34 Cardiomyopathies and Myocarditis

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641

From: Essential Cardiology: Principles and Practice, 2nd Ed.

Edited by: C. Rosendorff © Humana Press Inc., Totowa, NJ

34 Cardiomyopathies and Myocarditis

Edward K. Kasper, ^MD

INTRODUCTION

Cardiomyopathies are diseases of the heart muscle associated with cardiac dysfunction. The World Health Organization/International Society and Federation of Cardiology task force on the definition and classification of cardiomyopathies has defined five subtypes of cardiomyopathy (1):

dilated, hypertrophic, restrictive, arrhythmogenic right ventricular dysplasia, and unclassified cardiomyopathies. The term specific cardiomyopathy is used in reference to cardiomypathies associated with specific, usually systemic, disorders. Table 1 lists echocardiographic characteristics of the major types of cardiomyopathy.

DILATED CARDIOMYOPATHY

Left ventricular enlargement and decreased contractility are the defining elements of dilated cardiomyopathy. The right ventricle is often involved as well. Dilated cardiomyopathy is the most common form of cardiomyopathy, accounting for more than 90% of all cardiomyopathies. The most common presentation is with signs and symptoms of heart failure, although perhaps as many as 50%

of the cases are asymptomatic or undiagnosed.

Causes of Dilated Cardiomyopathy

A variety of insults can cause dilated cardiomyopathy. We have had a long-standing interest in the causes of cardiomyopathy. Table 2 reviews the causes of initially unexplained cardiomyopathy in our tertiary care referral center experience (2,3). All patients underwent a complete evaluation for the etiology of the cardiomyopathy, including endomyocardial biopsy, laboratory studies, and cardiac catheterization if appropriate. In population-based studies, coronary disease and hypertension are the major causes of cardiomyopathy. In our referral cohort of 1278 patients, no cause could be found in 51% of the cases. Myocarditis occurred in about 9% of the cases, a finding similar to that seen in the Myocarditis Treatment Trial (4).

Familial cardiomyopathy may be a more common finding than reported in our series, as we did not evaluate first-degree relatives of patients with idiopathic dilated cardiomyopathy with echocardiography. When this was done by Michels and colleagues, 20% of patients with idiopathic dilated cardiomyopathy had first-degree relatives with the disease (5). Indeed, studies of families with dilated cardiomyopathy have demonstrated autosomal dominant, autosomal recessive, X-linked, and mitochondrial modes of inheritance (6). There are several distinct phenotypes, including dilated cardiomyopathy, dilated cardiomyopathy with conduction system disease, dilated cardiomyopathy with skeletal myopathy, and dilated cardiomyopathy with hearing loss. The first disease gene to be located was actin. Furthermore, mutations in a number of sarcomeric genes first associated with hypertrophic cardiomyopathy have also been shown to cause dilated cardiomyopathy including B-myosin heavy chain and cardiac troponin T. A more complete list of the causes of dilated cardiomyopathy can be found in Table 3.

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Table 1

Echocardiographic Findings in Cardiomyopathy

Dilated Hypertrophic Restrictive Ventricular volume Increased Decreased Decreased or normal LV contractility Decreased Increased Usually normal Atrial size Increased Usually normal Markedly increased Other findings Often MR LVOT gradient Diastolic dysfunction

Natural History of Clinical Course

Prognosis is tied to the underlying cause of unexplained cardiomyopathy (2). As compared to patients with idiopathic cardiomyopathy, patients with peripartum cardiomyopathy had better survival. Patients with infiltrative cardiomyopathies, HIV infection, or a cardiomyopathy caused by doxorubicin had significantly worse survival when compared with idiopathic cardiomyopathy (Fig. 1). In addition, not all infiltrative cardiomyopathies are associated with equally poor survival. Patients with a cardiomyopathy due to sarcoidosis have better survival than do patients with either hemochromatosis or amyloidosis and a cardiomyopathy (Fig. 2). With the exception of peripartum cardiomyopathy, the natural history of dilated cardiomyopathy is one of progressive heart failure, arrhythmia, and eventual death or heart transplantation. Current therapies for heart failure, including angiotensin-converting enzyme (ACE) inhibitors, b-blockers, and aldosterone antago- nists have improved this prognosis (7).

