The Health Consequences of SMOKING 1968 SUPPLEMENT TO THE 1967 Public Health Service Review U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Public Health Service 1968 Supplement to Public Health Service Publication No. 1696 Library of Congress Catalog No. 68-60025 For sale by the Supexintendent of Documents. U.S. Govanmrnt Printing Office Wadingcon. D.C. 20402 - Price 55 cents Foreword Section 5 (d) (1) of Public JAW 80-02, the Federal Cigarette Label- ing and Advertising Xct, requires the Secretary of Health, Educa- t.ion, and Welfare to submit an annual report to the Congress "concerning (A) current information on the health consequences of smoking and ( 1%) such ~e~onlnlentlntiolls for legislation as he nlxy deem npproprintc." This 1068 Supplement to the 1067 Public Health Service review, "The Health Consequenws of Slnoking", was prepill+ed for the Secretary pursuant to this section. The Secretary's report was delivered to the Congress ou July 1, 1068. It is printed below. The information presented in the accompanying report, "The Health Con- sequences of Smoking, 1968 Supplement," confirms or strengthens the conclu- sions of two previous studies published by this Department-the 1964 Report of the Surgeon General's Adrisory Committee on Smoking and Health, and the 1965 Report on the Health Consequences of Smoking. These conclusions are that smoking is a serious health hazard in this country, one which is bringing about much unnecessary disease and death within our population. In the words of the 1964 Report, adequate remedial action is re- quired. In my opinion, the remedial action taken until now has not been adequate. I therefore recommend : 1. The warning statement required by the Federal Cigarette Labeling and Adrertising Act should be strengthened. This Department would support the wording recommended last year by the Federal Trade Commission, or a suitable paraphrase of the wording.* 2. This warning should be required to be placed not only on the cigarette package but on cigarette rending machines and in all advertisements. 3. Levels of "tar" and nicot.ine in cigarette smoke should be published on cigarette packages, on rigarette vending marhines, and in all advertisements. Authorization is also needed to make it possible to add other harmful agents to this listing. 4. Appropriations should be made to the Federal Trade Commission to permit the Commission to test all cigarette brands on a quarterly basis for "tar" and nicotine and other harmful agents in cigarette smoke. Secretary. o The wording recommended by the Federal Trade Commission (Report to Congress, June 36, 1967) was "Warning: Cigarette Smoking is Dangerous to Health and May Cause Death from Cancer and Other Diseases." iii Preface The following pages provide a review of current information on the hea.lth conseqwnces of smoking. as will be seen, the evidence attesting to the harmful effect of smoking on health has continued to mount during t.he past. year, with new research findings confirming the clini- WI, eI;l)ermlenka~, and epidemiological relationships I)etween tobacco smoking and many forms of illness related to it. The convergence of research findings continues without. substantial negat.i\-e scie.ntific evidence. Sew considerations are presented concerning some bio- mechanism in\-ol\-et1 in the pnthogenesis of cardiovascular and bron- cl~opulnionnry diseases. This 1968 Supplemcnt;tl Report reviews the recent research literature on cardiovascular disease, chronic broncllopulmonary disease and can- cer that has become a.vailablc since TAe Henlt?~ Conxeprtewcs of Xm.ok- ing, A Public Health Sercice Recieza: 1967 was published. This publication in turn was a review of the research literature which had al)l)enrecl in the 31/s years since the Surgeon General's Advisory Corn- mittee issuecl its monumental report in 19&L The current research findings should be consi'dered in the perspeotire of the resea.rch evi- dence previously presented in t.he 1964 and 1967 reports. Problems created by oigarette smoking hare made t,his a difficult health issue. Effective preventive programs must be created if we are to meet smoking's grave challenge to human health successfully and reduce t:he burden of suffering and economic loss involved. Swgeon General. Acknowledgments The National Clearinghouse for Smoking and Health, Daniel Horn, Ph. D., Director, was responsible for the preparation of this report; Albert C. Rolbye, Jr., KD., M.P.H., LLX, n-as senior editor and David 0. Wember, M.D., was st,aff director. The professional staff of t.he National Clearinghouse for Smoking and Health owes a debt of gratitude to the many expe&s in the scien- t,ific and technical fields, both in and outside of the government who have provided much advice and assistance. Their contributions are gratefully acknowledged. Special thanks are due the following: AUERBACH, OSCAR, M.D.-Senior medical investigator, Veterans Administration Howital, East Orange, N. J. ATRES, STEPIIEN RI., M.D.-Director, Cardiopulmonary Laboratory, Saint Vin- cent's Hospital and Medical Center of New York, Sew York, N.Y. BELLET, SAXLXL, M.D.-Director, Division of Cardiology, Philadelphia General Hospital, Philadelphia, Pa. BINQ, RICHARD J., M.D.-Professor and chairman, Department of Medicine, Wayne State University, Detroit, Mich. BOCK, FRED G., Ph. D.-Director, Orchard Park Laboratories, Roswell Park JIeruorial Institute, Orchard Park, N. Y. BOERTK, ROBERT, Ph. D., XD.-National Heart Institute, Sational Institutes of Health, Bethesda, Md. BORES, HOLLIS, M.D.-Clinical investigator, Veterans Administration Hospital, Denver, Cola. BRAUR'WALD, EUGENE, M.D.-Department of Medicine, University of Oalifornia at San Diego, San Diego, Calif. BIK-GNFIPTI, IDA L.-Health educator, Adult Heart-Preventive Programs Sec- tion, Heart Disease and Stroke Control Program, Sational Center for Chronic Disease Control, U.S.P.H.S., Arlington, Va. C~XADWICK, DOXALD R., JI.D.-Director, Sational Center for Chronic Disease Control, U.S.P.H.S., Arlington, Va. CHANCE, BXITTON, Ph. D., SC. D.-Director, Johnson Research Foundation, Chair- man, Department of Biophysics and Physical Biochemistry, School of Illedi- tine, University of Pennsylvania, Philadelphia, Pa. COOPER. THEODORE, M.D.--Director, Sational Heart Institute, National Institutes of Health, Bethesda, Nd. DOYLE, JOSEPH T., U.D.-Professor of medicine, Albany Medical College, Albany, N.Y. EUERER, FaEn-Statistician, Biometric Research Branch, Sational Heart Insti- tute, Sation8.1 Institumtes of Health, Bethesda, Jfd. ELIOT, ROBERT S., M.D.-Assc&ate professor of medicine, Department of Jledi- tine, Division of Cardiology, College of afedicine, University of Florida, Gainesville, Fla. Vi EXDICOTT, KESSETH ;\I., M.D.-Director, Sational Cancer Institute, Sational Institutes of Health, Bethesda, Nd. EPSTEIS, FREDERICK H., l\l.D.-Professor of epidemiology. Department of Epidemiology, University of Michigan, School of Public Health, Ann Arbor, Mich. FALK, HANK L., Ph. D.-Associate scientific director for carcinogenesis etiology, National Cancer Institute, National Institutes of Health, Bethesda Md. FARIIEIL, EJIMAXUEL, M.D., Ph. D.-Profesrjor and chairman, Department of Pathology, University of Pittsburgh. Pittsburgh, Pa. FERRIS, BENJAMIN G., Jr., M.D.-Professor, Del)artment of Physiology, Harvard School of Public Health, Harvard University, Boston. Mass. Fox, SAXUEL M., III, M.D.-Chief, Heart Disease and Stroke Control Program, Sational Center for Chronic Disease Control, U.S.P.H.S., Arlington, \`a. E'ICEDERICKSOS, DOXALD S., JI.D.--Chief, Laboratory of Jlolewlar rJi.sease, Na- ational Heart Institute, Sational Institutes of Health, Bethesda, Jld. FROL~, ARTHUR H., M.D.-Heart Disease and Stroke Control Program, Sational Center for C?hronic Disease Control, U.S.P.H.S., Applied Physiology Labora- tory, Georgetown rniversity, Washington, D.C. GELLER. Hawlx--Chief. Operational Studies Section, Canwr Control Program. National Center for Chronic Disease Control, U.S.P.H.S., Arlington, Va. GITTLESOHN, ALLAS, Ph. D.-Johns Hopkins University, School of Public Health, Baltimore, Md. G~DnJARx.4SOS, SIG>%UNDUR, Ph. D.-Department of l\ledicine, \\T'aylle State University, Detroit, Xch. HA>~JIOND, E. CWLER, SC. D.-Vice president, epidemiology and statistical re- search, American Cancer Society, Sew York, S.Y. HESS, CATHERINE B., M.D.-Assistant to the chief, Oancer Control Program, Sational @enter for Chronic Disease Control, U.S.P.H.S., Arlington, Va. HIGGISS, I.T.T., XD., JI.R.C.P.-Professor, Department of Epidemiology, rni- rersity of Michigan, School of Public Health, Ann Arbor, Nich. HOFFJ~AXX, DIETRICH, Ph. D.-Associate member, Environmental Carcinogene- sis, Sloan-Kettering Institute for Cancer Research, New York, S.Y. IMBODEN, CLARENCE A., Jr., M.D.-Division of Regional hIedica1 Programs, Sa- tional Institutes of Health, Bethesda, Md. ISHII, KAREO, M.D.-Chief, Serology Division, National Cancer Center, Research Institute, Tokyo, Japan. KANSEL, WILLIAX B., M.D.-Medical director, Heart Disease Epidemlolo~ Study, National Heart Institute, National Institutes of Health, Framingham, Mass. KELLER, ANDREW Z., D.M.D., M.P.H.-Chief, Research in Geographic Epidemi- ology Research Service, Veterans Administration Central Office, Department of Medicine and Surgery, Washington, D.C. KESNER, HARRIS N., XL).--Jledical consultant, Heart Disease and Stroke Con- trol Program, Sational Ceutrr for Chronic Disease Control, TI.S.P.H.S., Arling- ton, Va. KERSHBUA~K, ALFRED, M.D.-Assistant chief, Division of Cardiology, Philadelphia General Hospital, Philadelphia, Pa. KOTIN, PAUL, M.D.-Director, Division of Environmental Health Sciences, U.S. P.H.S., Research Triangle Park, S.C. KRLXHOLZ, RICHARD A., M.D.-Director, Medical Chest Department and Pul- monary Function Laboratory, Charles F. Kettering Jlrmorial Hospital, Ketter- ing, Ohio. LILIENFELD, ABRAHAII, M.D.-Professor and chairman, Department of Chronic Diseases, Johns Hopkins School of Hygiene and Public Health, Baltimore, ;\Id. vii MCLEAN, Ross, M.D.--Professor of medicine (pnlmonar~ disease), Emory Uni- versity, School of Medicine, Atlanta, Ga. MCXILLAN, GARUSER C., JI.D.--Sational Heart Institute, Sational Institutes of Health, Bethesda, Md. MEPER, JOHN S., M.D.-Professor and Chairman, Department of Il'eurology, College of Medicine, \Va~ne State l:niversity, Detroit, Jlich. MOOBE, GEORGE E., M.D.