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Background: Several studies indicate that ACE-activity is related to atherosclerosis. We investigated the correlation between ACE-activity, in plasma as well as in the atherosclerotic plaque, and in-stent restenosis., Methods and Results: ACE-activity was measured in blood samples from 178 patients who underwent a percutaneous coronary intervention with stent placement. During 8 months follow-up, 51 of these patients had an adverse clinical event. ACE-activity did not differ between patients with or without adverse events (21.5 vs. 23.1 nM/ml/min; P=0.36). Tissue samples were obtained with an atherectomy catheter before elective stent placement in another group of 13 patients with de novo stenosis. In this tissue, we determined the ACE-content immunohistologically. These patients were scheduled for follow-up quantitative coronary angiography after 12 months. In this group, the quantity of ACE was not correlated to the late luminal loss (0.31 vs. 0.38 mm; P=0.76)., Conclusion: In this study, pre-procedural ACE-activity, in plasma as well as in the atherosclerotic plaque, does not predict the occurrence of in-stent restenosis.

Objective: To determine whether the angiotensin converting enzyme (ACE) and the angiotensin II type 1 receptor (AT(1)R A1166C) gene polymorphism interact to increase the risk of ischaemic events, and whether this can be explained by the progression of angiographically defined coronary atherosclerosis., Design: Prospective defined substudy of the lipid lowering regression trial (REGRESS)., Setting: University hospital., Patients: 885 male patients with stable coronary artery disease., Main Outcome Measures: Incidence of ischaemic events during a two year follow up; serial quantitative coronary arteriography (mean segment diameter and minimum obstruction diameter) at baseline and after two years., Results: Patients who carried both the ACE-DD and AT(1)R-CC genotype had significantly more ischaemic events during the two year follow up than those carrying other genotype combinations (p = 0.035, Mantel-Haenszel test for linear association). There was no association between the two genotypes and mean segment diameter or minimum obstruction diameter at baseline or after two years., Conclusions: The suggestion that ACE-DD and AT(1)R-CC genotypes interact to increase the risk of ischaemic events is confirmed. However, this increased risk was not accompanied by increased progression of angiographically defined coronary atherosclerosis.

In the present review, we discuss the role of clinical dosing of angiotensin converting enzyme (ACE) inhibitors in the treatment of left ventricular dysfunction. Although the precise mechanism of action of ACE inhibitors is still unresolved, the clinical efficacy of ACE inhibitors in the treatment of left ventricular dysfunction is well established. However, it is unclear whether the doses used in clinical trials translate directly into daily practice. Several reasons may cause differences between clinical practice and controlled trials: (1) clinical trials used higher doses than in normal practice; (2) some patients may be relatively 'resistant' to ACE inhibition; and/or (3) ACE activity increases during ACE inhibitor therapy and may provide escape mechanisms when the drug regimen is not strictly adhered to. Therefore, it is of interest that recent trials suggest that only the higher doses of ACE inhibition are clinically efficacious. In conclusion, it is suggested that optimal benefit from treatment with an ACE inhibitor in patients with left ventricular dysfunction requires sufficient and frequent dosing of the ACE inhibitor, e.g., enalapril 10 mg twice daily or captopril 25 mg three times daily.

Many tissue ACE-assays suffer from underestimation of the ACE-activity at low sample dilutions. However, measurement of ACE-activity as the amount of hippuric acid produced by cleavage of the commonly used substrate hippuryl-histidyl-leucine might circumvent this problem. In this study, we investigated whether sample dilution affects the measurement of ACE-activity in rat tissue and serum. We found that serum ACE-activity was not affected by sample dilution. In homogenates of aorta, kidney, left ventricle, and lung, however, ACE-activity increased 1.6-2.8 times with increasing sample dilution until, ultimately, a plateau was reached at dilution factor 100, 50, 20, and 100, respectively. In addition, tissue homogenates inhibited the activity of exogenous ACE, whereas serum did not. These data suggest that the dilution effect probably results from interactions of inhibitory substances from the homogenates with ACE. The implications of these findings are that tissue ACE-activity measurements by any assay should be performed using sample dilution at the plateau. In many studies in the literature, specifications of sample dilution are lacking. Our findings demonstrate that caution is warranted in the interpretation of these studies.

