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Smoking, alcohol and coronary artery occlusion
Atherosclerosis, 43 (1982) 211-282 Elsevier/North-Holland Scientific
277 Publishers,
Ltd.
Smoking, Alcohol and Coronary Joseph J. Barboriak, Raymond
Artery Occlusion
Alfred J. Anderson G. Hoffmann
and
Reseurch Service. Wood Vetercou Administrution Medicul Center and the Depurtment of Phrrrmcrcologr md Toxicology. und Preventive Medicine (Biostutistics Section). The Me&d College of Wisconsin, Milwaukee. WI (U.S.A.) (Received 17 August, 1981) (Accepted 14 December, 1981)
Summary The effects of smoking and alcohol intake on the extent of coronary artery occlusion were studied in 2989 men undergoing a diagnostic coronary arteriography. Smoking showed an exposure-related enhancing effect on the extent of coronary artery occlusion. Conversely, alcohol consumption demonstrated an attenuating dose-related effect, offsetting the increased coronary occlusion associated with smoking. Alcohol intake should be considered in studies evaluating the risk factorscoronary artery disease interaction. Key words: Alcohol intake - Coronary artery occlusion - Smoking
Introduction Increased use of coronary arteriography has allowed direct studies of the association between the individual risk factors and the extent of coronary heart disease (CHD). Smoking has been demonstrated to be positively related to coronary artery occlusion [ 11, while alcohol intake has been associated with a reduced coronary artery occlusion disease in men and animals [2-41. Since drinking, especially if extensive, is usually associated with the smoking habit [4,5], a study of the individual effects of these two variables requires correction for the possible confounding This work was supported in part by Grant HL-14378 Veterans Administration, and the U.S. Brewers Association.
from the National
Address correspondence and reprint requests to: Joseph J. Barboriak, Veterans Administration Medical Center, Wood, WI 53193, U.S.A.
0021-9150/82/0000-0000/$02.75
8 1982 Elsevier/North-Holland
Scientific
Institutes
of Health,
Sc.D., Research
Publishers,
the
Service/lSl,
Ltd.
278
influence of the other factor. Availability of data from a large group of patients undergoing diagnostic coronary arteriography has allowed identification of subgroups of individuals who are smokers but abstain from alcohol, as well as of nonsmoking imbibers of alcoholic beverages. In the present communication, we report on the separate effects of smoking and drinking on the extent of CHD, as well as on the modification of the effects of one variable by the other.
Methods
The data were collected from 2989 consecutive male patients who had diagnostic coronary arteriography at one of two Milwaukee area hospitals and had volunteered for the study. The criteria for arteriography were unstable angina pectoris, moderate to severe stable angina, previous myocardial infarction and recurrent chest pain of unknown etiology. Information on smoking experience and the amount of alcohol consumed was obtained from a questionnaire. The data on the number of drinks were converted into equivalents of absolute alcohol as previously reported [4]. The test-retest reliability of the alcohol questionnaire (Pearson’s coefficient) ascertained by asking 500 patients to fill out the questionnaire 2-3 weeks after the first inquiry was 0.85. Coronary arteriography was performed by the Sones and Shirey’s [6] and Judkin’s [7] techniques, and the results were evaluted by experienced cardiologists and radiologists and scored uniformly and blind to the questionnaire information using the scoring system of Rowe et al. [8]. In this system, the occlusion is rated by 20% increments and proper weight is given to the dominance of the coronary branches. The final score ranges from 0 (no occlusion) to 300 (all main branches included). Smoking experience was graded on the basis of the number of cigarettes smoked daily and the duration of smoking exposure. In this adaptation [1] of the procedure described by Hammond and Horn [9], the patients were divided into nonsmokers (no present smoking or history of smoking), moderate smokers (smokers of cigars, pipes or up to 20 cigarettes daily for less than 20 years), and heavy smokers (smoking more than 20 cigarettes daily for 10 years or more, or 20 cigarettes daily for longer than 20 years). Mean occlusion scores for each smoking and drinking subgroup were compared in a two-way analysis of variance with age, plasma cholesterol and triglyceride levels, obesity, history of hypertension and diabetes as covariates. This analysis also provided mean occlusion scores adjusted for the effects of the other risk factors. In addition, multiple regression analysis was used to evaluate trends in occlusion score with alcohol and smoking adjusting for plasma cholesterol and triglycerides, history of hypertension, age, obesity and diabetes [lo]. Results
I’he findings are summarized in Fig. 1. The size of the individual groups ranged from 77 (for nonsmokers consuming more than 6 ounces [ 180 ml] of alcohol weekly)
279
to 678 (for heavy smokers consuming l-6 ounces [30-180 ml] of alcohol weekly). Regardless of the amount of alcohol consumed, the increasing smoking exposure was associated with higher occlusion scores. In male patients abstaining from alcohol 160 1
0'
< 1 (30) l-6(30-180) >6
(180)
Oz(ml)Alcohol/week
Fig. I. Interrelationships between the extent of coronary artery occlusion, experience. Number of patients in parentheses. Vertical bars= SEM.
