Review Article

Can Angiotensin-converting Enzyme Inhibitors Reverse Atherosclerosis?

Authors: John P. Higgins, MD, MPhil

Abstract

Angiotensin II, a potent vasoconstrictor, is mainly present in the vascular endothelium. Multiple studies have confirmed that angiotensin-converting enzyme (ACE) inhibitors, which block the formation of angiotensin II, lower blood pressure and also improve heart failure. These agents not only have beneficial hemodynamic effects but also bestow additional benefits on vascular function and prevent clinical cardiovascular events in patients at risk for coronary artery disease. These latter benefits may represent effects of ACE inhibitors on local endocrine pathways, inflammatory processes, and atherosclerosis taking place within the arterial wall. Current evidence suggests that, although ACE inhibitors may not substantially reverse atherosclerotic plaque already present, they may slow the progression of such atherosclerotic lesions. In addition, by modulating inflammatory pathways within and adjacent to the atherosclerotic lesion, they may stabilize an unstable plaque and therefore decrease the risk of plaque rupture and its complications.

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References

1. Lindpaintner K, Ganten D. Tissue renin-angiotensin systems and their modulation: The heart as a paradigm for new aspects of converting-enzyme inhibition. Cardiology 1991; 79( Suppl 1): 32–44.
 
2. Unger T, Ganten D, Lang RE. Effect of converting enzyme inhibitors on tissue converting enzyme and angiotensin II: Therapeutic implications. Am J Cardiol 1987; 59: 18D–22D.
 
3. 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.
 
4. Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy TE, 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: 669–677.
 
5. Kober L, Torp-Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lyngborg K, 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: 1670–1676.
 
6. 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.
 
7. Solomon SD. Beyond remodeling: A new paradigm for angiotensin-converting enzyme inhibitors following myocardial infarction. J Cardiovasc Pharmacol 2001; 37( Suppl 1): S31–S34.
 
8. 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: 145–153.
 
9. Hollenberg NK. What does the future hold? ACE inhibition, angiotensin II receptor blockade, and diabetic nephropathy. Blood Press Monit 2000; 5( Suppl 2): S3–S6.
 
10. Unger T. The role of the renin-angiotensin system in the development of cardiovascular disease. Am J Cardiol 2002; 89: 3A–10A.
 
11. Stoll M, Steckelings UM, Paul M, Bottari SP, Metzger R, Unger T. The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest 1995; 95: 651–657.
 
12. Unger T, Culman J, Gohlke P. Angiotensin II receptor blockade and end-organ protection: Pharmacological rationale and evidence. J Hypertens 1998; 16( Suppl): S3–S9.
 
13. Kimura B, Sumners C, Phillips MI. Changes in skin angiotensin II receptors in rats during wound healing. Biochem Biophys Res Commun 1992; 187: 1083–1090.
 
14. Nakajima M, Hutchinson HG, Fujinaga M, Hayashida W, Morishita R, Zhang L, et al. The angiotensin II type 2 (AT2) receptor antagonizes the growth effects of the AT1 receptor: Gain-of-function study using gene transfer. Proc Natl Acad Sci U S A 1995; 92: 10663–10667.
 
15. Linz W, Wiemer G, Scholkens HA. Contribution of bradykinin to the cardiovascular effects of ramipril. J Cardiovasc Pharmacol 1993; 22( Suppl 9): S1–S8.
 
16. Regoli D, Harabe J. Pharmacology of bradykinin and related kinins. Pharmacol Rev 1980; 32: 1–46.
 
17. Johnston CI. Angiotensin II type 1 receptor blockade: A novel therapeutic concept. Blood Press 2000; 1( Suppl): 9–13.
 
18. Johnston CI, Naitoh M, Burrell LM. Rationale and pharmacology of angiotensin II receptor antagonists: Current status and future issues. J Hypertens 1997; 15( Suppl): S3–S6.
 
19. Zhuo JL, Froomes P, Casley D, Liu JJ, Murone C, Chai SY, et al. Perindopril chronically inhibits angiotensin-converting enzyme in both the endothelium and adventitia of the internal mammary artery in patients with ischemic heart disease. Circulation 1997; 96: 174–182.
 
