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The QUO VADIS (the effects of QUinapril On Vascular Ace and Determinants of ISchemia) study was a randomized, double-blind, placebo-controlled trial designed to evaluate the effects of long-term angiotensin-converting enzyme (ACE) inhibition on angiotensin II formation in human vasculature. Patients (n = 187) scheduled for coronary artery bypass surgery used study medication 27 +/- 1 days before surgery. Segments of internal mammary arteries were exposed to increasing doses (0.1 nM-1 microM) of angiotensin I and II in organ baths. The rate of local angiotensin II formation is a function of the reciprocal of the difference between the pEC50's of the dose response curves to angiotensin I and II (-log/mol) and of the area between the curves (units). Quinapril (40 mg) and captopril (3 x 50 mg) similarly and significantly reduced mean blood pressure compared with placebo (p = 0.04). Difference between pEC50's was 0.90 +/- 0.08 in quinapril patients compared with 0.60 +/- 0.08 for placebo (p = 0.01); the area between curves was 91 +/- 8 for quinapril patients compared with 67 +/- 8 for placebo (p = 0.03). Angiotensin II formation was decreased to a lesser extent with captopril and was not statistically different from placebo (p = 0.3); the difference between pEC50's was 0.83 +/- 0.15; the area between curves was 84 +/- 12. This is the first randomized study to demonstrate that long-term oral treatment with an ACE inhibitor reduces vascular angiotensin II formation in humans.

Background: Cigarette smoking is a major risk factor for developing coronary artery disease and is associated with increased coronary morbidity and mortality in patients with established atherosclerosis. This report describes the influence of smoking on coronary endothelial function in normotensive patients with coronary artery disease, but without left ventricular dysfunction, severe hypercholesterolemia, or insulin-dependent diabetes mellitus. Methods: Placebo-treated patients (n = 54) from a larger study assessing coronary endothelial function were classified at baseline as smokers or nonsmokers for this subgroup analysis. Patients underwent coronary angiography at baseline and again after 6-month follow-up. Results: At baseline, there was a trend for a greater decrease in target segment diameter (n = 54) in smokers compared with nonsmokers (- 17.2 ± 5.3% vs. -8.0 ± 2.5%, acetylcholine 10−4 mol/1). All measured coronary artery segments (n = 202) showed similar responses (- 7.3 ± 2.7% vs. - 3.8 ± 1.3%, acetylcholine 10−4 mmol/1, for smokers vs. nonsmokers, respectively). After 6 months, smokers showed an even greater vasoconstrictor response to acetylcholine whereas nonsmokers did not (- 21.7 ± 5.3% vs. - 8.3 ± 2.5%, acetylcholine 10−4 mmol/1). The vasodilatory response to nitroglycerin was similar in smokers and nonsmokers. Conclusions: In current smokers, a marked decline in endothelium-dependent vasomotor response was observed over a 6-month period.

This pilot study investigated the efficacy of high-dose gemfibrozil (2400 mg/day) in treating patients with elevated lipoprotein (a) [Lp(a)]. Lp(a) has been shown to be an independent risk factor for the development of coronary heart disease (CHD).Eleven patients with serum Lp(a)/=45 mg/dl participated in this 12-week study. Initially, all patients received oral gemfibrozil 600mg twice daily. At 4-week intervals, the dose was increased by 600mg for patients able to tolerate the increase up to a maximum of 2400 mg/day.Eight patients completed the study. Three of these patients met the predetermined criterion of a clinically meaningful Lp(a) reduction of 33%. The mean percentage change in Lp(a) was not statistically significant with values of -18.3 +/- 15.4% (p = 0.14, 1-tailed). All patients demonstrated a significant decrease in plasma triglycerides. The mean percentage change was -62.5 +/- 1.8% (p0.001, 1-tailed). The mean percentage change in total cholesterol was -12.4 +/- 3.8% (p = 0.007, 1-tailed). Gemfibrozil was considered suspect in five of 16 adverse events reported, but only one of these (dyspepsia) caused withdrawal from the study. For all patients participating in the study no adverse event was characterised as severe.While the small number of patients does not allow any definitive conclusion on effectiveness to be drawn, the results suggest that further randomised studies utilising larger patient numbers appear warranted.

