FAMILIAL HYPERTROPHIC CARDIOMYOPATHY FROM MUTATIONS TO FUNCTIONAL DEFECTS

Hypertrophic cardiomyopathy is characterized by left and/or right vent ricular hypertrophy, which is usually asymmetric and involves the inte rventricular septum. Typical morphological changes include myocyte hyp ertrophy and disarray surrounding the areas of increased loose connect ive tissue. Arrhythmias and premature sudden deaths are common. Hypert rophic cardiomyopathy is familial in the majority of cases and is tran smitted as an autosomal-dominant trait. The results of molecular genet ics studies have shown that familial hypertrophic cardiomyopathy is a disease of the sarcomere involving mutations in 7 different genes enco ding proteins of the myofibrillar apparatus: beta-myosin heavy chain, ventricular myosin essential Light chain, ventricular myosin regulator y light chain, cardiac troponin T, cardiac troponin I. alpha-tropomyos in, and cardiac myosin binding protein C. In addition to this locus he terogeneity, there is a wide allelic heterogeneity, since numerous mut ations have been found in all these genes. The recent development of a nimal models and of in vitro analyses have allowed a better understand ing of the pathophysiological mechanisms associated with familial hype rtrophic cardiomyopathy. One can thus tentatively draw the following c ascade of events: The mutation leads to a poison polypeptide that woul d be incorporated into the sarcomere. This would alter the sarcomeric function that would result (1) in an altered cardiac function and then (2) in the alteration of the sarcomeric and myocyte structure, Some m utations induce functional impairment and support the pathogenesis hyp othesis of a ''hypocontractile'' state followed by compensatory hypert rophy. Other mutations induce cardiac hyperfunction and determine a '' hypercontractile'' state that would directly induce cardiac hypertroph y. The development of other animal models and of other mechanistic stu dies linking the genetic mutation to functional defects are now key is sues in understanding how alterations in the basic contractile unit of the cardiomyocyte alter the phenotype and the function of the heart.