-Director, Rosaell Park Memorial Institute, Buffalo, N.Y. MOUKT, FRAXK W., M.D.-Acting chief, Chronic Respiratory Disease Control Program, Sational Center for Chronic Disease Control, U.Y.P.H.S., Arlington, \`a. XURPHY, ED~IOND A., M.D., SC. D.-Associate professor, University of Colorado Medical Center, Medicine and Biostatistics, Denver, Colo. ~`ADEL, JAY A.. JI.D.-Carclioras~nlar Research Institute, University of California JIedical Center, San Francisco, Calif. PAYSE. GERALI) H., M.D.--Chief, Adult Heart-Preventive Programs Section, Heart Disease and Stroke Control Program, Kational Center for Chronic Disease C'ont rol, T.S.l'.H.S., Arlington, \`a. PETERSON, WILLIAM F., AID-Chief, Obstetrics and Gyneco1og.v Service. USAF Hospital, Andrews Air Force Base, Washington, D.C. PETTY, THOMAS L., M.D.-Assistant professor of medicine, University of Colorado Medical Center, Denver, Colo. PTRI, PRITPBL S., M.D.-Department of Medicine, Wayne State University Medical School, Detroit, Mich. QIIISLAS, CARROL B., M.D.-Deputy chief, Heart Disease and Stroke Control Pro- gram, Sationnl Center for Chronic Disease Control, U.P.P.H.S., Arlington, Va. ROBIXS, MoRTos-chief, Program Statistics and Analysis Section, Heart Disease and Stroke Control Program, Sational Center for Chronic Disease Control, U.S.P.H.S., Arlington, Va. Ross, WILLIAX L., JI.D.-Chief. Cancer Control Program, Sational Center for Chronic Disease Control, U.S.P.H.S.. Arlington, Ya. SCHACHTER, JOSEPH-Statistician, Adnlt Heart Activities, Heart Disease nud Stroke Control Program, Sational Center for Chronic Disease Control, U.S. P.H.S., Arlington, Ta. SVHL?~~AS, LEOSARD JI., JI.D.-Professor of epidemiology, l'nirewity of Minne- sota, School of Public Health, Minneapolis, Minn. STAJILER, JEREYIAII. JI.D.--(`hiwgo Board of Health. Health Research Founda- tion, Chicago, Ill. THOX, T~osras .J.--St;ltirtic,iatl, Program Stntistirs and Analysis Section, Heart Disease and Stroke Control Program, Sntional Center for Chronic Disease Control, lV.S.I'.H.S.. Arlington, Tn. \YEsT~-RA. Enwrs E., M.D.-Heart Disease and Stroke Control Program, Sational Center for (`hronie Disease Control, l~.S.l'.H.S., Chief, .$lrplied I'h~siolog~ Laboratory. Georgetown Vnirrrsitr, Washingtou, D.C. IVYSUER. ERSEST I,., Jl.D.-Asweiate member, Sloan-Kettering Institute for Cancer Research. Sew York. S.T. %T~(EI.. WII.I.IAN a., M.D.--1seist:int Director for Collahorntive Stndies. Sational Heart Institute, Sational Institutes of Health, Bethesda, Md. The following professional staff of the Sational Clearinpl~ouse for Smoking ant1 IIenlth contributed to the preparation of this report: Selwp 31. Wniqyon-, Dorothy E. Green, Ph. D., Robert S. Hutchings, Ric.hnrd 11'. White, Emil (`orwin, and Robert F. Clarke, Ph. D. Special thanks are due Jennie 31. ,Jennings and Donald R. Sllopland. . . . VIII Foreword_-----______________________---_--------------- Preface-------__-___-----_-________-------------------- Acknowledgments _________ -_- ____________ ---_--__----_-_ Part I. Current Information on the Health Consequences of Smoking__----_-_-_-___--------------_------- Highlights of the Report- -__--___-- __________ Smoking and Overall Mortality- - _ _ _ - _ _ _ _ _ - - _ - Part II. Technical Reports on the Relationship of Smoking to Specific Disease Categories ___________ -------_--_ Chapter 1. Smoking and Cardiovascular Diseases- Chapter 2. Smoking and Chronic Bronchopul- monary Diseases (Non-neoplastic) _ _ Chapter 3. Smoking and Cancer- __ - - - _ _ _ _ _ _ _ _ _ Page . . . 111 V vi 1 3 5 11 13 63 87 ix PART I Current Information on the Health Consequences of Smoking Highlights of The Report LIdtlitioi~nl physiological and epiclen~iologiral evidence confirms the previous findings that cigarette smoking is the most important cause of chronic non-neoplnstic hroncliopulmoiinryv disease in the United States. Cigarette smoking can adversely affect pulmonary function and disturb cxrdioplllnlollarv ~~h~siolog~. It is suggested that tllis can lead to cardiopuln~on:~rg disease, notably pulnlon:lry ]lypertension xnd car pulmonale in those intlividuals who 1Mve se\-ere chronic obstructive bronchitis. 3 SmoA-ing and Cancer Additional rvidcnce substantiates the prcrious finclings that ciga- rette smoking is the main cause of lung cancer in men. Cigarette smok- ing is causnll\- related to lung cancer in n-omen but accounts for a smaller proportion of cases than in men. Smoking is a significant factor in the causation of cancer of tile larynx and in the development of can- cer of the oral cavity. Further ep*idemiological data strengthen the association of cigarette smoking with cancer of the bladder and cancer of the pancreas. Smoking and Overall Mortality The 1964 Advisory Committee's Report (3) clearly and em- phatically outlined the dangers of cigarette smoking to health. The conclusions of the Committee, as outlined in the 1067 Report (2)) were as follows! CIGYYRETTE smoking is associated wit11 n `i&percent increase in the age-specific death rates of n~;~lcs. and to a lew'r extent with in- creased death rate of females. The total number of excess deaths causally related to cigarette smoking in the l'.S. population cannot be accurately estimated. Tn view of the continuing and mounting evidence from many sources, it. is the judgment of the Committee that cigarette smoking contribnte9 sul)stantinllv to mortality from certain specific diseases and to the overall tleath'rate. In general, the greater the. number of cigarettes smoked daily, the higher the, death rate. For men who smoke fewer than 10 cigarettes a day, according to the seven prospectiT-e studies, the death rate from all causes is about 40 ljercent higher than for nonsmokers. For those who smoke from IO to 19 cigarettes a day, it is about 70 percent higher than for nonsmokers: for those who smoke 20 to 39 n clay, 00 percent higher, and for those x-ho smoke 40 or more, it is 120 percent higher. Cigarette smokers who stopped smoking before enrolling in the seven studies hare a death rate about 40 percent higher than non- smokers? as against 70 percent higher for current cigarette smokers. Men who brpn smoking before age 90 hare a substnntiallr higher death rate than those who bepn after age 9~. Compared rlth non- smokers, the mortality risk of cprette smokers. after adjustments for differences in age. Increases w-lth duration of smoking (number of years), and is higller in those who stopped after age 55 than for those who stopped at an earlier age. In two stirdies which recorded the degree of inhalation, the mor- tnlitv ratio for :I given amount of smoking was greater for inhalers than` for noninhalers. The ratio of death rates of smokers to that of nonsmokers is highest at the earlier ages (40-N) represented in these studies, and declines with increasing age. Possible relationships of death rates to other forms of tobacco use were also investigated * * *. Th e death rates for men smoking less than -5 cigars n day are ahont the same as for nonsmokers. For men smoking more than 5 cigars daily, death rates are slightly higher. There is some indication that these higher death rates occur primarily 5 ward trend is reported in lung cancer death rates for the cntjre pcmp (smokers, es-smokers, and those ~110 never snroketl. co111l)ined) along wit11 n very sharp rctluc-tiou in cipwttc siiioking II\- the ph~sic~in11, is the Ibest n\ailnble PSillll~)lC of :I controlled wssatloll ~spriiiif~nt with retlurtioii of risks re511lt i11p fro111 rctliictioii of ~111oI;iuy. Tlie fintlii~gs of tliis report snpport the \.ic\v that cl)icleiliiolo~ic:il tl:\t:i sl~owll1g lower dent11 lY1tt5 :1111011g fol~lllel ~mokcrs tIl:lu amoiig cwitinaing smokcr5 cannot Iw tlisilriswl ai tliic to ~clwti\-e I)i:i~ niid that tlie lwne- fits of gi\-ing 111) ~111oliing haye l3rol~nl~ly IWCI~ iindci5t:ltctl. 5. Clgnrctte smokc~i~-: li:il-e lii~lirr ixtes of tliG;ll)ilit\- tll:ln n~~i~~ii~ok- PI'S, \~Ilt?tllt~~ llli?ilSlll~t~tl by tl;l\S lO?t fro111 \YOl'Ii :llllO;lf tll? Pllll)lO~Pd Iwpi~lntioii. 1)~ tlnys q&t ill'in Iwtl. 01' 11~ tile ino5t ,pnrixl i~i~wiire --dnp of "re.-;trictetl :Icti\-it?-" tliic to illncc~ 01' ilrjrir\-. T)at:l froiii the Sntionnl ITealtI1 Siir\-ey l)ro\~itlc :I I);ts(~ for e.+ti,rl:rti~y tliat in 1 yeal' iii tllr I'iiitctl StiltC'S aI1 :icl~litiorl;ll 77 1riilliol1 1Jr:ll~-tl:lj~i \\`el't' loqt flY)llI u-ark, an :~cltlition;il 8s nlillion 111:111-~l:i~.i \vert' 5lw11t ill i1r lwtl, alld ai1 :~dditinn:~l XX iirillioii i11;1n-t1;1~-~ of 1wti~ic~tcvl :1c`t ix-it F \wre cspe1+ e11cwl bccnn5c c*ig:1Wtte s;11lOkt'1.5 llil\.C' liigIlI(~r (lixllbilit,y 1':ltW tll:lll IlOll- smokers. For 11~11 :ye 4.i to (;4. 28 lwuw~t of tlrc tllwl,ility (lay- (IS- 1)erienced represent the excess associated with cignrctte duoking. In the 1067 Report tl1c follow in, m qliwt ion9 \wrv r~111I~li:1~izctl : 1. How much mortnlity and PSWSS diwl~ility :IW ;l+ociated with smoking 1 2. How nrwh of this earl- ljlort:xlit,y ant1 esce~~ tlisahility nollld not, linvc occ~n12ml if Iwople 11ntl Ilot t ;IliCll nl' ciprrt te :irroki1i,~? 3. ITOK mnch of tliis early nloi?:llity ant1 exws5 (li-:\I)ilit y ccailtl be nrertetl I)!- the crssntion or reduction of cipnrettc .SJllolii11~? 1. What are tlic l~ioi~ir~~linuisiiis R-herthy these eflwts take place and what arc tire crit icnl factors iii these niecl~nnisnis? The problem of ho\\- Iwst to me:1~11rc the relation-Ilip betn-een amok- ing and inortnlitv was presented by three menningfiil measiires of romparisoii : 1. Mortality Ratios: Obtained by cliriding the death rate for a clns- sification of smokers by tl1e death rate of a comparable group of nm- smokers * * * A nlortnlitv ratio has been considered to reflect the degree to wliictll :1 cIasxificGtioi1 \-:iri:\l)Ic itltwtifir-: or 111:iv acwmiit l'ol varintion~ in tlwtli rates. -1s s\ic*li. it is ;I Itiwqiiy of i.rl:iti'\-e risk v-liich indicates the importance of that, variable relative to uncontrolled vnri- ables-an iiicliwtor of jmf~~fifr/ /~;0/0~ji~ul .~;~q/1;fiuinw. 2. I)iffei~eiicw ii1 Jlort:llit\- IZntcs : Ol+t:\illctl I)\- 5liI)t rncting froiii the death r:ite for wroker5, the death rate of a c~~n~Ix113hle gronI) of nonsmokers * * *. Thi? measllre rcdlwts the atl~lwl l~rnl~xl~ilit~ of death in :I !