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Clinical Cardiology Passive Smoking and Heart Disease Mechanisms and Risk Stanton A. Glantz, PhD, William W. Parmley, MD Objective.-Recent clinical, laboratory, and epidemiological evidence that pas- sive smoking causes heart disease was reviewed, with particular emphasis on un- derstanding the underlying physiological and biochemical mechanisms. Data Sources.-Publications in the peer-reviewed literature were located via MEDLINE, citation in other relevant articles, and appropriate reports by scientific agencies. Greatest emphasis was given to work published since 1990. Conclusions.-Passive smoking reduces the blood's ability to deliver oxygen to the heart and compromises the myocardium's ability to use oxygen to create aden- osine triphosphate. These effects are manifest as reduced exercise capability in people breathing secondhand smoke. Secondhand smoke increases platelet ac- tivity, accelerates atherosclerotic lesions, and increases tissue damage following ischemia or myocardial infarction. The effects of secondhand tobacco smoke on the cardiovascular system are not caused by a single component of the smoke, but rather are caused by the effects of many elements, including carbon monoxide, nicotine, polycyclic aromatic hydrocarbons, and other, not fully specified elements in the smoke. Nonsmokers exposed to secondhand smoke in everyday life exhibit an increased risk of both fatal and nonfatal cardiac events. (JAIYIA. 1995;273:1047-1053) IN 1991, we reviewed the available epi- demiological, clinical, physiological, and biochemical evidence, and concluded that environmental tobacco smoke (ETS) caused heart disease in nonsmokers.t We estimated that ETS contributed about 37 000 heart disease deaths to the total of 53 000 annual deaths due to ETS, mak- ing passive smoking the third leading preventable cause of death, after active smoking and alcohol. Since then, there have been several other reviews of the literature that have reached similar con- clusions,1_6 and the American Heal•t As- sociation has concluded that passive smoking is an important risk factor for From the Division of Cardiology, Department of Medicine, Cardiovascular Research Institute, Univer- sity of California, San Francisco. Reprint requests to Division of Cardiology, University of California, San Francisco, CA 94143 (Dr Gtantz). heart disease in both adults' and chil- dren $ The Occupational Safety and Health Administration included the ef- fects of ETS on the heart in its risk assessment of passive smoking as part of a proposed rule that workplaces be essentially smoke-free.' This article up- dates our earlier review,l with particu- lar emphasis on new information that provides a clearer understanding of the mechanisms by which passive smoking causes heart disease. EFFECTS OF ETS ON OXYGEN DELIVERY, PROCESSING, AND EXERCISE Passive smoking reduces the blood's ability to deliver oxygen to the myocar- dium.The carbon monoxide in ETS dis- places and competes with oxygen for binding sites on red blood cells.10.1 Chil- dren of smoking parents have elevated levels of 2,3-diphosphoglycerate, an en- zyme that increases the disassociation of oxygen from hemoglobin in red blood cells in an effort to compensate for chronic oxygen deprivation $,'2,'5-17 While the reduction in oxygen-carrying capac- ity of blood caused by increased car- boxyhemoglobin is small compared with smokers, it can have important physi- ological implications because the body normally extracts more than 90% of the oxygen from the blood during exercise 18 People with existing heart disease show increasing electrocardiographic evidence of ischemiatszo and experience more ar- rhythmias21 as carboxyhemoglobin in- creases, even at low levels. In addition to reducing the blood's ability to deliver oxygen to the heart, there is direct evidence from animal studies that passive smoking reduces the ability of the heart muscle to con- vert oxygen into the "energy molecule" adenosine triphosphate. In a study in rabbits, the activity of the mitochon- drial enzyme cytochrome oxidase fell 25% after a single 30-minute exposure to secondhand smoke, and the activity continued to decline wi.th prolonged ex- posure.' After 8 weeks of exposure of 30 minutes per day, its activity was re- duced by half. Thus, not only does sec- ondhand smoke reduce the ability of the blood to deliver oxygen to the myocar- dium, but it also reduces the ability of the myocardium to effectively use the oxygen it receives ? Clinical Cardiology section editors: William A. Gaasch, MD, University of Massachusetts Medical School, Worcester; Margaret A. Winker, MD, Senior Editor, JAMA. This article is one of a series sponsored by the American Heart Association. JAMA, April 5, 1995-Vol 273, No. 13 Passive Smoking and Heart Disease-Glantz & Parmley 1047

Passive smoking has also been showii to significantly increase the amount of lactate in venous blood, which indicates that during passive smoking the heart increasingly relies on anaerobic metabo- lism.24 People with coronary heart dis- ease cannot exercise as long or reach as high a level of exercise after breathing secondhand smoke than when breath- ing clean air1421~26 and are more likely to develop arrhythmias with exercise?7 Healthy young adults exposed experi- mentally to secondhand smoke show higher resting heart rates, higher blood carboxyhemoglobin levels, a significant reduction in the amount of oxygen ab- sorbed during exercise, and a shorter time to exhaustion when running on a treadmill.192`' These studies also demon- strated an increased perceived level of exertion during exercise and an increase in maximum heart rate, carbon dioxide output, and the time to recover resting heart rate at the end of exercise, to the point that normal healthy individuals took as long as people with heart dis- ease to recover their resting heart rate following exercise.142' PLATELETS Secondhand cigarette smoke activates blood platelets, which increases the like- lihood of formation of a thrombus and can damage the lining of the coronary arteries and facilitate the development of atherosclerotic lesions.18-33 Large platelets and mean platelet volume are independent risk factors for recurrent or more serious