Cardiovascular actions of apelin-receptor agonism during Renin-Angiotensin system activation, exercise and in patients with chronic stable heart failure
Barnes, Gareth David
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The apelin-apelin receptor (APLNR) system is an important regulator of cardiovascular homeostasis both in health and disease. Principal actions of the apelin-APLNR system are positive inotropism, vasodilatation, diuresis and a potential anti-inflammatory role in vascular tissue. The significance of this system is highlighted in heart failure and pulmonary hypertension. Preclinical models of these diseases report downregulation of apelin- APLNR, whilst knockout strains develop more severe phenotypes, more rapidly. Moreover treatment with exogenous apelin retards or prevents disease progression. In man plasma apelin concentrations are reduced in heart failure and vary with disease severity. Initial increases are reported in mild heart failure suggesting a compensatory role, but are depressed in severe heart failure. Limited data profile myocardial APLNR expression in heart failure and in keeping with plasma apelin concentrations, expression is reduced in severe heart failure. Of interest, the APLNR most closely resembles the angiotensin II type 1 receptor (AT1R), sharing similar tissue expression and sequence homology, but mediates opposing physiological actions. Furthermore, emerging preclinical data support receptor interactions between the APLNR and AT1R that modify their native signalling pathways. It is likely that the apelin-APLNR system serves to antagonise the renin-angiotensin system. Given the established role of angiotensin II, arguably the most important peptide in cardiovascular pathophysiology, any system influencing its actions merits further investigation. Current clinical studies are limited to 20 minutes infusions and understanding its cardiovascular effects requires more prolonged administration. There are concerns of tachyphylaxis and interaction with the renin-angiotensin-aldosterone system (RAAS), possibly reducing efficacy of APLNR agonism in clinical settings. In a series of randomised, blinded crossover clinical trials 60 healthy volunteers and 20 patients with chronic stable heart failure were enrolled to assess the effects of (Pyr1)apelin-13 infusion at rest, during acute and subacute infusion, exercise and upregulation of the renin-angiotensin system. I have identified that APLNR agonism is unaffected by prevailing levels of angiotensin II activity in local vascular beds and systemic haemodynamic infusions. Furthermore, the efficacy of (Pyr1)apelin-13 is retained in healthy volunteers and patients with chronic stable heart failure during acute and subacute infusions. Finally, systemic (Pyr1)apelin-13 does not alter exercise performance in healthy individuals. My findings support a role in targeting the APLNR in chronic heart failure and predict that efficacy will be retained in chronic dosing. Future research directed at other patient groups with ventricular dysfunction is merited, in order to further characterise the utility of this system. These studies are encouraging; however, longer term studies may reveal effects beyond haemodynamic alterations and examine the effects on cardiac fibrosis and endothelial function. A long acting agonist is required to fully evaluate the role of APLNR signalling in cardiovascular disease.