alcohol
intake
and smoking
or consuming less than 1 ounce (30 ml) weekly, the coronary occlusion score increased from 130 for nonsmokers to 157 for heavy smokers (P =C0.01). In groups consuming more than 6 ounces (180 ml) weekly, the corresponding increase in occlusion score was from 117 to 135. Similarly, the inverse effect of alcohol intake on the extent of coronary artery occlusion could be observed at each of the three smoking levels. The average occlusion score of heavy smokers consuming over 6 ounces of alcohol (180 ml) per week was 134, while the corresponding value for abstainers or light drinkers was 157. Due to the opposing effect of the two tested variables, the occlusion-enhancing effect of smoking was, to some extent, offset by the occlusion-retarding action of alcohol consumption. As a result, occlusion scores for the nonsmoking alcohol-abstainers and heavy smokers consuming more than 6 ounces of alcohol per week were quite similar (130 vs 134). A multiple regression analysis was carried out to examine the combined effects of alcohol intake and smoking. After adjusting for other factors, both alcohol intake and smoking were found to yield statistically significant regression coefficients (smoking, r = 6.45; alcohol intake, r = - 1.46; both P -C0.0 1). However, there was no interaction between smoking and alcohol intake, indicating that the effects of the two variables were independent of each other.
280
Discussion Results of the present study indicate that the enhancing effect of smoking on the development of coronary artery occlusion may be modified by the attenuating effect of alcohol. Since the extent of coronary artery occlusion correlates strongly with the usual clinical indicators of ischemic heart disease such as myocardial infarction [l], proper evaluation of the association between smoking and clinical indicators of the heart disease should also consider the possible effect of alcohol consumption. The significance of alcohol intake is indicated by the observation that over 80% of male heart patients have reported drinking alcoholic beverages [ 111, and that noticeable reduction of coronary occlusion may be seen with consumption of as little as one daily drink. The observed increase in coronary occlusion score of nondrinking smokers as compared with nonsmokers parallels the autopsy data of smokers [ 12,131, indicating more extensive arterial lesions. Similarly, the association of alcohol intake with lower prevalence coronary heart disease, suggesting less coronary stenosis, has been reported in several prospective studies [ 14,151. Little definitive information is available on the possible mechanism(s) of the ‘protective’ effect of alcohol and ‘occlusion-promoting’ activity of smoking. The level of high density lipoprotein cholesterol (HDLC) which is reduced in smokers [ 16,171 and elevated by alcohol consumption [ 16,181 is affected by both variables. A lower prevalence of coronary artery disease in individuals with higher HDL cholesterol levels was reported by a number of investigators [ 19,201. In view of its addictive potential, as well as the reported higher prevalence of malignancies associated with its use [21,22], alcohol is clearly not the preferred means of controlling the coronary artery disease. It may be hoped, however, that identification of metabolic processes involved in the ‘protective’ action of alcohol (possibly induction of the hepatic mixed-function oxidases) [23] will help find alternate approaches which will be effective in the reduction of coronary occlusion without the harmful side effects of alcohol. For proper interpretation of the results and their application to the population at large, one should also consider that the data were obtained with patients who have had coronary arteriography and presumably some symptoms of CHD. However, sufficient support is available from large prospective studies investigating the individual effects of alcohol intake [14] and smoking [24,25] on CHD to indicate more general validity of the findings in the present study. In conclusion, our findings suggest that the effect of smoking and of other risk factors on the extent of coronary artery occlusion and prevalence of.CHD may be underestimated if one does not consider the attenuating action of simultaneous alcohol consumption. Such ‘occlusion-reducing’ effect of alcohol may be seen with relatively low alcohol intake.
