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Abstract Background.— With increased efforts to lower serum cholesterol levels, it is important to quantify associations between serum cholesterol level and causes of death other than coronary heart disease, for which an etiologic relationship has been established. Methods.— For an average of 12 years, 350 977 men aged 35 to 57 years who had been screened for the Multiple Risk Factor Intervention Trial were followed up following a single standardized measurement of serum cholesterol level and other coronary heart disease risk factors; 21 499 deaths were identified. Results.— A strong, positive, graded relationship was evident between serum cholesterol level measured at initial screening and death from coronary heart disease. This relationship persisted over the 12-year follow-up period. No association was noted between serum cholesterol level and stroke. The absence of an association overall was due to different relationships of serum cholesterol level with intracranial hemorrhage and nonhemorrhagic stroke. For the latter, a positive, graded association with serum cholesterol level was evident. For intracranial hemorrhage, cholesterol levels less than 4.14 mmol/L (<160 mg/dL) were associated with a twofold increase in risk. A serum cholesterol level less than 4.14 mmol/L (<160 mg/dL) was also associated with a significantly increased risk of death from cancer of the liver and pancreas; digestive diseases, particularly hepatic cirrhosis; suicide; and alcohol dependence syndrome. In addition, significant inverse graded associations were found between serum cholesterol level and cancers of the lung, lymphatic, and hematopoietic systems, and chronic obstructive pulmonary disease. No significant associations were found of serum cholesterol level with death from colon cancer, with accidental deaths, or with homicides. Overall, the inverse association between serum cholesterol level and most cancers weakened with increasing follow-up but did not disappear. The association between cholesterol level and death due to cancer of the lung and liver, chronic obstructive pulmonary disease, cirrhosis, and suicide weakened little over follow-up. Conclusions.— The association of serum cholesterol with specific causes of death varies in direction, strength, gradation, and persistence. Further research on the determinants of low serum cholesterol level in populations and long-term follow-up of participants in clinical trials are necessary to assess whether inverse associations with noncardiovascular disease causes of death are consequences of noncardiovascular disease, whether serum cholesterol level and noncardiovascular disease are both consequences of other factors, or whether these associations are causal.(Arch Intern Med. 1992;152:1490-1500) References 1. References 1, 4, 7, 8, 10-12, 14, 16-18, and 59. 2. Pooling Project Research Group. Relationship of blood pressure, serum cholesterol, smoking habit, relative weight, and ECG abnormalities to incidence of major coronary events: final report of the Pooling Project . J Chronic Dis. 1978;31:201-306.Crossref 3. WHO Expert Committee on the Prevention of Coronary Heart Disease. Prevention of Coronary Heart Disease: World Health Organization Technical Report Series 678 . Geneva, Switzerland: World Health Organization; 1982. 4. Neaton JD, Wentworth D. Serum cholesterol, blood pressure, cigarette smoking and death from coronary heart disease: overall findings and differences by age for 316,099 white men . Arch Intern Med. 1992;152:56-64.Crossref 5. Barrett-Connor E, Suarez L, Khaw K, Criqui MH, Wingard DL. Ischemic heart disease risk factors after age 50 . J Chronic Dis. 1984;37:903-908.Crossref 6. Benfante R, Reed D. Is elevated cholesterol level a risk factor for coronary heart disease in the elderly? JAMA. 1990;263:393-396.Crossref 7. Anderson KM, Castelli WP, Levy D. Cholesterol and morbidity: 30 years of follow-up from the Framingham Study . JAMA. 1987;257:2176-2180.Crossref 8. Tornberg SA, Jakobsson KFS, Eklund GA. Stability and validity of a single serum cholesterol measurement in a prospective cohort study . Int J Epidemiol. 