Skip to main content
SpringerLink
Log in

RAS blockade with ARB and ACE inhibitors: current perspective on rationale and patient selection

  • REVIEW
  • Published:
Clinical Research in Cardiology Aims and scope Submit manuscript

Abstract

Cardiovascular disease represents a continuum that starts with risk factors such as hypertension and progresses to atherosclerosis, target organ damage, and ultimately to myocardial infarction, heart failure, stroke or death. Renin-angiotensin system (RAS) blockade with angiotensin converting enzyme (ACE) inhibitors or angiotensin AT1-receptor blockers (ARBs) has turned out to be beneficial at all stages of this continuum. Both classes of agent can prevent or reverse endothelial dysfunction and atherosclerosis, thereby reducing the risk of cardiovascular events. Such a reduction has been shown mainly for ACE inhibitors in patients with coronary artery disease, but recent studies revealed that ARBs are not inferior in this respect. However, no such data are currently available on the combination of these drugs. Both ACE inhibitors and ARBs have been shown to reduce target organ damage in organs such as the kidney, brain and heart, and to decrease cardiovascular mortality and morbidity in patients with congestive heart failure. Experimental data point to an influence of ACE inhibitors and ARBs on the number and function of endothelial progenitor cells revealing additional mechanisms of action of these drugs. The VALIANT trial has shown equivalent effects of ARB valsartan and the ACE-inhibitor captopril in patients post myocardial infarction, but the dual RAS-blockade, compared to monotherapy, did not further reduce events. In secondary prevention, the most-recently published ONTARGET study provides evidence that on top of a better tolerability AT1-receptors antagonists are equal to ACE inhibitors in the prevention of clinical endpoints like cardiovascular mortality and morbidity, myocardial infarction and stroke. The combined RAS blockade, however, achieved no further benefits in vascular high-risk patients and was associated with more adverse events. In chronic heart failure, ValHeFT and CHARM-ADDED have shown that combined RAS inhibition with ACE inhibitor and valsartan or candesartan reduced morbidity and mortality in certain patient subgroups. Accumulating evidence also points to benefits of the combination therapy in individuals with proteinuric nephropathies. In conclusion, while combined RAS-inhibition is not generally indicated in patients along the cardio-reno-vascular continuum, it has already proven to be effective in heart failure patients with incomplete neuroendocrine blockade. In secondary prevention, monotherapy with either RAS inhibitor is equally efficacious. Furthermore, novel pharmacologic agents such as renin inhibitors may prove useful in preventing common side effects of RAS blockade such as angiotensin escape and AT1-receptor upregulation, giving clinicians additional therapeutic tools to optimally treat the individual patient.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Bahlmann FH, de Groot K, Mueller O, Hertel B, Haller H, Fliser D (2005) Stimulation of endothelial progenitor cells: a new putative therapeutic effect of angiotensin II receptor antagonists. Hypertension 45:526–529

    Article  PubMed  CAS  Google Scholar 

  2. Barnett AH (2005) Preventing renal complications in diabetic patients: the diabetics exposed to telmisartan and enalaprIL (DETAIL) study. Acta Diabetol 42(Suppl 1):S42–S49

    Article  PubMed  CAS  Google Scholar 

  3. Baumhäkel M, Böhm M (2007) Erectile dysfunction correlates with left ventricular function and precedes cardiovascular events in cardiovascular high-risk patients. Int J Clin Pract 61:361–366

    Article  PubMed  Google Scholar 

  4. Bosch J, Yusuf S, Pogue J, Sleight P, Lonn E, Rangoonwala B, Davies R, Ostergren J, Probstfield J (2002) Use of ramipril in preventing stroke: double blind randomised trial. BMJ 324:699–702

    Article  PubMed  CAS  Google Scholar 

  5. Braunwald E, Domanski MJ, Fowler SE, Geller NL, Gersh BJ, Hsia J, Pfeffer MA, Rice MM, Rosenberg YD, Rouleau JL (2004) Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 351:2058–2068

    Article  PubMed  CAS  Google Scholar 

  6. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S (2001) Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345:861–869

    Article  PubMed  CAS  Google Scholar 

  7. Brown JD, Plutzky J (2007) Peroxisome proliferator-activated receptors as transcriptional nodal points and therapeutic targets. Circulation 115:518–533