281
Acknowledgements The authors the Milwaukee
wish to acknowledge the assistance Cardiovascular Data Registry.
and interest
of the members
of
References 1 Anderson, A.J., Barboriak, J.J. and Rirnm, A.A., Risk factors and angiographically determined coronary occlusion, Amer. J. Epidemiol., 107 (1978) 8. 2 Barboriak, J.J., Anderson, A.J., Rimm. A.A. and Tristani, F.E.. Alcohol and coronary arteries, Alcoholism: Clin. Exp. Res., 3 (1979) 29. 3 Barboriak, J.J., Anderson, A.J. and Hoffmann. R.G.. Interrelationship between coronary artery occlusion, high-density lipoprotein cholesterol and alcohol intake, J. Lab. Clin. Med., 94 (1979) 348. 4 Klurfeld, D.M. and Kritchevsky, D., Differential effects of alcoholic beverages on experimental atherosclerosis in rabbits, Exp. Mol. Path., 34 (1981) 62. 5 Craig, T.J. and Van Natta, P.A.. The association of smoking and drinking habits in a community sample, J. Stud. Alcohol, 38 (1977) 1434. 6 Sones, F.J. and Shirey, E.K., Cine coronary arteriography, Mod. Concepts Cardiovasc. Dis.. 3 1 (1962) 735. 7 Judkins. M.P., Selective coronary radiography - A percutaneous transfemoral technic, Radiology, 89 (1967) 815. 8 Rowe, G.G., Thomsen, J.H., Stenlund, R.R., McKenna, D.H., Sialer, S. and Corliss, R.J., A study of hemodynamics and coronary blood flow in man with coronary artery disease, Circulation, 39 (1969) 139. 9 Hammond, E.C. and Horn, D., Smoking and death rates - Report on forty-four months of follow-up of 187,783 men, Part 1 (Total mortality), J. Amer. Med. Ass., 166 (1958) 1159. 10 Winer, B.J., Statistical Principles in Experimental Design, 2nd edition. McGraw-Hill. New York, 1971. 11 Barboriak, J.J., Barboriak, D.P., Anderson, A.J. and Hoffman. R.G., Drinking patterns of patients with heart disease, Alcoholism: Clin. Exp. Res., 4 (1980) 209. 12 Pate], Y.C., Eggen, D.A. and Strong, J.P.. Obesity, smoking and atherosclerosis - A study of interassociations, Atherosclerosis, 36 (1980) 481. 13 Auerbach, 0. and Garfinkel, L., Atherosclerosis and aneurysm of aorta in relation to smoking habits and age, Chest, 78 (1980) 805. 14 Klatsky, A.L., Friedman, G.D. and Siegelaub, A.B.. Alcohol consumption before myocardial infarction - Results from the Kaiser-Permanente epidemiologic study of myocardial infarction, Ann. Intern. Med., 81 (1974) 294. 15 Stason, W.B., Neff, R.K., Miettinen, O.S. and Jick, H.. Alcohol consumption and non-fatal myocardial infarction, Amer. J. Epidemiol., 104 (1976) 603. 16 Barboriak, J.J., Anderson, A.J., Rimm. A.A. and King, J.F., High density lipoprotein cholesterol and coronary artery occlusion, Metabolism, 28 (1979) 735. 17 Pozner, H. and Billimoria, J.D., Effect of smoking on blood-clotting and lipid and lipoprotein levels, Lancet, i (1970) 1318. 18 Castelli, W.P., Doyle, J.T., Gordon, T., Hames, C.G., Hjdrtland, M.C., Hulley, S.B., Kagan, A. and Zukel, W.J., Alcohol and blood lipids - The cooperative lipoprotein phenotyping study. Lancet. ii (1977) 153. 19 Berg, K., Borresen, A.L. and Dahlen, G., Serum-high-density-lipoprotein and .atherosclerotic heart disease, Lancet, i (1976) 499. 