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From endothelial dysfunction to clinical events Concept and update on the ENCORE trials

L. Haegeli, K. Quitzau and T.F. Lüscher1 Steering Committee and the Investigators of the ENCORE trials

University Hospital, Zürich, Switzerland

1 Correspondence: Thomas F. Lüscher, MD, FESC, FRCP, Professor and Head of Cardiology, University Hospital, CH-8091 Zürich, Switzerland.

Abstract

In Western Countries morbidity and mortality are still mainly related to coronary artery disease and its complications, such as angina pectoris and myocardial infarction. An early event in atherosclerosis is endothelial dysfunction. For this reason, therapeutic interventions aiming to restore coronary endothelial dysfunction may be clinically relevant.

A number of studies have been performed in surrogate circulations, such as the human forearm, although not much is known about the effects of intervention in the coronary circulation. For the ENCORE I trial 343 patients with coronary artery disease undergoing percutaneous transluminal angioplasty, with or without stenting, have been randomized. After the coronary interventions, endothelial function was assessed by intracoronary (i.c.) infusion of increasing dosages of acetylcholine in a coronary segment without stenotic lesions. Quantitative coronary angiography (QCA) and Doppler flow velocity measurements were used to measure coronary responses to acetylcholine. Endothelium-independent responses are tested by i.c. adenosine and nitroglycerine. Patients were randomly assigned in a double-blind fashion to four treatment groups: placebo, nifedipine at 30–60 mg. day–1, cerivastatin at 400 µg . day–1 or their combination. Studies have been repeated in 247 patients after an interval of 6 months and the trial was completed in August 2000. This trial will determine whether or not endothelial function in patients with coronary artery disease is improved within 6 months by calcium antagonists and/or a statin alone or in combination.

The ENCORE II trial is scheduled to run for 2 years. It examines the correlation between endothelial function and structural atherosclerosis (as assessed by QCA and intravascular ultrasound [IVUS]) in 200 patients each treated with cerivastatin at a dose of 200 or 800 µg . day–1 compared with 200 patients treated with a combination of cerivastatin at a dose of 800 µg . day–1 and nifedipine at a dose of 30–60 mg . day–1. Endothelium-dependent responses of epicardial coronary arteries to acetylcholine at baseline as well as structural vascular changes, as assessed by IVUS, will be correlated and followed over 2 years. After 2 years the acetylcholine test, QCA and IVUS are to be repeated. Over 150 patients have so far been enrolled in the trial.

The ENCORE trials will show at the clinical level whether or not calcium antagonists and statins, alone or in combination, reverse early coronary endothelial dysfunction. In addition, these trials will address the question whether endothelial dysfunction and its pharmacological improvement are associated with progression or regression of atherosclerotic coronary artery disease. Finally, it may provide evidence whether this is reflected in fewer clinical events as suggested by several small observational studies.

Key Words: Coronary artery disease • atherosclerosis • endothelial dysfunction • nifedipine • cerivastatin