    Article  PubMed  CAS  Google Scholar 

  8. Böhm M, Baumhäkel M, Probstfield JL, Schmieder R, Yusuf S, Zhao F, Koon T (2007) Sexual function, satisfaction, and association of erectile dysfunction with cardiovascular disease and risk factors in cardiovascular high-risk patients: substudy of the ongoing telmisartan alone and in combination with ramipril global endpoint trial/telmisartan randomized assessment study in ACE-intolerant subjects with cardiovascular disease (ONTARGET/TRANSCEND). Am Heart J 154:94–101

    Article  PubMed  Google Scholar 

  9. Candido R, Jandeleit-Dahm KA, Cao Z, Nesteroff SP, Burns WC, Twigg SM, Dilley RJ, Cooper ME, Allen TJ (2002) Prevention of accelerated atherosclerosis by angiotensin-converting enzyme inhibition in diabetic apolipo-protein E-deficient mice. Circulation 106:246–253

    Article  PubMed  CAS  Google Scholar 

  10. Cheng W, Kajstura J, Nitahara JA, Li B, Reiss K, Liu Y, Clark WA, Krajewski S, Reed JC, Olivetti G, Anversa P (1996) Programmed myocyte cell death affects the viable myocardium after infarction in rats. Exp Cell Res 226:316–327

    Article  PubMed  CAS  Google Scholar 

  11. Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H (2002) Cardiovascular morbidity and mortality in the Losartan Intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 359:995–1003

    Article  PubMed  Google Scholar 

  12. Dickstein K, Kjekshus J (2002) Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal trial in myocardial infarction with Angiotensin II Antagonist Losartan. Lancet 360:752–760

    Article  PubMed  CAS  Google Scholar 

  13. Diet F, Pratt RE, Berry GJ, Momose N, Gibbons GH, Dzau VJ (1996) Increased accumulation of tissue ACE in human atherosclerotic coronary artery disease. Circulation 94:2756–2767

    PubMed  CAS  Google Scholar 

  14. Doulton TW, He FJ, Macgregor GA (2005) Systematic review of combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade in hypertension. Hypertension 45:880–886

    Article  PubMed  CAS  Google Scholar 

  15. Dzau V, Braunwald E (1991) Resolved and unresolved issues in the prevention and treatment of coronary artery disease: a workshop consensus statement. Am Heart J 121:1244–1263

    Article  PubMed  CAS  Google Scholar 

  16. Düsing R (2005) Sexual dysfunction in male patients with hypertension: influence of antihypertensive drugs. Drugs 65:773–786

    Article  PubMed  Google Scholar 

  17. Elliott WJ, Meyer PM (2007) Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet 369:201–207

    Article  PubMed  CAS  Google Scholar 

  18. Fogari R, Zoppi A, Poletti L, Marasi G, Mugellini A, Corradi L (2001) Sexual activity in hypertensive men treated with valsartan or carvedilol: a crossover study. Am J Hypertens 14:27–31

    Article  PubMed  CAS  Google Scholar 

  19. Fox KM (2003) 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 362:782–788

    Article  PubMed  CAS  Google Scholar 

  20. Friedrich EB, Teo KK, Böhm M (2006) ACE inhibition in secondary prevention: are the results controversial? Clin Res Cardiol 95:61–67

    Article  PubMed  CAS  Google Scholar 

  21. Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS, Ferguson TB Jr, Fihn SD, Fraker TD Jr, Gardin JM, O’Rourke RA, Pasternak RC, Williams SV, Gibbons RJ, Alpert JS, Antman EM, Hiratzka LF, Fuster V, Faxon DP, Gregoratos G, Jacobs AK, Smith SC Jr (2003) ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). Circulation 107:149–158

    Article  PubMed  Google Scholar 

  22. Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J, Pfeffer MA, Swedberg K (2003) Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 362:772–776

    Article  PubMed  CAS  Google Scholar 

  23. Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, Luomanmaki K, Dahlöf B, de Faire U, Morlin C, Karlberg BE, Wester PO, Bjorck JE (1999) Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 353:611–616

    Article  PubMed  CAS  Google Scholar 

  24. Heart Outcomes Prevention Evaluation Study Investigators (2000) Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 355:253–259

    Article  Google Scholar 

  25. Hoppe UC (2007) Treatment of heart failure with ACE inhibitors and beta-blockers: what is next? AT1-receptor antagonists? Clin Res Cardiol 96:196–198

    Article  PubMed  CAS  Google Scholar 

  26. Hoshida S, Kato J, Nishino M, Egami Y, Takeda T, Kawabata M, Tanouchi J, Yamada Y, Kamada T (2001) Increased angiotensin-converting enzyme activity in coronary artery specimens from patients with acute coronary syndrome. Circulation 103:630–633