Evaluation of Dilated Cardiomyopathy

The ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult suggest that physicians should focus their evaluation of the etiology of dilated cardiomyopathy on those diagnoses with the potential for improvement (7). A complete history and physical examination, including a family history of cardiomyopathy, heart failure, and early sudden death, is the foundation. The history should focus on possible causes such as hypertension, coronary disease, diabetes, valvular disease, rheumatic fever, chest irradiation, cardiotoxic agents, illicit drugs, alcohol, systemic disorders, and possible infectious etiologies. Screening for thyroid disease with a TSH is suggested, while laboratory screening for specific cardiomyopathies rests on clinical sus- picion. ECG should be done to look for evidence of prior infarct and the presence of rhythm and conduction disturbances. Echocardiography is the most cost-efficient means to understand the anat- omy of the heart, including not only left ventricular function but also valvular and pericardial function. Coronary arteriography may be important if revascularization proves to be an effective treatment for left ventricular dysfunction. Endomyocardial biopsy has a limited role in the diagnosis of infiltrative diseases when clinically suspected, but should not be done routinely.

Treatment of Dilated Cardiomyopathy

Treatment rests on the diagnosis of a specific disorder: for example, replacement of thyroid hor- mone in hypothyroidism. In general, the treatment for dilated cardiomyopathy is outlined in the chapter on heart failure.

HYPERTROPHIC CARDIOMYOPATHY

The findings in hypertrophic cardiomyopathy include left or right ventricular hypertrophy, often asymmetric and involving the ventricular septum. A maximal left ventricular wall thickness greater than or equal to 15 mm is the usual diagnostic finding, but abnormal genotypes are associated with almost any degree of LV wall thickness. Mildly increased LV wall thickness (13 to 14 mm) can also be seen in highly trained athletes and must be differentiated from hypertrophic cardiomyopathy.

Obstructive and nonobstructive forms of hypertrophic cardiomyopathy exist, with the nonobstruc-

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Table 2

Final Diagnoses in 1230 Patients With Initially Unexplained Cardiomyopathy

Diagnosis Number (%)

Idiopathic cardiomyopathy 616 (50)

Myocarditis 111 (9)

Ischemic heart disease 91 (7)

Infiltrative disease 59 (5)

Amyloid 36

Sarcoidosis 14

Hemochromatosis 9

Peripartum cardiomyopathy 51 (4)

Hypertension 49 (4)

HIV 45 (4)

Connective-tissue disease 39 (3)

Scleroderma 12

Systemic lupus erythematosus 9

Marfan’s syndrome 3

Polyarteritis nodosa 3

Dermatomyositis or polymyositis 3

Nonspecific connective-tissue disease 3

Ankylosing spondylitis 2

Rheumatoid arthritis 1

Relapsing polychondritis 1

Wegener’s granulomatosis 1

Mixed connective-tissue disease 1

Substance abuse 37 (3)

Alcohol 28

Cocaine 9

Doxorubicin therapy 15 (1)

Other causes 117 (10)

Restrictive cardiomyopathy 28

Familial 25

Valvular heart disease 19

Endocrine dysfunction

Thyroid disease 7

Carcinoid 2

Pheochromocytoma 1

Acromegaly 1

Neuromuscular disease 7

Neoplastic heart disease 6

Congenital heart disease 4

Complication of coronary bypass surgery 4

Radiation 3

Critical illness 3

Endomyocardial fibroelastosis 1

Thrombotic thrombocytopenic purpura 1

Rheumatic carditis 1

Drug therapy (not including doxorubicin)

Leukotrienes 2

Lithium 1

Prednisone 1

Total 1230 (100)

Adapted from ref. 2.

