|dc.contributor.author||Barnes, Gareth David||
|dc.description.abstract||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
|dc.publisher||The University of Edinburgh||en
|dc.relation.hasversion||Japp AG, Cruden NL, Barnes G et al. Acute cardiovascular effects of apelin in humans: potential role in patients with chronic heart failure. Circulation 2010;121:1818-1827.||en
|dc.relation.hasversion||Barnes G, Japp AG, Newby DE. Translational promise of the apelin-APJ system. Heart 2010;96:1011-1016.||en
|dc.relation.hasversion||Barnes GD, Alam S, Carter G et al. Sustained cardiovascular actions of APJ agonism during renin-angiotensin system activation and in patients with heart failure. Circ Heart Fail 2013;6:482-491.||en
|dc.relation.hasversion||Zhao L, Ashek Al, Wang L, Barnes G et al. Heterogeneity in lung 18FDG uptake in PAH: potential of dynamic 18FDG -PET with kinetic analysis as a biomarker for pulmonary remodeling targeted treatments. Circulation 2013;128(11):1214-1224.||en
|dc.relation.hasversion||Tsang H, Leiper J, Hou Lao K, Barnes G et al. Role of asymmetric methylarginine and connexin 43 in the regulation of pulmonary endothelial function. Pulm Circ 2013;3(3):675-691.||en
|dc.relation.hasversion||Alam SR, Shah AS, Richards J, Barnes G et al. Ultrasmall superparamagnetic particles of iron oxide in patients with acute myocardial infarction: early clinical experience. Circ Cardiovasc Imaging 2012;5(5):559-565.||en
|dc.relation.hasversion||Pedersen CM, Barnes G, Schmidt MR et al. Ischaemia-reperfusion injury impairs tissue plasminogen activator release in man. Eur Heart J 2012;33(15):1920-1927.||en
|dc.relation.hasversion||Langrish JP, Li X, Wang S, Barnes GD et al. Reducing personal exposure to particulate air pollution improves cardiovascular health in patients with coronary heart disease. Environ Health Perspect 2012;120(3):367-372.||en
|dc.relation.hasversion||Pedersen CM, Schmidt MR, Barnes G et al. Bradykinin does not mediate remote ischaemic preconditioning or ischaemia-reperfusion injury in vivo in man. Heart 2011;97(22):1857-1861. 26.||en
|dc.title||Cardiovascular actions of apelin-receptor agonism during Renin-Angiotensin system activation, exercise and in patients with chronic stable heart failure||en
|dc.type||Thesis or Dissertation||en
|dc.type.qualificationname||PhD Doctor of Philosophy||en