Modulation of the renin-angiotensin-aldosterone system – pivotal in heart failure treatment

The therapy of heart failure has evolved considerably over the last few decades. Whereas in the early years the focus was on improvement of cardiac pump function and symptomatic therapy by reducing overload through diuretic therapy, attention has now shifted toward prevention of (worsening of) the syndrome. This conceptual shift has been brought about by our recent understanding of the pathophysiological mechanisms underlying the progression of heart failure, in particular neurohormonal activation and cardiac remodeling, and the potential of neurohormonal antagonists such as ACE inhibitors, bblocking agents and aldosterone receptor antagonists, to modulate these processes and thereby significantly reduce or retard heart failure-related morbidity and mortality. The reninangiotensin system and aldosterone are two of the major, closely related neurohormonal systems involved in the pathogenesis of left ventricular dysfunction. Initially, ACE inhibitor therapy for heart failure was based on the concept that as, at least in more severe heart failure, circulating renin and angiotensin II levels are increased, the ACE inhibitor was considered to be a vasodilator of potential importance. Parallel to subsequent observations that ACE inhibitors beneficially affected morbidity and mortality in heart failure, this concept changed toward one in which it was realized that, in addition to the the circulating, endocrine-acting RAS, many tissues produce components of a local tissue renin-angiotensin system, and the concept that angiotensin II, in addition to being a potent vasoconstrictor, also had growth-promoting properties and was able to stimulate other neurohormonal systems, such as the sympathetic nervous system. The beneficial effects of ACE inhibitors on morbidity and mortality become apparent after a relatively long-term treatment period and are not necessarily accompanied by clear-cut hemodynamic improvement or an increase in exercise capacity. Hence, one may correctly assume that the long-term beneficial effects of these agents relate to their chronic structural effects on the heart and the vascular wall, effects which combine inhibition of cardiac and vascular remodeling, an improvement in endothelial function and a reduction in myocardial ischemia, and which all result from modulation of the local tissue renin-angiotensin system, and which relate not or significantly less to their modulating effect on the circulating renin-angiotensin levels.