Effects of reducing fatty acid metabolism on mechanical function in regionally ischemic hearts

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Abstract
Fatty acids in excess impair mechanical function and electrical stability in ischemic hearts. Whether oxfenicine, an agent capable of reducing fatty acid metabolism, can prevent these consequences and in so doing improve hemodynamic performance was tested. Two groups of working swine hearts (n = 15), extracorporeally perfused with whole blood, were compared over 90 min of controlled coronary perfusion. An emulsion of triacylglycerols (Intralipid) with heparin were administered systemically to augment serum fatty acids 3-fold (0.3-0.92 .mu.mol/ml). Labeled [U14C]palmitate was administered selectively into the left anterior descending coronary circulation to follow fatty acid oxidation. Coronary flow in this bed was decreased by 50% over the final 30 min of perfusion. Saline (n = 7) or oxfenicine (17-33 mg/kg, n = 8) was administered to placebo or treated animals at 30 min perfusion. 14CO2 production from labeled palmitate was decreased by 55% (P < 0.025) at normal flows in oxfenicine-treated hearts and was reduced further during ischemia. Tissue levels of acyl carnitine were significantly reduced and acetyl CoA levels significantly increased in oxfenicine-treated hearts both in aerobic and ischemic myocardium. These changes were associated with an improvement in mechanical function. Left ventricular systolic and developed pressures and maximum left ventricular dP/dt [change in pressure with time] were increased by 36 .DELTA.%, P < 0.01; 46 .DELTA.%, P < 0.025; and 41 .DELTA.%, P < 0.025, respectively, at end ischemia as compared with placebo hearts. Inhibiting fatty acid metabolism improves mechanical function in regionally ischemic hearts, possibly by lessening the accumulation of inhibitory fatty acid intermediates.