Repairing the myofilaments to heal the heart.

FAMILIAL HYPERTROPHIC CARDIOMYOPATHY (FHC) is a genetic disease caused by autosomal dominant mutations in the genes that encode sarcomeric proteins. Hundreds of FHC diseasecausing mutations have been identified (reviewed in Ref. 14). These mutations are predominantly although not exclusively missense mutations. In vivo and in vitro studies support the notion that FHC alleles produce mutant proteins that incorporate into the myofilament. The abnormal proteins exert dominant-negative effects, particularly thin filament proteins like -tropomyosin (TM), although gain-in-function effects may have a role in disease caused by myosin heavy chain mutants (14). The cellular and molecular events triggered by the causal mutations have not been fully elucidated. Specifically, it remains to be determined how a defect in myofilament function results in a complex cellular, myocardial, and disease phenotype. In this issue of the American Journal of Physiology-Heart and Circulatory Physiology, Jagatheesan et al. (8) investigate reversal of a myofilament Ca sensitivity defect produced by a FHC-associated mutation of -TM. The -TM glutamic acid-to-glycine mutation at residue 180 (Glu180Gly) described in this article is of particular interest for several reasons. Although thin filament mutations account for a relatively low percentage of FHC mutations in a population presenting for clinical testing, those affected by this mutation have relatively early onset of disease and sudden cardiac death (15–17). This mutation occurs in a key domain of TM involved in stabilizing troponin (Tn) to the thin filament via binding of TM to TnT. While animal models of this mutant have been variable, perhaps because of differences in genetic background, the transgenic -TM Glu180Gly line described by this group has been shown previously to mimic many aspects of the human phenotype, including increased Ca sensitivity of the myofilaments, diastolic dysfunction, cardiac hypertrophy, myocardial fibrosis, and early cardiac demise (11). The finding of a progressive and deadly phenotype makes this an attractive model to test reparative therapies. This report enhances our understanding of cellular and molecular events that lead to hypertrophic remodeling and fibrosis. The authors created a double-transgenic mouse model by crossing the -TM Glu180Gly transgenic with a line expressing a chimeric TM containing an -TM amino terminus and the carboxy terminus of -TM, the cardiac fetal isoform. This line was previously demonstrated to produce myofilaments with decreased sensitivity to Ca (9). The doubletransgenic mice created by crossing these lines not only displayed normalized myofilament Ca sensitivity; most importantly, the mice exhibited a normal organ-level phenotype with no pathological abnormalities and apparent normalization of the life span of the double-transgenic mice. These findings indicate that the abnormal myofilament function produced by the -TM Glu180Gly mutant plays a central role in signaling the subsequent development of cardiac hypertrophy and fibrosis.