, Volume 69, Issue 3, pp 265–277 | Cite as

Insight into the Mode of Action of ACE Inhibition in Coronary Artery Disease

The Ultimate ‘EUROPA’ Story
Review Article


ACE inhibition is now recognized as superior to placebo on outcomes in stable coronary artery disease (CAD), including total and cardiovascular mortality, fatal and nonfatal myocardial infarction, heart failure, revascularization and stroke. This review examines clinical evidence for the mode of action of ACE inhibitors in CAD, which is dominated by the results of a single trial, EUROPA, and its substudies.

The generally accepted mode of action for ACE inhibitors in CAD is blood pressure reduction. However, the EUROPA data demonstrate that endothelial protection, with the effect of arresting or reducing the processes of atherosclerosis is also important. Chronic overexpression of tissue ACE in CAD disrupts the angiotensin II/bradykinin balance with a net result of endothelial dysfunction. ACE inhibitors reduce production of angiotensin II, which prevents vasoconstriction, reduces adhesion molecules and growth factors, decreases oxidative stress and prevents apoptosis. A concomitant decrease in the degradation of bradykinin as a result of ACE inhibition raises levels of this kinin, leading to vasodilation and an antiapoptotic action, as well as opposition of the negative actions of angiotensin II.

We now have clinical trial evidence of these processes in CAD patients participating in the EUROPA study by measurement of markers of endothelial function, including nitric oxide synthase (eNOS), the rate of apoptosis and levels of von Willebrand factor (vWf ). Serum from CAD patients was found to significantly downregulate eNOS protein expression and activity versus that of healthy controls (p <0.01), most probably as a result of upregulation of tissue ACE. One year of treatment with perindopril upregulated eNOS protein expression and activity (19% and 27% vs placebo; p < 0.05). Similarly, vWf was elevated at baseline and significantly reduced after 1 year of treatment with perindopril (p< 0.001). Increased endothelial apoptosis by serum of CAD patients was accompanied by excess angiotensin II and tumour necrosis factor-α and a reduction in bradykinin; all of these parameters were reversed by treatment. We therefore have clinical results showing that perindopril normalizes the angiotensin II/bradykinin balance, reduces inflammation and prevents endothelial apoptosis. Accumulating preclinical evidence for the absence of a class effect for ACE inhibitors includes differences in terms of effect on eNOS and rate of endothelial apoptosis. These differences appear to be related to tissue affinity, penetration of atherosclerotic plaque and affinity for the target enzyme. Consideration of these features is important when administering ACE inhibition as secondary prevention in CAD patients. In this context, current European guidelines for stable angina pectoris recommend prescription of agents and doses with proven efficacy in secondary prevention.