    PubMed  CAS  Google Scholar 

  27. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B (2005) ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 112:e154–e235

    Article  PubMed  Google Scholar 

  28. Julius S (1999) Long-term potential of angiotensin receptor blockade for cardiovascular protection in hypertension: the VALUE trial. Valsartan antihypertensive long-term use evaluation. Cardiology 91(Suppl 1):8–13

    Article  PubMed  CAS  Google Scholar 

  29. Komers R, Simkova R, Kazdova L, Ruzickova J, Pelikanova T (2004) Effects of ACE inhibition and AT1-receptor blockade on haemodynamic responses to l-arginine in Type 1 diabetes. J Renin Angiotensin Aldosterone Syst 5:33–38

    Article  PubMed  CAS  Google Scholar 

  30. Krum H, Carson P, Farsang C, Maggioni AP, Glazer RD, Aknay N, Chiang YT, Cohn JN (2004) Effect of valsartan added to background ACE inhibitor therapy in patients with heart failure: results from Val-HeFT. Eur J Heart Fail 6:937–945

    Article  PubMed  CAS  Google Scholar 

  31. Leri A, Claudio PP, Li Q, Wang X, Reiss K, Wang S, Malhotra A, Kajstura J, Anversa P (1998) Stretch-mediated release of angiotensin II induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system and decreases the Bcl-2-to-Bax protein ratio in the cell. J Clin Invest 101:1326–1342

    Article  PubMed  CAS  Google Scholar 

  32. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I (2001) Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345:851–860

    Article  PubMed  CAS  Google Scholar 

  33. Li Q, Li B, Wang X, Leri A, Jana KP, Liu Y, Kajstura J, Baserga R, Anversa P (1997) Overexpression of insulin-like growth factor-1 in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress, and cardiac hypertrophy. J Clin Invest 100:1991–1999

    Article  PubMed  CAS  Google Scholar 

  34. Lonn E, Shaikholeslami R, Yi Q, Bosch J, Sullivan B, Tanser P, Magi A, Yusuf S (2004) Effects of ramipril on left ventricular mass and function in cardiovascular patients with controlled blood pressure and with preserved left ventricular ejection fraction: a substudy of the heart outcomes prevention evaluation (HOPE) trial. J Am Coll Cardiol 43:2200–2206

    Article  PubMed  CAS  Google Scholar 

  35. Malhotra R, Sadoshima J, Brosius FC III, Izumo S (1999) Mechanical stretch and angiotensin II differentially upregulate the renin-angiotensin system in cardiac myocytes in vitro. Circ Res 85:137–146

    PubMed  CAS  Google Scholar 

  36. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, Narkiewicz K, Ruilope L, Rynkiewicz A, Schmieder RE, Struijker Boudier HA, Zanchetti A, Vahanian A, Camm J, De Caterina R, Dean V, Dickstein K, Filippatos G, Funck-Brentano C, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL, Kjeldsen SE, Erdine S, Narkiewicz K, Kiowski W, Agabiti-Rosei E, Ambrosioni E, Cifkova R, Dominiczak A, Fagard R, Heagerty AM, Laurent S, Lindholm LH, Mancia G, Manolis A, Nilsson PM, Redon J, Schmieder RE, Struijker-Boudier HA, Viigimaa M, Filippatos G, Adamopoulos S, Agabiti-Rosei E, Ambrosioni E, Bertomeu V, Clement D, Erdine S, Farsang C, Gaita D, Kiowski W, Lip G, Mallion JM, Manolis AJ, Nilsson PM, O’Brien E, Ponikowski P, Redon J, Ruschitzka F, Tamargo J, van Zwieten P, Viigimaa M, Waeber B, Williams B, Zamorano JL (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 28:1462–1536

    PubMed  Google Scholar 

  37. 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 (1999) Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. The RESOLVD pilot study investigators. Circulation 100:1056–1064

    PubMed  CAS  Google Scholar 

  38. McMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL, Olofsson B, Yusuf S, Pfeffer MA (2003) Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 362:767–771

    Article  PubMed  CAS  Google Scholar 

  39. McMurray J, Solomon S, Pieper K, Reed S, Rouleau J, Velazquez E, White H, Howlett J, Swedberg K, Maggioni A, Kober L, Van de WF, Califf R, Pfeffer M (2006) The effect of valsartan, captopril, or both on atherosclerotic events after acute myocardial infarction: an analysis of the Valsartan in acute myocardial infarction trial (VALIANT). J Am Coll Cardiol 47:726–733