1988;17:797-803.Crossref 9. Deubner DC, Wilkinson WE, Helms MJ, Tyroler HA, Hanes CG. Logistic model estimation of death attributable to risk factors for cardiovascular disease in Evans County, Georgia . Am J Epidemiol. 1980;112:135-143. 10. Neaton JD, Kuller LH, Wentworth D, Borhani NO. Total and cardiovascular mortality in relation to cigarette smoking, serum cholesterol concentration, and diastolic blood pressure among black and white males followed up for five years . Am Heart J. 1984;108:759-769.Crossref 11. Pekkanen J, Linn S, Heiss G, et al. Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without pre-existing cardiovascular disease . N Engl J Med. 1990;322:1700-1707.Crossref 12. Shaper AG, Pocock JJ, Walker M, Phillips AN, Whitehead TP, Macfarlane PW. Risk factors for ischaemic heart disease: the prospective phase of the British Regional Heart Study . J Epidemiol Community Health. 1985;39:197-209.Crossref 13. Kannel WB, Wolf PA, Garrison RJ, eds. Survival following initial cardiovascular events: thirty-year follow-up . The Framingham Study: An Epidemiological Study of Cardiovascular Disease . Washington, DC: US Dept of Health and Human Services; 1988:35. US Dept of Health and Human Services publication NIH 88-2969. 14. Stamler J, Wentworth D, Neaton JD. Is the relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? JAMA. 1986;256:2823-2828.Crossref 15. Rose G, Shipley M. Plasma cholesterol concentration and death from coronary disease: 10-year results of the Whitehall Study . BMJ. 1986;293:306-308.Crossref 16. Kannel WB, Wolf PA, Garrison RJ, eds. Some risk factors related to the annual incidence of cardiovascular disease and death using pooled repeated biennial measurements: Framingham Heart Study, 30-year follow-up . The Framingham Study: An Epidemiological Study of Cardiovascular Disease . Washington, DC: US Dept of Health and Human Services; 1987:34. US Dept of Health and Human Services publication 87-2703. 17. Goldbourt U, Yaari S. Cholesterol and coronary heart disease mortality: a 23-year follow-up of study of 9902 men in Israel . Arteriosclerosis . 1990;10:512-519.Crossref 18. Farchi G, Menotti A, Canti S. Coronary risk factors and survival probability from coronary and other causes of death . Am J Epidemiol. 1987;126:400-408. 19. Chen Z, Peto R, Collins R, Mac Mahon S, Lu J, Li W. Serum cholesterol concentration and coronary heart disease in population with low cholesterol concentrations . BMJ. 1991;303:276-282.Crossref 20. WHO Clofibrate Trial, Committee of Principal Investigators. A co-operative trial in the primary prevention of ischemic heart disease using clofibrate . Br Heart J. 1978;40:1069-1118.Crossref 21. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results, I: reduction in incidence of coronary heart disease . JAMA. 1984;251:351-364.Crossref 22. Frick MH, Elo MO, Happa K, et al. Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease . N Engl J Med. 1987;317:1237-1245.Crossref 23. Hjermann I, Velve Byre K, Holme I, Leren P. Effect of diet and smoking intervention on the incidence of coronary heart disease: report from the Oslo Study Group of a randomized trial in healthy men . Lancet. 1981;2:1303-1310.Crossref 24. Multiple Risk Factor Intervention Trial Research Group. Coronary heart disease death, non-fatal acute myocardial infarction and other clinical outcomes in the Multiple Risk Factor Intervention Trial . Am J Cardiol. 1986;58:1-13.Crossref 25. Multiple Risk Factor Intervention Trial Research Group. Mortality rates after 10.5 years for participants in the Multiple Risk Factor Intervention Trial: findings related to a prior hypothesis of the trial . JAMA. 1990;263:1795-1801.Crossref 26. Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease . JAMA. 1975;231:360-381.Crossref 27. Carlson LA, Rosenhamer G. Reduction of mortality in the Stockholm Ischemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid . Acta Med Scand. 1988;223:405-418.Crossref 28. Buchwald H, Varco RL, Matts JP, et al. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia: report of the Program on the Surgical Control of the Hyperlipidemias (POSCH) . N Engl J Med. 1990;323:946-955.Crossref 29. Brensike JH, Levy RI, Kelsey SF, et al. Effects of therapy with cholestyramine on progression of coronary arteriosclerosis: results of the NHLBI Type II Coronary Intervention Study . Circulation. 1984;69:313-324.Crossref 30. Arntzenius AC, Kromhout D, Barth JD, et al. Diet, lipoproteins, and the progression of coronary atherosclerosis: the Leiden Intervention Trial . N Engl J Med. 1985;312:805-811.Crossref 31. Blankenhorn DH, Nessim SA, Johnson RL, Sanmarco ME, AzenSP, Cashin-Hemphill L. Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts . JAMA. 1987;257:3233-3240.Crossref 32. Brown BG, Lin JT, Schaefer SM, Kaplan CA, Dodge HT, Albers JJ. Niacin or lovastatin, combined with colestipol, regress coronary atherosclerosis and prevent clinical events in men with elevated apolipoprotein B . Circulation. 1989;80( (suppl II) ):266. Abstract. 33. Sherwin R, Wentworth D, Cutler J, Hulley SB, Kuller L, Stamler J. Serum cholesterol levels and cancer mortality in 361,662 men screened for the Multiple Risk Factor Intervention Trial . JAMA. 1987;257:943-948.Crossref 34. Rose G, Blackburn H, Keys A, et al. Colon cancer and blood-cholesterol . Lancet. 1974;1:523-526. 35. Kark JD, Smith AH, Harnes CG. The relationship of serum cholesterol to the incidence of cancer in Evans County, Georgia . J Chronic Dis. 1980;33:311-322.Crossref 36. Cambien F, Ducimetiere P, Richard J. Total serum cholesterol and cancer mortality in a middle-aged male population . Am J Epidemiol. 1980;112:388-394. 37. Miller, SR, Tarlter PI, Papatestas AE, Slater G, Aufses AH. Serum cholesterol and colon cancer . J Natl Cancer Inst. 1981;67:297-300. 38. Salonen JT. Risk of cancer and death in relation to serum cholesterol: a longitudinal study in an eastern Finnish population with high overall cholesterol level . Am J Epidemiol. 1982;116:622-630. 39. International Collaborative Group. Circulating cholesterol level and risk of death from cancer in men aged 40 to 69 years: experience of an international collaborative group . JAMA. 1982;248:2853-2859.Crossref 40. Sorlie PD, Feinleib M. The serum cholesterol-cancer relationship: an analysis of time trends in the Framingham Study . J Natl Cancer Inst. 1982;69:989-996. 41. Schatzkin A, Hoover RN, Taylor PR, et al. Serum cholesterol and cancer in the NHANES I Epidemiologic Follow-up Study . Lancet. 1987;2:298-301.Crossref 42. Tornberg SA, Holm L, Carstensen JM, Eklund GA. Cancer incidence and cancer mortality in relation to serum cholesterol . J Natl Cancer Inst. 1989;81:1917-1921.Crossref 43. Isles CG, Hole DJ, Gillis CR, Hawthorne VM, Lever AF. Plasma cholesterol, coronary heart disease, and cancer in the Renfrew and Paisley survey . BMJ. 1989;298:920-924.Crossref 44. Iso H, Jacobs DR, Wentworth D, Neaton JD, Cohen J. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the Multiple Risk Factor Intervention Trial . N Engl J Med. 1989;320:904-910.Crossref 45. Tanaka H, Ueda Y, Hayashi M, et al. Risk factors for cerebral hemorrhage and cerebral infarction in a Japanese rural community . Stroke. 1982;13:62-72.Crossref 46. Yano K, Reed DM, Maclean CJ. Serum cholesterol and hemorrhagic stroke in the Honolulu Heart Program . Stroke. 