1. Program Outline
Content Points:
This program provides an overview of the following topics:
The renin-angiotensin system and tissue angiotensin-converting enzyme (ACE): Effects on endothelial function
Vasculoprotective effects of tissue ACE inhibition
Trials of ACE inhibitors with good tissue potency in patients with coronary artery disease (CAD) and normal left ventricular (LV) function: TREND, BANFF, QUO VADIS, QUIET, and HOPE
The implications of the tissue ACE trials for medical decision-making: Impact that tissue-ACE avidity of ACE inhibitors may have on clinical outcomes

2. Causes and consequences of endothelial dysfunction: A unifying model
Content Points:
A dramatic increase in knowledge has established (1) the central role of the endothelium in cardiovascular health and disease, and (2) the importance of tissue ACE in mediating endothelial function and cardiovascular disease processes.1
Cardiovascular risk factors such as dyslipidemia, hypertension, diabetes, and smoking can cause physiological and vascular changes, which affect the endothelium and lead to cardiovascular disease.2
One of the earliest changes is an increase in oxidative stress causing endothelial cells to decrease production of some vasoactive substances and increase production of others.
Oxidative stress and impaired endothelial function are associated with decreases in nitric oxide (NO) and increases in local mediators and tissue ACE, leading to an upsurge in angiotensin II (A II).
These changes in the endothelium promote vasoconstriction, inflammation, thrombosis, vascular remodeling, and plaque rupture, potentially leading to acute coronary syndromes.
The potential role of endothelial dysfunction for predicting long-term risk of cardiovascular events in patients with CAD will be discussed on the following slide.

3. Endothelial function predicts cardiovascular events: 5-year follow-up in angina patients
The ability of endothelial function to predict long-term risk for cardiovascular events was studied in 73 patients with angina pectoris who were admitted to a hospital for coronary angiography to evaluate chest pain.3
Patients underwent brachial artery ultrasound to measure flow-mediated dilation (FMD) as an indicator of endothelial function at the start of the study. This slide summarizes the incidence of cardiovascular events in patients with normal vs impaired endothelial function during a 5-year follow-up.
Patients with normal endothelial function (FMD > 10%, n = 27) and patients with endothelial dysfunction (FMD < 10%, n = 46) differed in their cardiovascular outcomes.
Significantly more patients with endothelial dysfunction required coronary revasularization: coronary angioplasty, 7% versus 37%, P = .03; coronary bypass grafting (CABG), 0% versus 15%, P = .009.
Patients with endothelial dysfunction had a 20% incidence of myocardial infarction (MI) compared with 11% in the group with normal endothelial function. The difference was not statistically significant, which the authors attributed to the low incidence of MI (12 cases) during follow-up.
In forecasting all cardiac events, impaired FMD had an 86% sensitivity and a 93% negative predictive value.
Endothelial dysfunction was found to be an independent predictor of cardiac events. In patients with a high pretest probability of CAD, measurements of FMD can be used to predict risk of long-term cardiac events.

4. Role of ACE and ACE inhibition
ACE plays a critical role in maintaining a balance between vasoconstriction and growth promotion, and vasodilation and growth inhibition.
ACE catalyzes the production of angiotensin I (A I) to A II, a potent vasoconstrictor. Increases in A II promote the release of other vasoconstrictors including endothelium-derived constricting factor and endothelin. A II also mediates production of plasminogen activator inhibitor 1 (PAI-1), which encourages vascular thrombosis.4,5
ACE is the principle enzyme invloved in the breakdown of bradykinin, a vasoactive substance that stimulates production of NO, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF), which are potent vasodilators.
As this slide shows, ACE inhibitors interfere with the conversion of A I to A II, reducing vasoconstriction and potentially negative effects on the fibrinolytic system. ACE inhibitors also interfere with the breakdown of bradykinin, leading to greater production of NO and other vasodilators and increased vasodilation.

