TABLE A7.-Differences in serum liln'ds between smokers and nonsmokers (cont.) (Actual "umber of individunls show" in parentheses)' [SM = Smokers NS = Nonsmokers] Author, year, country, reference Number and type of population Rl?Slllts comments Higgins and Kjelsberg, 1967. 1J.S.A. (83). Pinrherly nnd Wright, l!l67. E"gl*"d (1,50). 5,030 male and female residents of Tecumseh. Michigan, 16-79 years of age. 2,000 men participating in executive health examinations 2%70 years of age. M&8 Fe??llZh NS __ __ _. _. _. 209.9 (360) 210.1f1,439) Cigarette 212.5( 1,426) 212.4 (910) Percentage with .wrunz The authors noted that smokers Serum cholesterol choleatcroZ>170 showed significantly higher mg. percent mg. percsnt ( p20 cigarettes/dny(Sll) 249.4 30.0 Van Buchem, 1967, Nethevlands (181)). 918 randomly chose" Semm cholesterol The Ruthors found no meles 4c-59 yearn O-209 mg. pement 210-?4!i mg. Percent >eso nw. Percent correlation between smoking of age for entry NS . . . . . 12.4 (32) 14.0 (44) 14.2 (41) and serum cholesterol levels. into prospective Cigarette SM 71.6 ( 184) 67.8(213) 68.2(197) study. Other ,_....______.._. 16.0 (41) 18.2 (57) 17.6 (51) Hwle et al., 1968, 1J.S.A. (28). 1.104 male factory employees 20-64 yrars nf age. Serum cholcsted Scram Beta-lipoprotein Beta-lipoproteins were found mg. percant my. percent to increase with nge. but NS ,. ._ ._ __ __ _. __ __ _. ._ __ SM 243(519) 1 ,,O.O5 215.0 P40(114) . . . . . ., Pipe and cigar(128) ......... ......... ......... ......... Systolic blood preaaure No association found Ages 29-44 45-59 between systolic blood ................... 138.8 143.0 pressure and smoking. ................... 132.5 140.3 ................... 134.7 144.0 ................... 129.4 141.6 ................... 132.2 138.9 ................... 136.1 141.5 ................... 136.0 141.9 Edwards et al., 1,737 male Proportion of n&err with "Hypmtmion" (~200~100 mm. Hg.) 1959, England patients of NS _. , . . . . . . . . . . 2'7.2 percent (151) (56). general prac- Cigarettes _. . . . . . . . . . . . 20.5 percent (730) titioners over Pipe _. _. 25.9 percent (341) 60 yeTarS of age. Karvonen et al., 526 males in Systolic blood pm.wuw No data on pipe and 1959. Finland various regions West Fixland East Finlund Hebim ki cigar smokers. No (97). of Finland NS ., ._. ,. . 139.2(64) 142.6 (39) 132.8 (62) statistical significance 2s s9 years of SM _. 133.2(91) 135.4 (103) 129.8 (166) noted. BBC. Diastolic blood pmssure NS . _, 84.7 86.8 89.6 SM . . 81.9 84.1 86.8 Clark et al., 1,859 male civil Mean systolic Mean diastolic Nonsmoker and smoker 1967. U.S.A. servants. blood-prcsuwe blood-pressarc groups were of similar (43). NS(728) .,...,.,..,..... .,.. . . . . . . 137.0 (p~O.05) 83.gl (pZO.05) average a???. SM (407) 133.6 R2.5 ( TABLE AS.-Blood pressure differences between smokers and nonsmokers (cont.) (Actual number of individuals show" in parentheses)' [SM = Smokers NS = Nonsmokers] Number and type Results l-ef.Se"Ce of population Comments Higgins and 5.030male and Age adjweted Age adjusted Kjelsburg. female residents mean systolic blood ~msuuw mean diastolic blood pressure 1967. U.S.A. of Tecumseh, Michigan, M&8 F#?l&lJ M&s Females (8s). 16-79 years of age. NS t, .137.9 (360) 84.5 (1439) 136.6 (360) 82J(1439) 1 (p25grams 127.9 (70) 128.1(218) 77.6 77.1 All amounts 129.1(519) 128.6(447) 78.7 773 Tibblin, 1967. 895 males in - Blood pressrcre Sweden 1 l&145/ 150-170/ Numbers in parentheses GGtehorg, Sweden, ~110/~70(89) (187). 75-95(468) born in 1913. loo-110(220) >175/>lI5(75) represent total in blood NS . . . _. . . 18.0 23.0 25.5 34.7 Pressure group. l-14 cigarettes . .29.2 29.2 25.6 18.7 The author noted >I5 cigarettes . 28.1 20.9 15.5 17.3 a stepwise decrease with Pipe and cigar . .11.2 8.6 10.0 4.0 level of blood pressure as smoking increased. `Unless otherwise specified, disparities between the total "umber of i"- dividuals and the sum of the individual smoking categories nre due to the exclusion of either occasional, miscellaneous. mixed, or ex-sm"kem. TABLE A17.-Zmidence of new coronaq heart disease by smoking category and behavior type for men 39-49 years of age (Numbers in parentheses are number of CHD cases in each subgroup) Smoking group FlXlIl.?T Current and Cigarettes Behavior NeVer cigaf;cete former pipe type smoked and cigar only 1-15 16-25 26 and over Total A .._ ., . . `5.3(5) 13.3 (7) 1.3(l) 1.6(l) 15.X(15) 14.9 (16) 9.3(45) B . . . . . . . . 1.3(Z) 5.1 (3) 2.2(Z) 7.3(4) 3.1 (3) 4.9 (4) 3.3(18) Total 2.9 (7) 9.1(10) 1.8(3) 4.9 (5) 9.3(1X) 10.4(20) 6.2(63) Analysis of variance table SOUITC Sum of squares d.f. Mean square F P Within cells _. _. . . _. 