THE EFFECTS OF HYPERTROPHY AND DIABETES ON CARDIAC PYRUVATE-DEHYDROGENASE ACTIVITY

Alterations in substrate selection and utilisation are characteristics of heart failure of different etiologies and these changes may be inv olved in the development of contractile dysfunction. Regulation of pyr uvate dehydrogenase (PDH) is crucial in determining the relative contr ibution of glucose oxidation to energy production; however, the role o f PDH in the development of heart failure has not been clarified. In t his study, we present a reliable and simple method for assaying both t he active and total forms of PDH (PDHa and PDHt respectively) in cardi ac tissue, and have compared the effects of pressure overload hypertro phy and diabetes on PDH activity. PDHa and PDHt were measured in extra cts of hypertrophied hearts after 5 weeks of pressure overload or in h earts after 7 weeks following induction of diabetes. There was no sign ificant change in PDHt in the hypertrophied group, but the fraction of PDH in the active form significantly decreased from 61 +/- 1% in cont rols to 36 +/- 1% (P<0.05). Following diabetes, there was a decrease i n the ratio of PDHa:PDHt from 60 +/- 3% to 11 +/- 1% (P<0.0001) and PD Ht activity [6.2 +/- 0.9 to 2.7 +/- 0.4 mu mol/min/g wet weight (P<0.0 2)]. This study reports for the first time that (i) concomitant with t he development of compensated hypertrophy, there is a decrease in the fraction of PDH in the active form; and (ii) in the diabetic heart, th ere is marked decrease in total PDH activity in addition to a decrease in the fraction of PDH in the active form. These results indicate tha t myocardial substrate delivery to the mitochondria may be impaired in both hypertrophy and diabetes, which may lead to the energy depleted state observed in heart failure. (C) 1997 Academic Press Limited.