Search this site:

Clin. Cardiol. Vol. 23 (Suppl. IV), IV-4–IV-8 (2000)

Overview of the Relationship Between Ischemia and Congestive Heart Failure

Willem J. Remme, M.D., Ph.D.

Director of Research, Sticares Cardiovascular Research Foundation, Rotterdam, The Netherlands

Summary: Ischemic heart disease is the principal etiology of heart failure in the Western world. Myocardial ischemia is important in cardiac remodeling, a process that leads to a progressive change in the shape and size of the heart and significantly worsens the prognosis of patients with heart failure. Preventing ischemic events, therefore, is an important goal in the management of patients with coronary artery disease. Statins have been shown to reduce the number of ischemic events in these patients, whereas the benefit of beta-blocker and aldosterone antagonist therapy on ischemic causes of heart failure remains unclear. Several large trials involving patients with asymptomatic left ventricular dysfunction after myocardial infarction or heart failure have shown that angiotensin-converting enzyme (ACE) inhibitors reduce the incidence of progressive heart failure, death, and ischemic events, thus establishing ACE inhibitors as first-line therapy for these patients. Other lines of evidence have suggested that ACE inhibitor therapy may also benefit patients with preserved left ventricular function, a hypothesis that is being evaluated in three large, controlled, randomized trials. One of these trials, the Heart Outcomes Prevention Evaluation (HOPE) study, was terminated prematurely because it demonstrated the significant positive effects of the ACE inhibitor ramipril on cardiovascular outcomes in patients with coronary artery disease and preserved left ventricular function. A growing body of data confirms the relationship between ischemia and heart failure and the benefits of ACE inhibitor treatment in a broad range of high-risk patients.

Key words: coronary artery disease, angiotensin-converting enzyme inhibitor, left ventricular function, HOPE study, cardiac injury, myocardial infarction

Introduction

Ischemic heart disease, a major risk factor for heart failure, is the most common cause of congestive heart failure in large trials conducted in the United States,1–4 as well as in several European studies,5–8 accounting for 50% to more than 80% of cases. In contrast, hypertension or a history of hypertension accounts for less than half of all cases of congestive heart failure. One community-based trial, however, exemplified the difficulty in diagnosing ischemic heart disease, which may lead to misdiagnosis and inadequate treatment.6

Ischemic heart disease confers a significantly worse prognosis in patients with left ventricular dysfunction. An analysis of the Studies of Left Ventricular Dysfunction (SOLVD) trials found that patients who developed myocardial infarction (MI) had an approximately two-fold higher rate of hospitalization for congestive heart failure and about a four-fold increase in death compared with those who did not develop MI.9 Similarly, an analysis of the Survival and Ventricular Enlargement (SAVE) trial found that prior MI (p<0.001), lower left ventricular ejection fraction (p<0.001), angina (p = 0.007), heart failure (p = 0.002), left ventricular and diastolic volume (p<0.001), and MI size (p<0.001) were significant predictors of cardiovascular death and/or left ventricular enlargement.10 Other studies also have reported a poorer prognosis in patients with congestive heart failure due to coronary heart disease than in patients in whom congestive heart failure was due to nonischemic causes.8

Several pathophysiologic mechanisms contribute to ischemic left ventricular dysfunction and heart failure (Fig. 1). As a risk factor for left ventricular dysfunction, ischemia presents a poor prognosis since ischemia is a self-propagating process (Fig. 2). Therefore, prevention of ischemia would likely lead to a reduction in heart failure.

Fig. 1  Ischemia and heart failure--the common link. Ischemia-induced mechanisms, which alone or in concert lead to ventricular dysfunction and subsequent heart failure. LV = left ventricular; Ca2+ = calcium; O2 = oxygen.

Fig. 2  Myocardial ischemia--a self-propagating process. O2 = oxygen; RAS = renin-angiotensin system.

Prevention of Ischemia

Pharmacologic intervention provides a wide variety of potential approaches to preventing coronary artery disease and subsequent left ventricular dysfunction or heart failure. The classes of agents that have been studied include 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins), beta blockers, aldosterone antagonists, and angiotensin-converting enzyme (ACE) inhibitors.

