitation is less common and results from right ventricular failure.

Murmurs are pansystolic and are of grades I to II/VI in intensity. They are related to ventricular geometry and wax and wane, respectively, with increasing or decreasing ventricular dimensions.

There is nothing unique about the second heart sound in patients with dilated cardiomyopathy. The loudness of the pulmonic component is frequently increased, and the second sound may split abnormally if bundle branch block is present.

Noninvasive Studies

All patients with newly diagnosed dilated cardiomyopathy should have a chest roentgenogram and undergo electrocardiography and transthoracic echocardiography.

Chest roentgenography Chest roentgenograms show evidence of pulmonary venous hypertension, sometimes with associated interstitial pulmonary edema. The heart is often markedly enlarged, with involvement of all four chambers [see Figure 1a and 1b]. The left atrium is usually abnormally large, but the enlargement is in proportion to the large size of the left ventricle.

 

Figure 1a. X-Ray: Dilated Cardiomyopathy, Posteroanterior View

Posteroanterior chest roentgenogram of a 52-year-old man with idiopathic dilated cardiomyopathy exhibit diffuse cardiomegaly. The left atrium (LA) can be seen as a faint double density on the posteroanterior film, but the enlargement of this chamber is not disproportionate to that of the left ventricle.

 

Figure 1b. X-Ray: Dilated Cardiomyopathy, Lateral View

Lateral view of patient in Figure 1a.

Electrocardiography The electrocardiogram is invariably abnormal. In at least 50% of patients, it shows a pattern of left ventricular hypertrophy. ST segment and T wave abnormalities are prevalent. Right or left bundle branch block is present in up to 20% of cases. P wave changes indicative of left or right atrial abnormalities, or both, are very common, as is first-degree atrioventricular (AV) block. Arrhythmias, particularly atrial and ventricular premature beats, are frequent. High-grade ventricular ectopy and especially asymptomatic, nonsustained ventricular tachycardia occur to a more severe degree in patients who have greater impairment of left ventricular function.28 Paroxysmal or established atrial fibrillation, which is often poorly tolerated, develops in up to 20% of patients and has been associated with a poor prognosis in those with advanced heart failure. Although the findings on ECG may occasionally mimic those associated with myocardial infarction, the presence of pathologic Q waves more commonly indicates an ischemic cardiomyopathy than an idiopathic cardiomyopathy.29

Echocardiography and magnetic resonance imaging Echocardiography shows cardiac chamber enlargement with diminished ventricular contractility [see Figure 2]. Radioisotope imaging of the cardiac chambers is seldom needed, but when performed, it also shows dilatation of one or both ventricles and diffuse, global reduction in ventricular contractility. Right ventricular dysfunction is associated with poor long-term survival.30 During exercise, the ejection fraction, which in healthy persons normally rises, often falls in patients with dilated cardiomyopathy. Although impaired ventricular contractility is the hallmark of this disorder, the extent of ventricular dilatation varies: mild dilatation that is associated with little myofibrillar loss has been described.31 Segmental rather than global wall motion abnormalities may occur in more than 50% of cases and appear to be associated with a more favorable prognosis. Thus, noninvasive techniques cannot reliably differentiate ischemic from nonischemic dilated cardiomyopathic processes.

 

Figure 2. Echocardiogram: Severe Dilated Cardiomyopathy

Apical four-chamber echocardiographic view of a patient with severe dilated cardiomyopathy. All four cardiac chambers are markedly enlarged. The left ventricular ejection fraction was 22%, and the left ventricular end-diastolic diameter was 74 mm.

Echocardiography and MRI are very helpful for detecting the hallmarks of right ventricular dysplasia: right ventricular dilatation and diminished contractility with well-preserved left ventricular function. MRI often shows infiltration and replacement of the right ventricular myocardium with fat.26,32 However, these noninvasive studies also often reveal some degree of left ventricular dysfunction.

Myocardial imaging using gallium-67 may occasionally identify patients with dilated cardiomyopathy and active myocardial inflammation, particularly inflammation due to sarcoidosis or myocarditis.

Cardiac catheterization and angiography After noninvasive testing, most adult patients with acute dilated cardiomyopathy should undergo cardiac catheterization and coronary and left ventricular angiography to exclude occult atherosclerosis. Cardiac catheterization may yield nonspecific findings. Elevation of the left and right ventricular end-diastolic pressures at rest or during exercise is the rule; cardiac output is normal or reduced and rises little if at all during exercise. Left ventricular angiography shows chamber enlargement, diffusely diminished left ventricular contractions, and a reduced ejection fraction. Mitral regurgitation may be observed; it is typically mild but may vary in severity. Angiography usually reveals normal coronary arteries. Right ventriculography may occasionally aid in the diagnosis of right ventricular dysplasia.

Endomyocardial Biopsy

The role of endomyocardial biopsy of the right ventricle is now quite limited. Although the biopsy-verified detection rate of active myocarditis ranges from 1% to 67%, the usual yield is 10% to 15% [see Figure 3a and 3b]. This low diagnostic yield, as well as uncertainty regarding the role of immunosuppressive therapy in the treatment of biopsy-proven myocarditis, has led most investigators to abandon routine use of this technique. Biopsy is occasionally helpful in establishing a definitive diagnosis (e.g., amyloidosis) and in searching for potentially treatable causes of the dilated cardiomyopathy in patients with systemic diseases known to affect the myocardium (e.g., sarcoidosis, scleroderma).

 

Figure 3a. Biopsy: Myocarditis

This endomyocardial biopsy specimen is from a 19-year-old man who presented with dilated cardiomyopathy and ventricular arrhythmias. The findings of focal lymphocytic infiltrates, interstitial edema, and myocyte degeneration are typical of myocarditis. The patient responded to prednisone.

 

Figure 3b. Biopsy: End-Stage Dilated Cardiomyopathy

This endomyocardial biopsy specimen is from an 80-year-old woman with end-stage dilated cardiomyopathy. There is marked hypertrophy of myocytes, interstitial and focal replacement fibrosis, and no evidence of interstitial inflammation. Immunosuppressive therapy was not indicated.

Special Diagnostic Considerations for Patients Receiving Chemotherapy

Anthracycline chemotherapy Various noninvasive techniques have been used to evaluate patients receiving anthracycline chemotherapy. The procedures employed have included measurement of systolic time intervals, derived simply from correlating the phonocardiogram and the ECG, and echocardiographic and radionuclide assessment of left ventricular function.8 All studies have found that left ventricular function diminishes as increasingly large doses of anthracycline drugs are administered. No study, however, has identified criteria that are particularly helpful in selecting patients en route to congestive heart failure far enough in advance to permit adjustment of anthracycline dosage or cessation of treatment. Of all of the noninvasive methods of monitoring cardiac function serially, radionuclide angiography seems to be the most useful.6,8

Doxorubicin chemotherapy Radionuclide imaging of the ventricles during exercise may be especially useful in revealing left ventricular dysfunction caused by doxorubicin. Abnormalities may persist long after cessation of chemotherapy. Although endomyocardial biopsy of the right ventricle can detect myocyte injury before discernible changes in ventricular function occur, this technique is seldom used to monitor doxorubicin therapy.

The following program for monitoring patients receiving doxorubicin has been suggested. In patients who have a baseline radionuclide left ventricular ejection fraction (LVEF) of 50% or more, radionuclide ventriculography is repeated after 250 to 300 mg/m2 of doxorubicin has been administered. Another ventriculogram is obtained after a cumulative dose of 400 mg/m2 in patients with other risk factors for cardiotoxicity (e.g., known previous cardiac disease, radiation exposure, ECG abnormalities, or cyclophosphamide therapy) and after a dose of 450 mg/m2 in patients who do not have such risk factors. Sequential studies are then recommended before each additional dose is given. Doxorubicin is discontinued if there is an absolute decline in the LVEF of 10% or more to a level of 50% or lower. For patients whose baseline LVEF is already 50% or lower, several recommendations are made: (1) no doxorubicin should be given if the LVEF is 30% or lower, (2) in patients with an LVEF of 30% to 50%, radionuclide angiography should be performed before each additional dose is given, and (3) doxorubicin should be stopped if the LVEF declines by 10% or more or if the final LVEF is 30% or lower.

DIFFERENTIAL DIAGNOSIS

Dilated cardiomyopathy must be distinguished from acute myocarditis of many different etiologies (the various myocarditides, in fact, can represent forms of acute dilated cardiomyopathy), as well as from valvular heart disease, coronary artery disease, and hypertensive heart disease. Acute myocarditis is usually caused by viruses, especially coxsackievirus B; fever and signs of systemic illness frequently accompany congestive heart failure. Pericarditis and elevation of the creatine kinase level occur in fewer than 30% of biopsy-verified cases of acute myocarditis. However, unexplained heart failure is commonly the only manifestation of myocarditis in patients with dilated cardiomyopathy.

Points that can assist in distinguishing dilated cardiomyopathy with functional mitral incompetence from rheumatic mitral regurgitation include the absence of a history of rheumatic fever, the absence of mitral valve calcification, the relative infrequency of atrial fibrillation, the presence of impaired left ventricular contractility, variation in the intensity of the murmur in response to the clinical state of the patient, and the presence of left atrial enlargement that is proportional to the degree of left ventricular dilatation.

