Cardiovascular Drugs and Therapy

, Volume 24, Issue 4, pp 331–339

Secondary Prevention of CAD with ACE Inhibitors: A Struggle Between Life and Death of the Endothelium

  • Roberto Ferrari
  • Gabriele Guardigli
  • Claudio Ceconi


Angiotensin-converting enzyme (ACE) inhibitors improve outcomes in patients with coronary artery disease (CAD), heart failure, and hypertension. This short review examines clinical evidence for such effects and the underlying mechanism of action. One potential mode of action for ACE inhibitors in CAD is blood pressure reduction. However, recent data suggest that the effects of ACE inhibitors on the endothelium may also be relevant in attenuating the progression of atherosclerosis. In CAD, chronic overexpression of tissue ACE disrupts the angiotensin II/bradykinin balance with a net result of endothelial dysfunction, mainly due to an increased rate of apoptosis. An imbalance between endothelial apoptosis (death) and its renewal from the bone marrow (life) causes discontinuity of the endothelial layer, favoring the initiation and progression of a biochemical sequence that leads to atherosclerosis, plaque rupture, and eventually acute coronary syndromes. There is clinical and experimental evidence that ACE inhibition improves the life and death cycle of the endothelium. By restoring the bradykinin/angiotensin II balance, ACE inhibition reduces the rate of endothelial apoptosis and experimental results suggest that ACE inhibition can also improve the production and mobilization of endothelial progenitor cells from bone marrow. We report our experience in this context with perindopril.