-year Iwriotl for the ~111okcr c)\xar that for tile 11ow111oker. *Is such it is a 11iea~ilre of p1~1w~~~~7 7~~07th s+pi~~o7~~~i~. :I I~I~:II~S for the intli\~itln:1l to rStiil1atc tlie ntltlctl ri~iltic increace in death rates as age advances, with the incrtf~e being particularly- marked after age 45. The cleat 11 mtrs for coronary- lleart disease for n~en and u-omen continue to shoed il cwiisl)iruon tlitrernice. In 1966 it was Xl.6 for males ancl 22K:i for feirmle-; per lOO,OOO population. While seven~l studiw of wriow ns;pec.ts of the association between cnronar~ hc:lrt tlisense nlortality and viparette smoking have been rrportetl dilring tllr l,:tct year. tile. most significant studies of this association are cont:~inrvl ill the 1067 report. Tht se\-rral ne\v .stlltlici of variom aspects of the association between coro~ul:\- hr:rrt tlistme Inortality and cigarette making follow. Friedman ($6) reportetl a strong positive correlation betm-een per ml)ita c*igawttc sales ant1 ~wro~~:~~~ 1leilr-t disease death rates by states. The correlation is 0.76 when d:lta only from tllosc states with relatively acmratc information of cigarette consnnlption are. analyzed. Related factors sw11 :\s urb:\nization or softness of the local mxter supply do not explain this degree of association. 16 Other studies tleal with the excess deaths associated with smoking. Strobe13 et al. ( I.#) reported that among 3,479 Sviss physicians, over 30 percent of tlic exce.ss deaths occurring over a g-year period among siuokers n-as due to coronary heart disease. In contrast to the study above and c1nt.a from the T-nit& States in whirh nl~proximatelr one-half of the excess deaths associated with sinokiug are attrilmted to cardiovascular causes (I.$!?), preliminary data from Hirayama (6;;) show that the excess deaths in Japan associ- ated with s1ii0kiii.g were priniarily cxpl~ained 1)y cancer of various site,s. Only Ii! percent of tlie excess dentlis were associated with cardio- vascular causes. This prospective study of %.5,118 adults over the age of 40 encompassed ;I followup period of 15 months. -1dditional follow- up by TJirayanla slwuld yield useful tlnta with respect to smoking and excess mortality from cardiovascnlar diseases in this ,Japnnese popu- lation group, p:vtticularly with regard to the younger adults in the study. Hyams, et al. (67)) on the other hand, speculate that the apparent increase in the occurrence of coronary heart di+ase among +Japa~wse males, especially rmder tlie age of fifty, may be tlnc to a t,rend toward Westernization in both diet and smoking habits among younger Japanese men. Hammond (,54), in his prospective study of over 1 million men and women, showed a positive relationship between the duration of the smoking habit and coronary heart disease mortality. In the Framing- ham Heart Study (71)) no association wa.s found between the. duration of the smoking habit and the incidence of mortality from heart &tacks among men who were "heavy smokers" (more than one package of oigarettes per day). These diswepancies between t,he relationship of smoking to the incidence of t&al coronary heart disease and mortality from acute ooronary heart disease may be accounted for, in part, by the differences in population ,q~~~ps studied and by the possibility that duration of smoking may have a greater association with t,he fatal forms of coronary heart disease.. Knmrel, et al. (70)) in more recent. data from the Framingham study, indiwte that the fatal and more severe forms of coronary disease are more st,rongly associated with c.igarette smoking that the less sel-ere forms (figure 1). Coronary Heart Disease Morbidity * Rlnc.1~ of the morbidity da,ta reported during this past year resulted from retroqwti\-e studies of patients or cross-sectional studies (106, 107, 127, 134, 151). In these studies the findings revealed that there o Also may include mortality data in this presentation. 17 2.50 - *ing,na Pectorlr Myocardial Fatal Infarction CHO S"ddW Death 2.20 .g 1.50- E e 2 e s LOO- NOW kleavv Non- NW- Heavv NOW Smoker Smoker Smoker Smok;` Smoker Smoker Smoker S&k& OES. = number obsewed EXP. = number expected Heavy smoking indicates more than 1 pack per day FIGLYRE I-Morbidity ratios for .qxvified manifrstntions of coronary heart disease. nruonfi men aged X&SD years at entry into Frnminghnm Heart Stuclr, classified by smoking habit : 12 years' experience. ~OCRCE : Iiannel, et al. (70). were reht i\,ely more smokers among the groups with coronary heart tliSfXW, tll;\ll :~llIOllg tilt? ~Olllp\l'iSOll, 01' COlltrOl pOllpS. In n retrospective stitlltly of myocardial infarction patients in *Japan, I-Iy"ms, et :\I. (67) reported siinilnr findings, particularly among the mm untler age 50. DitFrrences measured 1)~ an exposure index com- bining intensity and duration of smoking showed the same trend, t.liougl1 the tl:lt:i were not statistically significant. Dorkcu (.M. .I/) reported on t\vo retrospective studies in Hamburg, Gerni:liiy : one: a study of female patients; the other, a study of male patients. IIe. cwnc-ludctl tllnt there is a strong association between w~oking :tu~l nivoc;lrdinl infarction in both males and females under the age of 45. In Dublin. JIulrnh~, et al. (106, 108, 109) studied groups of male and fem;lle coronary heart tlisense patients under age GO. He. found that a much greater portion of the patients, in comparison with a sample of the general population, smoked cigarettes. Also, the intensity (amount, multiplied by tlurntion) of smoking was RS much as 234 times gre.nter among the male patients and 3 times great,er among the fe.mnle coronary heart disease patients as contrasted with the males and females in the general population. In a study of 6'75 aviators, smoking histories taken in 1963 did not sllow a positive association in the prevalence of coronary heart disease with either amount, duration, or intensity of smoking. These findings are based on 38 cases (5.7 percent) of coronary heart disease of all forms among a very select population and are therefore subject to large sampling variations (9G). Moreover, since smokers may have an escwsi\-e mortality tllwing an acute nlyocartlial infarction. as mcn- tioned before, prel--alence rates are not as good a measure of the asso- ciation between snloking and coronary heart disease as are incidence r&es. Epstein (,?9), although finding no prevalence differences between smokers and nonsmokers in his Tecumseh Study, found an increased incidence in cigarette smokers of both fatal and nonfatal coronary heart disease. In a short prospecti\-e study of 14,000 Kern-egian men (12,000 with smoking histories), ?;atvig (113) did find an increased risk of inci- dence of first myocardial infarction or angina pwtoris among those men 50-59 years of age who smoked. Since the 1967 Report, t,he continuing prospective epidemiologic studies have comewhat clarified the differential relationship between smoking and each of the manifestation categories of coronary heart disease : angina, nonfatal myocardinl infarction, fatal myocardial infarction and sudden death. Data from the Framingham Heart Study (G9) revealed that "heavy" cigarette smoking, more than 20 cigarettes per day, is positively asso- ciated with uncomplicated angina in males but not in females (figure 2). Similar findings were report,ed by Weinblatt (155) in a study of male subjects in the Health Insurance Plan with t,he associations more pronounced among those men who smoked two or more packages of cigarettes per day. As can be seen, in table 2, the arithmetic differ- ences in rates between smokers and nonsmokers are greater for myo- cardial infarction than for angina; however, t.he risk ratios are similar. In a ret,rospective study, Heyden-Stucki et al. (61) found no asso- ciation of smoking with angina or other chest complaints. The inconsistencies in data on the association bet.ween smoking and the development of angina may be due in part to differences in methods used to diagnose and classify angina and to record smoking habits in these epidemiologic studies. Further standardization in this area may help to determine more accurately the relationship of smok- ing to angina. 19 2.00 - 1.61 l.!iO- ; > : l.OO- d L NCl"- Smoker OES. = "umber Observed EXP. = number expected NOW l-20 >20 Smoker CigaretteSmokers FIGURE 2-Angina pectoris morbidity ratios among persons aged 3&59 years at eotry into Framingham Heart Study, classified by sex and number of cigarettes smoked : 12 years' experience. SOURCE : Kannel, et al. (69). TABLE a.-Age-adjusted incidence rates per 1,000 males aged 35-64, and morbidity ratios, for speci$ed manifestations of coronary heart disease, by smoking category: Health. Insurance Plan Study 13 year observation data] Smoking catrgory Myocardial infarction Angina Incidence Morbidity Incidence , Morbidity rate ratio rate ratio I- --+---- Current nonsmokers ____ --~~---~ . .._.._ - 3. 27 1. 0 1. 37 1. 0 Current cigarette smokers_-_- - - ~. _ - ~. 7. 01 2. 1 2. 62 1. 9 Less than 2 packs_~~.--~~~-----~-~- 5. 05 1. 5 2. 08 1. 5 2 or more packs--~---_----_.- __._. 20. 80 6. 4 6. 64 4. 8 Source: Feinblatt, E. (f56). 20 In the Western Collaborative Study, Rosenman et al. reported !iipher rates of silent mvocardial infarct ions in ~~outlger men, 311d liigher rates of recurrent myocnrclial infarctions at all ages among those who smoked nwre than 25 cigarettes per day (13.3. 124). Friedemann, et al. (44) reported reinfarctions occurred more fre- Dorkeii (27) found in a series of 330 men of all ages, in Hamburg, who surriyed at least R and up to 6 years after their first. nlgocardial illfarction, that 172 (5" percent) had stopped smoking completely after the first, infarction. In contrast, of 8~ sul)jects who had died from a second myocardial infarction or sudden coronary death after learing the hospital, oi11y I&S (Z.9 ljercent ) had given up smoking completely (PSit elevations in blood l)ressitre, ln~l)itunl smokers teiid to 1ral-e lower blood pressures thall do 110111;11~01it?1'S. Hut, gi\-en the ljresence of high blootl pressure in an indi\-itliwl, smoking acts as an additional risk factor for the developnlent of coronary heart disease. Heyden-Stucki et al. (61) report that, among 500 workers in Slvitzer- land, smokers, particularly heavy smokers, have lower blood pressure as a group than do nonsmokers. Smokers also were found to have normal or subnormal weights in contrast to nonsmokers who had a greater mean weight ; thus, confounding the relationship between snroking and blood pressure level. Tibblin (144) in a cohort study of Scandinavian men born in 1913, found a lower mean blood pressure among smokers than among nonsmokers. As the population was clas- sified according to levels of blood pressure, a step-wise decrease in the prevalence of smoking was noted as the level of blood pressure in- 21 TABLE 3.