Jeffrey A. Towbin
The myocardium can be affected by inflammatory (infectious or immune-mediated), metabolic, infiltrative, ischemic, or primary disease processes. These disorders may be inherited and may have significant overlap (eTable 489.1 ). Myocardial diseases may present acutely, with signs of congestive heart failure that include tachypnea, often with rales; tachycardia; an enlarged but quiet heart; soft heart sounds that may have a tic-tac rhythm; cardiac gallops; and either no murmurs or systolic murmurs of mitral or tricuspid regurgitation. Alternatively, they may present chronically with failure to thrive, decreased exercise tolerance, and more subtle findings of heart failure. Occasionally, the predominant process may be an arrhythmia, either atrial or ventricular tachycardia/fibrillation, or heart block. These present clinically with palpitations, syncope, or sudden death. The electrocardiogram and chest x-ray are useful in confirming the presence of heart disease, but are rarely diagnostic.
In acute presentations, the chest x-ray usually shows diffuse cardiac enlargement, passive pulmonary congestion, and interstitial edema; the electrocardiogram shows normal or reduced QRS voltages (because hypertrophy has not yet had time to develop), and S-T segment depression with T-wave inversion in the anterolateral precordial leads. The echocardio-gram often shows diffuse cardiac dilatation, decreased contractions, and atrioventricular valve regurgitation.
In the chronic presentation, the chest x-ray may show profound cardiomegaly (dilated type) or a heart of normal size. The lung fields are usually clear. The electrocardiogram often shows left ventricular hypertrophy, frequently with left axis deviation, increased left precordial and inferior forces, and S-T segment flattening with T-wave inversion. The clinical, ECG, and chest x-ray findings are frequently nonspecific.
Chronic myocardial diseases (cardiomyopathies) present in 1 of 5 configurations as defined in the American Heart Association 2006 classification .
1. Most commonly, the ventricle is dilated and shows decreased contractility; systolic function is impaired in this disorder, and there is ventricular wall thinning.1-4 Dilated cardiomyopathy is considered most often to be primary (genetic) or a sequela of viral myocarditis, nutritional, or toxic factors. Chronic tachycardia is an uncommon but important cause because therapy directed at the arrhythmia may significantly ameliorate the dysfunction.
2. Less often, the ventricular wall is thickened or hypertrophic and can cause obstruction to systolic outflow or impair diastolic filling.3-5 Thickening of the ventricles may affect the septum more than the ventricular free walls or may be uniform and concentric. Hypertrophy is frequently massive at the time of diagnosis, and systolic function may be hyperdynamic or normal. This hypertrophic form of cardiomyopathy is frequently genetic, resulting from mutations in genes encoding sarcomeric proteins, genes involved in energy metabolism, or as part of several neuromuscular disorders. Hypertrophic cardiomyopathy is generally transmitted in an autosomal dominant pattern, with relatively high penetrance if patients are followed lifelong. Genotype–phenotype correlations have been reported but are controversial. Routine molecular diagnosis is now available for most of the genes causing disease, and approximately 75% of patients can be identified by these studies. (See Chapter 481.) Other forms of ventricular hypertrophy with the appearance of hypertrophic cardiomyopathies occur in Pompe disease, Friedreich ataxia, mitochondrial disorders, and Fabry and Noonan syndromes, among others.
3. Sometimes there is a restrictive cardiomyopathy, extremely rare in childhood, with grossly impaired filling that produces a small heart with normal ventricular dimensions; systolic function is normal, but diastolic function is impaired and the atria are dilated.3-6 In some of these patients, the left ventricle may be hypertrophic. Restrictive cardiomyopathy is often associated with infiltration of the myocardium by cells or unusual chemicals and may be associated with muscle disorders. Approximately 20% or more of these patients have autosomal dominant inheritance, and sarcomere-encoding genes have been identified. It is generally sporadic and idiopathic, and the prognosis is poor, with a median survival of less than 2 years. Most affected children die suddenly.
4. Arrhythmogenic right ventricular dysplasia/cardiomyopathy is a misnomer. This disorder is usually of genetic origin, is usually dominantly inherited, and the genes identified thus far encode desmosomal proteins. Intercalated disks in these patients are disrupted. The dysplasia combines arrhythmias, usually ventricular tachycardia, with a dilated right ventricle and right ventricular systolic dysfunction. Although the right ventricle is typically affected first (but not invariably), the left ventricle is affected later.
