Etiology and Epidemiology

Dilated cardiomyopathy (DCM), the most common form of cardiomyopathy in children, is the cause of significant morbidity and mortality as well as a common indication for cardiac transplantation. The etiologies are diverse. Unlike adult patients with dilated cardiomyopathy, ischemic etiologies are rare in children, although these include anomalous origin of the left coronary artery from the pulmonary artery, premature coronary atherosclerosis (homozygous type II hypercholesterolemia), and coronary inflammatory diseases, such as Kawasaki disease. It is estimated that up to 50% of cases are genetic, including some with metabolic causes (see Table 433-1). Although the most common etiology of dilated cardiomyopathy remains idiopathic, it is likely that undiagnosed familial/genetic conditions and myocarditis predominate. The annual incidence of DCM in children younger than 18 yr is 0.57 cases per 100,000 per year. Incidence is higher in males, African Americans, and in infants less than 1 yr old.

Pathogenesis

The pathogenesis of the ventricular dilation and altered contractility seen in dilated cardiomyopathy varies depending on the underlying etiology. Genetic abnormalities of several components of the cardiac muscle including sarcomere protein, the cytoskeleton, and the proteins that bridge the contractile apparatus to the cytoskeleton, have been identified in autosomal dominant and X-linked inherited disorders. Dilated cardiomyopathy can occur following viral myocarditis and, although the primary pathogenesis varies from direct myocardial injury to viral-induced inflammatory injury, the resulting myocardial damage, ventricular enlargement, and poor function likely occur by a final common pathway similar to that which occurs in genetic disorders.

In 20-50% of cases, the DCM is familial with autosomal dominant inheritance most common (see Table 433-2). Duchenne and Becker muscular dystrophies (Chapter 601.1) are X-linked cardiomyopathies that account for 5-10% of familial dilated cardiomyopathy cases. These dystrophinopathies result in an abnormal sarcomere-cytoskeleton connection, causing impaired myocardial force generation, myocyte damage/scarring, chamber enlargement, and altered function.

Mitochondrial myopathies, like the muscular dystrophies, may present clinically with a predominance of extra cardiac findings and are inherited in a recessive or mitochondrial pattern. Disorders of fatty acid oxidation present with systemic derangements of metabolism (hypoketotic hypoglycemia, acidosis, liver dysfunction), some with peripheral myopathy and neuropathy, and others with sudden death or life-threatening cardiac arrhythmias

Anthracycline cardiotoxicity (doxorubicin [Adriamycin]) on rare occasion causes acute inflammatory myocardial injury, but more classically results in dilated cardiomyopathy and occurs in up to 30% of patients given a cumulative dose of doxorubicin exceeding 550 mg/m². The risk of toxicity appears to be exacerbated by concomitant radiation therapy.

Clinical Manifestations

Although more prevalent in patients less than 1 yr of age, all age groups may be affected. Clinical manifestations of dilated cardiomyopathy are most commonly those of congestive heart failure, but can also include palpitations, syncope, and sudden death. Irritability or lethargy can be accompanied by additional nonspecific complaints of failure to thrive, nausea, vomiting, or abdominal pain. Respiratory symptoms (tachypnea, wheezing, cough, or dyspnea on exertion) are often present. Uncommonly, patients may present acutely with pallor, altered mentation, hypotension, and shock. Patients can be tachycardic with narrow pulse pressure and have hepatic enlargement, and rales or wheezing. The precordial cardiac impulse is increased and the heart may be enlarged to palpation or percussion. Auscultation may reveal a gallop rhythm in addition to tachycardia and occasionally murmurs of mitral or, less commonly, tricuspid insufficiency may be present. The presence of hypoglycemia, acidosis, hypotonia, or signs of liver failure suggests an inborn error of metabolism. Neurologic or skeletal muscle deficits are associated with mitochondrial disorders or muscular dystrophies.

Laboratory Findings

Electrocardiographic screening reveals atrial or ventricular hypertrophy, nonspecific T-wave abnormalities, and occasionally atrial or ventricular arrhythmias. The chest x-ray demonstrates cardiomegaly and may reveal pulmonary vascular prominence or pleural effusions. The echocardiogram is often diagnostic, demonstrating the characteristic findings of left ventricular enlargement, decreased ventricular contractility, and occasionally a globular (remodeled) left ventricular contour (see Fig. 433-1). Right ventricular enlargement and depressed function are occasionally noted. Echo Doppler studies can reveal evidence of pulmonary hypertension, mitral regurgitation, or other structural cardiac or coronary abnormalities.

