TABLE AZ?.Smoking and thrombosis -- Author. wlmle Partial Rexaleif~ed YtiT. Numbrr and Expcrl. blood Pro- thrombc- Dlrrsma Plotrlet Platelet PlaL?let Platelet ctiuntt-y. type of mental clotting pInstin clotting adhrsive- count SUlViVal turnover Other Comments rcrcrcnte populntion conditions ' lime ":Ein tlme time "~88 -_-___- - Blnck- 16 dUlL 12 individuals PloU"U burn achizo- rmokcd 2 llypvtn et al., phlwnic hlph. time 1053. pnticntn. 8 nicotine (-) U.S.A. university atsndard (25). atud,,ntr. nil trR,id ii"!1 with cithcr IlflCr clumping Murphy. CVDur periods of time l%i3. COI'O. Dli nbstinence (-) c--j (-) (-) (-) (+) (4-l (2) U.S.A. hrn\y or cuntinua- dacrenae increase (Ill,. smokers 35- Lion of 72 YPBi-5 of smoking. aYe Ambrus 20 hoolthy Deep inhala- Thromboplaslir~ 2 studrnts and mule nr,n- tl"n of one yc,lmltlon I~~~plmc ill, Ml"k. smukinv nonfiltered 1-j (-) f--j (`c) C-J 1imr Rvomen: while filtered cxgarettrs showed respective decreesa of 11 nerwnt and 2, percrnt. Stromb!ad. 1959. Saedcn , Ii, ,. 11 mnie and femnle subjects (smokrrs and nonsmokers) were studicd for the eilect of the intra-arterial administration of nicotine (bra- chial artery) on blood flow to the hand as measured by veno~~l occlusion plpthysmozraphy. Increasing doses of nicotine were asso- ciated with increasing nombers of individuals manifesting vase- constriction. The vasoconStTxtive eKec!s of nicotine were abolished by the prior administration of either hexamethonium or Dentolinium. Bmnetr and Boake 9 male patients with intermittent clsodication (`I were heavy smokers) 1960X"srnlia 118,. were studied ior the cKect of smoking on blood flow to the leg a5 measured h,- vc11ous occlusion plethgsmogr-aphy. Smoking an un- filtered cigarette was found not to p:-educe aray consistent changes in blood Row to the caLf or foot of the affected leg. Freund and Ward. 1960. U.S.A. (68). 15 male prkon inmates (less then 35 years of age) and 14 male patients with peripheral vascular disease la~~roximatcly 65 years of ape, were studied ior the effect u: smoking on digital circulation as rwasurrd by skin temtxrsture. plc:hysmoglsphy, and radiosodium CIPP~R~CC from the skin. Smokina WRS iound to adversely affect the fib;: and third ~FISUIP~ in a stp~iricant manner (while plethva- montaphic valurs weac rsr-isb!r) only in the healthy prisoners and not at a,, in the Sargent group. Roth and Schick. 100 normal tndividuals undrruent 425 cxperlmcntal procedures con- 1960. U.S..4 (161). cerntng the eflrrt 01 srnok~~~ on the petipheznl circulation. Smak- ing II-Z, found to be as.oclsted with a drrrrxe in extremity skin tP"De**t"*C. 129 130 Chapter 2 Cardiovascular Diseases Part II 131 CONTENTS Page Coronary Heart Disease (CHD) .............................. 135 Introduction ..................................... Cigarette Smoking as 3 Major Risk Factor for -135 Coronary Heart Disease .......................... .136 Cigarette Smoking in Relation to Other Risk Factors for Coronary Heart Disease .................. .137 Hypertension ............................. .137 Cofflee Drmking _ _ _ . _ _ _ _ . , _ _ . . _ . ,141 Ventriculx Premature Beats ................... .142 Carbon hlonoxide .................................. ,142 Introduction ................................. -142 Sources of Carbon hlonoxide Esposu re and Human Absorption ......................... .143 Effects on Healthy Individuals ..................... .148 Effects on Persons With Atherosclerotic Cardiovascular Disease ....................... .I49 Studies on the Pathogenesis of Cardiovascular Disease ................................. .150 Nicotine ....................................... ..15 1 Acrolein ....................................... ..15 1 Cerebrovascular Disease ................................ .,.151 Effects of Smoking on the Coagulation System .................. .154 Summary of Recent Cardiovascular Findings .... , ... , ........... .155 Bibliography .............. _ .......................... .156 133 List of Tables Table I. - Age-standardized blood pressure changes (mm tlg) at followup for continuing cigarette smokers and quitters according to weight clrsnges _ . . . _ _ 139 Table 2. - Number of subjects who had developed hypertension at followup for continuing cigarette smokers and quitters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...140 Table 3. - Mean percent of carboxyhemoglobin saturation in smokers and nonsmokers by sex and race . _ . . _ _ . _ _ . . _ . _ _ 144 Table 4. - Alean percent of carbosybemoglobin saturation in smokers and nonsmokers by employment status _ . . _ . 14.5 Table 5. - Median percent carbo~yl~enloglobln (COHb) saturation and 90 percent range for smokers and nonsmokers by location _ . . . . . . . . . _ . _ . 146 Table 6. - Alean percent carboxyhemoglobin (COHb) saturation in cigarette smokers I hour after last cigarette . . . . 147 Table 7. - Age-standardired death rates and mortality ratios for cerebral vascular lesions for men and women by type of smoking (lifetime history) and age at start of study . . . . . . . . . . .._...____...._____._______.____ 153 134 COROXARY HEART DISE,\SE (CHD) itirrodlrcliorl Coronary Heart Disease (CHD) is the most frequent C`XUSS of death in the United States and is the most important single c3use of excess mortality among cigarette smokers. The evidence relatins smoking to CHD has been reviewed in previous reports on the health consequences of smoking (61. 62. 63. 64. 65. 66. 67. 6Sj. The following is a brief summary of the relationships between smoking and CHD presented in these reports. Cigarette smoking, hypertension, and elevated serum cholesterol are the major alterable risk factors for myocardial infarction and death from CHD. Cigarette smoking acts both independently as a risk factor and synergistically with the other CHID risk factors. The magmtude of the risk increases directly wi'th the amount smoked. The excess risk of CHD amon? smokers has been demonstrated in some Asian, Black, and Caucasian populations and is proportionately greater for younger men, especially those below age 80. Cessation of cigarette smoking results in a reduced mortality rate from CHD compared with the mortality rate for those who continue to smoke. Pipe and cigar smokers have a slightly higher risk of death from CHD than nonsmokers. but they incur a much lower risk than ciga- rette smokers. This has been attributed to the lower levels of inhala- tion that characterize most pipe and cigar smoking. Data from autopsy studies have shown coronary atherosclerosis to be more frequent and more extensive in cigarette smokers than in nonsmokers, and experimental work in humans and animals has suggested several mechanisms by which smoking may influence the- development of atherosclerosis and CHD. The formation of carboxy- hemoglobin, release of catecholamines, creation of an imbalance between myocardial oxygen supply and demand, and increased platelet .adhesiveness leading to thrombus formation have all been demonstrated in smokers and proposed as explanations for the excess CHD mortality and morbidity among smokers. 135 Cigarette Stnot?ittg as a .Ilajor Risk Facror for Corottary Heart Dherrse The evidence establishing smoking as a major risk factor in CI1D has been reviewed in previous reports (lil. 62. 63. 64. 62. 66. 67. 6s). During the last year new epidemiologic data have been published on the relationship between coronary artery disease and smoking. Bengtsson (9. 10) studied the smoking habits of women with myocardial infarction (hiI) in Goteborg, Sweden. He found that smoking w3.s significantly more common in a group of 46 women (80 percent smokers), ages 50-54, who had a myocardial infarction than in ;1 control group of 578 herllthy nonhospitalized women (37.2 percent smokers). Other investigators examined the effect of cigarette smoking on sunrival of people with acute myocardial infarction. In a study of 400 patients with documented myocardial infarction who survived to he admitted to a coronary care unit, Helmers (26, 27, 2s) found no significant difference between the percentages of smokers and nonsmokers among survivors studied after ihe first 24 hours. from 2 days until discharge, and from discharge to 3 years. Reynertson and Tzagournis (53). in a 5-year prospective study of 137 patients with