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« 0 Smo~Ci'~ng and Ca~d'~iovascolar Disaases. COUhY'J. SCHWARTZ AND HENRY C. McG1LL. JR.. Departrnent of Pathology The University of Texas Health Science Center and Departrrtentiof'Cardiopulrnonary Disease Southwest Foundatiomfor Research and Educationi San Antonio, Texas 78284 WALTER R. ROGERS Department of 8'ioengimeenng Southwest Research Institute San Antonio, Texas 78284 __ The mid-l!958i+ saw a growingconviction that lunz cancer and cigarette smok- ing are causally related. This concern cultninuted in ii landmark reports. one from the British Royal College of Physicians (J96'2 )2) and the other from an~ Advisory Committet. to the Surgeon, General! ( public Health Service 1964). In the former, it was concluded that ci:_arette smoking is indeed a cause of lung cancer: and in all likelihood' contributes to the devzlupmeno of coronary artery disease. The report of'the Advisory Cmmmicee to the Surgeon General, was conclusive. It, noted a, greatly incrzastd' mortality in male smokers,, together with a signi'Gcantlw• enhanced mortality from coronary ;utery di.ease. While a causal~ relationship between cigarette smoking and lung cancer was defunitive, the causal nature of the relationship between coronary disease and cigarette smoking was adjudged to be mar__inal and therefore scientifically inconclusive. T'he early failures to detect any clear causuil relutiunmhip betWeen~cigarette smoking and heart disease may retlert both the greater preoccupation at that time with lung cancer and the heterogeneous nature of the cordnary arteryy disease syndrome. Ut is interesting to note thnt, even in the Framincham Study (Kannel et al. 1'968'), the: early data showed only a relationship between vital capacity and ci_arette srncnkine. This shortcoming lias clearly been remedied in subsequent reports. tJndtrtitundine the nature of basic mechanisms that might link cigarette smokim_, to the development of various cardibvascul5r diseases wilL we believe., gixe us the ability to develop in s logical manner multiple levels of intervention needed to dii;suade al population to desist from cigarette smoking or to accept less palatable cigurettes: In this discussion we will de,cribe the various categories of'cardiovarseular di'se:ue, emphasizing those pon.,ihly influenced by ciiz:,+rette smoking. Addi- tionally. we shall attempt to cnutlinc the nature of' the relevnru' lesions utd! the basic meehani.rtts through which ,ntukin__ might intDitrnce pathogenesis and then discuss a cig•rrcttr-,muking mudcl' in the nunhumun primate. kuPiv cynr,tcrphultrs t i i ( 1005053103

0 s ,. . E21 C.J.' Sehwairtz, Ht:C. f4teGilt, J.., and VV.R: Atogers CJl1TEGaRf ES OF'CARDf 0VA5CULAfI'DISEASE The four principal categories of'cardiovascular disease upon which ci¢arette gtttoking might have somc acceleratin= or adverse influence are cardiac. disor- den of the peripheral' circuJation; strokr, and venous thrombosis: Within the cardiac category there are four subr:ategories, narnely, angina pectoris.. myocardial infarction. sudden cardiac death. and' cor pulmonale. The latter is listed simply bet:ausc of the undisputed role which cizarette smoking has in thee development of chronic bronchitis and'emphysema. Myocardial infarctimn, on the other hand. is associated' not only with, severe coronary atherosclerosis, but also with a vsriable degree of cardiome~_- aly, and, in parrticu'lar, with a high frequency of occlusive coronary artery thrombi, Coronary artery thrombosis accounts for in excess of 90% of cases of recent transmural infarction (Chandler et al. 1974'). Itt transmurai infarction, it is the presence of occlusive thrombosis that distinguishes this condition from both, angina pectoris and subendocardial in- farction. Factors, such as sm,,kin_, that might modify the origin or develop- ment of transmural infarction, may do so either by irtlitencing mural diseasee that is, atherogenesis, or, alternatively the prrocess of'thrombogenesis. Sudden unexpected cardiac death (SCD) has been the subject of a number of recent reviews ( Prineas. and Bll:uieburn 1975). Of particulnr importance is the growing realization that only approximately one*third! ot• SCD~ cases are associ- ated with traditi'onal myocardial infarction (Schwartz and Walsh 1i971). Of