Juan Carlos Osorio

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.

Simvastatin Preserves Cardiac Function in Genetically Determined Cardiomyopathy

Endothelial dysfunction characterizes heart failure (HF). Simvastatin (Sim) increases endothelial nitric oxide (NO) independent of lipid-lowering. We evaluated the effect of Sim on cardiac function, apoptosis, and NO availability in HF. Five-month-old cardiomyopathic (CM) hamsters were divided into 2 groups: Sim (20 mg/kg, 6 weeks, n = 6) and Untreated (n = 6). Age-matched normal hamsters served as controls (n = 6). Serial echocardiograms were performed to measure LV function. Myocardial apoptosis, eNOS, and capillary density were measured at 6 weeks. Cardiomyopathic hamsters had lower LV shortening fraction (SF) compared with controls (17 ± 3% vs 59 ± 2%), higher LV end-diastolic volume (30 ± 3 vs 6 ± 2 mL/m2), and lower LV mass/volume ratio (0.5 ± 0.04 vs 0.72 ± 0.02 mg/ml, P < 0.001). During follow-up, SF decreased (9 ± 2%) and LV volume increased (38 ± 1 mL/m2) in untreated hamsters (P < 0.05 from baseline) but did not change significantly in the Sim group (P < 0.05 vs untreated). Myocardial caspase-3 activity was higher and apoptotic nuclear density was lower in Sim compared with untreated CM hamsters (0.072 ± 0.02% vs 0.107 ± 0.03%, P < 0.01). Myocardial capillary density was highest in the Sim group (P < 0.05). eNOS expression was not different between groups. Sim retards the progression of HF in CM hamsters. This may be related to an increase in coronary microvasculature, increase in NO availability, and decreased apoptosis.

Bovine polymerized hemoglobin increases cardiac oxygen consumption and alters myocardial substrate metabolism in conscious dogs: role of nitric oxide.

We investigated the effect of bovine polymerized hemoglobin-based oxygen carrying (HBOC) solution on myocardial oxygen consumption (MVO2) and substrate use. At 15 min after the end of HBOC infusion (20% blood volume, i.v.) in nine permanently instrumented conscious dogs, mean arterial pressure and coronary blood flow were both increased by 41+/-5% and 93+/-20% (p<0.01) without affecting late diastolic coronary resistance and left ventricular dP/dtmax. Administration of HBOC did not affect arterial PO2 or O2 content, but significantly decreased coronary sinus PO2 and O2 content by 21+/-3% and 36+/-3%, respectively. MVO2 was increased from 7.2+/-0.8 to 15+/-1.8 ml O2/min (p<0.01). Despite an increase in triple product from 44+/-2 to 56+/-3 (p<0.01) 15 min after HBOC, the ratio of MVO2 and triple product was markedly elevated by 62+/-19%. Myocardial free fatty acid consumption was decreased from 14+/-1 to 4.5+/-2.2 microEq/min, whereas consumption of lactate increased from 19+/-6 to 69+/-10 micromol/ min and that of glucose increased from 1.0+/-0.5 to 10+/-3 mg/min (all p values, <0.05). These metabolic changes were not observed in dogs that received angiotensin II at a dose used (20-40 ng/kg/min, i.v.) to match those hemodynamic effects of HBOC. These results suggest that administration of HBOC increases coronary blood flow and MVO2 and shifts cardiac metabolism from using free fatty acid to using lactate and glucose in conscious dogs at rest. These metabolic changes are independent of the HBOC-induced change in hemodynamics.