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& u sue-specific myocardial renin-angiotensin system is markedly activated in failing myocardium, with resultant adverse effects on a number of cellular responses that occur in the evolution of cardiac hypertrophy, including promotion of calcium overload and matrix remodeling with increased fibrosis. Moreover, ACE inhibitors are nonspecific kininases. As a consequence, they potentiate the effects of bradykinin, a property that may have clinical significance and benefit.

ACE inhibitors improve long-term survival as well as clinical class in patients with low-ejection-fraction CHF. The SOLVD trials demonstrated that ACE inhibitors also have positive effects on postinfarction remodeling, resulting in reduced development of heart failure after an index myocardial infarction. ACE inhibitors may be especially important in diabetic patients because of their salutary influence on the progression of diabetic nephropathy and apparently favorable effects on carbohydrate metabolism with possible delay of onset of overt diabetes. Moreover, the HOPE trial documented reduced coronary event rates in diabetic patients receiving ACE inhibitors. This effect may be related to the observation that ACE inhibitors decrease PAI-1 levels in diabetic patients. Accordingly, in the absence of a specific contraindication and/or unacceptable side effects, virtually all patients with a low ejection fraction, including those with diabetes, should receive an ACE inhibitor. Relatively high doses are currently recommended, although what constitutes a truly optimal dose is uncertain. In patients who may be volume depleted there is a risk of induction of renal insufficiency and hyperkalemia when ACE inhibitors are employed, especially early after initiation of therapy. However, the presence of preexisting renal insufficiency per se is not a contraindication to the use of ACE inhibitors, but rather a signal to use them with extra caution. Many patients should have diuretics held or doses reduced as ACE inhibitor therapy is begun. BUN, creatinine, and electrolytes should be carefully monitored. Induction of renal insufficiency should alert the physician to the possibility of renal artery stenosis.

ACE inhibitors are well-tolerated in the vast majority of patients, with cough being the most common side effect responsible for discontinuation of therapy. Because diabetes is associated with a high incidence of coexisting renal insufficiency, extra vigilance to detect induction of renal toxicity is appropriate.

Beta-Adrenergic Blockers. Beta-adrenergic blocking drugs very significantly reduce mortality in CHF patients with low ejection fraction, once again consistent with the adverse effects of neurohumoral activation. Although these drugs have impressive effects on survival, their effects on clinical class are more subtle. Carvedilol is the beta-adrenergic blocker that has been used most extensively in published studies. This drug is unique in that it is also an alpha-adrener-gic blocker and has antioxidant properties, both of which have theoretical benefit. There is also considerable experience with metoprolol and bucindolol. Presently,

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