myocardial infarction.1 In one experiment, nonsmokers and smokers were asked to smoke two ciga- rettes si The smokers' platelets, which were more active than the nonsmokers' platelets at the beginning of the experi- ment, did not significantly change ac- tivity in response to the two cigarettes. Most likely, the smokers' platelets were maximally activated because of the chronic exposure to the toxins in ciga- rette smoke, so the addition of the rela- tively small (compared with what a smoker receives on an ongoing basis) amount of toxins in two. cigarettes had no additional effects. In contrast, smok- ing just two cigarettes significantly in- creased nonsmokers' platelet activity, to the point that it was not significantly different from that of habitual smokers. This situation demonstrates that the re- sponses of nonsmokers and smokers to toxins in the cigarette smoke are often very different. Inn an experiment that more closely parallels the experience of nonsmoke'rs, the same investigator31 measured plate- let activity in smokers and nonsmokers before and after they sat in a room for 20 minutes where cigarettes had been smoked just before the experimental subjects entered. Again, there was no significant change in the platelet activ- ity among the smokers, but a significant increase in platelet activity among the nonsmokers, to the point that their plate- let activation was not discernibly dif- ferent from the smokers. These data, together with other human experi- ments,';'~ indicate that nonsmokers are much more sensitive to secondhand smoke than smokers and that very low levels of ETS exposure can have major impact on nonsmokers' platelet activity. It also appears that the process satu- rates at low doses: once the nonsmoker has been exposed to even a low dose of secondhand smoke, the platelets are maximally activated, similar to that of a habitual smoker. These data also indi- cate that dose-based extrapolations from smokers to nonsmokers using "cigarette equivalents" will grossly underestimate the risks to nonsmokers of breathing secondhand smoke. Animal data also support this conclu- sion. In our studies of the effects of pas- sive smoking on heart disease, we have found that bleeding time, another mea- sure of platelet activity, is significantly shortened (meaning more activated platelets) in both rabbits39,40 and rats41 exposed to low doses of secondhand smoke, with no additional effects at higher doses. At a biochemical level, studies of ciga- rette-smoke extract on the effects of platelet activity suggest that the toxins in the cigarette smoke increase platelet- activating factor by interfering with the activity of the plasma enzyme plate- let-activating factor acetylhydrolase,°' which reduces platelet activity by neu- tralizing platelet-activating factor. Be- cause toxins in the cigarette smoke ap- pear to reduce the effectiveness of plate- let-activating factor acetylhydrolase in neutralizing platelet-activating factor, these toxins may contribute to an in- crease in platelet activity. Nicotine does not appear to be the only active agent in tobacco smoke; some other as-yet-un- defined element in the smoke also con- tributes to these effects on the plate- lets 3s•a2 This biochemical result is rein- forced by clinical studies that find that smokers treated with nicotine patches show fewer changes in platelet activity than continuing smokers despite having similar nicotine levels.4~3 ATHEROSCLEROSIS In addition to short-term toxic effects of cigarette smoke, there are long-term permanent effects. In particular, smok- ing contributes to the development of atherosclerosis. In addition to their role in acute thrombus formation, platelets are also important in the development of atherosclerosis ~," Once there is dam- age to the arterial endothelium through mechanical or chemical factors, plate- lets interact with or adhere to the sub- endothelial connective tissue and initiate a sequence that leads to formation of atherosclerotic plaque. When platelets interact with or adhere to subendocar- dial connective tissue, they are stimu- lated to release their granule contents. Endothelial cells normally prevent plate- let adherence because of the nonthrom- bogenic character of their surface and their capacity to form antithrombotic substances such as prostacyclin. Once the endothelial cells have been damaged, the platelets adhere and release mito- gens such as platelet-derived growth fac- tor, which encourages migration and pro- liferation of smooth-muscle cells in the region of the endothelial injury. If plate- let aggregation is increased because of exposure to ETS, the likelihood that platelets will adhere at that endothelial injury site will be increased. Experiments in humans have indi- cated that even short-term exposure to ETS-like active smoking'S-signifi- cantly increases the appearance of anuclear endothelial cell carcasses in the blood of people exposed to ETS (or other tobacco products) constituents.' The ap- pearance of these cell carcasses indi- cates damage to the endothelium, which is the initiating step in the atheroscle- rotic process. The appearance of these cells after passive smoking in nonsmok- ers is almost as great as in active smok- ing in nonsmokers.29 Passive smoking both among adoles- cents whose parents smoke and also in adults working in places where smoking is permitted exhibit lower levels of high- density lipoprotein than children breath- ing clean air.12," Similar results have been reported in adults who work in smoky environments46 This effect on cholesterol and the ratio of high-density lipoprotein to total cholesterol contrib- utes to the risk of developing athero- sclerosis. Many atherosclerotic plaques in hu- mans are either monoclonal or possess a predominantly monoclonal component, which indicates that the smooth-muscle cells of each plaque have a predominant cell type. Several animal studies, re- viewed previously,' demonstrated that polycyclic aromatic hydrocarbons, in particular 7,12-dimethylbenz(a,h)anthra- cene and benzo(a)pyrene, accelerate the development of atherosclerosis. Benzo (a)pyrene is an important constituent of ETS. The polycyclic aromatic hydrocar- bons appear to bind preferentially to both the low-density lipoprotein and high-density lipoprotein subfragments 1048 JAMA, April 5, 1995=Vol 273, No. 13 ' Passive Smoking and Heart Disdase---Glantz & Parmley

