Cardiomyopathy encompasses a broad range of inherited and acquired abnormalities affecting the myocardium. This heterogeneous group of disorders is an important cause of morbidity and mortality in the adolescent patient as a result of the presence of systolic or diastolic dysfunction, as well as the risk of coexisting arrhythmias and sudden cardiac death. It is important for the primary care physician involved in the care of adolescents to understand the different causes of cardiomyopathy and their typical clinical presentations. The cause, pathogenesis, clinical presentation, and diagnostic evaluation for adolescents with cardiomyopathy are reviewed. An overview of treatment modalities is also presented.
Key points
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Cardiomyopathies represent an import cause of morbidity and mortality in the adolescent population as a result of the presence of systolic or diastolic dysfunction as well as the risk of cardiac dysrhythmia and sudden death.
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Dilated cardiomyopathy is the most common form of cardiomyopathy seen in patients younger than 18 years and is characterized by ventricular dilation and systolic dysfunction, resulting in signs and symptoms of congestive heart failure.
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Hypertrophic cardiomyopathy is a genetically inherited condition resulting in significant ventricular hypertrophy and fibrosis, and represents the most common cause of sudden, unexpected death in adolescents.
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Restrictive cardiomyopathy is a rare form of cardiomyopathy that results in ventricular diastolic dysfunction and carries a poor transplantation-free survival from the time of diagnosis.
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Knowledge of the typical clinical presentations of cardiomyopathy is important for physicians involved in the care of adolescent patients in order to facilitate early evaluation and intervention and to achieve the best clinical outcomes.
Introduction
Cardiomyopathy encompasses a genetically and clinically heterogeneous group of heart muscle disorders. They are defined by the presence of abnormal myocardial structure resulting in systolic or diastolic dysfunction, in the absence of ischemic heart disease or abnormal loading conditions. In affected children and adolescents, cardiomyopathy can have severe consequences, with up to 40% of individuals progressing to death or cardiac transplantation within 5 years of diagnosis.
The classification of the cardiomyopathies is based on phenotype defined by clinical presentation and diagnostic evaluation of affected individuals, incorporating genetic diagnosis when possible. The most common cardiomyopathies encountered in adolescent patients include dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and restrictive cardiomyopathy (RCM). According to the US Pediatric Cardiomyopathy Registry, the annual incidence of cardiomyopathy is 1.13 per 100,000 children younger than 18 years, with DCM being the most common (56%), followed by HCM (30%). Arrhythmogenic right ventricular cardiomyopathy is a rare, genetically inherited form of cardiomyopathy, which typically manifests as arrhythmia, syncope, or sudden death. Phenotypic manifestation does not usually occur until the third decade of life or beyond. Presentation in adolescents is rare, and this form of cardiomyopathy is not discussed further in this review.
The different types of cardiomyopathy can be associated with a wide range of symptoms ranging from none to severe. Most patients have pure forms of these disorders, which fulfill strict diagnostic criteria, although some have overlapping features with mixed forms of disease. Early recognition of these conditions by clinicians is important to allow prompt initiation of treatment, which is aimed at improving myocardial performance and hemodynamics, alleviating symptoms, and prolonging survival. For patients in whom medical management fails, heart transplantation is an option, with excellent intermediate-term success.
Introduction
Cardiomyopathy encompasses a genetically and clinically heterogeneous group of heart muscle disorders. They are defined by the presence of abnormal myocardial structure resulting in systolic or diastolic dysfunction, in the absence of ischemic heart disease or abnormal loading conditions. In affected children and adolescents, cardiomyopathy can have severe consequences, with up to 40% of individuals progressing to death or cardiac transplantation within 5 years of diagnosis.
The classification of the cardiomyopathies is based on phenotype defined by clinical presentation and diagnostic evaluation of affected individuals, incorporating genetic diagnosis when possible. The most common cardiomyopathies encountered in adolescent patients include dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and restrictive cardiomyopathy (RCM). According to the US Pediatric Cardiomyopathy Registry, the annual incidence of cardiomyopathy is 1.13 per 100,000 children younger than 18 years, with DCM being the most common (56%), followed by HCM (30%). Arrhythmogenic right ventricular cardiomyopathy is a rare, genetically inherited form of cardiomyopathy, which typically manifests as arrhythmia, syncope, or sudden death. Phenotypic manifestation does not usually occur until the third decade of life or beyond. Presentation in adolescents is rare, and this form of cardiomyopathy is not discussed further in this review.
