Skip to main content
Log in

Effect of lipid-lowering therapy on vasomotion and endothelial function

  • Published:
Current Cardiology Reports Aims and scope Submit manuscript

Abstract

The recent clinical trials of lipid lowering have established the benefit of this therapy in men and women with, or at high risk for, cardiovascular disease. It is now thought that most of the reduction in the risk of clinical events is due to functional rather than anatomic changes in atherosclerotic arteries. Cholesterol-lowering drugs improve endothelial vasomotor function and vascular nitric oxide in patients with coronary artery disease over several months. These changes in vasomotor function may reflect other beneficial changes that are regulated by nitric oxide such as the reduced recruitment and activation of inflammatory cells and a shift in the coagulation balance to favor thrombolysis. These mechanisms may contribute to the reduction in myocardial ischemia and clinical events observed with lipid lowering in patients with vascular disease. Lipid-lowering therapy decreases cardiovascular events and is an important adjunct to coronary revascularization most likely because an improvement in endothelial function prevents the development and destabilization of new atherosclerotic lesions and subsequent ischemic events.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References and recommended reading

  1. The Scandinavian Simvastatin Survival Study Group: Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994, 344:1383–1389.

    Google Scholar 

  2. •• The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group: Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998, 339:1349–1357.

    Article  Google Scholar 

One of the latest large clinical trials of lipid lowering showing a benefit in over 9000 patients 3 to 36 months after admission to hospital for myocardial infarction or unstable angina. This study was large enough to confirm the benefit in overall mortality as well as cardiovascular endpoints, including stroke

  1. Sacks FM, Pfeffer MA, Moye LA, et al.: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996, 335:1001–1009.

    Article  PubMed  CAS  Google Scholar 

  2. Shepherd J, Cobbe SM, Ford I, et al.: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995, 333:1301–1307.

    Article  PubMed  CAS  Google Scholar 

  3. •• Downs JR, Clearfield M, Weis S, et al.: Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. Jama. 1998, 279:1615–1622.

    Article  PubMed  CAS  Google Scholar 

One of the latest large clinical trials of lipid lowering showing a benefit from lipid lowering therapy in the primary prevention of cardiovascular disease in men and women with mildly elevated LDL cholesterol and relatively low HDL cholesterol

  1. Wissler RW, Vesselinovitch D: Can atherosclerotic plaques regress? Anatomic and biochemical evidence from nonhuman animal models. Am J Cardiol. 1990, 65:33F-40F.

    Article  PubMed  CAS  Google Scholar 

  2. Kinlay S, Selwyn AP, Delagrange D, et al.: Biological mechanisms for the clinical success of lipid-lowering in coronary artery disease and the use of surrogate end-points. Curr Opin Lipidol. 1996, 7:389–397.

    Article  PubMed  CAS  Google Scholar 

  3. Libby P: Molecular bases of the acute coronary syndromes. Circulation. 1995, 91:844–850.

    Google Scholar 

  4. Plutzky J: Atherosclerotic Plaque Rupture: Emerging Insights and Opportunities. Am J Cardiol 1999, 84(1A):155–205.

    Google Scholar 

  5. Kinlay S, Ganz P: Role of endothelial dysfunction in coronary artery disease and implications for therapy. Am J Cardiol 1997, 80:11I-16I.

    Article  PubMed  CAS  Google Scholar 

  6. Ignarro LJ, Byrns RE, Buga GM, Wood KS: Endotheliumderived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical. Circ Res. 1987, 61:66–79.

    Google Scholar 

  7. Palmer RM, Ashton DS, Moncada S: Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988, 333:664–666.

    Article  PubMed  CAS  Google Scholar 

  8. Capuzzt RF, Zawadzki JV: The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980, 288:373–376.

    Article  Google Scholar 

  9. Selwyn AP, Kinlay S, Creager M, et al.: Cell dysfunction in atherosclerosis and the ischemic manifestations of coronary artery disease. Am J Cardiol. 1997, 79:17–23.

    Article  PubMed  CAS  Google Scholar 

  10. Meredith I, Yeung A, Weidinger F, et al.: Role of impaired endothelium-dependent vasodilation in ischemic manifestations of coronary artery disease. Circulation. 1993, 87 (Suppl V): V56-V66.

    Google Scholar 

  11. Ludmer PL, Selwyn AP, Shook TL, et al.: Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med. 1986, 315:1046–1051.

    Article  PubMed  CAS  Google Scholar 

  12. Cox DA, Vita JA, Treasure CB, et al.: Atherosclerosis impairs flow-mediated dilation of coronary arteries in humans. Circulation. 1989, 80:458–465.

    PubMed  CAS  Google Scholar 

  13. Celermajer DS, Sorensen KE, Gooch VM, et al.: Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992, 340:1111–1115.

    Article  PubMed  CAS  Google Scholar 

  14. Creager MA, Cooke JP, Mendelsohn ME, et al.: Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest. 1990, 86:228–234.

