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weight kininogen (HMWK) and low-molecular weight kininogen (LMWK) respectively. The major physiological effects of kinins include endothelium-dependent vasodilation, contraction of non-vascular smooth muscle, and mediation of the inflammatory response. The angiotensin-converting enzyme (ACE), besides being responsible of the conversion of angiotensin I in angiotensin II, can also cleave and inactivate both kinins, so that the inhibition of ACE by means of ACEIs results in an amplification of the physiological effects of bradykinin and kallidin, including endothelium-dependent vasodilation, which may contribute to the beneficial effects of ACEIs in patients with HF. (Neutral endopeptidase also deactivates kinins and other mediators. Based on this, inhibitors of neutral endopeptidase, such as omapatrilat, are currently under investigation as

experimental treatment for heart failure.

Several angiotensin II receptor antagonists (e.g

., candesartan, eprosartan, irbesartan,

losartan, telmisartan, and valsartan) are available for clinical use. Experience with ARBs in controlled clinical trials of patients with HF is considerably less than that with ACEIs. Nevertheless, in several placebo-controlled studies, long-term therapy with ARBs produced hemodynamic, neurohormonal, and clinical effects consistent with those expected after interference with the renin-angiotensin system61.

In patients with evidence of LV dysfunction early after MI, a recent trial demonstrated that ARBs had a benefit that was not inferior to that of ACEIs without an advantage in terms of tolerability62. However, the addition of an ARB to an ACEI did not improve outcomes and resulted in more side effects.

For patients unable to tolerate ACEIs because of cough or angioedema, the ARBs valsartan and candesartan63 have demonstrated benefit by reducing hospitalizations and mortality.

The combination of an ACEI and ARBs may produce more reduction of LV size than either agent alone64. The addition of ARBs to chronic ACEI therapy caused a modest decrease in hospitalization in 2 studies, with a trend to decreased total mortality in one and no impact on mortality in another66. 65

61 Sharma D, Buyse M, Pitt B, Rucinska EJ, for the Losartan Heart Failure Mortality Meta-analysis Study Group. Meta-analysis of observed mortality data from all-controlled, double- blind, multiple-dose studies of losartan in heart failure. Am J Cardiol 2000;85:187–92.

62 Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-906.

63 Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667–75.

64 Wong M, Staszewsky L, Latini R, et al. Valsartan benefits left ventricular structure and function in heart failure: Val-HeFT echocardiographic study. J Am Coll Cardiol 2002;40:970 –5.

65 Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667–75.

66 McMurray JJ, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003;362:767–71.

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