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The Role of Lipid-Lowering Therapy in Multiple Risk Factor Management

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Abstract

Epidemiological studies have demonstrated that the risk of death from coronary heart disease (CHD) increases in parallel with increasing serum cholesterol levels. The risk is highest in patients with severely elevated cholesterol levels [i.e. >6.2 mmol/L (240 mg/dl)]. However, even in patients with serum cholesterol levels of 4.7 to 5.7 mmol/L (180 to 220 mg/dl), mortality from CHD is 30 to 70% higher than in patients with cholesterol levels <4.7 mmol/L (180 mg/dl). A number of factors other than serum total cholesterol levels affect CHD risk.

It is increasingly accepted that dysfunction of the vascular endothelium contributes to the pathogenesis of atherosclerosis. Experimental evidence and clinical studies suggest that endothelium-derived nitric oxide (NO) plays an important role as an endogenous antiatherogenic molecule, and that reduced levels of NO may promote progression of atherosclerosis. Hypercholesterolaemia can hasten atherogenesis in part by reducing levels of NO.

In humans, it is possible to evaluate the effects of hypercholesterolaemia by measuring the vasodilator response to pharmacological or physical stimuli that increase the synthesis and release of endothelium-derived NO. The use of high resolution external ultrasound to assess post-ischaemic brachial artery vasodilation in patients with cardiovascular risk factors has demonstrated that endothelial dysfunction exists, even in the absence of overt atherosclerotic plaques. Impaired endothelium-dependent vasodilation has been observed in asymptomatic individuals with hypercholesterolaemia, as well as in patients with other recognised risk factors. Dietary and pharmacological lipid lowering has been shown to produce improvements in endothelial-dependent vasodilation.

Among normocholesterolaemic healthy young individuals without cardiac risk factors, endothelium-dependent vasodilation was more likely to be impaired in those with relatively higher total and low density lipoprotein-cholesterol levels (i.e. above versus below the 25th percentile). This suggests that an inverse and continuous relationship exists between the prevailing cholesterol level and endothelial function. The implication of these findings is that the treatment of hypercholesterolaemia remains, at present, an underutilised means of reducing CHD.

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References

  1. Castelli WP. Epidemiology of coronary heart disease: the Framingham study. Am J Med 1984; 76: 4–12

    Article  PubMed  CAS  Google Scholar 

  2. LaRosa JC, Hunninghake D, Bush D, et al. The cholesterol facts: a summary of the evidence relating dietary fats, serum cholesterol and coronary heart disease: a joint statement by the American Heart Association and the National Heart, Lung and Blood Institute. Circulation 1990; 81: 1721–33

    Article  PubMed  CAS  Google Scholar 

  3. Manninen V, Elo MO, Frick MH, et al. Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. JAMA 1988; 260: 641–51

    Article  PubMed  CAS  Google Scholar 

  4. Martin MJ, Hulley SB, Browner WS, et al. Serum cholesterol, blood pressure, and mortality: implications from a cohort of 361 662 men. Lancet 1986; II: 933–6

    Article  Google Scholar 

  5. Genest JJ, Martin-Munley SS, McNarmara JR, et al. Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation 1992; 85: 2025–33

    Article  PubMed  Google Scholar 

  6. Austin MA, King MC, Vranizan KM, et al. Atherogenic lipoprotein phenotype: a proposed genetic marker for coronary heart disease risk. Circulation 1990; 82: 495–506

    Article  PubMed  CAS  Google Scholar 

  7. Austin MA, Breslow JL, Hennekens CH, et al. Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA 1988; 260: 1917–21

    Article  PubMed  CAS  Google Scholar 

  8. Dreon DM, Fernstrom HA, Miller B, et al. Low-density lipoprotein subclass patterns and lipoprotein response to a reduced-fat diet in men. FASEB J 1994; 8: 121–6

    PubMed  CAS  Google Scholar 

  9. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383–9

    Google Scholar 

  10. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333: 1301–7

    Article  PubMed  CAS  Google Scholar 

  11. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: 1001–9

    Article  PubMed  CAS  Google Scholar 

  12. Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? Br Med J 1994; 308: 367–373

    Article  CAS  Google Scholar 

  13. Davies MJ, Richardson PD, Woolf N, et al. Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, and smooth muscle cell content. Br Heart J 1993; 69: 377–81

    Article  PubMed  CAS  Google Scholar 

  14. Brown BG, Zhao X-Q, Sacco DE, et al. Lipid lowering and plaque regression: new insights into prevention of plaque disruption and clinical events in coronary disease. Circulation 1993; 87: 1781–91