20. Luscher TF. Vascular protection: Current possibilities and future perspectives. Int J Clin Pract 2001; 117( Suppl): 3–6.
 
21. Dzau VJ. Mechanism of action of angiotensin-converting enzyme (ACE) inhibitors in hypertension and heart failure. Role of plasma versus tissue ACE. Drugs 1990; 39( Suppl 2): 11–16.
 
22. Piepho RW. Overview of the angiotensin-converting-enzyme inhibitors. Am J Health Syst Pharm 2000; 57( Suppl 1): S3–S7.
 
23. Campbell DJ. The site of angiotensin production. J Hypertens 1985; 3: 199–207.
 
24. Dzau VJ. Implications of local angiotensin production in cardiovascular physiology and pharmacology. Am J Cardiol 1987; 59: 59A–65A.
 
25. Diet F, Pratt RE, Berry GJ, Momose N, Gibbons GH, Dzau VJ. Increased accumulation of tissue ACE in human atherosclerotic coronary artery disease. Circulation 1996; 94: 2756–2767.
 
26. Dzau VJ, Sasamura H, Hein L. Heterogeneity of angiotensin synthetic pathways and receptor subtypes: Physiological and pharmacological implications. J Hypertens 1993; 11( Suppl): S13–S18.
 
27. van den Meiracker AH, Man in't Veld AJ, Admiraal PJ, Ritsema van Eck HJ, Boomsma F, Derkx FH, et al. Partial escape of angiotensin-converting enzyme (ACE) inhibition during prolonged ACE inhibitor treatment: Does it exist and does it affect the antihypertensive response? J Hypertens 1992; 10: 803–812.
 
28. Baruch L, Anand I, Cohen IS, Ziesche S, Judd D, Cohn JN. Augmented short- and long-term hemodynamic and hormonal effects of an angiotensin receptor blocker added to angiotensin-converting enzyme inhibitor therapy in patients with heart failure: Vasodilator Heart Failure Trial (V-HeFT) Study Group. Circulation 1999; 99: 2658–2664.
 
29. Raasch W, Dendorfer A, Ball B, Dominiak P. The lipophilic properties of angiotensin I-converting enzyme inhibitors do not influence their diffusion through cultured endothelium. Jpn J Pharmacol 1999; 81: 346–352.
 
30. Leonetti G, Cuspidi C. Choosing the right ACE inhibitor: A guide to selection. Drugs 1995; 49: 516–535.
 
31. Johnston CI, Fabris B, Yamada H, et al. Comparative studies of tissue inhibition by angiotensin-converting enzyme inhibitors. J Hypertens 1989; 7( Suppl): S11–S16.
 
32. Unger T, Ganten D, Lang RE, Scholkens BA. Is tissue converting enzyme inhibition a determinant of the antihypertensive efficacy of converting enzyme inhibitors? Studies with the two different compounds, Hoe498 and MK421, in spontaneously hypertensive rats. J Cardiovasc Pharmacol 1984; 6: 872–880.
 
33. Erman A, Winkler J, Chen-Gal B, Rabinov M, Zelykovski A, Tadjer S, et al. Inhibition of angiotensin-converting enzyme by ramipril in serum and tissue of man. J Hypertens 1991; 9: 1057–1062.
 
34. Dell'Italia LJ, Rocic P, Lucchesi PA. Use of angiotensin-converting enzyme inhibitors in patients with diabetes and coronary artery disease. Curr Probl Cardiol 2002; 27: 6–36.
 
35. Zimmerman BG, Sybertz EJ, Wong PC. Interaction between sympathetic and renin-angiotensin system. J Hypertens 1984; 2: 581–587.
 
36. Padfield PL, Morton JJ. Effects of angiotensin II on arginine-vasopressin in physiological and pathological situations in man. J Endocrinol 1977; 74: 251–259.
37. Taddei S, Virdis A, Ghiadoni L, Sudano I, Salvetti A. Effects of antihypertensive drugs on endothelial dysfunction: Clinical implications. Drugs 2002; 62: 265–284.
38. Zhuo JL, Mendelsohn FA, Ohishi M. Perindopril alters vascular angiotensin-converting enzyme, AT(1) receptor, and nitric oxide synthase expression in patients with coronary heart disease. Hypertension 2002; 39: 634–638.
 
