THE FILTER CIGARETTE AND CORONARY HEART DISEASE: THE FRAMINGHAM STUDY

109 6

physical activity and exercise in these subjects. Littler et all

discrepancy between indirect pressures and ambuin eight treated patients with hypertension, but records latory were selected for study because their indirect individuals the pressure readings seemed inappropriately high when considered against a general absence of target organ damage; in the same study a good correlation was observed between intra-arterial blood pressures and cuff pressures as obtained by the general practitioner or in the hospital setting in unselected untreated subjects with hypertension. However, a later study, which selected untreated subjects without clinical evidence of target organ damage, did show mean waking intra-arterial pressures to be significantly less than mean outpatient blood pressures, by 18 mm Hg on average. 12 The reason for the discrepancy between cuff and ambulatory readings is not clear. These observations are important in the decision to treat subjects with mild or moderate hypertension. 20 of our 59 subjects fulfilled the conventional definition of hypertension but their average ambulatory mean arterial pressure throughout the waking day was less than 108 mm Hg (i.e., equivalent to 140/90 mm Hg) and even lower during sleep when the average mean arterial pressure fell approximately 25% for waking levels. Both the American hypertension detection and follow-up program16 and the Australian therapeutic trial17 showed the benefit of treatment in reducing the morbidity and mortality in mild hypertension. A noteworthy difference between these two trials was the smaller mortality from cardiovascular disease in the placebo group of the Australian study when compared to either the "stepped care" or the "referred care" group of the hypertension detection and follow-up program. It was suggested 17 that the inclusion of some patients with clinically detectable end organ damage in the American trial may have selected subjects with a higher degree of cardiovascular risk. The Australian subjects, interestingly, had a lower initial mean arterial pressure (119 mm Hg) than our own subjects. One possibility, therefore, is that the better prognosis in both the placebo and treated groups of the Australian study, and the lack of apparent benefit of therapy in patients under 50 years of age in both trials may have been due to a lower, perhaps even normal, ambulatory blood pressure in a significant proportion of these individuals. There is no doubt that cuff pressures give a reasonable prediction of cardiovascular risk. We suggest, however, that the relationship between arterial pressure and subsequent cardiovascular morbid events might well be even greater if a more accurate assessment of true arterial pressure and its daily fluctuations could be obtained on a wider scale than is possible with present techniques. noted

a

Correspondence may be addressed to Prof. Hospital, Headington, Oxford OX3 9DU.

P.

Sleight, John Radchffe

REFERENCES 1 Littler WA, Honour AJ, Sleight P, Stott FD. Continuous recording of direct arterial pressure and electrocardiogram in unrestricted man. Br Med J 1972; iii: 76-78. 2 Julius S, Ellis EN, Pascaul AV, Matice M, Hansson L, Hunyor SN, Sandier LN. Home blood pressure determination: value in borderline (’labile’) hypertension. JAMA 1974, 229: 663-66. 3 Laughlin KD, Sherrard DJ, Fisher L. Comparison of clinic and home blood pressure levels in essential hypertension and variables associated with clinic-home differences

J Chron Dis 1980, 33: 197-206.

4 Sokolow M, Werdegar D, Kain HK, Hinman AT. Relationship between blood pressure measured casually and by portable recorders and severity of complications in essential hypertension. Circulation 1966; 34: 279-89. 5 Bevan AT, Honour AJ, Stott FD. Direct arterial pressure recording in unrestricted man Clin Sci 1969, 36: 329-44. 6 Litter WA, Honour AJ, Pugsley DJ, Sleight P. Continuous recording of direct arterial pressure in unrestricted patients its role in the diagnosis and management of high blood pressure Circulation 1975; 51: 1101-06.

THE FILTER CIGARETTE AND CORONARY HEART DISEASE: THE FRAMINGHAM STUDY

WILLIAM P. CASTELLI THOMAS R. DAWBER MANNING FEINLEIB

ROBERT J. GARRISON PATRICIA M. MCNAMARA WILLIAM B. KANNEL

Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts; Biometrics Research Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland, and Boston University Medical Center, Evans Research Foundation, Boston, Massachusetts, U.S.A.