59.471 2,245 0.026 . . Regression on age . _. _. _. _. . . . . 0.458 1 0.45R 17.296 0.001 Retwsen smoking groups 2 _. _. . _. 0.504 5 0.101 3.81 0.002 Between behavior types 2 0.329 1 0.329 12.43 0.001 Interaction . 0.396 5 0.079 2.99 0.011 1 Rates are age-adjusted nnnual incidence per 1,000 men. effect but ignoring interaction. thus yielding an estimate of each main ef- `Mean squares for "between smoking grwps" and "between behavior fsct unconfounded by other significant main effects. types" are each computed eliminating the general mean and the other main SOURCE: Jenkins. C. D. rt al. (90). TABLE Al8.--Zncidence of new coronary heart disease by smoking category and behavior type for men 50-59 years of age (Numbers in parentheses are number of CHD cases in each subgroup,) Smoking group Behavior NNCT iYPf snmkcd Former cigarette smokers Current and former pipe and cigar only 1-15 Cigarettes 16-25 26 and over Total A _... `12.4(5) B .._... .._ 10.0(4) Total 11.1(g) -. Sourre 1X.6(8) 5.1 II) 14.2(9) 21.8 (8) 8.4 (3) 14.9(11) Sum of S4"BTes 16.4(5) 21.5 (9) 30.0(14) 20.4(49) 4.?(l) 21.1 (7) 19.1 (5) 12.0(21) 11.5(6) 21.3(16) 26.0(19) 16X(70) Analysis of variance table - ..__ d.f. Mean S4"BlY F T- Within cells ............................................. 63.527 Rwression on axe ...................... ., .................... 0.171 Uetween smoking groups - ................................... 0.522 Between behavior types 1 ..................................... 0.296 lnternction .................................................... 0.129 1 Rates are age-r.djusted annual incidence ner 1,000 men. : Mean squares for "between smoking groups" and "between behavior types" are each computed eliminating the acnersl mean and the other main 911 0.070 1 0.171 2.54 0.111 5 0.104 1.496 0.188 1 0.296 4.24 0.040 5 0.026 0.37 0.870 effect but ignoring interaction, thus yielding an estimate of each main ef- fect unconfounded by other significant main effects. SOURCE: Jenkins, C. D. et al. (90). TABLE A20.-Experiments concernixg the cfects of smoking and nicotine OYI unimnl cc~~dio~~asc~~la~ function. Author. Ye**. Number and Smoking Heart Blood Cardiac Coronary country, type of procedure rate pressure output blood Comments reference population flow Bell& 39 experiments Inhalation Definite Definite Coronary artery ligation increased the frwuency et al., on dogs which of tobacco increase. increase. of nicotine-induced severe arrhythmias; these 1941. had undergone smoke in hecame less evident with increasing time since U.S.A. P"ron**y chamber. ligation. (21). artery liga- Nicotine Definite Definite tion up to intravenous increase. increase. 45 days before. 0.2-1.2 mg./kg. Burn and 10 rabbits, Experimental Isolated "trial specimen showed increased rate and Rand. 5 rxperimental, animals pre- incrensed amplitude of contractions with admin- 1958, 6 control, treated with istrati"" of nicotine proportional to pretreat- England isolated atria. intraperitoneal mat. These reactions were blocked by reserpine, (35). nicotine and and the authors consider nicotine effects to be the atria of mediated by catecholamine release from chro- both groups maffin store in myocardium. excised and perfused with nlrotine. ___~ West et al., 33 normal C0*0ll*lY Definite 1. Myocardial contractility increased 40-90 per- l%R, ndult mongrel intra- increase cent in 15/15 animals tested accompanied by U.S.A. dogs. arterial (systolic). ST segment depression and T-wave inversion (?OSi, nicotine: and blacked by tetraethylnmmonium chloride. I. 0.2~2.2 II. Coronary blood flow increased 19 percent upon !a./ka. left circumflex artery injection: coronary blood II. 0.04-l flow showed no change upon left anterior de- wz.lks. scending artery injection, 64 observations on 10 dogs. (Tetmethylammonium chloride blocked CBF in- crc*sc. ) The authors found no evidence of coronary vase- constriction in these healthy animals. s TABLE A20.-- -Experiments concerning the efects of smoking and nicotine on nnimd cardiovascular function (cont.) Author, ye**. country, reference Number and type of population Forte 27 observa- et al., tions on 6 1960. dogs. U.S.A. (65). Smoking Heart procedure rate Blood PRSS"lT Cardiac output c"E3," comments fl"W Intravenous nicotine up to 21.5 mg. given 8s 5-15 ag./kg / minute. Definite initial increase then decrease. No change. No significant change in either left ventricular work or myocardial oxygen extraction. Kicn and 21 ndult doss Cigarette Definite Definite Increase Effects of cigarette smoke were duplicated by in- Sherrod, smoke under increase. increase. following travenoua nicotine and epinephrine. 