    Google Scholar 

  40. Menard J, Azizi M (2007) The difficult conception, birth and delivery of a renin inhibitor: controversies around aliskiren. J Hypertens 25:1775–1782

    Article  PubMed  CAS  Google Scholar 

  41. Mochizuki S, Dahlof B, Shimizu M, Ikewaki K, Yoshikawa M, Taniguchi I, Ohta M, Yamada T, Ogawa K, Kanae K, Kawai M, Seki S, Okazaki F, Taniguchi M, Yoshida S, Tajima N (2007) Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomised, open-label, blinded endpoint morbidity-mortality study. Lancet 369:1431–1439

    Article  PubMed  CAS  Google Scholar 

  42. Negro R, Formoso G, Hassan H (2006) The effects of irbesartan and telmisartan on metabolic parameters and blood pressure in obese, insulin resistant, hypertensive patients. J Endocrinol Invest 29:957–961

    PubMed  CAS  Google Scholar 

  43. Nickenig G, Harrison DG (2002) The AT(1)-type angiotensin receptor in oxidative stress and atherogenesis: part I: oxidative stress and atherogenesis. Circulation 105:393–396

    Article  PubMed  CAS  Google Scholar 

  44. Nickenig G, Harrison DG (2002) The AT(1)-type angiotensin receptor in oxidative stress and atherogenesis: Part II: AT(1) receptor regulation. Circulation 105:530–536

    Article  PubMed  CAS  Google Scholar 

  45. Okunishi H, Miyazaki M, Toda N (1984) Evidence for a putatively new angiotensin II-generating enzyme in the vascular wall. J Hypertens 2:277–284

    Article  PubMed  CAS  Google Scholar 

  46. Parving HH (2007) AVOID: Aliskiren in the evaluation of proteinuria in diabetes. American Society of Nephrology Renal Week Oral Presentation, Poster SA-P01051

  47. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P (2001) The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 345:870–878

    Article  PubMed  CAS  Google Scholar 

  48. Pepine CJ, Probstfield JL (2004) A HOPE for PEACE? Update on the role of ACE inhibition in CAD patients, CME monograph, UF College of Medicine. Vasc Biol Clin Pract 6

  49. Perticone F, Ceravolo R, Pujia A, Ventura G, Iacopino S, Scozzafava A, Ferraro A, Chello M, Mastroroberto P, Verdecchia P, Schillaci G (2001) Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation 104:191–196

    PubMed  CAS  Google Scholar 

  50. Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober L, Maggioni AP, Solomon SD, Swedberg K, Van de WF, White H, Leimberger JD, Henis M, Edwards S, Zelenkofske S, Sellers MA, Califf RM (2003) Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 349:1893–1906

    Article  PubMed  CAS  Google Scholar 

  51. Pitt B, O’Neill B, Feldman R, Ferrari R, Schwartz L, Mudra H, Bass T, Pepine C, Texter M, Haber H, Uprichard A, Cashin-Hemphill L, Lees RS (2001) 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 87:1058–1063

    Article  PubMed  CAS  Google Scholar 

  52. Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, Camm AJ, Konstam MA, Riegger G, Klinger GH, Neaton J, Sharma D, Thiyagarajan B (2000) Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial—the Losartan Heart Failure Survival Study ELITE II. Lancet 355:1582–1587

    Article  PubMed  CAS  Google Scholar 

  53. Progress collaborative group (2001) Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 358:1033–1041

    Article  Google Scholar 

  54. Quyyumi AA (1998) Endothelial function in health and disease: new insights into the genesis of cardiovascular disease. Am J Med 105:32S–39S

    Article  PubMed  CAS  Google Scholar 

  55. Recio-Mayoral A, Kaski JC, McMurray JJ, Horowitz J, van Veldhuisen DJ, Remme WJ (2007) Clinical Trials Update from the European Society of Cardiology Congress in Vienna, 2007: PROSPECT, EVEREST, ARISE, ALOFT, FINESSE, Prague-8, CARESS in MI and ACUITY. Cardiovasc Drugs Ther 21:459–465

    Article  PubMed  CAS  Google Scholar 

  56. Ruggenenti P, Fassi A, Ilieva AP, Bruno S, Iliev IP, Brusegan V, Rubis N, Gherardi G, Arnoldi F, Ganeva M, Ene-Iordache B, Gaspari F, Perna A, Bossi A, Trevisan R, Dodesini AR, Remuzzi G (2004) Preventing microalbuminuria in type 2 diabetes. N Engl J Med 351:1941–1951