Summary

Long-term follow-up of

the

Framingham

cohort for coronary heart disease (CHD) has made it possible to test the hypothesis that end-points those who smoke filter cigarettes are less likely to get clinical manifestations of CHD than those who smoke non-filter cigarettes. Men were classified at the 7th biennial examination (1963-64) according to whether they smoked filter or non-filter cigarettes. 58% of the cigarette-smoking men under age 55 at this examination smoked filter cigarettes. These men had slightly lower prior smoking exposure than smokers of non-filter cigarettes. Despite what seemed to be a favourable cigarette-smoking history, the filter-cigarette smokers did not have lower CHD incidence rates than nonfilter smokers. This finding was unchanged even after multivariate logistic regression analysis to adjust for the slight differences in age, systolic blood pressure, and serum cholesterol between the two groups. Introduction THE introduction of low-tar and low-nicotine cigarettes partly prompted by the finding that number of cigarettes smoked is positively related to subsequent disease. This doseresponse relation suggested that cigarettes would be made less hazardous by removing, by filtration or other means, those substances responsible for the increased rates of cancer, pulmonary disease, and coronary heart disease (CHD). Of the more than 4000 chemical substances in cigarette smoke, nicotine and carbon monoxide are the most likely to be responsible for the cardiovascular consequences of smoking. Some studies show a parallel fall in nicotine and carbon monoxide in the low tar-low nicotine cigarettes whilst others show a rise in carbon monoxide dose with a fall in nicotine.

was

7. Keith NH,

Wagener HP, Barker NW. Some different types of essential hypertension: their course and prognosis. Am J Med Sci 1939, 197: 332-43 8. McPhie J. Left ventricular hypertrophy: Electrocardiographic diagnosis. Aust Ann Med 1958; 7: 317-27. 9. Ungerleider HE, Gubner R. Evaluation of heart size measurements Am Heart J 1942; 24: 494-510. 10. Henry DP, Starman BJ, Johnston DG, Williams RH. A sensitive radio enzymatic assay for norepinephrine in tissues and plasma. Life Sci 1975, 16: 375-84. 11. Sleight P, Floras J, Jones JV Automatic analysis of continuous intra-arterial blood pressure recordings. Index: blood pressure variability (Clement DL, ed) Lancaster, MTP Press, 1979; 55-60. 12. Watson RD, Stallard TJ, Flinn RM, Littler WA. Factors determining direct arterial pressure and its variability in hypertensive man Hypertension 1980, 2: 333-41 13. Gribbin B, Pickering TG, Sleight P. The effect of age and high blood pressure on baroreflex sensitivity in man Circ Res 1971; 29: 424-31. 14. Ayman D, Goldshine AD Blood pressure determinations by patients with essential hypertension I. The difference between clinic and home recordings before treatment. Am J Med Sci 1940; 200: 465-74. 15. Editorial. Home Blood pressure recordings Lancet 1975, i: 259-60. 16. Hypertension Detection and Follow-up Program Co-operative Group Five year findings of the hypertension detection and follow up program. I Reduction in mortality of persons with high blood pressure, including mild hypertension. JAMA 1979; 242: 2563-77 17. Australian Therapeutic Trial in Mild Hypertension. Report by the Management Committee. Lancet 1980; i: 1261-67.

110

The measurement of clinical disease end-points is the ultimate test of whether any alteration in the dose of noxious elements is beneficial. So far few large-scale studies have assessed CHD end-points. The very large American Cancer Society study’ showed that low tar/nicotine smokers had a 20% lower rate of CHD mortality in 6 years than high tar/nicotine smokers. Three prospective surveys in Scotland22 showed a slightly higher rate of ischaemic heart disease mortality among filter cigarette smokers. An English study, sponsored by the Tobacco Research Council, reported a 25% fall in risk of coronary heart disease in smokers of filter