Key words

Coronary artery disease Perindopril Endothelial apoptosis Endothelial renewal 


  1. 1.
    Ferrari R. Cardiovascular protection by angiotensin-converting enzyme inhibition. Eur Heart J Suppl. 2009;11:E1–3.CrossRefGoogle Scholar
  2. 2.
    Ferrari R, Fox K. Insight into the mode of action of ACE inhibition in coronary artery disease: the ultimate ‘EUROPA’ story. Drugs. 2009;69:265–77.CrossRefPubMedGoogle Scholar
  3. 3.
    Ceconi C, Fox KM, Remme WJ, et al. ACE inhibition with perindopril and endothelial dysfunction. Results of a substudy of the EUROPA study: PERTINENT. Cardiovasc Res. 2007;73:237–46.CrossRefPubMedGoogle Scholar
  4. 4.
    Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2007;28:1462–536.PubMedGoogle Scholar
  5. 5.
    Mancia G, Laurent S, Gabiti-Rosei E, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens. 2009;27:2121–58.CrossRefPubMedGoogle Scholar
  6. 6.
    Cordonnier DJ, Pinel N, Barro C, et al. Expansion of cortical interstitium is limited by converting enzyme inhibition in type 2 diabetic patients with glomerulosclerosis. The Diabiopsies Group. J Am Soc Nephrol. 1999;10:1253–63.PubMedGoogle Scholar
  7. 7.
    Jerums G, Allen TJ, Campbell DJ, et al. Long-term comparison between perindopril and nifedipine in normotensive patients with type 1 diabetes and microalbuminuria. Am J Kidney Dis. 2001;37:890–9.CrossRefPubMedGoogle Scholar
  8. 8.
    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;366:895–906.CrossRefPubMedGoogle Scholar
  9. 9.
    Patel A, MacMahon S, Chalmers J, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829–40.CrossRefPubMedGoogle Scholar
  10. 10.
    Dyker AG, Grosset DG, Lees K. Perindopril reduces blood pressure but not cerebral blood flow in patients with recent cerebral ischemic stroke. Stroke. 1997;28:580–3.PubMedGoogle Scholar
  11. 11.
    Nazir FS, Overell JR, Bolster A, Hilditch TE, Lees KR. Effect of perindopril on cerebral and renal perfusion on normotensives in mild early ischaemic stroke: a randomized controlled trial. Cerebrovasc Dis. 2005;19:77–83.CrossRefPubMedGoogle Scholar
  12. 12.
    PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6, 105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358:1033–41.CrossRefGoogle Scholar
  13. 13.
    Management of stable angina pectoris. Recommendations of the Task Force of the European Society of Cardiology. Eur Heart J. 2006;27:1341–81.Google Scholar
  14. 14.
    Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics 2008 update. A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117:25–146.Google Scholar
  15. 15.
    Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. 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;342:145–53.CrossRefPubMedGoogle Scholar
  16. 16.
    The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:782–8.Google Scholar
  17. 17.
    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;87:1058–63.CrossRefPubMedGoogle Scholar
  18. 18.
    Braunwald E, Domanski MJ, Fowler SE, et al. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351:2058–68.CrossRefPubMedGoogle Scholar
  19. 19.
    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;333:1670–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Remme WJ. Secondary prevention of coronary artery disease and the choice of the ACE inhibitor why EUROPA and not PEACE. Cardiovasc Drugs Ther. 2007;21:405–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Deckers JW, Goedhart DM, Boersma E, et al. Treatment benefit by perindopril in patients with stable coronary artery disease at different levels of risk. Eur Heart J. 2006; 27:796–801.Google Scholar
  22. 22.
    Buemi M, Corica F, Marino D, et al. Cardiovascular remodeling, apoptosis, and drugs. Am J Hypertens. 2000;13:450–4.CrossRefPubMedGoogle Scholar
  23. 23.
    Bertrand ME, Remme WJ, Fox KM, Ferrari R, Simoons ML. Effects of perindopril on long-term clinical outcome of patients with coronary artery disease and preserved left ventricular function. Int J Cardiol. 2007;121:57–61.CrossRefPubMedGoogle Scholar
  24. 24.
    Fox KM, Bertrand ME, Remme WJ, Ferrari R, Simoons ML, Deckers JW. Efficacy of perindopril in reducing risk of cardiac events in patients with revascularized coronary artery disease. Am Heart J. 2007;153:629–35.CrossRefPubMedGoogle Scholar
  25. 25.
    Yusuf S, Pogue J, Myers MG, et al. ACE inhibition in stable coronary artery disease. N Engl J Med. 2005;352:937–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials. ACE Inhibitor Myocardial Infarction Collaborative Group. Circulation 1998;97:2202–12.Google Scholar
  27. 27.
    Ferrari R. Effects of angiotensin-converting enzyme inhibition with perindopril on left ventricular remodeling and clinical outcome: results of the randomized Perindopril and Remodeling in Elderly with Acute Myocardial Infarction (PREAMI) Study. Arch Intern Med. 2006;166:659–66.CrossRefPubMedGoogle Scholar
  28. 28.
    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;342:821–8.Google Scholar
  29. 29.
    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;327:669–77.CrossRefPubMedGoogle Scholar
  30. 30.
    Fox KM. Management of coronary artery disease: implications of the EUROPA trial. Br J Cardiol. 2004;11:195–204.Google Scholar
  31. 31.
    Van de WF, Ardissino D, Betriu A, et al. Management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2003;24:28–66.Google Scholar
  32. 32.
    Jessup M, Brozena S. Heart failure. N Engl J Med. 2003;348:2007–18.CrossRefPubMedGoogle Scholar
  33. 33.
    Remme WJ, Deckers JW, Fox KM, Ferrari R, Bertrand M, Simoons ML. Secondary prevention of coronary disease with ACE inhibition–does blood pressure reduction with perindopril explain the benefits in EUROPA? Cardiovasc Drugs Ther. 2009;23:161–70.CrossRefPubMedGoogle Scholar
  34. 34.
    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;364:849–57.CrossRefPubMedGoogle Scholar
  35. 35.
    Dzau VJ, Bernstein K, Celermajer D, et al. Pathophysiologic and therapeutic importance of tissue ACE: a consensus report. Cardiovasc Drugs Ther. 2002;16:149–60.CrossRefPubMedGoogle Scholar
  36. 36.
    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;99:2375–85.CrossRefPubMedGoogle Scholar
  37. 37.
    Falk E. Pathogenesis of atherosclerosis. J Am Coll Cardiol. 2006;47:C7–C12.CrossRefPubMedGoogle Scholar
  38. 38.
    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;103:630–3.PubMedGoogle Scholar
  39. 39.
    Ferrari R, Guardigli G, Mele D, Valgimigli M, Ceconi C. Myocardial ischaemia: new evidence for angiotensin-converting enzyme inhibition. Eur Heart J. 2003;5:E11–7.CrossRefGoogle Scholar
  40. 40.
    Ferrari R. Angiotensin-converting enzyme inhibition in cardiovascular disease: evidence with perindopril. Expert Rev Cardiovasc Ther. 2005;3:15–29.CrossRefPubMedGoogle Scholar
  41. 41.
    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;21:269–79.CrossRefPubMedGoogle Scholar
  42. 42.
    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 IntraVascular Ultrasound Evaluation [PERSPECTIVE] Study). Am J Cardiol. 2007;100:159–63.CrossRefPubMedGoogle Scholar
  43. 43.
    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;28:2326–31.CrossRefPubMedGoogle Scholar
  44. 44.
    Daly CA, Fox KM, Remme WJ, Bertrand ME, Ferrari R, Simoons ML. 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;26:1369–78.CrossRefPubMedGoogle Scholar
  45. 45.
    Ceconi C, Fox KM, Remme WJ, et al. ACE inhibition with perindopril and biomarkers of atherosclerosis and thrombosis: results from the PERTINENT study. Atherosclerosis. 2009;204:273–5.CrossRefPubMedGoogle Scholar
  46. 46.
    Ceconi C, Francolini G, Bastianon D, Gitti GL, Comini L, Ferrari R. 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;21:423–9.CrossRefPubMedGoogle Scholar
  47. 47.
    Ferrari R, Bertrand ME, Remme WJ, Simoons ML, Deckers JW, Fox KM. Insight into ACE inhibition in the prevention of cardiac events in stable coronary artery disease: the EUROPA trial. Expert Rev Cardiovasc Ther. 2007;5:1037–46.CrossRefPubMedGoogle Scholar
  48. 48.
    Valgimigli M, Rigolin GM, Fucili A, et al. CD34+ and endothelial progenitor cells in patients with various degrees of congestive heart failure. Circulation. 2004;110:1209–12.CrossRefPubMedGoogle Scholar
  49. 49.
    Valgimigli M, Rigolin GM, Cittanti C, et al. Use of granulocyte-colony stimulating factor during acute myocardial infarction to enhance bone marrow stem cell mobilization in humans: clinical and angiographic safety profile. Eur Heart J. 2005;26:1838–45.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Roberto Ferrari
    • 1
    • 2
  • Gabriele Guardigli
    • 3
  • Claudio Ceconi
    • 1
    • 2
  1. 1.Chair of Cardiology, University of Ferrara, Cardiovascular InstituteArcispedale S. Anna HospitalFerraraItaly
  2. 2.Cardiovascular Research CentreSalvatore Maugeri Foundation, IRCCSFerraraItaly
  3. 3.University Hospital of FerraraFerraraItaly

Personalised recommendations