1989;20:1460-1465.Crossref 47. Multiple Risk Factor Intervention Trial Research Group. Multiple Risk Factor Intervention Trial. Risk factor changes and mortality . JAMA. 1982;248:1465-1477.Crossref 48. Multiple Risk Factor Intervention Trial Research Group. Design considerations in the NHLI Multiple Risk Factor Intervention Trial (MRFIT) . J Chronic Dis. 1977;30:261-275.Crossref 49. Sherwin R, Kaelber CT, Kezdi P, Kjelsberg MO, Thomas HE. The Multiple Risk Factor Intervention Trial (MRFIT), II: the development of the protocol . Prev Med. 1981;10:402-425.Crossref 50. Neaton JD, Grimm RH, Cutler J. Recruitment of participants for the Multiple Risk Factor Intervention Trial (MRFIT) . Controlled Clin Trials. 1988;8:415-535. 51. Lipid Research Clinics Program: Manual of Operations . Washington, DC; National Institutes of Health: 1974:1. US Dept of Health, Education, and Welfare publication NIH 75-628. 52. Cooper GR, Half AC, Widdowson GM, Bartsch GE, DuChene AG, Hulley SB. Quality control in the MRFIT local screening and clinic laboratory . Controlled Clin Trials. 1986;7:1585-1655. 53. Dischinger P, DuChene AG. Quality control aspects of blood pressure measurements in the Multiple Risk Factor Intervention Trial . Controlled Clin Trials. 1986;7:137S-157S.Crossref 54. Wentworth DN, Neaton JD, Rasmussen WL. An evaluation of the Social Security Administration MBR file and the Nation Death Index in the ascertainment of vital status . Am J Public Health. 1983;73:1270-1274.Crossref 55. International Classification of Diseases, Ninth Revision, Clinical Modification . Ann Arbor, Mich: Edwards Bros Inc; 1981. 56. Cox DR. Regression models and life tables (with discussion) . J R Stat Soc B. 1972;34:187-220. 57. Kalbfleisch JB, Prentice RL. The Statistical Analysis of Failure Time Data . New York, NY: John Wiley & Sons Inc; 1980. 58. Mac Mahon S, Peto R, Cutler J, et al. Blood pressure, stroke and coronary heart disease, I: prolonged difference in blood pressure: prospective observational studies corrected for the regression dilution bias . Lancet. 1990;335:765-774.Crossref 59. Prentice RL. Covariate measurement errors and parameter estimation in a failure time regression model . Biometrika. 1982;69:331-342.Crossref 60. Keys A, ed. Coronary heart disease in seven countries . Circulation. 1970;41( (suppl) ):1-211.Crossref 61. Report of the Working Group on Arteriosclerosis of the National Heart, Lung, and Blood Institute. 1981:2. US Dept of Health and Human Services publication NIH 81-2035. 62. NIH Consensus Development Conference. Lowering blood cholesterol to prevent heart disease . JAMA. 1985;253:2080-2086.Crossref 63. Iso H, Jacobs DR, Goldman L. Accuracy of death certificate diagnosis of intracranial hemorrhage and nonhemorrhagic stroke . Am J Epidemiol. 1990;132:993-998. 64. Ooneda G, Yoshida Y, Suzuki K, et al. Smooth muscle cells in the development of plasmatic arterionecrosis, arteriosclerosis, and arterial contraction . Blood Vessels. 1978;15:148-156. 65. Davey Smith G, Shipley MJ, Marmot MG, Rose G. Plasma cholesterol concentration and mortality: The Whitehall Study . JAMA. 1992;267:70-76.Crossref 66. Vitols S, Bjorkholm M, Gahrtan G, Peterson C. Hypocholesterolaemia in malignancy due to elevated low-density-lipoprotein receptor activity in tumour cells: evidence from studies in patients with leukemia . Lancet. 1985;2:1150-1154.Crossref 67. Budd D, Ginsberg H. Hypocholesterolemia and acute myelogenous leukemia: association between disease activity and plasma low-density lipoprotein cholesterol concentrations . Cancer. 1986;58:1361-1365.Crossref 68. Thomas ED, Clift RA, Fefer A, et al. Marrow transplantation for the treatment of chronic myelogenous leukemia . Ann Intern Med. 1986;104:155-163.Crossref 69. Stryker WS, Kaplan LA, Stein EA, Stampfer MJ, Sober A, Willett WC. The relation of diet, cigarettes smoking, and alcohol consumption to plasma beta-carotene and alpha-tocopherol levels . Am J Epidemiol. 1988;127:283-296. 