The clinical manifestations of end-stage aortic valve disease—either stenosis or regurgitation—may resemble a dilated cardiomyopathy. This is particularly true in aortic regurgitation, in which severe left ventricular failure can mask signs of aortic runoff and cause the diastolic murmur to disappear. The murmur in end-stage aortic stenosis may be faint, but it is rarely absent. Suspicion that aortic stenosis may be present in patients with severe left ventricular failure should be confirmed by echocardiography and cardiac catheterization.

The relation between ischemic disease and cardiomyopathy is uncertain. Usually, patients who show simultaneous signs of ischemic disease and cardiomyopathy also have a history of angina, myocardial infarction, or both, although some have painless, coincident coronary artery obstruction and dilated cardiomyopathy.

Hypertensive heart disease is usually the result of severe, long-standing hypertension. It primarily affects the left ventricle.

COURSE AND PROGNOSIS

By far the most common complication of dilated cardiomyopathy is progressive congestive heart failure, which is the cause of death in 75% of patients with this disease. Sudden death caused by arrhythmias is also frequent, especially in patients with complex ventricular ectopy and severe left ventricular dysfunction.28 Evidence of systemic embolism, pulmonary embolism, or both is found at autopsy in more than 50% of patients with dilated cardiomyopathy. Emboli can cause catastrophic complications but are an infrequent cause of death.33

The prognosis for patients with dilated cardiomyopathy varies considerably [see Figure 4]. The disease may pursue a fulminating course and result in death within a few weeks or months after the onset of symptoms. Conversely, some patients do remarkably well for years. Most deaths occur within 5 years after the oneset of symptoms.

 

Figure 4. Survival in Symptomatic Idiopathic Dilated Cardiomyopathy

Survival among patients with symptomatic idiopathic dilated cardiomyopathy in seven reported series. Study A, 1986–89 (basis for selection unspecified); study B, 1975–84 (population based); study C, 1973–87 (referral based); study D, 1962–82 (referral based); study E, 1960–73 (referral based); study F, 1972–82 (referral based); study G, 1965–86 (autopsy series). (N-the number of patients studied)

Spontaneous improvement in ventricular function occurs in 20% to 40% of cases, most frequently within 6 months of initial presentation but occasionally up to 4 years after the onset of symptoms.33 Active myocardial inflammation and lesser degrees of myofibrillar loss on endomyocardial biopsy correlate with spontaneous improvement in function.34 Improvement in baseline left ventricular ejection fraction and sphericity during dobutamine echocardiography in patients with dilated cardiomyopathy has been associated with spontaneous improvement in contractile function over time.35

The most reliable indicator of prognosis is the degree of ventricular dysfunction. Although the relation is not linear, the lower the ejection fraction or the greater the left ventricular enlargement, the poorer the long-term prognosis.33 Other morphologic features that are associated with a poor prognosis include left ventricular hypertrophy, a more spherically shaped left ventricular cavity, right ventricular dilatation, and a persistent restrictive left ventricular diastolic filling pattern despite optimized medical therapy.36 Clinical features that are associated with a more favorable outcome include female sex, an age younger than 50 years, and less advanced heart failure symptoms.33,34 Cardiopulmonary exercise testing can provide useful prognostic information and quantify the patient's functional capacity. A peak level of oxygen uptake that is lower than 14 ml/kg/min predicts a 1-year survival rate of 70% and is frequently used to identify patients in need of cardiac transplantation.37 Differences in etiology undoubtedly contribute to differences in prognosis.

TREATMENT

Medical Therapy

Treatment of congestive heart failure includes salt restriction and the administration of digitalis glycosides, diuretics, and vasodilators [see1:II Congestive Heart Failure]. Controlled trials of digoxin have now demonstrated that digoxin has beneficial long-term effects on ejection fraction, exercise capacity, and chronic symptoms of heart failure.38 Efficacy has been demonstrated in patients with mild to advanced symptoms, including those who are receiving concomitant vasodilator therapy. The Digitalis Investigation Group trial demonstrated that digoxin decreases heart failure hospitalizations but has no effect on long-term survival.38 To help prevent the development of ventricular arrhythmias in patients who are receiving diuretics, the serum potassium level should be kept in the upper-normal range (4.5 to 5.0 mmol/L), and the therapeutic trough digoxin level should be kept at approximately 1.0 ng/dl. Magnesium deficiency often accompanies hypokalemia and also contributes to the development of ventricular arrhythmias.

Vasodilators Vasodilator therapy should be considered the standard initial treatment in symptomatic patients with left ventricular dysfunction.39 Vasodilators can be classified in two broad categories: agents that reduce preload by causing venous dilatation and peripheral venous pooling, and agents that reduce afterload and aortic impedance by causing arterial and arteriolar dilatation. Preload-reducing agents help alleviate pulmonary and systemic congestive symptoms, whereas the arteriolar vasodilators help reverse deleterious effects of peripheral vasoconstriction. Consequently, arterial perfusion increases in several important areas, such as the kidneys and splanchnic beds. Patients often feel better, prerenal azotemia may improve, and diuretic requirements may fall.

Occasionally, specific vasodilators that act primarily on the venous or arteriolar circulation are useful (e.g., nitrates for relief of angina); however, agents that produce balanced reductions in preload and afterload, particularly the angiotensin-converting enzyme (ACE) inhibitors, are the most effective and widely prescribed drugs for the treatment of chronic congestive heart failure39 [see Table 3]. Prospective, randomized, placebo-controlled clinical trials have shown that ACE inhibitors produce sustained improvement in functional class and a decline in hospitalizations for decompensated heart failure.40,41 Captopril, which is short acting, and enalapril and lisinopril, which are both long acting, have all proved to be effective. Additional long-acting ACE inhibitors, including ramipril, quinapril, benazepril, and fosinopril, have been introduced. Although these agents are used primarily for the treatment of hypertension, they are also efficacious in the treatment of heart failure. Because ACE inhibitors interfere with the renin-angiotensin-aldosterone system, they may also correct dilutional hyponatremia in patients with severe congestive heart failure. Compared with other variables, hyponatremia is correlated strongly with a poor long-term prognosis; correction of the hyponatremia by administration of an ACE inhibitor improves the prognosis.

Table 3 Vasodilator Drugs Used in Therapy for Chronic Congestive Heart Failure

 

Effect on Venous System

Effect on Arterial System

Usual Dosage

Peak Action

Duration of Effect

Nitroglycerin

+ + +

+

0.3–0.6 mg q. hr

10–20 min

30–60 min

Isosorbide dinitrate

+ + +

+

5–20 mg q. 6–8 hr

15–45 min

2–4 hr

Hydralazine

0

+ + +

25–100 mg q. 6 hr

1–2 hr

4–6 hr

Captopril

+ +

+ + +

25–75 mg q. 6–8 hr

1–2 hr

4–8 hr

Enalapril

+ +

+ + +

5–20 mg q. 12 hr

4–8 hr

18–30 hr

Lisinopril

+ +

+ + +

5–40 mg q. 24 hr

4–6 hr

18–30 hr

0 = no effect  + = slight effect  + + = moderate effect  +++ = marked effect

Although there has been some concern that long-acting ACE inhibitors might cause more renal insufficiency and postural hypotension than captopril, it appears that their actions are essentially the same as those of captopril when used in equivalent doses.42 ACE inhibitors are powerful hypotensive agents; they should be initiated cautiously and in low starting doses. Uncommon but significant side effects include a troublesome cough, neutropenia, angioedema, and precipitation of renal failure in patients with renal artery stenosis.

Four well-designed trials—the first and second Veterans Affairs Vasodilator-Heart Failure Trials (V-HeFT I and II), the first Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS I), and the Studies of Left Ventricular Dysfunction (SOLVD)—have unequivocally demonstrated that certain vasodilators (ACE inhibitors and the combination of hydralazine and isosorbide dinitrate) relieve symptoms and improve prognosis in patients with mild to advanced heart failure.39 Therapy with enalapril appears to be superior to that with hydralazine and isosorbide dinitrate in prolonging survival.41 Now that vasodilator therapy has been shown to reduce mortality in symptomatic patients, investigators have shifted their focus to designing strategies to arrest abnormal ventricular remodeling before the onset of symptoms. The randomized SOLVD Prevention Trial, which enrolled more than 4,000 patients with asymptomatic left ventricular dysfunction (defined as an ejection fraction of 35% or less), demonstrated that enalapril reduced the number of initial hospitalizations for heart failure by 36% and produced a nonsignificant 12% risk reduction in cardiac mortality.43 Thus, the use of ACE inhibitors in asymptomatic patients with cardiomyopathy is strongly recommended.

