Childhood Hypertrophic Cardiomyopathy: A Disease of the Cardiac Sarcomere

Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy is an autosomal-dominant disorder in which 10 genes and numerous mutations have been reported. The aim of the present study was to perform a systematic screening of these genes in a large population, to evaluate the distribution of the disease genes, and to determine the best molecular strategy in clinical practice. The entire coding sequences of 9 genes (MYH7, MYBPC3, TNNI3, TNNT2, MYL2, MYL3, TPM1, ACTC, andTNNC1) were analyzed in 197 unrelated index cases with familial or sporadic hypertrophic cardiomyopathy. Disease-causing mutations were identified in 124 index patients ( approximately 63%), and 97 different mutations, including 60 novel ones, were identified. The cardiac myosin-binding protein C (MYBPC3) and beta-myosin heavy chain (MYH7) genes accounted for 82% of families with identified mutations (42% and 40%, respectively). Distribution of the genes varied according to the prognosis (P=0.036). Moreover, a mutation was found in 15 of 25 index cases with "sporadic" hypertrophic cardiomyopathy (60%). Finally, 6 families had patients with more than one mutation, and phenotype analyses suggested a gene dose effect in these compound-heterozygous, double-heterozygous, or homozygous patients. These results might have implications for genetic diagnosis strategy and, subsequently, for genetic counseling. First, on the basis of this experience, the screening of already known mutations is not helpful. The analysis should start by testing MYBPC3 and MYH7 and then focus on TNNI3, TNNT2, and MYL2. Second, in particularly severe phenotypes, several mutations should be searched. Finally, sporadic cases can be successfully screened.

Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death (SCD) in young adults. Current risk algorithms provide only a crude estimate of risk and fail to account for the different effect size of individual risk factors. The aim of this study was to develop and validate a new SCD risk prediction model that provides individualized risk estimates. The prognostic model was derived from a retrospective, multi-centre longitudinal cohort study. The model was developed from the entire data set using the Cox proportional hazards model and internally validated using bootstrapping. The cohort consisted of 3675 consecutive patients from six centres. During a follow-up period of 24 313 patient-years (median 5.7 years), 198 patients (5%) died suddenly or had an appropriate implantable cardioverter defibrillator (ICD) shock. Of eight pre-specified predictors, age, maximal left ventricular wall thickness, left atrial diameter, left ventricular outflow tract gradient, family history of SCD, non-sustained ventricular tachycardia, and unexplained syncope were associated with SCD/appropriate ICD shock at the 15% significance level. These predictors were included in the final model to estimate individual probabilities of SCD at 5 years. The calibration slope was 0.91 (95% CI: 0.74, 1.08), C-index was 0.70 (95% CI: 0.68, 0.72), and D-statistic was 1.07 (95% CI: 0.81, 1.32). For every 16 ICDs implanted in patients with ≥4% 5-year SCD risk, potentially 1 patient will be saved from SCD at 5 years. A second model with the data set split into independent development and validation cohorts had very similar estimates of coefficients and performance when externally validated. This is the first validated SCD risk prediction model for patients with HCM and provides accurate individualized estimates for the probability of SCD using readily collected clinical parameters. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2013. For permissions please email: journals.permissions@oup.com.