Statins

Large-scale primary11, 12 and secondary13, 14 prevention trials have demonstrated that statins reduce the incidence of major coronary events and death due to coronary heart disease. For example, over the 5.4-year median follow-up period in the Scandinavian Simvastatin Survival Study, coronary deaths were reduced by 42% (p = 0.0003), major coronary events by 34% (p<0.00001), and the need for revascularization procedures by 37% in patients with hypercholesterolemia (p<0.00001) who had a history of angina or MI.12 A similar benefit of statin therapy for the first acute major coronary event was noted during the average 5.2-year follow-up period of the Air Force/Texas Coronary Atherosclerosis Prevention Study of patients with average cholesterol levels (p<0.001) who did not have clinically evident coronary artery disease.13 Findings from a recent secondary prevention study suggest that treatment with a statin is at least as effective as revascularization procedures (angioplasty) in reducing the incidence of ischemic events in patients with stable coronary artery disease.15 Risk of an ischemic event was reduced by 36% (p = 0.0481) and the time to a first ischemic event was significantly longer (p = 0.03) with statin treatment.

Beta Blockers

Exercise-induced ischemia stimulates norepinephrine release, which positively correlates with the extent of ischemia.16 While norepinephrine affects the heart and circulation in a number of ways, such as increasing the automaticity of cardiac cells, causing peripheral vasoconstriction, and triggering apoptosis. It is unclear which effects are responsible for the progression of heart failure.17 Beta blockers inhibit the effects of norepinephrine on the sympathetic nervous system, producing long-term amelioration of the symptoms and the clinical status of patients with heart failure. Beta blockers also decrease the risk of death and the combined risk of death or hospitalization when used in conjunction with an ACE inhibitor.17, 18 However, some studies have shown that the addition of a beta blocker to existing therapy for heart failure is associated with a nonsignificant reduction in mortality,3 or even a significantly increased risk (p = 0.026) of worsening heart failure early in the course of treatment,19 with no effect on the risk of hospitalization for any reason.19 The second Cardiac Insufficiency Bisoprolol Study (CIBIS II) did demonstrate that the risk of hospitalization for any reason and hospitalizations for congestive heart failure or arrhythmias were substantially decreased with the addition of a beta blocker to conventional therapy of diuretics and ACE inhibitors in patients with moderate to severe heart failure.20 The risk of hospitalization due to ischemic causes (e.g., MI, angina), however, was not reduced with beta-blocker therapy. Overall, beta-receptor blockade (at least with bisoprolol) does not appear to provide additional benefit with respect to ischemic events in patients with heart failure who are on conventional heart failure therapy that includes an ACE inhibitor.3, 20

Aldosterone Antagonists

Aldosterone levels are higher in patients with heart failure and cause sodium and fluid retention and myocardial fibrosis, which eventually lead to ventricular remodeling and dysfunction of the heart and blood vessels.21–23 Blockade of aldosterone may therefore reduce the risk of progression of heart failure and death. The recent Randomized Aldactone Evaluation Study (RALES) found that the addition of the aldosterone antagonist, spironolactone, to standard therapy in patients with severe heart failure significantly reduced the risk of death (p<0.001). This reduction was in large part because of a lower risk of death from progressive heart failure and sudden death from cardiac causes. Spironolactone also significantly lowered the frequency of hospitalization for worsening heart failure (p<0.001).24 However, since the effect of spironolactone on ischemic causes of heart failure was not specifically studied, the benefit, if any, of aldosterone antagonist therapy on ischemic events remains to be determined.

Angiotensin-Converting Enzyme Inhibitors

While treating hypercholesterolemia or hypertension reduces the likelihood of an initial ischemic cardiac injury, the prevention of further injury can lower the risk of progression to heart failure. The use of ACE inhibitors for both secondary prevention and treatment of heart failure has been clearly established.25 In patients with recent MI, ACE inhibitor therapy decreases the risk of reinfarction or death.26–28 Several large trials have demonstrated that ACE inhibitor therapy significantly reduces the risk of developing severe or refractory heart failure and the risk of hospitalization for heart failure.1, 28–30 In the Acute Infarction Ramipril Efficacy (AIRE) study, for example, early administration of ramipril to patients with clinical evidence of either transient or ongoing heart failure after MI resulted in a substantial 27% reduction (p = 0.002) in premature death from all causes. The risk reduction for prespecified secondary outcomes, such as progression to heart failure, MI, and stroke, was 19% (p = 0.008).

