American Journal of Cardiology
Volume 105, Issue 1, Supplement , Pages 10A-20A , 4 January 2010

Progression of Cardiovascular Damage: The Role of Renin–Angiotensin System Blockade

  • Jeffrey L. Probstfield, MD

      Affiliations

    • Corresponding Author InformationAddress for reprints: Jeffrey L. Probstfield, MD, Clinical Trials Service Unit; Division of Cardiology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington
  • ,
  • Kevin D. O'Brien, MD

References 

  1. Dzau V, Braunwald E. Resolved and unresolved issues in the prevention and treatment of coronary artery disease: a workshop consensus. Am Heart J. 1991;121:1244–1263
  2. McFarlane SI, Kumar A, Sowers JR. Mechanisms by which angiotensin-converting enzyme inhibitors prevent diabetes and cardiovascular disease. Am J Cardiol. 2003;91(suppl):30H–37H
  3. Duprez DA. Role of the renin-angiotensin-aldosterone system in vascular remodeling and inflammation: a clinical review. J Hypertens. 2006;24:983–991
  4. Erdös EG. The ACE and I: how ACE inhibitors came to be. FASEB J. 2006;20:1034–1038
  5. Ferrario CM, Strawn WB. Role of the renin-angiotensin-aldosterone system and proinflammatory mediators in cardiovascular disease. Am J Cardiol. 2006;98:121–128
  6. Jacoby DS, Rader DJ. Renin-angiotensin system and atherothrombotic disease: from genes to treatment. Arch Intern Med. 2003;163:1155–1164
  7. Petrie MC, Padmanabhan N, McDonald JE, Hillier C, Connell JM, McMurray JJ. Angiotensin converting enzyme (ACE) and non-ACE dependent angiotensin II generation in resistance arteries from patients with heart failure and coronary artery disease. J Am Coll Cardiol. 2001;37:1056–10661
  8. Borland JA, Kelsall C, Yacoub MH, Chester AH. Expression, localization and function of ACE and chymase in normal and atherosclerotic human coronary arteries. Vasc Pharmacol. 2005;42:99–108
  9. Zisman LS. ACE and ACE2: a tale of two enzymes. Eur Heart J. 2005;26:322–324
  10. Santos RA, Simoes e Silva AC, Maric C, Silva DM, Machado RP, de Buhr I, et al Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci U S A. 2003;100:8258–8263
  11. Murphey L, Vaughan D, Brown N. Contribution of bradykinin to the cardioprotective effects of ACE inhibitors. Eur Heart J. 2003;5(suppl A):A37–A41
  12. Bonner G, Schunk U. Hypotensive effect of bradykinin in normotensives and patients with renovascular hypertension. Adv Exp Med Biol. 1986;198:321–327
  13. Struthers AD, MacDonald TM. Review of aldosterone- and angiotensin II-induced target organ damage and prevention. Cardiovasc Res. 2004;61:663–670
  14. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709–717
  15. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective aldosterone blocker, in patients with left-ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309–1321
  16. Goulter AB, Goddard MJ, Allen JC, Clark KL. ACE2 gene expression is up-regulated in the human failing heart. BMC Med. 2004;2:19
  17. Zisman LS, Keller RS, Weaver B, Lin Q, Speth R, Bristow MR, et al. Increased angiotensin-(1-7) forming activity in failing human heart ventricles: evidence for upregulation of the angiotensin-converting enzyme homologue, ACE2. Circulation. 2003;108:1707–1712
  18. Xiao HD, Fuchs S, Frenzel K, Teng L, Bernstein KE. Circulating versus local angiotensin II in blood pressure control: lessons from tissue-specific expression of angiotensin-converting enzyme (ACE). Crit Rev Eukaryot Gene Expr. 2004;14:137–145
  19. Fleming I. Signaling by the angiotensin-converting enzyme. Cir Res. 2006;98:887–896
  20. Rousseau A, Michaud A, Chauvet MT, Lenfant M, Corvol P. The hemoregulatory peptide N-acetyl-Ser-Asp-Lys-Pro is a natural and specific substrate of the N-terminal site of human angiotensin-converting enzyme. J Biol Chem. 1995;270:3656–3661