TABLE I-DISTRIBUTION OF SMOKING BEHAVIOUR OF MEN AT

EXAMINATION 12 IN RELATION TO SMOKING HABITS AT

EXAMINATION7

cigarettes.33 In

prospective survey reported here rates of CHD Framingham Heart Study men were related to type of cigarette smoked (filter or non-filter). It also compares the smoking history of individuals who switched to filter cigarettes with those who continued to smoke regular cigarettes, and tests for the contribution of filter use to the prediction of CHD in multivariate analysis. our

among

Methods

Framingham Heart Study Cohort participantshave undergone physical examinations every 2 years since 1948. Data presented here include those which were collected at the lst examination and at the 7th to 14th examinations, inclusive. Details asked about cigarette-smoking history at the 1st examination included the number of cigarettes smoked daily and the duration (years) of cigarette smoking. The first time a question about filter cigarette use was asked was the 7th examination, which took place during the 2-year period starting in September, 1963. The most recent examination for which cigarette-smoking data is available is examination 12. At this follow-up questions were asked about filter use, frequency of cigarette use per day, maximum cigarette consumption per day for any 1-year period, and number of years previous cigarette smokers had not smoked. For this report the 7th examination was the baseline at which individuals were classified according to smoking habits. Thus, only those who underwent examination 7 are considered in the tables that present data from the lst, 12th, or other follow-ups. Blood pressure, measured with the subject seated, and total serum cholesterol, measured by the AbellKendall method,S were recorded at the 7th biennial examination. These measurements, together with age in years, were used as independent variables in multivariate logistic regression analyses since they are consistent and powerful predictors of CHD risk. Regression coefficients (]3i) of the logistic function were calculated by maximum likelihood methods.6The standardised regression coefficients represent the relative strength of each independent variable in a given estimated equation as a predictor of the CHD end-point under consideration. The significance test associated with each coefficient indicates whether that variable contributes independent information, apart from that contributed by other variables in the equation, to the prediction of disease. Diagnoses of clinically apparent CHD were made according to methods and criteria that have been described.Only individuals who were free of pre-existing CHD at the 7th examination are considered in this report, and they were followed-up for the next 14 years (up to the 14th examination) for occurrence of new disease. The specific CHD end-points considered in this report are CHD death (both sudden and non-sudden death), myocardial infarction (MI) (all proven MI, whether fatal or not fatal), and total CHD (MI, coronary insufficiency, angina pectoris, and all CHD deaths).

Results 1605 men and 2132 women, aged 41-74 years, underwent the 7th biennial examination. Only the youngest women smoked cigarettes. Therefore no test of the hypothesis that filter and regular cigarettes differ in their relation with CHD was possible among women. The men were divided into a

*Plain or untipped. group who were above and a group who were below 55 years of age at examination 7, this age being approximately the midpoint of the age-range then. 60% of the younger group of men smoked cigarettes at examination 7, and 58. 0% of the cigarette smokers smoked filter cigarettes (table I). Although fewer of the older men smoked cigarettes, a similar proportion of smokers (56’507o) used filters. In both agegroups nearly all men who smoked filter cigarettes and continued to smoke carried on using filter cigarettes. More than half of the smokers of regular cigarettes (untipped) at examination 7 who were smoking cigarettes 10 years later were still smoking regular cigarettes. Other comparisons of ’exposure between the filter and regular cigarette groups are shown in tables II and III. Although a slightly higher proportion of filter smokers had stopped smoking cigarettes by examination 12 (table I) there were no significant differences between filter and non-filter smokers in duration of cessation of smoking among those who stopped smoking. Nor was there a difference in the number of cigarettes smoked TABLE II-SMOKING STATUS AT EXAM

12* FOR MEN BY EXAM7

AGE AND BY

SMOKING STATUS AT

No. of observations in parentheses. *Only those who underwent exam. 12

are

included in these calculations.

f Smokers only Quitters only STATUS* AT EXAM 1 FOR MEN BY AGE AT EXAM 7 AND TYPE OF CIGARETTE SMOKED AT EXAM 7

TABLE III-SMOKING

111 TABLE 1B’-R-TE PER

1000

AFTER

14

YEARS OF

OBSERVATION

STATUS AT EXAM

’Those with CHD

at

examination 7

are not

also positive for the older men, none are statistically different from zero. It should be noted that among the older men smoking cigarettes at examination 7, less than one third continued to smoke cigarettes until examination 12 (table I). Also, those who continued to smoke reduced their daily consumption. The hypothesis that MI, CHD death, or total CHD rates differ between men who smoked filter cigarettes and those who smoked regular cigarettes was tested by multiple logistic regression analyses (table VI) based on data for men who smoked at examination 7 but were free of pre-existing CHD. Thus, the positive standardised coefficients for the middleaged men (<55 years group) indicate that filter cigarette smokers have higher rates of MI than smokers of untipped cigarettes, after considering any differences in total cholesterol, systolic blood pressure, and age. These coefficients parallel the difference in univariate rates presented in table IV. There are no statistically significant differences between filter use and MI, CHD death, or total CHD.

