Utility of plasma apelin and other indices of cardiac dysfunction in the clinical assessment of patients with dilated cardiomyopathy
Introduction
Apelin has recently been identified as an endogenous ligand for the G-protein coupled APJ receptor [1]. Since the discovery of this short peptide the research on apelin's physiological responses has been intense. Thus far the peptide has been discovered to be involved in the regulation of immune response [2], brain signalling [3], hemodynamic homeostasis [4], [5], [6] as well as HIV-infection [7], [8]. In addition, Lee et al. [9] recently demonstrated that systemically administered apelin65–77 (apelin-13) mediates a decrease in both systolic and diastolic blood pressure in rats. Thereafter, several other reports have been focused on apelin's physiological role in cardiovascular system, but still very little is known about the functional effects and mechanisms of the apelin–APJ signalling pathway.
Vascular actions of apelin have been further elucidated in studies using apelin peptides of different sizes. In addition to apelin-13, the blood pressure lowering effects of the peptide have been addressed also to apelin66–77 (apelin-12) and apelin42–77 (apelin-36) [10]. On the other hand, there are also reports of apelin's vasopressor response in human vascular system [11], [12]. Most importantly, apelin has been shown to act as an endogenous inotrope regulating cardiac contractility [13], [14], [15], [16], [17], and playing an important role in paracrine signalling in the heart [18], [19], [20]. These results suggest that apelin might act as an endogenous protective regulator in the heart. The reported findings of circulating levels of apelin in patients with heart failure have been contradictory: both elevated [18] and decreased [19], [20], [21], [22] concentrations compared to healthy subjects have been observed. Down-regulation of the cardiac apelin system has been observed in experimental HF, as well [23].
The knowledge on apelin's physiological functions has increased rapidly, but the mechanisms underlying the regulation of the body's response to apelin as well as genetic up- and down-regulation at the tissue level are still poorly understood. We already know that apelin mRNA is expressed in many tissues, including the brain, lung, kidney, and particularly the heart, and that it has diverse effects in various tissues. For example, in the myocardium it exerts particularly strong inotropic effect, the mechanisms of which have been proposed to be involved with the activation of PLC, PKC, and sarcolemmal Na+–H+ (NHE) and Na+–Ca2+ exchange (NCX), leading to muscle contraction due to increase in intracellular Ca2+ ([Ca2+]i) concentration [13]. On the other hand, apelin-stimulated signal transduction pathways are transduced via inhibitory G-protein (Gi) coupled to APJ, leading to inhibitory effect on myocardial adenylate cyclase activity and subsequent decrease in [Ca2+]i [2].
Measuring peak oxygen consumption (VO2max) during exercise provides essential information about the severity of heart failure [24], [25], [26], and it is frequently used for selection of patients for cardiac transplantation [25], [26], [27]. Furthermore, peak oxygen consumption during exercise is the most powerful independent predictor of mortality in patients with mild to moderate chronic heart failure [24]. In addition, plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), and norepinephrine have been shown to reflect the severity of heart failure and also serve as prognostic indicators [28], [29], [30], [31], [32], [33].
In the present study, we set out to study the relationships between plasma levels of apelin and other known variables reflecting cardiac dysfunction. The primary aim was to establish whether plasma apelin levels can be used in the clinical assessment of heart failure patients.
