Background The apelin system is a novel peptidic pathway widely expressed in the
heart and vasculature. In preclinical studies, apelin receptor agonism mediates
nitric oxide-dependent vasodilatation, reduces ventricular preload and afterload and
potently increases myocardial contractility. In preclinical models of heart failure,
expression of the apelin pathway is down regulated but the haemodynamic effects of
apelin receptor agonism are preserved. These changes in expression appear to be
paralleled in patients with chronic heart failure but the cardiovascular actions of
apelin in vivo in man are, to date, unknown. Detailed clinical investigation is
therefore required to establish the role of apelin in human cardiovascular physiology
and pathophysiology and to explore the therapeutic potential of apelin receptor
agonism in patients with heart failure.
Objectives Through a series of in vivo clinical studies: 1) to establish the direct
vascular actions of apelin in the peripheral venous, peripheral arterial and coronary
arterial circulations; 2) to determine the contribution of the endothelium-derived
vasodilators, nitric oxide and prostacyclin, to the vascular actions of apelin; 3) to
establish the effects of apelin on cardiac contractility and systemic haemodynamics;
4) to compare the direct vascular and systemic haemodynamic effects of the fulllength
mature apelin peptide, apelin-36, with a shorter, biologically active carboxyl
(C)-terminal fragment, (Pyr1)apelin-13); and 5) to establish whether the local
vascular and systemic haemodynamic effects of apelin are altered in patients with
chronic heart failure.
Methods The cardiovascular effects of apelin were assessed in 32 healthy
volunteers, 6 patients undergoing elective diagnostic coronary angiography,
18 patients with stable New York Heart Association (NYHA) class II-III chronic
heart failure and 18 age- and sex-matched healthy controls. Dorsal hand vein tone
was assessed by the Aellig hand vein technique during local intravenous
infusions (0.1-3 nmol/min) of apelin-36, (Pyr1)apelin-13, and sodium nitroprusside
(SNP; 0.6 nmol/min). Forearm blood flow was measured by venous occlusion
plethysmography during intrabrachial infusions of apelin-36 and (Pyr1)apelin-13
(0.01-30 nmol/min) and subsequently in the presence or absence of a ‘nitric oxide
clamp’ (nitric oxide synthase inhibitor, L-NG-monomethylarginine (L-NMMA;
8 μmol/min), co-infused with SNP (90-900 ng/min)), or a single oral dose of aspirin
(600 mg) or matched placebo. Coronary blood flow was evaluated by quantitative
coronary angiography (QCA) and Doppler flow wire, and left ventricular pressures
measured by pressure wire before and after intracoronary injection of apelin-36
(20 and 200 nM), 0.9% saline and glyceryl trinitrate (GTN) (100 μg). Blood
pressure, heart rate, cardiac output and peripheral vascular resistance were assessed
by sphygmomanometry and thoracic electrical bioimpedance (TEB) during systemic
intravenous infusion of apelin-36 and (Pyr1)apelin-13 (30-300 nmol/min). Forearm
blood flow and systemic haemodynamic responses to (Pyr1)apelin-13 in patients with
chronic heart failure were then compared with age- and sex-matched healthy
controls.
Results Although SNP caused venodilatation (P<0.0001), apelin-36 and
(Pyr1)apelin-13 had no effect on dorsal hand vein diameter (P=0.2). Both apelin
isoforms caused vasodilatation in forearm resistance vessels (P<0.0001) but the
offset was slower with apelin-36. (Pyr1)apelin-13-mediated vasodilatation was
attenuated by the nitric oxide clamp (P=0.004) but unaffected by aspirin (P=0.7).
Intracoronary bolus of apelin-36 increased coronary blood flow and the maximum
rate of rise in left ventricular pressure, and reduced peak and end-diastolic left
ventricular pressures (all P<0.05). Both (Pyr1)apelin-13 and apelin-36 increased
heart rate and cardiac output whilst reducing peripheral vascular resistance (P<0.01
for all) with no overall effect on blood pressure. Intrabrachial infusions of
(Pyr1)apelin-13, acetylcholine and SNP caused forearm vasodilatation in patients and
controls (P<0.0001 for all). Vasodilatation to acetylcholine (P=0.01) but not apelin
(P=0.3) or SNP (p=0.9) was attenuated in patients with heart failure. Systemic
infusions of (Pyr1)apelin-13 increased cardiac index and lowered mean arterial
pressure and peripheral vascular resistance index in patients and matched controls
(all P<0.01) but increased heart rate only in controls (P<0.01).
Conclusions Although having no apparent effect on venous tone, acute apelin
receptor agonism causes peripheral and coronary vasodilatation and increases cardiac
contractility and output. Local vascular and systemic haemodynamic responses to
apelin are preserved in patients with stable symptomatic chronic heart failure. The
apelin system merits further clinical investigation to determine its role in
cardiovascular homeostasis and represents a novel potential therapeutic target for
patients with heart failure