5. Left ventricular noncompaction, the most recently classified form, is characterized by variable clinical features. Often aneurysmal left ventricular noncompaction is variable, potentially mimicking all other forms. However, the key feature of this disorder is left ventricular trabeculation in the apex of the free wall. Commonly, there is associated muscle disease. It usually has autosomal dominant inheritance, and the genes appear to be cyto-skeletal, sarcomeric, and energy encoding.
Inflammatory diseases of the myocardium may be infectious or autoimmune mediated, acute or chronic. Acute infection is the most common inflammatory process that directly affects the heart.1,7,8 Acute myocarditis can occur at any age, including in the fetus, and its course ranges from very mild to fulminant, with death in a few days or weeks. Often there is a history of a recent upper respiratory tract infection, and viruses are usually the causative agents. Historically, the enteroviruses (coxsackie and echoviruses) have been most common; adenoviruses then became frequent causes, and recently parvoviruses predominate. Polymerase chain reaction of myocardial biopsy specimens has been used to detect viral genomes in many patients with acute and chronic myocarditis. Many other viruses, including parvovirus, HIV, mumps, cytomegalovirus, and varicella can cause myocarditis, as can other pathogens including Rickettsiae, Toxoplasma gondii, Mycoplasma pneumoniae, Chlamydia trachomatis, and Borrelia burgdorferi, among others. Diphtheria exotoxin causes profound myocardial damage by interfering with mitochondrial energy metabolism and is often associated with heart block, ventricular tachycardia, and fibrillation; mortality is high. Trypanosoma cruzi (Chagas disease) is a common cause of myocarditis in South and Central America; the acute myocarditis can be severe and is the primary cause of death in the acute phase of the illness, although chronic myocardial dysfunction, occurring after a long latent period, is a far more common result.
Immune-mediated myocarditis can also occur acutely. Rheumatic myocarditis may occur early in acute rheumatic fever and is almost always accompanied by endocardial (mitral or aortic valve regurgitation) involvement and sometimes by pericarditis. Kawasaki syndrome often causes myocardial and pericardial inflammation, although myocardial dysfunction is rarely severe in the absence of significant obstructive coronary arterial lesions. Many other autoimmune diseases may affect the myocardium, including systemic lupus erythematosus, which may cause acute myocardial or pericardial inflammation, or chronic endocardial disease (Libman-Sacks endocarditis). Maternal systemic lupus erythematosus is also associated with conduction system damage and heart block in the fetus.
Treatment of acute myocarditis is supportive; bed rest, diuretics, inotropic agents, after-load reduction, and occasionally ventilatory support may all be necessary. Viral myocarditis is commonly associated with ventricular dysrhythmias and conduction abnormalities that may be potentiated by digoxin; if used, it should be given in low dose and with careful cardiac monitoring. Specific therapies include steroids in acute rheumatic (but not viral) myocarditis, gamma globulin and salicylates in Kawasaki syndrome, gamma globulin in viral myocarditis,9 antitoxin in diphtheria, and antimicrobials in bacterial, parasitic, mycoplasma, or rickettsial myocarditis. The diagnosis of myocarditis can be inferred by documenting a specific clinical pattern (as in rheumatic myocarditis, Kawasaki syndrome, or diphtheria), documenting myocardial inflammation by nuclear isotope scans or cardiac MRI with gadolinium, or by identifying a potentially causative virus in the myocardium by polymerase chain reaction. Less useful, isolation of virus from the throat or feces in association with an appropriate antibody response has been used in the past but is insensitive.
Chronic inflammation of the myocardium also occurs. Occasionally, viral myocarditis presents with chronic congestive heart failure, dysrhythmias, and cardiomegaly with hypertrophy. Finding inflammatory infiltrates on myocardial biopsy suggests ongoing inflammation and perhaps separates this disease from idiopathic dilated cardiomyopathy.8 However, many authors now suggest that the latter is a later manifestation of viral infection. Indeed, viral genomes can be isolated from the myocardium of many patients with dilated cardiomyopathy, even when an inflammatory infiltrate is not found on biopsy. This may reflect the patchy nature of the inflammatory process or the viral machinery itself. Viral genomes have not been amplified from the myocardium of control patients with structural heart disease, suggesting that this test is specific for persistent viral infection. Cardiomyopathy is believed to result from ongoing inflammation and release of inflammatory cytokines that may lead to myocyte death. Steroids or azathioprine have been used with only occasional success, probably because symptoms occur late in the process when cardiac reserve is exhausted.