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tive form being more common. For this reason, the term hypertrophic cardiomyopathy is now pre- ferred over previous terms, such as hypertrophic subaortic stenosis, that tended to emphasize the obstructive component.

Hypertrophic cardiomyopathy is one of the more common inherited cardiac disorders, with a prevalence in young adults of about 1 in 500. It is the second most common subtype of cardiomyopathy after dilated cardiomyopathy. It is a frequent cause of sudden death in competitive athletes (8).

Left Ventricular Outflow Tract Obstruction

Outflow tract obstruction is caused by hypertrophy of the basal portion of the septum in association with an elongated mitral valve leaflet and systolic anterior motion of the mitral valve. This leads to a narrowed outflow tract, an outflow tract gradient, and often mitral regurgitation as the mitral valve leaflets fail to coapt. The pressure gradient is responsible for the murmur usually described as harsh, located along the lower left sternal border, and made worse by release of Valsalva strain or standing from a squat position. In perhaps 5% of the cases, the obstruction is mid- ventricular rather than subaortic. The pressure gradient is often dynamic, made worse by increased contractility and decreased ventricular volume. Therefore, the gradient, usually defined as 30 mmHg or more, may be present in the resting state, provocable, or absent entirely.

Dilated cardiomyopathy Idiopathic

Familial/genetic

Myocarditis/immune (see Table 4) Drug toxicity

Alcohol Antidepressants Catecholamines Cobalt Cocaine Doxorubicin Interferon Lithium Prednisone Metabolic

Thyroid disease Diabetes mellitus Carcinoid

Pheochromocytoma Acromegaly Hypocalcemia Infiltrative disease

Amyloid Sarcoidosis Hemochromatosis Storage diseases Nutritional

Beriberi Carnitine Pellagra Selenium

Connective-tissue disease Systemic lupus erythematosus Polyarteritis nodosa

Scleroderma Rheumatoid arthritis

Dermatomyositis/polymyositis

Muscular dystrophies and neuromuscular disorder Tachycardia

Hypertension Radiation

Sepsis/critical illness

Hypertrophic cardiomyopathy Familial/genetic

Aortic stenosis Renal failure Hypertension Fabry disease

Restrictive cardiomyopathy Idiopathic

Familial/genetic Metastatic tumors Infiltrative

Amyloid Sarcoidosis Storage diseases Endocardial

Endomyocardial fibrosis Hypereosinophilic syndrome Radiation

Carcinoid heart disease

Arrhythmogenic right ventricular dysplasia Noncompacted myocardium

This is a relatively complete list.

Table 3

Causes of Cardiomyopathy

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Causes of Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy is inherited as an autosomal dominant trait. It is caused by at least 12 different disease genes, with more being reported every day (6,8). Most of these genes encode protein components of the cardiac sarcomere, such as b myosin heavy chain, cardiac troponin T, cardiac troponin C, cardiac myosin binding protein C, and so on. Several genes encode nonsarcome- ric proteins. Adding to this complexity is that for each disease gene, a variety of different mutations have been reported. These mutations account for perhaps 50 to 70% of all cases of hypertrophic cardiomyopathy and thus new mutations will certainly be described. The extent of left ventricular hypertrophy varies between different genes. Hypertrophy confined to the apex (apical hypertrophic cardiomyopathy) has been associated with cardiac troponin I mutations. Prognosis varies with the mutation, with b myosin heavy chain mutations presenting early in life and cardiac myosin binding protein C mutations presenting in the elderly. Finally, not all individuals with an abnormal genotype will express the phenotype of hypertrophic cardiomyopathy.

An important management point is the importance of family screening of new cases of hypertrophic cardiomyopathy. It is recommended that screening consist of a history and physical examination, 12-lead ECG, and two-dimensional echocardiography at annual evaluation during the adolescent

Fig. 1. Kaplan-Meier estimates of survival according to underlying cause of cardiomyopathy. (From ref. 2.