39. van der Ent M, Remme WJ, Bartels GL, Kruijssen DA, Krauss XH, van Hoogenhuyze DC. Early administration of ramipril in acute myocardial infarction: Neurohormonal and hemodynamic effects and tolerability. Cardiology 1997; 88: 548–555.
 
40. Cargnoni A, Comini L, Bernocchi P, Bachetti T, Ceconi C, Curello S, et al. Role of bradykinin and eNOS in the anti-ischaemic effect of trandolapril. Br J Pharmacol 2001; 133: 145–153.
 
41. Saino A, Pomidossi G, Perondi R, Valentini R, Rimini A, Di Francesco L, et al. Intracoronary angiotensin II potentiates coronary sympathetic vasoconstriction in humans. Circulation 1997; 96: 148–153.
42. Hornig B, Kohler C, Drexler H. Role of bradykinin in mediating vascular effects of angiotensin-converting enzyme inhibitors in humans. Circulation 1997; 95: 1115–1118.
43. Berkenboom G, Langer I, Carpentier Y, Grosfils K, Fontaine J. Ramipril prevents endothelial dysfunction induced by oxidized low-density lipoproteins: A bradykinin-dependent mechanism. Hypertension 1997; 30: 371–376.
 
44. Schror K. Role of prostaglandins in the cardiovascular effects of bradykinin and angiotensin-converting enzyme inhibitors. J Cardiovasc Pharmacol 1992; 20( Suppl 9): S68–S73.
 
45. van Wijngaarden J, Tio RA, van Gilst WH, de Graeff PA, de Langen CD, Wesseling H. Basic pharmacology of ACE-inhibitors with respect to ischaemic heart disease: Prostaglandins and bradykinin. Eur Heart J 1990; 11( Suppl B): 84–93.
 
46. Dzau VJ. Renal effects of angiotensin-converting enzyme inhibition in cardiac failure. Am J Kidney Dis 1987; 10: 74–80.
 
47. Stein JH, Congbalay RC, Karsh DL, Osgood RW, Ferris TF. The effect of bradykinin on proximal tubular sodium reabsorption in the dog: Evidence for functional nephron heterogeneity. J Clin Invest 1972; 51: 1709–1721.
 
48. Kerins DM, Hao Q, Vaughan DE. Angiotensin induction of PAI-1 expression in endothelial cells is mediated by the hexapeptide angiotensin IV. J Clin Invest 1995; 96: 2515–2520.
 
49. Ridker PM, Gaboury CL, Conlin PR, Seely EW, Williams GH, Vaughan DE. Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II: Evidence of a potential interaction between the renin-angiotensin system and fibrinolytic function. Circulation 1993; 87: 1969–1973.
 
50. Feener EP, Northrup JM, Aiello LP, King GL. Angiotensin II induces plasminogen activator inhibitor-1 and -2 expression in vascular endothelial and smooth muscle cells. J Clin Invest 1995; 95: 1353–1362.
 
51. Vaughan DE, Lazos SA, Tong K. Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells: A potential link between the renin-angiotensin system and thrombosis. J Clin Invest 1995; 95: 995–1001.
 
52. James IM, Dickenson EJ, Burgoyne W, Jeremy JY, Barradas MA, Mikhailidis DP, et al. Treatment of hypertension with captopril: Preservation of regional blood flow and reduced platelet aggregation. J Hum Hypertens 1988; 2: 21–25.
 
53. Brown NJ, Vaughan DE. Prothrombotic effects of angiotensin. Adv Intern Med 2000; 45: 419–429.
 
54. Oshima S, Ogawa H, Mizuno Y, Yamashita S, Noda K, Saito T, et al. The effects of the angiotensin-converting enzyme inhibitor imidapril on plasma plasminogen activator inhibitor activity in patients with acute myocardial infarction. Am Heart J 1997; 134: 961–966.
55. Emeis JJ, Tranquille N. On the role of bradykinin in secretion from vascular endothelial cells. Agents Actions 1992; 38( Suppl): 285–291.
56. Brown NJ, Nadeau JH, Vaughan DE. Selective stimulation of tissue-type plasminogen activator (t-PA) in vivo by infusion of bradykinin. Thromb Haemost 1997; 77: 522–525.
 
