The cardiovascular action of hexarelin

This is the most-cited synthesis of the hexarelin cardiology literature, published in the Journal of Geriatric Cardiology in 2014 by Yuanjie Mao, Takeshi Tokudome, and Ichiro Kishimoto at the Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center Research Institute (Osaka, Japan). The review consolidates a roughly 15-year body of preclinical and small-cohort clinical work showing that hexarelin exerts cardiac effects that are mechanistically and functionally distinct from its GH-releasing activity at the pituitary, and that these effects are anchored to the scavenger receptor CD36 expressed on cardiomyocytes and microvascular endothelium rather than to the GHSR-1a ghrelin receptor that mediates the somatotroph axis.

The review organises the literature along five lines. First, the acute haemodynamic work in healthy human volunteers (Bisi 1999 and related small cohorts) showing transient left-ventricular-ejection-fraction improvement after single-dose IV hexarelin, peaking around 30 minutes and resolving within an hour, without changes in blood pressure, heart rate, or circulating catecholamines. Second, the chronic dosing rat work (Locatelli 1999 and successors) showing that subcutaneous hexarelin prevents ischemia-reperfusion-induced cardiac dysfunction in hypophysectomised animals — the experimental dissection that confirms the cardioprotection is GH-independent because the animals are pituitary-removed and incapable of producing GH at all. Third, the molecular-target identification in Bodart et al. 2002, in which photoaffinity cross-linking and CD36-null genetic models established that the cardiac binding partner for hexarelin is CD36 itself and that the CD36-mediated coronary-perfusion-pressure effect is abolished in CD36-deficient animals. Fourth, the chronic-remodelling work showing attenuation of cardiac fibrosis, suppression of cardiomyocyte apoptosis, and protection against left-ventricular hypertrophy in disease-model rats. Fifth, the metabolic-cardiac literature on hexarelin's effects on fatty-acid uptake in the heart — CD36 is the principal fatty-acid translocase in cardiomyocytes, and hexarelin engagement of that receptor produces downstream effects on cardiac substrate utilisation that are unique to this molecule in the GHRP class.

The review's central conclusion is that the hexarelin cardiac biology is mechanistically well-characterised and uniquely deep relative to the rest of the GHRP class, but that the clinical-translation depth is limited: the human haemodynamic cohorts are small (n = 7 to n = 12), the chronic-disease-state human trials have not been conducted, and Mediolanum's pharmaceutical development of hexarelin as a cardiac indication was commercially abandoned. The hexarelin peptide page treats this review as the consolidated mechanistic case for the molecule's CD36-anchored cardiac biology and as the explanation for why hexarelin remains pharmacologically distinct from the modern selective secretagogue Ipamorelin despite the latter's cleaner pituitary profile.