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

The therapy of heart failure has evolved considerably over the last few dec ades. Whereas in the early years the focus was on improvement of cardiac pu mp function and symptomatic therapy by reducing overload through diuretic t herapy, attention has now shifted toward prevention of (worsening of) the s yndrome. This conceptual shift has been brought about by our recent underst anding of the pathophysiological mechanisms underlying the progression of h eart failure, in particular neurohormonal activation and cardiac remodeling , and the potential of neurohormonal antagonists such as ACE inhibitors, be ta-blocking agents and aldosterone receptor antagonists, to modulate these processes and thereby significantly reduce or retard heart failure-related morbidity and mortality. The renin-angiotensin system and aldosterone are t wo of the major, closely related neurohormonal systems involved in the path ogenesis 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 importanc e. Parallel to subsequent observations that ACE inhibitors beneficially aff ected morbidity and mortality in heart failure, this concept changed toward one in which it was realized that, in addition to the the circulating, end ocrine-acting RAS, many tissues produce components of a local tissue renin- angiotensin system, and the concept that angiotensin II, in addition to bei ng a potent vasoconstrictor, also had growth-promoting properties and was a ble to stimulate Ether neurohormonal systems, such as the sympathetic nervo us system. The beneficial effects of ACE inhibitors on morbidity and mortality become apparent after a relatively long-term treatment period and are not necessar ily accompanied by clear-cut hemodynamic improvement or an increase in exer cise capacity. Hence, one may correctly assume that the long-term beneficia l effects of these agents relate to their chronic structural effects on the heart and the vascular wall, effects which combine inhibition of cardiac a nd vascular remodeling, an improvement in endothelial function and a reduct ion in myocardial ischemia, and which all result from modulation of the loc al tissue renin-angiotensin system, and which relate not or significantly l ess to their modulating effect on the circulating renin-angiotensin levels.