Additional testing should include CBC, renal and liver function tests, CPK, cardiac troponin I, lactate, plasma amino acids, urine organic acids, and an acylcarnitine profile. Additional genetic and enzymatic testing may be useful (see Table 433-2). Cardiac catheterization and endomyocardial biopsy are not routine but may be useful in patients with acute dilated cardiomyopathy. Biopsy samples can also be assessed for the presence of mononuclear cell infiltrates, myocardial damage, storage abnormalities, and viral infection or genomes. It is important to consider screening of 1st-degree family members utilizing echocardiography and ECG.

Prognosis and Management

The 1- and 5-yr rates of death or need for transplantation in patients diagnosed with DCM is 31% and 46%, respectively. Independent risk factors at DCM diagnosis for subsequent death or transplantation include older age, congestive heart failure, lower left ventricular fractional shortening z score, and underlying etiology. Dilated cardiomyopathy is the most common cause for cardiac transplantation in pediatric and adult studies.

The therapeutic approach to patients with dilated cardiomyopathy includes a careful assessment to uncover possible treatable etiologies, screening of family members, and rigorous pharmacologic therapy. Decongestive therapy may improve symptoms of heart failure, prolong survival, and occasionally results in complete resolution of dysfunction. Patients are often treated with diuretics and angiotensin-converting enzyme (ACE) inhibitors. The use of digitalis and angiotensin receptor blockers may be of additional benefit. β-Adrenergic blockade with carvedilol or metoprolol is often utilized in patients with chronic congestive heart failure although pediatric specific outcome data have failed to show effectiveness. In patients presenting with extreme degrees of heart failure or circulatory collapse, intensive care measures are often required, including intravenous inotropes and diuretics, mechanic ventilatory support, and on occasion, mechanical circulatory support, which may include ECMO, ventricular assist devices, and ultimately cardiac transplantation. In patients with dilated cardiomyopathy and atrial or ventricular arrhythmias, specific antiarrhythmic therapy should be instituted.

Etiology and Epidemiology

Hypertrophic cardiomyopathy (HCM) is a heterogeneous, relatively common, and potentially severe form of cardiomyopathy. The causes of hypertrophic cardiomyopathy are heterogeneous and include inborn errors of metabolism, neuromuscular disorders, syndromic conditions, and genetic abnormalities of the structural components of the cardiomyocyte (see Table 433-1). Both the age of onset and associated features are helpful in identifying the underlying etiology.

HCM is a genetic disorder and frequently occurs as a result of mutations in sarcomere or cytoskeletal components of the cardiomyocyte. Mutations of the genes encoding cardiac β-myosin heavy-chain (MYH7) and myosin-binding protein C (MYBPC3) are the most common (see Table 433-2). Mutations are inherited in an autosomal dominant pattern with widely variable penetrance; many cases represent de novo mutations. Some patients have mutations in more than 1 gene; this may result in early onset and more severe symptoms. Additional genetic causes for HCM include nonsarcomeric protein mutations, such as the γ-2-regulatory subunit of AMP-activated protein kinase (PRKAG2) and the lysosome-associated membrane protein 2α-galactosidase (Danon disease, a form of glycogen storage disease). Syndromic conditions, such as Noonan syndrome, may manifest with hypertrophic cardiomyopathy at birth and recognition of extracardiac manifestations is important in making the diagnosis.

Glycogen storage disorders such as Pompe disease often present in infancy with a heart murmur, abnormal ECG, systemic signs and symptoms, and occasionally heart failure. The characteristic electrocardiogram in Pompe disease demonstrates prominent P waves, a short P-R interval, and massive QRS voltages; the echocardiogram confirms severe, often concentric, left ventricular hypertrophy.

Pathogenesis

Hypertrophic cardiomyopathy is characterized by the presence of an increased left ventricular wall thickness in the absence of structural heart disease or hypertension. Often the interventricular septum is disproportionately involved, leading to the previous designation of idiopathic hypertrophic subaortic stenosis (IHSS) or the current term of asymmetric septal hypertrophy. In the presence of a resting or provocable outflow tract gradient, the term hypertrophic obstructive cardiomyopathy (HOCM) is used. Although the left ventricle is predominantly affected, the right ventricle may be involved, particularly in infancy. The mitral valve can demonstrate systolic anterior motion of the mitral valve and mitral insufficiency. Left ventricular outflow tract obstruction occurs in 25% of patients, is dynamic in nature, and may in part be secondary to the abnormal position of the mitral valve as well as the obstructing subaortic hypertrophic cardiac muscle. The cardiac myofibrils and myofilaments demonstrate disarray and myocardial fibrosis.