1960, positive increase During cigarette smoke inhalation. it wns noted U.S.A. pressure via in blood that without blood pressure or output changes. (112). tracheostomy. pressure coronary blood flow did not increase and that Nicotine 20 and cardiac while adverse EKG changes were noted they eor- wg.lkg. intra- output. related morn closely with decreased cardiac oxy- venously. gen utilization than with actual cardiac work. Epinephrine 5 eg./ka. intra- VenouslY. Travel1 14 normal Intravenous Definite Nicotine-induced coronary blood flow and heart et al., rnbbits and nicotine increase rate increase in the atherosclerotic animals re- 1960, 16 rabbits 0.01-0.1 mg. in normals. wired 10 times and 2 times. respectively, the U.S.A. with severe amounts required in the normal animals. (189). cholesterol- induced athero- sclerosis. TABLE AZO.-Experiments concerning the eflects of smoking and nicoline on animal cardiovascular function (cont.) Author. yea=, eoutry, reference Number and type of population Smoking p*0Wdll*e comments Bell& I. 10 normal dogs Intravenous I. 125 percent The authors noted that: et al.. II. 9 dogs at nicotine, increase 1. The response of coronary blood flow to nico- 19G2. varying in- 20 ag./kg.l II. 82.5 percent tine resembled that of anoxemia in the pres- U.S.A. terva1s fol- minute for increase ence of coronary insufficiency. (22). lowing coro- 15-20 minutes. III. 83.3 percent 2. The greater the induced coronary impairment nary artery increase the smaller the increment in coronary blood ligation. flow. III. 7 dogs with varying grades of artilicially- induced coro- nary artery narrowing. Leaders 15 adult Left anterior Nicotine and norepinephrine both increased coro- and mongrel descending nary vascular resistance and myocnrdial contrac- Long. dogs. intracoronary tile force (the former measured by B constant- 19G2. injection of volume variable-pressure system) The action of U.S.A. nicotine or nicotine was blocked by pretreatment with hex- (125). norepinephrine. amethonium. pentolinium, resetpine. or gusme- thidine. Larson 13 adult Intravenous Definite Definite Systrmic vnscular resistance and pulmonary artery et al.. mongrel nicotine. incrense. increase. and left atria1 pressures showed biphasic re- l9G5. dogs. 0.02 mg./kg./ sponses of increase followed by decrease. U.S.A. minute for (194). lo-12 minutes. TABLE ABO.-Experiments concerning the effects of smoking and nicotine on animal cardiovascular function (cont.) i; Author, year. Number and Smoking c0untl-Y. type of procedure comments reference population Folle 7 dogs of 30 investigated I. Cigarette smoke inhalation I. No change in coronary vascular resistance. et al., (Remainder experienced to isolated left lower lobe II. 5/6 showed increase in coronary vascular resistance due, according to 1966, catheterization failures). nnd then blood perfused coronnry the author. to general sympathetic nervous system stimulation. U.S.A. arteries. III. 4/5 showed increase in coronary vascular resistance. The authors con- (84). Il. Cigarette smoke to rest of elude that the cardiac effects of tobacco arise almost entirely from lung and then blood passed to the extracardiac actions of smoking instead of the direct response general circulation. of the heart. III. Kieotine perfused directly into left coronary artery. Nadeau and James. 1967. U.S.A. (14P). 26 dogs Nicotine 0.01-10.0 pg. into sinus node artery. Heart rate showed initial slowing (due probably to vagal stimulation) fol- lowed by acceleration (due probably to vagal paralysis and catecholamine release). No systemic blood pressure changes noted. Romero and Talesnik, 1967. U.S.A. (156). 16 experiments on isolated cat heart. Nicotine in varying doses in perfusatr of coronary arteries. Over 5 pg. of nicotine was found to produce an initial bradycardia asso- ciated with increased coronary flow, followed by prolonged tachycardia with an initial decrease in coronary blood flow followed by a prolonged increase. Pretreatment with heramethonium or reserpine prevented both the myocardisl stimulation and the increase in coronary blood flow. The authors consider the action of nicotine to be a combination of a direct vasoconstrictive effect and an indirect catecholamine-releasing vasodilating effect. Put-i et al.. 1968. U.S.A. (252). 