    Article  PubMed  CAS  Google Scholar 

  15. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995; 92: 657–71

    Article  PubMed  CAS  Google Scholar 

  16. Celermajer DS. Endothelial dysfunction: does it matter? Is is reversible? J Am Coll Cardiol 1997; 30: 325–33

    Article  PubMed  CAS  Google Scholar 

  17. Libby P, Molecular bases of the acute coronary syndromes. Circulation 1995; 91: 2844–50

    Article  PubMed  CAS  Google Scholar 

  18. Ruschitzka FT, Noll G, Lüscher TG. The endothelium in coronary artery disease. Cardiology 1997; 88 Suppl. 3: 3–19

    Article  Google Scholar 

  19. Lowenstein CJ, Dinerman JL, Snyder SH. Nitric oxide: a physiological messenger. Ann Intern Med 1994; 120: 227–37

    PubMed  CAS  Google Scholar 

  20. Vanhoutte PM, Shimokawa H. Endothelium-derived relaxing factor and coronary vasospasm. Circulation 1989; 80: 1–9

    Article  PubMed  CAS  Google Scholar 

  21. Localzo J, Welch G. Nitric oxide and its role in the cardiovascular system. Prog Cardiovasc Dis 1995; 2: 87–104

    Article  Google Scholar 

  22. Lefer AM, Ma X-L. Decreased basal nitric oxide release in hypercholesterolaemia increases neutrophil adherence to coronar artery endothelium. Atheroscler Thromb 1993; 13: 771–6

    Article  CAS  Google Scholar 

  23. Shimokawa H, Vanhoute PM. Hypercholesterolemia causes generalized impairment of endothelium-dependent relaxation to aggregating platelets in porcine arteries. J Am Cardiol 1989; 13: 1402–8

    Article  CAS  Google Scholar 

  24. Gordon JB, Ganz P, Nabel EG, et al. Atherosclerosis and endothelial function influence the coronary vasomotor response to exercise. J Clin Invest 1989; 83: 1946–52

    Article  PubMed  CAS  Google Scholar 

  25. Ludmer PL, Selwyn AP, Shook TL, et al. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. New Eng J Med 1986; 315: 1046–51

    Article  PubMed  CAS  Google Scholar 

  26. Creager MA, Cooke JP, Mendelsohn ME, et al. Impaired vasodilatation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest 1990; 86: 228–34

    Article  PubMed  CAS  Google Scholar 

  27. Celermajer DS, Sorensen KE, Bull C, et al. Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction. J Am Coll Cardiol 1994; 24: 1468–74

    Article  PubMed  CAS  Google Scholar 

  28. 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

    Article  PubMed  CAS  Google Scholar 

  29. 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: 481–7

    Article  PubMed  CAS  Google Scholar 

  30. Anderson TJ, Meredith IT, Yeung AC, et al. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. New Eng J Med 1995; 332: 488–93

    Article  PubMed  CAS  Google Scholar 

  31. Levine GN, Frei B, Kouloukis SN, et al. Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation 1996; 93: 1107–13

    Article  PubMed  CAS  Google Scholar 

  32. Clarkson P, Adams MR, Powe AJ, et al. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolaemic young adults. J Clin Invest 1996; 97: 1989–94

    Article  PubMed  CAS  Google Scholar 

  33. Selke FW, Armstrong ML, Harrison DG. Endothelium-dependent vascular relaxation is abnormal in the coronary microcirculation of atherosclerotic primates. Circulation 1990; 81: 1586–93

    Article  Google Scholar 

  34. Creager MA, Gallagher Sh, Girerd XJ, et al. L-arginine improves endothelium-dependent vasodilation in hypercholes-terolemic humans. J Clin Invest 1992 Oct; 90(4): 1248–53

    Article  PubMed  CAS  Google Scholar 

  35. Mancini GBJ, Henry GC, Macaya C, et al. Angiotensin-converting enzyme: inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation 1996; 94: 258–65

    Article  PubMed  CAS  Google Scholar 

  36. Frielingsdorf J, Seiler C, Kaufman P, et al. Normalization of abnormal coronary vasomotion by calcium antagonists in patients with hypertension. Circulation 1996; 93: 1380–7

    Article  PubMed  CAS  Google Scholar 

  37. Gilligan DM, Quyyumi AA, Cannon RO. Effects of physiological levels of estrogen on coronary vasomotor function in post menopausal women. Circulation 1994; 89: 2545–51

    Article  PubMed  CAS  Google Scholar 

  38. Lieberman EH, Gerhard MD, Uehata A, et al. Estrogen improves endothelium-dependent, flow-mediated vasodilation in postmenopausal women. Ann Intern Med 1994; 121: 936–41

    PubMed  CAS  Google Scholar 

  39. Ohara Y, Peterson TE, Harrison DG. Hypercholesterolemia increases endothelial Superoxide anion production. J Clin Invest 1993; 92: 2546–51

    Article  Google Scholar 

  40. Rubanyi GM, Vanhouette PM. Superoxide anions and hyperoxia inactivate endothelium-derived relaxing factor. Am J Physiol 1986; 250 (5 Pt 2): H822–7

    PubMed  CAS  Google Scholar 

  41. 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: 2519–24

    Article  PubMed  CAS  Google Scholar 

  42. Steinberg HO, Bayazeed B, Hook G, et al. Endothelial dysfunction is associated with cholesterol levels in the high normal range in humans. Circulation 1997; 96: 3287–93

    Article  PubMed  CAS  Google Scholar 

  43. National Cholesterol Education Program. Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation 1994 Mar; 89: 1333–445

    Article  Google Scholar 

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  1. Department of Cardiology, Hospital Militar Central, and Universities of Salvador and Buenos Aires, Virrey Loreto 2111, 1426, Buenos Aires, Argentina

    Ricardo J. Esper

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Esper, R.J. The Role of Lipid-Lowering Therapy in Multiple Risk Factor Management. Drugs 56 (Suppl 1), 1–7 (1998). https://doi.org/10.2165/00003495-199856001-00001

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