20 Castelli, W.P., Doyle, J.T., Gordon, T., Hames. C.G., Hjldrtland, M.C., Hulley, S.B., Kagan, A. and Zukel, W.J., HDL cholesterol and other lipids in coronary heart disease, Circulation, 55 (1977) 767. 21 Schottenfeld, D.. Alcohol as a co-factor in the etiology of cancer. Brit. Med. J., I (1978) 1483. 22 Blackwelder. W.C., Yano, K., Rhoads, G.G.. Kagan, A., Gorton. T. and Palesch, Y., Alcohol and
282
mortality - The Honolulu Heart Study, Amer. J. Med., 68 (1980) 164. 23 Nikkila, E.A., Kaste, M., Ehnholm, C. and Viikari, J., Elevation of high-density lipoprotein in epileptic patients treated with phenytoin, Acta Med. Stand., 204 (1978) 517. 24 Townsend, J.L. and Meade, T.W., Ischemic heart disease mortality risks for smokers and non-smokers, J. Epidemiol. Comm. Hlth, 33 (1979) 243. 25 Miettinen, O.S., Neff. R.K. and Jick. H., Cigarette-smoking and nonfatal myocardial infarction Rate ratio in relation to age, sex, and predisposing conditions, Amer. J. Epidemiol., 103 (1976) 30.
277 Publishers,
Ltd.
Smoking, Alcohol and Coronary Joseph J. Barboriak, Raymond
Artery Occlusion
Alfred J. Anderson G. Hoffmann
and
Reseurch Service. Wood Vetercou Administrution Medicul Center and the Depurtment of Phrrrmcrcologr md Toxicology. und Preventive Medicine (Biostutistics Section). The Me&d College of Wisconsin, Milwaukee. WI (U.S.A.) (Received 17 August, 1981) (Accepted 14 December, 1981)
Summary The effects of smoking and alcohol intake on the extent of coronary artery occlusion were studied in 2989 men undergoing a diagnostic coronary arteriography. Smoking showed an exposure-related enhancing effect on the extent of coronary artery occlusion. Conversely, alcohol consumption demonstrated an attenuating dose-related effect, offsetting the increased coronary occlusion associated with smoking. Alcohol intake should be considered in studies evaluating the risk factorscoronary artery disease interaction. Key words: Alcohol intake - Coronary artery occlusion - Smoking
Introduction Increased use of coronary arteriography has allowed direct studies of the association between the individual risk factors and the extent of coronary heart disease (CHD). Smoking has been demonstrated to be positively related to coronary artery occlusion [ 11, while alcohol intake has been associated with a reduced coronary artery occlusion disease in men and animals [2-41. Since drinking, especially if extensive, is usually associated with the smoking habit [4,5], a study of the individual effects of these two variables requires correction for the possible confounding This work was supported in part by Grant HL-14378 Veterans Administration, and the U.S. Brewers Association.
from the National
Address correspondence and reprint requests to: Joseph J. Barboriak, Veterans Administration Medical Center, Wood, WI 53193, U.S.A.
0021-9150/82/0000-0000/$02.75
8 1982 Elsevier/North-Holland
Scientific
Institutes
of Health,
Sc.D., Research
Publishers,
the
Service/lSl,
Ltd.