22 mongrel dogs I. (14) Intravenous nicotine I. Nicotine produced a definite increase in the force and velocity of left SO &g./kg./minute fur 3-4 ventricular contraction. minutes II. Pretreatment with propranolol produced (relative to results of Group I) : Il. (8) Propranolol pretreat- (a) A further increase in left ventricular systolic pressure. ment, then 50 pg.lkg./minute (bl A decrease iv velocity of Jhortening. nicotine for 3-4 minutes (c) A significant increase in left ventricular end-diastolic pressure. The authors conclude that ~mp,rsnolol probably impairs the norepinephrine- like effects of nicotine on the myocardium while enhancing its peripheral "*80pre880* e*ects. - TABLE AZO.-Experiments concerning the effects oj smoking ad wicotixt OH u)lit)ld co?.dio(.~~scz~l~~~ fwctiox (cont.) Author. year. Number and Smoking country, type of pr"Ced"r.5 Comments reference population ___-. - BalWZs Beagle dogs with lesions I. Normals (3 ~G per experiment) : I. (a) No evidence of nrrhythmins: (b) A single or B few ectopic beats et al., induced in myocardium by (a) 4 Pg./kg. intravenous in 2/3 normal dogs. 1969. either: (1) Isoproterenol nicotine, (b) 40/1g./kg. II. Extrasystoles noted in 2/3 animals during the first day after cessation U.S.A. pretreatment, or (2) intravenous nicotine. of the arrhythmia induced by the lesion alone. but not thereafter. (16). ligation of the anterior 11. Experimental (3). 4 pg./kg. These sod nicotine-induced arrhythmias were of n short duration. descending coronary artery. intravenous nicotine Creensoan Cardiac muscle isolated from Nicotine 2-100 ug.,`cc. in Nicotine perfusion produced: et al., 1969, U.S.A. (74). the right ventricle of 10 adult dogs. Tyrode's solution perfusate. (1) A" increaw in myocardial contractile force apparently independent of adrcnergic innervation. (2) An increased nutomaticity of the Purkinje fiber system apparently due to release of catech"lamin& from rhromaffin tissue stores. (3) A decrease in conduction velocity. The authors conclude that the latter two effects probably predispose to ar- rhythmia formation. Saphir and Rapaport, 1969. U.S.A. (166). SR mongrel cats Nicotine 5-12 Kg. kg. injected intraarterially to mesenteric circulation. I. Mescnteric injection "I nicotine was followed with l-2 seconds by: (a) Increased left ventricular systolic pressure (LVSP). (b) Increased systemic resistance. (c) Enhanced myoeardial performance. II. Left ventricular injection of nicotine was followed by. (a) Increased LVSP. (b) Bradycardia. (c) Enhanced myocardial performance greater than that seen in mesenteric-injected group. III. Pretreatment with phenoxybenznmine diminished the increase in LVSP while proprnnolol pretreatment diminished the enhancement of my- "cardial performance while LVSP still showed a significaut increase. IV. Mesenteric sympathetic nerve section led to a diminished response. The authors conclude that the cnrdiovascular responses to nicotine msy be neurogenic in nature with receptors distributed in certain abdominal arteries. TABLE AZO.-Experiments concerning the effects of smoking and nicotine on animal cardiovascular function (cont.) - Author, year. country, reference Leb et al., 1970, U.S.A. (126). Smoking procedure Comments p&&ion 12 mongrel dogs and Nicotine 100 eg.lkg. for Effective Coronary Flow (ECF) is that part of the total coronary flow CBF measured with use of Rb3' and digital counter. 2 minute intravenously. (TCF) which is "effectively ' involved in nutrient exchange. Nicotine injection was followed by: (1) 96.6 percent increase in TCF. (2) 51.1 percent increase in ECF. (3) 73.1 percent increase in myocardial oxygen consumption and analysis revealed that capillary flow increased almost proportionately to my- ocardial oxygen consumption whereas the increase in TCF was far in excess. (4) Definite increases in cardiac output, heart rate. left ventricular work, and aortic pressure. Ross and Bless. 1970. U.S.A. (160). 10 dogs undergoing instantaneous coronary arterial flow measurement. Nicotine 10-100 fig. intra- coronary injection. Nicotine injection ~8s followed by: ( 1) Increased contractile force. (2) Decreased myocardial contraction time. (3) Decreased time necess8ry to reach peak tension. (4) Decreased total stroke systolic CBF. (5) Increased total stroke diastolic CBF. (61 Increased total stroke CBF. (7) Changes similar to intraarterial ppinephrine. (8 1 Changes blocked by pentolinium pretreatment. (9) No change in heart rate or blood pressure. The authors conclude that catecholamines released from the ventricular myocsrdium mediated these responses to nicotine. TABLE A21.