Gender and aging in a transgenic mouse model of hypertrophic cardiomyopathy

Mutations in the cardiac myosin heavy chain (MHC) can cause familial hypert rophic cardiomyopathy (FHC). A transgenic mouse model has been developed in which a missense (R403Q) allele and an actin-binding deletion in the alpha -MHC are expressed in the heart. We used an isovolumic left heart preparat ion to study the contractile characteristics of hearts from transgenic (TG) mice and their wild-type (WT) littermates. Both male and female TG mice de veloped left ventricular (LV) hypertrophy at 4 mo of age. LV hypertrophy wa s accompanied by LV diastolic dysfunction, but LV systolic function was nor mal and supranormal in the young TG females and males, respectively. At 10 mo of age, the females continued to present with LV concentric hypertrophy, whereas the males began to display LV dilation. In female TG mice at 10 mo of age, impaired LV diastolic function persisted without evidence of systo lic dysfunction. In contrast, in 10-mo-old male TG mice, LV diastolic funct ion worsened and systolic performance was impaired. Diminished coronary flo w was observed in both 10-mo-old TG groups. These types of changes may cont ribute to the functional decompensation typically seen in hypertrophic card iomyopathy. Collectively, these results further underscore the potential ut ility of this transgenic mouse model in elucidating pathogenesis of FHC.