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Home My WebLink AboutSPECIAL REPORT FOR PUBLIC HEARING Special Report Cardiovascular Effects of Secondhand Smoke Nearly as Large as Smoking Joaquin Barnoya, MD, MPH; Stanton A. Glantz, PhD Background—Secondhand smoke increases the risk of coronary heart disease by "30%. This effect is larger than one would expect on the basis of the risks associated with active smoking and the relative doses of tobacco smoke delivered to smokers and nonsmokers. Methods and Results We conducted a literature review of the research describing the mechanistic effects of secondhand smoke on the cardiovascular system, emphasizing research published since 1995, and compared the effects of secondhand smoke with the effects of active smoking. Evidence is rapidly accumulating that the cardiovascular system—platelet and endothelial function, arterial stiffness, atherosclerosis, oxidative stress, inflammation, heart rate variability,energy metabolism, and increased infarct size—is exquisitely sensitive to the toxins in secondhand smoke. The effects of even brief(minutes to hours)passive smoking are often nearly as large(averaging 80%to 90%)as chronic active smoking. Conclusions—The effects of secondhand smoke are substantial and rapid, explaining the relatively large risks that have been reported in epidemiological studies. (Circulation. 2005;111:2684-2698.) Key Words: smoking • cardiovascular diseases ■ endothelium ■ epidemiology ■ tobacco smoke pollution Secondhand smoke (SHS) increases the risk of heart the toxins in SHS. These mechanisms, rather than isolated disease by X30%,'-7 accounting for at least 35 000 events, interact with each other to increase the risk of heart deaths annually in the United States.Z8 Protection of non- disease. smokers through smoke-free environments leads to a de- The present article extends earlier reviews of the biological crease in heart disease mortality through a combination of effects of SHS on the cardiovascular system,3-5.'4-2' with reduced exposure to SHS and an environment that makes it particular emphasis on literature on the effects of low doses of easier for smokers to stop smoking.9 The California Tobacco tobacco smoke exposure and the speed of the effect on the Control Program that stressed smoke-free policies has been cardiovascular system. In many cases, the effects of even associated with preventing 59 000 deaths resulting from heart brief(minutes to hours)passive smoking are nearly as large disease between 1989 and 1997.10 An evaluation of a geo- as those from chronic active smoking. graphically isolated community (Helena,Mont) showed that the number of hospital admissions resulting from acute Epidemiological Studies myocardial infarction decreased after the implementation of a Epidemiological data on the relationship between passive law ending smoking in public and workplaces,an effect that smoking and heart disease have been accumulating since the partially reversed when enforcement of the law was sus- mid-1980s. Six meta-analyses have been published,3-z22 all pended by a lawsuit." The effects observed in epidemiolog- yielding relative risks of heart disease from passive smoking ical studies are both larger and faster than one would expect that range between 1.2 and 1.3. Since the last meta-analysis if there were a simple linear dose-response relationship was published, we found 6 new epidemiological studies on between level of smoke exposure in passive smokers and the association of passive smoking with heart disease (4 active smokers.12 Despite the fact that the dose of smoke case-control23-26 and 2 cohort studies272e).We excluded 223'25 delivered to active smokers is 100 times or more that of 32-25 case-control reports on the same data set and 1 delivered to a passive smoker, the relative risk of coronary cohort study because of serious misclassification bias?7.29 heart disease for smokers is 1.78,5 compared with 1.31 for Figure 1 shows the results of the 29 studies as the risk of passive smokers(Figure 1). Rapidly accumulating evidence, ischemic heart disease in never-smokers exposed to SHS however, indicates that many important responses of the relative to the risk in those who were not exposed to SHS. cardiovascular system (Table 1) are exquisitely sensitive to The pooled relative risk computed with a random-effects From the Center for Tobacco Control Research and Education,Cardiovascular Research Institute,and Division of Cardiology,University of California, San Francisco. Dr Barnoya currently is at the Unidad de Cirugia Cardiovascular de Guatemala. Reprint requests to Stanton A.Glantz,PhD,Professor of Medicine,University of California,San Francisco,530 Parnassus,Suite 366,San Francisco, CA 94143-1390.E-mail glantz@medicine.ucsfedu CO 2005 American Heart Association,Inc. Circurohon is available at httpd/www.circulalionaha.org DOI:10.1161/CIRCULATIONAHA.104.492215 Downloaded from http://circ.ahajouM84.org/by guest on February 23,2016 Barnoya and Glantz Cardiovascular Effects of Secondhand Smoke 2685 Steer and(m) a Saarland(p Kawachl(t) • Humble(1) liole(both) ., _.._.- Garland(Q Hirayama(I) )—{— Butler(I) ..—_ _ ..4_.-_...--__.__ — But$er(m) Butler(Q .__..-_a.-- - Sandler(m) (t) Svendsen(m) ---_ •He(t) - ---- - He(both) i • • ` Rosenlund(both) hicaduff(m)(m) MCEldtdl(1) Ciruzzi(both)(both) --- `- '-- -- taVecchla(both) 0 --- Lee(both) ---t--- Muscat(both) • .• Jackson(m) Jadtaen m - —Dobson(m) Dobson(I) i __ *-. Pksavos(m) fa-- Pitaavos(1) --.--1-— wtdncup(m) '�------ Combined t �. .1 1 10 Odds ratio for heart disease Figure 1.Summary of epidemiological studies on passive smoking and coronary heart disease,together with results of random-effects meta-analysis.There was no significant heterogeneity(P=0.1),but we used random-effects model to be conservative.Citations for indi- vidual studies are as follows: Steenland et a1,152 Kawachi et a1,153 Humble et aI,154 Hole et a1,155 Garland et a1,156 Hirayama,157 Butler,158 Sandler et a1,159 Svndsen et a1,168 He et a1,6 Roselund et a126 McElduff et a1,181 Ciruzzi et a1,162 LaVecchia et a1,163 Lee et a1,164 Muscat and Wynder,165 Jackson,166 Dobson et a1,167 Pitsavos et a1,24 and Whincup et a128 model (computed with Stata Version 7) was 1.31 (95% CI, that even people in the control reference group had some 1.21 to 1.41), similar to the estimates of earlier SHS exposure.)These results suggest that passive smoking meta-analyses.3-7a2 leads to between 68%and 86%of the risk of light smoking, In 2004, Whincup et a128 published a 20-year prospec- depending on the level of SHS exposure (Table 2). tive study of passive smoking and coronary heart disease that estimated that the risk associated with passive smok- ing was between 1.45 (95% CI, 1.10 to 2.08) and 1.57 TABLE 1. Effects of SHS on the Cardiovascular System (95% CI, 1.08 to 2.28), depending on the level of SHS exposure. These estimates are about twice as high as Platelet activation earlier estimates (Figure 1)and nearly as high as observed Endothelial dysfunction in light(1 to 9 cigarettes/d)active smokers(1.66;95%CI, Inflammation and infection 1.04 to 