M. Spindler et al., DIASTOLIC DYSFUNCTION AND ALTERED ENERGETICS IN THE ALPHA-MHC403 + MOUSE MODEL OF FAMILIAL HYPERTROPHIC CARDIOMYOPATHY/, The Journal of clinical investigation, 101(8), 1998, pp. 1775-1783
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.