of cholesterol, which may facilitate in- corporation of the carcinogenic com- pounds into the cells lining the coronary arteries and hence contribute to both cell injury and hyperplasia in the ath- erosclerotic process. In addition to this biochemical evidence demonstratingthe effects of specific com- ponents in ETS on the development of atherosclerotic lesions at a cellular and molecular level, recent animal experi- ments have demonstrated that short-term exposure to ETS significantly speeds the atherosclerotic process. Zhu et al39 ex- posed three groups of rabbits on a high- cholesterol diet to secondhand smoke 6 hours a day, 5 days a week for 10 weeks. The low-dose group was exposed to smoke at levels that would be observed in a smoky bar, whilethe high-dose group was exposed to pollution levels comparable with those observed in an automobile with the windows rolled up and four cigarettes per hour being smoked 44 After the rela- tively short period of 10 weeks or 300 hours of exposure, the fraction of pulmo- nary artery and aorta covered with lipid deposits doubled. This effect appears to be directly caused by elements in the cigarette smoke itself, rather than a reaction to the ETS that might have increased cir- culating catecholamines. (Increased lev- els of circulating catecholamines is one of the mechanisms by which cigarette smoking increases the risk of heart dis- ease in active smokers.) Sun et a140 ex- posed rabbits, in an experiment similar to that just described, to secondhand smoke, but gave half the rabbits the (3-blocking drug metoprolol. As ex- pected, the animals receiving metopro- lol developed fewer lipid deposits than those who were receiving saline placebo, but this effect was independent of whether the rabbits were breathing sec- ondhand smoke. Therefore, the effects of ETS on the development of arterial atherosclerosis was not mediated by the increased levels of catecholamines. One criticism has been that this rab- bit model of atherosclerosis requires the rabbits to be on a high-cholesterol diet. ' This experimental model of atheroscle- rosis, which has been used since 1908, requires the rabbits to have a high-cho- lesterol diet in order to develop any le- sions within a reasonable length of time.° However, Penn et al'0,s1 showed similar increases in plaque development in young cockerels (between 6 and 22 weeks old) who were exposed to secondhand smoke 6 hours a day, 5 days a week for 16 weeks. The cockerels were exposed to lower levels of secondhand smoke than the rabbits and were eating a normal, low-cholesterol diet. There was a sig- nificant acceleration in the growth of atherosclerotic plaques associated with passive smoking. After publication of the first study by Penn et al,j0 the tobacco industry pro- tested that the exposure levels were "unrealistically high," and urged them- through its Center for Indoor Air Re- search, which funded Penn's work-to repeat the experiment at lower levels of exposure 52 Penn et al5i conducted a sec- ond study, in which the cockerels were exposed to the smoke from a single ciga- rette at a time, yielding ETS pollution levels comparable to or below levels ob- served in bars. The second study pro- duced results similar to the first: ETS accelerated the development of athero- sclerotic plaque. The Center for Indoor Air Research has refused to continue funding any more work by Penn on this subject (written communication to Su- san Sherman regarding Gio Gori's tes- timony before the Occupational Safety and Health Administration, January 2, 1995). The carcinogens in smoke appear to be acting as a promoter to facilitate the development of plaques, rather than an initiator of plaques.52 In addition, it is unlikely that these effects are caused by the carbon monoxide in the smoke, be- cause other experiments where cocker- els were exposed to high doses of carbon monoxide did not produce similar ef- fects. In contrast, exposure to second- hand smoke for a relatively brief time (corresponding to about 0.4% of their life span) significantly accelerated the development of plaques. The fact that it is possible to induce atheroscleroticlike changes in two different species of ex- perimental animals with only a few weeks' exposure to secondhand smoke similar to that experienced by people in normal day-to-day life, is an important finding linking the epidemiological and biochemical evidence that passive smok- ing causes heart disease. The experi- mental studies on rabbits and cockerels, which do not suffer from the gap cre- ated by potential confounding variables in epidemiological studies, bridge this gap by showing that it is possible to induce atherosclerosis in experimental animals with ETS. Finally, there are also population- based data in humans showing that pas- sive smokers have significantly thicker carotid artery walls, in a dose-response relationship, than people who never were exposed to passive or active smoking.53 The increased carotid intimal-medial thickness persisted even after control- ling for differences in diet, physical ac- tivity, body mass index, alcohol intake, education, and maj or cardiovascular risk factors. At the midrange age of the study population (55 years), the increase in intimal-medial thickness for passive smokers was 23% of that observed in active smokers, despite the fact that the dose of tobacco smoke absorbed by pas- sive smokers is much less than that ab- sorbed by active smokers. This relatively large effect (compared with the dose) is consistent with what one would expect from the animal studies and is consis- tent with the comparable relatively large effect of ETS on the risk of heart dis- ease mortality and morbidity observed in epidemiological studies. FREE RADICALS IN ETS AND ISCHEMIC DAMAGE Free radicals are highly reactive oxy- gen products°',55 that are extremely de- structive to the heart muscle cell mem- brane as well as other processes within the cell. Passive smoking worsens the outcome of an ischemic event in the heart through the activity of free radicals dur- ing reperfusion injury; low exposures to nicotine or other cigarette smoke con- stituents significantly worsen