Abstract
Endothelial dysfunction is increasingly recognized as an early event in the pathogenesis of cardiovascular disease. This observation is consistent with the growing appreciation of the role of endothelium in maintaining cardiovascular health. Endothelial dysfunction and coronary artery disease are both linked to hypertension, hypercholesterolemia, diabetes mellitus, and cigarette smoking. Modification of these conditions improves both endothelial function and coronary artery disease outcomes. Dietary and lifestyle modifications and antioxidant vitamin supplementation have a beneficial effect on endothelial function, as do angiotensin‐converting enzyme inhibitors and lipid‐lowering agents. Future studies will determine whether interventions that specifically target endothelial dysfunction can reduce rates of clinical disease.
Keywords: angiotensin‐converting enzyme inhibitors, atherosclerosis, coronary artery disease, endothelial dysfunction, hypercholesterolemia, hypertension, nitric oxide, statins
Full Text
The Full Text of this article is available as a PDF (546.2 KB).
References
- 1. Zeiher AM, Drexler H, Saurier B, Just H: Endothelium‐mediated coronary blood flow modulations in humans: Effects of age, atherosclerosis, hypercholesterolemia, and hypertension. J Clin Invest 1993; 92: 652–662 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. 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 [DOI] [PubMed] [Google Scholar]
- 3. Panza JA, Casion PR, Kilcoyne CM, Quyyumi AA: Role of endothelium‐derived nitric oxide in the abnormal endothelium‐dependent vascular relaxation of patients with essential hypertension. Circulation 1993; 87: 1468–1474 [DOI] [PubMed] [Google Scholar]
- 4. Panza JA, Quyyumi AA, Callahan TS, Epstein SE: Effect of antihypertensive treatment on endothelium‐dependent vascular relaxation in patients with essential hypertension. J Am Coll Cardiol 1993; 31: 1145–1151 [DOI] [PubMed] [Google Scholar]
- 5. Creager MA, Roddy M‐A: Effect of captopril and enalapril on endothelial function in hypertensive patients. Hypertension 1994; 24: 499–505 [DOI] [PubMed] [Google Scholar]
- 6. McLenachan JM, Williams JK, Fish RD, Ganz P, Sel wyn AP: Loss of flow‐mediated endothelium‐dependent dilation occurs early in the development of atherosclerosis. Circulation 1991; 84: 1273–1278 [DOI] [PubMed] [Google Scholar]
- 7. Andrews HE, Bruckdorfer KR, Dunn RC, Jacobs M: Low‐density lipoproteins inhibit endothelium‐dependent relaxation in rabbit aorta. Nature 1987; 327: 237–239 [DOI] [PubMed] [Google Scholar]
- 8. Drexler H, Zeiher AM: Endothelial function in human coronary arteries in vivo: Focus on hypercholesterolemia. Hypertension 1991; 18 (supplII): II‐90–II‐99 [DOI] [PubMed] [Google Scholar]
- 9. Seiler C, Hess OM, Buechi M, Suter TM, Krayenbuehl HP: Influence of serum cholesterol and other coronary risk factors on vasomotion of angiographically normal coronary arteries. Circulation 1991; 88 (pt. 1): 2139–2148 [DOI] [PubMed] [Google Scholar]
- 10. Plotnick GD, Corretti MC, Vogel RA: Transient impairment of endothelium‐mediated brachial artery reactivity following a fatty meal (abstr). J Am Coll Cardiol 1996; 27: 287A [Google Scholar]
- 11. Cayatte AJ, Palacino JJ, Horten K, Cohen RA: Chronic inhibition of nitric oxide production accelerates neointima formation and impairs endothelial function in hypercholesterolemic rabbits. Arterioscler Thromb 1994; 14: 753–759 [DOI] [PubMed] [Google Scholar]
- 12. Harrison DG, Armstrong ML, Freiman PC, Heistad DD: Restoration of endothelium‐dependent relaxation by dietary treatment of atherosclerosis. J Clin lnvest 1987; 80: 1808–1811 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Celermajer DS, Sorensen KE, Georgakopoulos D, Bull C, Thomas O, Robinson J, Deanfield JE: Cigarette smoking is associated with dose‐related and potentially reversible impairment of endotheliumdependent dilation in healthy young adults. Circulation 1993; 88: 2149–2155 [DOI] [PubMed] [Google Scholar]
- 14. Heitzer T, Yla‐Herttuala S, Luoma J, Kurz S, Munzel T, Just H, Olschewski M, Drexler H: Cigarette smoking potentiates endothelial dysfunction of forearm resistance vessels in patients with hypercholesterolemia: Role of oxidized LDL. Circulation 1996; 93: 1346–1353 [DOI] [PubMed] [Google Scholar]
