Activation of pyruvate dehydrogenase (PDH) does not prevent the onset of heart failure in pressure overloaded rats

Shifting substrate oxidation in heart muscle from fatty acids to glucose (substrate-switch) may prevent the onset of heart failure and improve contractile function. First drugs are used clinically. We tested whether application of two agents (etomoxir and 10J) capable of inducing a substrate-switch is able to prevent the onset of heart failure in pressure-overloaded rats.

Methods: Hypertrophy was induced by banding of the aortic arch in rats for 2 or 12 weeks. Rats were treated with etomoxir (29.5µmol/kg/day) or with 10j (N-[2-Chloro-4-(piperazine-1-sulfonyl)-phenyl]-(R)-(+)-3.3,3-trifluoro-2-hydroxy-2-methyl-propionamide, 60µmol/kg/day), an inhibitor of pyruvate-dehydrogenase-kinase. Con-trols were sham-operated. Echocardiography was performed and hearts were analyzed for PDH- and CPT1-activity and expression of α- and β-MHC by real time RT-PCR.

Results: (n=5–18): Aortic banding caused an increase in heart to body weight ratio (g/kg) from 3.44±0.26 to 4.14±0.48 after 2 weeks and from 2.80±0.21 to 6.54±0.26 after 12 weeks. Ejection fraction was impaired after 12 weeks (from 73±8% to 57±11, p<0.05). All rats had pleural effusions and shortness of breath after 12 but not after 2 weeks. Total CPT-1- and PDH-activities were unchanged after 2 weeks. However, after 12 weeks total PDH-activity was increased and CPT-1 activity was decreased significantly. Neither etomoxir nor 10j affected these changes. However, etomoxir and 10j increased PDH-activity status, increased the expression of PDH-kinase and prevented a shift from α-MHC to β-MHC expression.

Conclusion: Pharmacologic inhibition of enzymes to induce a substrate-switch is associated with changes in myofibrillar isoform expression but does not prevent the onset of heart failure in pressure overloaded rat heart.