    PubMed  CAS  Google Scholar 

  15. Gryglewski RJ, Palmer RM, Moncada S: Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature. 1986, 320:4540–456.

    Article  Google Scholar 

  16. Liao JK, Shin WS, Lee WY, Clark SL: Oxidized low-density lipoprotein decreases the expression of endothelial nitric oxide synthase. J Biol Chem. 1995, 270:319–324.

    Article  PubMed  CAS  Google Scholar 

  17. Nabel EG, Selwyn AP, Ganz P: Large coronary arteries in humans are responsive to changing blood flow: an endothelium-dependent mechanism that fails in patients with atherosclerosis. J Am Coll Cardiol. 1990, 16:349–356.

    Article  PubMed  CAS  Google Scholar 

  18. Vita JA, Treasure CB, Nabel EG, et al.: Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation. 1990, 81:491–497.

    PubMed  CAS  Google Scholar 

  19. De Caterina R, Libby P, Peng HB, et al.: Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest. 1995, 96:60–68.

    PubMed  Google Scholar 

  20. Kubes P, Suzuki M, Granger DN: Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A 1991, 88:4651–4655.

    Article  PubMed  CAS  Google Scholar 

  21. Tsao PS, Buitrago R, Chan JR, Cooke JP: Fluid flow inhibits endothelial adhesiveness. Nitric oxide and transcriptional regulation of VCAM-1. Circulation. 1996, 94:1682–1689.

    PubMed  CAS  Google Scholar 

  22. Collins T, Read MA, Neish AS, et al.: Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers. Faseb J. 1995, 9 899–909.

    PubMed  CAS  Google Scholar 

  23. Marui N, Offermann MK, Swerlick R, et al.: Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells. J Clin Invest 1993, 92:1866–1874.

    PubMed  CAS  Google Scholar 

  24. Zeiher AM, Fisslthaler B, Schray-Utz B, Busse R: Nitric oxide modulates the expression of monocyte chemoattractant protein 1 in cultured human endothelial cells. Circ Res. 1995, 76:980–986.

    PubMed  CAS  Google Scholar 

  25. Tsao PS, Wang B, Buitrago R, et al.: Nitric oxide regulates monocyte chemotactic protein-1. Circulation. 1997, 96:934–940.

    PubMed  CAS  Google Scholar 

  26. Peng HB, Rajavashisth TB, Libby P, Liao JK: Nitric oxide inhibits macrophage-colony stimulating factor gene transcription in vascular endothelial cells. J Biol Chem. 1995, 270:17050–17055.

    Article  PubMed  CAS  Google Scholar 

  27. Azuma H, Ishikawa M, Sekizaki S: Endothelium-dependent inhibition of platelet aggregation. Br J Pharmacol. 1986, 88:411–415.

    PubMed  CAS  Google Scholar 

  28. Hogan JC, Lewis MJ, Henderson AH: In vivo EDRF activity influences platelet function. Br J Pharmacol. 1988, 94:1020–1022.

    PubMed  CAS  Google Scholar 

  29. Yao SK, Ober JC, Krishnaswami A, et al.: Endogenous nitric oxide protects against platelet aggregation and cyclic flow variations in stenosed and endothelium-injured arteries. Circulation. 1992, 86:1302–1309.

    PubMed  CAS  Google Scholar 

  30. Shireman PK, McCarthy WJ, Pearce WH, et al.: Elevated levels of plasminogen-activator inhibitor type 1 in atherosclerotic aorta. J Vasc Surg. 1996, 23:810–817; discussion 817–818.

    Article  PubMed  CAS  Google Scholar 

  31. Robbie LA, Booth NA, Brown AJ, Bennett B: Inhibitors of fibrinolysis are elevated in atherosclerotic plaque. Arterioscler Thromb Vasc Biol. 1996, 16:539–545.

    PubMed  CAS  Google Scholar 

  32. Gordon JB, Ganz P, Nabel EG, et al.: Atherosclerosis influences the vasomotor response of epicardial coronary arteries to exercise. J Clin Invest. 1989, 83:1946–1952.

    PubMed  CAS  Google Scholar 

  33. Nabel EG, Selwyn AP, Ganz P: Paradoxical narrowing of atherosclerotic coronary arteries induced by increases in heart rate. Circulation. 1990, 81:850–859.

    PubMed  CAS  Google Scholar 

  34. Quyyumi AA, Dakak N, Andrews NP, et al.: Contribution of nitric oxide to metabolic coronary vasodilation in the human heart. Circulation. 1995, 92:320–326.

    PubMed  CAS  Google Scholar 

  35. Egashira K, Inou T, Hirooka Y, et al.: Impaired coronary blood flow response to acetylcholine in patients with coronary risk factors and proximal atherosclerotic lesions. J Clin Invest 1993, 91:29–37.

    PubMed  CAS  Google Scholar 

  36. Lieberman EH, Gerhard MD, Uehata A, et al.: Estrogen improves endothelium-dependent, flow-mediated vasodilation in postmenopausal women. Ann Intern Med 1994, 121:936–941.