patients dying suddenly who were subsequently successfully resuscitated, only approximately 40% exhibited enzymic or electrocardioArzphic evidence of in- farction (Cobb et al. 1975). AJthou_h patients with SCDlfrequendy exhibit the traditiional! formula for ischemia~ namely large hearts and severe coronary atherosclerosis, they show a not unexpectedly l'ow frequency oi occlusive coronary thrombi' (Schwartz et al: 1975),. A variety of' other mechanisms potentially leading to SCD nted careful evaluatiion, including the roles of platelet' microembollsm, disturbances of the cond'ucting systera or its 'L. lood supply, intramyocardial small vessel disease, and other nonischemic causes of myocardial injury. Other categories of cardiovascular disease of particular relevance to this discussion include disorders of the peripheral circulation, cerebral infarction and transient ischemic attacks, and the important disorder of venous thrombosis with its serious thromboembolic scquelae: Disorders of the peripheral circula- tion~ include the clinical syndrome of intermittent claudication (c.f., angina pectoris)iand peripheral gangrene. Buerger's disea_se (also known as thromboangi'itis obliterans) was tint described in 19016 and has been the subject of much dtbate: Clinically the syndrome is contoned to the lower limbs, with thrombosis involving bothh arteries and the neighboring veins. This interesting though uncommon di,csse occurs predomin;uotly in young males and almost inkariubiy inih+r.tvy cigarette smokers. .1•• ~KCnrrierinn whirh n.r..nrnfn.A L"......... 'Fte.tn. ... ..... .V_. •.1 Aft '~l+4' 100Sll~W31~ 11

0 Smoking and IGardiovascular Dis.ases 168 Stroke, like disorders of the heart: is indeed a heterogeneous complex including intracerebrul' hemorrhage, infarction. subarachnoid hemorrhage. attd' ttansient ischemic attacks. lntracerebral hemormaLe, in most cases. is directlyy attributable to rupture of the lentuculoytriute arteries, occurring on the basis of bo6 hypertension and smsll miliary aneurysms. resembling ;trinus of heads. first described by Chsrcot and Bouchard (12365). The pathology of cercbral' infarction in many rcbprcts is similar to, that of myocardial infurction. ylb~t cases of infarction result from thromboatheroselerotic occlusion. but embolic obstructimn and hemodynsmic or low output crises are also of' pathogenic significance. Transient ischemic attacks may uncommonly be due to the combination of arterial stenosis und!recurrent but transicnt reductions in cardiac output or blood pressure (Enstcott et al: 1954). More commonly, however, they result trom atheromatous or thrombotic emboli arisirr_ either in the aortic arch or ccr••ical arteries as the result of plaque ulceration or the fragmentation of murul thrombi. Venous thrombosi,, occurring most frequently within thc deep leg % cins. is a major source of pulmonary thromboembolism. Venous thrombi' ori._inav: within the valve pockets and extend both proximally and distali.v, the fragile extensions being predmminantHy a coagulum of blood or clot rather thun al thrombus. It is these proximal extensions that fragment and cmbolize to the pulmonary arteries with a significant morbidity and mortality. CAUSA!'. RELATIO'1`']SHIPS'AMbMG,SELECTED CARDIOVASCULAR i9ISEASE'EIND POIIUTS AND CIGARETTE SMOKING In Table I our interpretations of'the relationships amom= cigarette smoking and selected disease end points are summarized. These relationships are reviewed in detail in a recent report of the Surgeon Gzneral!(Public Health Service 197y). It is, apparent that cigarette smokinL, is si_~niticmttly related& to the three major components of cardiac di,ense. namely antiina pectoris. myocardial inturction. and sudden cardiac death. In the former two cateaories. the as1ociation, are significant for both rnules and itmales, while for SCD the di,ta do not permit discrirninatipn between thr: sexes. Athero-cliero.is veverity and cigarette .mcnk- ing are sienifiicantly correl'uted in male.,. but in: femal;:snrt adequate data are available. Stroke is n~ hetcrm_cneous di.e;Lse complex that encmmp;Llses a number, of' disease end points including intru:crebr.,l hemorrhaLe: sub;u-achnoid hemor- rhase, cerebral int'arction. and tr.ut.icnt i,chernic ;tttucka. It is theref'bre not surprising that the relationship between cuprette +moking and stroke is incun- cltuive. This relation.,hip may be cl:uitiwd by refining the clinical dixusc end points in future rewsreK ctliirt.. For one ot' the stroke c:,tcg0rie+, namely transient' ischemic uttuk.,,, the data are regrettabl;v inadequate. There appe:uN to be little doubt about the correl•rtion, hetwcen ,mokiinL snd uhirum- boathero.clerotiic periphersl.•a+cular di.eu.+e. and b;:tHUcn, smoking and. : '

