Can ACE Inhibitors Promote Detrimental Vascular Effects After Percutaneous Injury?

Flavio Ribichini, Valeria Ferrero, William Wijns, Giuseppe Matullo, Alberto Piazza, Eugenio Uslenghi
2002 Hypertension  
Zhuo et al 1 reported interesting observations in vivo about the effects of angiotensin-converting enzyme (ACE) inhibition with perindopril on plasma ACE levels and cellular expression of ACE, AT 1 receptors, and nitric oxide synthase (NOS) isoforms in human blood vessels. Oral ACE inhibition at conventional doses (perindopril 4 mg/d) decreased plasma ACE activity by 70% and vascular ACE immunoactivity to 65% of control subjects detected by immunocytochemistry, and increased endothelial NOS
more » ... S) and inducible NOS (iNOS) expression in the vascular wall. However, the authors also observed a dramatic 80% increment of the AT 1 receptor binding in vascular smooth muscle cells, which might increase the potential of these receptors to counterbalance the beneficial effects of suppressed angiotensin II formation if AT 1 receptors were activated by alternative sources of angiotensin II. Whether the overexpression of AT 1 receptors may somehow limit, or even reverse, the beneficial effects of ACE inhibitors in specific clinical situations of vascular disease has stimulated the following comments. So far, mostly beneficial vascular effects have been reported in patients treated with ACE inhibitors. 2,3 However, 2 recent publications have shown that oral administration of ACE inhibitors following stented angioplasty actually augmented the incidence of restenosis instead of reducing it. 4,5 Conversely, the administration of AT 1 antagonist valsartan in the VAL-PREST Trial reduced the occurrence of stent restenosis in a small but placebo-controlled randomized trial. 6 Although these studies were not aimed at evaluating the clinical outcome, the angiographic findings are consistent with an opposite-to-the-expected effect of ACE inhibitors and a possible favorable outcome with AT 1 antagonists. In-stent restenosis is a proliferative response of the vessel wall to the injury caused by coronary stenting, and this phenomenon correlates in humans with plasma ACE concentration. 7,8 Furthermore, tissue ACE is upregulated locally during the vascular healing process. 9 ACE inhibition was thought to potentially contribute to the prevention of its occurrence, but emerging evidence does not support this hypothesis. A large angiographic analysis addressing this issue is being performed by our group. 10 Although retrospective in nature, the preliminary analysis of nearly 1000 consecutive patients yielded a much higher restenosis rate in 282 ACE-inhibited patients (36.6%) compared with 615 nontreated patients (22.9%) (ORϭ1.94, 95% CI: 1.45-2.59). Such a difference persisted after normalization for covariates. By multivariate analysis, ACE inhibition emerged as an independent predictor of stent restenosis (ORϭ1.84, 95%CI: 1.35-2.52, Pϭ0.001). 10 Zhuo et al 1 provide a valuable piece of information that supports these observations and allows us to speculate that the interactions between plasma and tissue ACE levels and the intracellular signaling of angiotensin II in patients treated with ACE inhibitors may be involved in the mechanisms that lead to exuberant neointimal growth through the over-expression of AT 1 membrane receptors. This might happen as a consequence of the chronic enzyme depletion that induces AT 1receptor over-expression and/or enhanced intracellular signaling of angiotensin II formed by the noninhibited fraction of plasma ACE, or by alternative metabolic pathways such as ACE-independent, chymase-mediated angiotensin II. The integration of the evidence briefly summarized in this letter supports the hypothesis formulated to explain the augmented incidence of in-stent restenosis in ACE-inhibited patients. 1. Zhuo JL, Mendelsohn FAO, Ohishi M. Perindopril alters vascular angiotensin-converting enzyme, AT 1 receptor, and nitric oxide synthase expression in patients with coronary heart disease. Hypertension. 2002;39(pt 2):634 -638. 2. Lonn EM, Yusuf S, Jha P, Montague TJ, Teo KK, Benedict CR, Pitt B. Emerging role of angiotensin-converting enzyme inhibitors in cardiac and vascular protection: current perspective. Circulation. 1994;90:2056 -2069. 3. Yusuf S, Sleiht P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145-153. 4. Meurice T, Bauters C, Hermant X, Codron V, VanBelle E, Mc Fadden EP, Lablanche JM, Bertrand ME, Amouyel P. Effect of ACE inhibitors on angiographic restenosis after coronary stenting (PARIS): a randomized, double-blind, placebo-controlled trial.
doi:10.1161/01.hyp.0000035252.27580.77 pmid:12364366 fatcat:wwlgygz47vgntafvuawvz44x6u