documented CHD at age 50 or less, were also unable to find sny relationship between CHD mortality rates and smoking habits. Smoking habits after entrance into the study were also considered and again rio difference in mortality rates was found. The Coronary Drug Project (17) found an effect of cigarette smoking on mortality after myocardial infarction. This group studied 2,789 men ages 30-64 years for 3 years after myocardial infarction and found a statistically significant correlation between cigarette smoking determined 3 months after a myocardial infarction and mortality (t-value of 2.94). None of these studies (Z 7, 26, 27, 28, 52) were able to examine the smoking habits of the group of people who die suddenly as a first manifestation of CHD, and therefore may have excluded that group in which there is the highest excess mortality due to cigarette smoking (31). Additional data from the Swedish twin study of Friberg, et al. (23) have been reported. They found an excess CHD mortality among smokers in dizygotic twins with different degrees of smoking, but no similar excess in monozygotic twins. Although the numbers \vcrc too lrnal1 to be significant, the authors suggest that this tends to >uppc>rt the theory that both smoking and CHD are constitutionally 136 determined. These data must be viewed with caution. however, since the difference was demonstrable only in the older age group (born 1901 - 1910). \J'hen the younger age group (born 191 1 - 19?5) ~3s considered, no excess CHD mortality was seen in the dizygotic group but a small excess was noted in the monozygotic group (three CHD deaths in the high smoking group and one in the low smoking group). Also the difference in cigarette consumption between the t!igh and low smoking groups was rslativeiy small (seven cigarettes per day). Consequently, data from this study are not sufficient to warrant the conclusion that both smoking and excess CHD mortality are constitutionally determined rather than smoking being a cause-of the excess CHD mortality. Cigarette Smoking in Relation to Other Risk Factors for Coronary Heart Dbease Cigarette smoking, elevated serum cholesterol, and elevated blood pressure are generally accepted as the three major modifiable risk factors for CHD. However, there is less agreement concerning other CHD risk factors - obesity, physical inactivity, diabetes mellitus. elevated resting heart rate, psycholopic type A behavior, etc. The following studies present recent evidence on the relation- ships between smoking and hypertension, coffee drinking, and ventricular premature beats. Results from several studies have shown that smokers on the average have slightly lower blood pressure than nonsmokers. Some investigators have attributed this finding to the fact that smokers on the average weigh slightly less than nonsmokers. Three current studies (24, 36. 55) discuss this relationship. Gyntelberg and Meyer (-74), based on their evaluation of 5,249 men ages 40-59, were of the opinion that lower blood pressure in smokers could not be accounted for by differences in weight. age, or physical fitness. Kesteloot and Van Houte (36), in a study of 42.804 men, performed a multiple regression analysis on age, weight, and height and found that cigarette smokers had lower blood pressure than nonsmokers; however, When they included serum cholesterol values in the analysis, the difference in blood pressure was reduced to approxi- mately I mm Hg. Although tllis difference was statistically signifi- cant based on the large population. the actual difference in blood pressure was too small to be of clinical importance. 