Fig. 2. Kaplan-Meier estimates of survival among patients with infiltrative cardiomyopathy. (From ref. 2.

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years (8). Adults with normal screening evaluations should be reevaluated every 5 yr, as hypertrophic cardiomyoapthy may present in later life. Genetic screening remains a research tool but may some day allow more directed screening.

Natural History and Clinical Course

The prognosis and clinical course of patients with hypertrophic cardiomyopathy is likewise variable. Patients may remain stable over long periods and reach normal longevity, while others present with sudden death. In general, patients who are symptomatic follow one or more of several pathways: (1) sudden death; (2) progressive dyspnea, chest pain, and presyncope/syncope in the face of normal or even supranormal LV function; (3) progression to LV systolic dysfunction and a dilated cardiomyopathy; or (4) atrial fibrillation with associated clinical deterioration or stroke (8). Manage- ment is directed at each of these possible clinical pathways.

Treatment of Hypertrophic Cardiomyopathy

Treatment is directed at symptom alleviation and prevention of sudden death. In asymptomatic patients, it may not be necessary to do anything other than explain the importance of avoiding competitive athletics and reporting symptoms of presyncope/syncope immediately. Pharmacological therapy is usually initiated with the onset of disabling symptoms. b-Blockers such as propranolol, atenolol, or metoprolol are usually used first. If b-blockers are not effective, a trial of verapamil may be warranted. However, verapamil has been associated with death in patients with resting LV outflow tract gradients and severe symptoms. Both agents have negative inotropic actions and slow heart rate. The response to such drugs is variable; few clinical trials have examined treatment in hypertropic cardiomyopathy, so therapy remains somewhat of a “trial and error” event. If a patient develops a dilated cardiomyopathy, he or she should be treated with agents shown to be effective for that disorder, and verapamil should be discontinued. Patients with LV outflow tract obstruction or intrinsic mitral valve disease deserve infective endocarditis prophylaxis.

For patients with severe drug refractory symptoms and marked LV outflow tract gradients (50 mmHg at rest or on stress testing), surgical myectomy or catheter-based alcohol septal ablation is often performed. Both of these procedures work best in patients with LV outflow tract obstruction rather than mid-cavitary obstruction. Both surgery and alcohol septal ablation reduce LV outflow tract gradients and improve symptoms. It is recommended that both procedures be confined to cen- ters with experience. For patients with severe drug refractory symptoms but no LV outflow tract gradient, heart transplantation may be necessary.

Those who survive sudden cardiac death are treated with an implanted cardioverter-defibrillator. The difficult issue is risk stratification to prevent sudden death. The highest risk has been associated with prior cardiac arrest, sustained ventricular tachycardia, family history of sudden cardiac death, nonsustained ventricular tachycardia on Holter monitoring, abnormal blood pressure response on stress testing, extreme LV hypertrophy (wall thickness 30 mm or more), and the presence of a high-risk genotype. Annual evaluation for patients with hypertrophic cardiomyopathy at risk for sudden death should include a history directed toward presyncope and syncope, an echocardio- gram, a stress test, and possibly a Holter monitor for 24 h (8).

Atrial fibrillation is usually poorly tolerated and because of this justifies aggressive attempts at maintenance of sinus rhythm. Warfarin is indicated for those with both paroxysmal and chronic atrial fibrillation.

RESTRICTIVE CARDIOMYOPATHY

This heart muscle disease is characterized by impaired ventricular filling and reduced diastolic ventricular volumes associated with normal or near-normal left ventricular function, normal wall thickness, and biatrial enlargement (9). It is a rare cause of cardiomyopathy, but more common in parts of the tropics. The key component is decreased ventricular compliance, without increased wall thickness in most cases, leading to decreased ventricular filling and hence biatrial enlargement.