This pilot study evaluates the effects of quinapril, an angiotensin-converting enzyme inhibitor with high tissue-binding affinity, on microvascular endothelial function in patients with mild (

Several clinical trials have shown that reducing serum cholesterol levels retards the progression of coronary atherosclerosis assessed by serial angiography. By contrast, as yet no studies have addressed the impact of increasing high density lipoprotein (HDL) cholesterol levels on progression of coronary artery disease (CAD). As HDL cholesterol is inversely related to the risk of CAD, we hypothesize that an intervention that raises low HDL cholesterol concentrations may have a beneficial effect on the course of CAD. Lopid Coronary Angiography Trial (LOCAT) was designed to test this hypothesis. Three hundred and ninety-five men, aged ⩽ 70 years, all of whom had previously undergone coronary bypass surgery, were randomly assigned to receive either slow-release gemfibrozil, 1200 mg once daily, or a matching placebo for on average 2 1 2 years. The lipid inclusion criteria were HDL cholesterol concentration ⩽ 1.1mmol/L, low density lipoprotein (LDL) cholesterol ⩽ 4.5 mmol/L, and serum triglyceride ⩽ 4.0 mmol/L. Subjects were not accepted if they had manifest diabetes, body mass index > 30 kg/m2, uncontrolled hypertension, or if they were regular smokers. All randomized subjects underwent baseline coronary angiography, which will be repeated at the end of the study. The angiograms will be analyzed using the Cardiovascular Measurement System, a validated computer-assisted image-analysis and quantitation package. The primary endpoints are the changes in the per-patient mean of 1) the average diameter of evaluable native coronary segments, and 2) the minimal luminal diameter of evaluable stenoses, and 3) the appearance of new lesions. Extensive lipoprotein and other metabolic studies and analyses of genetic polymorphisms are carried out to study the determinants of CAD progression. At baseline, the study subjects were 59.1 ± 6.8 (mean ± standard deviation) years old, had a body mass index 26.4 ± 2.2 kg/m2, and serum triglyceride, serum cholesterol, HDL cholesterol, and LDL cholesterol concentrations 1.64 ± 0.64, 5.17 ± 0.64, 0.82 ± 0.14, and 3.61 ± 0.53 mmol/L, respectively.

Abstract This 6-week, double-blind clinical trial evaluated lipid parameter responses to different dosages of atorvastatin in patients with primary hypercholesterolemia. Atorvastatin is a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor under development. After completing an 8-week placebo-baseline dietary phase, 81 patients were randomly assigned to receive either placebo or 2.5, 5, 10, 20, 40, or 80 mg atorvastatin once daily for 6 weeks. Plasma LDL cholesterol reductions from baseline were dose related, with 25% to 61% reduction from the minimum dose to the maximum dose of 80 mg atorvastatin once a day. Plasma total cholesterol and apo B reductions were also dose related. Previously, reductions in LDL cholesterol of the magnitude observed in this study have been seen only with combination drug therapy. In this study, atorvastatin was well tolerated by hyperlipidemic patients, had an acceptable safety profile, and provided greater reduction in cholesterol than other previously reported HMG-CoA reductase inhibitors.

Angiotensin-converting enzyme inhibitors improve endothelial function, inhibit experimental atherogenesis, and decrease ischemic events. The Quinapril Ischemic Event Trial was designed to test the hypothesis that quinapril 20 mg/day would reduce ischemic events (the occurrence of cardiac death, resuscitated cardiac arrest, nonfatal myocardial infarction, coronary artery bypass grafting, coronary angioplasty, or hospitalization for angina pectoris) and the angiographic progression of coronary artery disease in patients without systolic left ventricular dysfunction. A total of 1,750 patients were randomized to quinapril 20 mg/day or placebo and followed a mean of 27 +/- 0.3 months. The 38% incidence of ischemic events was similar for both groups (RR 1.04; 95% confidence interval 0.89 to 1.22; p = 0.6). There was also no significant difference in the incidence of patients having angiographic progression of coronary disease (p = 0.71). The rate of development of new coronary lesions was also similar in both groups (p = 0.35). However, there was a difference in the incidence of angioplasty for new (previously unintervened) vessels (p = 0.018). Quinapril was well tolerated in patients after angioplasty with normal left ventricular function. Quinapril 20 mg did not significantly affect the overall frequency of clinical outcomes or the progression of coronary atherosclerosis. However, the absence of the demonstrable effect of quinapril may be due to several limitations in study design.