    Article  PubMed  CAS  Google Scholar 

  57. Sadoshima J, Qiu Z, Morgan JP, Izumo S (1995) Angiotensin II and other hypertrophic stimuli mediated by G protein-coupled receptors activate tyrosine kinase, mitogen-activated protein kinase, and 90-kDa S6 kinase in cardiac myocytes. The critical role of Ca(2+)-dependent signaling. Circ Res 76:1–15

    PubMed  CAS  Google Scholar 

  58. Sadoshima J, Xu Y, Slayter HS, Izumo S (1993) Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell 75:977–984

    Article  PubMed  CAS  Google Scholar 

  59. Scaglione R, Argano C, Di Chiara T, Parrinello G, Colomba D, Avellone G, Donatelli M, Corrao S, Licata G (2007) Effect of dual blockade of renin-angiotensin system on TGFbeta1 and left ventricular structure and function in hypertensive patients. J Hum Hypertens 21:307–315

    PubMed  CAS  Google Scholar 

  60. Schefe JH, Menk M, Reinemund J, Effertz K, Hobbs RM, Pandolfi PP, Ruiz P, Unger T, Funke-Kaiser H (2006) A novel signal transduction cascade involving direct physical interaction of the renin/prorenin receptor with the transcription factor promyelocytic zinc finger protein. CircRes 99:1355–1366

    CAS  Google Scholar 

  61. Schieffer B, Schieffer E, Hilfiker-Kleiner D, Hilfiker A, Kovanen PT, Kaartinen M, Nussberger J, Harringer W, Drexler H (2000) Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability. Circulation 101:1372–1378

    PubMed  CAS  Google Scholar 

  62. Schmieder RE (2006) Endothelial dysfunction: how can one intervene at the beginning of the cardiovascular continuum? J Hypertens Suppl 24:S31–S35

    Article  PubMed  CAS  Google Scholar 

  63. Schmieder RE, Hilgers KF, Schlaich MP, Schmidt BM (2007) Renin-angiotensin system and cardiovascular risk. Lancet 369:1208–1219

    Article  PubMed  CAS  Google Scholar 

  64. Schmieder RE, Schrader J, Zidek W, Tebbe U, Paar WD, Bramlage P, Pittrow D, Böhm M (2007) Low-grade albuminuria and cardiovascular risk: what is the evidence? Clin Res Cardiol 96:247–257

    Article  PubMed  CAS  Google Scholar 

  65. Schupp M, Clemenz M, Gineste R, Witt H, Janke J, Helleboid S, Hennuyer N, Ruiz P, Unger T, Staels B, Kintscher U (2005) Molecular characterization of new selective peroxisome proliferator-activated receptor gamma modulators with angiotensin receptor blocking activity. Diabetes 54:3442–3452

    Article  PubMed  CAS  Google Scholar 

  66. Sealey JE, Laragh JH (2007) Aliskiren, the first renin inhibitor for treating hypertension: reactive renin secretion may limit its effectiveness. Am J Hypertens 20:587–597

    Article  PubMed  CAS  Google Scholar 

  67. Sleight P (2005) The ONTARGET/TRANSCEND trial programme: baseline data. Acta Diabetol 42(Suppl 1):S50–S56

    Article  PubMed  Google Scholar 

  68. Solomon SD, Skali H, Anavekar NS, Bourgoun M, Barvik S, Ghali JK, Warnica JW, Khrakovskaya M, Arnold JM, Schwartz Y, Velazquez EJ, Califf RM, McMurray JV, Pfeffer MA (2005) Changes in ventricular size and function in patients treated with valsartan, captopril, or both after myocardial infarction. Circulation 111:3411–3419

    Article  PubMed  CAS  Google Scholar 

  69. Steckelings UM, Kaschina E, Unger T (2005) The AT2 receptor–a matter of love and hate. Peptides 26:1401–1409

    Article  PubMed  CAS  Google Scholar 

  70. Steckelings UM, Rettig R, Unger T (2007) Angiotensin in the kidney: a key to understanding hypertension? Cell Metab 5:7–8

    Article  PubMed  CAS  Google Scholar 

  71. Strawn WB, Chappell MC, Dean RH, Kivlighn S, Ferrario CM (2000) Inhibition of early atherogenesis by losartan in monkeys with diet-induced hypercholesterolemia. Circulation 101:1586–1593

