Introduction

Heart failure (HF) is a major global health problem with more than 23 million people affected worldwide.1 While a range of conditions can lead to the development of chronic HF, coronary artery disease or ischaemic heart disease is by far the dominating aetiology. Furthermore, ischaemic heart disease is associated with progressively worse prognosis in the lower ranges of systolic function.2 Other important causes of HF include, but are not limited to, idiopathic dilated cardiomyopathy, hypertension, myocarditis, atrial fibrillation.3 ,4

Evolutionary processes have provided us with robust neurohumoral responses to counter hypovolaemia due to causes such as severe blood loss or dehydration. Powerful mechanisms such as renin-angiotensin-aldosterone system (RAAS) activation, natriuretic inhibition and peripheral vasoconstriction preserve volume, thereby ensuring adequate central organ perfusion, and facilitating survival under these threats. HF superficially mimics loss of circulatory fluids in that both conditions lead to reduced cardiac output (figure 1). This in turn leads to lowered perfusion of the renal juxtaglomerular apparatus, thereby signalling the activation of vasoconstrictive and fluid-retentive pathways. Several other mechanisms are also involved such as signals from osmoreceptors, chemoreceptors and baroreceptors. This sequence induces a physiological state of excessive neurohumoral activation.5 In acute HF, these responses are often compensatory and are beneficial in maintaining cardiac output. Nevertheless, the very mechanisms that protected our ancient ancestors during droughts, dehydrations and violent encounters have proven themselves to be deleterious and maladaptive in the modern setting of chronic HF. Additionally, the activation of neurohumoral pathways promotes the development of myocardial fibrosis resulting in detrimental structural changes known as adverse cardiac …