The different types of cardiomyopathy can be associated with a wide range of symptoms ranging from none to severe. Most patients have pure forms of these disorders, which fulfill strict diagnostic criteria, although some have overlapping features with mixed forms of disease. Early recognition of these conditions by clinicians is important to allow prompt initiation of treatment, which is aimed at improving myocardial performance and hemodynamics, alleviating symptoms, and prolonging survival. For patients in whom medical management fails, heart transplantation is an option, with excellent intermediate-term success.
DCM
Background
DCM refers to congestive cardiac failure secondary to dilation and systolic dysfunction (with or without diastolic dysfunction) of the ventricles. Normal left ventricular ejection fraction is 50% to 65%. Anything less than 50% could indicate the presence of DCM. All 4 cardiac chambers are dilated and at times hypertrophied, with dilation more pronounced than hypertrophy. In the United States, the incidence of DCM is 0.57 cases per 100,000 children, with genetic causes accounting for approximately 30% of DCM cases.
Cause
Multiple causes of myocardial damage have been identified, including infection (myocarditis), inborn errors of metabolism, neuromuscular disease, malformation syndromes, and toxins. Table 1 lists factors associated with myocardial damage and the development of DCM. However, in most cases, a specific cause is not identified and the cause remains idiopathic. An etiologic diagnosis could not be made in two-thirds of the cases of DCM in the North American Pediatric Cardiomyopathy Registry, followed by myocarditis (16%), neuromuscular disorders (9%), familial DCM (5%), inborn errors of metabolism (4%), and malformation syndromes (1%). The genetics of DCM depend on the underlying cause. In children, 20% to 48% have a positive family history of the disease. Inheritance is most commonly autosomal dominant, with X-linked, autosomal-recessive, and mitochondrial patterns of inheritance encountered less commonly. Multiple causative genes have been identified and predominantly encode 2 major subgroups of proteins, cytoskeletal, and sarcomeric proteins ( Table 2 ). Genetic testing is increasingly being performed by several commercial laboratories. In pure DCM, the yield of screening for many genes is low, with a causative gene abnormality identified in about 20% of cases.
| Category of Factors | Specific Factors |
|---|---|
| Viral infections | Coxsackie virus, human immunodeficiency virus, echo virus, rubella, varicella, mumps, Epstein-Barr virus, cytomegalovirus, measles, polio |
| Bacterial infections | Diphtheria, Mycoplasma , tuberculosis, Lyme disease, septicemia |
| Neuromuscular disorders | Duchenne or Becker muscular dystrophy, Friedreich ataxia, Kearns-Sayre syndrome |
| Metabolic disorders | Glycogen storage diseases, carnitine deficiency, fatty acid oxidation defects |
| Endocrine disorders | Thyroid disease, pheochromocytoma, hypoglycemia |
| Hematologic disease | Sickle cell disease, thalassemia, iron deficiency anemia |
| Coronary artery disease | Anomalous left coronary artery from the pulmonary artery, Kawasaki disease |
| Drugs | Anthracycline, cyclophosphamide, chloroquine, iron overload, alcohol |
| Cardiac arrhythmia | SVT, atrial fibrillation/flutter, ventricular tachycardia |
| Mutation Associated With DCM | ||
|---|---|---|
| Cardiac actin | Dystrophin | α-Myosin heavy chain |
| Desmin | Myosin-binding protein C | SUR2A |
| δ-Sarcoglycan | Muscle LIM protein | Lamin A/C |
| β-Myosin heavy chain | α-Actin-2 | Metavinculin |
| Cardiac troponin T | Phospholamban | Cardiac troponin I |
| α-Tropomyosin | Cypher/LIM binding domain 3 | Cardiac troponin type 2 |
| Titin | Tafazzin | Myopalladin |
History
Onset is usually insidious but may be acute in up to 25% of patients with DCM, especially if exacerbated by a complicating lower respiratory tract infection. Approximately 50% of patients with DCM have a history of a preceding viral illness. A detailed family history is important and is positive in 20% to 48% of cases.