-Mean age and man systolic and diastolic blood pressure, by sjnoL+irLy category: Los Angeles Heart Study, 1962 Current cigarette smoking status Blood pressure (mm. of Hg.) Number of, Years of Systolic Diastolic subjects age -1 -,-,- I Smokers.~~~~~~.~~-------~~~---------- 407 54 133. 6 82. 5 Nonsmokers--.~~-------~~.------~-~~~- 728 57 ~ 137. 0 83. 9 I SOURCE: Clark, V. A. (2s). creased. A similar trend for both systolic and diastolic pressures was also reported by Clark, et al. (23) as shown in table 3. In the study of 675 arintors (96) smoking intensity, although not found to be associated significantly with systolic or diastolic blood pressures, was positively associated with pulse pressure. Reid, et al. (122) in a comparative study of workers in Great Britain and the United States noted lower diastolic blood pressures among smokers than among nonsmokers in both groups; adjustment for Tveight variations reduced this difference appreciably. Rfulcnhp (207)) in a retrospective study of 100 women coronary heart disease patients under 60 years of age, reported that ,50 to 60 percent had diastolic. hypertension (>nO mm. HF.). Hypertension and ciga- rette smoking, together or separately, were present in over 80 percent of these patients. In the major prospective studies, when both smoking and hyper- tension were present, an interactive increase in the risk of developing coronary heart disease \yas noted. When to these two risk factors elevated cholesterol levels were added, the risk of developing coronary heart disease was further increased (figures 3 and 4). High A`Temm~ Cholesterol ad Relcrted Diet Certain of the retrospective and cross-sectional studies (6'9, 151) have, in general, demonstrated higher cholesterol levels in smokers than in nonsmokers. Pincherlc, et al. (119) and T,ane. et al. (9G) report similar finding?. Ai stud7 by Heyden-Stucki (GI) of ,500 Swiss workers found a similar trend but the differences between smokers and non- smokers with respect to cholesterol levels and other lipids were not statistically significant. A recent report (A'/;) describes some of the variability of interrela- tionships among smoking, blood pressure and cholesterol levels in different population groups througllout the world. It concludes that though nonsmokers tend to be heavier and have higher blood pressure levels than cigarette smokers, heavy smokers tend to be in the top 22 150- positive weight W.C.H. cd" any 2 any2 any 2 any 3 any 3 OnI" only On," only or all ""I" O"lY OnI" or 3cml" all 4 CHD 46 1 0 2 8 4 6 12 17 23 N 1,329 94 161 227 260 159 204 484 222 264 6 42 Relataonship between status with respect to four coronary risk factors thyper- cholesterolemia, hypeRen~hm. overweight. and cigareffe smokingt as evaluated on original examination and incidence of cltn~al coronary heart disease in men or,ginally age 40-59. free of definite CHD. and followed subsequently wtfhout systematic interventgon. Peoples Gas Light and Coke Company study. 1958-1962. W is overweight, le. a ratio of observed weight to desirable weight of 1.15 or greater, C is hypercholesterolemla. ie, Swum cholesferol level of 250 mg/lOO ml or greater. H is hypertensmn. ie. a diastolic blood pressure of 90 mm. Hg or greater: S is smokmg of ten or more cigarettes per day.' FIGURE 3-1ncic:enre of coronary heart disease among men aged 40-59 years at entry iuto I'ctiol~les Gas Light and Coke Company Study. classified as to pres- ence of specified risk factors: l!Xbl962. SOURCE: Stamler, et al. (1%). cleciles for blood pressure nnd rrlntiye x-eight. Cholesterol-smoking relationships described in these studies do not show a consistent pattern. Tn a controlled dietary intervention study of postjnfarction patients Leren (W) fount1 that smokiiq Ilabits did not iilflilence the serum cl~olesterol level or tllr cwronary llci1rt clisease relapse rate in the colltrol group. i~lllollg the stlltl) gronl) of clictcrs there was il suggestion, :~lthough not statid ically >igl~ilicxlit at tile 0.05 level. that smokers had a higher coronary heart disease relapse rate than nonsmokers. Physicd rnnctic4y The independent and combined effects of cigarette smoking and physical :ic.tiCty, as dr~~ribetl in the 1!)67 rrlwrt. vontillne to be demonstrated :IS more data are :Ic~,,l~llllllntetl. Tile apparent l)rotcctire effect of plrysical :ic*tiritJ appears to be more pronoiinwd with regard to myocarclial infarvtioll tlian :lllgiu:l [t;Ible 4, (255)]. Differences in methods of assessment of liistoq, of l~ll~sical acti\-ity ill cape versus 315-1310-66-3 23 6.00 - 1 .w - 0.00 Any one Any two Any three OBS = number observed EXP = number ex~ecfed Number of abnormalities FIGIXE 4-MFocardial infarction morbidity ratios among men aged 30-59 years at entry into Framingham Heart Study, classified according to presence of selected riak factors : 12 gears experience (Risk factors are: cholesterol lerei over 250 m&100 ml., systolic blood pressure over 160 mm. Hg., smoking over 1 pack of cigarettes per day). SOURCE: Kannel, et al. (70) control groups may account for some differences in the incidence rates noted. Hlackl~urn, et al. (10) folmd no relationship of smoking to the prev- ale,nce of postexercise KCG c.hanges in a study of 10,260 men age 10 to 59 years. TTo\vever. there were only .51!1 (.i.l percent) subjects with a, "positi\7" TSCG response. Sociologirn?. Pqvh~olqicn7 and Pwsonalify Variables Tn-o studies ($5. R/t) demonstrated an inverse relationship between t,he frequency of coronary heart disease and the educational level of the subjects. In the Bell Telephone System (Cd), those men without a college education had higher coronary heart disease rates than those with a college education. Also, those not at.tending college tended to smoke more. In a study of factors related to coronary heart disease among Cleve- land attorneys ($5)) the quality of the law schools attended by the sub- 24 3. 27 1. 0 6. 33 1. 9 2. 14 1. 6 3. 07 0. 9 1. 67 1. 2 3. 01 0. 9 1. 32 1. 0 7. 61 `2. 3 4. 71 1. 4 3. S.i 1. 2 11.27 3. 3 24. 09 i. 4 2. 0.i 1. .j 2. 37 1. 7 1. 9.5 1. 4 4.97 3. 6 5. 09 3. 7 12. "0 3. 9 jec.t were ranked independently by a law school professor. I,a\~-~ers attending s~~l~ools in tile "lliglrest law ~:cllc:~ol quality growl)" Ilad lower rates of coronary heart disease than those attending schools in the **lower law school qlwlity group." *use, t11ow ill tile 1attrr group had started snloking at an earlier age. Since additional differences were noted for other risk factors, smoking alone may not be responsible for tllr total differences in these rates. In both stnclies, it uxs liyl)othe- sized that with respect to susceptibility to derelopmellt of coronary heart disease, behavior patterns and attitucles estal~lishetl l)rior to professional traillillg and prior to stresses rcsnlting from job mobility and job tension, were nlore significant than the later stresses x-hich resulted from their present jobs. Rec,ent clata from the Western Collaboratire Group Stll(ly (IX) appear to show that among met1 X-49 Jears of age. cigarette smoking ~-as associated with several coronary heart, disease risk factors (table 5). Though these findings may be statistically significant, the differ- ences between smokers ancl nonsmokers I\-ere small. 25 TABLE 5.-Age-adjusted means for selected coronary heart disease risk -factors and personal chSaracteristics, by smoking category: U'estern -Collaborative-Grolrp Study, males 39-49 years of age [4)< years overage observ.dion data] I Smoking category - Variable NWX smoked I- Serum cholesterol- _ _ _. _ _. - _ _ _ _. - _ -___ Beta/alpha ratio _____ --_--_--__- __.__ Lipalbumin~~~~--~~-~-~~~-~--~.-~--~- Systolic blood pressure--_. - _ _ ___- _ - -_ Diastolic blood pressure--. - __ _ - _- _ - -_ Ponderal index _____ -----.---- ._____._ Physical activity on job..-- - - - -_ _ _ ____ _ Amount of exercise-_-_--_--_-_-----~- Income__-__-_-__-__________________ 217.2 1. 9 21. 1 1`26. 3 82. 0 12. 6 1. 95 2. 18 2. 75 T _- Sources Rosenman, R. H. (fZ5). Smoked 26 cigarettes or more per day 231.8 2. 1 19. 4 129. 9 81. 3 12. 7 1. 95 2. 05 2. 75 -- I - Percent diBerenw +6. 7 +10.5 -8. 1 $2. 9 -0. 9 +o. 8 0 -6. 0 0 TABLE 6.-Pewent df.vftlibution by behtlz*ior type of smokrrs and non- swokers: IVe.stem Collnborntire Group #t&y? mnles 39-p yews of ac7e 14% yews average observation data] Behavior type I I Smoking category Tota1 `--Never 1 Former Current 1-15 16-25 smoked smokers pipe or 26 cig- cigar&k5 cigarettes aretteS cigar only per day per day or more per day ,-~~-~ -___ Total ___._ -__-_- 100.0 I 1 100. 0 100.0 100.0 100. 0 100.0 100.0 -_________________- ;:;:;::::::::I ii:; 1 ii:; j :y :;:; ;;:; 1 Q;:; :!g Test of difference of distributions: Xz=24.;0; df=3; p=.@X. SOURCE: Rosenman, R. H. (125). Behavioral pattern type A is characterized by an enhanced com- petitiveness, drive, aggressiveness and hostility, and an excessive sense of time urgency as contrasted to type B. There was a difference in the distribution of personality types A and B among smokers and nonsmokers (table 6). The foregoing data refer to concurrent observations gathered in 1960-1961 on 3,182 men who were then free of manifestations of coronary heart disease. A follow-up of this population during the 26 nest 41/i Fears disclosed that cigarette smokers experienced substan- tially higher rates of coronary heart disease tllnn those who had never smokd This finding is based 011 clata for men 39-49 vx~rs of age, whic~li hair been adjusted for the c*onfouncling influences of related risk factors, such a': age, cllolesterol, etc. (table 7). TaRLE ?.-InCit/enCP ?f new coronary heart diseaw by WIoking CatPgory: Western Collaboratioe Group Studyl: males 30-49 years qf age [4x ~mrs arernge observation data] Rate per 10,KKl population ?;ever smoked---------~---~-~~.~.~ ._...... 540 36 29 Former cignrcttc smokers- __ _ _. _. . . . . . . . . 241 67 92 Pipe and cigar only ___._..._...__.... ._... ~. 406 27 16 1-15cigarettes-----.-~-~~~~.~.~ . . . .._. .__. 212 51 52 16-25 cigarettes__------------------------.~ 436 89 92 26 cigarettes and over--~-_-~-_-~-.-_-.- ._.. 