Whenever possible, an ACE inhibitor should be chosen as first-line therapy. Although dose-response curves for these agents have not been established, the recently completed Assessment of Treatment with Lisinopril and Survival (ATLAS) trial demonstrated that high-dose ACE inhibition was superior to low-dose therapy in decreasing hospitalizations but not in lowering long-term mortality.44 For patients who cannot tolerate ACE inhibitors, the combination of hydralazine and isosorbide dinitrate or an angiotensin receptor antagonist (e.g., losartan, valsartan, candesartan) may be a useful second choice. In the Evaluation of Losartan in the Elderly (ELITE) trial, losartan was actually found to be superior to enalapril in elderly patients with heart failure.45 However, the recently completed ELITE II trial found losartan and enalapril to have similar effects on survival.46 Amlodipine, a calcium channel blocking drug, may be useful for patients with ischemic heart disease and symptoms of both heart failure and angina.47

Antiarrhythmic agents Frequent or complex asymptomatic ventricular ectopy—defined as more than 10 premature beats a minute, multiform premature beats, or nonsustained ventricular tachycardia—is commonly observed in patients with cardiomyopathy who undergo ambulatory ECG monitoring. As is true in ischemic heart disease, an inverse relation exists between the severity of the ventricular arrhythmias and the LVEF. Empirical pharmacologic suppression of asymptomatic ventricular arrhythmias has not been demonstrated to reduce the risk of sudden death or improve long-term survival in these patients. Class IA antiarrhythmic agents such as quinidine and procainamide are generally ineffective when the ejection fraction falls below 35%, and these drugs can cause significant proarrhythmic effects. Disopyramide and flecainide should not be used, because they can precipitate severe heart failure in patients with preexisting left ventricular dysfunction. The newer class IB agents, such as mexiletine and tocainide, have minimal negative inotropic properties but have not been carefully studied in this population. Amiodarone is the most widely used agent because it has minimal negative inotropic effects, is a modest vasodilator, is highly effective in suppressing ventricular arrhythmias despite the presence of impaired left ventricular function, and is not likely to cause proarrhythmic effects. Two prospective, placebo-controlled trials of low-dose amiodarone for suppression of asymptomatic nonsustained ventricular tachycardia (NSVT) have yielded conflicting results. The Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA) trial demonstrated a 26% reduction in all-cause mortality and a trend toward decreased risk of sudden death in patients with moderate heart failure.48 In contrast, the Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure (STAT-CHF) reported no improvement in survival or reduction in sudden deaths in a similar population.49 There was a nonsignificant trend toward improved survival in patients with nonischemic cardiomyopathy. Thus, the empirical use of amiodarone in heart failure patients with asymptomatic ventricular arrhythmias is not recommended.

Anticoagulant therapy Because of the high frequency of pulmonary and systemic embolism, anticoagulant therapy, generally warfarin, is often prescribed when not contraindicated for patients with dilated cardiomyopathy and marked depression of left ventricular function (LVEF < 35%). Such therapy remains controversial because no controlled trials have examined its efficacy.50 Similarly, the efficacy of platelet inhibitors in preventing embolism has not been proved.

Corticosteroids Corticosteroids may be of modest value in cases of dilated cardiomyopathy that are associated with collagen vascular disease, which occur rarely, and in cases of cardiac sarcoidosis, which occur even more rarely The response of lymphocytic myocarditis to immunosuppressive therapy (prednisone alone or in combination with either cyclosporine or azathioprine) is unpredictable. Some patients exhibit a dramatic reduction in inflammation with concomitant clinical improvement, whereas others show either no response51 or an intermediate response. It is not clear why these differences exist. Although uncontrolled studies have shown that short-term immunosuppression improves left ventricular function and is sometimes associated with regression of ventricular dilatation, the randomized Multicenter Myocarditis Treatment Trial failed to identify which patients were most likely to experience improvement in ventricular function during 6 months of immunosuppressive therapy.52 Likewise, a single, uncontrolled short-term study using immunoglobulin G, a nonspecific immunomodulator, was shown to improve ventricular function in patients with acute dilated cardiomyopathy, but a recently completed randomized trial failed to confirm a benefit.53 Focus has now shifted to immunomodulatory agents and cytokine antagonists for treatment of inflammatory heart disease. Short-term benefits in ventricular mass and contractile function have also been reported during human recombinant growth hormone therapy for idiopathic dilated cardiomyopathy.54 An uncontrolled study using immunoadsorption of circulating autoantibodies resulted in improvement in ventricular function.55 Controlled trials are needed to evaluate this new treatment approach.

Inotropic agents Several new positive inotropic drugs have been developed for the treatment of heart failure. Most of these agents also possess vasodilator properties. Intravenous amrinone and milrinone are approved for use in the United States for the short-term treatment of patients with very advanced heart failure. Although these drugs may increase cardiac output, reduce elevated cardiac filling pressures, and alleviate symptoms, there is clear evidence that they do not prolong life and are often highly arrhythmogenic. Studies of oral milrinone and vesnarinone in patients with severe chronic heart failure demonstrated excessive mortality in the active treatment groups.56

Patients with advanced decompensated heart failure should be hospitalized to receive intravenous inotropic therapy. Administration of dobutamine, a beta-adrenergic stimulating drug, usually provides acute hemodynamic improvement and may also result in a modest sustained clinical improvement in patients with New York Heart Association functional class IV symptoms. Dosages should be initiated at 2.5 to 5.0 mg/kg/min; they should then be titrated upward in accordance with heart rate, blood pressure, cardiac output, and systemic vascular resistance and maintained for 72 hours. Acute hemodynamic improvement has also been reported with amrinone and milrinone therapies.57Controlled trials have not compared the safety or efficacy of these inotropic agents during continuous or intermittent treatment.

Beta blockers Emphasis has shifted away from the use of agents that stimulate cardiac contractility and has focused on beta-adrenergic blockers, which partially protect the myocardium from excessive sympathetic stimulation. Controlled studies have demonstrated that a variety of agents, including metoprolol, bisoprolol, carvedilol, and bucindolol, relieve symptoms and improve ejection fraction in chronic heart failure. The effect of beta blockers on mortality has been variable and may reflect intrinsic differences in the agents themselves or in the populations studied. In the Metoprolol Dilated Cardiomyopathy Trial, metoprolol was found to reduce clinical deterioration, but it did not improve overall survival.58 In contrast, in a larger trial—the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF)—sustained-release metoprolol was found to provide a substantial survival benefit.59 Similarly, the second Cardiac Insufficiency Bisoprolol Study (CIBIS 2) demonstrated a mortality benefit of this agent.60 Carvedilol, a nonselective beta blocker with vasodilator and antioxidant properties, has been shown to slow disease progression and reduce mortality.61,62 Symptomatic and survival benefits were observed in patients with mild to advanced heart failure as well as in those with ischemic and nonischemic disease. In contrast, the Beta-Blocker Evaluation of Survival Trial (BEST) recently failed to show a decrease in all-cause mortality for patients receiving bucindolol.63Given these conflicting results on outcome, agents that have demonstrated a significant survival benefit (sustained-release metoprolol, carvedilol, bisoprolol) should be selected for therapy. When used in congestive heart failure, the initial doses of beta blockers should be very low, and the daily dose should be gradually increased over weeks or months [see Table 4].

Table 4 Use of Beta-Adrenergic Blockers in Heart Failure*

Drug

Initial Dosage

Desired Dosage Range

Comments

Carvedilol

3.125 mg b.i.d.

25–50 mg b.i.d.

Initiation may require transient decrease in vasodilator therapy and increase in diuretic

Metoprolol XL/CR

6.25 mg b.i.d.

50–150 mg daily

Initiate therapy with non-extended-release preparation

Bisoprolol

1.25 mg daily

5 mg daily

*The agents listed have been shown to improve survival in heart failure in controlled clinical trials.
CR—controlled release  XL—extended release

Spironolactone The recently completed Randomized Aldatone Evaluation Study (RALES) found a 30% reduction in mortality and 35% reduction in hospitalizations for worsening heart failure in a large series of patients in New York Heart Association classes III and IV given rather small doses (25 to 50 mg daily) of the aldosterone antagonist spironoloactone.64

Defibrillation

The presence of late potentials on signal-averaged ECGs has not been an accurate predictor of sudden cardiac death in patients with advanced heart failure.65 Likewise, intracardiac electrophysiologic testing has also not been proved to be reliable in assessing prognosis or in guiding antiarrhythmic therapy in patients with dilated cardiomyopathy. In patients who have experienced symptomatic, sustained ventricular tachyarrhythmia or ventricular fibrillation that is refractory to drug therapy, an automatic, implantable cardioverter-defibrillator (ICD) may greatly improve prognosis.39,66

Although the Multicenter Automatic Defibrillator Implantation Trial (MADIT) demonstrated lower all-cause mortality for patients with asymptomatic NSVT and LVEF below 35% who received a prophylactic ICD, few patients in this study had nonischemic cardiomyopathy, and all patients had inducible ventricular tachycardia on electrophysiologic testing before randomization.66 Hence, these results are not directly applicable to the broad population of patients with dilated cardiomyopathy. Several multicenter defibrillator trials are now evaluating this approach in asymptomatic cardiomyopathy patients who have not undergone electrophysiologic risk stratification.