coefficients

FOR MI,

CHD DEATH, AND TOTAL CHD FOR MEN BY AGE AND SMOKING

7*

included.

by those who continued to smoke, or the maximum number of cigarettes ever smoked over one year. Comparison of smoking behaviour at examination 1 reveals differences between filter and non-filter smokers (table m)-a higher proportion of non-filter smokers at examination 7 had smoked cigarettes at examination 1. Furthermore, those who smoked regular cigarettes at examination 7 and who smoked at examination 1 seemed to have done so longer and were smoking more cigarettes at examination 1 than participants who smoked filter cigarettes at examination 7. Table IV shows the 14-year rates of occurrence per 1000 men for myocardial infarction, coronary heart disease (CHD) death, and total CHD by age and smoking status at the 7th examination. Among the younger men non-smokers had the lowest rates, and filter cigarette smokers the highest. No clear

are

Discussion

Information about the timing of the "switch" to filter cigarettes in Framingham is not available but is assumed to have taken place fairly soon after the introduction of filter cigarettes in 1950. By 1964 filter cigarettes took 65% of the cigarette market.8 A similar proportion was smoked by our subjects at examination 7, although differences would have been expected in view of the older age-structure of the

trend was observed among the older men. Differences in rates between non-smokers and smokers (filter and regular cigarettes combined) after adjustment for other risk factors were tested by multivariate logistic regression and are presented in table v, which shows a strong relation between cigarette smoking and CHD in middle-aged men. Although

Framingham sample compared with the general population. The nicotine content of the cigarettes that were smoked by the subjects of this report can be inferred from sales-weighted average nicotine deliveries of filter and regular cigarettes for the U.S.9 Between 1963 and 1977 (the period of follow-up covered in this report) the average nicotine delivery was 1 - 75 mg for regular cigarettes and 13 mg for filter cigarettes. Although the nicotine content of regular cigarettes remained fairly constant over the period, averages for filter cigarettes declined from about 14 mg to 11 mg in 1977. Most of this

TABLE V-STANDARDISED MULTIVARIATE LOGISTIC REGRESSION COEFFICIENTS AND t-VALUES FOR MEN WHO HAD NEW MI, CHD DEATH AND NEW CHD BETWEEN

’Tnose with CHD at examination 7 were excluded. -S:,-okIrs were given a value of 1, and non-smokers

a

value

EXAMINATIONS7 AND 14*

of 0, for this variable.

112 TABLE VI-STANDARDISED MULTIVARIATE LOGISTIC REGRESSION COEFFICIENTS AND t-VALUES FOR MEN WHO SMOKED CIGARETTES AT EXAM AND WHO HAD NEW MI, CHD DEATH AND NEW CHD BETWEEN THEN AND EXAMINATION 1

*Those with CHD

at

examination 7

I

1

were

excluded. and

filter cigarette smokers were given a value of 1,

7

14*

regular cigarette smokers a value of 0, for this variable.

decline in average filter cigarette yield was probably due to the rapid increase in sales of "ultra" low tar-nicotine cigarettes." Thus, the rapid change to filter cigarettes in the late 1950s and early 1960s and the apparent uniformity of cigarette nicotine content provide some assurance that the comparisons made in this report (despite the lack of specific brand information) between filter and regular cigarettes reflect true differences in exposure to nicotine. Data on the relative uniformity and differences in carbon monoxide exposure among filter and regular cigarette smokers are not available, but studies in England covering this period show no change in carbon monoxide delivery between filter and regular cigarettes. (Wald NJ, Coll R, personal communi-

cation). Filter-cigarette

smokers have consistently been shown to have a lower cancer mortalityl,II,12 than non-filter-cigarette smokers. This decrease has been attributed to the reduction in tar exposure, which is thought to be causally related to high cancer rates in cigarette smokers. However, the total impact of cigarette smoking on the health of individuals needs to be considered before drawing conclusions about the benefits of filter cigarettes. There is very little known, for example, about the specific constituents in tobacco smoke that might contribute to atherosclerosis or aggravate existing coronary or cardiovascular pathology. Only a dozen or so of the thousands of compounds in cigarette smoke have shown a possible connection with coronary heart disease, and only two, nicotine and carbon monoxide, have been looked at in

