title: Mechanical and energetic consequences of HCM-causing mutations.
abstract: Hypertrophic cardiomyopathy (HCM) was the first inherited heart disease to be characterized at the molecular genetic level with the demonstration that it is caused by mutations in genes that encode different components of the cardiac sarcomere. Early functional in vitro studies have concluded that HCM mutations cause a loss of sarcomere mechanical function. Hypertrophy would then follow as a compensatory mechanism to raise the work and power output of the affected heart. More recent in vitro and mouse model studies have suggested that HCM mutations enhance contractile function and myofilament Ca(2+) sensitivity and impair cardiac myocyte energetics. It has been hypothesized that these changes may result in cardiac myocyte energy depletion due to inefficient ATP utilization and also in altered myoplasmic Ca(2+) handling. The problems encountered in reaching a definitive answer on the effects of HCM mutations are discussed. Though direct analysis of the altered functional characteristics of HCM human cardiac sarcomeres has so far lagged behind the in vitro and mouse studies, recent work with mechanically isolated skinned myocytes and myofibrils from affected human hearts seem to support the energy depletion hypothesis. If further validated in the human heart, this hypothesis would identify tractable therapeutic targets that suggest that HCM, perhaps more than any other cardiomyopathy, will be amenable to disease-modifying therapy.
authors.affiliation: Department of Physiology and Center of Molecular Medicine (C.I.M.M.B.A.), University of Florence, Florence, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Ferrantini
authors.forename: Alexandra
authors.initials: A
authors.lastname: Belus
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Piroddi
authors.forename: Beatrice
authors.initials: B
authors.lastname: Scellini
authors.forename: Chiara
authors.initials: C
authors.lastname: Tesi
authors.forename: Corrado
authors.initials: C
authors.lastname: Poggesi
mesh_terms: D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D009200:Myocardial Contraction / Q000235:genetics*; D010641:Phenotype; D012518:Sarcomeres / Q000378:metabolism