57. Enseleit F, Hurlimann D, Luscher TF. Vascular protective effects of angiotensin-converting enzyme inhibitors and their relation to clinical events. J Cardiovasc Pharmacol 2001; 37( Suppl 1): S21–S30.
 
58. Dzau VJ. Theodore Cooper Lecture: Tissue angiotensin and pathobiology of vascular disease: A unifying hypothesis. Hypertension 2001; 37: 1047–1052.
 
59. Griendling KK, Ushio-Fukai M. Reactive oxygen species as mediators of angiotensin II signaling. Regul Pept 2000; 91: 21–27.
 
60. Ferrari R. Effect of ACE inhibition on myocardial ischaemia. Eur Heart J 1998; 19( Suppl 1): 130–135.
 
61. Daemen MJ, Lombardi DM, Bosman FT, Schwartz SM. Angiotensin II induces smooth muscle cell proliferation in the normal and injured rat arterial wall. Circ Res 1991; 68: 450–456.
 
62. Brilla CG, Rupp H, Funck R, Maisch B. The renin-angiotensin-aldosterone system and myocardial collagen matrix remodeling in congestive heart failure. Eur Heart J 1995; 16( Suppl O): 107–109.
 
63. Dixon IM, Ju H, Jassal DS, Peterson DJ. Effect of ramipril and losartan on collagen expression in right and left heart after myocardial infarction. Mol Cell Biochem 1996; 165: 31–45.
 
64. Southgate KM, Mehta D, Izzat MB, Newby AC, Angelini GD. Increased secretion of basement membrane-degrading metalloproteinases in pig saphenous vein into carotid artery interposition grafts. Arterioscler Thromb Vasc Biol 1999; 19: 1640–1649.
 
65. Funck RC, Wilke A, Rupp H, Brilla CG. Regulation and role of myocardial collagen matrix remodeling in hypertensive heart disease. Adv Exp Med Biol 1997; 432: 35–44.
 
66. Zannad F, Dousset B, Alla F. Treatment of congestive heart failure: Interfering the aldosterone-cardiac extracellular matrix relationship. Hypertension 2001; 38: 1227–1232.
 
67. Dzau VJ. Mechanism of protective effects of ACE inhibition on coronary artery disease. Eur Heart J 1998; 19( Suppl 1): 12–16.
 
68. Joki N, Kaname S, Hirakata M, Hori Y, Yamaguchi T, Fujita T, et al. Tyrosine-kinase dependent TGF-beta and extracellular matrix expression by mechanical stretch in vascular smooth muscle cells. Hypertens Res 2000; 23: 91–99.
69. Li Q, Muragaki Y, Hatamura I, Ueno H, Ooshima A. Stretch-induced collagen synthesis in cultured smooth muscle cells from rabbit aortic media and a possible involvement of angiotensin II and transforming growth factor-beta. J Vasc Res 1998; 35: 93–103. 70. Heitsch H, Brovkovych S, Malinski T, Wiemer G. Angiotensin-( l -7)-stimulated nitric oxide and superoxide release from endothelial cells. Hypertension 2001; 37: 72–76.
71. Kranzhofer R, Schmidt J, Pfeiffer CA, Hagl S, Libby P, Kubler W. Angiotensin induces inflammatory activation of human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1999; 19: 1623–1629.
 
72. Hernandez-Presa MA, Bustos C, Ortego M, Tunon J, Ortega L, Egido J. ACE inhibitor quinapril reduces the arterial expression of NF-κB-dependent proinflammatory factors but not of collagen I in a rabbit model of atherosclerosis. Am J Pathol 1998; 153: 1825–1837.
 
73. Farber HW, Center DM, Rounds S, Danilov SM. Components of the angiotensin system cause release of a neutrophil chemoattractant from cultured bovine and human endothelial cells. Eur Heart J 1990; 11( Suppl B): 100–107.
 