Background: This study was done to determine whether the difference in duration of action of the long-acting angiotensin-converting enzyme (ACE) inhibitor spirapril compared with the short-acting ACE inhibitor captopril affects clinical efficacy in patients with congestive heart failure., Methods and Results: The effects on exercise capacity, neurohumoral status, and quality of life were studied in 20 patients with mild to moderate congestive heart failure in a double-blind, randomized, comparative study in parallel groups with a duration of 12 weeks. All assessments during the study were performed in the morning, before intake of the study medication, to avoid the expected peak effect of the ACE inhibitors used. Mean peak oxygen consumption (peak Vo2) was 17.4 mL/min/kg (range, 14.2-19.9 mL/min/kg) and mean left ventricular ejection fraction was 28% (range, 13-40%). Exercise duration in the captopril group showed a significant increase after 12 weeks (P < .05) of treatment compared with the spirapril group. Peak oxygen consumption tended only to increase in the captopril-treated patients compared with the spirapril-treated patients. Serum ACE activity was significantly different between the two treatment groups during treatment (P < .0001) and showed only a significant decrease in the spirapril group. There was no difference in improvement of quality of life between the two treatment groups., Conclusions: This study showed that the effects of the ACE inhibitors spirapril and captopril on exercise capacity are not related to the degree of inhibition of serum ACE activity.

Background: Left ventricular dilation after acute myocardial infarction (MI) is mainly determined by infarct size. In addition, this detrimental structural adaptation seems to be augmented in patients with the ACE DD genotype. The ACE DD genotype is associated with increased ACE activity. The aim of the present study was to evaluate whether ACE activity per se may carry prognostic significance for subsequent left ventricular dilation as assessed by echocardiography during 1-year follow-up after acute MI., Methods and Results: Left ventricular end-systolic and end-diastolic volume indexes were assessed by two-dimensional echocardiography. In 102 consecutive patients, plasma ACE activity was determined 3.7 +/- 0.1 hours after the onset of MI. In 64 of these patients, left ventricular volume indexes obtained at baseline and 1 year after MI were used for the present analysis. Patients were divided ino a group having low ACE activity (< or = IU/L, n = 15) and a group having high ACE activity (> 12 IU/L, n = 49). Infarct size was a significant predictor of the increase in left ventricular volume indexes (P = .0001) in these patients. Multivariate regression analysis, after correction for infarct size, demonstrated that elevated plasma ACE activity is a significant predictor of the increase in left ventricular end-diastolic and end-systolic volume indexes (P = .0006 and P = .02, respectively) 1 year after MI., Conclusions: Elevated plasma ACE activity determined soon after the onset of MI may be a significant predictor of the development of left ventricular dilation and may identify patients at risk.

Utibapril is an angiotensin-converting enzyme (ACE) inhibitor with a proposed tissue-specific inhibitory profile. This implies that at a certain dose, utibapril should be able to inhibit tissue ACE activity without affecting plasma ACE. Moreover, if tissue ACE activity is rate limiting, functional conversion of angiotensin I should be decreased. Accordingly, we studied the dose-dependent effect of long-term treatment with utibapril on plasma and tissue ACE. Normal Wistar rats were randomly allocated to oral treatment with different doses of utibapril (0, 2, 10, 50, or 250 micrograms/kg/day) for 30 days. Tissue inhibition of ACE was assessed biochemically, whereas functional conversion of angiotensin I was determined in the isolated organ. Utibapril significantly inhibited plasma, renal, and vascular ACE but not ventricular ACE activity. Notably, however, only treatment with the highest dose of utibapril resulted in a significant inhibition of plasma ACE, whereas vascular ACE activity was already significantly inhibited after treatment with a lower dose of utibapril. In accordance, utibapril dose-dependently inhibited the contraction of isolated aortic rings to angiotensin I. Furthermore, angiotensin I-induced decreases in coronary flow in the isolated heart were significantly inhibited after treatment with the higher doses of utibapril. These data suggest the preferential inhibition of vascular ACE by utibapril in normal rats. Furthermore, the dose-dependent inhibition of the functional conversion of angiotensin I indicates that the tissue ACE activity may be rate limiting in vascular beds in rats.

