Hypertrophic cardiomyopathy (HCM), a relatively common disease, is diagnosed clinically by unexplained
cardiac hypertrophy and pathologically by myocyte
hypertrophy, disarray, and interstitial
fibrosis. HCM is the most common cause of
sudden cardiac death (SCD) in the young and a major cause of morbidity and mortality in elderly.
Hypertrophy and
fibrosis are the major determinants of morbidity and SCD. More than 100 mutations in nine genes, all encoding sarcomeric
proteins have been identified in patients with HCM, which had led to the notion that HCM is a disease of contractile sarcomeric
proteins. The
beta -myosin heavy chain (MyHC), cardiac
troponin T (cTnT) and
myosin binding protein-C (MyBP-C) are the most common genes accounting for approximately 2/3 of all HCM cases. Genotype-phenotype correlation studies suggest that mutations in the beta -MyHC gene are associated with more extensive
hypertrophy and a higher risk of SCD as compared to mutations in genes coding for other sarcomeric
proteins, such as MyBP-C and cTnT. The prognostic significance of mutations is related to their hypertrophic expressivity and penetrance, with the exception of those in the cTnT, which are associated with mild hypertrophic response and a high incidence of SCD. However, there is a significant variability and factors, such as modifier genes and probably the environmental factors affect the phenotypic expression of HCM. The molecular pathogenesis of HCM is not completely understood. In vitro and in vivo studies suggest that mutations impart a diverse array of functional defects including reduced
ATPase activity of
myosin, acto-
myosin interaction, cross-bridging kinetics, myocyte contractility, and altered Ca2+ sensitivity.
Hypertrophy and other clinical and pathological phenotypes are considered compensatory phenotypes secondary to functional defects. In summary, the molecular genetic basis of HCM has been identified, which affords the opportunity to delineate its pathogenesis. Understanding the pathogenesis of HCM could provide for genetic based diagnosis, risk stratification, treatment and prevention of cardiac phenotypes.