425 95 104 SOCRCE: Rosenman, R. H. (115). The coronary heart disease rate for those men smoking 26 or more cigarettes a day is seen to be about three times greater than for those who never smoked. The rate for former smokers is still rather high, even after adjustment for concomitant variables. The largest impact, of the adjustment procedure is noted among this group, and suggests that those who quit may have done so because they were already a relatively high-risk group for reasons other than smoking. The rela- tively low raie among men smoking only pipes and cigars is noted in this as in ot,her prospecti\-e studies. The nature of the association of smoking and coronary heart disease incidence among type ,I and type B personality groups is not easy to characterize or interpret. Among the type 11 group, the pipe and cigar smokers and the light cigarette smokers had the lowest rates of incidence of new coronary heart disease, while the highest rates were found among those smoking 26 or more cigarettes a day. For the type B group, the lolvest rates occurred among those who had never smoked, and the highest among the light cigarette smokers. The age- adjusted rates of new incidence of coronary heart disease per 10,000 men 3949 years of age are shown in table 8. Additional data t.o permit concomitant analysis of these variables and those in table 7 are needed. 27 T.\BLE 8.--lncLfence of new coronary heart disease by smoking category and beh,aaior type: Tl'estern Collaborative Group Study, males 39-Q years of age [4:/z years average observation data] - Rate per 10,000 population Smoking category Behavior type B Total~~~~~------------~----------~~.-~-~-~~~~~~~-. Ncversmoked~~~~.~~....~...~~-~---~~---------~---~ Former smokers-_.- . . . .._....._._ --.._------------- Pipeandcignrsonly ___...... -.-.-~-..-------------- Cigarettes: 1-15~~--~-----------~------------~-~-~-~-~-~-~ 16-25------~-----------~-~-~~~-~~.~~~~...~~~~. 26 and over-------~-~-~--~.-~-.- ____.___._.__._ 91 53 107 18 18 135 149 SOURCE: Rosenman. R. H. (l&5). 33 13 36 36 60 33 51 Lane, et al. (96) found significant relationships of smoking intensity and duration with personality factors-impulsiveness, emotional insta- bility and belligerence scales. Thomas (I&`) after reviewing rarious studies of psychological variables related to coronary heart disease, concludes that smoking may have different etrects on different personality types and at differ- ent anxiety levels. ill tdfiph? Risk Factors The acceptance of a multiple factor causation hypothesis for coro- nary heart disease emphasizes the. need for more sophisticated statis- tical analyses of appropriate data. Our understanding of the relative importance of rarions risk factors from the limited number of such special analyses has not been altered significantly from that obtained l)y more conventional statistical analyses (38). Clarification of the apparent independence of several of the major risk factors has resulted. Trurtt? et al. (245) emphasize that the major risk factors are noted to have a tlifferrnt ortler of importance by age and ses. Cigarette smoking is particularly important among younger males as noted in table 9. Genetic nnd Connfitutiona7 Studies Baer (5) found that heavy smokers among college males were taller than light, smokers and nonsmokers. Lane, et al. (%) also found sig- nificant associations between body size measurements, including ponderal index (though not with height or weight individually), and amount of smoking in the study of over 675 aviators. 28 TABLE 9.-Linear dkcriminant function coeficients (in standard units) for various risk factors in coronary heart d;sease, by sex and age: 12 Year Framingham St&y Age ___. . . . ~. - -, Cholesterol.. _ - ' Systolic blood pressure~.......~ Relative weight. _ Hemoglobin- - - - -~. Cigarettes smoked- _ ECG abnormality. _, SOURCE: Truett, J. (146.) Cederlof (18) has emphasize,d the value of studies of twins for investi,rratinp aspects of coronnr~ heart disease and prewnts certain suggested modifications in methoclolo,~. The 1967 Report (.I@) dis- cussed the studies by Cedcrlof on Swedish t\yin pairs (In. 30). His data on American twin pairs was recently prcscnted and showed re- sults similar to those of the SITedish twins (18). The problems with interpretation of thew studies nre sever:il. The small numbers of cases and the combinin,rr of dntu for both sexes in various subcategories make rates and ratios subject to significant ~linncc wriations. In addition, use of n questionnaire for nngin;TI, with only modest levels of reliability and vnlidity requires :I larger study population before definit ire conclnsions c:~n be nlnde. The lack of information on the distribution of risk factors other than smoking in subsamples of discordant twin pairs and the total group of twin pairs makes the compnrison of ratios for prevnlence of symptoms difficult to e.rnlu:~te. The inclusion in the "smoking." group of those who had stopped smokinp np to 3 venrs pre'ions to the study, would also te,ntl to diminish the differences betn-een smokers and nonsmokers. Ijefinitions of discordant snmking habits must conform to those differ- ences identified ns significant in the large-scale population studies. TIM fact' that discordance for smoking does occur ;unong monozy- gotic twins certainly indicates that the snlokinp habit cannot be deter- mined by genetic factors alone. Txl-in studies with further bophi&ca- tion of design, larger number of cases, better definitions of disease, and more significant identification of tliword;~nt exposures have the potential of contributing substantially to nur ~u~tlerstnnding of the interactive factors in coronary heart disease. 29 Tn an artic*le rel-ien-ing wme of the epidcmiolo~ical evidence in the 31/, years subsrqnent to tile 1964 report, Seltzer (1.29) concluded that - . there was no snbs~antinl evidence to indicate a flirther association of cigarette smoking with coronary heart disease Iw~ond that stated in the lY64 report. Seltzer nlludcd to \\-hat 1~ called "inconsistencies" in the recent literature relating to duration, aimunt, age, inhalation and mode of tolxwco smoking \vith coronary heart disease. The addition trf many more person years of esperirnce, from the new and continuing s:tltdies. provides data since the 1064 Report that wn be anal~ztcl age-spwific~ally. When this is done most of these "in- consistencies" disappear. Seltzer's cwi~cliisioi~ is v0ntixi.y to that of nlost cI)itlr~niiologists n-ho are familiar lvith the current research. Furt~hermore, he has not con- qidered the inll)ortant relevance of the esl~erinicn~aI, lxitI~ologicnl, and clinivnl data that have I)een r'q~ortecl since 1964 concerning cigarette .wioking nncl cardiorasciilnr diseases. Epidemiologicnl Rfzrdies The results of epidemiological studies on the relationship of smok- ing to serum lipid levels haT-e not been consistent. Several studies reported no significant difference in serum cholesterol (Z'6: 40. (il. 1:X)) and triglyceride Icwls (40. 61) between Pmokers and nonsmok- ers. In their study of twins, I{Iomstrancl. et al. (11) state that pro- longed smoking had an insignificant effect on all Fernm lipid levels in their monozygotic twins and only elevated phospholipids in their dizygntic group. However, they quote a personal con~munic:~tion from Carlson, et al. who fonnd elevated trigylceride levels in smokers in a prospective study of 6,000 persons. In a wry ~otiil)i,cliensire Stllily of 6;if former naval aviation cadets over n period of *3:\ years, Harlan, et al. (.X) investigated the rclnt.inn- ship of \-arious constitutionnl and cnvironn~entnl fwtors to serum lipid and lipoprotein levels. They fount1 that serum Sf O-12 (hcta) lipoproteins and cholesterol levels were related to cigarette smoking ~1x1 that the duration of smoking also had a significant correlation. The autllors felt that the relationship of smoking to these lipids was l~res~nna~ly dircrt, l~c~cau~~ cigare.tte smoking did not correlate with other fxtors related to lipicls. Experimenta Studies-Animal, Studies in dogs of the immecliate effects of tobacco smoke inhalation and nicotine :~dministrntion showed an increase in serum triglycerides but not cholesterol, in addition to a rise in free fatty acids (76). There 30 were no differences in cigarette, ci.gar or pipe smoke effects when the depth of inhalation was kept constant. Chronic administration of nicotine in dogs resulted in a 50 percent rise in serum chole~tcrol levels but did not affe.ct triglycerides (82). Kershbaum, et, al. (83') have also shoFn that pronethalol (a beta-receptor blocker) inhibits the serum- free fatty acid and triglyceride rise. induced by nicotine in dogs. In studies of the lipid and atherogenic effects of chronic nicotine administration in cholesterol-fed rabbits, one report found no effect in serum lipid levels but a significantly higher incidence of aortic fibrosis (51). Other investigators found that nicotine, increased the amount. of cholesterol in the blood ancl the intensity of lesions in the aorta (28). In cholesterol-fed rabbits administered vitamin D, Has.?, et, al. (59) found that, nicotine induced severe calcific athero-artcrio- sclerosis and occlusive thromboarteritis, especially conspicuous in cardiac? smooth and skeletal muscle. Astrup (2) has sho,Tn that in rabbits on a high cholesterol diet, chronic carbon monoxide exposure had a marked atherogenic effect. Gudbjarnason (52) has shown that chronic nicotine administration in dogs leads to a diminution in the rate of cholesterol turnover. Studies in Humans It. has previously been reported (78) that c'ip?wtte ~lllOliillp nlobil- izes free fatty acids, resulting in increased plasma concentrations. It was also found that this effect of smoking was the result of increased synpathetic and adrenal activity initiated by the absorbed nicotine (84)) the latter having no direct lipolytic action in adipose tissue (85). This response to smoking has now been confirmed by other inwsti- gators (41,9U,1ZU). Studies in man, on the immediate effect of cigarette smoking, hare shown no effect on serum concentrations of lipoproteins and lipopro- tein lipids (cholesterol, phospholipids, triglycerides) (78, 92, 115). In a recent study, however, an increase in serum beta-lipoproteins was observed 10 minutes after smoking (72). In a study of the comparative effects of cigarette, cigar and pipe smoking on free fatty acid mobilization and cntecholamine excretion, cigarette smoking was found to hare a much greater effect (81). Less nicotine. absorption in cigar and pipe smoking, clue to the absence of inhaling, was considered to be the explanation for the milder bio- chemical effects with these two forms of smoking (80). Kershbaum, et al. also compared the effects of various types of cigarettes on these parameters (79). They found no difference in free fatty acid and catecholamine response or nicotine absorption with several brands of filter and non-filter cigarettes. Cigarettes containing shredded lettuce leaf had no effect. 