Abstract 14981: The Gut Hormone Ghrelin Partially Reverses Energy Substrate Metabolic Alterations in the Failing Heart
The gut-derived hormone ghrelin, particularly in acylated form, plays a major role in daily regulation of systemic metabolism. Studies show that acyl ghrelin also exerts cardioprotective effects, hence its testing for treatment of human heart failure. Whether ghrelin can directly modulate cardiac energy substrate metabolism is presently unknown. We tested this hypothesis in chronically instrumented, conscious dogs: 5 with pacing-induced congestive heart failure (HF) and 4 normal controls. 1.2 nmol/kg/hour of human des-acyl ghrelin was infused intravenously for 15 min followed by 60 min washout (a return to baseline plasma ghrelin concentrations was confirmed post-washout) and then a subsequent infusion of acyl ghrelin at the same dose. 3H-oleate and 14C-glucose were co-infused, and paired blood samples were withdrawn from aorta and coronary sinus to measure cardiac oxygen consumption, free fatty acid (FFA) and glucose oxidation, and lactate uptake. Consistent with previous findings, baseline FFA and glucose oxidation were, respectively, 60% lower and threefold higher in HF compared to normal. Neither des-acyl ghrelin nor acyl ghrelin affected significantly cardiac function or hemodynamics. However, in HF we found the following changes in response to des-acyl ghrelin and acyl ghrelin, respectively: FFA oxidation increased from 11.68±1.0 to 15.4±1.3 and from 15.4±1.8 (post-washout) to 17.8±1.9nmol/beat (all P<0.05), while glucose oxidation decreased from 28.3±0.4 to 16.0±1.6 and from 28.5±3.7 (post-washout) to 16.7±2.6nmol/beat (all P<0.05). Cardiac lactate uptake did not change significantly. The shift to the less energetically efficient substrate FFA was reflected by a small but significant increase in MVO2 from 19.9±0.3 to 20.8±0.2 and from 20.4±0.6 (post-washout) to 21.5±0.5μL/beat. On the other hand, ghrelin did not cause significant cardiac metabolic changes in normal hearts. We show, for the first time, that acute increases in des-acyl ghrelin or acyl ghrelin do not interfere with cardiac metabolism in normal hearts, while they enhance FFA oxidation and reduce glucose oxidation in HF, thus partially correcting its metabolic alterations. However, this partial normalization does not lead to significant functional improvements.
- © 2013 by American Heart Association, Inc.