Table 1 Causal Relationships Among Selected Cardiovascular Disease End Points and Cigarette Smoking Consensus on relationship to cigarotte smoking positive negative - - Inconclusive. Nature of disease end point Sex with adequate data with adequate data confiicting, or Inadequate borderline . data Angina Ixaxturis M 0 Myocardial inf•rrction F M ~ Suddcn cardiac dcath F O 0 Athcrosclcrwis M ! Stroke F M 0 Trrnsicnt ischemic attacks F a • IlucrEcr's diseasc Periphcral vascular discasc Athw-rosclerotic aorti_c ancury.m Venuus thromtxx:.mlxwlic di.cst.c M ' M F r 'Puaaibk• infcrwtiun bctweca .muking and hinh 4.4nNrol piftz. - 9O14SUSUQT . . t ! I

Stnoking and Cardiovsseulir Disensesd 8S exclusively to males, also shows a stronc correlation with c't=arette smokinL. Data linkin, venous thrpmboernbolic disease and cigarette smokin_ remain. inconclusive (Table 1). This area cleculy requires intensiticatiom off aesearch efforts. It is also of interest that orall contraceptives and cigarette smoking may inter,tct'in tnhancinc both arterial and'venous thrombosis. ,~.. " MECHANISMS U111KIMIG SMOKING AND CARDIOVASCULAR DISEASE We are convinced of the need to explore and understand basic mechanisms of disease. Bwg outlining selected'disea_se end points and their principal components of -watho_enesis. we should be able to determine the potential basic mechanisms through which cigarette smoking might influence pathogenesis. The tive prin- cipal components ot pattiogznesis that have been identitied are atherosclerotic narrowing. arterial and venous thrombosis, cardiac anrhythmias, arteritis. and microembolism. Basic mechanisms throuph which cigarette smoking might influence thee process of' atheroeenesis include effects on lipoprotein4 cholesterol, and lipid metabolism: endotlieliai str~,tcture and function: arterial smooth muscle cell proliferation and connective tissue synthesis: the platelet release reaction: monocyte-macrophage function: and cellular and humoral immune systems. Aspects of this complex problem hah,ebeen recently reviewed by McGill e! al. (1978); In the pathogenesis of either arterial or venous thrombosis. ci_•aretrtz smoking is most likely to exert its influence via prostacyelin-thromboxarte generation, platelet-vascular wall interactions; endothelial injury. altered coa,-,u- lation and hemostatic mechanismse or disturbances in the immune system. In SCD ventricular fibrillation is an important intermediary mechanis= It appears that a number of basic mechanisms possibly influenced by cigarette smoking may be involved in the development of the lethai arrythmia5. These include ischemic rnyocardial in;ury, coronary artery spasm. damage to or functional! disturbances in conducting tissue, and' an altered ebectrica4- physiolocical! role of agents released by platelet microemboli in the microcircu- lation, either in, the genesis of focal areas of vasospasm. or in modifying myocardial excitability. Peripheral vascular disease has as its basis tlirombo-atheroselcrotic dis- ease: Basic mechanisms in%oived in its evolution ~nd upon which smoking might exert some influence :ue essentially similar to those for atherosclerosis or thrombosis in other parts of the circulation. Additionally microemboli of either an atheromstous or thrombotic origin may play an important role in .smme cases. Such~emboli :tre most likely to arise from ulceration or mural thrombo.is in the aorta or ilio-temorall artcrics: One special category of pcripher.tli vascular disease. Buerger's dises,e, iti clearly a nonatheroaclerotic di,order. but rather a vasculitis involvint both arrteries and veins associated witlt a migratory thrum- bophlcbitis: The two esatntiall component, in p•rthueenesi, are artcriti, and thrombosis. Basic mechani,rns, po,,ibly linking , +mukin__ and this dii.<order' include an abnormtal hypersensitivity in, some indiividuul. to tubaccu __lyticupro- s.