- 15. Khan BV, Harrison DG, Olbrych MT, Alexander RW, Medford RM: Nitric oxide regulates vascular cell adhesion molecule 1 gene expression and redox‐sensitive transcriptional events in human vascular endothelial cells. Proc Natl Acad Sci USA 1996; 93: 9114–9119 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Pepine CJ, Schlaifer JD, Mancini GBJ, Pitt B, O'Neill BJ, Haber HE, on behalf of the TREND Investigators : Influence of smoking status on progression of endothelial dysfunction. Clin Cardiol 1998; 21: 331–334 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Lash JM, Bohlen HG: Structural and functional origins of suppressed acetylcholine vasodilation in diabetic rat intestinal arterioles. Circ Res 1991; 69: 1259–1268 [DOI] [PubMed] [Google Scholar]
- 18. Lieberman EH, Uehata A, Polak J, Ganz P, Selwyn AP, Creager MA, Yeung AC: Flow‐mediated vasodilation is impaired in the brachial artery of patients with coronary artery disease or with diabetes mellitus (abstr). Clin Res 1993; 41: 217A [Google Scholar]
- 19. McVeigh GE, Brennan GM, Johnston GD, McDermott BJ, McGrath LT, Henry WR, Andrews JW, Hayes JR: Impaired endothelium‐dependent and ‐independent vasodilation in patients with type 2 (non‐insulin‐dependent) diabetes mellitus. Diabetologia 1992; 35: 771–776 [DOI] [PubMed] [Google Scholar]
- 20. Cooke JP, Singer AH, Tsao D, Zera P, Rowan RA, Billingham ME: Antiatherogem'c effects of L‐arginine in the hypercholesterolemic rabbit. J Clin Invest 1992; 90: 1168–1172 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Weidinger FS, McLenachan JM, Cybulsky MI, Fallon JT, Cooke JP, Ganz D: Hypercholesterolemia enhances macrophage recruitment and endothelial vasodilator dysfunction after balloon injury. Circulation 1991; 84: 755–767 [DOI] [PubMed] [Google Scholar]
- 22. Hamon M, Vallet B, Bauters C, Wernert N, McFadden EP, Lablanche JM, Dupuis B, Bertrand ME: Long‐term oral administration of L‐arginine reduces intimal thickening and enhances neoendothelium‐dependent acetylcholine‐induced relaxation after arterial injury. Circulation 1994; 90: 1357–1362 [DOI] [PubMed] [Google Scholar]
- 23. Rossitch E, Alexander E III, Black PM, Cooke JP: L‐arginine normalizes endothelial function in cerebral vessels from hypercholesterolemic rabbits. J Clin Invest 1991; 87: 1295–1297 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Drexler H, Zeiher AM, Meinzer K, Just H: Correcting endothelial dysfunction in coronary microcirculation of hypercholesterolemic patients by L‐arginine. Lancet 1991; 338: 1546–1550 [DOI] [PubMed] [Google Scholar]
- 25. Clarkson P, Adams MR, Powe AJ, Donald AE, McCredie R, Robinson J, McCarthy SN, Keech A, Celermajer DS, Deanfield JE: Oral L‐arginine improves endothelium‐dependent dilation in hypercholesterolemic young adults. J Clin Invest 1996; 97: 1989–1994 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Hornig B, Maier V, Drexler H: Physical training improves endothelial function in patients with chronic heart failure. Circulation 1996; 93: 210–214 [DOI] [PubMed] [Google Scholar]
- 27. Levine GN, Frei B, Koulouris SN, Gerhard MD, Keaney JF Jr. Vita JA : Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation 1996; 93: 1107–1113 [DOI] [PubMed] [Google Scholar]
- 28. Reilly M, Delanty N, Lawson JA, FitzGerald GA: Modulation of oxidant stress in vivo in chronic cigarette smokers. Circulation 1996; 94: 19–25 [DOI] [PubMed] [Google Scholar]
- 29. Weber C, Erl W, Weber K, Weber PC: Increased adhesiveness of isolated monocytes to endothelium is prevented by vitamin C intake in smokers. Circulation 1996; 93: 1488–1492 [DOI] [PubMed] [Google Scholar]
- 30. Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ: Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996; 347: 781–786 [DOI] [PubMed] [Google Scholar]
- 31. Leung W‐H, Lau C‐P, Wong C‐K: Beneficial effect of cholesterol lowering therapy on coronary endothelium‐dependent relaxation in hypercholesterolaemic patients. Lancet 1993; 341: 1496–1500 [DOI] [PubMed] [Google Scholar]
- 32. O'Driscoll G, Green D, Taylor RR: Simvastatin, an HMG‐CoA reductase inhibitor, improves endothelial function within 1 month. Circulation 1997; 95: 1126–1131 [DOI] [PubMed] [Google Scholar]
- 33. Egashira K, Hirooka Y, Kai H, Sugimachi M, Suzuki S, Inou T, Takeshita A: Reduction in serum cholesterol with pravastatin improves endothelium‐dependent coronary vasomotion in patients with hypercholesterolemia. Circulation 1994; 89: 2519–2524 [DOI] [PubMed] [Google Scholar]
