The Gut Hormone Ghrelin Partially Reverses Energy Substrate Metabolic Alterations in the Failing Heart
Background—The gut-derived hormone ghrelin, especially its acylated form, plays a major role in the regulation of systemic metabolism and exerts also relevant cardioprotective effects, hence it has been proposed for the treatment of heart failure (HF). We tested the hypothesis that ghrelin can directly modulate cardiac energy substrate metabolism.
Methods and Results—We used chronically instrumented dogs, 8 with pacing-induced HF and 6 normal controls. 1.2 nmol/kg/hour of human des-acyl ghrelin was infused intravenously for 15 min, followed by washout (re-baseline) and infusion of acyl ghrelin at the same dose. 3H-oleate and 14C-glucose were co-infused and arterial and coronary sinus blood sampled to measure cardiac free fatty acids (FFA) and glucose oxidation and lactate uptake. As expected, cardiac substrate metabolism was profoundly altered in HF, since baseline FFA and glucose oxidation were, respectively, >70% lower and >160% higher compared to control. Neither des-acyl ghrelin nor acyl ghrelin affected significantly function and metabolism in normal hearts. However, in HF, des-acyl and acyl ghrelin enhanced MVO2 by 10.2±3.5 and 9.9±3.7%, respectively, (P<0.05), while cardiac mechanical efficiency was not significantly altered. This was associated, respectively, with a 41.3±6.7 and 32.5±10.9% increase in FFA oxidation and a 31.3±9.2 and 41.4±8.9% decrease in glucose oxidation (all P<0.05).
Conclusions—Acute increases in des-acyl ghrelin or acyl ghrelin do not interfere with cardiac metabolism in normal, while they enhance FFA oxidation and reduce glucose oxidation in HF, thus partially correcting its metabolic alterations. This novel mechanism might contribute to the cardioprotective effects of ghrelin in HF.
- Received February 3, 2014.
- Accepted May 16, 2014.