Surgery

Not infrequently, patients with severe dilated cardiomyopathy (LVEF < 25%) and coronary atherosclerosis may demonstrate a significant improvement in left ventricular function after coronary bypass surgery. Surgery may be undertaken in such patients if an extensive and complete revascularization of the myocardium can be achieved and if there is reversible ischemia of viable myocardium. The presence of reversible ischemia might be surmised from a history of severe angina or from ECG changes. A favorable surgical outcome may be more likely to occur if reversible defects in two or more myocardial regions are shown by thallium scintigraphy or positron emission tomography (PET) during ischemia provoked by exercise or pharmacologic stress testing.21 The risk of bypass surgery remains high and is directly related to the extent of left ventricular dysfunction. However, there is growing evidence that surgical revascularization, even in the absence of angina, can relieve heart failure symptoms and improve exercise capacity and long-term prognosis in selected patients with extensive multivessel coronary artery disease and poor left ventricular function.67,68

When congestive heart failure is very advanced and the prognosis is exceedingly poor, heart transplantation is an excellent option if the patient does not have pulmonary hypertension or other significant, irreversible comorbidities.69 In the United States, there are now over 150 hospitals that perform heart transplantations; roughly 2,400 heart transplantations are performed annually, a comparatively low figure given that an estimated 14,000 to 15,000 patients could benefit from transplantation. With cyclosporine-based immunosuppressive therapy, 1-year survival is 85% to 90% and 5-year survival is approaching 70%.70 The longest survival exceeds 20 years. Although the cost of transplantation is high, the results clearly warrant its continued application in selected patients. Approximately 20% of patients awaiting heart transplantation die each year because of the scarcity of suitable donor hearts.

The mechanical heart has received much attention but currently has a limited role in the treatment of end-stage heart failure. Its greatest use at present is to sustain life in patients with end-stage heart failure until a transplantable heart is available.71 As an alternative to replacing the entire heart, left ventricular assist devices (LVADs), particularly the Novacor and HeartMate models, are now being used for prolonged (> 4 months) pretransplant hemodynamic support. Permanently implantable battery-powered prototypes are just beginning to undergo clinical trials.

Dynamic cardiomyoplasty has been applied to a small number of patients with advanced heart failure.72 The left or right latissimus dorsi muscle is mobilized and wrapped around the ventricles, and over several weeks, the latissimus dorsi is conditioned by electrical stimulation to function like myocardium. Although initial results were encouraging, 1-year mortality is 30% to 40%, and sudden death is a common late complication. Furthermore, this procedure cannot be used in patients with severe angina, recurrent ventricular tachyarrhythmias, marked left ventricular dilatation, or advanced right heart failure. Dynamic cardiomyoplasty is considered to be experimental and is performed in only a few medical centers. Likewise, left ventricular reduction surgery (the Batista procedure) for patients with nonischemic cardiomyopathy, marked left ventricular dilatation, and refractory heart failure symptoms is now rarely performed because of its high (30% to 40%) 2-year mortality.73 Mitral valve repair appears to significantly improve heart failure symptoms and lower intermediate-term (3-year) mortality in carefully selected patients with severe mitral regurgitation and markedly impaired left ventricular function.74 This encouraging single-center experience needs to be confirmed by others before this approach can be recommended.

Hypertrophic Cardiomyopathy

ETIOLOGY AND GENETICS

Although hypertrophic cardiomyopathy can develop sporadically, it is hereditary in more than 50% of cases and is transmitted as an autosomal dominant trait. Major advances have been made in defining the genetics of the disease. The first abnormality that was found was a defect in the gene that encodes the cardiac β-myosin heavy chain located on chromosome 14.75 Since then, approximately 140 additional defects have been discovered, all involving the cardiac contractile proteins, including troponin T, α-tropomyosin, myosin-binding protein C, essential and regulatory myosin light chains, and troponin I.76,77 The same genetic defect is found in all members of a given kindred who have the disease, although the phenotypic expression may vary in any given family. About 70% of the mutations are missense mutations (i.e., they result in the substitution of a single amino acid). The others result in deletions of amino acids from the affected genes. There is good evidence that the specific defect caused by the mutation may relate to prognosis. In a study of 25 unrelated families with hypertrophic cardiomyopathy, seven different missense mutations were discovered in 12 families.78 These missense mutations were located on the head or the head-rod junction region of the b-myosin heavy-chain gene. Six of the mutations altered the charge of the amino acid and were associated with a shortened average life expectancy of 33 years [see Figure 5]. The one mutation that did not change the charge of the amino acid was associated with virtually normal survival. Similar results were reported in a study of two families.79 Defects in the genes for troponin T and a-tropomyosin seem to be characterized by mild or minimal hypertrophy and are associated with a high incidence of sudden death.76,77 Defects in cardiac myosin-binding protein C are associated with late-life onset and a generally good prognosis.80 Genetic defects have also been identified in cases of sporadic disease, which suggests that spontaneous mutations of the gene responsible for hypertrophic cardiomyopathy can occur and that these defects may then be transmitted to offspring.81 Because transcripts of the β-myosin heavy-chain gene and other contractile proteins can be detected in blood lymphocytes, it is possible to screen family members of patients with identified genetic defects for preclinical or prenatal evidence of these defects.82

 

Figure 5. Survival Curves in Hypertrophic Cardiomyopathy

Kaplan-Meier survival curves for patients with hypertrophic cardiomyopathy caused by different mutations. The survival of patients with hypertrophic cardiomyopathy caused by cardiac troponin T mutations (introns 15 G1 (ρ) A, Ile79Asn, ΔGlu160, and Arg92Gln) is similar to that in persons with a malignant β-myosin heavy-chain mutation (Arg403Gln) but significantly shorter than that observed in persons with a benign myosin mutation (Val606Met).

Currently, the search for genetic defects in hypertrophic cardiomyopathy is an expensive and cumbersome process that is confined to a few major academic medical centers. However, within the near future, it is anticipated that screening tests using gene-chip technology will be widely available. These tests will allow the identification of affected family members before the phenotypic manifestations of the disease appear and will also enable physicians to search for the defects that are associated with a poor prognosis, perhaps permitting more aggressive treatment of such patients in the hope of preventing sudden cardiac death.

PATHOLOGY

The hallmark of the disease is unexplained myocardial hypertrophy, usually with thickening of the interventricular septum that is disproportionately greater than that of the free wall of the left ventricle just beneath the posterior mitral leaflet [see Figure 6a and 6b]. Thus, the disease has been termed asymmetrical septal hypertrophy (ASH). However, the hypertrophy is concentric in 20% of cases. Furthermore, two-dimensional echocardiographic studies indicate that there is an enormous variation in the location and extent of the hypertrophy.

 

Figure 6a. Coronal Section in Hypertrophic Cardiomyopathy

The thickening of the interventricular septum (IVS) is disproportionately greater than that of the left ventricular (LV) wall behind the posterior mitral leaflet, as shown in this coronal section of the heart of a 48-year-old woman with hypertrophic cardiomyopathy. The LV chamber is small and elongated. A wooden stick lies in the LV outflow tract.

 

Figure 6b. Close-up View: Hypertrophic Cardiomyopathy

A close-up view of the coronal section shown in Figure 6a. Note the proximity of the mitral valve to the IVS. Both the septal leaflet of the mitral valve and the immediately subjacent septal endocardium are markedly thickened

In its severest forms, the hypertrophy of the left ventricle reaches massive dimensions and encroaches on the left ventricular chamber, which becomes small, elongated, and slitlike. In rare cases, the hypertrophy involves the right ventricle as well.

The left ventricular papillary muscles are also greatly hypertrophied, and the anterior papillary muscle is often displaced medially and anteriorly. Movement of the septal leaflet of the mitral valve may be restricted by the hypertrophied septum; this defect, together with the papillary muscle abnormality, leads to mitral insufficiency.

In many cases, the septal mitral leaflet strikes against the upper part of the underlying septum. This juxtaposition causes thickening and even occasional calcification of the undersurface of the septal leaflet and of the immediately subjacent endocardium of the interventricular septum [see Figure 6a and 6b].

As a consequence of the massive septal hypertrophy, the interventricular septum may oppose the mitral leaflets in systole, causing obstruction to left ventricular outflow. The thickened anterior papillary muscle may also contribute to the genesis of this obstruction. Thus, hypertrophic cardiomyopathy may exist without left ventricular outflow obstruction, with a labile and inducible obstruction, or with a fixed obstruction; mitral insufficiency may or may not be present.

The histologic features are distinctive. The myofibrils in the hypertrophied muscle are bizarre and are arranged chaotically [see Figure 7aand 7b]. They are typically enlarged, vary in size and shape, and show strikingly heterogeneous morphology.1 In contrast, microscopic examination of tissue from patients in whom left ventricular hypertrophy has developed secondary to hypertension or aortic valve disease reveals myofibrils that are aligned in an orderly, parallel fashion and that are the same size and shape [see Figure 7a and 7b]. Once considered specific for hypertrophic cardiomyopathy, the myofibrillar disarray has been noted in many other conditions—usually those associated with marked isometric left ventricular work—as well as in a small number of normal neonates; however, the disorganization in these other conditions is not nearly as marked or extensive.

 

Figure 7a. Myofibrillar Pattern in Hypertrophic Cardiomyopathy

Different myofibrillar patterns are evident in tissue taken from the septum of a patient with hypertrophic cardiomyopathy (shown here) and from the hypertrophied left ventricle of a patient with hypertension (see Figure 7b). Note the chaotic arrangement of the cells in the higher-powered photomicrograph (magnified 250 times) of septal myocardium taken from the heart shown in Figure 6a and 6b.