| Common Presenting Symptoms | Less Common Presenting Symptoms |
|---|---|
| Fatigue | Chest pain |
| Shortness of breath | Orthopnea |
| Exercise intolerance | Hemoptysis |
| Syncope | Abdominal pain |
| Arrhythmia | Frothy sputum |
Physical Examination
It is possible for a patient to have DCM and yet have a perfectly normal physical examination. With established disease, features of congestive heart failure may be prominent. Common physical examination findings include the following:
| Systemic Findings | Cardiac Findings |
|---|---|
| Weak peripheral pulses | Tachycardia |
| Cool extremities | Displaced point of maximum impulse |
| Hepatomegaly | Active precordium |
| Low blood pressure, with decreased pulse pressure | Gallop rhythm |
| Shock | Accentuated P2 (with pulmonary hypertension) |
| Crackles or wheezing | Murmurs of mitral and tricuspid regurgitation |
| Peripheral edema |
Diagnostic Evaluation
Blood studies including a complete blood count, erythrocyte sedimentation rate, and C-reactive protein level may show evidence of acute inflammation in the setting of myocarditis. Similarly, antibody titers, viral culture, or polymerase chain reaction studies may suggest a viral cause. Serum carnitine levels may be low when the disease is caused by systemic carnitine deficiency. Biomarkers such as brain natriuretic peptide (BNP) and N -terminal prohormone BNP may be useful in the detection and risk stratification of patients with decompensated heart failure. A BNP level greater than 300 pg/mL was a strong predictor of death, transplantation, or heart failure hospitalization in a series of pediatric patients.
Chest radiography shows cardiomegaly and may show evidence of pulmonary congestion or pulmonary venous hypertension. Increase of the left mainstem bronchus reflects dilation of the left atrium. In rare fulminant cases, cardiomegaly may not be prominent because the ventricle has not yet had time to dilate.
Changes on the electrocardiogram (ECG) are nonspecific and may include sinus tachycardia, abnormal frontal plane QRS axis, left atrial enlargement, left ventricular hypertrophy, deep Q waves with ST segment depression, and tall T waves in leads I, aVL, V 5 , V 6 (reflecting left ventricular volume overload). It is important to identify evidence of myocardial ischemia, which might point to an anomalous coronary artery as the cause for heart failure. Cardiac arrhythmias such as supraventricular cardiomyopathy (SVT), or ventricular ectopy or tachycardia may be present in myocarditis. In some cases, sustained arrhythmias (eg, ectopic atrial tachycardia, atrial flutter, SVT) may be the cause of cardiomyopathy (ie, tachycardia-mediated cardiomyopathy).
Echocardiography and Doppler studies form the basis for the diagnosis in most patients. Dilation of the left ventricle with global systolic dysfunction is the hallmark of the disease. The left ventricular shortening fraction is usually less than 25% (ejection fraction <50%). The presence of valvular regurgitation, parameters of diastolic function, and pulmonary artery pressures may be assessed. Pericardial effusion may be present. It is crucial to exclude anatomic abnormalities, which may be the cause of the cardiomyopathy, including anomalous left coronary artery arising from the pulmonary artery, mitral valve disease, and coarctation of the aorta.
Treatment
There have been tremendous improvements in the treatment of DCM over the last 20 years. Treatment is mainly directed at improving symptoms of heart failure and prevention of disease progression and related complication, such as end-organ dysfunction and stroke. Comprehensive guidelines for the treatment of pediatric heart failure have been published by the International Society for Heart and Lung Transplantation. Many of the guidelines are based on small nonrandomized trials or are extrapolated from the adult literature. The mainstay of therapy includes afterload reduction using angiotensin-converting enzyme (ACE) inhibitors and β-blockade, with or without the use of diuretics to achieve euvolemia and minimize congestive symptoms. Digoxin continues to be widely used in the treatment of childhood DCM. Studies in adults failed to show a survival benefit from the use of digoxin but did report improvement of symptoms in some patients. Treatment of decompensated heart failure is focused on diuresis with loop diuretics and afterload reduction with nitroglycerin, nitroprusside, or nesiritide. In patients with heart failure and clinical evidence of hypotension or hypoperfusion with increased filling pressures, treatment with intravenous inotropes or vasopressor therapy or both should be considered. Phosphodiesterase III inhibitors, such as milrinone, are useful in the treatment of cardiogenic shock because they increase contractility and reduce afterload by peripheral vasodilation without a consistent increase in myocardial oxygen consumption.