-Experiments concerning the effects of smoking. and nicotine on the cardzovascular sy.stcw~ of lm~~tans Author, ye*=* countrY, reference Number and type of population Smoking Heart PlYlCCdUrC rate Blood Electrocardiogram Stroke Cardiac PW2*SUW ballistocardiogram volume output CC&0;d"=Y Comments flow Russek et al., 1955, U.S.A. (164). nargeron et al.. 1957, U.S.A. (17). I. 28 healthy 1 standard and 1 I. Increase. Increase. EKG: Denicotinized cigs- male smokers denicotinized I. 16/2R showed rettcs evoked changes 21-60 years cigarette. significant of a lesser degree of age (aver- changes. in normals and CHD age42). II. No sig- subjects. but in the II. 37 male patients II. Increase. Increase. nificant latter group there with overt changes. was no significant clinical CHD BCG : difference between 42-70 yearsof I. these changes. age (*"erage II. 18/37 showed 64j.6 were significant nonsmokers. change. - 14 of 30 healthy 1 cigarette Insignificant Increase. Definite Corunary vascular adult male vol- inhaled at increase. increase. resistance fell unteer smokers intervals of signifirnntly. and nonsmokers 20 seconds. Myocardial O2 who underwent "Saxl? untler\vent no successful significant change. catheterization Pyruvat< rstraction l&53 years fell slightly. of age. Authors consider lark of increase in heart rate as due to hawlinc nvprehensive tnrhycnrdia. _____ TABLE AZL-h'rperiments concerning the effects of smoking and nicotine on the cardiovascular system of humans (cont.) Author. Ye*=, countrY, reference Nut;;z;f""d population Smoking procedure Heart rstc Blood Electrocardiogram Stroke Cardiac masure ballistocardiogram volume output C-&W Comments flow 2 standard cigarettes in 25 minutes inhaled at minute intervals. Definite increase. Definite increase. - Increase. No signi- Myocardial 0, COI~SUIIIP- flcant tion rose ol?ghtly in change. 3 out of 7. The author considers that the EKG changes noted on smoking are probably due less to decreased coronary blood flow than to increased workload (oxygen need) where uxyuen supply does not increase. Noted no evidence of myocardial ischemia during smoking. Regan et al.. 1960, U.S.A. (1.54). `I males with history of EKG-pr~~en myocardial infsrctiun undergoing cardiac ca- theterization. Thomas and 113 clinically Murphy. healthy young 1060, males. U.S.A. (186). One standard cigarette smoked at own pace. Definite incresse. Definite Definite increase. increase. Definite increase. Pulse pressure showed a decrease. Smokers responded slightly hut signi- ficantly more actively than non- smokers. BCG changes were increasingly common with increasing age. weight, and serum cholesterol. TABLE A21.--Experiments concerning the effects of smoking and nicotine on the cardiovascular system of humans (cont.) Author. Year. country, reference Number and type of PoPulation Smoking Heart Procedure rate Blood Electrocardiogram Stroke Cardiac COr0"ZM-Y pressure ballistocardiogram volume output blood Comments flow Van Ah", 1960. Sweden (202). The author reviews a series of experiments performed between 1944-1954. Cigarette smoking. I"CTe*StL EKG: Slight ST segment depression and T-wave flattening. EKC changes more prominent in young, clinically healthy subjects than in older, habitual smokers. Intra- venous nicotine and smoking showed identical cardio- vascular effects. Smohing elicited angina pectoris in a number of CHD patients. Irving and 5 normal males, (a) Shamsmoking. (a) No No change. (a) No change. No change. Cardiac output Yamamoto, 15 patients with change. measured by dye 1963, diseases not de- (h) Non-inhalation (b) No No change. (b) No change. No change. dilution technique. England fined, 19-M years smoking. change. (X0). of age, all mod- (c) 2 standard (c) Definite Widened (c) Definite Definite crate-heavy cigarettes in increase. PUL?. increase. increase. cigarette smokers. 10 minutes. pressure. (d) Nicotine 0.6 (d) Definite Definite (d) Definite Definite mg. intra- increase. increase. increase. change. V~llOUSlY. m `JIAIXE A21.-E.rllc,~i,)lents concerning the effects of smoking and nicotine on the cardiovascular q&em of humans (cont.) Number and type of population Smoking Heart procedure rate Blood Electrocardiogram Stroke Coro"ary P)`ESs"re ballistocardiogrsm volume blood Comments Row I. 14 volLl"trers Single cigarette with clinical CHD, Is/14 smokers, riverap2 axe x0.5. II. 5 patients with nngina pectoris, all smokers, sve- rage *x6! 