 

Figure 7b. Myofibrillar Pattern in Hypertension

In contrast, note the orderly parallel arrangement of myofibrils in ventricular myocardium in the hypertensive patient.

Hypertrophic cardiomyopathy may be associated with a variety of patterns of regional involvement of the left ventricle. For example, midventricular obstruction has been described,1 and nonobstructive hypertrophic cardiomyopathy predominantly localized to the cardiac apex has been reported1; the latter variant, which is prevalent in Japan, is associated with giant negative T waves on ECG.

PATHOPHYSIOLOGY

As a result of the hypertrophy, left ventricular compliance is much reduced. Systolic performance, however, is not depressed, at least not initially. The heart is hypercontractile, and systole occurs with striking rapidity. Ejection fractions are often 80% to 90%, and the left ventricle may be virtually obliterated in systole. Systolic ejection is usually excellent, even in cases of congestive heart failure; thus, failure in patients with hypertrophic cardiomyopathy usually reflects diminished diastolic compliance rather than reduced systolic performance.

The ability to provoke obstruction or to increase or decrease already existing obstruction is influenced by many factors, which may be grouped into three broad categories: (1) factors that change myocardial contractility (agents that increase contractility intensify obstruction, whereas those that depress contractility reduce obstruction); (2) factors that influence left ventricular chamber size, that is, preload (the larger the chamber, the lesser the obstruction); and (3) factors that affect afterload (the arterial pressure against which the heart must empty in systole). Increasing afterload reduces obstruction.

Many factors influence these variables [see Table 5]. Some agents may affect obstruction in more than one way. For example, nitroglycerin aggravates obstruction in three ways: it increases heart rate, reduces chamber size, and reduces blood pressure (afterload).

Table 5 Factors That Influence the Degree of Obstruction in Hypertrophic Cardiomyopathy*

Factors That Increase Obstruction

Factors That Decrease Obstruction

Mechanism

Physiologic or Pharmacologic Factor

Mechanism

Physiologic or Pharmacologic Factor

Increase in contractility

Digitalis glycosides
Beta-adrenergic stimulation (e.g., isoproterenol, epinephrine)
Tachycardia
Premature beats

Decrease in contractility

Beta-adrenergic blockade (e.g., propranolol)
Heavy sedation and general anesthesia
Calcium channel blockers, disopyramide, and other drugs that depress myocardial function

Reduction in preload

Valsalva maneuver
Decrease in intravascular volume (e.g., from hemorrhage, diuresis, GI losses)
Standing
Nitroglycerin and related drugs
Vasodilator drugs
Tachycardia

Increase in preload

Intravascular volume expansion
Squatting
Bradycardia
Beta-adrenergic blockade

Reduction in afterload

Hypovolemia
Nitroglycerin and related drugs
Vasodilator drugs

Increase in afterload

Intravascular volume expansion
Squatting
Alpha-adrenergic stimulation (e.g., phenylephrine, mephentermine)
Handgrip exercise

*In general, anything that increases obstruction will increase the intensity of the associated murmurs, whereas factors that reduce obstruction will diminish murmur intensity.
May assist in diagnosis at the bedside.

DIAGNOSIS

Clinical Features

The major symptoms of hypertrophic cardiomyopathy are angina, syncope, palpitations, and those symptoms related to congestive heart failure. Angina is usually of the classic type, but because the severity of obstruction is influenced by several factors, angina sometimes develops without any obvious provocation. Angina that is relieved by the patient's assuming the recumbent position is virtually pathognomonic for hypertrophic cardiomyopathy, but this telltale sign is rarely encountered. Presumably, the increase in left ventricular size in recumbency acts to decrease the obstruction and thus alleviate the angina.

Although the coronary arteries of patients with hypertrophic cardiomyopathy tend to be enlarged, hypertrophic cardiomyopathy and coronary artery disease often coexist, especially in older people.1 Myocardial infarction in the absence of significant disease of the large coronary arteries has been reported1 and presumably occurred because coronary arteries could not supply adequate amounts of blood to the massively hypertrophied myocardium. Obstructive changes in small intramural coronary arteries have also been reported. Their significance is not known, but the severity of these obliterative changes is greatest adjacent to areas of myocardial fibrosis, suggesting a causal relation.22

It has been shown that patients with hypertrophic cardiomyopathy have a limited ability to dilate the coronary arteries in response to increased myocardial oxygen demand, a phenomenon that contributes to ischemia and angina. The presence of left ventricular outflow obstruction makes this limitation of coronary vasodilator reserve even more significant.

Syncope typically occurs with or shortly after completion of physical activity, but it may also develop at rest. Sometimes, arrhythmias lead to loss of consciousness. Congestive heart failure is manifested by the constellation of dyspnea, fatigue, and fluid retention.

Hypertrophic cardiomyopathy predisposes to arrhythmias, of which paroxysmal or sustained atrial fibrillation and ventricular premature beats are the most common. Because the left ventricle is so massively hypertrophied, the presystolic atrial contraction is extremely important for the preservation of cardiac output. Consequently, the onset of atrial fibrillation is often not well tolerated; a poorly controlled rapid heart rate, which impairs diastolic filling, also adds to the deleterious effect of atrial fibrillation. Atrial fibrillation may lead to hypotension, syncope, or congestive heart failure. Although symptoms of hypertrophic cardiomyopathy typically worsen during atrial fibrillation, one large study showed that the onset of atrial fibrillation did not have a negative effect on long-term prognosis.83

Systemic embolism is a common complication of atrial fibrillation in this disease. Sudden cardiac death can occur, even in asymptomatic patients. In some families, the incidence of premature sudden cardiac death is very high, a phenomenon that is related to the underlying genetic defect.1 Lethal arrhythmias are especially likely to occur in young patients.

Physical Findings

Physical findings in hypertrophic cardiomyopathy depend on the presence or absence of left ventricular outflow obstruction, the severity of obstruction, and the presence or absence of mitral regurgitation.

With or without obstruction, the initial carotid upstroke (percussion wave) is very rapid and forceful. If obstruction is present, a second, slower impulse in systole (tidal wave) may be felt after the initial rapid upstroke because left ventricular emptying is retarded [see Figure 8].

 

Figure 8. Pressure Tracings: Obstructive Hypertrophic Cardiomyopathy

Classic left ventricular and radial arterial pressure tracings are recorded simultaneously in a patient with obstructive hypertrophic cardiomyopathy. An initial rapid upstroke is observed in both recordings. As obstruction develops, a notch (arrow) appears in the left ventricular tracing, accompanied by a fall in the arterial pressure. Slower ejection follows, producing a second rise in the arterial tracing. The events are observed slightly later in the radial artery than in the left ventricle because some delay occurs in the transmission of the impulse to the radial artery.

Because the degree of obstruction may fluctuate, the quality of the carotid arterial pulse may vary greatly. The carotid arterial pulse should be palpated not only with the patient at rest but also after various maneuvers designed to provoke obstruction, particularly the Valsalva maneuver. A single brisk impulse may be converted to a double impulse if obstruction develops.

The jugular venous pressure is usually normal in the absence of congestive heart failure, although somewhat prominent A waves, reflecting diminished ventricular compliance, may be present.

Findings on palpation of the heart vary greatly. Results can be normal in patients who have massive hypertrophy but neither outflow obstruction nor mitral regurgitation. More typically, an abnormal cardiac impulse is felt. A presystolic impulse is generated by vigorous atrial contraction. A hyperdynamic systolic impulse may be felt, usually displaced somewhat to the left and inferiorly. In rare cases, two distinct impulses in systole can be felt in patients who have hypertrophic cardiomyopathy with outflow obstruction.

Auscultation almost invariably reveals an S4 gallop. The S2 may be paradoxically split, particularly if left ventricular obstruction is present. Because the obstruction may be dynamic and may fluctuate in severity, however, there can be much variation in the movement of the S2.

The murmurs of hypertrophic cardiomyopathy are caused by either left ventricular outflow obstruction or mitral regurgitation. The systolic murmur of outflow obstruction has a crescendo-decrescendo quality and is best heard at the third and fourth left intercostal spaces adjacent to the sternum. The murmur of mitral regurgitation typically has a more blowing quality, is holosystolic, and is best heard at the apex, with transmission to the axilla.

Characteristic of these murmurs is their marked variability with different maneuvers, of which the Valsalva maneuver is especially useful at the bedside [see Table 5]. This maneuver reduces left ventricular chamber size, thereby increasing the degree of left ventricular outflow obstruction; thus, the murmur associated with obstruction becomes louder [see Figure 9]. In addition, because left ventricular systolic pressure increases, the murmur of mitral regurgitation also intensifies. The increase in intensity of murmurs with the Valsalva maneuver is not an invariable finding in hypertrophic cardiomyopathy; when present, however, it is highly suggestive of the disease. In fact, except for some cases of mitral valve prolapse, there is virtually no other murmur that behaves similarly.