In ischemia, both the circulating renin-angiotensin system and local (tissue) ACE can be activated.31 The circulating renin-angiotensin system, which accounts for ¾10% of ACE in the body, regulates the cardiovascular system in the short term, while tissue ACE regulates cardiovascular homeostasis over the long term.31 The reduction in ischemic events with ACE inhibition in the SOLVD and SAVE trials was not evident until 6 to 12 months after the initiation of therapy.9, 29 This suggests that ACE inhibitors, unlike nitrates or calcium antagonists, which reduce myocardial ischemia by improving the myocardial oxygen supply–demand ratio, also act on the underlying pathophysiology of ischemia to affect cardiovascular structure and function (Table I).32

Table I Possible anti-ischemic mechanisms of angiotensin-converting enzyme inhibitors
Myocardial
Vascular
Optimizing oxygen supply/demand Antiatherogenic
Reduction in preload and afterload Antiproliferative effects
Reduction in left ventricular mass (vascular smooth muscle cells)
Attenuation sympathetic nervous Improved endothelial function
system stimulation Plaque stabilization
Antihypertensive activity Enhanced fibrinolysis
Adapted from Ref. No. 32 with permission.

The myocardial protective effects of ACE inhibitors in patients with left ventricular dysfunction or heart failure result from their ability to alter hemodynamics favorably. They reduce blood pressure and prevent remodeling of the left ventricle, which reduces wall stress and myocardial oxygen demand.32, 33

The more important long-term anti-ischemic effects of ACE inhibitors stem from their vasculoprotective effects (Table I), which include the prevention or stabilization of atherosclerotic plaques.

A study of a balloon injury model of atherosclerosis in rabbits who were on a high cholesterol diet found that the increase in the intima–media ratio could be prevented with ACE inhibition, but not with angiotensin II receptor blockade.34 In fact, the intima–media ratio was similar in control animals and in those treated with the angiotensin II receptor antagonist. Similar antiatherogenic findings with ACE inhibitor treatment have been reported by Thybo et al. in a study involving humans with previously untreated essential hypertension.35 At baseline, the media–lumen ratio was approximately 30% greater in the untreated patients with hypertension than in the normotensive control group. One year of ACE inhibitor treatment significantly decreased the media–lumen ratio in resistance vessels (p<0.01), whereas beta-blocker treatment induced no significant change. Angiotensin-converting enzyme inhibitor therapy significantly increased the lumen diameter (p<0.02), but there was no change in the media cross-sectional area of the vessels, suggesting that the structural changes involved reversal of remodeling rather than vascular growth inhibition. This normalization of vascular structure did not occur with a beta blocker given at an equivalent blood pressure-lowering dose, proposing that the effects were independent of blood pressure lowering.

The beneficial effects of ACE inhibitors on atherosclerosis and vessel structure appear in part to result from an effect on the endothelium, which regulates vascular structure and function through the release of vasodilating and vasoconstricting factors.36 Early in the course of atherosclerosis, the release of endothelium-derived relaxing factor (i.e., nitric oxide) is impaired. Studies in animal models and in humans demonstrate that ACE inhibitors improve endothelial dysfunction that results from atherosclerosis and hyperlipidemia.37–40 In rabbits that were on a high cholesterol diet, impaired endothelium-dependent relaxation was prevented with concomitant treatment with an ACE inhibitor, ramipril.37 A study in humans showed that after 6 months of ACE inhibitor treatment, patients with evidence of coronary artery disease, but without lipid abnormalities, had improved endothelial function, as measured by response to the endothelium-dependent vasodilator acetylcholine.38 Other studies have shown that improvement in endothelial function may be limited to ACE inhibitors like ramipril that have high affinity for tissue ACE.39, 40

Myocardial ischemia induces adrenergic activation and vasoconstriction. In exercise-induced ischemia, the degree of ischemia correlates with sympathetic activity, as measured by plasma norepinephrine levels.16 Moreover, patients with ischemic syndromes at rest (unstable angina) have heightened sympathetic tone and are likely to have continuous neurohormonal activation compared with patients who have stable angina.41 This continuous neurohormonal activation promotes a self-propagating process of reduced coronary perfusion, stenosis, increased systemic vasoconstriction, ischemia, and increased neurohormonal activation. Administration of an ACE inhibitor has been shown to suppress catecholamine activation and improve hemodynamic parameters during pacing-induced ischemia in patients with coronary artery disease.42