43.4. III. 14 patients with history of definite myo- cnrdinl infarc- tion, all smok- ers averaxe age 54.1. smoked at own rate in G-7 minutes. - 5 mnlc nnd 3 ? standard female patients cigarettes in with heslrd 10 minutes at myocardinl infarc- rest and under tion 48-69 years graded exercise. of nge Z/B non- smokers. Definite Definite increase increase in all in all groups. groups. I. 10 27 percent percent increase. increase. II. Inter- I"tmme- mediate diste change. change. III. 8 per- 1 percent cent increase. decrease. Definite increase at rest and at exercise. No signifi- No signifi- The author contrasts cant changes cant this response with at rest or changes that see" among during at rest or healthy young exercise. during individuals. exercise. .4uthr. Ye" r, Numlrr nnd Smoking Heart IJlood Electrocerdioarnm Stroke Cardiac country. tyne of procedure ret"2 P~PSB"~`? ballistocnrdiogram "olume OUtPUt C"b,x-&T COTLItleIltS reference nopulatiorr flow Sen Gupta 6 healthy male 1 untipped Increase Increase No change. and Ghosh, nonsmokers. cigarette in in all in all 196'7, 8 healthy male 5-7 minutes. KroIII)s. KP3"I)S. 6/8 showed ST India smokers. rhanges. (171). 6 patients with All showed ST CHD, nonsmokers and T-wave 3 patients with changes. CHD. smokers. All showed ST 36-64 years of age. and T-wave changes. AIXllUW rt al., lY68. U.S.A. (5). 10 male patients 1 rtandard high Definite Definite Product of systolic with classical nicotine cigs- increase. increase. blood pressure and angina pertoris. rctte in 5 hart rate showed a 32%5Y wars of age minutes. significant increase on smoking while left ventricular ejection time vnlurs did not. All patients developed angina more rapidly under a constant exercise load if they had smoked before exercising. Kerrivan 24 male and 1 2 filtered ciga- Delinite Delinite Cardiac The increase in et al., female healthy rettes in 15 increase incrensc index. cardiac index. heart lY68, smokers. average minutes with under under rest Definite rate. and blood U.S.A. age, 45. measures taken rest and and exercise increase pressure during (lfJ2). H male and 2 at rest and during exercise conditions. under rest exercise with smoking female healthy exercise. conditions. and was the sum of such nonsmokers, exercise increases seen with average age 33. conditions. smoking or exercise separately. Neither group showed increases in peri- Y pheral vascular resistance. TABLE APL-Experiments concerning the effects of smoking and nicotine on the cardiovasculw system of humans (cont.) Author, yea=. COU"bY. reference Number and type of population Smoking Heart procedure rate Blood Electrocardiogram Stroke Cardiac pressure ballistocardiogram volume output Cr,;;;=Y Comments flow Allison 30 healthy male 2 standard ciga- Definite Increase. Increase fol- Definite decrease in and Roth, subjects. rettes smoked increase. lowed by pulmonary blood 1969, 19-59 years of in 12-16 minute decrease .volume as indicated U.S A. age. period. within 20 by impedance methods (3). minutes. of thoracic pulse volume. Aronow and 10 male patients 1 low nicotine Definite Definite All patients developed Swanson. with classical cigarette in increase. increase. angina sooner if 1969, angina pectoris. 5 minutes. they smoked before U.S.A. 32-59 years of exercising. (7). age. Aronow and 10 male patients 1 non-nicotine No change. No change. No difference noted SWZHISO", with classical cigarette in in time or onset 1969, angina pectoris. 5 minutes. of exercise-induced U.S.A. 32-59 years of angina between (6). age. smoking and "on- smoking procedures. Marshall et al.. 1969, U.S.A. (229). 42 normotensive healthy male prisoners 18-50 years of age. 13 nonsmokers. 16 moderate smokers. 13 heavy smokers. 3/4 of one standard Insignificant Insignificant Blood pressure response cigarette. increase. increase. to cold pressor test noted to he greater in heavy smokers. Presyneopal reactions to 40 degree head-up tilt more frequent in smokers. TABLE A22.-Experiments concerning the effect of nicotine or smoking on catecholamine levels Author, year. country, Nu$royd Procedure Results reference subject -. Watts, 11 dogs 0.02-0.60 mg/kg. Nicotine administration was associated with significant increases in peripheral arterial 1960, nicotine intravenously. epinephrine levels. Ganglionic blocking agents prevented this effect. U.S.A. (am). Westfall and Watts, 1963. U.S.A. (210). 22 mongrel dogs Cigarette smoking via tracheal cannula; 1 cigarette/8 minutes for 35 minutes. Regular cigarette smoke evoked a statistically significant increase in adrenal vein, vena CBYB, and femoral artery levels of epinephrine. Cornsilk cigarette smoke evoked no change. W.&fall 21 male vol""teers 3 cigarettes smoked in Smoking at rate noted for 2% hours evoked a significant increase in urinary rpine- and Watts, approximately 25 30 minutes. phrine. but not norepinephrine levels. 1964, ye*4 of age: U.S.A. 11 nonsmokers. WI). 