137 Seltzer (55) studied 794 men selected for their initial good health and normal blood pressure (below 140 systolic and 90 diastolic) and followed them for changes in cigarette smoking habits, weight. and blood pressure. During the S-year period of the study 104 men gave up smoking. For every age group except those over 55. there was a significantly greater weight gain (8 lb) among the "quitters" than among the continuing smokers (3.5 lb). Blood pressure increased 4 mm Hg systolic and 2.5 mm Hg diastolic in the quitters with no change in systolic and a slight reduction in diastolic (-1.1 mm Hg) in persons who continued to smoke. in order to examine blood pressure changes in relation to weight change, both continuing smokers and quitters were grouped according to their weight changes during the period of study (Table 1). The most significant finding was an increase in the systolic blood pressure (+ 1 .77 mm Hg) among the quitters even in that group with significant weight loss. In contrast, the continuing smokers with significant wei$t loss had a decline in systolic blood pressure (-3.28 mm Hg). Diastolic blood pressure in quitters showed an increase with weight gain and no change with weight loss, while continuing smokeys showed a decrease in diastolic pressure with weight loss and no change with weight gain. The data on subjects whose blood pressure had increased to hypertensive levels (systolic > 1.50 and diastolic > 9.5) were evaluated, and it was found that quitters had a much higher frequency of becoming hypertensive than continuing smokers (Table 2). Seltzer, in interpreting these data, suggested that cigarette smoking tends to inhibit blood pressure increases, with only minimal pressure rises occurring even in instances of substantial weight gain. When this inhibiting effect of cigarette smoking is removed as in the case of the quitters, sharp rises in blood pressure become evident. He cautioned, however, that the development of hypertension in some quitters may have been responsible for decisions to lose weight and that his data do not allow an evaluation of the degree of blood pressure changes according to how recently cigarettes were given up. The results of the ischemic fleart disease study by Kahn, et al. (34) raise additional questions about Seltzer's data. Kahn followed 10,000 Jsraeli male civil service employees for 5 years to determine what factors were associated with an increased incidence of hypertension. He presented no data concerning persons who stopped smoking, but he did show that the incidence of hypertension increased with age and that the age-adjusted incidence of hyper- tension in smokers was over twice that of nonsmokers (76.9/ 1000 for smokers versus 35.4/1000 for nonsmokers). Seltzer reported no 138 TABLE 1. - Age-standardized blood pressure changes (mm IIg)l at followup for continuing cigarette sn~nkers and quitters according to weight chofrges Weight Change (LB) Significant No Significant Modcrate Smoking Clas wt LOS Wt Cl13ngc WI Gain II) lb lb NO. -25 to -5 No. -4 lo +4 No. +5 IO +12 Mean systolic BP changes; Continuing smokers 32 -4.00 84 -1.52 71 2.85 Quitters 13 1.77 27 2.22 27 4.04 Mean diastolic BP changes: Continuing smokers 32 -3.28 84 -2.04 71 0.13 Quitters 13 -0.31 27 -1.96 27 4.30 `Standardized on basis of age distribution of current cigarette smokers. Source: Seltzer, C.C. (j-5). Significanl WI c;ain II) - No. +I3 IO +30 24 I .sll 32 3 69 24 -0.04 32 3.94 TABLE 2. - Number of subjects who hod developed hyperrensiorl at followup for contirruhg cigorettc smokers and quirters Blood preaure Continuing cigarette snnokers Quitters levels Number Percent Number Pcrccnt Systolic blood pressure lSO+ 6 2.8 9 x.7 Systolic blood pressure 160+ 2 0.9 5 4.8 Diastolic blood pressure 9S+ 3 1.4 5 4.8 Source: Seltzer, C.C. (55). data on the incidence of hypertension in nonsmokers, and the age distribution for his group of smokers (the original source of the quitters) is heavily weighted toward younger age groups .(with only 33 of 214 men age 50 years or over). According to Kahn's data, this age group would be expected to have a lower incidence of hypertension, and, in fact, Seltzer found only small numbers of men who developed hypertension (eight with diastolic hypertension) (Table 2). Making interpretations based on such small numbers is hazardous; for example, the difference between current smokers and quitters in the incidence of diastolic hypertension could have been produced by only three men quitting smoking because they developed hypertension. Coffee Drinking The Boston Collaborative Drug Study (12) recently reported a correlation between coffee drinking (> 6 cups per day) and