  1. 1.
    Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS).The CONSENSUS trial study group. N Engl J Med 1987; 316: 1429–35CrossRefGoogle Scholar
  2. 2.
    Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD investigators. N Engl J Med 1991; 325: 293–302CrossRefGoogle Scholar
  3. 3.
    Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) study investigators. Lancet 1993; 342: 821–8Google Scholar
  4. 4.
    Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med 1992; 327: 669–77CrossRefGoogle Scholar
  5. 5.
    Kober L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) study group. N Engl J Med 1995; 333: 1670–6Google Scholar
  6. 6.
    Swedberg K, Held P, Kjekshus J, et al. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction: results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). N Engl J Med 1992; 327: 678–84PubMedCrossRefGoogle Scholar
  7. 7.
    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. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. Lancet 1995; 345: 669–85CrossRefGoogle Scholar
  8. 8.
    GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Gruppo Italiano per lo Studio della Sopravvivenza nell’infarto Miocardico. Lancet 1994; 343: 1115–22Google Scholar
  9. 9.
    Young JB. Reduction of ischemic events with angiotensin-converting enzyme inhibitors: lessons and controversy emerging from recent clinical trials. Cardiovasc Drugs Ther 1995; 9: 89–102PubMedCrossRefGoogle Scholar
  10. 10.
    Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients: the Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342: 145–53PubMedCrossRefGoogle Scholar
  11. 11.
    Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multi-centre trial (the EUROPA study). Lancet 2003; 362: 782–8PubMedCrossRefGoogle Scholar
  12. 12.
    Patel A, MacMahon S, Chalmers J, et al. Effects of a fixed combination of perindopril and indapamide on macro-vascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007; 370: 829–40PubMedCrossRefGoogle Scholar
  13. 13.
    Braunwald E, Domanski MJ, Fowler SE, et al. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2004; 351: 2058–68PubMedCrossRefGoogle Scholar
  14. 14.
    Pitt B, O’Neill B, Feldman R, et al. The QUinapril Ischemic Event Trial (QUIET): evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol 2001; 87: 1058–63PubMedCrossRefGoogle Scholar
  15. 15.
    Dahlof B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005; 366: 895–906PubMedCrossRefGoogle Scholar
  16. 16.
    Linz W, Wohlfart P, Schoelkens BA, et al. Late treatment with ramipril increases survival in old spontaneously hypertensive rats. Hypertension 1999; 34: 291–5PubMedCrossRefGoogle Scholar
  17. 17.
    Blankenberg S, McQueen MJ, Smieja M, et al. Comparative impact of multiple biomarkers and N-Terminal pro-brain natriuretic peptide in the context of conventional risk factors for the prediction of recurrent cardiovascular events in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation 2006; 114: 201–8PubMedCrossRefGoogle Scholar
  18. 18.
    Blankenberg S, Yusuf S. The inflammatory hypothesis: any progress in risk stratification and therapeutic targets? Circulation 2006; 114: 1557–60PubMedCrossRefGoogle Scholar
  19. 19.
    Shlipak MG, Ix JH, Bibbins-Domingo K, et al. Biomarkers to predict recurrent cardiovascular disease: the Heart and Soul Study. Am J Med 2008; 121: 50–7PubMedCrossRefGoogle Scholar
  20. 20.
    Sinning JM, Bickel C, Messow CM, et al. Impact of C-reactive protein and fibrinogen on cardiovascular prognosis in patients with stable angina pectoris: the AtheroGene study. Eur Heart J 2006; 27: 2962–8PubMedCrossRefGoogle Scholar
  21. 21.
    Ferrari R, Bertrand ME, Remme WJ, et al. Insight into ACE inhibition in the prevention of cardiac events in stable coronary artery disease: the EUROPA trial. Expert Rev Cardiovasc Ther 2007; 5: 1037–46PubMedCrossRefGoogle Scholar
  22. 22.
    Schieffer B, Bunte C, Witte J, et al. Comparative effects of AT1-antagonism and angiotensin-converting enzyme inhibition on markers of inflammation and platelet aggregation in patients with coronary artery disease. J Am Coll Cardiol 2004; 44: 362–8PubMedCrossRefGoogle Scholar
  23. 23.
    Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358: 1547–59PubMedCrossRefGoogle Scholar
  24. 24.
    Dagenais GR, Pogue J, Fox K, et al. Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials. Lancet 2006; 368: 581–8PubMedCrossRefGoogle Scholar
  25. 25.
    Remme WJ, Deckers JW, Fox KM, et al. Secondary pre-vention of coronary disease with ACE inhibition-does blood pressure reduction with perindopril explain the benefits in EUROPA? Cardiovasc Drugs Ther. In pressGoogle Scholar
  26. 26.
    Poole Wilson PA, Lubsen J, Kirwan BA, et al. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial. Lancet 2004; 364: 849–57PubMedCrossRefGoogle Scholar
  27. 27.
    Nissen SE, Tuzcu EM, Libby P, et al. Effect of anti-hypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA 2004; 292: 2217–25PubMedCrossRefGoogle Scholar
  28. 28.
    Asmar RG, London GM, O’Rourke ME, et al. Improvement in blood pressure, arterial stiffness and wave reflections with a very-low-dose perindopril/indapamide combination in hypertensive patient: a comparison with atenolol. Hyper-tension 2001; 38: 922–6Google Scholar
  29. 29.
    Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation 2006; 113: 1213–25PubMedCrossRefGoogle Scholar
  30. 30.
