Ashish R Panchal

Impaired Myocardial Fatty Acid Oxidation and Reduced Protein Expression of Retinoid X Receptor-α in Pacing-Induced Heart Failure

Background—The nuclear receptors peroxisome proliferator-activated receptor-&agr; (PPAR&agr;) and retinoid X receptor &agr; (RXR&agr;) stimulate the expression of key enzymes of free fatty acid (FFA) oxidation. We tested the hypothesis that the altered metabolic phenotype of the failing heart involves changes in the protein expression of PPAR&agr; and RXR&agr;. Methods and Results—Cardiac substrate uptake and oxidation were measured in 8 conscious, chronically instrumented dogs with decompensated pacing-induced heart failure and in 8 normal dogs by infusing 3 isotopically labeled substrates: 3H-oleate, 14C-glucose, and 13C-lactate. Although myocardial O2 consumption was not different between the 2 groups, the rate of oxidation of FFA was lower (2.8±0.6 versus 4.7±0.3 &mgr;mol · min−1 · 100g−1) and of glucose was higher (4.6±1.0 versus 1.8±0.5 &mgr;mol · min−1 · 100g−1) in failing compared with normal hearts (P <0.05). The rates of lactate uptake and lactate output were not significantly different between the 2 groups. In left ventricular tissue from failing hearts, the activity of 2 key enzymes of FFA oxidation was significantly reduced: carnitine palmitoyl transferase-I (0.54±0.04 versus 0.66±0.04 &mgr;mol · min−1 · g−1) and medium chain acyl-coenzyme A dehydrogenase (MCAD; 1.8±0.1 versus 2.9±0.3 &mgr;mol · min−1 · g−1). Consistently, the protein expression of MCAD and of RXR&agr; were significantly reduced by 38% in failing hearts, but the expression of PPAR&agr; was not different. Moreover, there were significant correlations between the expression of RXR&agr; and the expression and activity of MCAD. Conclusions—Our results provide the first evidence for a link between the reduced expression of RXR&agr; and the switch in metabolic phenotype in severe heart failure.

Beta-receptor blockade decreases carnitine palmitoyl transferase I activity in dogs with heart failure

BACKGROUND Pharmacological inhibition of carnitine palmitoyl transferase I (CPT-I), the enzyme controlling the rate of fatty acid transport into the mitochondria, prevents the contractile dysfunction, myosin isozyme shift and deterioration in sarcoplasmic reticulum Ca2+ handling that occurs in rat models of left ventricular hypertrophy. In this study we examine whether the improved cardiac function with beta blockade therapy in heart failure is associated with an alteration in CPT-I activity. METHODS AND RESULTS We examined dogs with coronary microembolism-induced heart failure treated for 12 weeks with metoprolol (25 mg twice daily). Myocardial activities of CPT-I, medium-chain acyl co-enzyme A dehydrogenase (MCAD, a beta-oxidation enzyme), citrate synthase, and triglyceride content were measured. The progressive decrease in cardiac function was prevented by treatment with metoprolol, as reflected by an improved ejection fraction over 12 weeks in the metoprolol group (from 35% to 40%) compared to the untreated heart failure dogs (decrease from 36% to 26%). Dogs treated with metoprolol had a marked decrease in CPT-I activity (0.46 +/- 0.03 vs. 0.64 +/- 0.02 micromol min(-1) g(-1) wet weight; P < .02) along with an increase in triglyceride concentration compared to untreated heart failure dogs (3.9 +/- 0.3 v 4.9 +/- 0.2 micromol/g wet weight, respectively; P < .003). By contrast, MCAD and citrate synthase activities did not change. CONCLUSION Metoprolol induced a decrease in CPT-I activity and an increase in triglyceride content. These results suggest that the improved function observed with beta blockers in heart failure could be due, in part, to a decrease in CPT-I activity and less fatty acid oxidation by the heart.

Post-Ischemic Treatment with Dipyruvyl-Acetyl-Glycerol Decreases Myocardial Infarct Size in the Pig

The beneficial effects of pyruvate in organ reperfusion injury have been documented, however the therapeutic use of pyruvate has been hindered by the lack of an appropriate delivery method. Pyruvic acid is unstable and high rates of sodium pyruvate infusion are toxic. Dipyruvyl-acetyl-glycerol (DPAG) ester was developed as a novel method for intravenous pyruvate delivery at a high rate without sodium overload. We tested the ability of DPAG to reduce myocardial infarct size when administered after severe myocardial ischemia in an anesthetized open-chest pig model of ischemia-reperfusion injury. Ischemia was induced by total occlusion of the distal 2/3 of the left anterior descending coronary artery for one hour, followed by two hours of reperfusion. Animals were either untreated (n = 7), or treated with intravenous DPAG (8.0 mg/kg−1 · min−1, n = 8) during the two hours of reperfusion. Infarct size was measured on blinded samples using tetrazolium staining. The DPAG treated group had elevated pyruvate levels (0.82 ± 0.07 mM) and reduced infarct size (20.1 ± 4.2% of the volume at risk, compared to 30.8 ± 4.6% in the untreated animals (p < 0.05)), with no difference in blood pressure or heart rate between groups. In conclusion, an intravenous infusion of DPAG safely increases arterial pyruvate concentration and reduces myocardial infarct size following myocardial ischemia.