Patients with Preserved Left Ventricular Function

Endothelial dysfunction is an early pathophysiologic insult in the course of cardiovascular disease, initiating a cascade of events that can lead to atherosclerosis, ischemia, or left ventricular dysfunction.43 Hence, the improvement in endothelial dysfunction noted with ACE inhibitor therapy suggests that a broad range of patients could potentially benefit from treatment. As noted previously, the beneficial effects of ACE inhibitor treatment on survival and major cardiovascular events have been demonstrated in patients with left ventricular dysfunction or heart failure.1, 10, 28 Whether ACE inhibitor treatment provides similar benefits in patients with preserved left ventricular function remained unknown until recently.

The Heart Outcomes Prevention Evaluation (HOPE) study is a double-blind, placebo-controlled, clinical trial involving patients at high risk for major cardiovascular events who were randomized to ramipril or placebo. The study cohort included patients with coronary artery disease, peripheral vascular disease, diabetes, dyslipidemia, but no left ventricular dysfunction or heart failure at baseline.44 The HOPE study was terminated prematurely because of significant reductions in death due to cardiovascular causes (26%, p<0.001), MI (20%, p<0.001), stroke (32%, p<0.001), and other major cardiovascular events (e.g., revascularization procedures [p¾0.002], heart failure [p<0.001]). The HOPE study, which is discussed in greater detail in the article by Bertram Pitt, M.D., in this supplement, provides compelling data on the anti-ischemic effects of ACE inhibition, particularly by ramipril, in patients with preserved left ventricular function.

Two other ongoing studies, the European trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) and the Prevention of Events with ACE inhibition (PEACE) study, have similar end points as the HOPE study--MI, cardiovascular, and all-cause mortality--but slightly different inclusion criteria. While the HOPE study included patients aged 55 years or over who were at high risk for a major cardiovascular event, the EUROPA study included patients older than 18 years who had evidence of coronary artery disease. The PEACE study included patients aged 50 years or older who had documented coronary artery disease but a normal ejection fraction. The EUROPA and PEACE studies should corroborate the findings of the HOPE study, extending the benefits of ACE inhibitor therapy to a larger patient population.

Conclusion

The predominant etiology of heart failure in the Western world is ischemic heart disease, which has an important role in cardiac remodeling and the subsequent progressive change in the shape and size of the heart. While remodeling occurs after an MI, ongoing myocardial ischemia also contributes to the progressive remodeling process. Ischemic manifestations significantly worsen the prognosis of patients with heart failure. Therefore, prevention of ischemic events would likely reduce the incidence of worsening heart failure. Treatment with statins has been shown to reduce ischemic events, whereas the effect of beta-blocker and aldosterone antagonist therapy on ischemic causes of heart failure remains unclear.

Several clinical trials of patients with asymptomatic left ventricular dysfunction after MI or heart failure have established ACE inhibitors as first-line therapy for heart failure because they reduce the incidence of worsening heart failure, death, and ischemic events. The beneficial effects of ACE inhibitors are mediated through their cardio- and vasculoprotective effects. Several lines of evidence have suggested that ACE inhibitor treatment also would be beneficial in a broader patient population; that is, patients with preserved left ventricular function. Three large, controlled, randomized trials have been initiated to evaluate the effects of ACE inhibitors on cardiovascular morbidity and mortality in patients with coronary artery disease and preserved left ventricular dysfunction. Of these trials, the HOPE study was terminated prematurely because of the impressive positive effects of the ACE inhibitor ramipril. A growing body of data confirms the relationship between ischemia and heart failure and the benefit of ACE inhibitor treatment in a broad range of patients.