31 In other lipid studies it was observed that smoking might increase the tendency of human blood serurn to crystallize cholesterol (87). Kershbaum has also sho\yn that cigarette smoking increases the blood steroid levels in humans (86). STLYJIIES ON THROMBUS FORMATION The 1067 Report reviewed the effects of smoking on in z&o throm- bus formation, varying platelet characteristics and other serum factors associated with blood coagulation. It is not in the scope of this report to go into a detailed analysis of blood coagulation and/or thrombosis. However, the role of smoking and blood lipids on thrombogenesis mill be briefly discussed, as they relate to thrombosis and c.ardiovascular disease. The role of cntecholamines (especially epinephrine) in thrombo- cwlesis must, 1~ stressed (111). The nic~otillr-illtlrlced catccholamine Lelense, lvhich plays a major role in cardiovascular dynamics might also be. the mediating factor in the. relation between cigarette smoking and thrombosis. Ardlie (I) has shown that catecholamines enhance --1TP or -1DP induced platelet a,, ~~regation. -1DP and noradrenaline in 10~ concentration (up to 0.M pg,/ml.) were found to increase platelet mobility (.G). The reverse was true in higher concentration. Rowsell (1%) has shown increases in both t,hrombus formation in an extracorporeal system and clotting time in silicon-coated tubes with moclerate doses of epincphrine. Large doses gave values closer to the control state. I3estermnn (8) has shown a diurnal variation in "plate- let" stickiness which might he associated with diurnal variations in catecholaminc release. Flynn (48) found no difference in platelet ag,rrregation between smokers and nonsmokers. Shimnmoto (13.7) prolwses that epinephrine has a primary effect on the arterial wall causing the release of a thromhoplastin-like sub- stance which then leads to increased platelet aggregation. An autopsy stutly in I~IIIII;IIIS 1)~ ~~nrrl~ch i.1) showed inweawd fibrous thickening in the ~nlls of arterioles and small arteries of 5 organs, in smokers as conlpared to nonw1okers. This effect might be secondary to platelet c>hnnp~ wllich then calwed damage to the arterial wall. As discussed earlier in the s;tudy by Hass (59), in which rabbits on a high choles- te.rol and \.itnmin T) tliet were given nicotine. at the site of the oc- currence of thrombus there was usually an inflammation of the arterial -ivall. Blood Lipid.9 Conner, et al. (26) and Varner, et, al. (2.53') have described various experiments in dogs and rabbits, in which infusion of long-chain saturated free fatty acids caused extensive thrombosis and death. In 32 ?*;t~o coagulation and platelet, aggregation were also increased. Long- chain unsaturated free fatty acids, ho\\-ever, did not have these effect,s although microscopic platelet. aggregation was observed (CC). Zn vitro studies hare showy that linoleic and linolenic acids might, hare a pro- tective effect against platelet a ggregation induced by long-chain satu- ratecl fatty acids (73,101). The rise in plasma-free fatty acids which follows cigarette smoking was associated with increased platelet adhesiveness (210). The long- chain fatty acid-induced platelet aggregation 1~~s suggested to be due to :CDP release from platelets (58). Harrison (57) suggests that in vifro platelet adhesiveness tests are influenced by AT)P release from damaged red cells and that the platelet change might really be a reflection of red cell abnormalities. Bray (I$) found that coronary heart disease patients hare an ex- xpgerated platelet aclhesireness in response to ADP or ATP. Several studies have sholr-n disturbances in lipid and carbohydrate metabolism in coronary heart disease patients (24, 95, 1%). Kurien (95) postulates that the increases in free fatty acid levels immediately after eitlier an acute myocardial illfilITtiOl1 or ccrehro- VRSCU~RP accident, result from tissue anosia with a secondary cate- cholamine release, which then leads to the increases in free fatty acids. Malhrotra (103) studied two population groups in India. There was no difference in the cholesterol, triglyceride, and free or esterified fatty acid levels bet\j-een the two groups. However, the incidence of coronary heart disease was much higher in the population n-hose diet and fat absorption predispose to an abundance of long-chain fatty acids. A majority of coronary heart. disease patients have an abnormal glucose tolerance test. In most of these patients there is a greater decrease in free fatty acids in response to glucose and a slower return to normal values (24, 136). Solot?' and Schwartz (236) hare determined tKo subgroups of these pntients: one `*_Y", in which the free fatty acid response to glucose resenlbled a nornlal curve except for an rsa,,- ~r(~erntrtl rise aftrr 5 hours: another "B", in which the free fatty acid response to glucose re- sembled that. of diabetics, there being a slower decrease and a sub- normal return of free fatty acid levels after 5 hours. The significant effect, however, is that type "B" patients had a relative hyporesponse of stearic acid (long-chain saturated) decline with a relatively de- creased rise in linoleic acid (long-chain unsaturated) after 5 hours. These findings may be related to the effect of saturated and un- saturated fatty acids on blood coagulation and suggest' further re- search to delineate the specific fatty acids elicited after smoking and in coronary heart disease patients. 33 This section should be read in conjunction with the findings re- rierred in the 1967 report. Experimentn? Studies Xadeau, et al. (119) cnnnulated the sinus node artery in an- esthetized dogs and noted chronotropic c,hanges in response to doses of nicotine ranging from 1.0 to 100 ,.~g./ml. Imranodal atropine abolished bratlyc~artlin and intraliodal l~rol~r:~nolol or llesnnletllonillin abolished tachycardia. Nicotine inllibited the effects of cervical wgus ner\-e stiniiilatinn witliout, modifying the response to intranodall;v injected acetplcholine. Nicotine did not inhibit the effect of stellate ganglion stimulation. These results illustrate the varying effects of nicotine under P'S])~l~illlPlltill contlition:: on tlie c~onil)licatetl netiral and humoral mechanisms affecting heart rate and rhythm. Sleight (1,35) and Bergel, et al. (7') have demonstrated carcliovas- cular depressor reflexes in dogs elicitrcl by nicotine stimulation of the surface of the left ventricle. Studies hare been undertaken in dogs to determine the effect of beta sympathetic receptor blockade by propranolol on the carcliac actions of nicotine. Westfall (158)) Edmundowicz (A'), Papacostas, et al. (116)) Shanks (1.32) and Puri (120) have noted that propranolol can prevent the usual positive inotropic effects of nicotine or norepinephrine stimulation on the m\-ocnrdium as well as the indirect beta dilator effects on peripheral vessels. This results proportionately in a greater increase in left ventricular afterload accompanied by a reciprocal decline of the velocity of myocnrtlial fiber shortening (120). It x-as also noted that resulting unopposed alplia receptor nctiriation by nicotine could lead to increased total peripheral resistance with impaired storke volume and cardiac output. This is further eridence that catecholamines, the release of which is induced by smoking. intrrmetliate the cnrtlio~xs- cular response to nicotine. The effect of nicotine in single and repeated administrations n-as +tlitlietl on tllv tt?l~lllillill \-asc*iil;~I* lml of tile Iwart l)y (`or~ilii. et al. (2;`). lie~iilts intlicntrd that in dogs with intact coronary circnlntions. the single intral-enous infusion of nicotine (1%) pg./kg. lmtl~ weight I' minute) incrcwed both tire left veiitricular capillary blood flow as well as tlie terminal ~ascnlar (`aparity: the c,hronic intramiisriilni~ ;Itliiiiili~tl.;itiol~ (O..Y irig. kg. Iwtl\- weiplit. piwii .7 tilii(+, (LIT for 2 months). however. had no such effect. In Contrast, in dogs with coil- striction of the c~o~~oii:i~~ arteries, iiivotine ndniinistratioii in either (single 01' rcprtiti\.c tloscs) fot2li resriltcd in ;I f;lll of (`~l~)illil~~ 1~100~1 flow lmt ai1 inctrrnse in the tei-iiliilal \xw~il;~r cxl):i(*ity. (`;i~)illary l~lootl flow as measured in these studies represents a nutrient inflow to the niyovartliuni. Sirotine :itIilliili~ti~atiolt rwiltetl in iill increaw in both 34 the \-elocitx of myocardixl shortening as vie11 as the force of con- traction, and these effects: of nicotine are itlentic21 to those of norepine- phrine. In addit,ion, there was also an iiicrra5e in thr rate of left ventricular pressure rise (dp/dt) ant1 a decline in left J-entricwlnr end- diastolic pressure (131). (`olemun, et al. (2,;) studied isolatctl cat papillary n~nwle~ to deter- niilie the mechanism of the nore~~ii~el~l~ri~~e-i~l~l~~ce~l ~tiililllation Of ni!-ocartlial oxygen cowunil)tion. They follntl tllilt ~lol~cl)iiit~l)lll~i~~e does Iiot illcreilstl tlir iiiy0c;irclial ticdue ox?pll clel~l;llltl 11111t?+ COll- tractility is increased, otller facstors being held colM;\llt. Sorel)ine- l)llrille i, known to increase m~oc:\r(li:~l contruct ility. FurtIler studies (49. 