CARDIAC ENERGY METABOLISM IN HEART FAILURE

Case Western Reserve University, Cleveland OH

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Abstract

DESCRIPTION (the applicant's description verbatim): Little is known about mitochondrial substrate oxidation in the failing heart. Patients with heart failure (HF) have a significantly greater rate of lipid oxidation, and decreased glucose uptake and carbohydrate oxidation compared to healthy age-matched individuals. The contractile performance of the heart at a given rate of oxygen consumption is greater when the heart is oxidizing glucose and lactate rather than fatty acids. The transport of long-chain fatty acids into the mitochondrion is regulated by the activity of carnitine palmitoyl transferase I (CPT-I), which is inhibited by malonyl-CoA. It is not known if malonyl-CoA content is lower in HF. The key step in carbohydrate oxidation is the decarboxylation of pyruvate by pyruvate dehydrogenase (PDH). The primary physiological mechanism for inhibition of PDH in the heart is inhibition by NADH and acetyl-CoA from fatty acid oxidation, thus inhibiting fatty acid oxidation increases PDH activity and pyruvate oxidation. Our hypothesis is that the failing heart has a decrease in malonyl-CoA inhibition of CPT-I as a result of lower tissue levels of malonyl-CoA, which results in accelerated fatty acid oxidation and product inhibition of PDH, and the contractile dysfunction. Further, we postulate that partially inhibiting the rate of fatty acid oxidation and increasing carbohydrate oxidation will improve contractile function in heart failure and slow the progression of the disease. The canine microembolism model of heart failure will be used. Our specific aims are: 1) Measure the oxidation rates of glucose, lactate and fatty acids by the heart in vivo in healthy and heart failure dogs under normal conditions and when cardiac work is increased with dobutamine. 2) Determine if cardiac mitochondria from dogs with heart failure have accelerated rates of fatty acid oxidation and impaired pyruvate oxidation. We will measure the expression and activity of CPT-I, the concentration of malonylCoA and the enzymes that regulate its production and degradation. We will also measure the activity of PDH and its inhibitory kinase, PDH kinase. 3) Determine if there is improved cardiac function in the failing heart when CPT-I activity and the rate of fatty acid oxidation are inhibited either acutely or for 12 weeks.