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(Circulation. 1996;94:258-265.)
© 1996 American Heart Association, Inc.

Articles

Angiotensin-Converting Enzyme Inhibition With Quinapril Improves Endothelial Vasomotor Dysfunction in Patients With Coronary Artery Disease

The TREND (Trial on Reversing ENdothelial Dysfunction) Study

G.B. John Mancini, MD; Gregory C. Henry, MS; Carlos Macaya, MD; Blair J. O'Neill, MD; Anthony L. Pucillo, MD; Ronald G. Carere, MD; Thomas J. Wargovich, MD; Harald Mudra, MD; Thomas F. Luscher, MD; Michael I. Klibaner, MD; Harry E. Haber, MPH; Andrew C.G. Uprichard, MD; Carl J. Pepine, MD; Bertram Pitt, MD

the University of British Columbia, Vancouver, British Columbia, Canada (G.B.J.M.); Parke-Davis Pharmaceutical Research, Ann Arbor, Mich (G.C.H., M.I.K., H.E.H., A.C.G.U.); Hospital Clinico Universitaro, Madrid, Spain (C.M.); Dalhousie University, Halifax, Nova Scotia, Canada (B.J.O.); Westchester County Medical Center, Valhalla, NY (A.L.P.); St Paul's Hospital, Vancouver, British Columbia, Canada (R.G.C.); University of Florida, Gainesville (T.J.W., C.J.P.); Klinikum Innenstadt der Universitat, Munchen, Germany (H.M.); Inselspital Bern, Switzerland (T.F.L.); and University of Michigan, Ann Arbor (B.P.).

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix References

 
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.

Key Words: angiotensin • coronary disease • endothelium-derived factors • acetylcholine

	Introduction

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Angiotensin-converting enzyme inhibitors can ameliorate the deleterious effects of elevated renin and angiotensin II levels in patients with hypertension, congestive heart failure, and acute myocardial infarction. Endothelial cells can synthesize their own tissue-based components of the renin-angiotensin system.^{1 2} The constrictive effect of tissue ACE via this locally generated angiotensin II and other endothelium-derived constrictive factors is normally counterbalanced by the primary endothelium-derived relaxing factor, nitric oxide.^{3 4} However, when the endothelium is damaged, the coronary arteries and resistance vessels lose the ability to fully vasodilate via this endothelium-dependent pathway.^{5 6} Endothelial dysfunction may be one of the first steps in the development of overt atherosclerosis.^{7 8 9 10 11} There is considerable evidence that human coronary arteries exhibit endothelium-mediated coronary vasodilatation, which is important pathophysiologically as well as clinically, and that this function is impaired in patients with coronary disease.^{12 13 14}

Animal studies of diet-induced or genetic models of hypercholesterolemia show that ACE inhibition plays a direct role in improvement of endothelial function.^{15 16} ACE inhibitors also inhibit the key cellular steps in intimal hyperplasia after balloon injury.¹⁷ The mechanisms that underlie the findings in animal studies and the postulated effects in humans are multifactorial. Inhibition of angiotensin II inhibits the inducement of hypertrophy and proliferation of vascular smooth muscle cells,^{18 19 20} stimulation of various growth-promoting agents,²¹ and generation of superoxide anion, which can degrade nitric oxide.²² Other potential antiatherosclerotic actions of ACE inhibitors include antagonism of macrophage function²³ and migration²⁴ in addition to inhibition of the sympathetic nervous system. Furthermore, ACE inhibition decreases the breakdown of bradykinin and thereby promotes release of nitric oxide, the key initial mediator of vasodilatory, antiaggregatory, and antiproliferative actions of the endothelium.^{25 26}

Quinapril hydrochloride is an ACE inhibitor characterized by a short accumulation half-life and potent binding affinity for both plasma and tissue ACE.^{27 28 29 30} The TREND study (Trial on Reversing ENdothelial Dysfunction) was undertaken to determine whether ACE inhibition by quinapril could ameliorate endothelial dysfunction in normotensive patients with coronary artery disease who were free of left ventricular dysfunction and severe dyslipidemia.

	Methods

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Population of Patients
One hundred and twenty-nine patients with documented coronary atherosclerosis were randomized in a double-blind manner to receive 6 months of oral quinapril (Accupril) 40 mg or placebo once daily after baseline assessment of endothelial dysfunction. Patient eligibility included single or double coronary artery disease (>50% diameter stenoses) that required a nonsurgical revascularization procedure (PTCA, atherectomy, stent, or laser) and one adjacent main coronary artery with <40% stenoses that had never been revascularized. This adjacent artery was designated as the target artery and exhibited endothelial dysfunction, defined as either a definite constrictive response (5% reduction in mean lumen diameter) or no response to acetylcholine (<5% change in mean lumen diameter).

Patients were excluded for the following reasons: vasodilation was seen in response to both acetylcholine challenges; a dominant right coronary artery was the only eligible target artery (because of possible induction of complete AV block by acetylcholine); age was >75 years; LDL cholesterol was >4.3 mmol/L (165 mg/dL); systolic blood pressure was >160 mm Hg and diastolic blood pressure was >90 mm Hg; history of coronary artery bypass grafting or coronary spasm; previous mechanical revascularization procedures within the previous 3 months; myocardial infarction within 7 days of randomization; left ventricular ejection fraction of <40%; type I diabetes mellitus; clinically significant hepatic or renal dysfunction; valvular heart disease; second- or third-degree AV block; or treatment with lipid-lowering agents within the previous 6 months. Patients with a history of hypertension were enrolled in the study only if their hypertension was fully controlled and their systolic and diastolic blood pressures were <160 mm Hg and <90 mm Hg, respectively.

Study Design
The protocol was approved by the Institutional Review Board of each center, and written informed consent was obtained from all patients. Patients discontinued all vasoactive medications except ß-blockers and sublingual nitrates at least 12 hours before the study. During catheterization, a 5F bipolar pacing catheter was positioned in the right ventricular apex and set in the demand mode at 10 bpm less than the baseline heart rate. During the initial catheterization, the target artery was identified and a baseline angiogram was taken. This was followed by two stepwise intracoronary infusions of acetylcholine of 10^-6 mol/L and 10^-4 mol/L delivered at 0.8 mL/min for 2 minutes through the guide or diagnostic catheters by use of a Harvard infusion pump or similar device. Careful attention was paid to the calculation of catheter dead space to ensure accurate delivery of acetylcholine to the coronary ostium. Angiography was repeated immediately after each infusion. A nitroglycerin bolus (range, 100 to 700 µg; mean, 206 µg) was then administered, followed by an angiogram identical to the one performed at baseline. This dose was not standardized because of the possibility that an occlusive response to acetylcholine or other adverse effects would be encountered. The intended goal was to ensure that the investigators could totally reverse any lingering effects of acetylcholine by ensuring maximal epicardial dilation with nitroglycerin.

All details of the catheterization and radiography were recorded to ensure duplication 6 months later. The patient then underwent the clinically indicated nonsurgical revascularization procedure. The patient was randomized and received the first dose of study medication within 12 to 72 hours. After 6 months, coronary angiography was repeated by use of identical baseline acetylcholine challenge procedures 76±2.4 hours (mean±SE) after the patient discontinued study medication. Patients also discontinued all vasoactive medications except ß-blockers or sublingual nitrates 12 hours before the challenges, as was done at baseline. In the event that a patient underwent a clinically necessary coronary angiogram <3 months after randomization, the angiogram with acetylcholine challenge was repeated at 6 months.

Quantitative Coronary Angiography
All films were analyzed in a blinded fashion at the University of British Columbia core angiographic laboratory by use of digital angiographic techniques described previously³¹ to compare luminal diameter and coronary endothelial reactivity. At least one boundary (proximal or distal) for each segment was referenced to a precise anatomic landmark, usually a branch origin, to aid in precise replication of segmental analyses at baseline and follow-up. The mean diameter of these segments was recorded from angiograms before acetylcholine infusions, after each infusion, and after nitroglycerin administration. Segment responses were calculated as a percent change in the mean diameter before and after the infusions. The core laboratory identified the target artery segment from the baseline angiogram by determining the segment that showed the worst endothelial dysfunction as defined above. Angiograms performed at 6 months were analyzed in the same way by use of views that were identical to the baseline study (see Figs 1 and 2). The core angiography laboratory also reviewed the procedure sheets and logs for the baseline and follow-up studies to ensure protocol adherence and replication of the radiographic conditions.

View larger version (136K): [in this window] [in a new window]   Figure 1. Response of a coronary target segment to acetylcholine (B) compared with the baseline study (A) before randomization. Results after 6 months of treatment with placebo are shown in C and D. A mild worsening of the constrictor response is evident.

Statistical Analysis
The hypothesis of the study was that treatment with quinapril for 6 months would result in improved endothelial function compared with placebo. A sample size of 108 patients was necessary to achieve 80% power to detect a 25% treatment effect with a two-sided 5% significance. The primary efficacy parameter was the net change in the acetylcholine-provoked percent constriction of the target segment between the baseline (prerandomization) and follow-up angiographic protocols. This was selected a priori because it provides a succinct indication of the effect of placebo or quinapril after the 6-month treatment period. The target segment was the segment in the target artery that exhibited the maximal constrictive response at baseline. The mean of the net percent change after 6 months was compared between the quinapril and placebo treatment groups. A 5% net change in segment response was used in categorical analyses to determine whether a given patient or segment improved or deteriorated during follow-up. Similarly, for a patient or segment to be designated categorically as a vasodilator or vasoconstrictor, the change had to be at least 5% from the preinfusion measurement in either direction, and this threshold was determined on an a priori basis. Data were analyzed by ANOVA and ANCOVA with repeated measures by use of the MIXED procedure of SAS.^{32 33} The baseline mean segment diameter served as a covariate. A secondary analysis of the primary efficacy parameter for all randomized patients was done by use of the method of Brown³⁴ to impute values for missing data. Categorical variables were analyzed by use of Mantel-Haenszel ² statistics that incorporated the study site as a stratifying variable. Analysis of all segments included an adjustment for the correlation among segments within a patient.³¹ Student's t tests and ² statistics were applied for baseline comparisons of patient characteristics. A logistic regression model was used to assess predictors of change in endothelial dysfunction. Secondary analyses based on all segments and analyses based on mean diameter responses were undertaken by use of one or more of these statistical methods, as described for the primary end point. All analyses were two-tailed, and a value of P.05 was considered significant. Results are presented as mean±SE.

	Results

Top Abstract Introduction Methods Results Discussion Appendix References

 
Baseline Patient Characteristics
A total of 129 eligible patients were randomized to quinapril (n=64) or placebo (n=65) within an average of 27 hours (range, 5 to 74 hours) after their coronary revascularization procedure. This cohort had left ventricular ejection fractions >40% and comprised 113 men and 16 women whose mean age was 58.6±1.3 years. All baseline characteristics were similar with the exception of a slightly lower systolic blood pressure in the quinapril group. Both values, however, were in the normotensive range (mean, 119 to 127 mm Hg). Of the 105 major coronary arteries chosen for study, 62 (59%) were circumflex, 40 (38%) were left anterior descending, and 3 (3%) were nondominant right coronary arteries. Mean baseline percent stenoses were 25%. Mean segment diameters were 2.0 to 2.2 mm. (See Table 1 for more information.)

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of Randomized Patients

Clinical Follow-up
After 5.9±0.1 months of therapy, 105 patients remained eligible for repeat catheterization and acetylcholine challenge. There were 13 quinapril patients and 11 placebo patients who withdrew before completing the study. Six of these 24 patients withdrew because of adverse events. Two placebo-treated patients had cardiovascular events (transient ischemic attack and fatal cardiac arrest secondary to ventricular fibrillation). Four quinapril-treated patients had the following adverse events: nonfatal anterior wall myocardial infarction; hypotension; blurred vision and rash; and dizziness, fatigue, and dyspepsia. The other 18 patients withdrew for lack of adherence to the protocol, for administrative or technical reasons during follow-up, or because of the patient's individual decision. The baseline characteristics of those 24 randomized patients who withdrew before completion of the study were similar to those who completed the study, except that the group that withdrew had a significantly higher proportion with a history of controlled hypertension (16 of 24 versus 60 of 129, respectively).

Table 2 shows key characteristics of the cohort that completed the protocol. The baseline and follow-up mean diameters of the segments were not different (mean values of 1.9 to 2.2 mm). There were also no differences in systolic or diastolic blood pressures, although the quinapril group showed an unanticipated and significant mean increase of 13.5 mm Hg (P=.014) after 6 months. Even so, both groups remained within the normotensive range. There were no significant differences in any of the lipid analyses. Evaluation of concurrent medications showed no difference between treatment groups.

View this table: [in this window] [in a new window]   Table 2. Comparison of Blood Pressure, Lipid Levels, and Coronary Segment Diameter in Patients Undergoing Assessment of Endothelial Function at Baseline and at Follow-up

Coronary Artery Vasomotor Function
At baseline, before randomization, the degree of acetylcholine-induced vasoconstriction in the target artery segment was similar in the placebo and quinapril groups. The initial infusion (10^-6 mol/L) caused an 5% constrictor response in both treatment groups, and the second infusion (10^-4 mol/L) caused a mean constrictor response of 9.4% and 14.3% in the placebo and quinapril treatment groups, respectively (P=NS). After 6 months, the placebo group had no change in responses, whereas the quinapril group showed significantly less constrictor response (1.6% and 2.3%) compared with the prerandomization response (6.1% and 14.3%; P<.014). In the quinapril group, responses expressed as net change from baseline (primary end point) improved by 4.5±3.0% and 12.1±3.0% at each acetylcholine dose, whereas the placebo group responses did not change (P<.002). These results remained significant even when baseline constrictive response at each dose level was used as a covariate (P=.003). Moreover, the results remained significant when patients who showed total occlusion at follow-up were excluded (P=.008) and when patients who showed total occlusion at either baseline or follow-up were excluded (P=.011). Finally, the secondary analysis that used imputed responses for randomized patients who did not complete the protocol was concordant with the primary analysis and showed a consistent trend across doses that favored quinapril (P=.015).

Furthermore, positive results were not restricted to the target segments. Responses in all segments paralleled those of the target segments (Table 3) and again, only the quinapril group showed improvements in the constrictor responses after 6 months. The difference in response between the placebo and quinapril groups was significant when based on either the 6-month assessment of percent change (P=.0004) or on the net change during follow-up (P=.018). The analyses of the response to the nitroglycerin bolus revealed no difference between treatment groups at baseline (P=.349) and no change at 6 months (P=.336).

View this table: [in this window] [in a new window]   Table 3. Response of Coronary Segments: Percent Change in Mean Diameter After Acetylcholine Infusions

Figs 1 and 2 show examples of coronary segments analyzed in the placebo and the quinapril groups. Fig 3 shows the net responses in the target segments (primary end point) and in all segments. Fig 3 underscores that the most dramatic differences were seen at the higher dose of acetylcholine. Even so, because the overall ANOVA indicates a lack of interaction between treatment and dose of acetylcholine, the differences between placebo and quinapril are consistent across the two dose levels. Figs 4 (target segments) and 5 (all segments) show the changes in mean segment diameter aggregated according to dose of acetylcholine. Both figures confirm that the abnormal responses in the placebo group were consistent at each dose of acetylcholine, the placebo group showed no improvements after 6 months, and the 6-month responses in the quinapril group at the 10^-4 mol/L dose of acetylcholine were improved compared with both the placebo group and the baseline response in the quinapril group. In addition, Fig 5 (all segments) shows that the quinapril group showed significant improvement compared with the placebo group, even at the lower-dose level of acetylcholine (P=.002).

View larger version (140K): [in this window] [in a new window]   Figure 2. Response of a coronary target segment to acetylcholine in a patient after 6 months of treatment with quinapril (format as for Fig 1). Note the constrictor response in the prerandomization studies (A and B) and the dilatory response at 6 months (C and D).

View larger version (26K): [in this window] [in a new window]   Figure 3. A, The primary efficacy parameter (net change in segment response after 6 months in the target segment, expressed as a percent ±SE, plotted on y axis) for two concentrations of acetylcholine (x axis). B, Analysis of all segments. Overall differences in response between the placebo and quinapril groups were significant for the target segment analysis (P=.002) and for all segments (P=.018). At the 10-4 mol/L dose, the difference between the placebo and quinapril groups was significant for both the target vessel analysis (P<.0003) and for all segments (P=.036).

View larger version (30K): [in this window] [in a new window]   Figure 4. Percent changes in mean segment diameter in the target segment in each group at baseline and follow-up. Data are grouped on the basis of the concentration of acetylcholine. At the 10-4 mol/L dose, the quinapril group shows improvement (overall P=.0003). The constrictor response within the quinapril group at this dose level is also significantly improved (P<.0001), as is the difference in follow-up constrictive responses between the placebo and quinapril groups (P<.001).

View larger version (33K): [in this window] [in a new window]   Figure 5. Percent changes in mean segment diameter in all segments (same format as Fig 4). The results are concordant with the analyses demonstrated in Fig 4. In addition, there was significantly less constriction after 6 months in the quinapril group than in the placebo group, even at the lower concentration of acetylcholine.

Frequency of Categorical Responses to Acetylcholine Infusions
The most extreme response to acetylcholine infusion is abrupt and total occlusion. At 6 months, this extreme response was rare, but there was a trend for this response to be seen more frequently in the placebo group compared with the quinapril group (9.3% versus 2.0%; P=.131; Table 4). A 5% improvement in response was significantly more common in the quinapril group in the target segments (53% versus 28%; P=.008) and nearly significant in all segments (37% versus 27%; P=.056). In contrast, fewer segments in the quinapril-treated group showed a >5% deterioration in response to acetylcholine (24% versus 32%; P=.369). In the primary target segments, this beneficial trend was in the same direction, 10% versus 24% (P=.117). At baseline, a subset of patients (n=83) exhibited vasoconstriction at both acetylcholine doses. At follow-up, 7.1% of the placebo group compared with 22% of the quinapril group (P=.022) exhibited complete reversal of vasoconstriction, ie, a vasodilatory response at both doses. For all segments, the results trended in the same way but did not reach significance (11.8% versus 20.2%, P=.102).

View this table: [in this window] [in a new window]   Table 4. Frequency of Categorical Responses to One or Both Acetylcholine Infusions*

Predictors of Improved Endothelial Function
A logistic regression model was used to identify predictors of improvement in endothelial function, defined as >5% net improvement during the 6-month follow-up. All clinical characteristics (Table 1) as well as the baseline response to acetylcholine were included in the analysis. Variables associated with a value of P<.10 were then subjected to a stepwise regression model. The only independent predictor was assignment to quinapril (P=.022). Improved endothelial function was not associated with smoking status, stenosis severity, blood pressure, sex, initial response to acetylcholine, lipid values, or any factor other than therapy with quinapril.

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix References

 
Our results indicate that 6 months of therapy with quinapril, an ACE inhibitor with high tissue-binding affinity, attenuates impaired endothelial vasomotor function in normotensive patients with coronary artery disease, preserved left ventricular function, and minimal or mild dyslipidemia. This time frame is similar to the treatment effect on endothelial dysfunction observed with DL-3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors with or without antioxidants.^{35 36} Indeed, although acute infusions of quinapril have been shown to stimulate nitric oxide–induced vasodilation in the forearms of hypertensive patients,³⁷ TREND demonstrates sustained amelioration even after cessation of oral therapy for 72 hours.

Endothelial dysfunction is an early manifestation of vascular injury, mediated to some degree by elevated levels of plasma and tissue angiotensin II. Recent long-term studies with ACE inhibitors in patients with decreased left ventricular function^{38 39} have shown a decrease in cardiac ischemic events. One pathogenic factor common to both heart failure and ischemic heart disease is endothelial damage or activation. This dysfunction is thought to disrupt normal vasomotor tone in numerous ways. It may potentiate the effect of the endothelium-derived constrictive factor endothelin-1, recognized as one of the most potent endogenous vasoconstrictors.^{40 41} Increased angiotensin II levels appear to induce endothelin activation. This activation also facilitates the conversion of angiotensin I to angiotensin II, acting as a feedback mechanism that promotes further vasoconstriction.^{42 43} Furthermore, angiotensin II has been shown to stimulate the NADH/NADPH oxidases of smooth muscle cells, which leads to increased generation of superoxide anions that can degrade nitric oxide.²⁰ Bradykinin degradation via the potent effect of ACE also increases vasoconstriction by diminishing the formation and/or actions of the endothelium-derived relaxant nitric oxide.⁴⁴ Fibrinolytic activity may also be impaired through generation of plasminogen activator inhibitor-1 (PAI-1).^{45 46} These increased PAI-1 levels may facilitate thrombus formation and further activate the endothelium.⁴²

Thus, the improvement shown by quinapril may be mediated through multiple mechanisms. The most important mechanisms, on the basis of results of this 6-month trial, are probably related to the effects of ACE inhibitors on both angiotensin II and bradykinin. Inhibition of the generation of angiotensin II will attenuate smooth muscle cell contraction and will also attenuate the generation of superoxide anions through stimulation of the NADH/NADPH oxidase systems of the smooth muscle cell.²⁰ Conceivably, this may lead to less inactivation of nitric oxide. Furthermore, bradykinin breakdown is inhibited by ACE inhibitors, and bradykinin-induced augmentation of nitric oxide release by the endothelial cell is promoted thereby.

The attenuation of endothelial dysfunction by ACE inhibition may help to explain the beneficial effects of ACE inhibitors in reducing the number of ischemic events and the need for revascularization in the SAVE and SOLVD studies.⁴⁷ Although the beneficial effects reported in these two studies could be attributed in part to a reduction in the extent of left ventricular dysfunction, the value of the present study is the demonstration that a beneficial effect of ACE inhibitors on endothelial dysfunction can be seen even in patients without left ventricular dysfunction. Accordingly, ACE inhibition therapy may have a role to play in the treatment of angina pectoris and silent myocardial ischemia or in reduction of the incidence of myocardial ischemia and the need for revascularization in patients without left ventricular dysfunction, since endothelial dysfunction is thought to be of importance early in the development of atherosclerosis and in the pathophysiology of both symptomatic and asymptomatic myocardial ischemia. In fact, this hypothesis is being tested in the QUinapril Ischemic Event Trial (QUIET),⁴⁸ a 3-year, randomized, double-blind, placebo-controlled trial to assess the ability of quinapril to reduce ischemic events in patients with established coronary artery disease and preserved left ventricular function. It is not known whether the lipophilicity and tight tissue binding²⁹ to vascular ACE receptors render quinapril uniquely capable of improving endothelial function in coronary patients without concomitant illnesses. Consequently, other ACE inhibitors will require further testing. Nevertheless, TREND is the first randomized, double-blind, placebo-controlled, clinical trial to provide a new, pathophysiological rationale for the use of ACE inhibitors to attenuate endothelial dysfunction in patients with coronary artery disease and without left ventricular dysfunction. These benefits were shown in the absence of changes in lipids or reductions in blood pressure.

	Appendix

Top Abstract Introduction Methods Results Discussion Appendix References

 
The following persons and study centers participated in the TREND study: H. Mudra, V. Klauss, K. Theisen (Klinikum Innenstadt der Universitat, Munchen, Germany); C. Pepine, T. Wargovich, T. Huber, D. Leach (University of Florida, Gainesville); L. Schwartz, C. Lazzam, J. Richards (The Toronto Hospital, Ontario, Canada); G. Timmis, W. O'Neill, C. Tollis, M. Gregory (William Beaumont Hospital, Royal Oak, Mich); A. Pucillo, D. Katz, M. Weiss, A. Kanakaraj, J. Reisch (Westchester County Medical Center, Valhalla, NY); R. Feldman, M. Standley, L. Craggs (Ocala [Fla] Heart Institute); P. Gilmore, T. Bass, G. Rohman, R. Wofford (University of Florida, Jacksonville); B. O'Neill, C.J. Foster, C. Peck, N. Fitzgerald, K. Foshay (Victoria General Hospital, Halifax, Nova Scotia, Canada); A. Dodek, J. Webb, R. Carere, M. Wilson (St Paul's Hospital, Vancouver, British Columbia, Canada); J.F. Marquis, L. Garrard, H. Dowell, H. Martin (University of Ottawa Civic Hospital, Ontario, Canada); C. Macaya, J. Goicolea, D. Alarcon (Hospital Clinico Universitario, Madrid, Spain); M. Knudtson, K. Hildebrand (Foothills Hospital, Calgary, Alberta, Canada); T. Luscher, B. Meier (Inselspital Bern, Switzerland); and R. Heuser, L. Hill, K. Waters, M. Kaluzniak (Arizona Heart Institute, Phoenix).

	Acknowledgments

 
The authors gratefully acknowledge Ester Leung, Eunice Yeoh, and Joseph Li for their expertise in the angiographic measurements; Karen Brown, Lynne Nibert, and Jenny Cromarty for help in manuscript preparation; Michele Texter and Susan Berman for editorial assistance; the Clinical Research Associates of Parke-Davis Research and Pharmaceutical Research Associates, Inc for their diligence; and the catheterization laboratory personnel and clinical coordinators of the participating centers whose enthusiasm, determination, and hard work made this study a reality. This study was supported by a grant from Parke-Davis Pharmaceutical Research.

	Footnotes

 
Reprint requests to G.B. John Mancini, MD, Vancouver Hospital and Health Sciences Centre, Room 3300, Laurel Pavilion, 950 W 10th Ave, Vancouver, British Columbia, Canada V5Z 4E3. E-mail jcromart@vanhosp.bc.ca.

Received January 3, 1996; revision received March 13, 1996; accepted March 13, 1996.

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