Familial hypertrophic cardiomyopathy: a paradigm of the cardiac hypertrophic response to injury

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease caused by mutations in sarcomeric proteins. It is characterized by left ventricular hypertrophy in the absence of an increased external load, and myofibrillar disarray. While hypertrophy is a common cardiac response to injury, disarray is the pathological hallmark of HCM. A large number of mutations in genes coding for sarcomeric proteins, ie the beta-myosin heavy chain (beta-MyHC), cardiac troponin (cTn)T, cTnI, alpha-tropomyosin, myosin-binding protein C (MyBP-C), and essential and regulatory myosin light chains in patients with HCM have been identified, Genotype-phenotype correlation studies have shown that mutations carry prognostic significance. Unlike mutations in the beta-MyHC gene, the prognostic significance of which reflect their hypertrophic expressivity, cTnT mutations are associated with a mild degree of hypertrophy, but a high incidence of sudden cardiac death. Mutations in MyBP-C are associated with mild hypertrophy, and a benign prognosis. However, the genetic background in which the mutations occur, and possibly environmental factors also, modulate phenotypic expression of HCM. Functional studies of mutations causing HCM have shed significant light into the pathogenesis of HCM and have led to the hypothesis that mutant sarcomeric proteins function as 'poison peptides' exerting a dominant-negative effect on the function of the cardiac myocytes, followed by structural changes and a compensatory hypertrophy.