References

  1. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature (Lond). 1993;362:801–809[CrossRef][Medline]
  2. Lüscher TF, Vanhoutte PM. The endothelium: modulator of cardiovascular function. Boca Raton: CRC Press; 1990. p. 1–250
  3. Lüscher TF, Noll G. The endothelium in coronary vascular control. Braunwald E. Heart disease, Update 3. Philadelphia: Saunders; 1995. p. 1–10
  4. Tanner FC, Noll G, Boulanger CM, Lüscher TF. Oxidized low density lipoproteins inhibit relaxations of porcine coronary arteries. Role of scavenger receptor and endothelium-derived nitric oxide. Circulation. 1991;83:2012–2020[Abstract/Free Full Text]
  5. Lüscher TF, Raij L, Vanhoutte PM. Endothelium-dependent vascular responses in normotensive and hypertensive Dahl rats. Hypertension. 1987;9:157–163[Abstract/Free Full Text]
  6. Linder L, Kiowski W, Bühler FR, Lüscher TF. Indirect evidence for release of endothelium-derived relaxing factor in human forearm circulation in vivo. Blunted response in essential hypertension. Circulation. 1990;81:1762–1767[Abstract/Free Full Text]
  7. Tschudi MR, Criscione L, Novosel D, Pfeiffer K, Lüscher TF. Antihypertensive therapy augments endothelium-dependent relaxations in coronary arteries of spontaneously hypertensive rats. Circulation. 1994;89:2212–2218[Abstract/Free Full Text]
  8. Cosentino F, Hishikawa K, Katusic ZS, Lüscher TF. High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells. Circulation. 1997;96:25–28[Abstract/Free Full Text]
  9. Wever RM, Lüscher TF, Cosentino F, Rabelink TJ. Atherosclerosis and the two faces of endothelial nitric oxide synthase. Circulation. 1998;97:108–112[Free Full Text]
  10. Ludmer PL, Selwyn AP, Shook TL, et al. Paradoxical vasocontriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med. 1986;315:1046–1051[Abstract]
  11. Zeiher AM, Schachlinger V, Hohnloser SH, Saurbier B, Just H. Coronary atherosclerotic wall thickening and vascular reactivity in humans. Elevated high-density lipoprotein levels ameliorate abnormal vasoconstriction in early atherosclerosis. Circulation. 1994;89:2525–2532[Abstract/Free Full Text]
  12. Gage JE, Hess OM, Murakami T, Ritter M, Grimm J, Krayenbuehl HP. Vasoconstriction of stenotic coronary arteries during dynamic exercise in patients with classic angina pectoris: reversibility by nitroglycerin. Circulation. 1986;73:865–876[Abstract/Free Full Text]
  13. Mittleman MA, Maclure M, Tofler GH, Sherwood JB, Goldberg RJ, Muller JE. Triggering of acute myocardial infarction by heavy physical exertion. Protection against triggering by regular exertion. Determinants of Myocardial Infarction Onset Study Investigators. N Engl J Med. 1993;329:1677–1683[Abstract/Free Full Text]
  14. Schächinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000;101:1899–1906[Abstract/Free Full Text]
  15. Frielingsdorf J, Seiler C, Kaufmann P, Vassalli G, Suter T, Hess OM. Normalization of abnormal coronary vasomotion by calcium antagonists in patients with hypertension. Circulation. 1996;93:1380–1387[Abstract/Free Full Text]
  16. Mancini GB, Henry GC, Macaya C, 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[Abstract/Free Full Text]
  17. Anderson TJ, Meredith IT, Yeung AC, Frei B, Selwyn AP, Ganz P. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med. 1995;332:488–493[Abstract/Free Full Text]
  18. Treasure CB, Klein JL, Weintraub WS, et al. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med. 1995;332:481–487[Abstract/Free Full Text]
  19. Waters D, Lesperance J, Francetich M, et al. A controlled clinical trial to assess the effect of a calcium channel blocker on the progression of coronary atherosclerosis. Circulation. 1990;82:1940–1953[Abstract/Free Full Text]
  20. Lichtlen PR, Hugenholtz PG, Rafflenbeul W, Hecker H, Jost S, Deckers JW. Retardation of angiographic progression of coronary artery disease by nifedipine. Results of the International Nifedipine Trial on Antiatherosclerotic Therapy (INTACT). INTACT Group Investigators. Lancet. 1990;335:1109–1113[CrossRef][Web of Science][Medline]
  21. Lees RS, Pitt B, Chan RC, et al. Baseline clinical and angiographic data in the Quinapril Ischemic Event (QUIET) Trial. Am J Cardiol. 1996;78:1011–1016[CrossRef][Web of Science][Medline]
  22. Vita JA, Yeung AC, Winniford M, et al. Effect of cholesterol-lowering therapy on coronary endothelial vasomotor function in patients with coronary artery disease. Circulation. 2000;102:846–851[Abstract/Free Full Text]
  23. Taddei S, Virdis A, Ghiadoni L, Uleri S, Magagna A, Salvetti A. Lacidipine restores endothelium-dependent vasodilation in essential hypertensive patients. Hypertension. 1997;30:1606–1612[Abstract/Free Full Text]
  24. Verhaar M, Honing LHH, van Dam T, et al. Nifedipine improves NO mediated vasodilation in hypercholesterolemia, independent of an effect on blood pressure or plasma lipids. Circulation. 1998;98:I–243 (Suppl)
  25. Bracht C, Yan XW, Sütsch G, Poget P, Brunner H, Kiowski W. Isradipine improves endothelium-mediated vasodilation in patients with hyperlipidemia independent of changes in cholesterol. J Am Coll Cardiol. 1997;29:45A (Suppl)
  26. Jukema JW, Zwinderman AH, van Boven AJ, et al. Evidence for a synergistic effect of calcium channel blockers with lipid-lowering therapy in retarding progression of coronary atherosclerosis in symptomatic patients with normal to moderately raised cholesterol levels. The REGRESS Study Group. Arterioscler Thromb Vasc Biol. 1996;16:425–430[Abstract/Free Full Text]
  27. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effect of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145–153[Abstract/Free Full Text]
  28. Lubsen J, Poole-Wilson PA, Pocock SJ, et al. Design and current status of ACTION: A Coronary disease Trial Investigating Outcome with Nifedipine GITS. Gastro-Intestinal Therapeutic System. Eur Heart J. 1998;(Suppl I):20–32
  29. Lüscher TF, Zeiher AM, Meinerts T, ENCORE Trial Investigators. Effects of calcium antagonism and HMG-Co-enzyme reductase inhibition on endothelial function and atherosclerosis: rationale and outline of the ENCORE Trials. J Cardiovasc Pharmacol. 1997;30(Suppl 3):S48–S52

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