M - 861 C.J. Schwant3, H.C. McGill, Jr:, and'W:R. Rogers ' tein together with disturbances in the immune systetn+ abnormal platelet func- tion in association with elevated carbuxyhemoelabin ('COHa) levels (Binvtin~_1! et al. 1971), and eadothelial and vascular injury. Why this disorder is almost exclusively the domain of the young male also needs critical appraisal- The patho,renesas of transient ischemic attacks in most cases is n:eurrent microembolism. Basic mechanisms of relevance; therefore. are not only those associated with atheroCkenesis and thrombocenesis. but also with the processes of plaque ulceration and the fragmentation of thrombi. Thrombus~ instability includin~_ the contribuoion of fibrinolysis might therefore be important in the origin of platelet mictotmboii. since ti~brin! t..rmally, hhelps wstabiliize thrombi!. It is difficult to identify mechanisms where! sr^okin_ might evem remotely facilitate plaque ulceration. The role of smoking in the modif catiian of both hemostatic and coagulation mechanisms is much Iess remote. SOME ASP'ECTS'OF CURRENT SMOKING RESEARCH With ciparette smoke cmntainin8 im excess of several thousand pqtentially noxious components (Publir Health Service 1979). aad with the habitof smoke inhalation, being a uniquely human practice. experimental studies: on the rela- tionship between ~ cigarette smoking; and cardiovascular disease pose numerous design and conceptual problems. We have undertaken studies of this relation- ship by developing a model to simulate the human exposure. Emplioyin¢g operant conditioning techniques. baboons (Papid eynoeephulus) have been trained to smoke cigarettes in a manner not dissimilar to their human courttzr- parts (McGill et al. 1'978; McGill and Rbgers 1980). With, this approach, we are currently studying the influence of prolongFd periods of cigarette smoking on selected' cardiovascular and respiratory disesue end points. together with a number of relevant intervenin8; variables. In terms of disease end points, atherosclerosis is a: maj:ir emphasis. Variables. selected because of their rrele- vance to basic pathogenic mechanisrtts, that are being examined include lipo- protein„ cholesterol, and Iipid levels: plutelet. leukocyte; and lymphocyte dy- namics; plasma factiorrVlIl levels; myocardial and endbthelial ultrastrnecture: grewth and'behavior of'arterial, smooth muscle cells in culture; and the response of smokin¢ and contro'4 animals to a purified tobaccp gly,coprotein. ) Additiional studies are iniprogrets to evaluate thc~intluence of acute (2-hr) rigarette smoke inhalation on endothelial' strveture and function as stuciied' by both transmission and scanning electrom microscopy, lipid and lipcnprottin ehanges, and selected indices of the endocrine response. Tabie 2 summarizes selectedi mc:ut, dosimetric indicators of smoke rxpo+ sttre for two periiods, nameiy weeks 94-1IS and. 176-179. of a 3-year experiment (W. R. Rogers et ai.. in prep. ). The animals smoked more than two packs of cigarettes per day, resultin8 in signitnc•,utt thouFh modest zlevatiuns of blood ruboni monoxide (CO), pl;t.,ma thiocyanate, and urinary cotinine le%els. The blood CO levels presented' in, Tablc 3, correspond to a percentage COHb