2.68). Earlier epidemiological studies that used Atherosclerosis marriage to a smoker as a surrogate for exposure did not Low HDL levels capture the entire exposure to SHS, including from work- Plaque instability places and public places such as restaurants and bars.As a result, they underestimated SHS exposure and simply Increased oxidized LDL compared more exposed people (nonsmokers married to a Increased oxidative stress smoker but exposed to SHS elsewhere) to less exposed Decreased energy metabolism people(nonsmokers married to nonsmokers but exposed to Increased insulin resistance SHS elsewhere). This comparison biases the risk estimate Outcome measures of the effect of SHS downward.By using cotinine,a stable Increased infarct size metabolite of nicotine,3O as the measure of exposure, Decreased heart rate variability Whincup et a128 were able to capture more of the total SHS Increased arterial stiffness exposure. (The reference group consisted of the lowest quartile of cotinine levels, 0 to 0.7 ng/mL, which means Increased risk of coronary disease events Downloaded from http://circ.ahajournals.org/by guest on February 23,2016 2686 Circulation May 24, 2005 TABLE 2. Comparative Effects of Passive and Active Smoking* SHS/Active SHS Effectt Exposure Active Effect# Effect,§9/0 Risk of heart disease(95%CI) Figure 1 1.31(1.21 to 1.41) Chronic 1.78(1.31 to 2.44)11 40 20 y28 1.57(1.08 to 2.281 Cotinine at study entry 1.66(1.04 to 2.68) 86 First 4 y28 3.73(1.32 to 10.98) Cotinine at study entry 3.32(0.87 to 12.64) 122 Platelet function Platelet activation"(SI PGI2)# 0.55±0.059 20 min 0.54±0.069 96 Platelet aggregate ratio32,32a(change) -0.09 20 min -0.15 60 Fibrinogen,B7 mg/dL(95%CI) 5.2(-1.2 to 12) Chronic 6.9(-0.9 to 14) 75 Fibrinogen,38 mg/dL(SE) 11.2±4.1 Chronic 18.1-±6.7 62 Plasma thromboxane,4 pg/mL 3.30±0.35 Acute 2.93±0.07 113 Plasma malondialdehyde,40 nmol/L per 109 platelets 4.2±0.17 Acute 3.9±0.07 108 Endothelium and arterial function Endothelial cell count 32.32a mean No. of anuclear cell carcasses 0.9 20 min 2.0 45 on 0.9-4 chamber(change) Coronary flow velocity reserve,43 cm/s 68.8±22.7 30 min 67.1-L-15.0 91 Flow-mediated dilation,45% 3.1±2.7 ?3 y 4.4±3.1 134 Aortic stiffness,67.88 mm Hg/mm 58 4 minutes 49 110 HDL,"mg/dL 48.26±3.47 Chronic 45.59±4.6 73 Increase in IMT,98µm/3 y 5.9 Chronic 14.3 41 Inflammatory markersB7(95%CI) White blood cells, x103 per 1 µL 0.6(0.3 to 0.8) Chronic 0.6(0.5 to 0.7) 100 C-reactive protein,mg/dL 0.08(0.02 to 0.1) Chronic 0.1 (0.08 to 0.2) 80 Homocysteine, µmol/L 0.4(0.2 to 0.6) Chronic 0.5(0.1 to 0.9) 80 Oxidized LDL,mg/dL 3.3(0.5 to 6) Chronic 3.9(1.4 to 7) 85 Antioxidants Vitamin C,120 median(interguartile range),µmol/L 53(41 to 79) Chronic 40(25 to 58) 57 Hypovitaminosis120(vitamin C <23 pmol/L),% 12 Chronic 24 50 Ratio of OHM to ascorbic acid122 10.3±7.00 >6 mo 11.2±6.9 78 Vitamin C in children123(mean±SE), mmoVL -8.8±1.5" Chronic -9.0±2.3 98 /3-Carotene125(mean±SE), µmoVL 0.129±0.022 Chronic 0.155±0.021 174 J3-Carotene,127µmol/L 0.15 Chronic 0.17 128 Red blood cell folate mean decrease,130 nmoVL(95%CI)tt -50(-69 to-31) Chronic -86(-101 to-71) 58 'Data are presented as mean±SD unless otherwise noted. tChange in variable associated with passive smoking among nonsmokers(after minus before SHS exposure). Difference in variable between smokers and nonsmokers(smoker minus nonsmoker). §Represents the difference between passive smoking effect divided by active smoking effect times 100%. 11Risk of death at 65 years of age,smoking 20 cigarettes per day(from Law et al5). (Cotinine levels 2.8 to 14.0 ng/mL. #Sensitivity index to prostacyclin. "High-dose SHS group. ttHigh exposure to SHS. Platelet Function among smokers was higher than activation in nonsmokers. The first mechanistic evidence explaining why SHS leads to After the experiment, activation remained the same in smok- an increase in the risk of heart disease incidence or death ers but was significantly increased in nonsmokers, to the came from studies on platelet activity. SHS activates blood point that their platelet activation was not discernibly differ- platelets, increasing the risk of thrombus formation and ent from that of the smokers.Bleeding time,another measure damaging the lining of arteries, which facilitates the devel- of platelet activation (decreased bleeding time indicates opment of atherosclerosis 4.5"9.31.32.32. increased activation), is decreased in rabbits33•3' and rats35 Platelet activation in response to SHS was first evaluated in exposed to realistic doses of SHS. an experiment that exposed smokers and nonsmokers to 20 In in vitro experiments,extracts of sidestream smoke (the minutes of SHS (Table 2).3' At baseline, platelet activation smoke emitted directly from the burning tip of the cigarette Downloaded from http://circ.ahajournals.org/by guest on February 23,2016 Barnoya and Glantz Cardiovascular Effects of Secondhand Smoke 2687 5,6 I i i i � . 38,8---11-DH-TXB ° ...i�..l".... I .4. — non-smokers _-. ,.. Milondialdehyde 1 i -o- non-smoker 2 I o.. smokers ._1.�. ,-' ... _. ..a- smokers i i 4 i 52 I iJ { }: ..tf, _ ..... i i. .' I• i •• •'. is 4.d,.....•i— • 3—i 4 &....--3..-21�-'s I --•' € Ni. at... 1 — 3:. : ? . 26.8 -• .f._-.-n...i ...i._..; .1.;... �.... :..1....! .. i 0 i ..i. i,...? •9 • '•C p I i I : I s..»At1. i -i 1 i I- i i 26.8 -+ •° —i. .� '. ..w 4 -y-....4--# .4—t- {-�.�..-!— 3.6 ..... .._.. ,. •••Y•-. �.. ---}-- . 't. 4. ....,j...... • . I I I ' i i i• i : 22,8 ' 1 2 3 4 5 12 Day 1 2 3 4 5 12 Day Figure 2. Exposure to 60 minutes of SHS increased measures of platelet activation;repeated exposures over several days led to levels in nonsmokers comparable to smokers.'P<0.05.Reproduced from Figure 1 of Schmid et a1,40 copyright 1996,with permission from Elsevier. into the air,the main component of SHS),show that,at equal nonsmokers more activated and close to the behavior of doses, sidestream smoke is a more potent platelet activator smokers. than extracts of mainstream smoke (the smoke inhaled by Platelet activation, however, is not the only player in active smokers). Rubenstein et a136 exposed human platelets thrombus formation.Blood vessel integrity is vital to prevent to sidestream and mainstream smoke extract from 1 Marlboro thrombus formation.A pathological event such as rupture of cigarette. Platelet activation was evaluated under static and an atherosclerotic plaque will lead to platelet adhesion to the flow conditions (blood flow increases platelet activation). arterial wall and platelet activation, culminating in the for- Under both conditions, sidestream was about 1.5 times more mation of a platelet plug (thrombus) and potentially vessel potent than mainstream smoke in activating platelets. occlusion and ischemia or infarction" Platelets activated by Fibrinogen,a mediator of platelet activation and an inflam- SHS also damage the endothelium,a vital layer of the arterial matory marker associated with a higher risk of heart dis- wall. ease,37 is elevated in passive smokers.5 Iso et a138 found that Japanese exposed to SHS had an 11.2±4.1-mg/dL Endothelial Dysfunction (mean±SE) higher mean