Pediatric Cardiomyopathies

Abstract

Pediatric cardiomyopathies are rare diseases with an annual incidence of 1.1 to 1.5 per 100 000. Dilated and hypertrophic cardiomyopathies are the most common; restrictive, noncompaction, and mixed cardiomyopathies occur infrequently; and arrhythmogenic right ventricular cardiomyopathy is rare. Pediatric cardiomyopathies can result from coronary artery abnormalities, tachyarrhythmias, exposure to infection or toxins, or secondary to other underlying disorders. Increasingly, the importance of genetic mutations in the pathogenesis of isolated or syndromic pediatric cardiomyopathies is becoming apparent. Pediatric cardiomyopathies often occur in the absence of comorbidities, such as atherosclerosis, hypertension, renal dysfunction, and diabetes mellitus; as a result, they offer insights into the primary pathogenesis of myocardial dysfunction. Large international registries have characterized the epidemiology, cause, and outcomes of pediatric cardiomyopathies. Although adult and pediatric cardiomyopathies have similar morphological and clinical manifestations, their outcomes differ significantly. Within 2 years of presentation, normalization of function occurs in 20% of children with dilated cardiomyopathy, and 40% die or undergo transplantation. Infants with hypertrophic cardiomyopathy have a 2-year mortality of 30%, whereas death is rare in older children. Sudden death is rare. Molecular evidence indicates that gene expression differs between adult and pediatric cardiomyopathies, suggesting that treatment response may differ as well. Clinical trials to support evidence-based treatments and the development of disease-specific therapies for pediatric cardiomyopathies are in their infancy. This compendium summarizes current knowledge of the genetic and molecular origins, clinical course, and outcomes of the most common phenotypic presentations of pediatric cardiomyopathies and highlights key areas where additional research is required.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT02549664 and NCT01912534.

Keywords: epidemiology; genetics; pediatrics.

Figure 1. Dilated Cardiomyopathy

End-diastolic apical four-chamber (left panel) and parasternal short axis end-diastolic (right panel) views of the left ventricle in a patient with severe dilated cardiomyopathy. The left ventricle is dilated and thin-walled. The apical view also demonstrates the decreased mass-to-volume ratio with sphericalization (increased short-to-long axis ratio) of the left ventricle.

Figure 2. Hypertrophic Cardiomyopathy

End-diastolic (left panel) and end-systolic (right panel) apical four-chamber views of the left ventricle in a patient with severe hypertrophic cardiomyopathy. Regional left ventricular hypertrophy is most notable in the mid-septum, lateral free wall, and lateral apex. The end-diastolic frame shows extension of the left ventricular cavity to the apex and the end-systolic frame shows systolic apical obliteration.

Figure 3. Restrictive Cardiomyopathy

End-systolic apical four-chamber view of the left and right ventricles in a patient with restrictive cardiomyopathy demonstrating mildly small right and left ventricular cavities with massive bi-atrial dilation.

Figure 4. Noncompaction Cardiomyopathy

End-diastolic apical four-chamber view of the left ventricular in a patient with noncompaction, demonstrating multiple finger-like protrusions of myocardial trabeculations into the apex, resulting in deep inter-trabecular interstices.

Figure 5. Genetic testing algorithm for pediatric cardiomyopathy

The pediatric patient being evaluated may have a clinical diagnosis of cardiomyopathy or may be seen because of a family history of cardiomyopathy. Genetic testing should be initiated in the most clearly affected individual in the family whenever possible. Positive testing is defined as genetic testing for cardiomyopathy that identifies a pathogenic mutation. Likely pathogenic variants should be handled on an individual basis. Within this algorithm, variants of uncertain significance are treated as a negative test result. In clinical practice, co-segregation studies should be performed if possible to improve interpretation. Genetic testing result interpretation is probabilistic and may change over time as new information is identified. Testing results should therefore be reviewed and updated every two to three years. When a pathogenic variant is identified, testing should be offered to affected relatives to confirm co-segregation with disease. Cardiac screening applies to individuals at-risk for developing cardiomyopathy based on their family history and/or genotype. All affected individuals should receive medical management for their specific diagnosis and symptoms. *CM, cardiomyopathy