A positive feedback loop contributes to the deleterious effects of angiotensin

When a basic scientist looks at heart failure, he sees a disease that appears to originate from any damage that causes low cardiac output, is progressive, and elicits a variety of physiological responses that attempt to correct the depressed cardiac function. Furthermore, these reflex physiological responses to low cardiac output—increased sympatho-adrenal tone, increased activity of the renin–angiotensin system and other systems that maintain blood pressure, left ventricular remodeling, and cardiac hypertrophy—seem deleterious, because the pump is overworked and failing and cannot be expected, in the long run, to respond well to increased load or increased inotropic stimulation. The disease looks like a downward spiral, a spiral that therapy must interrupt. Models of heart failure have provided rationales for therapy and experimentation. A cardio-renal model viewed heart failure as a problem of salt and water retention originating with alterations in renal blood flow; a cardio-circulatory, or hemodynamic, model ascribed heart failure to vasoconstriction and reduced pumping capacity of the heart. These models provided rationales for the use of diuretics, vasodilators, and inotropic agents as therapies but mechanistically did not account for the progressive worsening of the disease or the fact that inotropic interventions produce improvements in cardiac contractility but do not slow the progression of the disease or reduce mortality. More recently, attention has focused on some of the neural/paracrine/autocrine mechanisms that constitute the reflex responses to low output and on the importance of signaling pathways regulating cell growth, apoptosis, and cell survival (1–3). Mann and Bristow (4) have suggested a synthesis, the biomechanical model, that emphasizes that the components of altered cardiac function and cardiac remodeling interact, such that one will invariably cause the other, and both will be sustained by neurohumoral responses. Among the humoral factors involved, much attention has been focused on the renin–angiotensin–aldosterone axis and …