title: Familial hypertrophic cardiomyopathy: functional variance among individual cardiomyocytes as a trigger of FHC-phenotype development.
abstract: Familial hypertrophic cardiomyopathy (FHC) is the most frequent inherited cardiac disease. It has been related to numerous mutations in many sarcomeric and even some non-sarcomeric proteins. So far, however, no common mechanism has been identified by which the many different mutations in different sarcomeric and non-sarcomeric proteins trigger development of the FHC phenotype. Here we show for different MYH7 mutations variance in force pCa-relations from normal to highly abnormal as a feature common to all mutations we studied, while direct functional effects of the different FHC-mutations, e.g., on force generation, ATPase or calcium sensitivity of the contractile system, can be quite different. The functional variation among individual M. soleus fibers of FHC-patients is accompanied by large variation in mutant vs. wildtype β-MyHC-mRNA. Preliminary results show a similar variation in mutant vs. wildtype β-MyHC-mRNA among individual cardiomyocytes. We discuss our previously proposed concept as to how different mutations in the β-MyHC and possibly other sarcomeric and non-sarcomeric proteins may initiate an FHC-phenotype by functional variation among individual cardiomyocytes that results in structural distortions within the myocardium, leading to cellular and myofibrillar disarray. In addition, distortions can activate stretch-sensitive signaling in cardiomyocytes and non-myocyte cells which is known to induce cardiac remodeling with interstitial fibrosis and hypertrophy. Such a mechanism will have major implications for therapeutic strategies to prevent FHC-development, e.g., by reducing functional imbalances among individual cardiomyocytes or by inhibition of their triggering of signaling paths initiating remodeling. Targeting increased or decreased contractile function would require selective targeting of mutant or wildtype protein to reduce functional imbalances.
authors.affiliation: Institute of Molecular and Cell Physiology, Hannover Medical School Hannover, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brenner
authors.affiliation: Institute of Molecular and Cell Physiology, Hannover Medical School Hannover, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Seebohm
authors.affiliation: Institute of Molecular and Cell Physiology, Hannover Medical School Hannover, Germany.
authors.forename: Snigdha
authors.initials: S
authors.lastname: Tripathi
authors.affiliation: Institute of Molecular and Cell Physiology, Hannover Medical School Hannover, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Montag
authors.affiliation: Institute of Molecular and Cell Physiology, Hannover Medical School Hannover, Germany.
authors.forename: Theresia
authors.initials: T
authors.lastname: Kraft
keywords: MYH7-mutations; allelic imbalance; calcium sensitivity of cardiomyocytes; calcium sensitivity of muscle fibers; converter domain of myosin head; interstitial fibrosis; myocyte disarray; myosin head stiffness