Hypertrophic cardiomyopathy (HCM) is caused by dominant mutations in sarcomere genes. The diagnosis of HCM is usually established by identifying unexplained left ventricular hypertrophy (LVH) on cardiac imaging studies; however, LVH is not an invariable feature of disease. The expression of LVH is highly age-dependent, and LV wall thickness is frequently normal during childhood. Overt development of hypertrophy, and the ability to make a clinical diagnosis, does not typically occur until adolescence or later. Genetic testing allows identification of family members who have inherited the pathogenic sarcomere mutation (G +) before the emergence of clinical manifestations (LVH -). As such, a new and important subset of individuals with preclinical HCM (G+ / LVH-) can be identified early in life, before a clinical diagnosis can be made. Our evaluation of preclinical HCM has indicated that although there are no distinguishing morphologic features of early disease, there is evidence of myocardial dysfunction prior to the development of LVH. Subtle impairment of diastolic function is detectable in otherwise healthy sarcomere mutation carriers and can differentiate these family members from those who did not inherit the mutation. In contrast, systolic function appears relatively preserved in preclinical HCM, but impaired in overt disease. This preliminary finding suggests that both the sarcomere mutation and the characteristic changes in myocardial architecture (LVH, fibrosis and disarray) are required to perturb force generation. By studying this intriguing preclinical cohort, we can better understand the early stages of disease pathogenesis and potentially develop therapy to alter the clinical expression of sarcomere mutations.
Cardiomyopathy, Hypertrophic ; diagnosis ; genetics ; Genotype ; Humans ; Mutation ; Pedigree ; Phenotype ; Sarcomeres ; genetics