Introduction Apelin is the endogenous ligand for the G-protein coupled receptor, APJ. In preclinical models, apelin causes arterial and venous dilatation and is the most potent inotrope yet described. We sought to determine the local vascular and systemic haemodynamic effects of acute APJ agonism in vivo in healthy volunteers and patients with chronic heart failure (CHF).
Methods The effects of APJ agonism were assessed using apelin-36 (the full-length mature peptide) and (Pyr1)apelin-13 (a shorter, more potent C-terminal fragment). Dorsal hand vein diameter was measured in six healthy subjects by the Aellig technique during local intravenous infusions of apelin-36, (Pyr1)apelin-13 and sodium nitroprusside (SNP). Forearm blood flow (FBF) was measured by venous occlusion plethysmography in eight healthy subjects during intrabrachial infusions of apelin-36 and (Pyr1)apelin-13 and subsequently in the presence or absence of a “nitric oxide clamp” (nitric oxide synthase inhibitor, l-NG-monomethylarginine, co-infused with SNP), or a single oral dose of aspirin (600 mg) or matched placebo. FBF responses to intrabrachial (Pyr1)apelin-13, acetylcholine and SNP were also measured in 12 patients with stable CHF and 12 matched controls. Cardiac index (CI; assessed non-invasively by thoracic electrical bioimpedance) blood pressure and heart rate (HR) were measured during intravenous infusions of (Pyr1)apelin-13 and saline placebo in eight healthy volunteers, six patients with stable CHF and seven matched controls. The maximum rate of pressure rise within the left ventricle (dP/dtmax) was measured in four patients following intracoronary boluses of apelin-36 and saline placebo.
Results Although SNP caused venodilatation (p<0.0001), apelin-36 and (Pyr1)apelin-13 had no effect on the dorsal hand vein diameter (p = 0.2). Both apelin isoforms caused vasodilatation in forearm resistance vessels of healthy subjects (p<.0001). Apelin-mediated vasodilatation was attenuated by the nitric oxide clamp (p = 0.004) but was unaffected by aspirin (p = 0.7). In CHF patients and controls, apelin, SNP and acetylcholine caused vasodilatation in forearm resistance vessels (all p<0.0001). Responses to acetylcholine (p = 0.01) but not apelin (p = 0.3) or SNP (p = 0.9) were diminished in CHF patients compared with controls. Systemic apelin infusion increased CI and HR (both p<0.01) in healthy subjects without altering mean arterial pressure (MAP). In CHF patients and controls, apelin increased CI and lowered MAP (all p<0.05). HR increased in controls (p<0.01) but not CHF patients. Intracoronary injection of apelin appeared to increase cardiac contractility (dP/dtmax rise of 8%, p = 0.056).
Conclusion Apelin increases cardiac output and lowers blood pressure in humans, through both peripheral arteriolar vasodilatation and, possibly, increased cardiac contractility. These effects of apelin are preserved in patients with CHF, suggesting a potential therapeutic role for apelin agonism in heart failure.