any depth. Nicotine acutely raises systolic blood pressure, heart rate, and causes cutaneous and cardiac output catecholamine vasoconstriction,l3,i4 probably by increasing secretion.15 It acts directly on the myocardium to produce 5 positive chronotropic and inotropic cardiac muscle actions.’ The rise in free fatty acids, also probably due to catecholamine stimulation, 16 may aggravate cardiac dysfunctionl7 and contribute to the fatty cellular lesions of atherosclerosis. IS Nicotine increases the diurnal secretion of cortisol, 19 which has been associated with myocardial infarction and with more frequent and complex ventricular

arrhythmias.20

Nicotine-stimulated catecholamine release

platelet stickiness and aggregation.21 Initial clot formation, decreased fibrinolysis, decreased clotting time, change in the rate of initial clot formation, maximum clot tensile strength, and clot retraction,21 along with factors relating to platelet function, have been considered in work on

may increase

the pathogenesis of atherosclerosis. 22 Carbon monoxide has an affinity for haemoglobin that is 245 times that of oxygen, so it can severely reduce oxygen delivery to the myocardium. This interference in oxygen transport is increased by the way carboxyhaemoglobin shifts the oxyhaemoglobin dissociation curve to the left.23 Carbon monoxide also combines with myoglobin thus impairing the diffusion of oxygen to mitochondria in heart muscle, and with cytochrome oxidase, thus slowing oxidation at an enzymatic leve1.23 By decreasing left ventricular end-diastolic pressure left ventricular stroke index and cardiac index it has a decidedly negative inotropic effect on the myocardium.24 Ir patients with angina, carboxyhaemoglobin significantly shortens exercise time and the product of systolic blooc pressure and rate (the double product) needed to produce an S-T ischaemic segment depression is reduced.25 Carboxyhaemoglobin lowers the threshold for ventricular fibrillation in monkeys,26 and exposure of rabbits to carbon monoxide results in prominent ultrastructural changes in the heart.27 Carboxyhaemoglobin increases vessel wall hypoxia and permeability;28 such increased permeability to lipoproteins may promote atherosclerosis.29 Wald has reported a stronger association between carboxyhaemoglobin and coronary heart disease than between smoking history and coronary heart disease.30 The present results indicate that nicotine lowering does not have much effect on CHD risk in filter-cigarette smokers and such results may be compatible with the growing suspicion that carbon monoxide is probably one of the more harmful constituents in tobacco smoke. Cigarettes which have a low yield of tar and nicotine may not necessarily produce low yields of carbon monoxide. Indeed ordinary filter cigarettes without perforations in the filter lead to increased exposure to of levels and monoxide carbon higher

113

carboxyhaemoglobin,31,32

while low tar and nicotine cigarettes with perforations in the filter have lower carbon monoxide yields.32 Whether the ultra-low tar and nicotine cigarettes or the perforated filter will reduce CHD risk is not known. The most optimistic data, published by the Tobacco Research Council, suggest only about a 25% decrease in cabon monoxide exposure from such cigarettes. The multivariate analysis is an attempt to "control" for other factors known to be strongly related to CHD but which may differ between filter and regular cigarette smokers, other "confounding" variables, such as unmeasured lifestyle differences, may obscure the true relations between filter use and CHD. Furthermore, a substantial proportion of the older age-group had stopped smoking before the 7th biennial examination and therefore the power to detect differences in event rates between filter and regular cigarettes in this group is diminished. The high proportion of former smokers among the "non-smokers" makes the purity of the comparison between smoking and non-smoking men in the older age-group subject to some question. However, the comparison between filter and regular rates is not influenced because it is an "internal" comparison, comprised of only men who are long-term cigarette smokers. Although the slightly higher rates of MI among filter cigarette smokers suggest a possible deleterious impact of filters, most of this difference results from higher rates very early in the follow-up period. It is not possible to resolve whether this is due to a "harvesting" effect of filter cigarettes or to selection of filter cigarettes by men who have had subclinical "warning" of CHD. The latter seems most unlikely because most of the men had been smoking filter cigarettes for a number of years before examination 7. The tendency for filter cigarette smokers at examination 7 to have a more favourable smoking history, although consistent with most other data, also suggests that these men should have more favourable CHD outcomes. Since they do not, more suspicion should be raised about potential benefit of filter cigarettes. The promise of the filter philosophy is that the toxins which cause degradation of lung function, cancer, and CHD can be identified and removed, leaving a "safe" cigarette. There is no evidence that the filter cigarettes of the 60s and early 70s conferred any protection from coronary heart disease for men in the Framingham Study.