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Causes of Restrictive Cardiomyopathy

Outside the tropics, amyloidosis is probably the most frequent cause of restrictive cardiomyopathy. Other infiltrative causes include hemochromatosis, sarcoidosis, Fabry’s disease, and a variety of other uncommon disorders. In the tropics, endomyocardial fibrosis with and without eosinophi- lia is more common. Radiation, metastatic tumors, and familial inheritance may also cause restrictive cardiomyopathy. Finally, cases may be idiopathic.

Prognosis varies with the cause of the restrictive cardiomyopathy. Amyloidosis is again associated with a poor prognosis. Others causes of restrictive cardiomyopathy are associated with a pro- longed course, often of right heart failure with pronounced venous congestion. Dyspnea is often present as well, due to left atrial hypertension.

Treatment of Restrictive Cardiomyopathy

Treatment is often frustrating and is directed at the relief of congestion, as well as the underlying cause. Digoxin should be avoided in patients with amyloidosis. Otherwise, diuretics remain the mainstay of therapy. Constrictive pericarditis needs to be excluded, as this treatable disorder is easily confused with restrictive cardiomyopathy.

ARRYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA

Arrythmogenic right ventricular dysplasia (ARVD) is characterized by an enlarged right ventricle due to fibrofatty infiltration of the right ventricular free wall (10). Patients present with ventricular tachycardia of left bundle branch morphology or sudden death. The disease is frequently familial, and mutations in at least three genes have been associated with ARVD. It should be suspected in young patients resuscitated from sudden death without overt left ventricular dysfunction or underlying congenital heart disease.

Evaluation and Treatment of ARVD

The evaluation includes echocardiography, magnetic resonance imaging, and sometimes endomyocardial biopsy. In general, an enlarged, hypocontractile right ventricle is seen with evidence of fat infiltration on magnetic resonance imaging. Cardiac sarcoid may at times also present in a similar manner. Treatment includes the screening of family members and the placement of an automa- tic implantable cardioverter-defibrillator. Given the rarity of ARVD, referral to a center with expertise in this disorder is warranted.

MYOCARDITIS

Myocarditis is an inflammatory disease of the myocardium, which can lead to a dilated cardiomyopathy. It has been associated with a variety of infectious organisms, including bacteria, parasites, and fungi, as well as hypersensitivity drug reactions and autoimmune diseases (see Table 4).

The key concept is that some form of myocardial injury, usually viral, leads to an autoimmune reaction. This, in turn, causes a dilated cardiomyopathy. This section will concentrate on primary myocarditis, which most believe is a postviral autoimmune disease.

Causes of Myocarditis

As early as the 1800s, it was recognized that cardiac symptoms could be associated with mumps.

Sometime about 1929, cardiac inflammation was found in association with influenza. Enterovi- ruses, particularly the poliomyelitis virus, were associated with myocarditis in the late 1920s. Since then, a number of viruses have been identified in association with myocarditis including both DNA and RNA core viruses (Table 4), but cardiotropic strains of Coxsackie viruses were felt to be the most common cause of myocarditis. By polymerase chain reaction (PCR), viral genome was recently

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found in 38% of 624 patients with myocarditis and only 1.4% of control samples (11). The myocardial samples came from endomyocardial biopsy, autopsy, and explanted hearts. The most common virus genome identified in both children and adults with myocarditis was adenovirus followed by enterovirus, cytomegalovirus, parvovirus, influenza A, herpes simplex virus, Epstein-Barr virus, and respiratory syncitial virus. There were 26 patients with infection with two different viruses.

That adenoviruses and enteroviruses, such as Coxsackie, cause myocarditis should not be too surprising as both use common cellular receptors for entry into myocardial cells, and differences in affinity for the receptor may account for differences in susceptibility and pathogenesis. Other viruses that have been described as causes of myocarditis include human immunodeficiency virus and hepatitis C. In addition, myocarditis has recently been confirmed following smallpox vaccination in US military personnel (12,13).

The natural history is variable. The majority of patients probably have subclinical cardiac inflammation that clears spontaneously (14). A much smaller percentage present with overt disease.