70. Connett JE, Kuller LH, Kjelsberg MO, et al. Relationship between carotenoids and cancer: the Multiple Risk Factor Intervention Trial (MRFIT) study . Cancer. 1989;64:126-134.Crossref 71. Stahelin HB, Rosel F, Buers E, Brubacher G. Cancer, vitamins, and plasma lipids: Prospective Basel Study . J Natl Cancer Inst. 1984;73:1463-1468. 72. Menkes MS, Comstock GW, Vuilleumier JP, Helsing KJ, Rider AA, Brookmeyer R. Serum beta-carotene, vitamins A and E, selenium, and the risk of lung cancer . N Engl J Med. 1986;315:1250-1254.Crossref 73. Nomura AM, Stemmermann GN, Heilbrun LK, Salkeld RM, Vuilleumier JP. Serum vitamin levels and risk of cancer of specific sites in men of Japanese ancestry in Hawaii . Cancer Res. 1985;45:2369-2372. 74. Stahelin HB, Gey KF, Eichholzer M, et al. Plasma antioxidant vitamins and subsequent cancer mortality in the 12-year follow-up of the Prospective Basel Study . Am J Epidemiol. 1991;133:766-775. 75. Willett WC, Mac Mahon B. Diet and cancer: an overview . N Engl J Med. 1984;310:633-638.Crossref 76. Colditz GA, Stampfer MJ, Willett WC. Diet and lung cancer: a review of epidemiologic evidence in humans . Arch Intern Med. 1987;147:157-160.Crossref 77. Ziegler RG. A review of epidemiologic evidence that carotenoids reduce the risk of cancer . J Nutr. 1989;119:116-122. 78. Fontham ETH. Protective dietary factors and lung cancer . Int J Epidemiol. 1990;19( (suppl 1) ):S32-S42.Crossref 79. Lieber CS, Garro A, Leo MA, Mak KM, Worner T. Alcohol and cancer . Hepatology. 1986;6:1005-1019.Crossref 80. Pollock ES, Nomura AM, Heilbrun LK, Stemmermann GN, Green SB. Prospective study of alcohol consumption and cancer . N Engl J Med. 1984;310:617-621.Crossref 81. Muldoon MF, Manuck SB, Matthews KA. Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials . BMJ. 1990;301:309-314.Crossref 82. Pekkanen J, Nissinen A, Punsar S, Karvonen MJ. Serum cholesterol and risk of accidental or violent death in a 25-year follow-up . Arch Intern Med. 1989;149:1589-1591.Crossref 83. Davey Smith G, Shipley MJ, Marmot MG, Patel C. Lowering cholesterol concentrations and mortality . BMJ. 1990;301:552. 84. Virkkunen M. Serum cholesterol levels in homicidal offenders: a low cholesterol level is connected with a habitually violent tendency under the influence of alcohol . Neuropsychobiology. 1983;10:65-69.Crossref 85. Holinger PC, Klemen EH. Violent deaths in the United States, 1900-1975: relationships between suicide, homicide and accidental deaths . Soc Sci Med. 1982;16:1929-1938.Crossref 86. Kivela SL. Relationship between suicide, homicide and accidental deaths among the aged in Finland in 1951-1979 . Acta Psychiatr Scand. 1985;72:155-160.Crossref 87. Rossouw JE, Lewis B, Rifkind BM. The value of lowering cholesterol after myocardial infarction . N Engl J Med. 1990;323:1112-1119.Crossref 88. Strandberg TE, Salomaa VV, Naukkarinen VA, Vanhanen HT, Sarno SJ, Miettinen TA. Long-term mortality after 5-year multifactor primary prevention of cardiovascular diseases in middle-aged men . JAMA. 1991;266:1225-1229.Crossref 89. Holme I, Hjermann I, Hegleland A, Leren P. The Oslo Study: diet and antismoking advice: additional results from a 5-year primary prevention trial in middle-aged men . Prev Med. 1985;14:279-292.Crossref 90. World Health Organization European Collaborative Group. European collaborative trial of multifactorial prevention of coronary heart disease: final report on the 6-year results . Lancet. 1986;1:869-872. 91. Rose G. European collaborative trial of multifactorial prevention of coronary heart disease . Lancet. 1987;1:685.Crossref 92. Wysowski DK, Gross TP. Deaths due to accidents and violence in two recent trials of cholesterol-lowering drugs . Arch Intern Med. 1990;150:2169-2172.Crossref
Archives of Internal Medicine – American Medical Association
Published: Jul 1, 1992
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