Paradoxical downregulation of the glucose oxidation pathway despite enhanced flux in severe heart failure.

Free fatty acid (FFA) oxidation is depressed in severe heart failure due to reduced activity of mitochondrial fatty acid oxidation enzymes. It is unknown whether the concomitant enhancement in cardiac glucose use is a consequence of reduced FFA oxidation, or also due to potentiation of the carbohydrate oxidative pathway. FFA and glucose oxidation rates were measured in vivo in 9 normal dogs and 9 dogs with pacing-induced heart failure by infusing (3)H-oleate and (14)C-glucose. FFA oxidation was lower (39 +/- 9 vs. 73 +/- 5 nmol min(-1) g(-1)), while glucose oxidation was higher (42 +/- 8 vs. 17 +/- 6 nmol min(-1) g(-1)) in failing compared to normal hearts (P < 0.05). At the end of the in vivo experiment, clamp-frozen biopsies were harvested from the left ventricle. Messenger RNAs encoding for proteins involved in both glucose and fatty acid metabolism, and for citrate synthase, were significantly reduced. Protein expression of GLUT-1 and GLUT-4, and GLUT-4 translocation to the sarcolemma showed no significant differences between the two groups despite a significant reduction in mRNAs with heart failure. GAPDH mRNA, protein expression, and activity were all reduced. The E2 subunit of pyruvate dehydrogenase was decreased both at the mRNA and protein level, with no effect on either fractional or maximal activity. In conclusion, we found either no changes or moderate downregulation of key enzymes of the carbohydrate metabolism in failing hearts, which suggests that the increase in glucose oxidation in vivo was principally due to impaired FFA oxidation and that the maximal myocardial capacity to obtain energy from substrate is globally depressed.

Reduced left ventricular compliance and mechanical efficiency after prolonged inhibition of NO synthesis in conscious dogs.

Acute inhibition of NO synthesis decreases left ventricular (LV) work and external efficiency, but it is unknown whether compensatory mechanisms can limit the alterations in LV mechanoenergetics after prolonged NO deficiency. Eight chronically instrumented male mongrel dogs received 35 mg kg-1 day-1 of Nomega-nitro-L-arginine methyl ester orally for 10 days to inhibit NO synthesis. At spontaneous beating frequency, heart rate, coronary blood flow, peak LV pressure, end-diastolic LV pressure and the maximum derivative of LV pressure (dP/dtmax) were not significantly different vs. baseline, whereas LV end-diastolic diameter (32.5 +/- 1.0 vs. 37.6 +/- 1.4 mm) and LV stroke work (515 +/- 38 vs. 650 +/- 44 mmHg mm), were reduced (all P < 0.05). The slope of the LV end-systolic pressure-diameter relationship was increased at 10 days vs. baseline (13.9 +/- 1.0 vs. 9.6 +/- 0.9 mmHg mm-1, P < 0.05), while the end-diastolic LV diameter was smaller at matched LV end-diastolic pressures. At fixed heart rate (130 beats min-1), cardiac oxygen consumption was increased (12.2 +/- 1.5 vs. 9.9 +/- 1.0 ml min-1), and the ratio between stroke work and oxygen consumption was decreased by 33 +/-7 % (all P < 0.05) after NO inhibition. We conclude that sustained inhibition of NO synthesis in dogs causes a decrease in LV work despite an increased contractility, which is most probably due to reduced diastolic compliance and a decrease in external efficiency. Thus, prolonged NO deficiency is not compensated for on the level of LV mechanoenergetics in vivo.