Four clinicopathologic forms of myocarditis have been described (Table 5). Patients with fulminant myocarditis are usually young and have a distinct onset with a recent, recognizable viral illness.

They present abruptly with poor left ventricular function and near-normal-sized left ventricles. Ven- tricular walls are often thick due to a combination of lymphocytic infiltration and edema. Patients either spontaneously recover completely or die of cardiogenic shock or ventricular arrhythmias (15,16). We do not believe that immunosuppression has a role in the management of these patients.

Patients with acute myocarditis have an indistinct onset of symptoms, moderate to severe left ventricular dysfunction, and active or borderline myocarditis on endomyocardial biopsy. Such patients may respond to immunosuppression. Chronic active myocarditis has an indistinct onset and progressive left ventricular dysfunction, resulting in a restrictive picture. Endomyocardial biopsy shows inflammation and severe fibrosis, which does not respond to immunosuppression. Patients with chronic persistent myocarditis present with atypical chest pain or ventricular arrhythmias. Left ventricular dysfunction is not present. Endomyocardial biopsy shows inflammation.

Giant-cell myocarditis has a particularly poor prognosis, with a median survival of 5.5 mo after the development of symptoms as documented in the largest registry of such patients (17). The course is characterized by progressive heart failure with refractory ventricular arrhythmias. Patients tend to present in their 40s, and many have had a previous autoimmune disease. It is known to recur in transplanted hearts, but heart transplantation is the only therapy likely to offer a significant survival

Table 4 Causes of Myocarditis Infections

Viral: Coxsackie virus, echovirus, poliovirus, influenza, vaccinia, cytomegalovirus, adenovirus, parvovirus, herpes simplex, respiratory syncytial virus, Epstein-Barr virus, hepatitis, varicella zoster, human immunodeficiency virus

Bacterial: Streptococcus pyogenes, Staphylococcus aureus, Salmonella, Leptospira, Borellia burgdorferi, Mycoplasma pneumoniae, Chlamydia, Rickettsia

Fungi: Aspergillus, Candida

Parasites: Trypanosoma cruzii, Toxoplasma Smallpox vaccination

Peripartum Giant cell Eosinophilic

Chemical or drug hypersensitivity

Multiple antibiotics, diuretics, anticonvulsants, interferon Radiation

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advantage. Endomyocardial biopsy shows a diffuse, aggressive lymphocytic infiltrate with myocyte necrosis and the presence of giant cells without well-formed granuloma. Giant-cell myocarditis is different from cardiac sarcoidosis. The pathology is different, with cardiac sarcoidosis presenting with a patchy infiltrate and well-formed granuloma. The prognosis of cardiac sarcoid is better and patients with sarcoid are more likely to present with heart block and a long duration of symptoms (18).

Evaluation of Myocarditis

Diagnosis is based on endomyocardial biopsy. In general, the Dallas criteria remain the bench- mark for histologic diagnosis (19). Myocarditis is characterized by myocyte necrosis associated with an adjacent inflammatory infiltrate. Borderline myocarditis is diagnosed if there is no evident myocyte damage. Myocarditis can be suspected in patients who present with a nondilated, hypocontractile heart and an antecedent viral syndrome. Troponins may be elevated and sometimes pericarditis symptoms predominate.

Treatment of Myocarditis

Treatment remains controversial. The largest trial of immunosuppressive therapy for myocarditis did not support the use of such agents. There was no significant difference in survival (4). Since then, a number of reports have suggested that patients with cardiac inflammation may respond if the correct patients are chosen. In a trial of 22 patients with PCR-proven enteroviral or adenoviral genomes and persistent left ventricular dysfunction, treatment with interferon-b for 6 mo resulted in the elimination of viral genomes in all patients and improvement in left ventricular function in 15 of 22 patients (20). In another study of 112 patients with a histologic diagnosis of myocarditis, patients with circulating cardiac autoantibodies and no viral genome were most likely to respond to immunosuppression (21). Wojnicz et al. showed no difference in survival in 84 patients with dilated cardiomyopathy and increased myocyte HLA expression randomized to 3 mo of immunosuppression versus placebo (22). Approximately 27% of patients in this trial had myocarditis as diagnosed by the Dallas Criteria. Intravenous immunoglobulin did not augment left ventricular function when compared to placebo in adult patients with recent-onset dilated cardiomyopathy (23). However, left ventricular function did improve to a similar degree, about 16 EF units, in both groups. Only about 16% of patients in this trial had myocarditis as defined by the Dallas Criteria.