278
influence of the other factor. Availability of data from a large group of patients undergoing diagnostic coronary arteriography has allowed identification of subgroups of individuals who are smokers but abstain from alcohol, as well as of nonsmoking imbibers of alcoholic beverages. In the present communication, we report on the separate effects of smoking and drinking on the extent of CHD, as well as on the modification of the effects of one variable by the other.
Methods
The data were collected from 2989 consecutive male patients who had diagnostic coronary arteriography at one of two Milwaukee area hospitals and had volunteered for the study. The criteria for arteriography were unstable angina pectoris, moderate to severe stable angina, previous myocardial infarction and recurrent chest pain of unknown etiology. Information on smoking experience and the amount of alcohol consumed was obtained from a questionnaire. The data on the number of drinks were converted into equivalents of absolute alcohol as previously reported [4]. The test-retest reliability of the alcohol questionnaire (Pearson’s coefficient) ascertained by asking 500 patients to fill out the questionnaire 2-3 weeks after the first inquiry was 0.85. Coronary arteriography was performed by the Sones and Shirey’s [6] and Judkin’s [7] techniques, and the results were evaluted by experienced cardiologists and radiologists and scored uniformly and blind to the questionnaire information using the scoring system of Rowe et al. [8]. In this system, the occlusion is rated by 20% increments and proper weight is given to the dominance of the coronary branches. The final score ranges from 0 (no occlusion) to 300 (all main branches included). Smoking experience was graded on the basis of the number of cigarettes smoked daily and the duration of smoking exposure. In this adaptation [1] of the procedure described by Hammond and Horn [9], the patients were divided into nonsmokers (no present smoking or history of smoking), moderate smokers (smokers of cigars, pipes or up to 20 cigarettes daily for less than 20 years), and heavy smokers (smoking more than 20 cigarettes daily for 10 years or more, or 20 cigarettes daily for longer than 20 years). Mean occlusion scores for each smoking and drinking subgroup were compared in a two-way analysis of variance with age, plasma cholesterol and triglyceride levels, obesity, history of hypertension and diabetes as covariates. This analysis also provided mean occlusion scores adjusted for the effects of the other risk factors. In addition, multiple regression analysis was used to evaluate trends in occlusion score with alcohol and smoking adjusting for plasma cholesterol and triglycerides, history of hypertension, age, obesity and diabetes [lo]. Results
I’he findings are summarized in Fig. 1. The size of the individual groups ranged from 77 (for nonsmokers consuming more than 6 ounces [ 180 ml] of alcohol weekly)
279
to 678 (for heavy smokers consuming l-6 ounces [30-180 ml] of alcohol weekly). Regardless of the amount of alcohol consumed, the increasing smoking exposure was associated with higher occlusion scores. In male patients abstaining from alcohol 160 1
0'
< 1 (30) l-6(30-180) >6
(180)
Oz(ml)Alcohol/week
Fig. I. Interrelationships between the extent of coronary artery occlusion, experience. Number of patients in parentheses. Vertical bars= SEM.
alcohol
intake
and smoking
or consuming less than 1 ounce (30 ml) weekly, the coronary occlusion score increased from 130 for nonsmokers to 157 for heavy smokers (P =C0.01). In groups consuming more than 6 ounces (180 ml) weekly, the corresponding increase in occlusion score was from 117 to 135. Similarly, the inverse effect of alcohol intake on the extent of coronary artery occlusion could be observed at each of the three smoking levels. The average occlusion score of heavy smokers consuming over 6 ounces of alcohol (180 ml) per week was 134, while the corresponding value for abstainers or light drinkers was 157. Due to the opposing effect of the two tested variables, the occlusion-enhancing effect of smoking was, to some extent, offset by the occlusion-retarding action of alcohol consumption. As a result, occlusion scores for the nonsmoking alcohol-abstainers and heavy smokers consuming more than 6 ounces of alcohol per week were quite similar (130 vs 134). A multiple regression analysis was carried out to examine the combined effects of alcohol intake and smoking. After adjusting for other factors, both alcohol intake and smoking were found to yield statistically significant regression coefficients (smoking, r = 6.45; alcohol intake, r = - 1.46; both P -C0.0 1). However, there was no interaction between smoking and alcohol intake, indicating that the effects of the two variables were independent of each other.