although

Requests for reprints should be addressed to W. P. C., Department of Health and Human Services, Framingham Heart Study, 118 Loncoln Street, Framingham, Massachusetts 01701, U.S.A. REFERENCES 1 Hammond EC, Garfinkel L, Leidman H, et al. Some recent findings concerning cigarette smoking. In: Hiatt HH, Watson JD, Winston JA, Eds. Origins of human cancer-book A, Incidence of cancer in humans. New York: Cold Spring Harbor Laboratory, 1977 101-12. 2 Hawthorne VM, Fry JS. Smoking and health: The association between smoking behaviour, total mortality, and cardiorespiratory disease in West Central Scotland. J Epidemiol Comm Hlth 1978, 32: 260-66. 3 Dean G. Lee PN, Todd GF, et al Report on a second retrospective mortality study in North-East England Part 1: Factors related to mortality from lung cancer, bronchitis, heart disease and stroke in Cleveland County, with particular emphasis on the relative risks associated wih smoking filter and plain cigarettes London Tobacco Research Council, 1977, Research paper no. 14, part 1. 4 Daw ber TR, Meadors GF, Moore FE. Epidemiological approaches to heart disease: the Framingham Study. Am J Pub Hlth 1951; 41: 279-86 5 Abell LL, Levy BB, Brodie BB, et al. Simplified method for estimation of total cholesterol in serum and demonstration of its specificity. J Biol Chem 1952, 195: 357-66 6 Walker SA, Duncan OB. Estimation of the probability of an event as a function of several independent variables. Biometricka 1967; 54: 167-79 7 Shurtleff D Some characteristics related to the incidence of cardiovascular disease and death The Framingham Study, 18 years follow-up DHEW publication no (NIH) 74-559 Washington, D.C.: U S. Government Printing Office, 1974. 8 Miller RH The demand for cigarettes in the United States. U S Department of Agriculture, Economic Research Service, 1970.