reperfu- sion injury. The nicotine of just one cigarette doubled the reperfusion injury in dogs."' This is so low a dose of nicotine that it had no effect on the dogs' heart rate, blood pressure, regional myocardial shortening, or other hemodynamic mea- sures of cardiac function. These param- eters are commonly affected by nicotine in active and passive smokers 5'' After an ischemic episode in which the left anterior descending coronary artery was ligated for 15 minutes, the regional short- ening during reperfusion was reduced by 50% of the preischemic values. When the dogs were exposed to the nicotine from one cigarette, the muscle short- ened by 25% of control values. When the dogs were given a free radical scaven- ger with the nicotine, this effect was obliterated. Thus, exposure to a very low dose of nicotine doubled the impact of the reperfusion injury. The effects of free radicals induced by passive smoking have been explored at the cellular level ~,'9 Rats who were ex- posed to secondhand smoke from two cigarettes a day for 2 months exhibited severely damaged mitochondrial func- tion during reperfusion injury. The abil- ity of cardiac mitochondrial cells to con- vert oxygen into adenosine triphosphate was much more compromised during reperfusion injury among rats exposed to low doses of secondhand smoke than among control rats. This is another mechanism by which toxins in second- hand smoke interfere with myocardial energy metabolism. Smokers may be less sensitive to free radical damage from cigarette smoke than nonsmokers because of changes in JAMA, April 5, 1995-Vol 273, No. 13 Passive Smoking and Heart Disease-Glantz & Parmley 1049

0 , the levels of enzymes that control free radicals G0 When hamsters were exposed to the ETS from six cigarettes a day for 8 weeks, the activity of antioxidant en- zymes in their lungs nearly doubled. Similar changes were found in the lungs of smokers compared with nonsmokers. Thus, chronic exposure to cigarette smoke appears to increase the free radi- cal scavenging systems in smokers, a "benefit" that nonsmokers would not have when breathing someone else's smoke. In addition, passive smoking by hu- mans sensitizes lung neutrophils 61 As with platelets, neutrophils are an im- portant element of the body's defenses against infection and damage. Inappro- priately activated neutrophils, however, release oxidants that can play a role in tissue damage in passive smokers. In a group of passive smokers exposed to just 3 hours of sidestream smoke, there were significant increases in the circu- lating leukocyte counts and stimulated neutrophil migration. The responses to the exposure to secondhand smoke were greater in nonsmokers than in smokers, again suggesting that the biochemistry of ETS in passive smokers is different than in active smokers, rendering the passive smokers more sensitive to the toxins in ETS. MYOCARDIAL INFARCTION There are direct animal data to show that ETS promotes more tissue damage following myocardial infarction. Dogs ex- posed to secondhand smoke 1 hour daily for 10 days, who were then subjected to blockage of a coronary artery, devel- oped myocardial infarctions that were twice as large as those of controls who breathed clean air.2 This effect was not caused by elevated circulating levels of nicotine or carboxyhemoglobin, since the infarcts were created the day after the last day of ETS exposure. Zhu et alal investigated the effects of ETS expo- sure on infarct size by exposing rats to secondhand smoke 6 hours a day for 3 days, 3 weeks, or 6 weeks, then occlud- ing the left coronary artery for 35 min- utes and reperfusing the artery. Infarct size increased in a dose-dependent fash- ion, with the longest exposure (180 hours total ETS exposure) yielding infarcts that were nearly twice as large as those in the control group that breathed clean air (Figure 1). There was no evidence of a threshold effect. Although smokers seem to be less sen- sitive to effects of passive smoking than nonsmokers, it is important to recog- nize that even low doses of cigarette smoke can have important effects on smokers. For patients with coronary ar- tery disease, smoking one cigarette sig- nificantly increases coronary vascular resistance.63 Thus, if smoked at a time when demands for oxygen and blood sup- ply to the heart are increasing,5',' even a single cigarette can dramatically re- duce the ability of smokers' coronaries to transmit blood. In addition, in ha- bitual smokers smoking a single ciga- rette, compliance of coronary arterial walls is reduced and may increase the likelihood of rupture of atherosclerotic plaque, an important element in myo- cardial infaretion." It is likely that low doses of cigarette smoke will have simi- lar effects in passive smokers. EPIDEMIOLOGICAL STUDIES Wells' summarized 12 studies (count- ing end points for men and women sepa- rately even if they were reported in the same article, since cardiovascular risk is different for men and women and ef- fects of passive smoking may differ) that examined heart disease mortality asso- ciated with passive smoking (seven stud- ies of nonsmoking women married to men who smoke" and five of non- smoking men married to women who smokes7,es-7 a,vs) (Two other studies were excluded because they were published only as abstracts,76,'` but they also showed an increased risk. The fact that the only known unpublished data on pas- sive smoking and heart disease are posi- tive is evidence against the claim' that there is a publication bias against nega- tive studies on ETS.) Of these 12 stud- ies, 11 show an elevation in risk of death from heart disease for nonsmokers mar- ried to smokers (Figure 2) after con- trolling for other risk factors for ische- mic heart disease. Wald,sl in his analysis of passive smoking and lung cancer, made the point that one can do a simple analysis of the results of multiple epi- demiological studies by simply counting the studies that show relative risks (RRs) above and below 1.0. The prob- ability of observing 11 of 12 studies with an increased risk by chance if passive smoking did not affect the risk of heart disease death is only .003. In addition, eight of these studies show a positive dose-response relationship. These re- sults are consistent with the conclusion that passive smoking increases the risk of heart disease death. WellsS pooled the results from all 12 studies using the same approach as the US Environmental Protection Agency to estimate the effects of passive smok- ing and lung cancer.112 Pooling resulted in an RR for dying of heart disease of 1.2 (95% confidence interval [CI],1.1 to 1.4). Therefore, we can be more than 95% confident that passive smoking affects the risk of dying from heart disease and more than 97.5% confident that passive 75, 0 0 18 90 ETS Exposure, h ETS Clean Air~ 180 Figure 1.