10 smokers. Westfall et al.. Mongrrel dogs Standard cigarette smoke Smoke inhalation evoked a rise in cardiac output, stroke volume, blood pressure. and 1966. exposure via endotracheal plasma cstecholamine levels. Pretreatment with propranolol diminished the cardiac U.S.A. tube. Smoke inhalation output and stroke volume responses hut increased the blood pressure response-the (209). every third inspiration for latter effect due to the release of alpha-receptor activity by beta-blockade. 3 minutes. d TDLE A23.--Experiments concerning the atherogenic effect of nicotine administration Author, year, country, Number and type Procedure Results reference of animal -___- _____ Adler et al.. Rabbits Nicotine 1.5 mg. intravenously in 5 percent The authors noted an artcrionecrosis of the aorta, affecting mainly the 1906, solution C of 7 days per week for more than inner muscular layers. Macroscopically, early changes consisted of U.S.A. 4 months. small areas of caleareous ridging and aneurysmal dilatation without (2). notable fatty degeneration or intimal discontinuity. Microscopically. early changes appear& in the muscle cells of the media, and "chalky" deposits were noted between the elastic fibers. HuePer, 1943, U.S.A. (86). I. 6 mongrel dogs. Nicotine subcutaneously. Increasing dosage up 1. 4/6 animals died of infection and showal marked edema and focal up to 2.5 cc. of 3 percent solution for 1 hyalinization of the media of the aorta and large elastic arteries. month, 2/6 animals were sacrificed and showed thickening and hyalinizs- tion nf the walls of the coronary arteries and edema of the media as well as endothelial proliferation of other arteries. II. 60 rats. Increasing doses up lo 1 cc. of 1 percent II. Much less nortic involvement than that found in the dogs; infre- solution for 1 month. quent arteriolar changes consisting of fibrosis and thickening of the media. Maslova, 1956, USSR (180). Czochra- Lysanowicz et al., 1969, U.S.A. (46). Rabbits 1. (10) Nicotine subcutaneously 1 percent solution 0.2 cc. daily for 115 days. II. (14) Nicotine plus 0.2 grams cholesterol per day. III. (10) Cholesterol only Rnbhits I, (10) 1.0 g. cholesterol/day for 100 days. 11. (10) Cholesterol plus 0.0015 g. nicotine/ day intravenously. IIJ. (4) Nicotineonly. I. Aortic wall---acute swelling of elastic fibers with focal fragmenta- tion and partial disintegration- no intimal fat deposits seen. Coronary vessels--thickening of the vessel wall-no fat deposits. II. Aorta--"massive" deposits of "cholesterol" in the intima and vasa vasorum with "loosening" of the sortie wall. Coronary vessels- the larger vessels showed moderate fat deposition and the smaller vessels showed swelling of the elastica. III. Aorta-isolated lipid deposition in the arch and ascending portions only. Coronary vessels---no fat deposition. Index of aortic lesion density (cholesterol infiltration) : I. 2.5. II. 3.4. III. No aortic lesions noted. Author, year, cnuntry. reference Number and type of animal Procedure Rrsults Wenzel et al., 1959, U.S.A. ( 127). Rabbits Thienes 1960, lJ.S.A. (1X4). Newborn rats and mice. Grosgogeat et al., 1965. Frnnce (75). Male rabbits I. (12) Cuntrol untreated. II. (12) Control diet plus 1 percent cholesterr,l nnd 5 percent cottonseed oil added. 111. (12) Control diet plus oral nicotine 2.28 mg./kg./day. Iv. (12) ncaimen II DIu!; ~711 nicotine 2.28 m~./kg./day. V. (12) Regimen II plus oral nicotine 1.42 mg./kg./day. VI. (12) Regimen II ~,los oral nicotine 0.57 mg./kg./day. Nicotine subcutaneously up to 5 mg./kg. twice daily by the end of 1 month. Animals nntrrpsied at I year. I. ( 10) Nicotine subrutaneoujly 0.15 m,E./day. (10) Controls-saline injected. Sacrificed at from 20-120 days. II. (27) Same as Group I (27) Controls--saline injected. Sacrificed at 90 days. Significant diffrrrnws in a<,rtic subendothclinl fibrosis betwwn control and exw~imental yrwps noted w11y in II and IV. In group IV, the nicotine-treated grcn~~) showed mow srwre change III. (66) Nicotine subcutaneously 0.:3&1.5 mg./dny. Sacrificed at 30 days. IV. (24) Nicotine subcutaneously 0.75 ma./day. (24) Controls--saline injected. One-half of each group ate cholesterol- enriched diet (0.5.-1.0 percent choles- terol added). Sacrificed at 60 days. TABLE A23.-Experiments concerning the atherogenic effect of nicotine administration (cont.) Author. year, countrY, reference Number and type of animal Procedure ReSUlt.3 Hass et al.. 1966, U.S.A. (80). Male rabbits 1. II. III. IV. V. VI. Nicotine Diet Vitamin D (8) Control Control Control I. Infrequent medial calcific disease without lipid locnlization. (7) Control Cholesterol Control II. No medial caleific disease but frequent intimal atheroma formation. 14) Nicotine Control Control III. Rare cnlcific medial degeneration; no intimal atheromatous disrase. 