covariate-adjusted fibrinogen level The endothelium is the first layer in the arterial bed that is in than nonexposed nonsmokers. This increase is 62% of the contact with the blood; it maintains vessel integrity and difference between active smokers and nonexposed non- controls vascular tone and the vascular inflammatory pro- smokers, 18.1±6.7 mg/dL (Table 2). Another study found cess.18 In response to hemodynamic changes (eg, increased that teenagers living with a smoker at home had higher blood flow)and acetylcholine,the endothelium secretes nitric fibrinogen levels than those living in a smoke-free home oxide(NO),leading to vasodilation. In response to epineph- (mean±SD, 241±51 and 218±33 mg/dL, respectively)39 rine,the endothelium secretes endothelin,leading to vasocon- Thromboxane,another marker of platelet activation,is also striction. Endothelial damage can result in decreased vessel increased in passive smokers, in some cases to levels ob dilation and increased contraction,prothrombotic and proin served in active smokers (Figure 2 and Table 2).40 Healthy flammatory states,and cell proliferation in the arterial wall. As a result,endothelial dysfunction contributes to atheroscle- smokers and nonsmokers were exposed to the smoke of 30 rotic plaque formation and progression, plaque rupture, and cigarettes for 60 minutes in an 18-m3 room for 5 consecutive decreased blood flow because of thrombosis and vasospasm, days and one more time on day 12.Before the first exposure leading ultimately to cardiovascular disease 42 to SHS,all measures of platelet activation(malondialdehyde [MDA], serum and plasma thromboxane B2 [s-TX B2 and Endothelium-Dependent Vasodilation p-TX B2], and 11-dehydro-thromboxane B2 [11-DHTXB2]) SHS has immediate effects on endothelium-dependent vaso- were higher in smokers than nonsmokers. Exposure to SHS dilation, which is manifest clinically in 15 to 30 min- for 1 hour increased these measures of platelet activation utes.17.43,44 Using the coronary flow velocity reserve, a (except s-TX B2)more in nonsmokers than in smokers,to the clinical surrogate measure of endothelial function, Otsuka et point that several of them approached the baseline levels a143 showed that 30 minutes of breathing SHS (at levels observed in smokers (Table 2). Six hours after exposure comparable to those in a bar) impaired endothelium- ended, activation markers in nonsmokers remained signifi- dependent vasodilation in coronary arteries of nonsmokers cantly elevated for MDA and p-TX B2 compared with almost to the same extent as seen in habitual smokers(Table 2). baseline. After repeated daily 60-minute exposures to SHS, Chronic SHS exposure also has deleterious effects on the baseline levels of these markers in nonsmokers increased endothelium-dependent vasodilation. Arterial flow-mediated (Figure 2 and Table 2)4°These results indicate that repeated dilation, another measure of endothelium-dependent vasodi- exposures to SHS renders platelet function measures of lation, was impaired in subjects with a history of SHS Downloaded from http://circ.ahajournals.org/by guest on February 23,2016 2688 Circulation May 24, 2005 exposure for?3 years.This impairment was dose dependent; cells in the artery wall lead to increased vascular permeability arterial dilation (measured as percentage change in vessel and atherosclerosis. diameter at rest and during reactive hyperemia)in response to The endothelial cytoskeleton is vital to repair endothelial increased flow was 1.8±2.0% (mean±SD), 3.1±2.2%, and cell disruption resulting from multiple insults (eg, SHS and 4.1±3.3%in subjects with heavy(>6 h/d),moderate(4 to 6 atherosclerosis).Actin filaments,part of the cytoskeleton,are h/d), and light (1 to 3 h/d) exposure, respectively.* In important regulators of cell signaling,locomotion,and adhe- addition, the level of impairment was similar in passive and sion and wound repair mechanisms 56 To evaluate the effects active smokers(Table 2).45 These results were also confirmed of nicotine on actin filament organization in endothelial cells, in healthy women 46 Cucina et a1S7 cultured endothelial cells from the aorta of Studies in animals have confirmed the phenomena ob- calves with nicotine at concentrations between 6X 10-4 and served in humans.47 Rabbits exposed to SHS for 30 minutes 6X 10-8 mol/L,which includes levels found in passive smok- twice a day for 3 weeks showed an -s50% decrease in ers,and found disruptions of actin filament organization after endothelium-dependent vasodilation compared with unex- 24 hours of exposure to nicotine.These changes disappeared posed rabbits. Other animal data show that high cholesterol when anti—platelet-derived growth factor BB antibodies were and SHS have additive effects on endothelial dysfunction.48 added to the culture, suggesting that anti—platelet-derived In utero and neonatal exposure to SHS leads to endothelial growth factor BB is responsible for the changes. This same dysfunction. Hutchinson et al49 found that newborn rats cytoskeletal reorganization was observed in aortic smooth exposed in utero to SHS for 21 days had impaired endothe- muscle cells cultured with similar nicotine concentrations for lium-dependent relaxation (measured as a decrease in the 24 hours.58 In addition to causing endothelial damage,passive vasodilation effect of acetylcholine). smoking disrupts the endothelial repair system.56 NO mediates endothelium-dependent vasodilation. In pas- sive and active smokers,50 decreased production of endothe- Oxidant Damage to the Endothelium lial NO is a mechanism by which the risk of heart disease is Cigarette smoke extract impairs NO mediated endothelial function in isolated endothelial cells from both humans and increased. In response to acetylcholine, the enzyme NO uses L-arginine nine togenerate NO in the endothelium, animals as a result of increased production of superoxide synthase anion (031.59 Cigarette smoke extract increases 02- by leading to vasodilation (hence the term endothelium- dependent vasodilation).Light(<1 pack per week)and heavy stimulation of NADPH,which,in turn,reduces NO bioactiv (•1 pack per week)smokers have similarly decreased levels ity and results in endotheliab�dysfunction 60 Acrolein, an of endothelial NO,S1 suggesting that cigarette smoke has an important constituen�of SHS, is a compound in SHS that effect at low exposure that saturates at high exposures. causes these effects. Acrolein and other gas-phase oxidants Rabbits exposed to SHS for 10 weeks have larger aortic in cigarette smoke remain stable in blood and thus are capable intimal-medial lesions and decreased endothelium-dependent of acting directly on the vascular endothelium. vasodilation and NO production compared with unexposed Recovery of Function After SHS Exposure Ends control rabbits.52 Rabbits fed a diet with the NO precursor Endothelial function partially recovers in humans after long- L-arginine while exposed to SHS did not suffer the decrease term exposure to SHS ends.One year after exposure(?1 h/d in endothelium-dependent vasodilation that was observed in for >2 years) to SHS had ended, endothelium-dependent