-The effect of passive smoking on infarct size in rats subjected to a 35-minute occlusion of the left coronary artery (from Zhu et al"). Infarct size increases in a dose-dependent manner without a threshold effect. ETS indicates environmental to- bacco smoke; data are means with SE bars. smoking increases the risk of death from heart disease. Applying this risk on a population basis yields an estimated 62 000 heart disease deaths in 1985,5 com- pared with only 3000 from lung cancer ' Because of declines in smoking and in- creases in smoke-free environments, Wellss estimates that this toll would have fallen to 47 000 by 1994. When WellsS limited his analysis to the five studies that best controlled for confounding variables for heart disease deaths, he obtained a higher adjusted RR for passive smoking and heart dis- ease mortality of 1.7 (95% CI, 1.3 to 2.3). Therefore, the more potentially con- founding factors were controlled for, the higher the risk that Wells found attrib- uted to secondhand smoke. The tobacco industry often criticizes studies for fail- ing to account for confounding variables' on the grounds that failure to account for confounders artificially inflates the observed RR and makes it appear that ETS is more dangerous than it really is.Wells found just the opposite result. In addition to the epidemiological stud- ies that used death as an end point, there are also 11 studies (considering men and women separately) that examined non- fatal cardiac disease (Figure 3), such as a nonfatal myocardial infarction, pres- ence of angina, or malignant electrocar- diographic changes 67,69,'S," Nine of., these studies show an elevation in risk. The probability of observing nine posi- tive studies out of 11 if there was no effect of passive smoking on nonfatal cardiac events is only .03. Wells' formal analysis (written communication, August 1994) to pool these studies yields a RR for nonfatal coronary events associated with exposure to secondhand smoke of 1050 JAMA, April 5, 1995-Vol 273, No. 13 . Passive Smoking and Heart Disease-Glantz & Parmley

Garland et alss Hole et a167 ~ Humble et alls B Jackson69 0 Z~: Sandler et ah° Butler72•73 Hirayama74 FS-vendsen et al7s Hole et als' Jackson69 Sandte~ et ah° Butler72.73 AII 0.1 1 10 Relative Risk Figure 2.-The effect of passive smoking on the risk of fatal myocardial events from published epidemiological studies.~70.n'S Pooled risk estimates include all studies as determined by Wells 5 Horizontal bars indicate 95 % confidence in- tervals; upper bounds are off the scale for the Garland et a166 and Jackson69 studies. 1.3 (95% CI, 1.1 to 1.6). Three of these studies show a dose-response relation- ship, with higher exposures of second- hand smoke associated with larger in- creases in risk. The fact that passive smoking increases the risk of nonfatal coronary events as well as fatal coro- nary events is consistent with what we know about the physiology and biochem- istry of how passive smoking affects the heart. Some of these studies used marriage to a current smoker as the measure of exposure to ETS,611-71,'5-"T',116 whereas oth- ers used marriage to an ever-smoker (even if the spouse was currently a non- smoker) as the measure of exposure to ETS 6°•6','2-7a,a',ss,87,as Given the fact that the effects of smoking (and, presumably, passive smoking) on the heart decline quickly89 when exposure ends, the de- sign of these studies is often biased against detecting an effect of ETS on heart disease. In addition, the fact that the observed risks are of comparable magnitude across studies done in many countries and controlling for a variety of the other risk factors for heart disease strengthens the confidence one can have in reaching a conclusion that passive smoking causes heart disease. CONCLUSION The ability of the heart and vascular system to adapt to changing conditions is an important factor when considering the health effects of ETS, particularly when one compares the effects of ETS in nonsmokers with smokers. People who smoke cigarettes are chronically and con- tinually adversely affecting their car- diovascular system,10 which adapts to compensate for all the deleterious ef- ~ E 0 3: He et al84 •He et a185 Hole et a167 Dobson et all's Jacksons9 Lee87 Svendsen et a175 Dobson et al8° Jackson69 Lee87 Le Vecchia et al88 AI I 0.1 - 1 10 Relative Risk Figure 3.-The effect of passive smoking on the risk of nonfatal myocardial events from published epidemiological studies.6169,'S,8^-aa Pooled risk estimates are from Wells (written communication, August 1994) and include the data from LaVecchia et al 88 which was not available for the publisheds computations. Horizontal bars indicate 95 % confidence intervals; upper bounds are off the scale for the Jackson69 study. fects of smoking. Nonsmokers, however, do not have the "benefit" of this adap- tation, so the effects of passive smoking on nonsmokers are much greater than on smokers. This difference probably arises for two reasons: first, nonsmok- ers' hearts and vascular systems have not attempted to adapt to the chemicals in secondhand smoke. Second, it appears that the cardiovascular system is ex- tremely sensitive to many of the chemi- cals in secondhand smoke. Smokers may have achieved the maximum response possible to at least some of the toxins in the smoke, so the small additional ex- posures associated with passive smok- ing have little or no effect on habitual smokers because the additional dose of these toxins is small compared with what the smoker normally receives. These two facts make it imperative to consider the effects of ETS on the car- diovascular system of passive smokers separately from the effects on active smokers. The qualitative