ABSTRACT
Heart failure is most often caused by a decrease in the mass and/or function of the
myocardium, leading to impaired ability of the heart to function as a pump. This primary
defect is often associated with and compounded by a variety of systemic alterations
including the activation of neurohormonal pathways and vascular dysfunction, both of
which further antagonize overall cardiovascular homeostasis. It is not surprising that the
treatment of heart failure for many years focused on improving hemodynamic function
through the development and use of agents that increase myocardial contractility and/or
reduce vascular tone. However, despite the clinical testing of numerous potent positive
inotropic and direct vasodilator agents, with rare exceptions these agents have not led to
improved clinical outcomes. In contrast, the most successful agents have been those that
inhibit neurohormonal pathways (e.g., beta-blockers and angiotensin system inhibitors).
The clinical success of these agents can not be attributed to their direct hemodynamic
actions, which in some cases are adverse (e.g., beta-blockers). Rather, the shared mode of
action of neurohormonal antagonists appears to be the slowing of myocardial remodeling
and disease progression.