  21. Wang D, Carretero OA, Yang XY, Rhaleb NE, Liu YH, Liao TD, et al. N-acetyl-seryl-aspartyl-lysyl-proline stimulates angiogenesis in vitro and in vivo. Am J Physiol Heart Circ Physiol. 2004;287:H2099–H2105
  22. Peng H, Carretero OA, Brigstock DR, Oja-Tebbe N, Rhaleb NE. Ac-SDKP reverses cardiac fibrosis in rats with renovascular hypertension. Hypertension. 2003;42:1164–1170
  23. Hu J, Igarashi A, Kamata M, Nakagawa H. Angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide (Ab); retards Ab aggregation, deposition, fibril formation; and inhibits cytotoxicity. J Biol Chem. 2001;276:47863–47868
  24. Fleming I, Kohlstedt K, Busse R. New fACEs to the renin-angiotensin system. Physiology. 2005;20:91–95
  25. Mancini GB, Henry GC, Macaya C, O'Neill BJ, Pucillo AL, Carere RG, et al 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
  26. Schartl M, Bocksch WG, Dreysse S, Beckmann S, Franke O, Hünten U. Remodeling of myocardium and arteries by chronic angiotensin converting enzyme inhibition in hypertensive patients. J Hypertens Suppl. 1994;12:S37–S42
  27. Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:253–259
  28. 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. Consensus Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (Consensus). N Engl J Med. 1987;316:1429–1435
  30. Wiemer G, Schölkens BA, Becker RHA, Busse R. Ramiprilat enhances endothelial autocoid formation by inhibiting breakdown of endothelium-derived bradykinin. Hypertension. 1991;18:558–563
  31. Benzing T, Fleming I, Blaukat A, Müller-Esterl W, Busse R. Angiotensin-converting enzyme inhibitor ramiprilat interferes with the sequestration of the B2 kinin receptor within the plasma membrane of native endothelial cells. Circulation. 1999;99:2034–2040
  32. Minshall RD, Tan F, Nakamura F, Rabito SF, Becker RP, Marcic B, et al. Potentiation of the actions of bradykinin by angiotensin I-converting enzyme inhibitors: the role of expressed human bradykinin B2 receptors and angiotensin I-converting enzyme in CHO cells. Circ Res. 1997;81:848–856
  33. Strauss MH, Hall AS. Angiotensin receptor blockers may increase risk of myocardial infarction: unraveling the ARB-MI paradox. Circulation. 2006;114:838–854
  34. Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, et al Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995–1003
  35. Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, et al. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003;21:875–886
  36. Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, et al. 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. 2003;362:772–776
  37. Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667–1675
  38. Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Køber L, Maggioni AP, et al Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:1893–1906
  39. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–860
  40. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–869
  41. Yusuf S, Ostergren JB, Gerstein HC, Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on the development of a new diagnosis of diabetes mellitus in patients with heart failure. Circulation. 2005;112:48–53
  42. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, et al Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004;363:2022–2031
  43. Verma S, Strauss M. Angiotensin receptor blockers and myocardial infarction. BMJ. 2004;329:1248–1249
  44. Senbonmatsu T, Ichihara S, Price E, Gaffney FA, Inagami T. Evidence for angiotensin II type 2 receptor-mediated cardiac myocyte enlargement during in vivo pressure overload. J Clin Invest. 2000;106:R25–R29
  45. D'Amore A, Black MJ, Thomas WG. The angiotensin II type 2 receptor causes constitutive growth of cardiomyocytes and does not antagonize angiotensin II type 1 receptor-mediated hypertrophy. Hypertension. 2005;46:1347–1354
  46. Kim MP, Zhou M, Wahl LM. Angiotensin II increases human monocyte matrix metalloproteinase-1 through the AT2 receptor and prostaglandin E2: implications for atherosclerotic plaque rupture. J Leukoc Biol. 2005;78:195–201