Currently, the treatment of myocarditis is in evolution. Patients with a fulminant presentation usually will not need immunosuppression. In patients with chronic active myocarditis and chronic persistent myocarditis, immunosuppression is either ineffective or unwarranted. Patients with giant- cell myocarditis are treated with immunosuppression, but this is rarely effective. In the future we should be able to predict which patients with acute myocarditis will respond to immunosuppression, and likely tailor therapy to the stage of the disease.

Table 5

Clinicopathologic Forms of Myocarditis

Fulminant Acute Chronic active Chronic persistent

Onset Distinct Indistinct Indistinct Indistinct

LV function Severe dysfunction Moderate Moderate dysfunction Normal dysfunction

Biopsy Multiple foci active Active or Active or borderline Active or

borderline borderline

Clinical Complete recovery Dilated Restrictive Normal

prognosis or death cardiomyopathy cardiomyopathy

Histologic Resolution Resolution Ongoing inflammation Ongoing

prognosis and fibrosis myocarditis

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Peripartum Cardiomyopathy

Peripartum cardiomyopathy is included here because in our experience 62% of patients had myocarditis on endomyocardial biopsy (24). In the United States, this occurs in 1 of every 1300 to 4000 deliveries. It is defined as left ventricular systolic dysfunction developing in the final month of pregnancy or within 5 mo after delivery in the absence of preexisting heart disease. In our experience, recovery of left ventricular function occurs in the majority of patients and the 5-yr survival is excellent. Subsequent pregnancies have been associated with a reoccurrence of left ventricular dysfunction (25). In 28 women whose left ventricular function had returned to normal, there was no mortality but 21% of patients developed symptoms of heart failure. In 16 women whose heart function had failed to normalize, the mortality was 19% and 44% of the women developed heart failure. These data are helpful in counseling women regarding future pregnancies.

CONCLUSION

Diseases of the myocardium, cardiomyopathies, leading to heart failure represent fertile ground for further research. I expect molecular techniques to substantially affect our ability to diagnose and care for patients with cardiomyopathy. The next decade will likely see the advent of biologi- cally based therapies to both prevent the phenotypic development of cardiomyopathy and to manage the disease once present.

REFERENCES

1. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of Cardiomyopathies. Circulation 1996;93:841–842.

2. Felker GM, Thompson RE, Hare JM, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000;342:1077–1084.

3. Felker GM, Hu W, Hare JM, et al. The spectrum of dilated cardiomyopathy. The Johns Hopkins experience with 1,278 patients. Medicine (Baltimore) 1999;78:270–283.

4. Mason JW, O’Connell JB, Herskowitz A, et al. A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators. N Engl J Med 1995;333:269–275.

5. Michels VV, Moll PP, Miller FA, et al. The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N Engl J Med 1992;326:77–82.

6. Fatkin D, Graham RM. Molecular mechanisms of inherited cardiomyopathies. Physiol Rev 2002;82:945–980.

7. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary A Report of the American College of Cardiology/American Heart Asso- ciation Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Man- agement of Heart Failure): Developed in Collaboration with the International Society for Heart and Lung Transplan- tation; Endorsed by the Heart Failure Society of America. Circulation 2001;104:2996–3007.

8. Maron BJ, McKenna WJ, Danielson GK, et al. ACC/ESC clinical expert consensus document on hypertrophic cardiomyopathy: a report of the American Colege of Cardiology Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol 2003;42:1687–1713.