1-14) on anesthetized ol)ewchest dogs to deter- mine the relative inflnenc*e~ of cli;tiigi~ in eitllcr tile colltrac.tilc state or in ten,4on dewlopn~ent on m\-owrdinl t irsur 0syp11 wnwmpt ion, intliwte that both are signifiwnt filCtOrS. Has;11 osygeii wqIlirenlents, :lcti\-ation energy, and the cwt of contrnc*tile eleillent ~hortrning :piiis;t ;L loatl :lppe:w to inflnencc i11\-ocartlial I iaue osygelr cyol~s~llllp- tion to :I lesser degree. (`hitl*y, et al. (21. ;?2) Stuclied the relation-hii) of llorcl)iilcl)llrili~~ to heart failure and the functional state nf tlie liunl:~n n~yoc2rclium. They reemphasize the role of norepineI)lrrine iii nlterity ilryacardinl fiber length and contractile status as delll0llStl7ltf?d ill lllu~l~111 left ventricular papillary muscles removed from patients i\t the time of mitral rxlre replacement. *lyres (4) has noted products of anaerobic cnrdinc nletabolism in dogs made ischemic by exposure to ~~IIGOI~ monositlc. Tlleie will be presented in a subsequent section of this chapter. Weisslrr. et ;\I. (1.X)) in experiments with isolated perfused rut hearts, have rrl)ortetl on the importance of glucose as a substrate for anaerobic nietal)olism of the heart subjected to anoxia for SO minutes. When glucose was added to the anaerobic perfusnte, the electrical and mechanical performmic~e of the heart improved markedly, as did the recovery of the heart dur- ing the subsequent period of reos?yenation. Lactate pro(luc~tion was fivefold greater in the glucose-supl)orted nnosic Iwart th;tll in the nnosic heart without glucose. In similar fashion, niorpllologic cli;lnpes of the mitochondria ancl longitudinal tubules of tile ;lilOxic* lleart noted 1)~ electron microscopy, were averted by the illclll>iotl of plllcwe ill the perfusion fluid. This experiment suggests tllat glnc~w nlight hell) trnil)ornrily to prevent niy)wrtlial infarct ion, cnwetl by relative myocnrdinl anoxia, b3 proriding 8 substrate for ail;ierol)ic* (`:l~tliilc' met.&01 ism. The isolated perfused rat heart W:IS also stlltlietl 1)~ Iira~l~frltl, et al. (I.?) to cleternline the eflects of nicotine on l~so~oii~al, ~~iito~Itoi~~li~i;~l. :llltl supernatant enzpic systenis of tile myoc:~r(linlrt. Tlwy .snggested I tllnt Ilicotine toxicity may be esl)reswd ill ternis of (1;1111ilF(' to tile 35 1ysoson~a1 membrane and the cell wall. Shibata, et. al. (IZB?) studied the. ;~(Lt ion of nicotine on tile transmembrane potential and contractility of isolated rat ntrin. They suggest that while nicotine may influence nrembrane electrodynamics, there, may also be a direct action on the contractile mechanism of the cardiac muscle cell by changing the duration of the action potential, which implies alterations in potassium fluxes. Sicotine-induced cahanges, in dogs, in action potentials and conduc- tion depression, with enhancement of Purkinje fibre "automaticity," may lead to the development of ventricular fibrillation (.50). Post myocnrdial infarction dogs were much more sensitive to the adminis- tration of nicotine, as measured by electrocardiographic changes, than were normal dogs, especially in the acute stage of myocardinl infarc- tion (6). Webb, et al. (154) state that changes in fibrillation thresholds after riyxrette smoking noted in dogs, by analogy, "may have relevance to the higher incidence of coronary deaths without increased incidence of angina in cigarette smokers." 8 fu.iPs in Wumans The 19Ki report noted that sudden death from previously undetected coronary heart disease appeared to occur frequently among cigarette smokers. Kuller (94) showed in a study of sudden death in Raltimore that arteriosclerotic heart disease was a major cause (61.4 percent) of tleath. Ko smoking histories were recorded. Luke, et al. (99) reviewed 275 consecutive autopsied cases of sudden unexpected death from natural causes? in individuals age 20 to 4,5 years, and noted that asymptomatic. coronary artery disease comprised 28 percent of the causes of snclden death. AgainY no smoking data were taken. Data t)ooletl from 10 studies available to Rurch, et al. (17)) indicated that, ~ardiornscnlar disease accounted for BI percent of 8,151 adult sudden deaths. Present. clinical evidence. indicates that ventricular asystole or fibrillation may be the mechanism of sudden cardiovascular death in most. cases. It is known that hypoxia, hypercapnia, isrhemia, elec- trolyte, disturbances, and increased catecholamine activity all can predispose to ventricular fibrillation. From available physiological rvitlence noted elsewhere in this and the bronchopulmonnry clrapter? ~1~1 also in the I!IG'i Report, it would appear that smoking can directly or indirectly contribute to the development of these predisposing con- ditions. It is well accepted clinically that ventricular, nodal, or atria1 premature contractions can be increased or induced by cigarette smok- inF, as well as by other factors, and ~11 be retlttced by the cessation of caiprettc smoking in both normal and ischemic hearts. These pre- nlature (*ontractions are frequently prec~nrsors of their resl)ec$ivr t:lc,ll?c~:iI.fli:Is. .Ilso, a l)erson with an acute or impending nlyoc~ardial infarction subjected to the sympathondrenal effect of snmliillg cor11d 36 more readily develop a fatal arrhythmia (75). The relationship of smoking to cardiac arrhythmias must be studied further to determine more exactly both the physiolo,q and the mechanisms involved in sudden deaths from cardiovascular disease. Iierrigan, et al. (74) studied cardiac output in both smokers and nonsmokers vho had no evidence of coronary heart, disease and found rises in cardiac. output in response to exercise and to cigarette smok- ing separately and then in combination. They note that the total increase in cardiac output appears to be t.he sum of the exercise and the smoking effects, Smoking may create an additional myocardial tissue oxygen demand above and beyond the demand attributable to exercise. Moses, et al. (105) reported that pretreatment of healthy normals with glucose blocks the increased cardiac output response to cigarette smoking by inhibiting the increases in stroke I-olume but, not heart, rate. Frankl, et al. (&) noted that after 5 nornlal male chronic smokers were given propranolol, cigarette smoking caused a significant in- crease in systemic blood pressure and a significant decrease in cardiac output. Thus cigarette smoking after propranolol administration may be especially hazardous. Yanuwnoto noted similar results (160). Sen Gupta, et al. (130) studied 11 ischemic cardiac patients and 14 healthy controls for abnormal ECG changes after smoking one cigarette and noted specific or nonspecific changes in almost all of the cardiac patients as compared to few changes in the healthy smok- ers and no abnormalities in the healthy nonsmokers. Pentecost, et al. (117) studied the acute effects of cigarette smoking in patients with angina or post-myocardial infarction as compared with normal con- trols. Sormal men and those with angina in the absence of infarction beha\-ed similarly with an increase in pulse rate, mean pressure, stroke volume, and cardiac output. The majority of the patients among the post-myocardial infarction group showed a marked fall in stroke volume and cardiac output while smoking. In another study (.&?) to evaluate the interrelationship of smoking and exercise effects on cardiac output, a fall in cardiac output that, occurred in some post- infarction coronary patients as a result of smoking alone was noted. Also noted were decreases in cardiac output after smoking and exer- cising as compared to post-exercise cardiac output in the same patients before they smoked. Starr (139) suggests that the ballistocardiographic (BCG) find- ings in cardiac disease and after cigarette smoking may luovide ~alunble information about the rate of accelerat,ion of myocardial contractile velocity that cannot be deternlilled by studying cardiac output or stroke volume alone. h disease,d heart has a slower accbelera- t,ive rate of contraction. BCG abnormalities have frequently been 37 related to cigarette wmking in subjects with or without heart disease, iii(~ludiiig angina 1)rc~toi.i~. The IK'G findings of ~Jackson, et al. (68) indicate that tip:lrette wInking itself may have acute and chronic h:lrnlful effects on nlyocnrtli:tl function, since duration of smoking was also correlated xith certain abnormalities. Gazes, et al. (47), 13ral~ll\ri~ld, et al. (1.1), and Rlensch, et aI. (91) ha\-e folliA higher plasiri~ iio~el~iiiel~llriile levels in coronary lwtients at. rest aid after sniokiiig 2s compared to normals. I111)1)1~. a11t1 the hip11 energy output of heart muscle as compared to skeletal muscle may make the myoglobin impairments by carbon monoxide of possible etiologic importance in cigarette smoking and llwrt disease. 315-131 O-684 39 Hydrogen cyanide appears to be rapidly conve,rted to thiocyanates by the body, but, the absorption by the lung of cyanide from cigarette smoke might. possibly result. in higher serum cyanide levels in the coro- nary arteries than in the systemic circulation. As noted in the 1964 Report, the cyanide ion is capable of stopping cellular respiration abruptly through inactivation of cytochrome oxidase. In sublethal exposures, the cyanide ion is gradually released from its combination with the ferric ion of cytochrome oxidase, converted to thiocyanate ion and excreted in tire urine. ThiocJnnate blood levels in smokers are three times higher than in nonsmokers and relative differences in urinary excretion are even more pronounced. Cytochrome oxidase is very im- portant in cellular respiration of all body cells. In view of the ex- tremely high myocardial cellular needs for aerobic metabolism? it is possible that the cvnnicle ion inactivation of cytochrome oxidase also can occur in myocardial cells and be of critical importance, especially in light, of other risk factors such as impaired coronary blood flow, the carbon monoxide effect, and the known increases in myo- cardial tissue oxygen demand caused by the smoking/nicotine-induced catecholamine release. Further research is needed to determine whether or not cyanide ions in concentrations equivalent to those found in cigarette smokers, have a harmful effect on the myocardium, in terms of both acute and chronic exposures. Glucose Metabolism and Possible Cardiovascular Effects Epstein (37) has reviewed the relationships of hyperglycemia to coronary heart disease. Although he states that there appeared to be no relationship of cigarette smoking to the hyperglycemia that was associated with the prevalence of coronary heart disease in the Tecumseh population, Higgins (63) reports that the Tecumseh ciga- rette smokers, both male and female, had approximately a 10 mg. per- cent elevation in blood glucose as compared to nonsmokers, although the percentage elevations above the median levels were not statistically significant. Since Epstein (39) reported that cigarette smokers in the Tecumseh study population had a higher incidence of coronary heart disease, it would be interesting