Myocarditis causing a dilated cardiomyopathy is a common finding in HIV infection.10,11 Although the HIV virus has been isolated from the myocardium at autopsy or localized by polymerase chain reaction, other viral genomes are recovered at least as frequently in HIV-infected children, suggesting that HIV infection may predispose patients to persistent myocardial infection with other viruses. Other forms of inflammatory heart disease, such as the typical forms of myocarditis, can also lead to chronic dilated cardiomyopathy
Myocardial function may be impaired by dietary deficiencies or excesses of various substances, or by enzymatic defects that impair energy utilization.12-14 Low calcium or magnesium levels may occasionally cause cardiac dilatation and heart failure, particularly in premature infants. Clinically, there may be hyperreflexia. Electrocardiograms usually show a prolonged Q-T interval and occasionally atrioventricular block. Severe hypophosphatemia may also cause reversible heart failure. Hypokalemia and hyperkalemia are discussed in Chapter 466. Severe hypoglycemia can cause cardiac dilatation and heart failure in newborns, particularly in infants born prematurely, with intrauterine growth retardation, with severe cyanotic heart disease, or in infants of diabetic mothers. Infants of diabetic mothers can also have hypertrophic hearts with or without obstruction that resemble hypertrophic cardiomyopathy with asymmetric septal hypertrophy or concentric hypertrophy. The heart usually returns to normal over several months (see Chapter 484). In fact, if not normalized by 3 months of age, other etiologies should be considered.
Deficiencies of vitamins (thiamine, causing beriberi), trace metals (selenium, causing Keshan disease), amino acids (taurine), or cofactors (carnitine) can cause cardiac dilatation and heart failure. These deficiencies can either be nutritional or, rarely, due to an inborn error of metabolism. For example, carnitine deficiency may be secondary to a variety of chronic illnesses, including mitochondrial myopathies, or may be a primary process.12 Treatment in all is toward redressing the specific deficiency. Hormonal abnormalities can also cause myocardial dysfunction. Hypothyroidism not only causes bradycardia, low cardiac output, and pericardial effusion, but also can cause myocardial degeneration with S-T and T-wave changes. Pheochromocytoma may produce left ventricular hypertrophy and heart failure from sustained or paroxysmal hypertension; in addition, high catecholamine blood levels can cause subendocardial hemorrhages and myocardial degeneration that further impair cardiac function.
Other causes of myocardial dysfunction include toxic effects of drugs (chloroquine, ipecac, cocaine, and adriamycin, the latter of which may cause severe, long-lasting myocardial damage), radiation (particularly mediastinal radiotherapy for lymphoma),15 metabolic by-products (uremic cardiomyopathy, which is rapidly reversible with hemodialysis),16 and severe anemia.
Genetic metabolic disorders are increasingly recognized as a cause of severe myocardial disease in early infancy. These disorders generally produce cardiomyopathy by interfering with energy metabolism. Specific defects may affect transport of substrate or cofactors into mitochondria (eg, carnitine-palmitoyl transferase-1 deficiency),12 or directly affect mitochondrial enzymes involved in β-oxidation of fatty acids (eg, long-chain and medium-chain acyl dehydrogenase deficiency)13 or electron transport. These defects can be associated with dilated, hypertrophic, overlapping dilated and hypertrophic, or left ventricular (LV) noncompaction cardiomyopathy and often produce profound but episodic cardiac failure. Although rare, diagnosis of these disorders is important because familial incidence is frequent.
Many substances can infiltrate the myocytes or interstitium and impair cardiac function. Abnormal deposition of glycogen (especially type II glycogen storage, or Pompe disease; see Chapter 154) or glycolipid (Fabry disease) in the myocytes causes massive ventricular hypertrophy and can produce obstruction. Hemosiderin may be deposited in the inter-stitium, causing myocardial fibrosis and subsequent systolic and diastolic dysfunction. This may be primary, but is more commonly secondary to repeated blood transfusions in thalassemia, sickle cell disease, and aplastic anemia. Mucopolysaccharidoses can produce myocardial degeneration.14 Hurler and Hunter syndromes also cause intimal thickening of the coronary arteries and, with Morquio and Scheie syndromes, can cause valvar regurgitation (Chapter 160). Other syndromes associated with myocardial infiltration and fibrosis include cystinosis, amyloidosis, and sarcoidosis, but rarely in childhood.