    Dzau VJ, Bernstein K, Celermajer D, et al. The relevance of tissue angiotensin-converting enzyme: manifestations in mechanistic and endpoint data. Am J Cardiol 2001; 88: 1–20LCrossRefGoogle Scholar
  31. 31.
    Esther CR, Marino EM, Howard TE, et al. The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice. J Clin Invest 1997; 99: 2375–85PubMedCrossRefGoogle Scholar
  32. 32.
    Buemi M, Corica F, Marino D, et al. Cardiovascular remodeling, apoptosis, and drugs. Am J Hypertens 2000; 13: 450–4PubMedCrossRefGoogle Scholar
  33. 33.
    Falk E. Pathogenesis of atherosclerosis. J Am Coll Cardiol 2006;47:C7–12PubMedCrossRefGoogle Scholar
  34. 34.
    Hoshida S, Kato J, Nishino M, et al. Increased angiotensin-converting enzyme activity in coronary artery specimens from patients with acute coronary syndrome. Circulation 2001; 103: 630–3PubMedCrossRefGoogle Scholar
  35. 35.
    Ferrari R. Angiotensin-converting enzyme inhibition in cardiovascular disease: evidence with perindopril. Expert Rev Cardiovasc Ther 2005; 3: 15–29PubMedCrossRefGoogle Scholar
  36. 36.
    Ferrari R, Guardigli G, Mele D, et al. Myocardial ischaemia: new evidence for angiotensin-converting enzyme inhibition. Eur Heart J 2003; 5: E1 1–7Google Scholar
  37. 37.
    Bots ML, Remme WJ, Luscher TF, et al. ACE inhibition and endothelial function: main findings of PERFECT, a sub-study of the EUROPA trial. Cardiovasc Drugs Ther 2007; 21: 269–79PubMedCrossRefGoogle Scholar
  38. 38.
    Ceconi C, Fox KM, Remme WJ, et al. ACE inhibition with perindopril and endothelial dysfunction. Results of a sub-study of the EUROPA study: PERTINENT. Cardiovasc Res 2007; 73: 237–46Google Scholar
  39. 39.
    Rodriguez-Granillo GA, Vos J, Bruining N, et al. Long-term effect of perindopril on coronary atherosclerosis progression [from the PERindopril’s Prospective Effect on Coronary aTherosclerosis by Angiography and Intra-Vascular Ultrasound Evaluation (PERSPECTIVE) Study]. Am J Cardiol 2007; 100: 159–63PubMedCrossRefGoogle Scholar
  40. 40.
    Rodriguez-Granillo GA, De Winter S, Bruining N, et al. Effect of perindopril on coronary remodelling: insights from a multicentre, randomized study. Eur Heart J 2007; 28: 2326–31PubMedCrossRefGoogle Scholar
  41. 41.
    Ceconi C, Fox KM, Remme WJ, et al. ACE inhibition with perindopril and biomarkers of atherosclerosis and thrombosis: results from the PERTINENT study. Atherosclerosis. In pressGoogle Scholar
  42. 42.
    Daly CA, Fox KM, Remme WJ, et al. The effect of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: results from the PERSUADE substudy. Eur Heart J 2005; 26: 1369–78PubMedCrossRefGoogle Scholar
  43. 43.
    Bruining N, De Winter S, Roelandt JRTC, et al. Coronary calcium significantly affects the results of quantitative coronary ultrasound in atherosclerosis progression-regression studies [abstract]. Eur Heart J 2008; 29 (Suppl. 1): 786Google Scholar
  44. 44.
    Remme WJ. Secondary prevention of coronary artery disease and the choice of the ACE inhibitor why EUROPA and not PEACE. Cardiovasc Drugs Ther 2007; 21: 405–7PubMedCrossRefGoogle Scholar
  45. 45.
    Ferrari R. ACE-inhibition for secondary prevention of cardiovascular events: should we change our recommendation after PEACE? Cardiovasc Drugs Ther 2006; 20: 11–2PubMedCrossRefGoogle Scholar
  46. 46.
    Voors AA, van Veldhuisen DJ, van Gilst WH. The current role of ACE-inhibitors for secondary prevention in cardiovascular disease; from pathogenesis to clinical practice. Cardiovasc Drugs Ther 2006; 20: 69–73PubMedCrossRefGoogle Scholar
  47. 47.
    Comini L, Bachetti T, Cargnoni A, et al. Therapeutic modulation of the nitric oxide pathway: are all ACE inhibitors equivalent? Pharmacol Res 2007; 56: 42–8PubMedCrossRefGoogle Scholar
  48. 48.
    Ceconi C, Francolini G, Bastianon D, et al. Differences in the effect of angiotensin-converting enzyme inhibitors on the rate of endothelial cell apoptosis: in vitro and in vivo studies. Cardiovasc Drugs Ther 2007; 21: 423–9PubMedCrossRefGoogle Scholar
  49. 49.
    Johnston C, Fabris B, Yamada H, et al. Comparative studies of tissue inhibition by angiotensin converting enzyme inhibitors. J Hypertens 1989; 7: S1 1–6Google Scholar
  50. 50.
    Dive V, Cotton J, Yiotakis A, et al. RXP 407, a phosphinic peptide, is a potent inhibitor of angiotensin I converting enzyme able to differentiate between its two active sites. Proc Natl Acad Sci U S A 1999; 96: 4330–5PubMedCrossRefGoogle Scholar
  51. 51.
    Ceconi C, Francolini G, Olivares A, et al. Angiotensin-converting enzyme (ACE) inhibitors have different selectivity for bradykinin binding sites of human somatic ACE. Eur J Pharmacol 2007; 577: 1–6PubMedCrossRefGoogle Scholar
  52. 52.
    Ghiadoni L, Magagna A, Versari D, et al. Different effect of antihypertensive drugs on conduit artery endothelial function. Hypertension 2003; 41: 1281–6PubMedCrossRefGoogle Scholar
  53. 53.
    Hornig B, Landmesser U, Kohler C, et al. Comparative effect of ace inhibition and angiotensin II type 1 receptor antagonism on bioavailability of nitric oxide in patients with coronary artery disease: role of superoxide dismutase. Circulation 2001; 103: 799–805PubMedCrossRefGoogle Scholar
  54. 54.
    Management of stable angina pectoris. Recommendations of the Task Force of the European Society of Cardiology. Eur Heart J 2006; 27: 1341–81CrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  1. 1.Department of CardiologyUniversity of FerraraFerraraItaly
  2. 2.Fondazione Salvatore Maugeri IRCCSFerraraItaly
  3. 3.Department of CardiologyRoyal Brompton HospitalLondonUK

Personalised recommendations