myocardial infarction that persisted after controlling for the effect of cigarette smoking. This was a retrospective study of 276 patients with a hospital discharge diagnosis of myocardial infarction and 1,103 age, sex, and hospital-matched controls discharged with other diagnoses. In addition to the usual limitations of retrospective studies, this study has several characteristics that make interpretation difficult. In controlling for the effect of cigarette smoking, the investigators divided the smokers into those who smoked one pack or less per day and those who smoked more than one pack per day. Because cigarette consumption is highly correlated with coffee consumption (29, 39), it can be expected that within such broad smoking categories those who were heavy coffee drinkers tended to be heavier smokers than those who consumed smaller amounts of coffee. It is also possible that the hospitalized controls represented persons who drank less coffee than the general population because of serious chronic illnesses. These characteristics of the study design do not allow firm conclusions to be made concerning the extent to which the relationship between coffee drinking and myocardial infarction is independent of the relationship of both variables to cigarette smoking. The question of the independent nature of this relationship is also dealt with in a prospective study by Klatsky, et al. (39) of 464 patients with myocardial infarction who previously had had multi- phasic health checkups. Both ordinary controls and CHD risk factor-matched controls were drawn from 250,000 people who had undergone the same multiphasic health checkups. The investigators did not find an independent correlation between coffee drinking and myocardial infarction when risk-matched controls were used. 141 The Framingham Study (I$) recently published data on coffee drinking based on a I?--year followup of 5,209 mrn and women ages 30-67. An incrensed risk cfdeath from all causes was demonstrated in coffee drinkers, but this relationship was accounted for by the associ- ation between coffee consumption and cigarette smol;i,g. No association between coffee drinking and myocardial infarction or between coffee drinking and the development of CHD, stroke, or intermittent clsudication was demonstrated. Heyden, et al. (29) also found no relationship between excessive coffee consumption (> 5 cups per day) and atherosclerotic vascular disease. Vettrrictrlar Prmratrtre Beats Ventricular premature beats have been shown to be a risk factor for sudden death from CHD. Vedin, et al. (69). in a study of 793 men 111 Goteborg, Sweden, examined the frequency of rhythm and COl~dUc~iOJ~ disturbances at rest and during exercise. They found no statistically significant correlation between cigarette smoking habits and the presence of supraventricular or ventricular premature beats at rsst or during exercise. CARBON MONOXIDE Itrtrodrictiott Carbon monoxide has long been recognized as a dangerous gas, but until recently concentrations which produced carboxyhemo- globin levels below 15 to 20 percent were thought to have little effect on humans. Currently there is considerable interest in determining the effect of chronic exposure to low levels of carbon monoside (65. 66, 67, 68). Carbon monoxide is present in concentrations of 1 to 5 pelcent of the gaseous phase of cigarette smoke (II, 45). The concentr%tion varies with temperature of combustion as well as with factors which control the oxygen supply such as the porosity of the paper and packing of the tobacco. The amount of carbon monoxide produced increases as the cigarette burns down. Carboxyhemoglobin levels in smokers vary from 2 to IS percent depending on the amount smoked, degree of inhalation, and the time elapsed since smoking the lrtst cigarette. Carbon monoxide, which has 230 times the affinity of oxygen for hemoglobin, impairs oxygen transportation in at lcast Iwo ways: 142 First, it competes with oxygen for hemoglobin binding sites. Second. it increases the affinity of the remaining hemo@obin for osyfen. thereby requiring a larger gradient in Paz between the blood and tissue to dsliver a given amount of oxygen; this increased gradient is usually produced by a lowering of the tissue Po2. Carbon monoxide also binds to other heme-containing pig ments, most notably myoglobin, for which it has e\`en a greater affinity than for hemoglobin under conditions of low Paz. The significance of this binding is unclear, but may be important in tissues, such as the heart muscle, which have both high oxygen requirements and large amounts of myoglobin. Sources of Carbon hlonoxide Exposure and flumarl A bsorpriorl Several researchers (13, 32, 35. 