**6. The Apelin System in Health and Disease**

The apelin system displays major physiological roles in vascular and lymphatic development [155,156], in neurology [157], and in the digestive system [158]. The activation of the apelin system has demonstrated many beneficial effects in cardiovascular, kidney, skin, and metabolic diseases [128,142,150,159–164]. Apelin has aroused a special interest in the field of cardiology since it is one of the most powerful dose-dependent positive inotropic agents known to date, as demonstrated in perfused hearts [153]. Moreover, apelin is a very-well known vasodilator involved in the stimulation of NO vascular release [165]. Indeed, APJ agonism shows sustained and preserved local vascular and systemic hemodynamic responses in patients with stable symptomatic chronic heart failure and standard medical therapy [166]. However, there are some controversial data on the precise role of the apelin system in the pathogenesis of human heart failure. Some reports suggest that the apelin/APJ system is down-regulated in heart failure and upregulated in left ventricular remodelling [167,168]. This might point to a systemic compensatory effect to recover cardiac contractility. Indeed, acute administration of apelin restores cardiovascular functions in chronic heart failure [169]. However, the potential utility of apelin in cardiovascular disease needs further investigation.

The use of apelin as a biomarker in human heart failure has been challenging. Some reports point out that apelin does not reliably predict acute heart failure in patients presenting dyspnoea, and it is not a prognostic marker in those with confirmed heart failure or with chronic heart failure secondary to idiopathic dilated cardiomyopathy [170,171]. In contrast, plasma apelin concentrations add prognostic value in conjunction with brain natriuretic peptide (BNP) to the risk of mortality at 6 months in patients with ST-segment elevation myocardial infarction [172].