The renin-angiotensin system has been implicated in vascular function and disease. Angiotensin-converting enzyme and angiotensin II are believed to be the most important components. However, alternative factors, such as angiotensin-I/II-(1-7) and chymase, have also been shown to be of significance in animal models. In this paper, we review some facts and provide additional proof for the functional significance of angiotensin-I/II-(1-7) and chymase in humans.

We hypothesized that angiotensin-converting enzyme (ACE) insertion/deletion polymorphism may be related to arterial phenotypic differences that could explain the adverse effects of deletion polymorphism. Accordingly, contractile responses to angiotensin I and II (0.1 nmol.1(-1)-1 micromol.1(-1), endothelium-dependent relaxation to methacholine (0.01-100 micromol.1(-1), and the effect of NG-monomethyl-L-arginine (L-NMMA; 100 micromol.1(-1) on phenylephrine (10 micromol.1(-1) induced contraction, were studied in isolated rings of internal mammary arteries obtained from patients undergoing coronary bypass surgery. The results were analysed according to the ACE genotype of the patient (II, n = 8; ID, n = 11; DD, n = 9) as well as the presence/absence of either allele. The arteries from patients with the D allele (ID/DD) displayed a lower sensitivity to methacholine (P < 0.05 vs II), which suggested that the capacity of the endothelium for nitric oxide release in response to stimulation was also lower. By contrast, the increase in phenylephrine-induced contraction, by pre-incubation with L-NMMA, was more pronounced in the group with the DD allele (31 +/- 5%) than with the ID (11 +/- 11%) and II alleles (1 +/- 11%, P < 0.05 vs DD), which suggested a higher level of basal nitric oxide release. Finally, the differences in the responses to angiotensin I and II, which were used to evaluate the vascular conversion of angiotensin I, indicated that the level of angiotensin I conversion was higher in patients with the D allele (ID/DD, P < 0.05 vs II). The findings of this study indicate that ACE insertion/deletion polymorphism is related to arterial phenotypic differences in endothelial function and angiotensin I conversion.

Objectives: This study sought to determine whether patients who are homozygous for the deletion (D)-type allele of the angiotensin-converting enzyme gene display augmented ventricular dilation after myocardial infarction., Background: Recent evidence suggests that the deletion-type allele of the angiotensin-converting enzyme gene (DD genotype) is associated with an increased prevalence of myocardial infarction and myocardial hypertrophy. However, it is unknown whether the DD genotype is associated with adverse cardiac remodeling. To address this question we determined the genotype in patients enrolled in the Captopril and Thrombolysis Study (CATS), a prospective trial in which patients received either captopril or placebo during and after thrombolysis for a first anterior myocardial infarction., Methods: Cardiac volume was determined by echocardiography immediately after thrombolysis and at 1-year follow-up. The genotype for the angiotensin-converting enzyme was determined in 96 patients. Norepinephrine levels were assessed during and immediately after thrombolysis., Results: Immediately after thrombolysis, cardiac volume did not differ between genotype groups. However, at 1-year follow-up, both end-systolic and end-diastolic left ventricular volumes were significantly greater in the DD-genotype group. Norepinephrine increased to higher levels in the DD-genotype group that received placebo therapy. Captopril treatment effectively blunted both the norepinephrine increase and cardiac dilation in the DD-genotype group., Conclusions: This exploratory study suggests that homozygosity for the angiotensin-converting enzyme deletion-type allele is associated with augmented neurohumoral activation as well as augmented cardiac dilation after an acute anterior myocardial infarction, an effect that may be susceptible to angiotensin-converting enzyme inhibition.