the rabbits exposed to SHS and eating a normal diet.53 The dilation (measured as the percentage change in arterial effects of SHS on NO production observed in the aortic diameter at rest and during reactive hyperemia) was signifi- endothelium have also been described in the pulmonary cantly better in former passive smokers (percentage change, artery endothelium.54 Therefore,SHS might also contribute to 5.1±4.1%, mean±SD) than in current passive smokers the pathophysiology of pulmonary hypertension. (2.3±2.1%; P=0.01), although both groups were impaired • SHS leads to endothelial dysfunction after short- and compared with control subjects (8.9±3.2%).62 Only partial long-term exposure through inhibition of NO synthase. The endothelium recovery might be attained because of the level of endothelial dysfunction observed in passive smokers damage that SHS produces in the endothelial repair is comparable to the dysfunction observed in active smokers mechanism.57 in both short- and long-term settings. Antioxidants may improve endothelial dysfunction in pas- sive smokers.Schwarzacher et a163 evaluated the effects of an Direct Damage to the Endothelium antioxidant diet on endothelium-dependent vasodilation in Direct endothelial cell injury has also been described. SHS hypercholesterolemic rabbits exposed to SHS. Rabbits exposure for 20 minutes is associated with increased levels of breathed SHS for 6 h/d for 10 weeks and were given either an circulating endothelial cell carcasses' (Table 2). Mullick et antioxidant supplement (vitamin E 1000 U/kg chow and a155 exposed rats to 6 weeks of SHS(6 h/d,5 d/wk)and found (3-carotene 600 mg/kg chow)or no supplement for 21 weeks. damage to carotid artery endothelial cells.The cytoplasm of Through an intact endothelium, acetylcholine leads to a exposed cells contained abnormal vacuoles and bundles of reduction in mean blood pressure. A decreased response to compromised microtubules.In addition,there was disruption the blood pressure—lowering effects of acetylcholine was of the junctional complexes between adjacent cells and observed in hypercholesterolemic rabbits, and a larger de- elevation of the basal surface of endothelial cells off the crease was observed in those exposed to SHS (percent internal elastic membrane.55 These injuries in the endothelial decrease in blood pressure at a high dose of acetylcholine in Downloaded from http://circ.ahajournals.org/by guest on February 23,2016 Barnoya and Glantz Cardiovascular Effects of Secondhand Smoke 2689 SHS/hypercholesterolemic, -22±10% [mean±SE]; in con- smokers were indistinguishable from levels in active smokers trols, -80±2%a). The antioxidant diet partially blocked the (45.59±4.6 mg/dL)(Table 2).77 HDL levels are also lowered SHS-induced impairment of blood pressure responses (per- with increasing smoking intensity (sum of cigarettes con- cent change in blood pressure at high dose of acetylcholine in sumed by all workers in an office in 1 day divided by the SHS/hypercholesterolemic/vitamin supplemented, -68±21%). number of all workers in the office).Nonsmoking women in The reduction in heart disease morbidity and mortality with the middle tertile and highest tertiles of SHS exposure were the implementation of smoke-free environments that has been 1.7 (95% CI 1.2 to 2.5) and 1.6 (95% CI 1.1 to 2.4) times documented in epidemiological studiesio•" can be partially more likely to have low levels (<45 mg/dL) of HDL than explained by these data demonstrating endothelial recovery those in with the lowest intensity of exposure,respectively.76 after SHS exposure ends. Acute exposure to SHS also lowers HDL levels.Moffat et a178 exposed 12 male subjects to 6 hours of SHS at concen- Effects on Arterial Stiffness trations similar to those found in a bar.HDL levels 8,16,and In addition to impairing the ability of blood vessels to dilate, 24 hours later were significantly reduced from baseline at all SHS also increases arterial stiffness (Table 2)64-67 Healthy 3 times(18%, 14%,and 13%reductions,respectively).At the male subjects breathing SHS from 15 cigarettes in an unven- time of the last measurement (24 hours after the exposure), tilated room for 1 hour experienced a significant increase in HDL levels still remained significantly below baseline aortic arterial stiffness.The augmentation index,a measure of (39.7±7.3 [mean±SD] versus 45.2±7.1 mg/dL, respec- arterial wave reflection that is closely related to aortic tively). There were no differences in dietary and exercise stiffness,increased by 15.7%,from -1.715.2%(mean±SE) patterns between exposed and control groups 78 at baseline to 14±4.8% at the end of 1 hour. About half the HDL2, the antiatherogenic subfraction of HDL, is de- ' increase had occurred at 15 minutes, and it reached steady creased by SHS exposure.78.79 Women exposed at work to state after 30 minutes, the time at which the rise in both SHS for 6 h/d for at least the past 6 consecutive months had brachial and aortic systolic blood pressure occurred.° The HDL2 levels significantly lower than those of unexposed effects of SHS on arterial stiffness occur before they are women.The decrease in passive smoking women was similar clinically manifest. These changes are larger than the ones to the decrease in smokers (31% and 33%HDL2 percentage that occur when a nonsmoker smokes a single cigarette.66 decrease from the levels in unexposed, respectively)77 In Another human experimental study showed that aortic men, acute exposure (6 hours) also reduces HDL2.7$ A stiffness, measured with the aortic pressure-diameter loop, significant reduction from baseline values was found as early increased within 4 minutes of passive smoking,similar to the as 8 hours and persisted even after 24 hours after exposure effects observed in active smokers 67.68 Increased arterial (37% and 28%reductions from baseline,respectively). stiffness with SHS exposure has also been reported in a Passive smoking is also associated with lower levels of cross-sectional epidemiological study." Adults chronically HDL in children.79-8i After adjusting for potential confound- exposed to SHS at home,work,and other places with a body ers,Neufeld et a182 found that exposed children had an HDL mass index(BMI)of>27 kg/m2(but not less)experienced an concentration that was 3.7 mg/dL lower than in unexposed increase in carotid stiffness index with SHS exposure (ad- children. In adults, a 1-mg/dL decrease in HDL level is justed carotid stiffness index from 12.23±1.28 [mean±SE] associated with a 2% to 3% increase in coronary heart in the unexposed to 20.6714.18 in those exposed to SHS). disease.73 Racial and gender differences have been noted in Significant interactions were found between SHS, age(?55 the effects of SHS on lipid metabolism in children;data from years), and carotid intima-media thickness (IMT cohorts of white and black twin children have shown an ?0.707 mm) on carotid arterial stiffness index. SHS is also interaction between race and gender.79 In children exposed to associated with increased carotid intimal thickness.