differences be- tween the effects of ETS on smokers and nonsmokers explain the high RRs associated with passive smoking com- pared with active smoking, even though passive smokers absorb much smaller doses of the toxins in cigarette smoke than smokers do.0 In particular, the practice-often advocated by the tobacco industry and its scientific consultants when considering secondhand smoke- of thinking about "cigarette equivalents" or simple dose-based extrapolations from smokers to nonsmokers will lead to gross underestimations of the risks of passive smoking to the cardiovascular system. Tobacco industry proponents frequently state that even a heavily exposed pas- sive smoker breathes in the equivalent of less than one cigarette per day.83 This assertion ignores the complex chemis- try of ETS; some toxins in ETS are higher than in smoke inhaled by smok- ers, some are lower.l',ffi,si The tobacco industry justifies this assertion by us- ing chemicals that are relatively rich in mainstream smoke compared with ETS; using some of the carcinogens in ETS yields the equivalent of several ciga- rettes a day.' In any event, leaving aside the philosophical question of whether anyone ought to be required to breathe even one cigarette a day under any cir- cumstances, the ETS experienced by many people in their daily lives is enough to produce substantial adverse effects on the cardiovascular system. Using different methodologies, sev- eral investigators have estimated the population burden associated with pas- sive smoking and heart disease, yield- ing estimates of 30 000 to 60 000 deaths annually in the United States,i-1A92with about three times as many nonfatal car- diovascular events. This is a tremen- dous public health impact and one that warrants strong action, commensurate with that devoted to health problems that affect a smaller percentage of the population such as illegal drugs and the acquired immunodeficiency syndrome,°3 to protect workers, children, and the general public. The simplest and most cost-effective control measure is to man- date smoke-free workplaces, schools, and public places.°,1,1,°4-°g This article is based on testimony presented be- fore the Occupational Safety and Health Adminis- tration on September 21, 1994, in support of its proposed Indoor Air Quality rule9 The Occupa- tional Safety and Health Administration partially supported Dr Glantz for time spent preparing that testimony. I JAMA, April 5, 1995-Vol 273, No. 13 Passive Smoking and Heart Disease-Glantz & Parmley 1051

References 1. Glantz SA, Parmley WW. Passive smoking and heart disease: epidemiology, physiology, and bio- chemistry. Circulation. 1991;83:1-12. 2. Environmental Tobacco Smoke in the Work- place: Lung Cancer and Other Heal tlc Effects. Wash- ington, DC: National Institute for Occupational Safety and Health; 1991. Current Intelligence Bul- letin 54; document DHHS (NIOSH) 91-108. 3. Steenland K. Passive smoking and the risk of heart disease. JAMA. 1992;267:94-99. 4. Leone A. Cardiovascular damage from smoking: a fact or belief? Int J Cardiol. 1993;38:113-117. 5. Wells AJ. Passive smoking as a cause of heart disease. J An2 Coll Cardiol. 1994;24:546-554. 6. Office of Environmental Health Hazard Assess- ment. Cardiovascular Health Effects of Exposure to Environmental Tobacco Smoke. Berkeley; Cali- fornia Enviromental Protection Agency; 1994. Pub- lic review draft. 7. Taylor AE, Johnson DC, Kazemi H. Environ- mental tobacco smoke and cardiovascular disease: a position paper from the Council on Cardiopulmo- nary and Critical Care, American Heart Associa- tion. Circulation. 1992;86:1-4. 8. Gidding SS, Morgan W, Perry C, et al. Active and passive tobacco exposure: a serious pediatric health problem: a statement from the Committee on Atherosclerosis and Hypertension in Children, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 1994;90: 2582-2590. 9. US Occupational Safety and Health Adminis- tration. Indoor air quality (proposed rule). Federal Register. April 5, 1994;59:15968-16039. 10. US Dept of Health and Human Services. The Healtla Consequences of Smoking: Cardiovascular Disease: A Report of the Surgeon General. Wash- ington, DC: US Public Health Service, Office on Smoking and Health, 1983. DHHS (PHS) 84-50204. 11. US Dept of Health and Human Services. The Health Consequences of Involuntary Smoking: A Report of the Surgeon General. Office on Smoking and Health, Centers for Disease Control, Public Health Service, 1986. Document DHHS (CDC) 87- 8398. 12. Moskowitz W, Mosteller M, Schieken R, et al. Lipoprotein and oxygen transport alterations in passive smoking preadolescent children: the MCV Irwin study. Circulation. 1990;81:586-592. 13. US Environmental Protection Agency. Air Quality Criteria for Carbon Monoxide. Washing- ton, DC: US Environmental Protection Agency; 1990. USEPA document EPA/60018-90/045A. 14. Leone A, Mori L, Bertanelli F, Fabiano P, Filippelli M. Indoor passive smoking: its effect on cardiac performance. Int J Cardiol. 1991;33:247- 252. 15. Pomrehn P, Hollarbush J, Clarke W, Lauer R. Children's HDL-chol: the effects of tobacco, smok- ing, smokeless, and parental smoking. Circulation. 1990;81:726. 16. Moskowitz WB, Mosteller M, HewittJK, Eaves LJ, Nance WE, Schieken RM. Univariate genetic analysis of oxygen transport regulation in children: the Medical College of Virginia twin study. Pediatr Res. 1993;33:645-648. 17. Feldman J, Shenker IR, Etzel RA, et al. Pas- sive smoking alters lipid profiles in adolescents. Pediatrics. 1991;88:259-264. 18. Lamb D. Physiology of Exercise: Responses and Adaptation. New York, NY: Macmillan Pub- lishing Co; 1984. 19. Dwyer EMJ, Turino GM. Carbon monoxide and cardiovascular disease. N Engl J Med. 1989;321: 1474-1475. 20. Allred EN, Bleecker ER, Chaitman BR, et al. Short-term effects of carbon monoxide exposure on the exercise performance of subjects with coronary artery disease. N Engl J Med. 1989;321:1426-1432. 21. Sheps DS, Herbst MC, Hinderliter AL, et al. Production of arrhythmias by elevated carboxyhe- moglobin in patients with coronary artery disease. Ann Intern Med. 1990;113:343-351. ' 22. GvozdjakJ, GvozdjakovaA, KucharskaJ, Bada V. The effect of smoking on myocardial metabolism. Czech Med. 1987;10:47-53. 