Typically, systolic pump function is preserved or even hyperdynamic, though systolic dysfunction may occur late. Outflow tract obstruction with or without mitral insufficiency may be provoked by physiologic manipulations such as the Valsalva maneuver, positional changes, and physical activity. Frequently, the hypertrophic and fibrosed cardiac muscle demonstrates relaxation abnormalities (diminished compliance) and left ventricular filling may be impaired (diastolic dysfunction).

Clinical Manifestations

Many patients are asymptomatic, and 50% of cases present with a heart murmur or during screening when another family member has been diagnosed with HCM. Symptoms of HCM may include palpitations, chest pain, easy fatigability, dyspnea, dizziness, and syncope. Sudden death is a well-recognized but uncommon manifestation that often occurs during physical exertion.

Characteristic physical examination findings include an overactive precordial impulse with a lift or heave, abnormal peripheral pulses (hyperdynamic or diminished), a systolic ejection murmur in the aortic region not associated with an ejection click, and an apical blowing murmur of mitral insufficiency.

Diagnosis

The electrocardiogram typically demonstrates left ventricular hypertrophy with ST segment and T-wave abnormalities. Intraventricular conduction delays and signs of ventricular preexcitation (Wolff-Parkinson-White syndrome) may be present and should raise the possibility of Danon disease or Pompe disease. Chest radiography demonstrates normal or mildly increased heart size with a prominence of the left ventricle. Echocardiography is diagnostic in identifying, localizing, and quantifying the degree of myocardial hypertrophy (Fig. 433-2). Doppler interrogation defines, localizes, and quantifies the degree of ventricular outflow tract obstruction and also demonstrates and quantifies the degree of mitral insufficiency. Diastolic dysfunction can be confirmed by M-mode, flow, and tissue Doppler techniques.

Figure 433-2 Echocardiograms demonstrating hypertrophic cardiomyopathy. A, Parasternal long-axis view of a patient with severe concentric left ventricular hypertrophy. B, Four-chamber view of a patient with asymmetric septal hypertrophy. LV, left ventricle; LVPW, left ventricular posterior wall; RV, right ventricle; SEPT, septum.

Cardiac catheterization may be indicated in some cases of hypertrophic cardiomyopathy to define the left ventricular outflow gradient with and without pharmacologic provocation, to perform electrophysiologic investigation for assessment of arrhythmia risk, or in rare cases, endomyocardial biopsy.

Additional diagnostic studies include metabolic testing, genetic testing for specific syndromic conditions, or genetic testing for mutations in genes known to cause isolated HCM (see Table 433-2). The clinical availability of these tests is expanding. In adults, where isolated HCM is a common genetic diagnosis, it has been possible to identify a subset of mutations that confer an increased risk for arrhythmia or sudden death. As identification of the molecular basis of disease in children increases, similar correlations are expected to emerge. In addition, genetic diagnosis is useful to identify at risk family members that require ongoing surveillance.

Prognosis and Management

Children under 1 yr of age or with inborn errors of metabolism or malformation syndromes have a significantly poorer prognosis. The risk of sudden death in older patients is greater in those with a history of cardiac arrest, ventricular tachycardia, exercise hypotension, syncope, excessive (>3 cm) ventricular wall thickness, and a ventricular obstruction gradient over 30 mm Hg. Although intrafamilial variability in symptoms occurs, a family history of sudden death is a highly significant predictor of risk.

Competitive sports and strenuous physical activity should be prohibited as most sudden deaths in patients with HCM occur during or immediately after vigorous physical exertion. β-Adrenergic blocking agents (propranolol, atenolol) or calcium channel blocking agents (verapamil) may be useful in diminishing ventricular outflow tract obstruction, modifying ventricular hypertrophy, and improving ventricular filling. Although significant symptomatic improvement occurs in some patients, the risk for development of heart failure or sudden death has not been lessened. In patients with atrial or ventricular arrhythmias, specific antiarrhythmic therapy should be utilized. Patients with documented ventricular arrhythmias, strong family histories of arrhythmias or sudden death, or patients with syncope should be treated with an implantable cardioverter defibrillator (ICD).

