From CONSENSUS to CHARM—how do ACEI and ARB produce clinical benefits in CHF?

Two decades of research from CONSENSUS to CHARM using modulators of the renin–angiotensin–aldosterone system (RAAS) in chronic heart failure (CHF) patients have shown convincing clinical benefits, but the majority of clinicians prescribing these drugs are still unclear about what mechanisms are responsible for the observed benefits. Of the candidate mechanisms hitherto proposed, there emerges a theme that best fits the spectrum of known factors from pathophysiology of heart failure to how the drugs enhance longevity of patients. This concept can be summarised as follows: after the onset of heart failure, neurohormones are activated resulting in raised levels of angiotensin, aldosterone and catecholamines, which are all known cardiotoxic agents. Cumulatively over time, they are responsible for accelerated cardiomyocyte attrition, manifesting as a faster reduction of cardiac pumping reserve, leading to worsening heart failure, more neurohormonal activation, thus propagating a vicious cycle spiralling towards an earlier fatality. The vicious cycle can be interrupted by dampening the excessive neurohormonal activities, thereby minimising cardiomyocyte losses and preserving cardiac functional reserve for longer. This culminates in maintenance of a reasonable quality of life and enhanced longevity. Such a mechanistic understanding would enable clinicians to have a better perspective on how to apply data from various clinical trials involving these drugs into clinical practice, to optimise and tailor therapy to the individual patient so that each patient can gain maximal benefits. [Copyright &y& Elsevier]