Infiltration may also be caused by neoplastic processes. The infiltration may be generalized, as in leukemia and lymphoma, or may be localized. Localized tumors are described in Chapter 487.
Myocardial ischemia is rare in childhood. It may be due to embolism, particularly in the perinatal period when venous thrombi easily cross the foramen ovale, but is more commonly caused by coronary artery abnormalities. Most frequent among these are congenital defects in which the coronary arteries communicate with another vascular bed, producing ischemia through a vascular steal syndrome: anomalous origin of the left or right coronary artery from the pulmonary artery (see Chapter 484), arteriovenous fistula, and arteriocameral fistula. Coronary insufficiency also results from inborn errors of metabolism (homozygous type 2 hyperlipidemia, homocystinuria), idiopathic calcification of the coronary arteries, and vasculitides. The most common vasculitis affecting the coronary arteries occurs in Kawasaki syndrome (see Chapter 488). Other vasculitides, including juvenile rheumatoid arthritis, polyarteritis nodosa, and systemic lupus erythematosus, may also affect coronary arteries. Obliterative coronary arteritis has been associated with transplant rejection. All of these diseases can produce myocardial ischemia, the extent of which varies with the size and number of arteries involved and the amount of collateral formation. There may be cardiac dilatation, arrhythmias, and often mitral regurgitation due to damage to the papillary muscles.
Chronic atrial or ventricular tachycardias are associated with a dilated cardiomyopathy that can be cured if the arrhythmia is controlled. Myocardial ischemia is the likely but unproven mechanism.
PRIMARY DISEASE OF MYOCYTES
Diseases that primarily alter the structure of the myocyte can be separated into known neuromuscular disorders and unknown (or idiopathic) disorders. The most common neuromuscular disorders affecting myocytes include: Friedreich ataxia, which usually causes cardiac hypertrophy but can also result in dilatation and heart failure in older children and adolescents, and progressive (Duchenne or Becker) muscular dystrophy, which results in dilated cardiomyopathy in essentially all affected boys by the teen years (and their carrier mothers later in life) but may cause left ventricular hypertrophy and S-T and T-wave changes. There are many less common diseases, often with abnormalities in mitochondrial structure or function, that affect cardiac as well as skeletal myocytes.
Familial examples of isolated dilated cardiomyopathy have also been reported. Usually, inheritance is autosomal dominant, but recessive, mitochondrial, and X-linked inheritance also exists. X-linked inherited forms have been found to occur due to mutations in dystrophin (the Duchenne and Becker muscular dystrophy gene), tafazzin or TAZ (the Barth syndrome gene), or LAMP2 (the Danon disease gene). Mutations in genes encoding cytoskeletal and sarcomeric proteins appear to be most commonly seen in dilated cardiomyopathy with autosomal dominant inheritance.
Dilated cardiomyopathy occurs in children of all ages. Treatment is supportive and includes nutritional supplementation, diuretics, inotropic agents, vasodilators, and β-adrenergic blockade. Many children are candidates for cardiac transplantation.
One specific pathologic type of cardiomyopathy is endocardial fibroelastosis, in which the ventricles or atria are lined with thick white tissue that on microscopy shows marked endocardial and subendocardial fibroelastic proliferation. These changes may be secondary to severe obstructive lesions; they may occur in the left ventricle and atrium with severe aortic stenosis or coarctation of the aorta, in the left atrium with mitral atresia and a small foramen ovale, or in the right ventricle with severe pulmonary stenosis or atresia. More often they are primary. Primary (idiopathic) endocardial fibroelastosis, a disease of unknown origin, usually occurs under 1 year of age. The disease may appear in clusters, suggesting an infective origin. Many of these infants have had positive skin reactions to inactivated mumps antigen, and more recently, mumps viral genome was identified by polymerase chain reaction from the myocardium of patients with endocardial fibroelastosis, but not others. The endocardial thickening is accompanied by myocardial hypertrophy, impaired myocardial function, and mitral and tricuspid regurgitation. The clinical features are those of any chronic myocardial disorder with congestive heart failure, as are the radiologic and electrocardiographic features. Because the clinical findings are nonspecific, the diagnosis can be proved only by biopsy or autopsy; however, the echocardiogram often shows bright endocardial echoes. Treatment is symptomatic. Most children get worse and die months or years after the onset, but spontaneous remissions have been described.