Direct, convergent hypersensitivity of calcium-activated force generation produced by hypertrophic cardiomyopathy mutant alpha-tropomyosins in adult cardiac myocytes

Familial hypertrophic cardiomyopathy is a clinically and genetically divers e autosomal dominant disorder characterized by ventricular hypertrophy and myocyte disarray in the absence of known hypertrophic stimuli(1,2). It has been linked to many cardiac contractile proteins, including four point muta tions in alpha-tropomyosin(3,4,5) (Tm). Here we use adenoviral-mediated gen e transfer into adult cardiac myocytes in vitro to show that all four hyper trophic cardiomyopathy alpha-Tm proteins can be expressed and incorporated into normal sarcomeric structures in cardiac myocytes at similar levels as normal alpha-Tm proteins after 5-6 days in culture. Isometric force recordi ngs of single cardiac myocytes demonstrated inappropriate increased force o utput at submaximal calcium concentration with a specific mutant allele hie rarchy. These data indicate that the severity of direct calcium-sensitizing effect of mutations in alpha-Tm may predict the clinical severity of mutan t alpha-Tm-associated hypertrophic cardiomyopathy.