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Title: Cardiovascular effects of apelin in vivo in man
Author: Japp, Alan Gordon
ISNI:       0000 0004 2748 3815
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2013
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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.
Supervisor: Newby, David; Flapan, Andrew Sponsor: British Heart Foundation ; Chest, Heart and Stroke Scotland
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: apelin ; Apelin receptor ; apj ; vascular biology