    PubMed  CAS  Google Scholar 

  37. Zeiher AM, Drexler H, Wollschlager H, Just H: Modulation of coronary vasomotor tone in humans. Progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation. 1991, 83:391–401.

    PubMed  CAS  Google Scholar 

  38. Egashira K, Hirooka Y, Kai H, et al.: Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia. Circulation. 1994, 89:2519–2524.

    PubMed  CAS  Google Scholar 

  39. Anderson TJ, Meredith IT, Yeung AC, et al.: The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med. 1995, 332:488–493.

    Article  PubMed  CAS  Google Scholar 

  40. Leung WH, Lau CP, Wong CK: Beneficial effect of cholesterollowering therapy on coronary endothelium-dependent relaxation in hypercholesterolaemic patients. Lancet. 1993, 341:1496–1500.

    Article  PubMed  CAS  Google Scholar 

  41. 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.

    Article  PubMed  CAS  Google Scholar 

  42. Huggins GS, Pasternak RC, Alpert NM, et al.: Effects of shortterm treatment of hyperlipidemia on coronary vasodilator function and myocardial perfusion in regions having substantial impairment of baseline dilator reverse. Circulation 1998, 98:1291–1296.

    PubMed  CAS  Google Scholar 

This paper demonstrated a reduction in myocardial ischemia with lipid lowering therapy that was too short a time interval for plaque regression. The benefit was more likely due to improvements in endothelium-dependent vasomotion

  1. •• Andrews TC, Raby K, Barry J, et al.: Effect of cholesterol reduction on myocardial ischemia in patients with coronary disease. Circulation. 1997, 95:324–328.

    PubMed  CAS  Google Scholar 

  2. van Boven AJ, Jukema JW, Zwinderman AH, et al.: Reduction of transient myocardial ischemia with pravastatin in addition to the conventional treatment in patients with angina pectoris. REGRESS Study Group. Circulation. 1996, 94:1503–1505.

    PubMed  Google Scholar 

  3. Seiler C, Suter TM, Hess OM: Exercise-induced vasomotion of angiographically normal and stenotic coronary arteries improves after cholesterol-lowering drug therapy with bezafibrate. J Am Coll Cardiol. 1995, 26:1615–1622.

    Article  PubMed  CAS  Google Scholar 

  4. Kroon AA, Aengevaeren WR, van der Werf T, et al.: LDL-Apheresis Atherosclerosis Regression Study (LAARS). Effect of aggressive versus conventional lipid lowering treatment on coronary atherosclerosis. Circulation. 1996, 93:1826–1835.

    PubMed  CAS  Google Scholar 

  5. O’Driscoll G, Green D, Rankin J, et al.: Improvement in endothelial function by angiotensin converting enzyme inhibition in insulin-dependent diabetes mellitus. J Clin Invest. 1997, 100: 78–684.

    Google Scholar 

  6. Tamai O, Matsuoka H, Itabe H, et al.: Single LDL apheresis improves endothelium-dependent vasodilatation in hypercholesterolemic humans. Circulation. 1997, 95:76–82.

    PubMed  CAS  Google Scholar 

  7. • PittB, Waters D, Brown WV, et al.: Aggressive lipid-lowering therapy combined with angioplasty in stable corinary artery disease. N Engl J Med. 1999, 341:70–76.

    Article  Google Scholar 

This study demonstrated and improvement in endothelial function within hours of aggressive lipid lowering achieved by LDL apheresis

  1. Laufs U, La Fata V, Plutzky J, Liao JK: Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998, 97:1129–1135.

    PubMed  CAS  Google Scholar 

  2. • Laufs U, Fata VL, Liao JK: Inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase blocks hypoxia-mediated down-regulation of endothelial nitric oxide synthase. J Biol Chem. 1997, 272:31725–31729.

    Article  PubMed  CAS  Google Scholar 

This study demonstrated the lipid-independent effects of statins on nitric oxide synthase in cell culture models. The importance of this effect in atherosclerotic arteries is yet to be determined

  1. Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, et al.: Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest. 1998, 101:2711–2719.

    Article  PubMed  CAS  Google Scholar 

  2. • Rosenson RS, Tangney CC: Antiatherothrombotic properties of statins: implications for cardiovascular event reductio (see comments). JAMA. 1998, 279:1643–1650.

    Article  PubMed  CAS  Google Scholar 

In this study of cultured bovine endothelial cells, statins were able to prevent the inhibitory effect of oxidized LDL cholesterol on nitric synthase mRNA expression. The statins also reduced the amount of immunoreactive endothelin-1 levels

  1. Williams JK, Sukhova CK: Pravastatin has cholesterol-lowering independent effects on the artery wall of atherosclerotic monkeys. J Am Coll Cardiol. 1998, 31:684–691.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kinlay, S., Plutzky, J. Effect of lipid-lowering therapy on vasomotion and endothelial function. Curr Cardiol Rep 1, 238–243 (1999). https://doi.org/10.1007/s11886-999-0029-5

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11886-999-0029-5

Keywords

Navigation