FAMILIAL HYPERTROPHIC CARDIOMYOPATHY - A PARADIGM OF THE CARDIAC HYPERTROPHIC RESPONSE TO INJURY

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease cau sed by mutations in sarcomeric proteins. It is characterized by left v entricular hypertrophy in the absence of an increased external load, a nd myofibrillar disarray. While hypertrophy is a common cardiac respon se to injury, disarray is the pathological hallmark of HCM. A large nu mber 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 regu latory 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 expressivi ty, cTnT mutations are associated with a mild degree of hypertrophy, b ut a high incidence of sudden cardiac death. Mutations in MyBP-C are a ssociated with mild hypertrophy, and a benign prognosis. However, the genetic background in which the mutations occur, and possibly environm ental 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 sarcome ric proteins function as 'poison peptides' exerting a dominant-negativ e effect on the function of the cardiac myocytes, followed by structur al changes and a compensatory hypertrophy.