57. 60. 70) have estimated the relative contribution of cigarette smoking and air pollution to the human carbon monoxide burden as measured by carboxyhemoglobin levels (COHb). Kahn, et al. (35), in a study of 16,649 blood donors. determined that smoking was the most important contributing factor, followed by industrial work exposure. Nonsmoking industrial workers had COHb levels of 1.38 percent, and nonsmokers without industrial exposure had levels of .7S percent. Cigarette smokers. on the other hand, had very high levels. Smokers with industrial exposure had levels of 5.01 percent, while smokers without industriai exposure had levels of 4.44 percent (Tables 3 and 4). Stewart, et al. (57) found similar results in a nationwide survey of blood donors and noted marked variation in mean COHb levels in residents of different cities measured at different times of the year (Table 5). However. in all areas, smokers still had COHb levels two to three times higher than nonsmokers and had increasing COHb levels with increasing level of cigarette consumption (Table 6). Similar findings were reported by Torbati, et al (60) in a study of 500 male Israeli blood donors. Nonsmoking workers exposed to atitomobile exhaust - London taxi drivers (32) and garage and service station operators (13) ~ have higher baseline levels of carboxyhemoglobin than nonsmokers of the general population. But even in these high exposure occupations smokers have markedly higher COHb levels (8.1 and 10.8 percent) than nonsmokers (6.3 and 5.5 percent). An extreme is represented by New York City tunnel workers who are exposed to an average of 63 ppm CO with peak exposure levels as high as 217 ppm CO: cigarette smokers still maintained much higher COHb levels (5.01 percent) than nonsmokers (2.93 percent) (8). 143 TABLE 3. -Mean percent of carbo.~yhemoglobit1 saturation in smokers and notwnokers by sex alId race Total Sample 1 Nonsmokers Smokers1 No. jz+s,- NO. x+q No. 2 +s, Total Sample 16,649 2.30 t 0.02 10,157 0.85 2 0.01 6,492 4.58 t 0.03 hlalc 10,542 2.66 + 0.03 5,888 1.00 + 0.01 4>654 4.76 + 0 04 Female 6,107 1.68 + 0.03 4,269 0.64 + 0.01 1.838 4.10 + 0.06 White 15,167 2.28 to.02 9.474 0.85 f. 0.01 5.693 4 66 + 0.04 htale 9,669 2.65 f 0.03 5,508 1.00 * o.o\ 4,161 4 tl3 * 0.04 Female 5,498 1.63 f. 0.03 3,966 0.64 * 0.01 1,532 4 19 + 0.06 Black 1,429 2.59 5 0.06 641 Male 829 2.91 *0.10 347 Female 600 2.15 c 0.09 294 `Smokers are defined as those who smoked on the day of giving blood. NOTE. - % = mean percent: ST= standard error of mean percent. Source: Kahn, A., et al. (35). 0.86 t 0.03 788 4.00 f 0.08 1.07 2 0.05 482 4.24 + O.lC 0.62 + 0.04 306 3.63 f 0 12 TABLE 4. - hfearz percerzt of carbo.~.~llzt~rnoglobin saturation in smokers arzt! Izutzwzokers by euzployrnerzt statzis I Nonsmokers Smokrrs' xiss; I No. I.38 t 0.04 I 1,738 5.01 t O.OG G.955 0.7M f 0.0 1 I 4,224 4.44 f u.u`l Persons not employed 1,678 0.6 3 +_ 0.02 531 4 24 f 0. I I `Industrial workers are employed in either durably or ~mndur,~bls good> manufacturing (craflsmen. operalives. or I~borrrs). Smokers are defined iis those who smoked on lhe day UC giving I~lood. NOTE. - i = mean percent; S, = stnnd.lrd error of mean percent. Source: Kahn, A., et al. (35). TABLE 5. - Median percent carbo~yylrerrloglobin (COHb) saturation and 90 percetrt range for smokers and wmtnokers by location Location Anchorage Chicago Denver Dciroit rlonolulu Houston Los Angeles hliami Milwaukee New Orleans NW York PhOWlX St. Louis S.111 Lake City Slin IFruncisco SeJttle Vermont. NW Ilampshire Washington, DC Cigarette Smokers Nonsmokers . Median Range 4.1 0.9 - 9.5 5.8 2.0 - 9.9 5.5 2.0 - 9.8 5.6 1.6 - IO.4 4.9 1.6 - 9.0 3.2 1.0 - 7.8 6.2 2.0 - 10.3 S.0 1.2 - 9.1 4.2 1.0 - 8.9 5.5 2.0 - 9.6 4.8 1.2 - 9.1 4.1 09 - 8.7 5.1 1.7 - 9.2 5.1 1 5 - 9.5 5.4 1.6 - 9.8 5.7 1.7 - 9.6 4.8 1.4 - 9.0 4.9 1.2 - 8.4 hlcdian K3llge 1.5 0 6 .