. Table 2 s Selected Physical and Chemical Dosimetry Measures ofCigarette Smoking and Control'Baboons Duration of smoking i Cigarettes per day Put3` %olume tml) CQ 1(mIYd1) Pjasqna thiocy,anate (µg/ml) l:riiiatytotinine lµJm1D 42.9 .3513 0.24 4.80 i 3.49 42:7' 46.0 -16,7 39.0 47.0 50.0 0.08 0.22 0.08 1.66' 4'.s0 2.24 0.62 2:,S 0.23' As indicated in Table 3. the mean serum total cholesterol. triglyceride. and very low-density lipoproteins plus low-density lipoprotein cholesterol le:elis of smokers were less ;than those of'shams, but the differences are not stati5ti- callysignifbcant. The hi_h-density IGpoproteincholesterol' levelsofsrnokers s were reditced (P < 10) compared to ihose of'shams. Fasting blood slucose leveis of smokers werr si=ttil'icantiy grcater (P < .05) than those of sh:uns. Several selected hematologic characteristics of smokers and sh3ms~ are given in Table 4. Cigarette smoking baboons exhibiteti, a sdgnificant (P < .05) leucocytosis and differential cell counts ittdiicatedl that this response was largely atttibutable to a, tyrnphocytosis. The platelct counts, hemoglobin levels; and hetnatocrits of'smokers and shams did!not differ signifcantly: Table 3 Serum Cholesterol, Triglyceride. Lipoprotein, and Fasting Blood Glucose Concentrations in Cigarette-Srtnoking and Control Baboons Mean selected Experimentai category response variables (weeks 1i63-179) smokers shamismakero Total cholesterol (mg/dll 1'53' 165 Triglyceride (nd/dl) 51.8 56.3 VLD'L.' + LDL" cholesterol (mg/dl) 53.6 58.7 HD'L''chulesterol (in8/dl) 90:7 99.8' Fs+tins blood eluco%c lmvldlD 95.0 89.8 •V ery 1uw-deasicy lipopnxein: 'Low+density lipupnuhin. 'Hi}k-dtmity tipopraein.

«. !8TCJ. Schwartz. H.C. IWeG7c, Jr., and W.R. Rog.rs Tabla 4 Selected!Hernatohogic Characieristics of Cigarette Smoking and Control Baboons ~ Mean hematologic response variables L. ukocytes (11IU'/mm') Lymphocytes (10'7mm') Platelets (11b'Imm') Hrmoglobin (tidl) Hrmauocrit ( K ) smoker . 7.59 5.56 289 12.9. 38.8' sham i smoker sham 6'.42 8.28 7.92 4.02 - - 278: 298 279 12.8 13.5 13'.3 38.6 40.2 39.8 Factor-VIQ1 levels were signif cantly reduced! (P <' .05) in cigarette smok - ing, baboons (Table 5). These preliminary findines may ind'irettly indicate an influenceof ci;arettesmokins on vascular endothelium. Further studies will hopefully clarify this interesting point. In sumrnary, we haxc used operant conditioning techniques with the baboon to provide a model sxctem in which the effects of cigarette smoking on cardiovascular diseases, can be studied' ezperimentally. Our, initial' results con- firrm that the b•rboon, is a human-like model for such study. Future studics should provide valuable information on basic mechanisms lunking, ~,moking and eardiovascular diseuses.. ACKNOWI.EDCl1REPITS This research was supported. by grant HL-19362 from the National Heart. Lung, and SloodJnstitute. Table 5 Factor-Vlll Leveis After 3 Ye1.rs of, Cigarette Smoking Experimental category R Mean factor VII M of, human level) Smoker Sham smoker 1a 16 238 307 Facur-VI11 a+rva imclcn+l en hv D.T.S': Timmermrm. Seripps Clinic. San, DieYt+: uxine

Stooklny andiCkrdiovascular Diseasesd 89 REFERENCES Birn•ctiir;l. M.A.. K. Brinson. and B.K. ChaJcrabarti. 1971. The etTect of short-term exposure to.carbon monoxide on platciet stickiness. Br. J: Sur;t: 58:d'37'. Chand/er. A.B.. 1. Chapman. L.R. Erhardt. W.C. Roberts. C.1: Schsvartz. D. Sinapius. D.M. Spain. S. Sheny. P.M. Ness, and T.L. Simon. 1974. Coronary thrombosis in myocardial infarction. Report of a workshop on thr role of'crsro- nary ttirom'bosis in the pathogenesis of acute tnM1ocardial infarction. Am. J. Cardiol. 33:823. Charcot., 1:M. and C. Bouchard. 1868. N?ouveiles recherches sur la pathorenie de' ('hemorrhagie cerebrale. rlrch: Ph.•sinl. Nr,rm. Pathol. 1:643. Cobb. L.A.. R:S: Baum. H. Aliarez. ill; and W.A. S.natfer. 