° SHS, HDL levels were lower in whites than in blacks SHS has immediate and substantial effects on arterial (43.2±8.0 [mean±SD] versus 52.7±8.4 mg/dL, respec- stiffness. It is possible that these effects are related to the tively). These data suggest that white males exposed to changes in endothelial function discussed earlier. passive smoking may be more susceptible to the effects of SHS than blacks or females. Effects on HDL In addition to endothelial damage, passive smokers are at Inflammation and Infection increased risk of heart disease because SHS accelerates the Inflammation is a precursor of atherosclerotic plaque.83 Both development of atherosclerosis 33.7°-72 HDL is vital in pre- passive smoking children and adults have higher levels of venting atherosclerosis.73 It mediates cholesterol efflux from inflammatory markers. macrophage cells, inhibits foam cell formation, restores and Acute-phase proteins (inflammatory markers) are in- protects from endothelial dysfunction, and prevents the oxi- creased in children breathing SHS at home compared with dation of LDL. As a result, low HDL levels have been children not breathing SHS.84 These proteins were higher associated with an increased risk of heart disease.74 among Japanese boys living with smokers than in boys not Passive smoking leads to lower levels of HDL in exposed to smoke after adjustment for potential confounders, adults73•76 Passive smokers (exposed to SHS for z6 h/d for including asthma or wheezing history, allergic diseases, ?4 d/wk for at least the past 6 months) had HDL levels of feeding method in infancy, and heating type in the home.In 48.26±3.47 (mean±SD)mg/dL compared with 55.59±4.24 boys exposed to?11 cigarettes per day at home,there was an mg/dL in those unexposed to SHS. HDL levels in passive increase in levels of component of the complement (C3c), Downloaded from http://circ.ahajoumals.org/by guest on February 23,2016 2690 Circulation May 24, 2005 haptoglobin(Hp), a, acid glycoprotein (a,-AG), and cerulo- A study done in mice found that after 5 weeks of exposure to plasmin (not significant). In girls exposed to . 1.1 cigarettes cigarette smoke (carboxyhemoglobin level of 14.4±3.5% per day,there was an increase in Hp,a,-AG,and ceruloplas- [mean±SD] in exposed versus 2.9±1.2% in unexposed), min(not significant).No association was found between SHS carotid intimal area was significantly increased in the ex- exposure and C3c in girls, perhaps because of the small posed compared with the unexposed group (0.05±0.034 number of girls with high exposure levels included in the versus 0.023±0.021 mm2).97 A population-based cohort study." study of middle-aged adults found that passive smokers Activated neutrophils and leukocyte count85 increase in (mean exposure, 10 h/wk) was associated with a 20% nonsmokers with as little as 3 hours of breathing SHS.S6 increase in the rate of IMT over a 3-year follow-up period Chronic SHS exposure also increase inflammatory mark- (progression rate increased by 5.9 µm/3 y) compared with ers.87"Panagiotakos et al87 found that adults breathing SHS nonexposed nonsmokers.98 This increase in IMT persisted for>30 minutes at least 1 d/wk had higher leukocyte count, even after controlling for demographic characteristics, other C-reactive protein, and homocysteine, but not fibrinogen, cardiovascular risk factors, and lifestyle variables. In addi- than did unexposed adults (adjusted for several potential tion, the mean IMT increase in progression rate over the 3 confounders). Another study done in Poland also found a years observed in passive smokers was 41%of that observed significant increase in plasma homocysteine levels in male in current active smokers (14.3 µm/3 y) (Table 2). passive smokers.89 The effect of passive smoking ranged Passive smokers have a higher number of stenotic coronary from 100%(white blood cell count)to 75%(fibrinogen)of arteries than do nonpassive smokers. A case-control study the effect observed in active smokers (Table 2). from China found that the number of stenotic coronary Animal data also support the hypothesis that the effects of arteries in women increased with exposure to SHS from their SHS on the cardiovascular system are mediated in part husbands' smoking. The number of stenotic arteries (left through inflammation. After exposing mice to SHS from 2 anterior descending artery, left circumflex artery, and right cigarettes for 30 minutes/d for 4 months,Zhang et a190 noted coronary artery)increased significantly with increasing num- an increase in interleukin-6, a proinflammatory cytokine. ber of years and cigarettes smoked by the subjects' The fine particulate matter in SHS probably plays an - husbands 99 important role in mediating these effects. Particulate air Hepatic lipid peroxidation leads to the accumulation of pollution, which is quite similar to the particulate matter in • cholesteryl esters in atherosclerotic plaque and a more rapid SHS, evokes both pulmonary and systemic inflammatory uptake of LDL cholesterol by human macrophages.10°Mac- responses in humans.21 Four weeks of exposure to fine rophages then develop into foam cells,the predominant cells particulate matter (<10 µm) led to an increase in poly in an early atherosclerotic lesion.101•102 Passive smoking morphonuclear leukocyte band cell counts (another type of increases lipid peroxidation in humans.103-'°6 Just 30 minutes inflammatory cell) in hypercholesterolemic rabbits'and a of exposure to SHS from 16 cigarettes leads to significant corresponding progression in atherosclerotic lesions. increases in the susceptibility of LDL to Cue+-initiated Chronic infection has been proposed to contribute to the , atherosclerotic process just as inflammation does 93 An inter oxidation and serum end products of lipid peroxidation.Animal action between SHS and chronic infection (ie, chronic ob- structive pulmonary disease,recurrent urinary tract infection, mutation in the arterial wall is increased by SHS expo • and chronic bronchitis) has been documented. In a sure.53-55.107 Plasma containing fluorescently labeled LDL from rats exposed once to SHS for 4 hours was perfused into community-based study,passive smokers had an increase in early(nonstenotic plaques;odds ratio[OR], 1.3;95%CI, 1.0 carotid arteries from unexposed rats.Compared with controls, to 1.8) and advanced (vessel stenosis >40%; OR, 1.5; 95% LDL accumulation was significantly increased in the arteries CI, 1.0 to 2.2) atherogenesis that was confined to subjects perfused with SHS exposed plasma (1.6±0.4 and 6.9±1.8 with chronic infection." mV/min[mean±SE],respectively).107 Another study in mice Mouse experiments suggest that AIDS patients might be found increased LDL accumulation in the 3 sections of the more susceptible to opportunistic infections if exposed to aorta (arch, thoracic, and abdominal) that depended on the SHS. Using the murine AIDS model, Zhang et a195 showed dose of SHS.108 Mice breathed SHS for 6 hours a day for 7, that SHS exposure for 12 weeks inhibited the proliferation of 10, and 14 weeks. Compared with unexposed controls, T cells, increased the release of tumor necrosis factor-a, atherosclerotic lesions were greater in the