Innovative interventional procedures to anatomically or physiologically reduce the degree of LV outflow tract obstruction have been utilized. Dual chamber pacing, alcohol septal ablation, surgical septal myomectomy, and mitral valve replacement have all met with limited success.

First-degree relatives of patients identified as having HCM should be screened with electrocardiography and echocardiography. Genetic testing is available clinically. It is important to first test the affected individual in the family rather than “at risk” individuals since 20-40% of cases of HCM will not demonstrate mutations in currently available panels of genes. If a causative mutation is identified, “at risk” members of the family can be effectively tested. In families with HCM without demonstrable gene mutations, repeat noninvasive cardiac screening with ECG and echo should be undertaken in at risk individuals every 3-5 yr for patients under 12 yr of age and yearly throughout the teenage years and young adulthood. The clinical course of other affected family members and the results of genetic testing may be of some use in stratifying risk in an affected child.

Etiology and Epidemiology

RCM accounts for <5% of cardiomyopathy cases. Incidence increases with age, and it is more common in females. In equatorial Africa, RCM accounts for a large number of deaths. Infiltrative myocardial causes and storage disorders frequently result in associated LV hypertrophy and may represent HCM with restrictive physiology. Noninfiltrative causes include mutations in genes encoding sarcomeric or cytoskeletal proteins. The majority of RCM cases are considered idiopathic.

Pathogenesis

Restrictive cardiomyopathy is characterized by normal ventricular chamber dimensions, normal myocardial wall thickness, and preserved systolic function. The abnormal myocardium demonstrates impaired ventricular compliance and filling. Filling pressures in the ventricle are typically elevated and are transmitted to the atria which become dilated. Autosomal dominant inheritance has been demonstrated for families with mutations in sarcomeric and cytoskeletal genes.

Clinical Manifestations

Abnormal ventricular filling, sometimes referred to as diastolic heart failure, is manifest in the systemic venous circulation with edema, hepatomegaly, or ascites. Elevation of left-sided filling pressures result in cough, dyspnea, or pulmonary edema. With activity, patients may experience chest pain, shortness of breath, syncope/near syncope, or even sudden death. Pulmonary hypertension and pulmonary vascular disease develop and may progress rapidly. Heart murmurs are typically absent, but a gallop rhythm may be prominent. In the presence of pulmonary hypertension, an overactive right ventricular impulse and pronounced pulmonary component of the second heart sound are present.

Diagnosis

The characteristic electrocardiographic finding of prominent P waves is usually associated with normal QRS voltages and nonspecific ST and T-wave changes. Right ventricular hypertrophy occurs in patients with pulmonary hypertension. The chest x-ray may be normal or demonstrate a prominent atrial shadow and pulmonary vascular redistribution. The echocardiogram is often diagnostic, demonstrating normal-sized ventricles with preserved systolic function and dramatic enlargement of the atria (Fig. 433-3). Flow and tissue Doppler interrogation reveal abnormal filling parameters. Differential diagnosis from constrictive pericarditis is critical, as the latter can be treated surgically. Magnetic resonance imaging may be necessary to demonstrate the thickened or calcified pericardium often present in constrictive pericardial disease.

Prognosis and Management

Pharmacologic treatment modalities are of limited use and the prognosis of patients with restrictive cardiomyopathy is generally poor with rapid clinical deterioration. Sudden death is common, with a 2-yr survival of 50%. When signs of heart failure exist, judicious use of diuretics can result in clinical improvement. As a result of the dramatic atrial enlargement, these patients are predisposed to the development of atrial tachyarrhythmias and thromboemboli. As a result, antiarrhythmic agents may be necessary and anticoagulation with platelet inhibitors or coumadin is indicated.

Cardiac transplantation is the treatment of choice in many centers for patients with restrictive cardiomyopathy, and the results are excellent in patients without pulmonary hypertension, pulmonary vascular disease, or severe congestive heart failure.