1'975. Resuscitatiom from out-0f-hospital!centreculnr ttbrillation. 4 years follow-up. Cirrr,lcuian (suppl,. 111)'S2:223'. Davies, M.J.. N, Woolf, and: W.B. Robertson; 1976. PPathology of acute mn•ocardial, iafarctiom with particular reference to occlusive coronary thrombi. Br. Meurr J. 38:659. Eastcott. H.H.G. 1969. Arterial sargerr. Pitman Publishing Co.. Ltd.. London. Ed,tcott. H.H.Ci.. G:W. Pickering. and C.G: Rob. 1954. Reconstrniction of interttal carotid artery in a patient with intermittent attacks of hemiplegia. Lancer 2:994. Heberden. W. 18'118: Cornmenturies on dtr Iristury and cure of diseuses. «'ells and' Lilly. Boston. Kannel.,W.B.. W.P. Castelli'„and P:1it. McNamara. 1968. Ggarette smoking andlrisk of'.coronary, heart disease: Epidemiobogic clues to pathogenesis: The Framingham Study. Norl. Cancer Inst. .blanogr. 2'5:9. McGill. H.C.. Jr. and W.R. Rogers. 1980. The baboon as a model for cigarette smoking. In SYmposirrm on, the use of nonh'uman primates in cardiuvwscular diseases. San Antonio. Texas. /ln pressl McGill. H.C.. 1t.. W.:R. Rogers. R.L. Wilbur: and' D.E. Johnson. 1978'. Cigarette smoking baboon modei:' Demonstration of Yeasibility: Proc. Soc. F-rp. Binl: .l!'ed: 1157c672: ~ Miller, R.D:., H:B. Burchell. and I.E. Edwards. 1!95'l. Myocardial infarction with andd withoutiacute coronary occlusion. ArcG. Intern. Med. 88:597. Prineas. R'.1. and H. Blnckbum. ed. "975. Suddert~ coronary death outside hospital. Symposium on Sudden Coronary De:rth Ouuide Hospitals., Minneapolis. 1974. Circulation (suppl. lUi ) 52:1. Public Health1 Service. 1'9l`rl. Smoking and healrh. A report nf the adiasnry committee to the Surgeon General of the :'ublic lJbulrlr Sen•ice. DIHEJM publication number (PHS) 1103. Government Printing Otdice. Wushington., D.C: 1979. S/naking andhealth: A rryNmr uf rhe Surgeon General: DH$W publica- tion number (P'HSo 19-5(D066'. Govemment' Printing Otiice. Washinrtton. D C. Royal College of Physici:uts; of London. 1962. Smnking, and heaJik; twnmure' and' report an smukinK' in rrlution ru cancer of the lunR and, other diseases. Pitman Medical Puhli+hinL Co.. Ltd:, London. Russell. R.W.R. 1961. O'bservations on the retinal blood vessels in monocular blind- nexu. Lncet 2:'14'?: Schwaru. C.J. and W.J. Walsh. 1971. The pathmlogic ba..ies uf sudden death. Pru.4: Curdir,rYar. Dia. 1'.Z':165:

. . 904 C.J. Sehwarts: H.C. MeGill, Ji•., and'W:A1 Ftog.rs Schwartz. C.):, A.B. Chandler. R.G: Crerrity,. and H.K: Maito. 1978, Clinical utd, pathological, zspet:ts of arterial thrombosis, and. thromtioetnbolismi Adr: Fxp. Med. Biol. W:111. . . ~• :CQMMEPJTS . WYDtDHR: 1have been concerned for many years at how little attention we have paid to the effects of smoking on cardiovascular disease. Here see some very, pertinent data, relative to ! al major cause of death., I have two questions: 1. 1 take it you: have measured the catecholamines in your monkeys: could you tells us about this? and 2.. If you were asked what would be the less,hartttful cigarette, in respect to cardiovascttlar disease and you had to make a, recommendation to this group~. would you like to see a reduction in nicotine and' CO. and what else? What would you recommend, to us with your current state of'knowledge? SCHWARTZ I don't think I can make a recommendation. 