to see what the interrelationship of the incidence of coronary heart disease is to the cigarette smokers who hare elevated blood glucose levels. Cohen, et al. (2'4) have reported abnormal glucose tolerance in some postinfarction patients, suggesting the possibility that this group has difficulty utilizing glucose. It is known that smoking induces release of catecholamines which can create an increased demand for glucose by the body. Wahlberg (152) had noted that in patients with atherosctlcrotic dicense but n-ithout clinical diabetes mellitus, the glu- cose tolerance n-as pathologic in 46 percent as compared with 10 per- cent of controls, and normal in 33 percent as compared with 71 percent 40 controls. From this he infers that subclinical diabetes mellitus may predispose to vascular disease in the same way as clinical diabetes mellitus. Kingsbury, et al. (8.9) studied a small group of male patients with peripheral arteriosclerotic disease to determine the serum glucose, non- esterified fatty acids, and immunorenctire insulin responses to sub- cutaneous adrenaline and to smoking. I'nder basal conditions. the fatty acid response was normal. Vhile adrenaline consistently caused a rise in serum glucose. cigarette smokin, w either had no effect or lowered the fasting concentration. In 5 patients smoking caused an elevation in the immunoreactire insulin which could not be explained by blood sugar changes. The implication is thnt these patients were hypersecre- tors of insulin. l?nfortunately? detailed smoking histories are not available for these individuals. Szanto (I@), in a very small study of habitual smokers, noted a `.IY-l'erinsulinism?' response during oral glucose tolerance testing after smoking two cigarettes. This response aas markedly reduced when tile test was repeated after a 14-day absti- nence from smoking. The view that h~perinsulinemia is associated with atheropenesis has been suggested (114. 118, 14.!?! Iti7) and dis- cussed by Mahler (102). If smoking directly or indirectly causes a hyperinsulin response in some individuals, then this may possibly be one mechanism by which cigarette smoking may enhance atherogenesis. Kershbaum, et al. (8(i) have noted higher plasma ll-hydroxy cor- ticosteriod levels in smokers. Whether the "hyperinsulinism" reported to be present in smokers is related to increased adrenal corticosteriods remains to be determined. Hyperinsulinism could be a response to the frequent catecholamine-induced hyperglycemia caused by cigarette smoking in individuals without. significant clinical or subclinical coronary heart disease; but conceivably the hyperinsulinism response might be more pathological in coronary patients. Also, the potassium and other ion changes caused by glucose shifts in response to shifts in insulin levels may predispose, to cardiac arrhythmias and sudden death. Addition& Considerations Regarding Coronary Blood Flow Coronary blood flow, besides being influenced by the size of the inner lumen of the coronary vessel wall and its ability to dilate for the purpose of increasing flow of oxygenated blood when needed by heart. muscle, is also dependent upon the viscosity of the blood (IG). The concepts of fluid mechanics, such as laminar or turbulent flow, are well known. For any given aperture and pumping pressure, fluid flow will depend somewhat upon the physical characteristics of the fluid itself. It has been demonstrated in both cigarette smokers (1%)) and in patients with myocardial infarction that llemoconcentratioll occurs (15,137), sometimes to a relatively small degree, ill terms of absolute changes in hematorrit, but the changes in viscosity are much greater 41 than niight hare been predicted from consideration of hematocrit changes alone. *It this point, other factors related to fluid mechanics also enter in, such as the quality and amount of lipids in the blood. Burch, et-al. (15) hare demonstrated that increased fatty acids in- crease the force necessary to "shear" the blood, thus contributing to a reduction in the capacity of the blood to flow in laminar fashion through a given aperture. When coronary arteries are impaired by partial obstruction of the inner lumen or by decreased distensibility, there may be a critical interaction with blood viscosity causing marked turbulence of flow and thus reducing further the potential for increas- ing coronary blood flow. additional evidence has been presented which tends to confirm and extend the positive findings previously reported in the 1964 and 1967 reports. 1. Epidemiological studies show that "heavy" cigarette smoking is strongly associated with an increased risk of dying from coronary heart disease. 2. New data confirm and help to clarify the relationship between cigarette smoking and other "risk factors" in the development of coronary heart disease suggesting that both independent and inter- acting effects are involved. 3. Evidence indicates that cigarette smoking may accelerate the ~~at~liopl~~siologir:~l (`11at1ge*s of pre-eXi.Qcllt co~ronary 1lPill.t disease and contribute to sudden cardiovascular death. This relationship helps to explain why stronger epidemiological correlations between cigarette smoking and coronary heart disease tend to be found in incidence studies rather than in prevalence studies where the population is under-represented for those people who hare had fatal outcomes from coronary heart disease. 4. Present evidence continues to support the position that giving up cigarette smoking is beneficial to cardiovascular health. 5. Some progress is being made in the study of the interrelationships of selected 1)syclwlogical factors, smokin g behavior, and the develop- ment of coronary heart disease. Recent data provide a basis for the formulation of a theoretical concept by means of which it is possible to correlate the interaction of w-era1 known co1~o~lilr~ heart tlisende ri.5k factors with the ~~hysio- logical mechanisms 1)~ which cigarctt(b wlokiiig nl:ly ilffP(`t tllc niyocardiuni. The epidemiologic~al studies continue to indicate that "heavy" cigarette sniokinp is strongly associated with a fatal outcome from coronar;v heart tlisease. This fact may be accounted for by a mechanism 42 whereby, in the presence of impaired coronary circulation due to coro- nary heart disease, cigarette smoking may "trigger" myocardial oxy- gen deficits of critical degree. One or more of the following mechanisms may be involved in this process : 1. The increase of myocardial wall tension aud velocity of contrac- tion, largely mediated through norepinel~hrine released in response to cigarette smoking, thereby increasing the myocnrdial demand for oxygen and other nutrients. 2. The relative reduction of nutrient capillary blood flov in the region of the m\-ocartlium distal to and dependent upon blood flow through a p;lrtiaIIy occluded coronary artery. 3. The impairment of oxygen dissociation from hemoglobin due to the formation of carbosyhemoglobin from carbon monoxide, thereby diminishing the a\-ailability of oxygen to the myocardium. 4. The reduction of the sul)ply of oxygen available to the myo- cardium as a consequence of hypoxemia due to severely impaired pul- monary function from chronic obstructive bronchitis. 5. The impairment of coronary blood flow as a result of the in- creased blood viscosity associated ATit h~perlipemia or hemoconcen- tration. 6. The increase in platelet adhesiveness which might contribute to thrombus formation or coronary occlusion. 7. The predisposition to acute cardiac arrhythmias as a consequence of harmful neurogenic reflexes or catecholamine release. 8. The possible, although presently speculati\-e, contributions to impairment of myo'ardial cellular respiration by cyanide ion. Thus, the interaction of the factors which decrease oxygen supply to the myocardium and those which increase the myocardial demand for oxygen may play a major role in precipitating the fatal outcome in some individuals with coronary heart disease. On the other hand, it is possible that the same factors, in less severe clinical circumstances, could precipitate temporary coronary insufficiency or contribute to nonfatal myocardial infarctions or cardiac arrhythmias. The pathophysiological factors associated with cigarette smoking may further interact with other known epidemiological risk factors associated with coronary heart disease such as high serum rholesterol and high blood pressure. Although not a "risk factor", unusually high physical stress may also create l~hysiological demands for additional oxygen supply to the myocnrdium. The finding that those who discontinue vipnrctte smoking ha\-e :I lower risk of dying from coronary Ileart diwnse tlwl those w-110 con tinne to smoke might be accounted for 1,~ the potential reversibility of many of the p~~tl~oph~siolopicnl eflect5 of smoking on the cnrdio- vascular system. It is reasonable to expecbt partial rever+ibility of factors that interfere with oxygen supply, such as the carbon monoxide 43 effecxt? anti the increased platelet adhesiveness, hyperlipemia, and hemo- concentration noted in cigarette smokers. Moreo\yer, the increased myocardiaI oxygen requirements associated with the cigarette smoking- inducetl c~:~techolanline response and neurogenic reflexes could be expected to be eliminated upon cessation of cigarette smoking. In some patients, the cardiopulmonary benefits of stopping smoking may reduce pulmonary hypertension. An increased ability to predict future cardiovascular events in individual persons will depend upon more precise definition and measurement of the pathophysiologic factors associated with ciga- rette smoking and their correlation with information about the epi- demiologicxl risk factors. Because of tlw increasing convergence of epidemiological and physiological fintlings relating cigarette smoking to coronary heart disease, it is concluded that cigarette smoking can contribute to t'lle tlevelopnlent of cardiovascul:~r disease illid particularly to death from coronary heart disease. ShIOT. J. Height, weight, and ponderal index of college male smokers and nonsmokers. Journal of Psychology 64 : 101-108. Septembrr 1%X (6) &XLkT, s., KERSHBAV11, A., ~IEADE, R. II., *JR., SCHWARTZ. 1,. Th? PffeCt of tobacw) smoke ant1 ni(.otim 01) thcb n11rm:11 Ircbart :)i)d in tht, l)re+ell(`)* of mywardial damage produced by coronary ligation. 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