decrease the need for cardiac transplantation. 53 These paradoxical responses have been attributed to the fact that many inotropic and vasodilating agents enhance cardiac performance at the expense of further neuroendocrine activation that ultimately contributes to progressive LV dysfunction, whereas ACE inhibitors and-blockers exert their beneficial effects through a reduction in neuroendocrine activity. 11, 13, 14 Although activation of neurohormonal systems accounts for the negative results with some drugs, this concept fails to explain the negative results of other drugs that do not appear to worsen the neurohormonal profile, such as vesnarinone54 and ibopamine. 55 In addition, HMG-CoA reductase inhibitors, which have no hemodynamic effect, may prevent the development of heart failure and possibly improve survival in patients with LV dysfunction. 56, 57 It is conceivable that in many patients with heart failure and underlying CAD, the effects of medical therapy can be explained, at least in part, by the influence of these agents on the pathophysiology and progression of CAD. Lipid-lowering therapy may stabilize lipid-rich plaques, preventing plaque rupture that may result in myocardial infarction or sudden death58; such therapy may also improve endothelial function and reduce ischemia. 59, 60 In addition, in patients with CAD and LV dysfunction, ACE inhibitors and-blockers may have specific beneficial actions beyond those achieved in patients without CAD, related to their effects on the vasculature and ischemic myocardium. ACE inhibitors may improve endothelial dysfunction61 and inhibit proliferation of vascular smooth muscle cells, 62 and-adrenergic–blocking agents not only reduce myocardial ischemia but also may reduce the risk of plaque rupture. 63 On the other hand, chronic adrenergic stimulation directly with a positive inotropic agent or indirectly via a systemic vasodilator may be detrimental in ischemic and/or hibernating myocardium with limited flow reserve and may result in myocyte necrosis or ischemia if adequate perfusion is not first restored. 64–66 Chronic adrenergic stimulation may also enhance the risk of plaque rupture. 63, 67, 68