280
Discussion Results of the present study indicate that the enhancing effect of smoking on the development of coronary artery occlusion may be modified by the attenuating effect of alcohol. Since the extent of coronary artery occlusion correlates strongly with the usual clinical indicators of ischemic heart disease such as myocardial infarction [l], proper evaluation of the association between smoking and clinical indicators of the heart disease should also consider the possible effect of alcohol consumption. The significance of alcohol intake is indicated by the observation that over 80% of male heart patients have reported drinking alcoholic beverages [ 111, and that noticeable reduction of coronary occlusion may be seen with consumption of as little as one daily drink. The observed increase in coronary occlusion score of nondrinking smokers as compared with nonsmokers parallels the autopsy data of smokers [ 12,131, indicating more extensive arterial lesions. Similarly, the association of alcohol intake with lower prevalence coronary heart disease, suggesting less coronary stenosis, has been reported in several prospective studies [ 14,151. Little definitive information is available on the possible mechanism(s) of the ‘protective’ effect of alcohol and ‘occlusion-promoting’ activity of smoking. The level of high density lipoprotein cholesterol (HDLC) which is reduced in smokers [ 16,171 and elevated by alcohol consumption [ 16,181 is affected by both variables. A lower prevalence of coronary artery disease in individuals with higher HDL cholesterol levels was reported by a number of investigators [ 19,201. In view of its addictive potential, as well as the reported higher prevalence of malignancies associated with its use [21,22], alcohol is clearly not the preferred means of controlling the coronary artery disease. It may be hoped, however, that identification of metabolic processes involved in the ‘protective’ action of alcohol (possibly induction of the hepatic mixed-function oxidases) [23] will help find alternate approaches which will be effective in the reduction of coronary occlusion without the harmful side effects of alcohol. For proper interpretation of the results and their application to the population at large, one should also consider that the data were obtained with patients who have had coronary arteriography and presumably some symptoms of CHD. However, sufficient support is available from large prospective studies investigating the individual effects of alcohol intake [14] and smoking [24,25] on CHD to indicate more general validity of the findings in the present study. In conclusion, our findings suggest that the effect of smoking and of other risk factors on the extent of coronary artery occlusion and prevalence of.CHD may be underestimated if one does not consider the attenuating action of simultaneous alcohol consumption. Such ‘occlusion-reducing’ effect of alcohol may be seen with relatively low alcohol intake.
281
Acknowledgements The authors the Milwaukee
wish to acknowledge the assistance Cardiovascular Data Registry.