  47. Tsuyuki RT, McDonald MA. Angiotensin receptor blockers do not increase risk of myocardial infarction. Circulation. 2006;114:855–860
  48. McMurray J, Solomon S, Pieper K, Reed S, Rouleau J, Velazquez E, et al 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. 2006;47:726–733
  49. Brown NJ, Kumar S, Painter CA, Vaughan DE. ACE inhibition versus angiotensin type 1 receptor antagonism: differential effects on PAI-1 over time. Hypertension. 2002;40:859–865
  50. Clasen R, Schupp M, Foryst-Ludwig A, Sprang C, Clemenz M, Krikov M, et al. PPARγ-activating angiotensin type-1 receptor blockers induce adiponectin. Hypertension. 2005;46:137–143
  51. Nakaya K, Ayaori M, Hisada T, Sawada S, Tanaka N, Iwamoto N, et al. Telmisartan enhances cholesterol efflux from THP-1 macrophages by activating PPARγ. J Atheroscler Thromb. 2007;14:133–141
  52. Staessen JA, Li V, Richart T. Oral renin inhibitors. Lancet. 2006;368:1449–1456
  53. Pilz B, Shagdarsuren E, Wellner M, Fiebeler A, Dechend R, Gratze P, et al Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in double-transgenic rats. Hypertension. 2005;46:569–576
  54. Yusuf S, Hawken S, Ôunpuu S, Dans T, Avezum A, Lanas F, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364:937–952
  55. Engeli S, Böhnke J, Gorzelniak K, Janke J, Schling P, Bader M, et al. Weight loss and the renin-angiotensin-aldosterone system. Hypertension. 2005;45:356–362
  56. Henriksen EJ, Jacob S. Modulation of metabolic control by angiotensin converting enzyme (ACE) inhibition. J Cell Physiol. 2003;196:171–179
  57. Paul M, Mehr AP, Kreutz R. Physiology of local renin-angiotensin systems. Physiol Rev. 2006;86:747–803
  58. Sharma AM. Is there a rationale for angiotensin blockade in the management of obesity hypertension?. Hypertension. 2004;44:12–19
  59. Shiuchi T, Cui TX, Wu L, Nakagami H, Takeda-Matsubara Y, Iwai M, et al. ACE inhibitor improves insulin resistance in diabetic mouse via bradykinin and NO. Hypertension. 2002;40:329–334
  60. Abuisse H, Jones PG, Marso SP, O'Keefe JH. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes: a meta-analysis of randomized clinical trials. J Am Coll Cardiol. 2005;46:821–826
  61. Dagenais GR, Pogue J, Fox K, Simoons ML, Yusuf S. Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials. Lancet. 2006;368:581–588
  62. Bosch J, Yusuf S, Gerstein HC, Pogue J, Sheridan P, Dagenais G, et al. Effect of ramipril on the incidence of diabetes. N Engl J Med. 2006;355:1551–1562
  63. Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, et al Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomized controlled trial. Lancet. 2006;368:1096–1105
  64. Ceconi C, Fox KM, Remme WJ, Simoons ML, Bertrand M, Parrinello G, et al. ACE inhibition with perindopril and endothelial function (Results of a substudy of the EUROPA study: PERTINENT). Cardiovasc Res. 2007;73:237–246
  65. 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;362:782–788
  66. Koh KK, Han SH, Chung WJ, Ahn JY, Jin DK, Kim HS, et al. Comparison of effects of losartan, irbesartan, and candesartan on flow-mediated brachial artery dilation and on inflammatory and thrombolytic markers in patients with systemic hypertension. Am J Cardiol. 2004;93:1432–1435
  67. Ruilope LM, Redon J, Schmieder R. Cardiovascular risk reduction by reversing endothelial dysfunction: ARBs, ACE inhibitors, or both? Expectations from the ONTARGET Trial Programme. Vasc Health Risk Manag. 2007;3:1–9
  68. Schmieder RE, Delles C, Mimran A, Fauvel JP, Ruilope LM. Impact of telmisartan versus ramipril on renal endothelial function in patients with hypertension and type 2 diabetes. Diabetes Care. 2007;30:1351–1356
