Partial inhibition of fatty acid oxidation increases regional contractile power and efficiency during demand-induced ischemia

Objective: Clinical trials in patients with stable angina show that drugs that partially inhibit myocardial fatty acid oxidation reduce the symptoms of demand-induced ischemia, presumably by reducing lactate production and improving regional systolic function. We tested the hypothesis that partial inhibition of fatty acid oxidation with oxfenicine (a carnitine palmitoyl transferase-I inhibitor) reduces lactate production and increases regional myocardial power during demand-induced ischemia. Methods: Demand-induced ischemia was produced in anesthetized open-chest swine by reducing flow by 20% in the left anterior descending coronary artery and increasing heart rate and contractility with dobutamine (15 μg kg^-1 min^-1 i.v.) for 20 min. Glucose and fatty acid oxidation were measured with an intracoronary infusion of [U-¹⁴C] glucose and [9,10-³H] oleate, and hearts were treated with oxfenicine (2 mmol l^-1; n=7) or vehicle (n=7). Regional anterior wall power was assessed from the left ventricular pressure-anterior free wall segment length loops. Results: During demand-induced ischemia, the oxfenicine group had a higher rate of glucose oxidation (6.9±1.1 vs. 4. 7±0.8 μmol min^-1; P<0.05), significantly lower fatty acid uptake, but no change in total or active PDH activity. The oxfenicine group had significantly lower lactate output integrals (1.11±0.23 vs. 0.60±0.11 mmol) and glycogen depletion (66±6 vs. 43±8%), and higher anterior wall power index (0.95±0.17 vs. 1.30±0.11%) and anterior wall energy efficiency index (91±17 vs. 129±10%). Conclusions: Partial inhibition of fatty acid oxidation reduced non-oxidative glycolysis and improved regional contractile power and efficiency during demand-induced ischemia.