Hypertrophic cardiomyopathy: preclinical and early phenotype

Hypertrophic cardiomyopathy (HCM) is caused by dominant mutations in sarcomere genes. Although the diagnosis of HCM is traditionally based on identifying unexplained left ventricular hypertrophy (LVH) by cardiac imaging, LVH is not an invariable feature of disease. The expression of LVH is highly age-dependent, and LV wall thickness is typically normal during childhood. Overt cardiac hypertrophy often does not develop until adolescence or later. With genetic testing, family members who have inherited a pathogenic sarcomere mutation (G+) can be identified prior to a clinical diagnosis (LVH-). This allows characterization of a new and important subset, denoted preclinical HCM (G+/LVH-). Although there are no distinguishing morphologic features of early disease, there is evidence of myocardial dysfunction prior to the development of LVH. Otherwise healthy sarcomere mutation carriers frequently have subtle impairment of diastolic function, detectable by tissue Doppler interrogation. These findings can assist in differentiating such at-risk family members from those who did not inherit the mutation, despite the presence of normal LV wall thickness. In contrast, systolic function appears relatively preserved in preclinical HCM but impaired in overt disease, suggesting that both the sarcomere mutation and the characteristic changes in myocardial architecture (LVH, fibrosis, and disarray) are required to perturb force generation. Better characterization of preclinical HCM will identify the initial manifestations of sarcomere mutations, characterize intermediate disease phenotypes, and foster efforts to develop novel therapeutic strategies based on genetic identification of at-risk individuals and early initiation of therapy to prevent disease progression when treatment may be most effective.