References

  1. The SOLVD Investigators: Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685–691
  2. The SOLVD Investigators: Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293–302
  3. CIBIS Investigators and Committees: A randomized trial of b-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation 1994;90:1765–1773
  4. Bart BA, Ertl G, Held P, Kuch J, Maggioni AP, McMurray J, Michelson EL, Rouleau JL, Stevenson LW, Swedberg K, Young JB, Yusuf S, Sellers MA, Granger CB, Califf RM, Pfeffer MA, for the SPICE investigators: Contemporary management of patients with left ventricular systolic dysfunction. Results from the Study of Patients Intolerant of Converting Enzyme Inhibitors (SPICE) Registry. Eur Heart J 1999;20:1182–1190
  5. Eriksson H, Svardsudd K, Caidahl K, Bjuro T, Larsson B, Welin L, Ohlson LO, Wilhelmsen L: Early heart failure in the population. The study of men born in 1913. Acta Med Scand 1988;223:197–209
  6. Parameshwar J, Shackell MM, Richardson A, Poole-Wilson PA, Sutton GC: Prevalence of heart failure in three general practices in north west London. Br J Gen Pract 1992;42:287–289
  7. Remes J, Reunanen A, Aromaa A, Pyorala K: Incidence of heart failure in eastern Finland: A population-based surveillance study. Eur Heart J 1992;13:588–593
  8. Zannad F, Briancon S, Julliere Y, Mertes PM, Villemot JP, Alla F, Virion JM, and the EPICAL investigators: Incidence, clinical and etiologic features, and outcomes of advanced chronic heart failure: The EPICAL study. J Am Coll Cardiol 1999;33:734–742
  9. Yusuf S, Pepine CJ, Garces C, Pouleur H, Salem D, Kostis J, Benedict C, Rousseau M, Bourassa M, Pitt B: Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet 1992;340:1173–1178
  10. St. John Sutton M, Pfeffer MA, Moyé L, Plappert T, Rouleau JL, Lamas G, Rouleau J, Parker JO, Arnold MO, Sussex B, Braunwald E, for the SAVE investigators: Cardiovascular death and left ventricular remodeling two years after myocardial infarction: Baseline predictors and impact of long-term use of captopril: Information from the Survival and Ventricular Enlargement (SAVE) trial. Circulation 1997;96:3294–3299
  11. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW, McKillop JH, Packard CJ, for the West of Scotland Coronary Prevention Study Group: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301–1307
  12. Scandinavian Simvastatin Survival Study Group: Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–1389
  13. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AMJ, for the AFCAPS/TexCAPS Research Group: Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS. J Am Med Assoc 1998;279:1615–1622
  14. Sacks FM, Pfeffer MA, Moyé LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E, for the Cholesterol and Recurrent Events Trial Investigators: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996;335:1001–1009
  15. Pitt B, Waters D, Brown WV, van Boven AJ, Schwartz L, Title LM, Eisenberg D, Shurzinske L, McCormick LS, for the Atorvastatin versus Revascularization Treatment Investigators: Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med 1999;341:70–76
  16. Hashimoto M, Okamoto M, Yamagata T, Yamane T, Watanabe M, Tsuchioka Y, Matsuura H, Kajiyama G: Abnormal systolic blood pressure response during exercise recovery in patients with angina pectoris. J Am Coll Cardiol 1993;22:659–664
  17. Packer M, Cohn JN, Eds., on behalf of the Steering Committee and Membership of the Advisory Council to Improve Outcomes Nationwide in Heart Failure: Consensus recommendations for the management of chronic heart failure. Am J Cardiol 1999;83(suppl):1A–38A
  18. Task Force of the Working Group on Heart Failure of the European Society of Cardiology: The treatment of heart failure. Eur Heart J 1997;18:736–753
  19. McKelvie RS, Yusuf S, Pericak D, Avezum A, Burns RJ, Probstfield J, Tsuyuki RT, White M, Rouleau J, Latini R, Maggioni A, Young J, Pogue J, for the RESOLVD Pilot Study Investigators: Comparison of candesartan, enalapril, and their combination in congestive heart failure: Randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. Circulation 1999;100:1056–1064
  20. CIBIS II Investigators and Committees: The Cardiac Insufficiency Bisoprolol Study (CIBIS II): A randomised trial. Lancet 1999;353:9–13
  21. Weber KT, Villarreal D: Aldosterone and antialdosterone therapy in congestive heart failure. Am J Cardiol 1993;71(suppl):3A–11A
  22. Barr CS, Lang CC, Hanson J, Arnott M, Kennedy N, Struthers AD: Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol 1995;76:1259–1265