Section snippets
Patients and study protocol
The study population consisted of 65 (50 men and 15 women; mean SD age 53 ± 12 years) well-characterized patients with idiopathic dilated cardiomyopathy (IDC) from the region of Kuopio University Hospital in Eastern Finland. The diagnostic criteria for IDC were impaired left ventricular systolic function (ejection fraction (EF) < 45%, measured at the time of diagnosis) and left ventricular dilatation (left ventricular end-diastolic diameter (LVEDD) > 27 mm/m2) in the absence of any underlying
Patient characteristics
For the whole group of IDC patients the median VO2max was 18.3 ml/min/kg, the range being 8.2–47 ml/min/kg. On the basis of VO2max the patients were divided in three groups: patients with near normal exercise capacity (> 18 ml/min/kg, n = 33; group A), patients with moderately deteriorated exercise capacity (14–18 ml/min/kg, n = 18; group B), and patients with significantly reduced exercise capacity (< 14 ml/min/kg, n = 14; group C), reflecting the severity of heart failure [8], [32], [37]. The
Discussion
Idiopathic dilated cardiomyopathy is a primary myocardial disorder of unknown cause characterized by cardiac dilatation and impaired myocardial contractility and systolic function [38]. The activation of adaptive mechanisms in response to heart failure plays an important role in the progression of cardiac dysfunction [39]. Hemodynamic alterations related to heart failure have been extensively studied, and they have been shown to be of both diagnostic and prognostic value. Recently, it has been
Acknowledgements
The authors thank Tuula Lumijärvi, Helka Koisti, and Minna Ala-Kopsala for performing the natriuretic peptide and apelin assays. We also thank Raija Isomäki for her expert technical assistance in the cytokine assays. The staff in the Cardiology unit of Kuopio University Hospital is also gratefully acknowledged for their assistance in conducting the study. This study was supported by grants from the North Savo Fund of the Finnish Cultural Foundation and Finnish Foundation for Cardiovascular
References (49)
- et al.
Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor
Biochem Biophys Res Commun
(1998) - et al.
Apelin, the natural ligand of the orphan receptor APJ, is abundantly secreted in the colostrum
Biochim Biophys Acta
(1999) - et al.
Apelin peptides block the entry of human immunodeficiency virus (HIV)
FEBS Lett
(2000) - et al.
The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism
Regul Pept
(2001) - et al.
Central and peripheral cardiovascular actions of apelin in conscious rats
Regul Pept
(2005) - et al.
Apelin increases contractility in failing cardiac muscle
Eur J Pharmacol
(2006) - et al.
Apelin protects myocardial injury induced by isoproterenol in rats
Regul Pept
(2006) - et al.
Circulating and cardiac levels of apelin, the novel ligand of the orphan receptor APJ, in patients with heart failure
Biochem Biophys Res Commun
(2003) - et al.
Apelin: a new plasma marker of cardiopulmonary disease
Regul Pept
(2006) - et al.
Down-regulation of cardiac apelin system in hypertrophied and failing hearts: possible role of angiotensin II–angiotensin type 1 receptor system
J Mol Cell Cardiol
(2006)
Comparison between New York Heart Association classification and peak oxygen consumption in the assessment of functional status and prognosis in patients with mild to moderate chronic congestive heart failure secondary to either ischemic or idiopathic dilated cardiomyopathy
Am J Cardiol
Cardiopulmonary exercise testing identifies low risk patients with heart failure and severely impaired exercise capacity considered for heart transplantation
J Am Coll Cardiol
Neurochemical evidence of cardiac sympathetic activation and increased central nervous system norepinephrine turnover in severe congestive heart failure
J Am Coll Cardiol
Circulating concentrations of proinflammatory cytokines in mild or moderate heart failure secondary to ischemic or idiopathic dilated cardiomyopathy
Am J Cardiol
BNP and congestive heart failure
Prog Cardiovasc Dis
Prevalence and etiology of idiopathic dilated cardiomyopathy (summary of a National Heart, Lung, and Blood Institute Workshop)
Am J Cardiol
Comparison of plasma N-brain natriuretic peptide, peak oxygen consumption, and left ventricular ejection fraction for severity of chronic heart failure
Am J Cardiol
Utility of amino-terminal pro-brain natriuretic peptide, galectin-3, and apelin for the evaluation of patients with acute heart failure
J Am Coll Cardiol
Transcardiac extraction of circulating endothelin-1 across the failing heart
Am J Cardiol
Elevation of plasmatic endothelin in patients with heart failure
Arch Med Res
Anglo-Scandinavian Cardiac Outcomes Trial Investigators. Plasma B-type natriuretic peptide reflects left ventricular hypertrophy and diastolic function in hypertension
Int J Cardiol
Determinants of increased angiotensin II levels in severe chronic heart failure patients despite ACE inhibition
Int J Cardiol
Coronary sinus and ascending aortic levels of aldosterone, angiotensin II, and B-type natriuretic peptide in patients with aortic stenosis and in patients with coronary heart disease
Am J Cardiol
Physiological role of a novel neuropeptide, apelin, and its receptor in the rat brain
J Neurochem
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