In patients with severe symptomatic DCM refractory to medical management, mechanical assist devices have been increasingly used as device technology has improved. In adolescent patients, the use of a mechanical assist device results in successful bridging to transplantation in 80% of cases. Heart transplantation remains the therapy of choice for end-stage DCM. Transplantation of children with DCM has the best survival of all the diagnostic groups. The Pediatric Heart Transplant Study Group recently analyzed 1098 patients with DCM listed for heart transplantation. Mortality on the waiting list was 11%, and overall survival after listing for transplantation was 72% at 10 years.
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Most cases of DCM have no known cause (idiopathic)
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Family history may be positive in 20% to 48% of cases
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Echocardiography is diagnostic and helpful in ruling out other anatomic abnormalities that may present as heart failure
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Treatment includes management of heart failure symptoms and prevention of complications
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Heart transplantation is the therapy of choice for end-stage DCM
HCM
Background
HCM is defined by the presence of a hypertrophied, nondilated ventricle in the absence of an underlying hemodynamic cause (eg, systemic hypertension, aortic stenosis, coarctation of the aorta). Although once believed to be a rare disorder, HCM is believed to occur with an incidence of 1 in 500 in the general population and remains the most common cause of sudden death in adolescents and adults younger than 35 years. HCM accounts for 30% of pediatric cardiomyopathy with an incidence of 0.47/100,000. This condition can represent a complex mix of pathophysiologic mechanisms, including diastolic dysfunction, left (and in some cases, right) ventricular outflow tract obstruction, mitral regurgitation, myocardial ischemia, and cardiac arrhythmias. Treatment strategies are focused on alleviation of symptoms and prevention of sudden death.
Cause
The more common forms of HCM are inherited as an autosomal dominant trait and are caused by mutations in at least 10 identified genes. The most common are mutations on the genes that encode sarcomeric proteins and are listed in Table 3 . There are also rare familial forms of HCM caused by nonsarcomeric genes, including mitochondrial defects, potassium channel defects, and genes involved in calcium handling control mechanisms. A gene defect can be identified in 60% to 70% of patients. This finding suggests that novel HCM mutations are yet to be discovered. Earlier onset of the manifestations of HCM in childhood may represent a more heterogeneous group of disorders with a greater diversity than is seen in the adult population. Table 4 provides a classification of HCM based on groupings of familial, syndromic, neuromuscular, and metabolic disorders.
| Sarcomeric Mutations Associated With HCM | |
|---|---|
| β-Myosin heavy chain | Cardiac troponin I |
| α-Myosin heavy chain | α-Tropomyosin |
| Myosin essential light chain | Myosin-binding protein C |
| Myosin regulatory light chain | Titin |
| Cardiac troponin T | Actin |
| Category | Specific Conditions |
|---|---|
| Familial HCM | Sarcomeric HCM, maternally inherited HCM syndromes |
| Syndromic HCM | Noonan syndrome, Beckwith-Wiedemann syndrome, cardiofacial-cutaneous syndrome, Costello syndrome, lentiginosis (LEOPARD syndrome) |
| Neuromuscular disease | Friedreich ataxia |
| Metabolic disorders | Anabolic steroid therapy and abuse, carnitine deficiency, glycogenoses type 2, 3, and 9 (Pompe disease, Forbes disease, phosphorylase kinase deficiency), glycolipid lipidosis (Fabry disease), glycosylation disorders, I-cell disease, lipodystrophy, lysosomal disorders (Danon disease), mannosidosis, mitochondrial disorders, mucopolysaccharidoses type 1, 2, and 5 (Hurler syndrome, Hunter syndrome, Scheie syndrome), selenium deficiency |
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