23. Gvozdjakova A, Kucharska J, Gvozdjak J. Ef- fect of smoking on the oxidative processes of car- diomyocytes. Cardiology. 1992;1992:81-84. 24. McMurray RG, Hicks LL, Thompson DL. The effects of passive inhalation of cigarette smoke on exercise performance. Eur J Appl Physiol. 1985; 54:196-200. 25. Khaifen ES, Klochkov VA. Effect of passive smoking on physical tolerance of ischemia heart disease patients. Ter Arkh. 1987;59:112-115. 26. Aronow W. Effect of passive smoking on an- gina pectoris. N Engl J Med. 1978;29921-24. 27. Leone A, Bertanelli F, Mori L, Fabiato P, Ber- tanelli G. Ventricular arrhythmias by passive smoke in patients with pre-existing myocardial infarction. J Am Coll Cardiol. 1992;19:256A. Abstract. 28. Pittilo RM, Mackie IJ, Rowles PM, Machine SI, Woolf N. Effects of cigarette smoking on the un- trastructure of rat thoracic aorta and its ability to produce prostacyclin. Thromb Haemost. 1982;48: 173-176. 29. Davis J, Shelton L, Watanabe I, Arnold J. Pas- sive smokingaffects endothel3um and platelets. Arch Inter r, Med. 1989;149:386-389. 30. Sinzinger H, Kefalides A. Passive smoking se- verely decreases platelet sensitivity to antiaggre- gatory prostaglandins. Lancet. 1982;2:392-393. 31. Burghuber 0, Punzengruber C, Sinzinger H, Haber P, Silberbauer K. Platelet sensitivity to pros- tacyclin in smokers and non-smokers. Chest. 1986; 90:34-38. 32. Sinzinger H, Virgolini I. Are passive smokers at greater risk of thrombosis? Wien Klin Wochen- s c lz r. 1989; 20:694-698. 33. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol: modifications of low-density lipoprotein that increase its athero- genicity. N Engl J Med. 1989;320:915-924. 34. Martin JF, Bath PM, Burr ML. Influence of platelet size on outcome after myocardial infarc- tion. Lancet. 1991; 338:1409-1411. 35. Davis JW, Hartman CR, Lewis HD Jr, et al. Cigarette smoking-induced enhancement of plate- let function: lack of prevention by aspirin in men with coronary artery disease. JLab Clin Med. 1985; 105:479-483. 36. Davis JW, Shelton L, Eigenberg DA, Hignite CE, Watanabe IS. Effects of tobacco and non-to- bacco cigarette smoking on endothelium and plate- lets. Clin Pharmacol Ther. 1985;37:529-533. 37. Davis J, Shelton L, Hartman C, Eigenberg D, Ruttinger H. Smoking-induced changes in endo- thelium and platelets are not affected by hydroxy- ethylrutosides. Br J Exp Pathol. 1986;67:765-771. 38. Davis JW, Shelton L, Eigenberg DA, Hignite CE. Lack of effect of aspirin on cigarette smoke- induced increase in circulating endothelial cells. Hae- mostasis. 1987;7:66-69. 39. Zhu B-Q, Sun Y-P, Sievers R, Isenberg R, Glantz SA, Parmley WW. Passive smoking increases ex- perimental atherosclerosis in cholesterol-fed rab- bits. J Am Coll Cardiol. 1993;21:225-232. 40. Sun Y-P, Zhu B-Q, Sievers RE, Glantz SA, Parmley WW. Metoprolol does not attenuate ath- erosclerosis in lipid-fed rabbits exposed to envi- ronmental tobacco smoke. Circulation.1994;89•2260- 2265. 41. Zhu B-Q, Sun Y-P, Sievers RE, Glantz SA, Parmley WW, Wolfe CL. Exposure to environmen- tal tobacco smoke increases myocardial infarct size in rats. Circulation. 1994;89:1282-1290. 42. Miyaura S, Eguchi H, Johnson JM. Effect of a cigarette smoke extract on the metabolism of the proinflammatory autacoid, platelet-activating fac- tor. Circ Res. 1992;70:341-347. 43. Benowitz NL, Fitzgerald GA, Wilson M, Zhang Q. Nicotine effects on eicosanoid formation and he- mostatic function: comparison of transdermal nico- tine and cigarette smoking. J Am Coll Cardiol. 1993;22:1159-1167. 44. Ross R. The pathology of atherosclerosis: an update. N Engl J Med. 1986;314:488-S0o. 45. Prerovsky I, Hladovec J. Suppression of the desquamating effect of smoking on the human en- dothelium by hydroxyethylrutosides. Blood Ves- sels. 1979;16:239-240. 46. White JR, Froeb HF. Serum lipoproteins in nonsmokers chronically exposed to tobacco smoke in the workplace. Presented at the Eighth World Conference on Tobacco and Health; March 30-April 3, 1992; Buenos Aires, Argentina. Abstract. 47. Ott W, Landan L, Switzer P. A time series model for cigarette smoking activity patterns: model validation for carbon monoxide and respirable par- ticles in a chamber and an automobile. J Expo Anal Environ Epidemiol. 1992;2(suppl 2):175-200. 48. Wu JM. Increased experimental atherosclero- sis in cholesterol-fed rabbits exposed to passive smoke: taking issue with study design and methods of analysis. J Am Coll Cardiol. 1993;22:1751-1752. Letter. 49. Zhu B-Q, Sun Y-P, Sievers RE, Isenberg WM, Glantz SA, Parmley WW. Increased experimental atherosclerosis in cholesterol-fed rabbits exposed to passive smoke: taking issue -nith study design and methods of analysis. J Am Coll Cardiol. 1993; 22:1752-1753. Reply to letter. 50. Penn A, Snyder CA. Inhalation of sidestream cigarette smoke accelerates development of artio- sclerotic plaques. Circulation. 1993;88(part 1):1820- 1825. 51. Penn A, Chen LC, Snyder CA. Inhalation of steady-state sidestream smoke from one cigarette promotes atherosclerotic plaque development. Cir- cu lation. 1994; 90:1363-1367. 52. Penn A, Currie J, Snyder CA. Inhalation of carbon monoxide does not accelerate arterioscle- rosis in cockerels. Eur J Pha:rmacol. 1992;22$:155- 164. 53. Howard G, Burke GL, Szklo M, et al. Active and passive smoking are associated with increased ca- rotid artery wall thickness: the Atherosclerosis Risk in Communities Study. Arch Intern Med. 1994;154: 1277-1282. 54. Church DF, Pryor WA. Free-radical chemistry of cigarette smoke and its toxicological implica- tions. Environ Health Perspect. 1985;64:111-126. 55. Ferrari R, Ceconi C, Curello S, et al. Oxygen free radicals and myocardial damage: protective role of thiol-containing agents. Am J Med. 1991;91 (suppl 3C):95S-105S. 56. Przyklenk K. Nicotine exacerbates postischemic contractile dysfunction of `stunned' myocarclium in the canine model: possible role of free radicals. Cir- cu lation. 1994;89:1272-1281. 57. Benowitz NL. Nicotine and coronary heart disease. Trends Cardiovasc Med. 1991;1:315-321. 58. van Jaarsveld H, Kuyl JM, Alberts DW. Ex- posure of rats to low concentration of cigarette smoke increases myocardial sensitivity to ischaemial reperfusion. Basic Res Cardiol. 1992;87:393-399. 