OBJECTIVESTo determine the effect of angiotensin-converting enzyme (ACE) inhibition on brachial flow-mediated vasodilation.BACKGROUNDQuinapril, an ACE inhibitor with high affinity, has been shown to improve coronary endothelial dysfunction in patients with coronary artery disease. The effectiveness of different vasoactive agents to improve human endothelial function is unknown.METHODSHigh resolution ultrasound was used to assess endothelium-dependent brachial artery flow-mediated vasodilation (FMD) in patients with coronary disease. We studied 80 patients (mean age 58 ± 0.9 years) in a partial-block, cross-over design trial. Patients were randomized to one of four different drug sequences to receive quinapril 20 mg, enalapril 10 mg, losartan 50 mg or amlodipine 5 mg daily. Each patient received three drugs with a two-week washout period between treatments. The primary end point was the absolute difference in FMD after eight weeks of each study drug compared with their respective baselines analyzed in a blinded fashion.RESULTSThere was mild impairment of FMD at baseline (7.3 ± 0.6%). The change in FMD from baseline was significant only for quinapril (1.8 ± 1%, p < 0.02). No change was seen with losartan (0.8 ± 1.1%, p = 0.57), amlodipine (0.3 ± 0.9%, p = 0.97) or enalapril (−0.2 ± 0.8%, p = 0.84). No significant change in nitroglycerin-induced dilation occurred with drug therapy. The improvement in quinapril response was not seen in those with the DD ACE genotype (0.5 ± 2.1%) but was seen in those with the ID and II genotype (3.3 ± 1.2 and 3.2 ± 1.9%, respectively, p = 0.03).CONCLUSIONOnly quinapril was associated with significant improvement in FMD, and this response is related to the presence of the insertion allele of the ACE genotype.

Background Angiotensin-converting enzyme (ACE) inhibitors may exert some of their benefits in the therapy of hypertension, congestive heart failure, and acute myocardial infarction by their improvement of endothelial dysfunction. TREND (Trial on Reversing ENdothelial Dysfunction) investigated whether quinapril might improve endothelial dysfunction in normotensive patients with coronary artery disease and no heart failure, cardiomyopathy, or major lipid abnormalities so that confounding variables that affect endothelial dysfunction could be minimized. Methods and Results Using a double-blind, randomized, placebo-controlled design, we measured the effects of quinapril (40 mg daily) on coronary artery diameter responses to acetylcholine using quantitative coronary angiography. The primary response variable was the net change in the acetylcholine-provoked constriction of target segments between the baseline (prerandomization) and 6-month follow-up angiograms. The constrictive responses to acetylcholine were comparable in the placebo (n=54) and quinapril (n=51) groups at baseline. After 6 months, only the quinapril group showed significant net improvement in response to incremental concentrations of acetylcholine (4.5±3.0% [mean±SEM] versus −0.1±2.8% at 10 − 6 mol/L and 12.1±3.0% versus −0.8±2.9% at 10 − 4 mol/L, quinapril versus placebo, respectively; overall P =.002). Conclusions TREND shows that ACE inhibition with quinapril improved endothelial dysfunction in patients who were normotensive and who did not have severe hyperlipidemia or evidence of heart failure. These benefits of ACE inhibition are likely due to attenuation of the contractile effects and superoxide-generating effects of angiotensin II and to enhancement of endothelial cell release of nitric oxide secondary to diminished breakdown of bradykinin.