weighted average "tar" and nicotine deliveries of U.S. cigarettes from 1957 to present. In: Wynder EL, Hecht SS (eds). Lung Cancer UICC Tech Rep Ser Geneva: International Union Against Cancer, 1976; 25: 151-52. 10. Maxwell Associates. The Maxwell Fact Book. Syracuse, New York, Maxwell Consumer Services Reports, March 31, 1975. 11 Wumder EL, Stellman DS. The impact of long-term filter cigarette usage on lung and larynx cancer. J Nat Cancer Inst 1979, 62. 12. Bross IDJ, Gibson R. Risks of lung cancer in smokers who switch to filter cigarettes. Am J Pub Hlth 1968; 58: 1396-403 13. Tachmes L, Fernandez RJ, Sadmer MA. Hemodynamic effects of smoking cigarettes of high and low nicotine content. Chest 1978, 74: 243-46. 14. Aronow WS, Dendinger J, Rokaw SN. Heart rate and carbon monoxide level after smoking high-, low-, and non-nicotine cigarettes Ann Intern Med 1971; 74: 697-702. 15. Ball K, Turner R. Smoking and the heart. The basis for action. Lancet 1974; ii: 822-26. 16. Kershbaum A, Bellet S, Dickstein ER, et al. Effect of cigarette smoking and nicotine on serum free fatty acids Circ Res 1961; 9: 631-38. 17. Oliver MF, Yates PA Induction of ventricular arrhythmias by elevation of arterial free fatty acids in experimental myocardial infarction. Cardiology 1971, 56: 359-64. 18. Castelli WP, Nickerson RH, Newell JM, et al. Serum NEFA following fat, carbohydrate and protein ingestion, and during fasting as related to intracellular lipid deposition. J Atheroscl Res 1966; 6: 328-41. 19. Hill P Nicotine: An etiological factor for coronary heart disease. In: Wynder EL, Hoffman D, Gon GB, eds. Proceedings of the 3rd World Conference on Smoking and Health, vol. 1, Modifying the risk for the smoker. D.H.E.W. publication no. (NIH) 76-1221. Washington D.C Government Printing Office, 1976: 313-19. 20. Moss AJ, Goldstein S, Greene W. Precursors of ventricular arrhythmias during early pre-hospital phase of acute myocardial infarction. Circulation 1971, 11: 44. 21. Hawkins RI. Smoking, platelets, and thrombosis. Nature 1972; 236: 450-52. 22. Ross R, Glomset JA The pathogenesis of atherosclerosis. N Engl J Med 1976, 295: 420. 23. Wald NJ. Carbon monoxide as an etiological agent in arterial disease-some human evidence. In: Wynder EL, Hoffmann D, Gori GB, (eds). Proceedings of the 3rd World Conference on Smoking and Health, vol. 1, Modifying the risk for the smoker D.H.E.W. publication no. (NIH) 76-1221. Washington D.C.: Government Printing Office, 1976: 297-307. 24. Aronow WS Carbon monoxide and cardiovascular disease. In: Wynder EL, Hoffmann D, Gon GB (eds). Proceedings of the 3rd World Conference on Smoking and Health, vol. 1, Modifying the risk for the smoker. D.H.E.W. publication no. (NIH) 76-1221. Wshington D.C.: Government Printing Office, 1976: 321-28. 25. Aronow WS, Rokaw SN. Carboxyhemoglobin caused by smoking non-nicotine cigarettes. Effects in angina pectoris. Circulation 1971; 44: 782-88. 26. DeBias DA, Banerjee CM, Birkhead NC, et al Effects of carbon monoxide inhalation on ventricular fibrillation. Arch Environ Hlth 1976; 31: 42-46 27. Astrup P, Kjeldsen K, Wanstrup J. Enhancing influence of carbon monoxide on the development of atheromatosis in cholersterol-fed rabbits. J Atheroscl Res 1967; 7: 343-54. 28. Siggaards-Andersen J, bonde Petersen F, Hansen T, et al. Plasma volume and vascular permeability during hypoxia and carbon monoxide. Scand J Clin Lab Invest 1968; 22 9. Wakeham H. Sales

(suppl 103): 39-48. Astrup P. Studies on carbon monoxide and nicotine. In: Wynder EL, Hoffman D, Gon GB (eds). Proceedings of the 3rd World Conference on Smoking and Health, vol. 1, Modifying the risk for the smoker D.H.E W. publication no. (NIH) 76-1221, Washington D.C.: Government Printing Office, 1976 331-41. 30. Wald N, Howard S. Smoking, carbon monoxide and arterial disease. Ann Occup Hyg

29.

1975, 18: 1-14. 31. Wald NJ.

Mortality from lung cancer and coronary heart disease in relation to changes smoking habits. Lancet 1976; i: 136-38. Wald N, Idle M, Smith PG, et al Carboxyhemoglobin levels in smokers of filter and plain cigarettes. Lancet 1977; i: 110-12. in

32.

"Society, increasingly impressed with the seemingly unending achievements in medicine, has developed an almost insatiable appetite for health services and is now faced with the dilemma of decision as to the fraction of the nation’s gross national product to be devoted to the enterprise we now call ’medical care’ What is it that so seriously burdens the health care system? It is not those diseases which, thanks to successful research, can be prevented or cured-pernicious anaemia, tuberculosis, smallpox, pneumonia and many others. It is the management of those diseases which we cannot cure and, instead, the victims are offered expensive supportive but temporary measures; among them I would include heart transplantation, the treatment of many forms of cancer, and most virus diseases for which we lack immunising procedures. I venture to predict that this half-way medical technology will increase its pseudo-curative offerings, that these will be demanded by an inadequately informed public, and that no health care system in the world will be able to afford them. Those who state that we now spend too much on research and who wish to deflect such funds into the health care system could not be more wrong! Our only hope is to seek with renewed vigour the ultimate understanding which will lead to rational preventive or curative treatments as successful as those we have gained for the infections and other diseases ..."Sir ANDREW WATT 1<-,BY, regius professor of surgery, University of Glasgow. Graduation speech, July 11, 1981.