1 don't have enough data to, make a decision as. to which would, be the leastharmfui or the least hazardous ciearette. I think, we reall jr need. to manipulate the future ! studies onhigh-nicotinen low-tar cigarettes and various combinations, and, perform permutation studies in the baboon model specifically, to try, to get at that. We did, not measure catecholamines in the chronic study that has just bet:ncompltted. We are.,in fact. measuring,cortisols and catechols,in the acute'studies that are being undertaken at the moment.We were trying to look, at the equivalent effect of'ten cigarettes in baboons over a, 2-hour period, that is, in, animals that have never been subjected to any cigarette smoke eaposure at all. We attempted this to see just, what the~ acute effects might be., The assumption was that there could be a continuous additive injury-type phenomet:on going on over many years. We want to see if we~ can identify any acute basic changes that take place in the tissues at an ultrastructural and a basic biiochemicali level. . r wY•NDERc This is a crucial' point. If you measure cotinine-niicotine levels in the bioodstneatteof cigar andipipe smokers, you tind that they areashigh as those among cigarette smokers. Since we know there i's•no increased risk for coronary disease among cigar or pipe smokers, e'ven with their elevated cotinine-nicuune levels. I wonder if you are going to study catecholamines? SCHWARTZ:, We are: indeed. I' can just comment that the plasma cortisol levels go up dramatically with the ten-cigarette: exposure. It'r a dramatic effect. Of course, plasma cortisolitself has been: shown to correlate dramatically with the severity ofi atherosclerosis. :r:

Gt7R1: I would just like to reconcile some apparent' differences between your ;Yy~# presentation and! Dr. Astrup's presentation. Is it true that' what you were referring tu before was speciticallv obtained with CO exposurr°only,. not withlci arette smokine) Would' ou care to comment on whether there is '' ~ y an implication that other smoke components may counteract the effects of _ CO7' • ;'SCHWaRT2: The data, has not yet been totally analyzed. It may be possible. with more varied' anadysis, to look at independent effects of CO levels versus other factors. I can't answer that question. Our study basically gives the results of chronic smoking exposure in nonhuman, primates on lipids- ant. various other things. whereas •Dr. Astrup's data is qµice clearly the effect of CO. I don't think these are necessarily in eontl6ct, but we obviously have a more complicated sys- tem. ~ GORt: Dr. Astrup presented!some similar data at a meeting in Berlin almost a 1' year ago. I' remember that even at that time he showed some different results at different times during the experiment and could not confirm previous experience concernin,... ASTRUP: ...direct toxicity of CO on the endotheliall lining?' GORI: Right. At that'time, we werralsospeaking of the necessity of carrying on studies with CO in different anitnals, particularly in primates. Do you - think that the results that Dr. Schwartz has reported are more pertinent'to the human, situation than what one could have obtained with rabbits or with guinea pigs? A:STRtuP: I' think they are, because he uses tobacco smoke. I think it is J' important, to distinguish between the various components in tobacco smoke for identifying the real'toxic ones. , • . . ~ SCHWARTZ: I agree with Dr. Astrup that one really needs to be able to do. _ these things, both i^ terms of the total smoking situation and tr.e manipu- lation of different types of cigarettes gi'ving,differenrtypes of response. lnn addition, in the acute studies example. ti think we should be looking, at some of the smoking components, spet:iticallyas independent %ariables: