Regulation by carnitine of myocardial fatty acid and carbohydrate metabolism under normal and pathological conditions

This review focuses on the regulation of myocardial fatty acids and glucose metabolism in physiological and pathological conditions, and the role of L -carnitine and of its derivative, propionyl-L-carnitine. Fatty acids are the major oxidation fuel for the heart, while glucose and l actate provide the remaining need. Fatty acids in cytoplasm are transformed to long-chain acyl-CoA and transferred into the mitochondrial matrix by th e action of three carnitine dependent enzymes to produce acetyl-CoA through the beta-oxidation pathway. Another source of mitochondrial acetyl-CoA is from the oxidation of carbohydrates. The pyruvate dehydrogenase (PDH) compl ex, the key irreversible rate limiting step in carbohydrate oxidation, is m odulated by the intra-mitochondrial ratio acetyl-CoA/CoA. An increased rati o results in the inhibition of PDH activity. A decreased ratio can relieve the inhibition of PDH as shown by the transfer of acetyl groups from acetyl -CoA to carnitine, forming acetylcarnitine, a reaction catalyzed by carniti ne acetyl-transferase. This activity of L-carnitine in the modulation of th e intramitochondrial acetyl-CoA/CoA ratio affects glucose oxidation. Myocardial substrate metabolism during ischemia is dependent upon the sever ity of ischemia. A very severe reduction of blood flow causes a decrease of substrate flux through PDH. When perfusion is only partially reduced there is an increase in the rate of glycolysis and a switch from lactate uptake to lactate production. Tissue levels of acyl-CoA and long-chain acylcarniti ne increase with important functional consequences on cell membranes. Durin g reperfusion fatty acid oxidation quickly recovers as the prevailing sourc e of energy, while pyruvate oxidation is inhibited. A considerable body of experimental evidence suggests that L-carnitine exer t a protective effect in in vitro and in vivo models of heart ischemia and hypertrophy. Clinical trials confirm these beneficial effects although cont roversial results are observed. The actions of L-carnitine and propionyl-L- carnitine cannot be explained as exclusively dependent on the stimulation o f fatty acid oxidation but rather on a marked increase in glucose oxidation , via a relief of PDH inhibition caused by the elevated acetyl-CoA/CoA rati o. Enhanced pyruvate flux through PDH is beneficial for the cardiac cells s ince less pyruvate is converted to lactate, a metabolic step resulting in t he acidification of the intracellular compartment. In addition, L-carnitine decreases tissue levels of acyl moieties, a mechanism particularly importa nt in the ischemic phase.