The purpose of these studies was to characterize the rates of fatty acid oxidation in reperfused myocardium and test the influence of excess fatty acids (FA) on mechanical function in the ...extracorporeally perfused, working swine heart model. Seventeen animals were prepared. Eight were untreated (LOW FA group; serum FA averaged 0.55 ± 0.07 μmol/ml) and nine received a constant infusion of 10% Intralipid with heparin to raise serum FA to about 1.4 ± 0.21 μmol/ml (HIGH FA group). Coronary flow in both groups was held at aerobic levels for an equilibration period of 40 minutes, acutely reduced regionally in the anterior descending circulation by 60% for 45 minutes, and acutely restored to aerobic levels for 60-minute reflow. Appreciable mechanical depression (-47 δ% from aerobic values; p<0.01) during reperfusion was noted in both groups. This was associated with modest reductions in myocardial oxygen consumption (p<0.05) and losses of total tissue carnitine stores (p at least <0.02). Reperfused myocardium showed a strong preference for and aerobic use of FA during reflow such that CO2 production from labeled palmitate exceeded preischemic levels (+89 δ% in LOW FA hearts; +111 δ% in HIGH FA hearts). This suggested relative preservation or restoration of certain elements in mitochondrial function during reflow. The findings argue for uncoupling between substrate metabolism and energy production, accelerated but useless energy drainage, or some impairment between energy transfer and function of contractile proteins as possible explanations for the persistent depression of mechanical function (stunning) during reperfusion. Excess FA affected a modest decline in mechanical efficiency at aerobic flows but was without further influence during moderate-to-severe ischemia or reflow. Stunning was not associated with significant tissue accumulations of acyl CoA or carnitine.
We tested the influence of L-propionylcarnitine (LPC) in modifying mechanical stunning during reflow. Nineteen adolescent anesthetized swine were extracorporeally perfused at control coronary flows ...for 20 min, supplemented with excess fatty acids (average values 1.1 +/- 0.1 mumol/ml), and subjected to 45 min regional ischemia (-60 delta % decrease in anterior descending flow) followed by 35 min reperfusion. Responses in 10 placebo hearts were compared with those obtained from 9 animals treated with 50 mg/kg LPC at 0 min perfusion and 40 mg/kg at 40 min perfusion. Ischemia in placebo hearts caused a 62.6 delta % decrease in active shortening in anterior descending bed, which failed to recover (-41.4 delta % from control values) during reflow. Conversely, in LPC-treated hearts, decreases in active shortening (-38.6 and -11.6 delta %) during ischemia and reflow, respectively, were significantly smaller (P less than or equal to 0.05). This improved motion was associated with greater rates of myocardial oxygen consumption but similar levels of fatty acid oxidation and fatty acid intermediates. Thus LPC significantly reversed mechanical stunning in myocardial ischemia/reperfusion protocols, presumably because of its positive inotropic properties. This derivative, otherwise innocuous in nature, could represent an attractive new treatment choice for future clinical use.
Fatty acid metabolites (long-chain esters of CoA and carnitine) which collect in ischemic myocardium can form amphiphiles capable of disrupting subcellular performance. It is important to document ...the role of these amphiphiles in intact tissue. D-Octanoylcarnitine was chosen because of its previously described effects on inhibiting palmitoylcarnitine transferase (PCT-II) in in vitro and in vivo liver preparations. This inhibition will shift tissue levels of CoA and carnitine intermediates and thus alter amphiphile levels. The compound's actions in cardiac muscle are unknown. Dose response curves were developed in intact hearts to test the influence of D-octanoylcarnitine at pharmacological concentrations. Measurements were obtained in working, extracorporeally perfused, swine hearts. Drug was administered either systemically (IV) or via direct intracoronary (IC) infusions into the left anterior descending coronary circulation. Excess fatty acids were provided to ensure adequate fatty acid substrate for oxidation. Coronary flow was controlled at aerobic levels. Systemic administration of D-octanoylcarnitine (0.8-6.8 mM) resulted in transient peripheral hypotension which caused correlative decreases in 14CO2 production from labeled palmitate. Infusion of D-octanoylcarnitine (0.5-3.9 mM) IC did not cause appreciable hypotension and was not associated with suppression of fatty acid oxidation. No build-up of carnitine esters was noted in treated hearts but acyl CoA levels were reduced (p less than or equal to 0.002). This latter finding was modestly related to increasing dose schedule of the compound in the IC group. The lack of suppression in fatty acid oxidation argues against significant inhibition of PCT II and lessens the attractiveness of using D-octanoylcarnitine in intact myocardium to selectively block fatty acid utilization at this locus.
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