74. Auch-Schwelk W, Duske E, Claus M, Graf K, Grafe M, Fleck E. Endothelium-mediated vasodilation during ACE inhibition. Eur Heart J 1995; 16( Suppl C): 59–65.
 
75. Vaughan DE. Fibrinolytic balance, the renin-angiotensin system and atherosclerotic disease. Eur Heart J 1998; 19( Suppl G): G9–G12.
 
76. Vaughan D. Pharmacology of ACE inhibitors versus AT1 blockers. Can J Cardiol 2000; 16( Suppl E): 36E–40E.
 
77. Goodfield NE, Newby DE, Ludlam CA, Flapan AD. Effects of acute angiotensin II type 1 receptor antagonism and angiotensin converting enzyme inhibition on plasma fibrinolytic parameters in patients with heart failure. Circulation 1999; 99: 2983–2985.
 
78. Vaughan DE, Rouleau JL, Ridker PM, Arnold JM, Menapace FJ, Pfeffer MA. Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction: HEART Study Investigators. Circulation 1997; 96: 442–447.
 
79. Ganz P, Creager MA, Fang JC, McConnell MV, Lee RT, Libby P, et al. Pathogenic mechanisms of atherosclerosis: Effect of lipid lowering on the biology of atherosclerosis. Am J Med 1996; 101: 10S–16S.
 
80. Ross R. Atherosclerosis: An inflammatory disease. N Engl J Med 1999; 340: 115–126.
 
81. Calver A, Collier J, Moncada S, Vallance P. Effect of local intra-arterial NG-monomethyl- l -arginine in patients with hypertension: The nitric oxide dilator mechanism appears abnormal. J Hypertens 1992; 10: 1025–1031.
 
82. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 2000; 101: 948–954.
 
83. Hornig B, Landmesser U, Kohler C, Ahlersmann D, Spiekermann S, Christoph A, 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: 799–805.
 
84. Antony I, Lerebours G, Nitenberg A. Angiotensin-converting enzyme inhibition restores flow-dependent and cold pressor test-induced dilations in coronary arteries of hypertensive patients. Circulation 1996; 94: 3115–3122.
 
85. Anderson TJ, Elstein E, Haber H, Charbonneau F. Comparative study of ACE-inhibition, angiotensin II antagonism, and calcium channel blockade on flow-mediated vasodilation in patients with coronary disease (BANFF study). J Am Coll Cardiol 2000; 35: 60–66.
 
86. Hornig B, Arakawa N, Haussmann D, Drexler H. Differential effects of quinaprilat and enalaprilat on endothelial function of conduit arteries in patients with chronic heart failure. Circulation 1998; 98: 2842–2848.
 
87. Vallance P, Chan N. Endothelial function and nitric oxide: Clinical relevance. Heart 2001; 85: 342–350.
 
88. 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.
 
89. Schlaifer JD, Mancini GB, O'Neill BJ, Pitt B, Haber HE, Pepine CJ. Influence of smoking status on angiotensin-converting enzyme inhibition-related improvement in coronary endothelial function: TREND Investigators Trial on Reversing Endothelial Dysfunction. Cardiovasc Drugs Ther 1999; 13: 201–209.
 
90. Dzau VJ. Tissue renin-angiotensin system in myocardial hypertrophy and failure. Arch Intern Med 1993; 153: 937–942.
 
91. Itoh H, Mukoyama M, Pratt RE, Gibbons GH, Dzau VJ. Multiple autocrine growth factors modulate vascular smooth muscle cell growth response to angiotensin II. J Clin Invest 1993; 91: 2268–2274.
 
92. Dostal DE, Booz GW, Baker KM. Angiotensin II signaling pathways in cardiac fibroblasts: Conventional versus novel mechanisms in mediating cardiac growth and function. Mol Cell Biochem 1996; 157: 15–21.
 
93. Schieffer B, Schieffer E, Hilfiker-Kleiner D, Hilfiker A, Kovanen PT, Kaartinen M, et al. Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: Potential implications for inflammation and plaque instability. Circulation 2000; 101: 1372–1378.
 