9. Kushwaha SS, Fallon JT, Fuster V. Restrictive cardiomyopathy. N Engl J Med 1997;336:267–276.

10. Marcus F, Towbin JA, Zareba W, et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C):

a multidisciplinary study: design and protocol. Circulation 2003;107:2975–2978.

11. Bowles NE, Ni J, Kearney DL, et al. Detection of viruses in myocardial tissues by polymerase chain reaction. evidence of adenovirus as a common cause of myocarditis in children and adults. J Am Coll Cardiol 2003;42:466–472.

12. Halsell JS, Riddle JR, Atwood JE, et al. Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel. JAMA 2003;289:3283–3289.

13. Murphy JG, Wright RS, Bruce GK, et al. Eosinophilic-lymphocytic myocarditis after smallpox vaccination. Lancet 2003;362:1378–1380.

14. Lieberman EB, Herskowitz A, Rose NR, Baughman KL. A clinicopathologic description of myocarditis. Clin Immunol Immunopathol 1993;68:191–196.

15. McCarthy RE, Boehmer JP, Hruban RH, et al. Long-term outcome of fulminant myocarditis as compared with acute (nonfulminant) myocarditis. N Engl J Med 2000;342:690–695.

16. Felker GM, Boehmer JP, Hruban RH, et al. Echocardiographic findings in fulminant and acute myocarditis. J Am Coll Cardiol 2000;36:227–232.

17. Cooper LT Jr, Berry GJ, Shabetai R. Idiopathic giant-cell myocarditis—natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators. N Engl J Med 1997;336:1860–1866.

18. Okura Y, Dec GW, Hare JM, et al. A clinical and histopathologic comparison of cardiac sarcoidosis and idiopathic giant cell myocarditis. J Am Coll Cardiol 2003;41:322–329.

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19. Aretz HT. Myocarditis: the Dallas criteria. Hum Pathol 1987;18:619–624.

20. Kuhl U, Pauschinger M, Schwimmbeck PL, et al. Interferon-beta treatment eliminates cardiotropic viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation 2003;107:2793–2798.

21. Frustaci A, Chimenti C, Calabrese F, et al. Immunosuppressive therapy for active lymphocytic myocarditis: viro- logical and immunologic profile of responders versus nonresponders. Circulation 2003;107:857–863.

22. Wojnicz R, Nowalany-Kozielska E, Wojciechowska C, et al. Randomized, placebo-controlled study for immunosuppressive treatment of inflammatory dilated cardiomyopathy: two-year follow-up results. Circulation 2001;104:

39–45.

23. McNamara DM, Holubkov R, Starling RC, et al. Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy. Circulation 2001;103:2254–2259.

24. Felker GM, Jaeger CJ, Klodas E, et al. Myocarditis and long-term survival in peripartum cardiomyopathy. Am Heart J 2000;140:785–791.

25. Elkayam U, Tummala PP, Rao K, et al. Maternal and fetal outcomes of subsequent pregnancies in women with peripartum cardiomyopathy. N Engl J Med 2001;344:1567–1571.

RECOMMENDED READING

Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of Cardiomyopathies. Circulation 1996;93:841–842.

Felker GM, Thompson RE, Hare JM, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000;342:1077–1084.

Hunt SA, Baker DW, Chin MH, et al. ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary A Report of the American College of Cardiology/American Heart Asso- ciation Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Man- agement of Heart Failure): Developed in Collaboration With the International Society for Heart and Lung Transplan- tation; Endorsed by the Heart Failure Society of America. Circulation 2001;104:2996–3007.

Maron BJ, McKenna WJ, Danielson GK, et al. ACC/ESC clinical expert consensus document on hypertrophic cardiomyopathy: a report of the American Colege of Cardiology Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol 2003;42:1687–1713.

Kushwaha SS, Fallon JT, Fuster V. Restrictive cardiomyopathy. N Engl J Med 1997;336:267–276.