DIASTOLIC DYSFUNCTION AND ALTERED ENERGETICS IN THE ALPHA-MHC403 + MOUSE MODEL OF FAMILIAL HYPERTROPHIC CARDIOMYOPATHY/

An arginine to glutamine missense mutation at position 403 of the beta -cardiac myosin heavy chain causes familial hypertrophic cardiomyopath y. Here we study mice which have this same missense mutation (alpha MH C403/+) using an isolated, isovolumic heart preparation where cardiac performance is measured simultaneously with cardiac energetics using P -31 nuclear magnetic resonance spectroscopy. We observed three major a lterations in the physiology and bioenergetics of the alpha MHC403/+ m ouse hearts, First, while there was no evidence of systolic dysfunctio n, diastolic function was impaired during inotropic stimulation. Diast olic dysfunction was manifest as both a decreased rate of left ventric ular relaxation and an increase in end-diastolic pressure. Second, und er baseline conditions alpha MHC403/+ hearts had lower phosphocreatine and increased inorganic phosphate contents resulting in a decrease in the calculated value for the free energy released from ATP hydrolysis . Third, hearts from alpha MHC403/+ hearts that were studied unpaced r esponded to increased perfusate calcium by decreasing heart rate appro ximately twice as much as wild types. We conclude that hearts from alp ha MHC403/+ mice demonstrate work load-dependent diastolic dysfunction resembling the human form of familial hypertrophic cardiomyopathy, Ch anges in high-energy phosphate content suggest that an energy-requirin g process may contribute to the observed diastolic dysfunction.