94. MacMahon S, Sharpe N, Gamble G, Clague A, Mhurchu CN, Clark T, et al. Randomized, placebo-controlled trial of the angiotensin-converting enzyme inhibitor, ramipril, in patients with coronary or other occlusive arterial disease: Part II—Collaborative Research Group Prevention of Atherosclerosis with Ramipril. J Am Coll Cardiol 2000; 36: 438–443.
 
95. 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.
 
96. Pitt B, O'Neill B, Feldman R, Ferrari R, Schwartz L, Mudra H, 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: 1058–1063.
 
97. Cashin-Hemphill L, Holmvang G, Chan RC, Pitt B, Dinsmore RE, Lees RS. Angiotensin-converting enzyme inhibition as antiatherosclerotic therapy: No answer yet—QUIET Investigators Quinapril Ischemic Event Trial. Am J Cardiol 1999; 83: 43–47.
 
98. Teo KK, Burton JR, Buller CE, Plante S, Catellier D, Tymchak W. Long-term effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis: The Simvastatin/Enalapri1 Coronary Atherosclerosis Trial (SCAT). Circulation 2000; 102: 1748–1754.
 
99. Nissen S. Coronary angiography and intravascular ultrasound. Am J Cardiol 2001; 87: 15A–20A.
 
100. Meurice T, Bauters C, Hermant X, Codron V, VanBelle E, McFadden EP, et al. Effect of ACE inhibitors on angiographic restenosis after coronary stenting (PARIS): A randomised, double-blind, placebo-controlled trial. Lancet 2001; 357: 1321–1324.
 
101. Kjoller-Hansen L, Steffensen R, Grande P. The Angiotensin-converting Enzyme Inhibition Post Revascularization Study (APRES). J Am Coll Cardiol 2000; 35: 881–888.
102. Yusuf S, Gerstein HC. Diabetes Reduction Approaches with Medication (DREAM) Study. Available at: http://www.hamiltonhealthsciences.ca/sites/dream/. Accessed January 30, 2003. 103. Fox KM, Henderson JR, Bertrand ME, Ferrari R, Remme WJ, Simoons ML. The European trial on reduction of cardiac events with perindopril in stable coronary artery disease (EUROPA). Eur Heart J 1998; 19( Suppl J): 152–155.
104. Warnica JW, Gilst WV, Baillot R, Johnstone D, Block P, Myers MG, et al. Ischemia Management with Accupril post bypass Graft via Inhibition of angiotensin coNverting enzyme (IMAGINE): A multicentre randomized trial—Design and rationale. Can J Cardiol 2002; 18: 1191–1200.
 
105. Yusuf S. From the HOPE to the ONTARGET and the TRANSCEND studies: Challenges in improving prognosis. Am J Cardiol 2002; 89: 18A–26A.
 
106. Pfeffer MA, Domanski M, Rosenberg Y, Verter J, Geller N, Albert P, et al. Prevention of events with angiotensin-converting enzyme inhibition (the PEACE study design): Prevention of Events with Angiotensin-Converting Enzyme Inhibition. Am J Cardiol 1998; 82: 25H–30H.
 
107. MacMahon S, Chalmers J. The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) Trial, in Pepine CJ (ed): 11th Meeting of the European Society of Hypertension. Milan, Italy, European Society of Hypertension, 2001, p 20.
108. Reis SE, Holubkov R, Conrad Smith AJ, Kelsey SF, Sharaf BL, Reichek N, et al. Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: Results from the NHLBI WISE study. Am Heart J 2001; 141: 735–741.
109. Oosterga M, Voors AA, Buikema H, Pinto YM, Haber HE, Ebels T, et al. Angiotensin II formation in human vasculature after chronic ACE inhibition: A prospective, randomized, placebo-controlled study—QUO VADIS Investigators. Cardiovasc Drugs Ther 2000; 14: 55–60.
110. Oosterga M, Voors AA, Pinto YM, Buikema H, Grandjean JG, Kingma JH, et al. Effects of quinapril on clinical outcome after coronary artery bypass grafting (the QUO VADIS study): Quinapril on Vascular Ace and Determinants of Ischemia. Am J Cardiol 2001; 87: 542–546.
111. McKelvie RS, Yusuf S, Pericak D, Avezum A, Burns RJ, Probstfield J, et al. 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 1999; 100: 1056–1064.

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