  23. Rocha R, Chander PN, Khanna K, Zuckerman A, Stier CJ: Mineralcorticoid blockade reduces vascular injury in stroke-prone hypertensive rats. Hypertension 1998;31:451–458
  24. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J, for the Randomized Aldactone Evaluation Study Investigators: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709–717
  25. Garg G, Yusuf S, for the Collaborative Group on ACE Inhibitor Trials: Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. J Am Med Assoc 1995;273:1450–1456
  26. The Fourth International Study of Infarct Survival (ISIS-4) Collaborative Group: ISIS-4: A randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet 1995;345:669–685
  27. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico: GISSI-3: Effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet 1994;343:1115–1122
  28. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators: Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;342:821–828
  29. Pfeffer MA, Braunwald E, Moyé LA, Basta L, Brown EG Jr, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer M, Rouleau J, Rouleau JL, Rutherford J, Wertheimer JH, Hawkins CM, for the SAVE Investigators: Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. N Engl J Med 1992;327:669–677
  30. Køber L, Torp-Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lyngborg K, Videbaek J, Cole DS, Auclert L, Pauly NC, Aliot E, Persson S, Camm AJ, for the Trandolapril Cardiac Evaluation (TRACE) Study Group: A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1995;333:1670–1976
  31. Dzau VJ: Angiotensin-converting as a multimechanistic factor in CAD. J Myocard Ischemia 1995;7:6–14
  32. Young JB: Reduction of ischemic events with angiotensin-converting enzyme inhibitors: Lessons and controversy emerging from recent clinical trials. Cardiovasc Drugs Ther 1995;9:89–102
  33. Nakashima Y, Fouad FM, Tarazi RC: Regression of left ventricular hypertrophy from systemic hypertension by enalapril. Am J Cardiol 1984;53:1044–1049
  34. Fennessy PA, Campbell JH, Mendelsohn FA, Campbell GR: Angiotensin-converting enzyme inhibitors and atherosclerosis: Relevance of animal models to human disease. Clin Exp Pharmacol Physiol 1996;23(suppl 1):S30–S32
  35. Thybo NK, Stephens N, Cooper A, Aalkjaer C, Heagerty AM, Mulvany MJ: Effect of antihypertensive treatment on small arteries of patients with previously untreated essential hypertension. Hypertension 1995;25(4 Pt1):474–481
  36. Furchgott RF: Role of endothelium in responses of vascular smooth muscle. Circ Res 1983;53:557–573
  37. Finta KM, Fischer MJ, Lee L, Gordon D, Pitt B, Webb RC: Ramipril prevents impaired endothelium-dependent relaxation in arteries from rabbits fed an atherogenic diet. Atherosclerosis 1993;100:149–156
  38. Mancini GB, Henry GC, Macaya C, O'Neill BJ, Pucillo AL, Carere RG, Wargovich TJ, Mudra H, Luscher TF, Klibaner MI, Haber HE, Uprichard AC, Pepine CJ, Pitt B: Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing ENdothelial Dysfunction) Study. Circulation 1996;94:258–265
  39. Anderson TJ, Overhiser RW, Haber H, Charbonneau F: A comparative study of four antihypertensive agents on endothelial function in patients with coronary disease. J Am Coll Cardiol 1998;31(suppl):327A
  40. Erman A, Winkler J, Chen-Gal B, Rabinov M, Zelykovski A, Tadjer S, Shmueli J, Levi E, Akbary A, Rosenfeld JB: Inhibition of angiotensin-converting enzyme by ramipril in serum and tissue of man. J Hypertens 1991;9:1057–1062
  41. Remme WJ: Bradykinin-mediated cardiovascular protective actions of ACE inhibitors: A new dimension in anti-ischaemic therapy? Drugs 1997;54(suppl 5):59–70
  42. Bartels GL, van den Heuvel FM, van Veldhuisen DJ, van der Ent M, Remme WJ: Acute anti-ischemic effects of perindoprilat in men with coronary artery disease and their relation with left ventricular function. Am J Cardiol 1999;83:332–336
  43. Dzau VJ: Mechanism of protective effects of ACE inhibition on coronary artery disease. Eur Heart J 1998;19(suppl J):J2–J6
  44. The Heart Outcomes Prevention Evaluation Study Investigators: Vitamin E supplementation and cardiovascular events in high-risk patients. N Engl J Med 2000;342:154–160

Supported by a grant from Monarch Pharmaceuticals.

Address for reprints:
Willem J. Remme, M.D., Ph.D.
Director of Research
Sticares Cardiovascular Research Foundation
Oever 7
3161GR Rhoon-NL
The Netherlands

©1997-2002 Foundation for Advances in Medicine and Science