  69. Marketou ME, Zacharis EA, Koukouraki S, Stathaki MI, Arfanakis DA, Kochiadakis GE, et al. Effect of angiotensin-converting enzyme inhibitors on systemic inflammation and myocardial sympathetic innervation in normotensive patients with type 2 diabetes mellitus. J Hum Hypertens. 2008;22:191–196
  70. Mehta JL, Li D. Identification, regulation and function of a novel lectin-like oxidized low-density lipoprotein receptor. J Am Coll Cardiol. 2002;39:1429–1435
  71. Limor R, Kaplan M, Sawamura T, Sharon O, Keidar S, Weisinger G, et al. Angiotensin II increases the expression of lectin-like oxidized low-density lipoprotein receptor-1 in human vascular smooth muscle cells via a lipoxygenase-dependent pathway. Am J Hypertens. 2005;18:299–307
  72. Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest. 1994;94:2493–2503
  73. Nikkari ST, O'Brien KD, Ferguson M, Hatsukami T, Welgus HG, Alpers CE, et al. Interstitial collagenase (MMP-1) expression in human carotid atherosclerosis. Circulation. 1995;92:1393–1398
  74. Cipollone F, Prontera C, Pini B, Marnin M, Fazia M, De Cesare D, et al Overexpression of functionally coupled cyclooxygenase-2- and prostaglandin E synthase in symptomatic atherosclerotic plaques as a basis of prostaglandin E2-dependent plaque instability. Circulation. 2001;104:921–927
  75. Cipollone F, Fazia M, Lezzi A, Pini B, Cuccurullo C, Zucchelli M, et al Blockade of the angiotensin II type 1 receptor stabilizes atherosclerotic plaques in humans by inhibiting prostaglandin E2-dependent matrix metalloproteinase activity. Circulation. 2004;109:1482–1488
  76. Lonn E, Shaikholeslami R, Yi Q, Bosch J, Sullivan B, Tanser P, et al. 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 Protection Evaluation (HOPE) trial. J Am Coll Cardiol. 2004;43:2200–2206
  77. Devereux RB, Dahlöf B, Gerdts E, Boman K, Nieminen MS, Papademetriuo V, et al. Regression of hypertensive left ventricular hypertrophy by losartan compared with atenolol: the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial. Circulation. 2004;110:1456–1462
  78. Koh KK, Chung W-J, Ahn JY, Han SH, Kang WC, Seo YH, et al. Angiotensin II type 1 receptor blockers reduce tissue factor activity and plasminogen activator inhibitor type-1 antigen in hypertensive patients: a randomized, double-blind, placebo-controlled study. Atherosclerosis. 2004;177:155–160
  79. Matsumoto T, Minai K, Horie H, Ohira N, Takashima H, Tarutani Y, et al. Angiotensin-converting enzyme inhibition but not angiotensin II type 1 receptor antagonism augments coronary release of tissue plasminogen activator in hypertensive patients. J Am Coll Cardiol. 2003;41:1373–1379
  80. Lonn E, Yusuf S, Dzavik V, Doris C, Yi Q, Smith S, et al. Effects of ramipril and vitamin E on atherosclerosis: the Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E (SECURE). Circulation. 2001;103:919–925
  81. Ludwig M, Stapff M, Ribeiro A, Fritschka E, Tholl U, Smith RD, et al. Comparison of the effects of losartan and atenolol on common carotid artery intima-media thickness in patients with hypertension: results of a 2-year, double-blind, randomized, controlled study. Clin Ther. 2002;24:1175–1193
  82. Zanchetti A, Crepaldi G, Bond MG, Gallus G, Veglia F, Mancia G, et al. Different effects of antihypertensive regimens based on fosinopril or hydrochlorothiazide with or without lipid lowering by pravastatin on progression of asymptomatic carotid atherosclerosis: principal results of PHYLLIS—a randomized double-blind trial. Stroke. 2004;35:2807–2812
  83. Smith SC, Allen J, Blair SN, Bonow RO, Brass LM, Fonarow GC, et al AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation. 2006;113:2363–2372

 This work was supported by Boehringer Ingelheim GmbH.

 Statement of author disclosure: Please see the Author Disclosures section at the end of this article.

PII: S0002-9149(09)02481-3

doi: 10.1016/j.amjcard.2009.10.006

American Journal of Cardiology
Volume 105, Issue 1, Supplement , Pages 10A-20A , 4 January 2010