- 34. Treasure CB, Klein JL, Weintraub WS, Talley JD, Stillabower ME, Kosinski AS, Zhang J, Bocuzzi SJ, Cedarholm JC, Alexander RW: Beneficial effects of cholesterol‐lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med 1995; 332: 481–487 [DOI] [PubMed] [Google Scholar]
- 35. 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 [DOI] [PubMed] [Google Scholar]
- 36. Andrews TC, Raby K, Barry J, Naimi CL, Allred E, Ganz P, Selwyn AP: Effect of cholesterol reduction on myocardial ischemia in patients with coronary disease. Circulation 1997; 95: 324–328 [DOI] [PubMed] [Google Scholar]
- 37. O'Driscoll G, Green D, Taylor RR: Simvastatin, an HMG‐coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation 1997; 95: 1126–1131 [DOI] [PubMed] [Google Scholar]
- 38. Yusuf S, Pepine CJ, Garces C. Pouleur H, Salem D, Kostis J, Benedict C, Rousseau M. Bourassa M. Pitt B: Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet 1992; 340: 1173–1178 [DOI] [PubMed] [Google Scholar]
- 39. Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy TE, Davis BR, Geltman EM. Goldman S, Flaker GC, Klein M. Lamas GA, Packer M. Rouleau J. Rouleau JL, Rutherford J, Wertheimer JH, Hawkins CM, on behalf of the SAVE Investigators: Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: Results of the Survival and Ventricular Enlargement Trial. N Engl J Med 1992; 327: 669–677 [DOI] [PubMed] [Google Scholar]
- 40. Rutherford JD, Pfeffer MA. Moye LA. Davis BR, Falker GC, Kowey PR, Lamas GA, Miller HS, Packer M, Rouleau JL, on behalf of the SAVE Investigators: Effects of captopril on ischemic events after myocardial infarction: Results of the Survival and Ventricular Enlargement Trial. Circulation 1994; 90: 1731–1738 [DOI] [PubMed] [Google Scholar]
- 41. 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 [PubMed] [Google Scholar]
- 42. ISIS‐4 (Fourth Internationa] Study of Infarct Survival) Collaboratory Group : ISIS‐4: Randomised factorial trial assessing early oral captopril, oral mononitrate. and intravenous magnesium sulphate in 38,050 patients with suspected acute myocardial infarction. Lancet 1994; 345: 669–685 [PubMed] [Google Scholar]
- 43. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico : GISSI‐3: Effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6‐week mortality and ventricular function after acute myocardial infarction. Lancet 1994; 343: 1115–1122 [PubMed] [Google Scholar]
- 44. Prasad A, Husain S, Mincemoyer R, Panza JA, Cannon RO III, Quyyumi AA: Coronary endothelial dysfunction improves with angiotensin‐converting enzyme inhibition (abstr 348). Circulation 1996; 94 (suppl): I–61 [Google Scholar]
- 45. Prasad A, Husain S, Mincemoyer R. Hathaway L, Quyyumi AA: Converting enzyme inhibition improves endothelial dysfunction in humans by increasing nitric oxide activity (abstr 743‐2). J Am Coll Cardiol 1997; 27: 192A [Google Scholar]
- 46. Mancini GBH, Henry GC, Macaya C, O'Neill BJ, Pucillo AL, Carere RG, Wargovich TJ, Mudra H, Luscher TF, Klibaner MI: Angiotensin‐converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease: The TREND (Trial on Reversing ENdothelial Dysfunction) Study. Ciirulation 1996; 94: 258–265 [DOI] [PubMed] [Google Scholar]
- 47. Pitt B, Pepine C, O'Neill B, Haber H, Pressler M, Mancini GBJ: Modulation of ACE inhibitor efficacy on coronary endothelial dysfunction by low‐density lipoprotein cholesterol (abstr 714‐5). J Am Coll Cardiol 1997; 27: 70A [Google Scholar]
- 48. Schlaifer JD, Mancini GBJ, O'Neill BJ, Pitt B, Haber HE, Pepine CJ: Influence of smoking status on angiotensin‐converting enzyme inhibition‐related improvement in coronary endothelial function (abstr 223). Eur Heart J 1997; 18 (suppl): 15 [DOI] [PubMed] [Google Scholar]
- 49. Lai C, Onnis E, Orani E, Pirisi R, Soro A, Cherchi A: Effects of enalapril in normotensive patients with stable effort angina: A double blind, placebo controlled study. Drugs Exp Clin Res 1990; 16: 299–305 [PubMed] [Google Scholar]
- 50. Schneeweiss A, Marmor AT, Rettig‐Sturmer G: Anti‐ischemic effects of cilazapril in patients with both hypertension and angina. Cardiology 1991; 79: 46–48 [DOI] [PubMed] [Google Scholar]
- 51. Lee AFC, Dick JBC, Struthers AD: Can lisinopril improve endothelial function in hyperlipidemics? (abstr 921‐93). J Am Coll Cardiol 1997; x27: 46A [Google Scholar]