    PubMed  CAS  Google Scholar 

  72. Tan KC, Xu A, Chow WS, Lam MC, Ai VH, Tam SC, Lam KS (2004) Hypoadiponectinemia is associated with impaired endothelium-dependent vasodilation. J Clin Endocrinol Metab 89:765–769

    Article  PubMed  CAS  Google Scholar 

  73. Teo K, Yusuf S, Sleight P, Anderson C, Mookadam F, Ramos B, Hilbrich L, Pogue J, Schumacher H (2004) Rationale, design, and baseline characteristics of two large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials. Am Heart J 148:52–61

    Article  PubMed  Google Scholar 

  74. The CONSENSUS Trial Study Group (1987) Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 316:1429–1435

    Google Scholar 

  75. ONTARGET Investigators, Yusuf S, Teo KK, Poque Y, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P, Anderson C (2008) Telmisartan, ramipril, or both in patients at high risk for vascular events. N EnglJ Med 358:1615–1616

    Article  Google Scholar 

  76. UK Prospective Diabetes Study Group (1998) Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 317:713–720

    Google Scholar 

  77. Unger T, Stoppelhaar M (2007) Rationale for double renin-angiotensin-aldosterone system blockade. Am J Cardiol 100:25J–31J

    Article  PubMed  CAS  Google Scholar 

  78. Van dH I, Voors AA, van Veldhuisen DJ (2007) Treatment of heart failure with ACE inhibitors and beta-blockers: what is next? Aldosterone receptor antagonists? Clin Res Cardiol 96:193–195

  79. Viberti G, Wheeldon NM (2002) Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation 106:672–678

    Article  PubMed  CAS  Google Scholar 

  80. Warnholtz A, Nickenig G, Schulz E, Macharzina R, Brasen JH, Skatchkov M, Heitzer T, Stasch JP, Griendling KK, Harrison DG, Böhm M, Meinertz T, Munzel T (1999) Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin-angiotensin system. Circulation 99:2027–2033

    PubMed  CAS  Google Scholar 

  81. Wassmann S, Nickenig G (2006) Pathophysiological regulation of the AT1-receptor and implications for vascular disease. J Hypertens Suppl 24:S15–S21

    Article  PubMed  CAS  Google Scholar 

  82. Weber M (2003) The telmisartan Programme of Research tO show Telmisartan End-organ proteCTION (PROTECTION) programme. J Hypertens Suppl 21:S37–S46

    Article  CAS  Google Scholar 

  83. Yamazaki T, Komuro I, Kudoh S, Zou Y, Shiojima I, Mizuno T, Takano H, Hiroi Y, Ueki K, Tobe K (1995) Angiotensin II partly mediates mechanical stress-induced cardiac hypertrophy. Circ Res 77:258–265

    PubMed  CAS  Google Scholar 

  84. Yao EH, Yu Y, Fukuda N (2006) Oxidative stress on progenitor and stem cells in cardiovascular diseases. Curr Pharm Biotechnol 7:101–108

    Article  PubMed  CAS  Google Scholar 

  85. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G (2000) 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 342:145–153

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Klinik für Innere Medizin III - Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Kirrberger Straße, 66421, Homburg/Saar, Germany

    Christian Werner, Magnus Baumhäkel & Michael Böhm

  2. Population Health Research Institute, McMaster University-Hamilton Health Sciences, L8L 2X2, Hamilton, ON, Canada

    Koon K. Teo & Salim Yusuf

  3. Medizinische Klinik 4, Universitätsklinikum Erlangen, Krankenhausstr. 12, 91054, Erlangen, Germany

    Roland Schmieder

  4. Klinik für Nieren-, Hochdruck- und Rheumakrankheiten, Krankenhaus München Schwabing, Kölner Platz 1, 80804, München, Germany

    Johannes Mann

  5. Center for Cardiovascular Research (CCR), Institut für Pharmakologie Charité – Universitätsmedizin Berlin, Hessische Str. 3-4, 10115, Berlin, Germany

    Thomas Unger

Authors
  1. Christian Werner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Magnus Baumhäkel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Koon K. Teo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roland Schmieder
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Johannes Mann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thomas Unger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Salim Yusuf
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michael Böhm
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Böhm.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Werner, C., Baumhäkel, M., Teo, K.K. et al. RAS blockade with ARB and ACE inhibitors: current perspective on rationale and patient selection. Clin Res Cardiol 97, 418–431 (2008). https://doi.org/10.1007/s00392-008-0668-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00392-008-0668-3

Keywords

Search

Navigation