The Gut Hormone Ghrelin Partially Reverses Energy Substrate Metabolic Alterations in the Failing Heart

Abstract

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.

Intracoronary Des-Acyl Ghrelin Acutely Increases Cardiac Perfusion Through a Nitric Oxide-Related Mechanism in Female Anesthetized Pigs

“…Regarding its effect on cardiac function, the currently reported data show opposite effects, depending on physiological or pathological conditions. Hence, in human paced atria or in hearts of normal dogs, neither ghrelin nor des-acyl ghrelin was found to exert any action (17,41); in a rat model of myocardial injury, in contrast, desacyl ghrelin was found to exert a protective effect, however to a lower extent than ghrelin (42). Lastly, in the guinea pig papillary muscle, a negative inotropic effect was observed (43).…”

Acetylation mediates Cx43 reduction caused by electrical stimulation

“…Dogs (n=4) were chronically instrumented with pacing leads as previously described [23]. The left ventricle was paced at 210 to 240 beats/min.…”

“…The left ventricle was paced at 210 to 240 beats/min. This protocol leads to dilated cardiomyopathy with systolic and diastolic dysfunction after 4 weeks of tachypacing [23]. Chronically instrumented dogs that did not undergo cardiac pacing were used as normal controls (n=4).…”

Class I Histone Deacetylase Inhibition for the Treatment of Sustained Atrial Fibrillation

“…Dog Instrumentation. Fifteen purpose-bred male dogs (22-25 kg) were chronically instrumented as previously described (Mitacchione et al, 2014;Woitek et al, 2015). First, anesthesia was induced using propofol (6 mg/kg i.v.)…”

“…During the cardiac pacing protocol, hemodynamic measurements were taken every week from conscious dogs placed on the laboratory table, as previously described (Mitacchione et al, 2014;Woitek et al, 2015). The aortic catheter was attached to a strain-gauge transducer to measure aortic pressure.…”