Strategies to Limit Remodeling

For a long time, infarct scar had been considered an inert tissue. However, utilizing molecular and cellular biologic technologies, we know that infarct scar is composed of biologically active components such as myofibroblasts with contractile behavior and the capacity of producing type I collagen (90). This activity contributes to the formation of fibrous tissue in noninfarcted myocardium. ACE inhibition or angiotensin 1 receptor antagonism has proven effective in attenuating this metabolic activity. In the early phase postinfarction, which encompasses the first several days, there is evidence from randomized trials that improvement in loading conditions, either with intravenous (IV) nitroglycerin (91) or with ACE inhibitors, may reduce infarct expansion. However, the data with iv nitroglycerin remain controversial, and the acute impact of early ACE inhibition on LV vol appears small. By contrast, long-term ACE inhibition has demonstrated remarkable benefits in postinfarct patients, particularly in those with LV dysfunction.

In seminal investigations on rats with experimental infarctions, captopril significantly decreased ventricular dilation and prolonged survival (92). The experimental work was rapidly followed by two small clinical trials in humans that first demonstrated that the process of LV remodeling could be attenuated in man by treatment with ACE inhibition (93,94). In the study published by Pfeffer et al. (93), patients with a first anterior infarction and an EF of 45% or less were randomized to captopril or placebo. While captopril attenuated remodeling, treated patients with the most severe LV dilatation had an occluded infarct artery and a large infarct. In a subanalysis of the HEART study, BNP elevation after MI further proved that neurohormonal activation occurs and persists in patients with AMI, even in the presence of preserved LV function. Despite significant clinical effects and benefits on LV remodeling, ramipril use in patients soon after MI has been show to have only a modest impact on BNP levels (95).

The clinically important question of whether tissue-specific ACE inhibitors have more antiremodeling benefit over nontissue-specific ones has been addressed. Konermann et al. (96) randomized 52 patients with their first AMI to receive captopril (non-tissue-specific) or fosinopril (tissue-specific) started 7 d after the event. Cine magnetic resonance was done at the beginning of the trial and at 26 wk to assess remodeling. The investigators found that the use of either ACE inhibitor had no major difference in their influence on LV remodeling. However, equivalence must be viewed in the context of the small sample size. In this regard, a meta-analysis of 845 patients with a 3-mo echocardiography follow-up, de Kam et al. (97), found the very early use (<9 h) of ACE inhibitors after the onset of AMI, LV dilatation was only significantly reduced in those patients in which thrombolysis failed. Other mechanisms may be responsible for the beneficial effects of ACE inhibitors in successfully reperfused patients. Nevertheless, whether there is clinical significance of small (15 mL) differences in LV vol requires testing in large randomized trials.

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