exposed mice even interleukin-6 cytokines,and enhanced lipid peroxidation from at 7 weeks of exposure. In the thoracic aorta, at week 14, the retrovirus-infected mice.These effects would make mice 33±11% of the intima was covered by grossly discernible with murine AIDS more susceptible to opportunistic infec- lesions compared with 10±8%in controls.108 Knight-Lozano tions95 and suggest that AIDS patients might be particularly at et all" exposed mice to SHS from 2 cigarettes for just 15 risk of opportunistic infections if exposed to SHS. min/d for 21 and 42 days; arteriosclerotic lesion size in- Human and animal data support the conclusion that SHS creased 76% and 156%, respectively compared with unex- exposure increases inflammation, which is another potential posed mice. Similar increases in atherosclerotic lesion after mechanism by which SHS causes heart disease. breathing SHS has been described in cockerels (22 weeks, 0.4% of projected lifespan)70•71 and rabbits (10 weeks of Progression of Atherosclerosis exposure)33 Nicotine does not appear to be required for SHS SHS contributes to the progression of atherosclerosis.Carotid to increase arterial lipid lesions, because there were similar IMT is a standard surrogate measurement of atherosclerosis 96 effects from SHS from nicotine-free cigarettes 72 Other com- Downloaded from httpJ/circ.ahajournals.org/by guest on February 23,2016 Barnoya and Glantz Cardiovascular Effects of Secondhand Smoke 2691 ponents of the tobacco smoke appear to be important in terms greater risk of ventricular hypertrophy. These events make of promoting atherosclerosis. recovery of the myocardium more difficult and the myocar- SHS also contributes to atherosclerotic plaque instability, dium more susceptible to a second event or heart failure. which triggers thrombosis, the cause of occlusion and most acute vascular events. Matrix metalloproteinases, degrading Oxidative Stress enzymes secreted by endothelial and smooth muscle cells,are Free oxygen radicals,also known as reactive oxygen species, thought to weaken the arterial wall, thus contributing to lead to oxidative stress, blood vessel injury, and oxidized destabilization and rupture of atherosclerotic plaques.1 0.111 LDL. Free radicals are produced in cells as a result of the Nicotine, at concentrations found in passive smokers (10-$ respiratory process that uses oxygen.'"Under normal condi- mol/L), upregulates collagenase I, a type of matrix metallo- tions, endogenous antioxidants protect the vascular system proteinase,in human artery smooth muscle cells.12 After 18 from oxidative stress damage. In addition to free radicals hours of incubation with nicotine, there was a 4.5-fold produced in the body, SHS is a source of free radicals that increase in collagenase I. Other matrix metalloproteinases lead to oxidative stress and antioxidant depletion."s The were also upregulated by nicotine. oxidants in SHS act directly to depress NO production by the SHS leads to atherosclerosis through various mechanisms, endothelium independently of any effect on mitochondrial including abnormal lipid profile (low HDL and high LDL), respiration.60 The oxidative stress from passive smoking increased susceptibility to lipid peroxidation leading to in- influences the cardiovascular system in 2 ways: by directly crease lipid uptake by macrophages, stenosis of coronary delivering free radicals to the vascular system and by con- arteries, and plaque instability. None of these events occurs suming antioxidants that would normally be available to alone;their effects are cumulative—perhaps even multiplica- protect against endogenous free radicals resulting from the tive—and are all affected by SHS. respiratory process. Various surrogate measures have been used to document Infarct Size the oxidative stress generated by SHS,including a decrease in SHS exposure increases experimentally induced infarct size antioxidant levels (eg, vitamin C and carotene) and an in animals in a dose-dependent manner.35 Zhu et a135 exposed increase in oxidative stress biomarkers. In addition, it has rats to 6 weeks of SHS (6 hid, 5 d/wk)at levels observed in been noted that these surrogate markers return to baseline bars,then induced infarcts by tying off and releasing the left levels after dietary supplementation with antioxidants in the coronary artery. At the longest duration of exposure (180 presence of SHS, although such supplementation does not hours total),infarcts were nearly twice as large as those in the appear to affect the long-term risk of heart disease.19 unexposed group.35 In another study to evaluate the effects of SHS on infarct size in the neonatal and adolescent period, Decreased Antioxidant Levels pregnant rats received cumulative SHS exposures for 3 Antioxidant depletion as a marker of oxidative stress has been weeks; neonatal rats,for 4 weeks after birth;and adolescent analyzed after exposure to SHS. The assumption is that rats, from weeks 6 to 12 after birth. Results showed that antioxidants are being consumed under conditions of oxida- exposure to SHS in the neonatal to adolescent period for 12 tive stress and that the depletion of endogenous antioxidants weeks significantly increased experimentally induced infarct would be an indirect reflection of oxidative stress resulting size,especially in female rats. In utero exposure for 3 weeks from passive smoking. SHS has been shown to decrease tended to increase infarct size(P=0.08),especially in female levels of individual and total plasma antioxidants.Vitamin C rats.13 (ascorbic acid) levels are lower in passive (53 µmol/L; As a consequence of myocardial infarction,the left ventri- interquartile range,41 to 79µmol/L)and active(40 p.mol/L; de changes in size, shape,and thickness in the infarcted and interquartile range,25 to 58µmol/L)smokers compared with noninfarcted segments of the ventricle through a process nonsmokers (70 µmol/L; interquartile range, 56 to 82 known as ventricular remodeling.Remodeling,which results µmol/L) (significant differences between the 3), with SHS from a combination of changes in left ventricular dilation and having about two thirds the effect of active smoking (Table hypertrophy of residual noninfarcted myocardium,influences 2).120 Hypovitaminosis was diagnosed in passive (12%) and ventricular function.14 Left ventricular hypertrophy, which active(24%)smokers but in none of the unexposed Ronsmok- leads to ventricular remodeling and increases the risk of a ers(Table 2).Exposure to SHS was on average 35 h/wk,and cardiovascular event and mortality,115 has also been observed no significant differences were found in vitamin C intake in 6-month-old rabbits exposed to SHS from 3 cigarettes for among the 3 groups.'20.'2' 30 minutes twice daily for 21 days.16 After exposure, left Acute exposure to SHS(30 minutes from 16 cigarettes)led ventricle weight and the ratio of left ventricle to body weight to an immediate one-third decrease in serum ascorbic acid were significantly higher in the exposed group(2.99±0.12 g (the reduced form of vitamin C)in healthy adults.106 Ascorbic and 0.95±0.05 g/kg (mean±SEM), respectively) compared