15) Nicotine Cholesterol Control IV. The largest number of atheromatous lesions. (9 1 Control Cholesterol Vitamin D V. No medial calcific disease. 14) Nicotine Cholesterol Vitamin D VI. Consistent medial caleific disease. (Sacrificed at various times) Control-no treatment. Nicotine-subcutaneous injections in oil- increasing amounts 2 times per week. Vitamin D--subcutaneous injections UP to 6-8x 1oJ IU. Cholesterol-250-500 mg. cholesterol added Choi. 1967, Albino rabbits per 100 g. diet. I. Nicotine l-5 mg./kg./day intraperi- toneally. I. Increasing nicotine dosages were associated with decreased atheroma formation (findings not statistically significant). Korea (42). Cholesterol 1 g.lday (in varying II. Nicotine alone produced no atheroma formation but was associated combinations with controls) with the presence of aortic medial calcification and endothelial II. Nicotine alone. hyaerplasia. III. Cholesterol alone. (Sacrificed at 60 days) III. Cholesterol alone was associated with a definite increase in atheroma formation. Stefanovich Female albino, I. (10) Diet supple- Percent of am-tic In both stock and cholesterol-fed animals, nicotine was also noted to et al.. rabbits. mented with 2.0 1969, percent choles- U.S.A. terol. Nicotine in- (178). tramuscularly 2.78 mg./kg./day. 5/7 days. 11. (10) Cholesterol only. III. (10) Nicotine only. IV. (1") Contrul. __ ~- -___- __~ surface involuad with athwoscleTosia I. 9.4 II. 5.7 III. 0.1 TV. increase aortic triglyceride content and to decrease aortic free cho- lesterol content. TABLE A25.-Experiments concerning the effect of smoking and nicotine upon blood lipids (Human Studies) Author. ye**, country, reference Number and type of population Smoking Plasma free procedure fatty acids Serum Serum cholesterol triglycerides Other Comments Page et "I., 1959, U.S.A. (147). 13 male and I female laboratory workers 17-51years of *ge. 2 nonfiltered cigarettes in 10 minutes and blood 1Wels measured over30- minute period. No change. Serum lipoproteins No change (10 subjects). Kershbaum 31 male et al., patients or 1961. staff 16-72 U.S.A. years of age, (104). I normals, 1 CHD. 17 other medical diagnoses. I. 17 subjects smoked 2 "on-filter cigarettes in 10 minutes. II. 9 controls. III. 5 subjects smoked 6 cigarettes in 40 minutes. Mean rise No change. No change. The authors consider the in- I, 351 fiEq./L. crease among controls to be II. 9.X pEq./L. due to fasting. III. 27%2,304 /LEq./L. Kershbaum I. 17 male I., II., III., Mean rise No difference found between re- rt al.. patients 2 non-filter I. 858 fiEq./L. suits following inhalation or 1962, with healed cigarettes in II. 320 &E&L. noninhalation. U.S.A. myocardial 10 minutes. III. 292 /.lEq./L. Statistically significant difference (10.9). infarctions. IV. No smoking. IV. 20 /IEq./L. found between increases in II. 16 non-CHD Groups II and III and patients. Group I. III. 10 normals. 2 IV. 13 normals. TABLE R25.-~;:.cl)cl'iltl(,?ll.s conwwi?lg the effect of srt/ok;ing and nicolim Icpon blood lipids (cont.) Author. yen*. country, Number and Smoking type of prorrdurr (Human Studies) 1 SM - Smokers NS = Nonsmokers] Plasma free fatty acids Serum Serum cholesterol triglycerides Other Comments Definite irlcreasp at start of smoking peri~xl. -. - 3 patients with trimc- Both free and total urinary thaphan camphor- catecholamines increased with sulfanate (Arfonad) smoking and the author pretreatment and 8 considers them as mediators formerly sdrenalecto- of the FFA increase. mizcd patients showed either minimal or no elevation. - ~-___ NS-dcfinitc No change NS- -definite incveasc at 6 hours. SM--definite increase at 6 hours. in either increasr $?roup. at 2 hours. SMslight increase at 2 hours. Author. year, c'ountrg. reference. Number and type of population Serum Serum cholesterol t.riglycerides Other Comments Frank1 5 male and 1 2 stnndnrd No rhanpe. Subjects werr in nonfasting, et al., female riaarettes nonbnsnl state. 1966, healthy inhaled in U.S.A. smokers 10 minutes. (66). 24- 2!l scars rrf age. Kcrshbnum 43 norm"1 male I. Terminal et al., heavy cigarette segment of l!W, or cifial cigar in 20 l1.S.A. smokers. minutes~- 15 (I,,,;) 21 4G years subjects. of ape. II. :i riparettes in 20 minutes 15 subjects (includintz ti from group I). III. Cipnwttr inhalation or nuninhalation G subjects. I. Indefinite increase. II. Dcfinitc inrwesc. III. I"urcaw with inhnlatio" zrcatcr thnn with "on- inhalation in every suhjeci. Cip:u. smoking in 11 subjects hhuwed a" intermediate in- creaw in the excretion of "rin:lry catecholamines as . compalctl to thnt with +a- rvtte smoking. Klensch, 56 observations 1 standard l)eli"itc Ir~