 

Figure 9. ECG of Murmer in Obstructive Hypertrophic Cardiomyopathy

Variations in the quality of the murmur associated with obstructive hypertrophic cardiomyopathy are observed before (a), during (b), and after (c) the Valsalva maneuver. From top to bottom are shown the electrocardiogram, the phonocardiogram at the second left intercostal space (2 LICS), the phonocardiogram at the apex, and the external recording of the carotid pulse. Before the Valsalva maneuver, a soft systolic murmur is recorded at the apex. The arterial pulse contour is normal. During the Valsalva maneuver, there is a dramatic increase in the intensity of the murmur. After Valsalva release, the murmur becomes softer, but the carotid pulse exhibits the classic spike-and-dome configuration characteristic of obstructive hypertrophic cardiomyopathy.

Nitroglycerin may also make the murmur or murmurs louder. Standing increases the intensity of the murmurs, whereas squatting or recumbency may diminish it. A few patients have a faint murmur of aortic insufficiency.

Imaging and Tracing Studies

Roentgenographic findings in patients with hypertrophic cardiomyopathy are not specific. Variable degrees of cardiac enlargement, particularly of the left ventricle and the left atrium, are seen. Occasionally, both right and left atrial enlargement may be truly massive, resembling that seen in rheumatic heart disease. Pulmonary venous congestion may be present secondary to elevated left ventricular diastolic pressure.

The ECG usually shows an extreme degree of left ventricular hypertrophy. In asymptomatic patients without gallops or murmurs, marked and unexplained left ventricular hypertrophy may be the only sign of the disease. Because of the massive septal hypertrophy, abnormal Q waves resembling those that occur in myocardial infarction may be seen, particularly in the anterolateral and inferior leads [see Figure 10]. Giant negative T waves have been seen in hypertrophic cardiomyopathy involving primarily the ventricular apex.1

 

Figure 10. ECG in Obstructive Hypertrophic Cardiomyopathy

Abnormal Q waves suggestive of an old anterior myocardial infarct are observed in leads V3 through V6 in an ECG recorded in a 45-year-old woman with obstructive hypertrophic cardiomyopathy.

The diagnosis of hypertrophic cardiomyopathy should be considered in any young patient whose ECG suggests myocardial infarction but who does not have a history of infarction. ECG abnormalities often precede clinical or echocardiographic evidence of the disease.

Echocardiography is extremely useful in recognizing and assessing the severity of this condition. The thickness of the interventricular septum can be measured and compared with that of the free wall of the left ventricle at a point just beneath and behind the posterior mitral valve leaflet. Normally, the ratio of septal thickness to left ventricular free wall thickness is less than 1.3:1. In hypertrophic cardiomyopathy, the septum may be quite large, approaching four to five times the normal thickness of 1 cm. Asymmetrical hypertrophy of the interventricular septum has been reported in several other disorders, especially those associated with long-standing right ventricular hypertension, such as pulmonic stenosis and pulmonary hypertension. It is also found in neonates and in patients with posterior myocardial infarction. Nevertheless, in the context of other clinical and ECG features, asymmetrical septal hypertrophy is a highly specific, although not pathognomonic, marker of hypertrophic cardiomyopathy.

Several patterns of distribution, severity, and extent of ventricular hypertrophy have been detected in hypertrophic cardiomyopathy by two-dimensional echocardiography [see Figure 11a, 11b, 11c, and 11d]. Ultrasonography may reveal the presence and severity of an obstruction and whether it is fixed or labile. Normally, the anterior leaflet of the mitral valve moves in a posterior direction in systole, a phenomenon easily shown by echocardiography. In hypertrophic cardiomyopathy, when left ventricular outflow obstruction exists, systolic anterior movement of the anterior (septal) mitral valve leaflet occurs, and the mitral valve approaches the interventricular septum in systole [seeFigure 11a11band 11c]. This finding may be constant or variable, depending on whether the obstruction is fixed or labile.

 

Figure 11a. Hypertrophic Cardiomyopathy: Short-axis View

Two-dimensional echocardiograms show the classic features of hypertrophic cardiomyopathy. Shown here is the parasternal long-axis view in systole.

 

Figure 11b. Long-axis View: Schematic

Diagram of echocardiogram shown in Figure 11a. Note the tremendous hypertrophy of the interventricular septum (IVS) and left ventricular posterior wall (LVPW) with disproportionate thickening of the septum. Slight systolic anterior movement (SAM) of the mitral valve (MV) can be seen.

 

Figure 11c. Hypertrophic Cardiomyopathy: Short-axis View

In the parasternal short-axis view in diastole, the marked and symmetric thickening of the IVS can again be seen.

 

Figure 11d. Short-axis View: Schematic

>Diagram of echocardiogram shown in Figure 11c (LV-left ventricle; Ao-aorta; PPM-posterior papillary muscle; LA-left atrium; RV-right ventricle).

The pressure gradient across the left ventricular outflow tract can be calculated from the echocardiogram. Although systolic anterior motion of the mitral valve has been described in other cardiac conditions, it is highly specific (97%) for obstructive hypertrophic cardiomyopathy. However, because many patients lack obstruction, this finding is not a particularly sensitive marker of the disease. Doppler echocardiography has also proved to be very accurate in determining the pressure gradient across the left ventricular outflow tract.1Ultrasonography is very useful for following disease progression, particularly in children and young adults with familial disease.

MRI may also be used to define the pattern of hypertrophy. On exercise-induced thallium-201 imaging, transient perfusion defects typical of ischemia have been noted in many patients with hypertrophic cardiomyopathy who have angiographically normal large coronary arteries.84These abnormalities may be related to obliterative changes in small coronary arteries.

Cardiac Catheterization

Catheterization in patients with hypertrophic cardiomyopathy usually reveals elevated left ventricular end-diastolic pressure as a consequence of diminished left ventricular compliance. Reduced compliance produces an increase in the height of the left atrial A wave, which may reach 25 to 30 mm Hg. If obstruction is present, a pressure gradient exists between the left ventricle and the aorta [see Figure 8and12]. The obstruction may be fixed or labile. Such procedures as the Valsalva maneuver, the administration of nitroglycerin, and the infusion of inotropic agents, such as isoproterenol, may be used to provoke or aggravate obstruction.

 

Figure 12. Brockenbrough Phenomenon

Simultaneous left ventricular and radial arterial pressure tracings in a patient with obstructive hypertrophic cardiomyopathy show the Brockenbrough phenomenon in response to a ventricular premature beat (VPB). The gradient across the left ventricular outflow tract is about 80 mm Hg. After the VPB (indicated by arrows on the ECG and the left ventricular tracing), there is a compensatory pause. In the beat that follows the compensatory pause, the radial pulse pressure narrows, and the arterial pressure falls despite an increase in the left ventricular systolic pressure.

One particularly useful maneuver is to induce ventricular premature beats with a catheter and observe the hemodynamic response. Left ventricular contractility is markedly augmented after a ventricular premature beat, producing not only an increase in left ventricular systolic pressure but also an increase in the severity of obstruction in the beat after the compensatory pause. Consequently, in the recording of the arterial pressure of the beat after the compensatory pause, the systolic pressure usually falls and the pulse pressure narrows (the Brockenbrough phenomenon) [see Figure 12]. Although not invariably present in hypertrophic cardiomyopathy, the Brockenbrough phenomenon is virtually pathognomonic for the disease.

Left ventricular angiography characteristically shows a small, hyperdynamic chamber. The apex of the ventricle is often obliterated in systole. Papillary muscles are thickened, and mitral regurgitation (usually mild) may be seen.

DIFFERENTIAL DIAGNOSIS

Hypertrophic cardiomyopathy is often overlooked and confused with valvular and subvalvular membranous aortic stenosis, mitral regurgitation, infundibular pulmonic stenosis, and ventricular septal defect. The brisk carotid pulses (especially if bifid), the ECG abnormalities, and the increase in the intensity of the murmurs with the Valsalva maneuver are useful differential points. The diagnosis usually can be confirmed by echocardiography.

COURSE AND PROGNOSIS

The course and prognosis are exceedingly variable. Most patients do very well for years,85 although some experience progression of symptoms. Unfortunately, sudden death is all too common, especially in children and in men younger than 25 years with the familial form of the disease.86 Furthermore, sudden death may result from arrhythmias even in patients without significant left ventricular hypertrophy or outflow tract obstruction. Although it is believed that most cases of sudden death are caused by arrhythmias, some may be the result of serious hemodynamic abnormalities, such as the development of sudden outflow obstruction with exercise. Genetic studies have identified specific abnormalities that seem to be harbingers of a poor prognosis.78,79

Progressive left ventricular hypertrophy develops in many patients; those with more severe degrees of hypertrophy appear to have a poorer prognosis.1 In some patients who initially have no obstruction or only an inducible one, a fixed obstruction eventually develops. Progressive left ventricular hypertrophy is especially likely to develop in adolescents and young adults87; in older patients, hypertrophy often remains stable or progresses very slowly. However, progressive hypertrophy appearing for the first time in the sixth or seventh decade has recently been described for myosin-binding protein C defects.80 In rare cases, hypertrophic cardiomyopathy may progress to a state of ventricular dilatation and failure indistinguishable from dilated cardiomyopathy. Long-term survival is common, especially in adults. The mortality in most large series is 2% to 3% a year, but the rate may be lower in the general population of patients with hypertrophic cardiomyopathies, which includes many elderly patients with the disease.

SCREENING

A 24-hour Holter monitor should be used to test for potentially lethal arrhythmias in patients with hypertrophic cardiomyopathy, especially if there is a strong family history of sudden cardiac death. The presence of nonsustained ventricular tachycardia, which is often asymptomatic, on prolonged ECG monitoring seems to correlate with an increased incidence of sudden cardiac death in adults,86 but not necessarily in children.

Because hypertrophic cardiomyopathy has a familial incidence, close relatives should be screened for the disease. Appropriate measures are a routine history, physical examination, ECG, and echocardiography. In the near future, screening may also include searching for an abnormal gene. One frequently asked question is what degree of hypertrophy can be considered normal in people who exercise vigorously. In a study of 947 elite, highly trained athletes, only 16 had an echocardiographically measured left ventricular wall thickness greater than 13 mm; the thickest left ventricular wall measured 16 mm.88 All 16 individuals participated in extremely strenuous endurance sports. However, in comparably athletic women, none had a left ventricular wall thickness greater than 12 mm.89 Some investigators suggest that the following findings support a diagnosis of hypertrophic disease rather than physiologic hypertrophy: (1) documentation of hypertrophic cardiomyopathy in a relative of the athlete, (2) transmitral Doppler evidence of impaired left ventricular filling, usually demonstrated as a diminished peak early diastolic filling rate, (3) left ventricular wall thickness greater than 15 mm, and (4) left ventricular cavity size less than 45 mm.90

TREATMENT

Medical Therapy for Symptomatic Patients

Medical therapy is the preferred initial approach for symptomatic patients who have hypertrophic cardiomyopathy with or without obstruction.

Beta blockers and calcium channel blockers Beta-adrenergic blocking drugs are the most widely used medications and have been used to treat this disease for many years.86 They provide effective relief of angina, dyspnea, and syncope and improve exercise capacity in many symptomatic patients. In addition, they may help prevent arrhythmias. Propranolol has been the most widely used beta blocker, with usual dosages ranging from 160 to 320 mg/day orally. Much higher dosages may be necessary in some patients for the initial relief of symptoms or to relieve the recurrence of symptoms in patients taking usual dosages. Other beta blockers may be as effective as propranolol if given in equivalent amounts, although those that possess intrinsic sympathomimetic activity, such as pindolol and acebutolol, should probably be avoided.

Verapamil, a calcium channel blocker, has also proved to be very effective in the treatment of symptomatic hypertrophic cardiomyopathy with or without obstruction.86 Verapamil has also been shown to be effective in preventing silent myocardial ischemia detected by exercise-induced thallium-201 imaging in patients with hypertrophic cardiomyopathy.91 In addition to reducing myocardial oxygen consumption and relieving obstruction, there is evidence that verapamil, when used for a long period, may lead to better diastolic compliance.92 Warnings against the hypotensive and negative inotropic actions of verapamil should be heeded. These effects may be particularly deleterious in patients with severe outflow obstruction and left ventricular failure. In high doses, the drug may also cause potentially serious bradycardia by depressing the sinus node or by inducing AV block.

The role of other calcium channel blockers is less clear. Intravenous diltiazem and sublingual nifedipine have led to improved diastolic compliance of the hypertrophied left ventricle in some studies but not in others.

Occasionally, combinations of beta blockers and calcium channel blockers may be effective in patients who are unresponsive to either type of drug alone. However, caution is required when the two are used in combination. In patients with angina, nitroglycerin and its companion drugs are contraindicated.

Disopyramide Disopyramide, an antiarrhythmic agent with negative inotropic properties, may reduce obstruction and relieve symptoms in some patients. Dosages of 150 to 200 mg orally four times a day are recommended.

Diuretics Diuretics may be used in patients with congestive heart failure, but they must be used cautiously because patients with hypertrophic cardiomyopathy are very sensitive to intravascular volume depletion.

Digitalis glycosides Digitalis glycosides, which increase contractility, may worsen obstruction. They are generally contraindicated, although they may help control the ventricular rate in patients with atrial flutter or atrial fibrillation. Beta blockers or verapamil are preferable to digitalis glycosides for rate control in atrial fibrillation. Every attempt, including repeated cardioversion, should be made to maintain sinus rhythm. However, in some patients, maintenance of sinus rhythm may ultimately prove to be impossible. Patients with sustained atrial fibrillation are at high risk for systemic embolization and should be given warfarin to produce an international normalized ratio of 2 to 3, unless there is a strong contraindication to its use.

Prophylactic measures Bacterial endocarditis, usually involving the aortic valve but occasionally the mitral valve, can occur. Therefore, appropriate endocarditis prophylaxis is mandatory.

The prevention of sudden cardiac death remains a major challenge in the management of patients with hypertrophic cardiomyopathy. Markers of an increased risk of sudden cardiac death include young age, massive hypertrophy, sustained or nonsustained ventricular tachycardia on Holter monitoring, a history of ventricular fibrillation, a strong family history of sudden cardiac death, and a history of syncope.93 As previously noted, certain genetic defects, such as troponin T gene mutations, seem to convey a high risk of sudden death.77 A recent study also found a marked increase in the left ventricular collagen matrix in young people with this disease who died suddenly.87

There is no clear evidence that either beta blockers or calcium channel blockers prevent sudden death, although one uncontrolled study suggested that very high doses of propranolol (5 to 23 mg/kg/day) were helpful in preventing sudden death in young people with this disease.94 In England, amiodarone has been widely used in the treatment of hypertrophic cardiomyopathy. One study using historical controls found evidence that amiodarone, given in a median dosage of 300 mg/day orally, prevented sudden cardiac death in patients with episodes of ventricular tachycardia demonstrated by ambulatory ECG monitoring. Not all researchers have experienced good results with amiodarone. In one group of 50 patients treated with this drug, seven patients died (six suddenly) during an average follow-up of 2.2 years.95 Amiodarone has many potentially serious side effects [see 1:VI Ventricular Arrythmias]. Therefore, the drug must be used cautiously and in the lowest possible dose.

Invasive electrophysiologic studies have been of limited value in assessing patients, especially low-risk patients, with hypertrophic cardiomyopathy for the risk of sudden cardiac death. Such studies have been more useful in assessing patients who have experienced cardiac arrest or who have major risk factors for sudden death. Electrophysiologic abnormalities were found in 81% of a group of 155 patients with major risk factors for sudden death.96 In a group of 30 survivors of sudden cardiac arrest, 21 had sustained ventricular arrhythmias. Seventeen of these patients were treated with ICDs and four with antiarrhythmic drugs.97 These high-risk patients are most likely to benefit from implantation of automatic ICDs.98 The presence of abnormal late potentials on signal-averaged ECGs may be useful in screening young patients who may be at risk for sudden cardiac death, but this has not yet been confirmed.

MEDICAL THERAPY FOR ASYMPTOMATIC PATIENTS

The proper management of asymptomatic patients who have hypertrophic cardiomyopathy is not certain. We usually maintain asymptomatic patients on beta blockers. Unfortunately, there is no evidence that any form of therapy prevents progression of the disease.92 In asymptomatic individuals in families with a high incidence of sudden cardiac death, more aggressive workup and treatment are indicated. If ventricular tachycardia is detected on ambulatory ECG monitoring in such individuals, antiarrhythmic treatment with amiodarone or use of an ICD for primary prevention of sudden death should be considered.98 It is likely that as genetic studies become more available, aggressive therapy for preventing sudden cardiac death will be directed at those patients who are found to have the more lethal genetic abnormalities.

There is general agreement that patients with hypertrophic cardiomyopathy should be prohibited from engaging in competitive sports because of the risk of sudden cardiac death. A task force has made specific recommendations in this regard.99

Cardiac Pacing

Accumulating experience with sequential AV pacing continues to confirm the effectiveness of this technique in the treatment of some patients who continue to be symptomatic on drug therapy.100,101 Depolarization of the ventricles, initiated by an electrode in the tip of the right ventricle, diminishes left ventricular outflow tract obstruction. In a large series of patients so treated, symptoms improved in many patients in the course of several months. One study has suggested that patients older than 65 years are most likely to benefit from pacer therapy.102 In a study comparing myectomy with AV pacing in similar patients, there was a much greater improvement in symptoms in the surgical patients (90%) than in the patients receiving AV pacing (47%).103 Although further long-term follow-up is necessary in these patients, it is probable that dual-chamber pacing can eliminate the need for cardiac surgery in some patients and postpone it in others. The effect on prognosis is unknown. Cardiac pacing is not recommended in symptomatic patients who do not have obstruction.104

Surgery

Surgery is recommended in symptomatic patients with fixed obstruction who do not respond to medical therapy or to synchronized pacing, but it may also be justifiable in patients with inducible gradients whose symptoms are quite severe and are not effectively controlled by medical measures. Only about 10% to 15% of patients with hypertrophic cardiomyopathy, however, ultimately undergo surgery. Many different operative procedures have been devised, but the one most often used involves myotomy or myectomy, or both, of the left ventricular outflow tract, usually around the septum.86 This operation relieves the obstruction and usually is done via a transaortic approach using cardiopulmonary bypass. In some cases, mitral valve replacement may be necessary to correct associated mitral regurgitation or may be required because the ventricular septum is unusually thin, making septal myotomy or myectomy unsafe. Mitral valve replacement, without myotomy or myectomy, also may relieve the gradient. Generally, the results of surgical therapy have been satisfactory. In the longest reported follow-up, in which patients were followed for a mean period of 11.5 years (some were followed for as long as 25 years), 40% of patients survived. Approximately 25% of the patients died of complications of the hypertrophic cardiomyopathy, with a steady annual attrition rate from the disease of approximately 2%. More recent surgical results are even better; survival rates of 85% at 5 years and 72% at 10 years are not uncommon.105 The great majority of the survivors experience symptomatic relief, and very few need a second operation or progress to dilated cardiomyopathy. Marked asymmetrical septal hypertrophy, severe anterior motion of the mitral leaflet or leaflets, and prolonged isovolumetric relaxation time are important preoperative variables that identify patients most likely to benefit from septal myectomy.106 Although surgery relieves symptoms and improves the quality of life for survivors, it unfortunately does not prevent sudden cardiac death.

Controlled Septal Ablation

The most recent treatment for hypertrophic cardiomyopathy involves the production of a small infarct within the hypertrophied septum.107,108,109 In this procedure, a catheter is introduced into one or more septal perforating arteries. After the artery has been occluded, a small amount of absolute ethanol is injected via the catheter into the septum. This creates a small infarct localized to the septum. If successful, there is an almost immediate reduction in the outflow tract gradient [see Figure 13]. In expert hands, the procedure is successful 90% of the time. Mortality is approximately 2%; 10% of patients may require permanent pacing.

 

Figure 13. Chemical Septal Ablation in Hypertrophic Cardiomyopathy

Results of chemical septal ablation in a 77-year old woman with obstructive hypertrophic cardiomyopathy are shown. Simultaneous left ventricular and radial artery pressure recordings (a) show a gradient of approximately 140 mm Hg across the left ventricular outflow tract. Moments after injection of alcohol into the interventricular septum (b), the gradient is abolished. (LV-left ventricle; RAD-radial artery)

At this time, we favor the procedure in older patients (i.e., patients older than 65 years) or in younger patients with comorbid conditions that increase the risks of surgery. To be eligible for the procedure, patients should have (1) medically refractory symptoms, (2) well-preserved left ventricular systolic function, (3) thickening of the interventricular septum of at least 18 mm, (4) a resting or inducible intraventricular pressure gradient of 50 mm Hg or greater, and (5) suitable coronary artery anatomy.

Restrictive Cardiomyopathy

ETIOLOGY

Restrictive cardiomyopathies are usually the product of an infiltrative disease of the myocardium, such as amyloidosis, hemochromatosis, or a glycogen storage disease.2,110,111 Evidence also suggests that in certain diabetic patients, a form of restrictive cardiomyopathy may develop. However, cases of idiopathic restrictive cardiomyopathy are not uncommon.110 A familial form of restrictive cardiomyopathy associated with AV block and skeletal myopathy has been reported.112

PATHOPHYSIOLOGY

The myocardium is rigid and noncompliant, impeding ventricular filling and raising cardiac filling pressures. Systolic performance is often reduced, but the overriding problem is impaired diastolic filling, which produces a clinical and hemodynamic picture that mimics constrictive pericarditis.

DIAGNOSIS

The most common clinical manifestation is congestive heart failure. Evidence of right-sided heart failure-edema, hepatomegaly, and ascites-often predominates. The systemic venous pressure is elevated and exhibits the characteristic early diastolic dip-and-plateau pattern associated with restricted ventricular filling. At cardiac catheterization, this pattern is recorded in both ventricles and atria [see Figure 14]. With inspiration, venous pressure rises rather than falls (Kussmaul sign). An early diastolic third sound is often heard. The heart is usually enlarged, and the ECG frequently shows low voltage. Arrhythmias are common.

 

Figure 14. Pressure Tracing in Restrictive Cardiomyopathy

Shown is a right atrial pressure tracing in a patient with restrictive cardiomyopathy secondary to amyloidosis; some functional tricuspid regurgitation is present. The cardiac rhythm is atrial fibrillation. Large systolic (V) waves appear, followed by a typical early diastolic dip-and-plateau configuration.

Two-dimensional echocardiography may be helpful in the diagnosis of cardiac amyloidosis. The cardiac walls are often thickened and have a characteristic granular, speckled appearance.113 Echocardiographic data can also provide prognostic information. In a large group of patients with amyloid heart disease, survival was negatively influenced by greater wall thickness and reduced systolic function, which were seen on two-dimensional echocardiography.113 Enhanced diffuse myocardial uptake of technetium-99m pyrophosphate in radionuclide scintigraphy may also be found in patients with cardiac amyloidosis. Because restrictive cardiomyopathies are often caused by a specific process, they constitute one of the few cardiac diseases in which a definitive diagnosis can be made by percutaneous myocardial biopsy.

DIFFERENTIAL DIAGNOSIS

Restrictive cardiomyopathy must be differentiated from constrictive pericarditis, a distinction that is not always easy to make. Clues to the nature of a restrictive cardiomyopathy may be provided by the presence of other signs of the underlying disease process. The presence of a small heart favors a diagnosis of constrictive pericarditis.

The conditions may also be distinguished hemodynamically because constrictive pericarditis may involve the two ventricles equally and produce a so-called plateau of filling pressures. Thus, the left ventricular diastolic, left atrial, pulmonary wedge, right ventricular, right atrial, and systemic venous pressures are similar in magnitude and configuration. Ventricular interdependence, evidenced by an inspiratory increase in right ventricular systolic pressure and a decline in left ventricular systolic pressure, has recently been suggested as the most sensitive and specific hemodynamic criterion for diagnosing pericardial constriction.114

In contrast, restrictive cardiomyopathies tend to cause greater impairment to left than to right ventricular filling. Thus, the left-sided filling pressures are almost always higher than those recorded in the right side of the heart and may result in pulmonary arterial systolic pressures greater than 50 mm Hg—a pressure level that is a distinct rarity in constrictive pericarditis. Patterns of diastolic filling, as determined by Doppler echocardiography and radionuclide ventriculography, may also distinguish restrictive cardiomyopathy from constrictive pericarditis.115 MRI can be of particular value in assessing the extent of pericardial thickening in patients with suspected constrictive pericarditis.

In some cases, restrictive cardiomyopathy cannot be distinguished from constrictive pericarditis, and surgical exploration may be warranted.

TREATMENT

In most cases, there is no therapy for restrictive cardiomyopathies, which ultimately result in death from congestive heart failure or arrhythmias. However, in some patients with idiopathic restrictive cardiomyopathy, the prognosis may be quite good.110 Removal of excessive iron by frequent phlebotomies may improve myocardial function in those patients whose cardiomyopathies are caused by hemochromatosis. To ensure that phlebotomy is depleting myocardial iron stores in patients with hemochromatosis, some researchers have recommended periodic endomyocardial biopsies.116 AL (amyloid light chain-related) amyloidosis may show some response to intermittent oral melphalan and prednisone.111

Obliterative (Restrictive-Obliterative) Cardiomyopathy

The hypereosinophilic syndrome accounts for the rare cases of obliterative cardiomyopathy encountered in the United States. The syndrome is characterized by profound eosinophilia and multiple organ involvement. Degranulation of many of the eosinophils is a characteristic feature, which suggests that the release of substances from the eosinophils is causally related to the damage to the heart and other organs that occurs in this highly fatal disease. Deposits of eosinophil granule proteins have been identified within the intracardiac thrombi and endocardium, a finding that also suggests a direct link between the eosinophils and the cardiac damage. Clinically, obliterative cardiomyopathy is characterized by inexorably progressive congestive heart failure, systemic embolism, and cardiac arrhythmias and conduction disturbances. Although there may be a transient response to adrenal glucocorticoids or antitumor therapy, there is no effective treatment of this disorder.

Worldwide, the most common cause of obliterative cardiomyopathy is endomyocardial fibrosis, which is particularly common in eastern Africa. Some researchers believe that many cases of endomyocardial fibrosis represent the end stage of a hypereosinophilic syndrome.2Characteristically, there is massive endocardial thickening of both ventricles, although one ventricle may be more severely affected than the other. Fibrous bands extend into the myocardium, and mitral and tricuspid insufficiency are common. Patients usually die of congestive heart failure. In a large series of patients, the survival rates were 76% at 1 year, 68% at 2 years, and 36% at 5 years.117 Biventricular fibrotic involvement and the presence of mitral or tricuspid regurgitation are associated with poor long-term survival. There is no effective medical treatment. However, surgery consisting of endocardial stripping and relief of mitral or tricuspid insufficiency has been undertaken.118 The results have been reasonable, although the surgical mortality has been high.

Acknowledgments

Figure 2 Echocardiogram courtesy of the Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Boston.

Figures 3a, 3b and 6a,6b Photographs courtesy of Dr. John Fallon, Department of Pathology, Massachusetts General Hospital, Boston.

Figure 11a, 11b, 11c, 11d Tom Moore. Echocardiograms and diagrams courtesy of Dr. Robert A. Levine, Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Boston.

Figure 13 Tracings courtesy of Dr. Michael A Fifer, Knight Cardiac Catheterization Laboratory, Massachusetts General Hospital, Boston.

Table 2 Adapted from chart supplied by Dr. Walter Abelmann, Beth Israel Hospital, Boston.

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