Etiology and Epidemiology

Pathophysiology

Myocarditis is characterized by myocardial inflammation, injury or necrosis, and ultimately fibrosis. Cardiac enlargement and diminished systolic function occur as a direct result of the myocardial damage. Typical signs of congestive heart failure occur and may progress rapidly to shock, atrial or ventricular arrhythmias, and sudden death. Viral myocarditis may also become a chronic process with persistence of viral nucleic acid in the myocardium, and the perpetuation of chronic inflammation secondary to altered host immune response including activated T lymphocytes (cytotoxic and natural killer cells) and antibody-dependent cell mediated damage. Additionally, persistent viral infection may alter the expression of major histocompatibility complex antigens with resultant exposure of neoantigens to the immune system. Some viral proteins share antigenic epitopes with host cells, resulting in autoimmune damage to the antigenically related myocyte. Cytokines such as tumor necrosis factor-α and interleukin-1 are inhibitors of myocyte response to adrenergic stimuli and result in diminished cardiac function. The final result of viral-associated inflammation can be dilated cardiomyopathy.

Clinical Manifestations

Manifestations of myocarditis range from asymptomatic or nonspecific generalized illness to acute cardiogenic shock and sudden death. Infants and young children more often have a fulminant presentation with fever, respiratory distress, tachycardia, hypotension, gallop rhythm, and cardiac murmur. Associated findings may include a rash or evidence of end organ involvement such as hepatitis or aseptic meningitis.

Patients with acute or chronic myocarditis may present with chest discomfort, fever, palpitations, easy fatigability, or syncope/near syncope. Cardiac findings include overactive precordial impulse, gallop rhythm, and an apical systolic murmur of mitral insufficiency. In patients with associated pericardial disease, a rub may be noted. Hepatic enlargement, peripheral edema, and pulmonary findings such as wheezes or rales may be present in patients with decompensated congestive heart failure.

Diagnosis

Electrocardiographic changes are nonspecific and may include sinus tachycardia, atrial or ventricular arrhythmias, heart block, diminished QRS voltages, and nonspecific ST and T-wave changes, often suggestive of acute ischemia. Chest roentgenograms in severe, symptomatic cases reveal cardiomegaly, pulmonary vascular prominence, overt pulmonary edema, or pleural effusions. Echocardiography often shows diminished ventricular systolic function, cardiac chamber enlargement, mitral insufficiency, and occasionally, evidence of pericardial infusion.

Endomyocardial biopsy may be useful in identifying inflammatory cell infiltrates or myocyte damage and performing molecular viral analysis using polymerase chain reaction (PCR) techniques. Catheterization and biopsy, although not without risk (perforation and arrhythmias), should be performed by experienced personnel in patients suspected to have myocarditis or if there is strong suspicion for unusual forms of cardiomyopathy such as storage diseases or mitochondrial defects. Supportive but nonspecific tests include sedimentation rate, CPK isoenzymes, cardiac troponin I, and brain natriuretic peptide (BNP) levels.

Differential Diagnosis

The predominant diseases mimicking acute myocarditis include carnitine deficiency, other metabolic disorders of energy generation, hereditary mitochondrial defects, idiopathic dilated cardiomyopathy, pericarditis, EFE, and anomalies of the coronary arteries (see Table 433-1).

Treatment

Primary therapy for acute myocarditis is supportive (Chapter 436). Acutely, the use of inotropic agents, preferably milrinone, should be entertained but used with caution because of their proarrhythmic potential. Diuretics are often required as well. If in extremis, mechanical ventilatory support and mechanical circulatory support with ventricular assist device implantation or ECMO may be needed to stabilize the patient’s hemodynamic status and act as a bridge to recovery or cardiac transplantation. Diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers are of use in patients with compensated congestive heart failure in the outpatient setting, but may be contraindicated in those presenting with fulminant heart failure and cardiovascular collapse. In patients manifesting with significant atrial or ventricular arrhythmias, specific antiarrhythmic agents (for example, amiodarone) should be administered and ICD placement considered.

Immunomodulation of patients with myocarditis is controversial. Intravenous immune globulin may have a role in the treatment of acute or fulminant myocarditis and corticosteroids have been reported to improve cardiac function, but the data are not convincing in children. Relapse has been noted in patients receiving immunosuppression who have been weaned from support. There are no studies to recommend specific antiviral therapies for myocarditis.

Prognosis

The prognosis of symptomatic acute myocarditis in newborns is poor, and 75% mortality has been reported. The prognosis is better for children and adolescents, although patients who have persistent evidence of dilated cardiomyopathy often progress to need for cardiac transplantation. Recovery of ventricular function has been reported in 10-50% of patients, however.