59. van Jaarsveld H, Kuyl JM, Alberts DW. Anti- oxidant vitamin supplementation of smoke-exposed rats partially protects against myocardial ischaemic/ reperfusion injury. Free Radic Res Commun.1992; 17:263-269. 60. McCusker K, Hoidal J. Selective increase of antioxidant enzyme activity in the alveolar macro- phages from cigarette smokers and smoke-exposed hamsters. Am Rev Respir Dis. 1990;141:678-682. 61. Anderson R, Theron AJ, Richards GA, Myer MS, van Rensburg AJ. Passive smoking by humans sensitizes circulating neutrophils. Am Rev Respir Dis. 1991;144:570-574. 62. Prentice RC, Carroll R, Scanlon PJ, Thomas JXJ. Recent exposure to cigarette smoke increases myocardial infarct size. J Am Coll Cardiol.. 1989; 13:124A. Abstract. 63. Quillen JE, Rossen JD, Oskarsson HJ, Minor RLJ, Lopez AG, Winniford MD. Acute effect of cigarette smoking on the coronary circulation: con- striction of epicardial and resistance vessels. J Am Coll Cardiol. 1993;22:642-647. 64. Fenton RA, Dobson JGJ. Nicotine increases heart adenosine release, oxygen consumption, and 1052 JAMA, April 5, 1995-Vol 273, No. 13, Passive Smoking and Heart Disease-Glaniz & Parmley

contractility. Am J Physiol (Heart).1985;249:H463- H469. 65. Kool MJF, Hoeks APG, Boudier HAJS, Reneman RS, Van Bortel LMAB. Acute and chronic effects of smoking on arterial wall properties in habitualsmokers. JAm Coll Cardiol. 1993•,22:1881- 1886. 66. Garland C, Barrett-Connor E, Suarez L, Criqui M, Wingard D. Effects of passive smoking on is- chemic heart disease mortality of nonsmokers. Am J Epidemiol. 1985;121:645-650. 67. Hole DJ, Gillis CR, Chopra C, Hawthorne VM. Passive smoking and cardiorespiratory health in a general population in the west of Scotland. BMJ. 1989;299:42.3-427. 68. Humble C, Croft J, Gerber A, Hames C, Ty- roler H. Passive smoking and twenty year cardio- vascular disease mortality among nonsmoking wives in Evans County, Georgia. Am J Public Health. 1990;80:599-601. 69. Jackson RT. The Auckland Heart Study. Auck- land, New Zealand: University of Auckland; 1989. 70. Sandler DP, Comstock GW, Helsing KJ, Shore DL. Deaths from all causes in in nonsmokers who lived with smokers. Am J Public Health. 1989;79: 163-167. 71. Helsing K, Sandler D, Chee E. Heart disease mortality in nonsmokers living with smokers. Am J Epiderniol. 1988;127:915-922. 72. Butler TL. The Relationship of Passive Smok- ing to Various Health Outcomes Among Seventh Day Adventists in California. Los Angeles: Uni- versity of California; 1988. 73. Butler TL. The relationship of passive smoking to various health outcomes among Seventh-Day Adventists in California. In: Program and abstracts of the Seventh World Conference on Tobacco and Health; April 1-5, 1990; Perth, Australia. Abstract 316. 74. Hirayama T. Passive smoking. N Z Med J. 1990; 103:54. 75. Svendsen KH, Kuller LH, Martin MJ, Ockene JK. Effects of passive smoking in the Multiple Risk Factor Intervention Trial. Am J Epidemiol. 1987; 126:783-795. 76. Hunt SC, Martin MJ, Williams RR. Passive smoking by nonsmoking wives is associated with an increased incidence of heart disease. In: Program and abstracts of the annual meeting of the Ameri- can Public Health Association; 1986; Las Vegas, Nev. 77. Palmer J, Rosenberg L, Shapiro S. Passive smoking and myocardial infarction. CVD-Epide- miol Newslett. 1988;43:29. 78. Rennie D. Smoke and letters. JAMA. 1993;270: 1742-1743. 79. Rennie D. Smoke and letters. JAMA. 1994;271: 1575. 80. Bero LA, Glantz SA, Rennie D. Publication bias and public health policy on environmental to- bacco smoke. JAMA. 1994;272:133-136. 81. Wald N. Does breathing other people's tobacco smoke cause lung cancer? BMJ.1986;293:1217-1222. 82. Respiratory Health Effects of Passive Smok- ing: Lung Cancer and Other Disorders. Washing- ton, DC: US Environmental Protection Agency; 1992. USEPA document EPA/600/6-90/006F. 83. Secondhand smoke: is it a hazard? Consumer Rep. 1995;60:27-33. 84. He Y, Li L-S, Wan Z-H, Li L-S, Zheng X-L, Gru L-L. Women's passive smoking and coronary heart disease. Chung Hua Yu Fang I Hsueh Tsa Chih. 1989;23:19-22. 85. He Y, Lam TH, Li TS, et al. Passive smoking at work as a risk factor for coronary heart disease in Chinese women who have never smoked. BMJ. 1994;308:380-384. 86. Dobson AJ, Alexander HM, Heller RF, Lloyd DM. Passive smoking and the risk of heart attack or coronary death. Med J Aust. 1991;154:793-797. 87. Lee P. Deaths from lung cancer and ischaemic heart disease due to passive smoking in New Zea- land. N Z Med J. 1989;102:448. 88. LaVecchia C, D'Avanzo B, Franzosi MG, Tognoni G. Passive smoking and the risk of acute myocardial infarction (letter). Lancet. 1993;341:505- 506. 89. US Dept of Health and Human Services. The Health Benefzts ofSmoking Cessation: A Report of the Surgeon General. Washington, DC: Office on Smoking and Health, Centers for Disease Control, Public Health Service; 1990. Document DHHS (CDC) 90-8416. 90. Wu-Williams A, Samet J. Environmental to- bacco smoke: exposure-response relationships in epidemiologic studies. Risk Analysis. 1990;10:39- 48. 91. National Research Council Conunittee on Pas- sive Smoking. Environmental Tobacco Smoke: Mea- suring Exposures and Assessing Health Effects. Washington, DC: National Academy Press; 1986. 92. Wells AJ. An estimate of adult mortality in the United States from passive smoking. Environ Int. 1988;14:249-265. 93. Glantz S. Actual causes of death in the United States. JAMA. 1994;271:660. 94. Stillman F, Becker D, Swank R, et al. Ending smoking at the Johns Hopkins medical institutions: an evaluation of smoking prevalence and indoor pollution. JAMA. 1990;264:1565-1569. 95. Woodruff T, Rosebrook B, Pierce J, Glantz S. Lower levels of cigarette consumption found in smoke-free workplaces in California. Arch Intern Med. 1993;153:1485-1493. 96. Siegel M. Involuntary smoking in the restau- rant workplace: a review ofemployee exposure and health effects. JAMA. 1993;270:490-493. 97. Pierce JP, Evans N, Farkas AJ, et al. Tobacco Use in California: An Evaluation of the Tobacco Control Program, 1989-1993. San Diego: Univer- sity of California; 1994. 98. Pierce JP, Shanks TG, Pertschuk M, et al. Do smoking ordinances protect non-smokers from en- vironmental tobacco smoke at work? Tobacco Con- trol. 1994;3:15-20. i I JAMA, April 5, 1995-Vol 273, No. 13 Passive Smoking and Heart Disease-Glantz & Parmley 1053