- 3.2 I .7 I.0 - 3 2 2.0 o.!, - 3.7 1.6 0.7 - 2.7 I.4 0.7 - 2.5 1.2 06-35 1.u I.0 - 3.0 1.2 0 4 - 3.0 1.2 0.5 - 2.5 1.6 I.0 - 3 u 1.2 0.6 .- 2 5 1.2 0.5 2 5 1.4 0.9 - !.I I.? 0 G 2,s 1.5 0 h 2.1 1.5 0.M - 2 7 I.2 0 K - ?..I s 1.2 0.6 2.5 l-- Source: Stewurt, K.D., et III. (57). TABLE 6. - Mean percent carhoxyl~emoglobirr (COiIb) saturation in cigarette smokers I hour after bst cigarette Location Nonsmoker Packs of Cigucttcs Smoked Per day CK %-I I 1 5i 2 hlilwukuc Now Htimp\hirc, Vermont New York City Washington, DC LOS Angclcs Chicago 1.3 3.0 4.2 5.3 6.2 4,7 1.4 3.3 4.4 5.1 67 5.3 1.4 3.1 4.3 4.1 5.x 63 1.4 3.8 4.6 5.2 5.x 6 6 2.0 4.0 5.2 6.0 1.4 7.5 2.0 4.x 5.4 6.3 7. I 1.1 Source: Slewart, R.D.. et al. (57) Studies on the CO burden of each cigrette have determined the body burden of CO per cigarette to be 7.10-S.66 ml (40). and the increase in COHb level produced by smoking one ci_rar?tte to he .94 to I .6 percenr after I:! hours of abstinence (40. 33). The hali-life for the washout of CO in healthy college smokers (40) was catculated to be from 3 to 5 hours. Several studies have been published on the effects of carbon monoxide on healthy individuals. Small doses of CO (COZb levels 2.4-5.4 percent) were found to have no effect on heart rate (56). Raven, et al. (5f), in a study of young men exposed during exercise on a treadmill to 50 ppm CO (COlIb levels 2.5 percent in nonsmokers and 4.1 in smokers), found no decrease in maximum aerobic capacity when the subjects were tested at 25" C. In a similar experiment conducted at 35" C by the same researchers (20). there was a decrease in maximum aerobic capacity in nonsmokers exposed to SO ppm CO, but not in smokers despite an increase in the carboxyhemoglobin levels of I.5 percent in both groups. They postulated a possible physiologic adaptation of smokers to carbon monoxide. Ekblom and Huot (22) studied five young men who inhaled CO to reach given COHb levels. They reported that as COHb levels increased, there was a decrease in maximal oxygen uptake and lower heart rates at maximal treadmill exercise. Sagone, et al. (54), in a study of 9 cigarette smokers and I8 nonsmokers ages 20-32, showed significantly higher values for COHb, red cell mass, hemoglobin, and hematocrit in the smokers. Levels of 2,3 DPG were unaltered while oxyhemoglobin affinity I'50 and A'fP levels were significantly lower in the smokers. The three smokers with highest red cell mass had normal arterial blood gases and one smoker had very high values of red cell mass which returned to normal after he stopped smokin,. 0 The authors interpret these data-as evidence of tissue hypoxia. Millar and Gregory (43), in a study of both fresh heparinized blood and ACD-stored blood from a bIood bank, showed a reduction in the oxygen carrying capacity of up to 10 percent in the blood of cigarette smokers; this reduction persisted for the full 21-day storage life of blood bank blood. Cole, et al. (16), in a study of pregnant women, found COHb levels in the fetus to be 1.8 times a~ great as those in the 148 simu!taneou,ly measured bloat! ot t!1t` m0tI1rr. Fct31 l~100d \v3s exposed to carbon monoxide in vitro. and Iztd! h~mo~!ol~in \vas found to 113~2 a shift of the osyh~mo~obin disassociation curve to the left as occurs \vit!l adult !lemo_clobin. The !li$ler fetal CO!!b levels were attributed to tile lower fetal Po2 and a resultant decrease in the ability of oxygen to compete for t!X fetal I~emoglobin. It was felt by the authors that the hi& COHb levels may be responsible for the lower birth wei$t of infants born to mothers who smoke. Effecis ofi Persons wirll A rheroscleroric Carrliovascdar Disease Aronow and Isbe!! (5) and Anderson, et a!. (I) have shown a decrease in the mean duration of exercise before the onset of pain in patients with angina pectoris exposed to low levels of carbon monoxide (50 and 100 ppm). Carboxyhemoglobin levels were significantly elevated (2.9 percent after 50 ppm; 4.5 percent after 100 ppm) and the systolic blood pressure, heart rate, and product of s>.stolic blood pressure times heart rate (a measure of cardiac work) were a!! significantly lower at onset of angina pectoris. In a continuation of this work. Aronow, et al. (2. 3) studied eight patients durin: two separate cardiac catheterizations, one during which each patient smoked three cigarettes and one during Lvhich each patient inhaled carbon monoxide until the maximal coronary sinus COHb level equalled that produced by smoking during the first catheterization. All eight had angiographically demonstrated CHD (> 75 percent obstruction of at least one coronary artery). Smoking increased the systolic and diastolic blood pressure, heart rate. left ventricular end-diastolic pressure (LVEDP), and coronary sinus. arterial, and venous CO levels. No changes were noted in left ventricular contractility (dp/dt), aortic systolic ejection period. or cardiac index, and decreases were found in stroke index and coronary sinus. arterial, and venous Pq When carbon monoxide was inhaled. increased LVEDP and coronary sinus, arterial, and venous CO levels were noted; there were no changes in systolic and diastolic blood pressure, heart rate, or systolic ejection period; and decreases in left ventricular dp/dt, stroke index, cardiac index and coronary sinus. arterial, and venous Paz were found. .These data suzoest that carbon monoxide has a negative inotropic effect OR m;&ardia! tissue resulting in the decrease in contractility (dp/dt) and stroke index. \I'hen the positive effect of nicotine on contrac- tility and heart rate is added by cigarette smoking, the net effect is increased cardiac work for the same cardiac output. in the heart with 149 coronary artery disease there is a greatly restricted capacity to increase blood flow in response to this increase in cardiac work. The result is early cardiac decompensation manifested by elevation in LVEDP and angina pectoris. Aronow, et al. have also shown decreased exercise time prior to onset of angina pectoris in persons exercised after riding for 90 minutes on the Los Angeles Freeway (4). In a related study, they demonstrated a decrease in exercise time before claudication in a group of patients with intermittent claudication who were exposed to 50 ppm CO (6). Studies otr the Putlrogertesis of Curdiovascniur Disease In a review of some of their work on carbon monoxide, Astrup and Kjeldsen (7) noted that in cholesterol-fed rabbits exposed to I70 ppm carbon monoxide for 7 weeks (COHb 16 percent) and then to 310 ppm for 2 weeks, the cholesterol content of the aorta was 2.5 times higher than that of cholesterol-fed, air breathing controls. Groups of cholesterol-fed rabbits intermittently exposed to carbon monoxide for 13 or 4 hours per day produced three- to fivefold increases in the cholesterol content of their aortas. Cholesterol-fed rabbits made hypoxic at IO and 16 percent oxygen had 3 to 3.5 times tlie aortic cholesterol content, while those exposed to 26 and 28 percent oxygen had a considerable decrease in cholesterol aciumulation. Theodore, et al. (5s) studied the aortas of monkeys, baboons, dogs. rats, and mice fed a normal diet but exposed to very high levels of CO (COHb levels 33 percent) and found no atheromatous changes in their aortas. Further work by Astrup and Kieldsen (38) revealed that in rab- bits fed normal diets but exposed to 180 ppm carbon monoxide for 2 weeks, there were local areas in their hearts of partial or total necro% of myofihrils; in the arteries there was endothelial swelling, formation of subendothelial edema, and degeneration of the myocytes. When the aortas of these rabbits were examined (37), the Iuminal coats showed pronounced changes characterized by sevcrc edematous reaction with extensive swellin, 0 and formation of srrbendothelial blisters and plaques. The authors postulate that carbon monoxide increases endothelial permeability to albumin which results in formation of edema leading to changes indijtirl~Ir;il,,lt~l~ from early atherosclerosis. 150