acid has an antioxidant effect; its oxidized form, dehy- with the control group (2.48±-0.07 g and 0.77±0.02 g/kg, droascorbic acid(DHAA),is a marker of oxidative stress.In respectively). chronically exposed passive smokers (> 10 h/wk of SHS Through endothelial dysfunction, platelet adhesion, and exposure for >6 months), the proportion of DHAA to total plaque instability,SHS is a trigger for myocardial infarction. ascorbic acid resembles levels in smokers (10.3±7.00% After the infarction has occurred, SHS renders the myocar- [mean±SD] and 11.2±6.9%, respectively) and is signifi- dium more susceptible to a larger area of infarction and cantly higher than levels in nonsmokers (7.07±6.24%) (Ta- Downloaded from http://circ.ahajournals.org/by guest on February 23,2016 0 2692 Circulation May 24, 2005 ble 2).122 With ascorbic acid used as a marker of oxidative revealed that passive and active smokers have dose- stress,passive smoking leads to oxidative stress in both long- dependent decreased folate levels.13O After adjustment for and short-term exposures. covariates(age, sex, race, socioeconomic status,daily folate Children and adolescents who are passive and active intake from 24-hour recall,vitamin use,and alcohol use),the smokers also have lower levels of vitamin C.123 After odds of having low red blood cell folate(<340 nmol/L)were adjustment for age,gender, vitamin C intake, and multivita- 1.3 (95% CI, 1.1 to 1.5), 1.5 (95% CI, 1.3 to 1.9), and 2.4 min use, cotinine levels were significantly associated with (95%CI,2.0 to 2.8)for moderate-and high-exposure passive lower levels of vitamin C in children exposed at home to low smokers and active smokers compared with low-exposure and high levels of SHS and active smokers (serum cotinine passive smokers,respectively.This same trend was observed levels <2, 2 to 15, and >15 ng/mL, respectively).123 After for serum folate level. Among those with heavy exposure controlling for age,gender,vitamin C intake, and multivita- (serum cotinine 0.4 to<15 ng/mL),serum and red blood cell min use,children exposed to high levels of SHS had about the folate levels were 60%of those seen in smokers(Table 2). same reduction in serum ascorbic acid levels observed in Passive smoking adults and children have lower levels of children who were active smokers(Table 2). Preston et al124 antioxidant vitamins, about two thirds of the effect observed found plasma vitamin C levels to be on average 3.2 pmol/L in active smokers. SHS leads to depletion of endogenous lower in children exposed to SHS compared with unexposed antioxidants, leaving the cardiovascular system without its children(both groups had similar dietary intake of vitamin C). natural barrier against oxidative stress. Carotenoids, another group of antioxidants, are also de- creased by SHS. These plant pigments include $3- and Effects of Antioxidant Supplementation on a-carotene, lycopene, and cryptoxanthin. Alberg et al125 and Oxidative Stress Biomarkers van der Vliet126 used serum collected in a private census in Antioxidant supplementation might protect against the dele- 1975 as part of another study to assess the relationship terious effects of SHS by providing additional antioxidant between breathing SHS (assessed as living with a smoking capacity to the body.90'05.131.132 Experiments have been spouse) and several micronutrients. Nonsmokers who lived conducted in humans and animals supplemented either with a with smokers had lower serum total carotenoid (significant single vitamin or a multivitamin.Vitamin E supplementation for men), a-carotene (significant for women), (3-carotene (100 mg a-tocopherol for 14 days)in children breathing SHS (significant for men),and cryptoxanthin(significant for both lowered thiobarbituric acid—reactive substances (TBARS) genders)concentrations than nonsmokers who lived in house- (plasma and erythrocyte) and erythrocyte-oxidized glutathi- holds with no smokers. (The nonsignificant changes were in one, both indexes of lipid peroxidation.131 TBARS lead to the same direction as the significant changes. The failure to increase lipid uptake by macrophages that give rise to the reach significance may reflect, in part, the high background atherosclerotic plaque. In another experiment, mice were levels of SHS exposure that was present when the data were exposed to SHS for 5 h/d and fed a vitamin E supplemented collected in 1975.) These carotenoid measures were also diet for 10 days. Vitamin E prevented the lipid peroxidation decreased in active smokers (Table 2).125 observed in the exposed and nonsupplemented controls.'33 Dietrich et al127 evaluated plasma samples from 83 smok- Vitamin C has been shown to mitigate the increase in ers,40 passive smokers,and 36 nonsmokers.Passive smokers oxidative stress biomarkers as a result of SHS exposure. In had been exposed to SHS from >1 cigarette per day at least passive smokers, the lipid peroxidation biomarker F2- 5 d/wk for a•1 years.Smoke exposure status was assessed by isoprostane (F2-IsoP) decreased by 17.2 pmol/L or 11.4% in cotinine levels, and dietary history was collected with a those supplemented with vitamin C for 2 months compared self-administered questionnaire. J3-Carotene levels in passive with those receiving placebo.134 In a another experiment, smokers (0.15 µmol/L) were significantly lower than in nonsmoking human subjects breathed SHS from 16 cigarettes nonsmokers(0.24 µmol/L) but were not significantly differ- for 30 minutes on 2 different days. One day,they received a ent from the levels in smokers (0.17 µmol/L) (Table 2). normal diet; on the other day, they were given a vitamin C $3-Carotene was also decreased in Italian women married to supplement (3 g ascorbic acid) before breathing SHS. Mea- smoking husbands.128 Levels were lower among women in surements of total plasma antioxidant trapping potential the 2 highest exposure categories (11 to 20 and >20 ciga- (TRAP)and TBARS were taken 1.5 hours after the breathing rettes per day), with a dose-response relationship. After session. When subjects breathed SHS with no vitamin C dietary intake, vitamin supplementation, alcohol consump- supplementation, they had a significant decrease in TRAP tion, and BMI were controlled for, the association persisted. and an increase in TBARS. When they were given the The decrease was highest (27%) in those with the highest vitamin C supplement,SHS failed to decrease TRAP and the level of exposure (>_21 cigarettes per day). This study was formation of TBARS was significantly lower than in the day done in Italy where most of the population is exposed to SHS without the supplement,leading the authors to conclude that outside the home;therefore,even those women who reported total plasma antioxidant potential and oxidative stress pro- no exposure at home had elevated cotinine levels(mean,7.95 duced by SHS can be prevented with vitamin C ng/mL), leading to an underestimate of the effects of SHS supplementation.'85 exposure at home. A combination of antioxidants has also been shown to Folate,a vitamin emerging as a potential tool for prevent- protect against the oxidative