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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