5. Circulating vs tissue ACE
Recognition of the importance of tissue ACE began with the identification of 2 renin-angiotensin systems (RAS) functioning in 2 different environments and affecting cardiovascular health and disease.
The circulating RAS has an endocrine effect and regulates acute blood pressure and hemodynamics. The tissue RAS has an autocrine/paracrine effect and influences long-term changes in vascular structure and function.
Over 90% of ACE is expressed locally in the tissue, primarily in the vascular wall, but also in the heart, kidney, and brain; less than 10% of ACE circulates in the plasma.5
The tissue RAS and tissue ACE affect the vasculature by local regulation of vasoactive substances in the endothelium.6

6. Vasculoprotective effects of tissue ACE inhibition
ACE inhibitors reduce cardiovascular risk through cardioprotective and vasculoprotective effects by blocking both the circulating and tissue RAS; this decreases the production of A II and promotes accumulation of bradykinin, which increases NO production.7-9
The vasculoprotective and antiatherogenic effects of ACE inhibition include the reduction of vascular smooth muscle cell proliferation and migration.
ACE inhibition exerts antithrombotic effects and protects from plaque rupture by decreasing platelet aggregation and PAI-1 levels, inhibiting matrix synthesis, increasing t-PA levels, and decreasing inflammation and monocyte adhesion.

7. JNC VI guidelines: Compelling indications and treatment choices for hypertension therapy
Major clinical trials have been important in the development of the latest Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VI) hypertension treatment guidelines.9 The guidelines specify initial drug choices based on both the severity of hypertension and the presence of comorbid conditions and complications.
For people with hypertension and diabetes, appropriate drug classes include ACE inhibitors, calcium antagonists, and diuretics given in low doses. Based on recent data from ALLHAT (Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial) the use of a-blockers as initial therapy can no longer be recommended.10 Despite lowering blood pressure, a-blocker doxazosin was much less beneficial than diuretic therapy on cardiovascular outcomes in hypertensive patients.
For people with type 2 diabetes, proteinuria, and hypertension, ACE inhibitors are the preferred treatment.
Patients with hypertension and heart failure should be treated with ACE inhibitors and diuretics.
Elderly patients with isolated systolic hypertension should be preferentially treated with diuretics, but they may also be treated with calcium channel blockers, specifically long-acting dihydropyridines.
Patients with a history of MI should receive ACE inhibitors if they have systolic dysfunction; for those with normal systolic function, b-blockers are satisfactory.
The clinical trials of ACE inhibitors in patients with CAD and LV dysfunction paved the way for more recent studies in patients with CAD and normal LV function. These trials will be discussed in the following slides.

8. Tissue ACE trials in patients with CAD and preserved LV function
Over the past few years, investigators have conducted a series of important trials of ACE inhibitors with good tissue potency, including TREND (Trial on Reversing ENdothelial Dysfunction), BANFF (Brachial Artery Normalization of Forearm Function), QUO VADIS (effects of Quinapril on Vascular ACE and Determinants of Ischemia), QUIET (Quinapril Ischemic Events Trial), and HOPE (Heart Outcomes Prevention Evaluation).
These trials evaluated the efficacy of the newer more tissue-avid ACE inhibitors in patients with CAD and preserved left ventricular function to determine their ability to improve endothelial function and influence cardiovascular outcomes.
These trials are reviewed in the upcoming slides.

9. Relative avidity of ACE inhibitors in plasma and tissue
In pharmacologic studies, ACE inhibitors have been shown to vary considerably in binding affinity for tissue ACE.11-14
Among the new of group of tissue-avid ACE inhibitors, quinapril, with quinaprilat as its active metabolite, possesses the highest affinity for ACE in both tissue and plasma.
Tissue ACE and the endothelium appear to play an important role in the development of atherosclerosis. It seems plausible that differences among agents in tissue ACE-binding affinity might translate into differential clinical responses.

10. TREND: Endothelial function and ACE inhibition
TREND was a 6-month study in 129 adults with CAD and normal left ventricular function to assess the effect of quinapril on impaired endothelial function in epicardial coronary arteries.15
To measure endothelial function, investigators used serial intracoronary acetylcholine and intracoronary angiography. The normal response to acetylcholine is vasodilation, but patients with atherosclerosis respond with inappropriate vasoconstriction. By giving different interventions and measuring patients’ responses, investigators can determine the effect of a particular intervention on coronary artery vasomotion.
This slide summarizes the results for the primary end point of TREND: net change in diameter of the target segment after 6 months of treatment.
The vasodilatory response in target segments was significantly greater with quinapril than with placebo; the investigators believed this represented improved endothelial function.
The overall net increase in target segments was significantly greater with quinapril than with placebo (P = .002). The difference in vasodilatory response between quinapril and placebo was even more striking at the higher acetylcholine dose (P < .0003).
The TREND investigators concluded that ACE inhibition with quinapril significantly improves endothelial function in epicardial coronary arteries in patients with minimal nonobstructive coronary disease.

11. BANFF: Absolute changes in FMD
The BANFF trial compared the effect of 4 widely used vasoactive agents on endothelial function in 80 patients with CAD and preserved left ventricular function.16
Patients with CABG, uncontrolled hypertension, dyslipidemia, cigarette smoking, and those receiving lipid-lowering therapy were excluded from the study.
Treatment included the ACE inhibitors quinapril 20 mg/day (n = 56) or enalapril 10 mg/day (n = 55), the angiotensin-receptor blocker losartan 50 mg/day (n = 38), and the calcium channel antagonist amlodipine 5 mg/day (n = 45). Patients took 3 drugs for 8 weeks each, separated by a 2-week washout period. Doses were chosen because they reduced BP similarly.
Endothelial function was evaluated by measuring reactive hyperemia to determine FMD changes of the brachial artery.
Of the 4 agents, only quinapril produced a significant improvement in FMD.
The results suggest that ACE inhibitors, as well as other commonly used vasoactive agents, differ in their effectiveness at improving endothelial function.

12. QUO VADIS: Effects of quinapril on ischemia
QUO VADIS was a two part study involving patients with CAD and preserved LV function who were undergoing CABG. In part 2 of QUO VADIS, shown here, 149 patients were randomized to treatment with quinapril or placebo. The study medication was used for up to 1 year post CABG.17
The investigators evaluated patients with exercise testing, Holter monitoring, and considered data on clinical ischemic events, including recurrence of angina pectoris, MI, ischemic stroke, or transient ischemic attack.
Total exercise duration was comparable between the quinapril and placebo groups.
48-hour Holter (continuous ECG) monitoring showed a nonsignificant trend toward reduced ischemic events in the quinapril versus placebo groups (13% versus 20%, respectively).
After CABG patients receiving quinapril had a significant 80% reduction in ischemic events compared with placebo (P = .03).
These results suggest that long-term tissue ACE inhibition reduces ischemic events in post-CABG patients. The proposed causes for the reduction in ischemic events with quinapril include improved plaque stability, improved endothelial function, or therapeutic angiogenesis.
In the first part of QUO VADIS (not shown here), preoperative treatment with quinapril, but not captopril or placebo, blocked conversion of angiotensin I to A II in vascular segments removed at surgery.18 This effect on A II, as well as improved vascular responses in patients, suggests that there are functional differences between the two drugs.

13. QUIET: Cardiac death, nonfatal MI, or VT/VF
QUIET investigated the effects of ACE inhibition on plaque regression and clinical outcome in patients with coronary artery disease and normal LV function.19
QUIET enrolled 1750 low-risk patients 12 to 72 hours after revascularization.
Patients enrolled in QUIET received 20 mg quinapril daily or placebo. Follow up was 3 years.
The results revealed no significant differences between the quinapril and placebo groups in combined ischemic events; however, the group that received quinapril showed a trend toward a reduction in cardiac deaths, nonfatal MI, and resuscitated cardiac arrest.20
The angiographic effects of quinapril were neutral, based on follow-up angiography in about 30% of the patients.
Analyses of the data suggested that the unanticipated low rate of events resulted in the study being underpowered and precluded a definitive conclusion.

14. QUIET: Effect of quinapril on CAD progression according to LDL-C level
A subanalysis of the QUIET data indicates that the beneficial effects of quinapril on atherosclerosis may be related to low density lipoprotein cholesterol (LDL-C) levels.21
In patients with elevated LDL-C (> 130 mg/dL), quinapril assignment was associated with no progression of atherosclerosis.
In contrast, the progression of atherosclerosis continued in the patients with higher LDL-C levels who received placebo.

15. HOPE: Scope of the trial
HOPE was a randomized trial lasting 4.5 years to investigate the preventive use of the tissue ACE inhibitor ramipril 10 mg daily in patients with CAD and preserved LV function.22
The study included 9297 high-risk patients 55 years of age or older with a history of CAD, stroke, peripheral vascular disease, or diabetes plus 1 other cardiovascular risk factor (hypertension, elevated total cholesterol, low high density lipoprotein cholesterol, smoking, or microalbuminuria).
Patients with heart failure or low ejection fractions (< 40%), or currently on ACE inhibitor or vitamin E therapy were excluded.
Treatment included ramipril 10 mg daily or placebo ± vitamin E 400 mg.
The study duration was 5 years, but the ramipril arm was discontinued early (4.5 years) because the beneficial effect of ramipril was clearly evident.
Primary outcome measure was a composite of MI, stroke, and death from cardiovascular causes. These end points was also analyzed separately.
Secondary outcome measures were death from any cause, need for revascularization, hospitalization for unstable angina or heart failure, and diabetic complications.
Other outcome measures were worsening angina, cardiac arrest, heart failure, unstable angina and electrocardiogram changes, and development of diabetes.

16. HOPE: Risk reduction with ACE inhibition
Results of the HOPE trial show that treatment with ramipril 10 mg daily significantly reduced the combined occurrence of death, MI, and stroke by 22% compared with placebo (P < .001).19
There were significant risk reductions for cardiovascular death (25%, P < .001), nonfatal MI (20%, P < .001), nonfatal stroke (31%, P < .001), and in the need for revascularization procedures (16%, P < .001).
The risk of new onset diabetes in the ramipril group was reduced by 32% (P = .002) and diabetic complications were reduced by 16% (P < .001).
The reductions in risk were similar across all patient groups, regardless of age, gender, and whether or not the patient had diabetes, cardiovascular disease, hypertension, microalbuminuria, or a history of MI.
Only a small part of the benefit could be attributed to a reduction in blood pressure, since the majority of patients (52%) did not have hypertension at baseline and the mean reduction in blood pressure was extremely small (3/2 mm Hg).18
The HOPE trial supports and extends the findings of TREND, BANFF, QUO VADIS, and QUIET. It provides the strongest confirmation to date that tissue ACE inhibition is an important factor in reducing coronary morbidity and mortality.

17. Tissue ACE trials in patients with CAD and preserved LV function: Benefits observed
The recent trials of ACE inhibitors with good tissue potency demonstrated the beneficial effects of ACE inhibition in patients with CAD and normal LV function.
TREND/BANFF showed that quinapril 20 to 40 mg daily significantly improves endothelial function; BANFF further showed that the relative tissue binding affinity of ACE inhibitors influences their impact on the endothelium.15,16
QUO VADIS showed that quinapril 40 mg daily significantly reduces the risk of cardiac events in post-CABG patients.17
QUIET showed a trend towards a reduction in ischemic events with quinapril 20 mg daily over a 3-year follow-up.21
HOPE showed that long-term treatment with ramipril 10 mg daily significantly reduces cardiovascular morbidity and mortality in patients, whether or not they have hypertension.20

18. Tissue ACE trials in patients with CAD and preserved LV function: Implications for clinical practice
The results of the tissue ACE trials demonstrate that tissue ACE inhibition reduces cardiovascular risk.
Improvement of endothelial function is a likely mechanism for this beneficial effect on clinical outcomes.

19. Summary
Tissue ACE plays a significant role in endothelial function, which is a major determinant of cardiovascular health and disease.
The tissue ACE trials demonstrated   
- Benefits of tissue ACE inhibition in patients with CAD and normal LV function - Relative degree of tissue-binding capacity influences how effectively an ACE inhibitor improves endothelial function - Tissue ACE inhibition is associated with improved cardiovascular outcomes in patients with CAD and normal LV, whether or not they have hypertension