Andersons pediatric cardiology 1646

Hypertrophic Cardiomyopathy Definition HCM is defined by the presence of left ventricular hypertrophy (LVH) in the absence of alternate cardiac abnormal loading conditions or systemic disease that may result in LVH.6,7 Asymmetric septal hypertrophy was first described in the late 19th and early 20th centuries; however, the clinical, pathologic, and hemodynamic characterization of the disease began in earnest in the 1950s and 1960s.8–14 The angiographic and histologic findings,9,15–17 which initially informed the understanding of HCM, were supplemented by early echocardiographic18–20 and genetic characterization15,21 of the disease The identification of a disease-causing mutation in the β-myosin heavy chain was the first step in identifying the molecular basis of HCM.22 To date, more than 1000 mutations in 20 genes have been linked to the formation of HCM The majority of the mutations are located in the eight sarcomeric genes known to cause HCM, in addition to a number of Z-disk and calcium-handling genes that have putative disease-causing mutations.23–25 Epidemiology Historically, HCM has been reported in approximately 1 : 500 young adults.26 The genetic advances of the last two decades have suggested that the prevalence data from the Coronary Artery Risk Development in Young Adults study may have underestimated the true burden of disease, which may be closer to mutation-based estimates of disease (1 : 200),27 although this is a topic of debate The heterogeneity of HCM phenotypes (morphologic hypertrophy variants, fibrosis, etc.) as well as the age-related penetrance of the disease affect these assessments The population frequency of gene mutations suggests that phenotypic disease will likely be higher in older populations and when more sensitive imaging modalities (i.e., cardiac magnetic resonance imaging [CMRI]) are utilized.28 The prevalence appears to be similar across racial/ethnic groups,29,30 with a slight preponderance of disease in males.31 Approximately half of patients with HCM will have a known pathogenic HCM mutation.32,33 Pediatric HCM is generally a more heterogeneous group of disorders It includes a higher incidence of inborn errors of metabolism and syndromic disease, especially at younger ages The two largest pediatric population-based studies of HCM in children from the United States34 and Australia35 have reported an overall incidence of 0.3 to 0.5 cases per 100,000 Clinical Outcomes Patients with HCM generally have a good prognosis during childhood, although this varies dramatically based on both severity of disease and underlying diagnosis.34,36,37 Sudden death due to ventricular arrhythmias is the most feared complication of disease; however, heart failure,36,38–40 atrial fibrillation,38,41,42 cardioembolic stroke,43 and microvascular disease/angina44–46 contribute to disease burden in children and as patients reach adulthood Sudden Death Early case series from tertiary referral centers reported a significant risk of sudden death and overall mortality in HCM of 2% to 6% per year.47–49 In these studies, young males, as opposed to other groups, were identified as particularly prone to die suddenly Subsequent studies revealed marked heterogeneity in the course of disease and a generally more benign prognosis.50–52 Although the risk of disease progression and overall prognosis has evolved with time, adolescence continues to be regarded as a time of relatively high risk for sudden death and aborted sudden death.34,53 Recent data suggest that the disease-related mortality event rate is approximately 0.5%/year in adults54 and that the overall outcome for adolescents and young adults does not appear to be significantly different.36 Heart Failure The heterogeneity of the HCM in children is reflected in both the frequency and severity of disease.34,37 Pediatric HCM is distinguished from adult disease, which is primarily driven by sarcomeric mutations and by the relative frequency of syndromic and metabolic disease.34,35 Given the disparate pathophysiology, it is not surprising that outcomes differ by diagnosis Multiple studies have reported worse outcomes for infants below 1 year of age; however, this appears to be driven in part by the particularly poor prognosis for patients below 1 year of age with inborn errors of metabolism and malformation syndromes.34,39,40,55 Patients with a mixed hypertrophic and dilated or restrictive phenotype also appear to have a worse prognosis.37 Independent of the diagnosis, patients with lower systolic function and those who present with symptomatic heart failure appear, unsurprisingly, to have a poorer prognosis.37,56 Etiology Sarcomeric Disease Approximately 50% of nonsyndromic children with familial HCM will have a pathogenic mutation identified,32,33,57 with an overall de novo mutation rate of about 30% in unselected patients.32,58 Risk scores may have been developed to help predict a positive genotype.59,60 Mutations in MYH7 and MYBPC3 are present in approximately 75% of individuals in whom a mutation is identified, whereas a minority of patients will have a mutation in the thick- or thin-filament genes (see Box 61.1).61–63 Mutations in other sarcomeric, Z-disk, and sarcolemmal genes have also been linked to HCM; however, further studies are needed to confirm the pathogenicity.64–70 The difficulty in assessing the pathogenicity of many of the mutations has been attributed to the frequency of de novo mutations, marked heterogeneity in phenotypic disease with incomplete and gender-specific penetrance, as well as the time-dependent nature of phenotypic disease.71–76 Patients with multiple mutations have been reported to have more severe disease77,78; however, recent data have cast doubt on the frequency and significance of double mutations.79 The topic of mutation pathogenicity has been further complicated by the increasing availability of population-based DNA sequence data, which have revealed that variants that disrupt the reading frame of protein-encoding genes are relatively frequent.80 Studies examining this have noted a relatively high number of disease-associated variants within the population without cardiomyopathy, although the frequency of such variants is lower in the case of sarcomeric genes.81 Early studies using high-throughput screening in HCM have identified a number of potential variants within sarcomeric and nonsarcomeric genes,76,82 and this list is only likely to grow New resources such as the Exome Aggregation Consortium (ExAC) dataset (http://exac.broadinstitute.org) may help to clarify the clinical significance of variants in HCM and other cardiomyopathies.83 The rapid growth ...includes a higher incidence of inborn errors of metabolism and syndromic disease, especially at younger ages The two largest pediatric population-based studies of HCM in children from the United States34 and Australia35 have... The heterogeneity of the HCM in children is reflected in both the frequency and severity of disease.34,37 Pediatric HCM is distinguished from adult disease, which is primarily driven by sarcomeric mutations and by the relative frequency