and interest
of the members
of
References 1 Anderson, A.J., Barboriak, J.J. and Rirnm, A.A., Risk factors and angiographically determined coronary occlusion, Amer. J. Epidemiol., 107 (1978) 8. 2 Barboriak, J.J., Anderson, A.J., Rimm. A.A. and Tristani, F.E.. Alcohol and coronary arteries, Alcoholism: Clin. Exp. Res., 3 (1979) 29. 3 Barboriak, J.J., Anderson, A.J. and Hoffmann. R.G.. Interrelationship between coronary artery occlusion, high-density lipoprotein cholesterol and alcohol intake, J. Lab. Clin. Med., 94 (1979) 348. 4 Klurfeld, D.M. and Kritchevsky, D., Differential effects of alcoholic beverages on experimental atherosclerosis in rabbits, Exp. Mol. Path., 34 (1981) 62. 5 Craig, T.J. and Van Natta, P.A.. The association of smoking and drinking habits in a community sample, J. Stud. Alcohol, 38 (1977) 1434. 6 Sones, F.J. and Shirey, E.K., Cine coronary arteriography, Mod. Concepts Cardiovasc. Dis.. 3 1 (1962) 735. 7 Judkins. M.P., Selective coronary radiography - A percutaneous transfemoral technic, Radiology, 89 (1967) 815. 8 Rowe, G.G., Thomsen, J.H., Stenlund, R.R., McKenna, D.H., Sialer, S. and Corliss, R.J., A study of hemodynamics and coronary blood flow in man with coronary artery disease, Circulation, 39 (1969) 139. 9 Hammond, E.C. and Horn, D., Smoking and death rates - Report on forty-four months of follow-up of 187,783 men, Part 1 (Total mortality), J. Amer. Med. Ass., 166 (1958) 1159. 10 Winer, B.J., Statistical Principles in Experimental Design, 2nd edition. McGraw-Hill. New York, 1971. 11 Barboriak, J.J., Barboriak, D.P., Anderson, A.J. and Hoffman. R.G., Drinking patterns of patients with heart disease, Alcoholism: Clin. Exp. Res., 4 (1980) 209. 12 Pate], Y.C., Eggen, D.A. and Strong, J.P.. Obesity, smoking and atherosclerosis - A study of interassociations, Atherosclerosis, 36 (1980) 481. 13 Auerbach, 0. and Garfinkel, L., Atherosclerosis and aneurysm of aorta in relation to smoking habits and age, Chest, 78 (1980) 805. 14 Klatsky, A.L., Friedman, G.D. and Siegelaub, A.B.. Alcohol consumption before myocardial infarction - Results from the Kaiser-Permanente epidemiologic study of myocardial infarction, Ann. Intern. Med., 81 (1974) 294. 15 Stason, W.B., Neff, R.K., Miettinen, O.S. and Jick, H.. Alcohol consumption and non-fatal myocardial infarction, Amer. J. Epidemiol., 104 (1976) 603. 16 Barboriak, J.J., Anderson, A.J., Rimm. A.A. and King, J.F., High density lipoprotein cholesterol and coronary artery occlusion, Metabolism, 28 (1979) 735. 17 Pozner, H. and Billimoria, J.D., Effect of smoking on blood-clotting and lipid and lipoprotein levels, Lancet, i (1970) 1318. 18 Castelli, W.P., Doyle, J.T., Gordon, T., Hames, C.G., Hjdrtland, M.C., Hulley, S.B., Kagan, A. and Zukel, W.J., Alcohol and blood lipids - The cooperative lipoprotein phenotyping study. Lancet. ii (1977) 153. 19 Berg, K., Borresen, A.L. and Dahlen, G., Serum-high-density-lipoprotein and .atherosclerotic heart disease, Lancet, i (1976) 499. 20 Castelli, W.P., Doyle, J.T., Gordon, T., Hames. C.G., Hjldrtland, M.C., Hulley, S.B., Kagan, A. and Zukel, W.J., HDL cholesterol and other lipids in coronary heart disease, Circulation, 55 (1977) 767. 21 Schottenfeld, D.. Alcohol as a co-factor in the etiology of cancer. Brit. Med. J., I (1978) 1483. 22 Blackwelder. W.C., Yano, K., Rhoads, G.G.. Kagan, A., Gorton. T. and Palesch, Y., Alcohol and
282
mortality - The Honolulu Heart Study, Amer. J. Med., 68 (1980) 164. 23 Nikkila, E.A., Kaste, M., Ehnholm, C. and Viikari, J., Elevation of high-density lipoprotein in epileptic patients treated with phenytoin, Acta Med. Stand., 204 (1978) 517. 24 Townsend, J.L. and Meade, T.W., Ischemic heart disease mortality risks for smokers and non-smokers, J. Epidemiol. Comm. Hlth, 33 (1979) 243. 25 Miettinen, O.S., Neff. R.K. and Jick. H., Cigarette-smoking and nonfatal myocardial infarction Rate ratio in relation to age, sex, and predisposing conditions, Amer. J. Epidemiol., 103 (1976) 30.