stress resulting from passive ing heart disease, probably by decreasing homocysteine smoking. This has been confirmed in human and animal levels,129 is decreased by SHS. Data from NHANES Ill studies.Giving passive smokers(exposure to al cigarette per Downloaded from http://circ.ahajournals.org/by guest on February 23,2016 Barnoya and Glantz Cardiovascular Effects of Secondhand Smoke 2693 day for a5 d/wk indoors) antioxidant supplements (vitamin ment. The rest of the enzymes showed the same trend, C, a-lipoic acid, and vitamin E) for 2 months resulted in although the decrease was not significant.136 lower F2-IsoP levels than in a control group (adjusted for baseline F2-IsoP, BMI, sex, alcohol intake, number of years Mitochondrial Damage exposed to SHS, average number of cigarettes exposed per Another global effect of SHS is inhibition of energy produc- day,hours since last exposure to SHS before to blood draw, tion by the mitochondria. Animal studies have shown that baseline plasma antioxidants,and lipids).134 Mice exposed to SHS impairs the ability of the heart muscle to convert oxygen SHS for 30 min/d,2 cigarettes every 10 minutes,for 4 months into the energy molecule adenosine triphosphate.137-'39 The showed a significant increase in lipid peroxidation 99 Lipid activity of one of the enzymes that mediates this process, peroxidation was significantly decreased in both SHS- cytochrome oxidase,fell 25% after a single 30-minute expo- exposed and -nonexposed mice that received antioxidant sure to SHS,and the activity continued to decline with longer supplementation(including 0-carotene, bioflavonoids, coen- exposure.'37 zyme Q10, n-a-tocopherol, t.-ascorbic acid, magnesium, Mitochondrial damage in passive smokers includes de- N-acetylcysteine,retinol,selenium,and zinc).In the exposed creased adenine nucleotide translocator(ANT)and mitochon- mice, lipid peroxidation decreased almost to the level ob- drial superoxide dismutase (SOD2) activity and mitochon- served in the unexposed mice that received the supplement. drial DNA (mtDNA) damage in aortic tissue. Low levels of In another study, mice were supplemented with an ANT and SOD2 are markers of increased oxidative stress. antioxidant-rich byproduct of olive oil,olive mill wastewater, Knight-Lozano et al109 exposed mice with normal and high for 2 days and then exposed to SHS (1 cigarette for 20 cholesterol to SHS from 2 cigarettes every 15 minutes,6 h/d, minutes) for 4 days. The urinary excretion of the oxidative 5 d/wk for 21 and 42 days.The 21-day group was exposed to stress marker 8-iso-prostaglandin Fla(8-iso-PGF2.)was mea- filtered air for 21 days before the SHS exposure period.SHS sured daily. Compared with the group not receiving supple- was associated with a significant decrease in ANT and SOD2 ment, in the supplemented group, 8-iso-PGF2a did not in- in the high-cholesterol mice, with a significant interaction crease at 48 hours (44±4.2% increment in the group not between SHS exposure and high cholesterol in decreasing the supplemented), and there was a smaller increase in 8-iso- activity in both enzymes. This result suggests that SHS- PGF2,„at 96 hours(34±18%versus 55±10%a increases in the induced oxidative stress reduces mitochondrial ANT and supplemented and not supplemented groups,respectively).132 SOD2 activities.In addition,SHS exposure resulted in higher The authors of this study concluded that the antioxidant-rich levels of aortic mtDNA damage regardless of diet compared byproduct of olive oil can mitigate the increase in oxidative with unexposed mice.Increased duration of exposure resulted stress resulting from passive smoking. in even higher levels of mtDNA damage,and high cholesterol These data suggest that a supplement with various antioxi- accentuated the effects of SHS. In unexposed mice,mtDNA dants might also be effective in compensating for the deple- damage was higher in mice with high cholesterol compared lion of antioxidants resulting from SHS exposure. Taking with those with normal cholesterol, indicating that the dele- antioxidant supplements,however,probably will not prevent terious effects of SHS on mtDNA damage are potentiated by the damage associated with SHS because such supplements high cholesterol levels.These data suggest that SHS leads to do not seem to reduce the risk of heart disease in general.19 increased mtDNA damage in aortic tissue,possibly mediated by oxidative stress. High cholesterol levels accentuate the DNA Damage From Oxidative Stress deleterious effects of SHS on aortic mitochondria. Enzymes used as markers of oxidative stress and DNA Given the increased oxidative stress and DNA damage in damage resulting from oxidative stress have been found to be the mitochondria resulting from passive smoking, other elevated in passive smokers.135 A cross-sectional study found energy sources have to be used. The anaerobic pathway, that passive smokers(6.6±1.6[mean±SE]h/d of exposure at another source of energy in the body, leads to an increase in work) have higher levels of enzymes that increase with lactate in venous blood. It has been noted that passive exposure to reactive oxygen species. Superoxide dismutase smokers have increased levels of lactate in venous blood.140 (SOD), glutathione peroxidase (GPDX), glutathione reduc- This clinical finding is consistent with the conclusion that tase (GR), and catalase were found to be elevated in the passive smoking leads to mitochondrial damage, affecting exposed(only GPDX[10%higher]and GR[4%higher]were directly the body's ability to produce energy to sustain significant)compared with the unexposed group.135 In addi- exercise. tion, the DNA adduct 8-hydroxy-2-deoxyguanosine (8- OHdG), a marker of DNA damage resulting from oxidative Heart Rate Variability stress that has been shown to be elevated in smokers, was Acute exposure (2 periods of 2 hours during an 8-hour analyzed. Passive smokers had a significant 63% increase in experiment in an airport smoking lounge) to SHS reduces 8-OHdG.135 An antioxidant supplement(300 µg 0-carotene, heart rate variability.'4'Heart rate variability,the beat-to-beat 60 mg vitamin C, 30 IU a-tocopherol, 40 mg zinc, 40 pg variations in heart rate reflected in the R-R interval variation selenium, and 2 mg copper) was then administered to these in the ECG, gives information about the propensity toward same subjects for 60 days (exposed and unexposed).Passive malignant ventricular arrhythmias and cardiac death.21,142 smokers who received the antioxidant supplement had SOD Two hours of exposure was associated with a 12%reduction activity levels 18% and 8-OHdG levels 62% below those of in heart rate variability. This reduction has been associated the SHS-exposed subjects who did not receive the supple- with an increased risk of ventricular fibrillation or ventricular Downloaded from http://circ.ahajournals.org/by guest on February 23,2016 2694 Circulation May 24, 2005 tachycardia in patients after a myocardial infarction or in makes it easier for people to stop smoking?-11•147 Further- those with chronic heart failure. During the subsequent 2 more,it has been estimated that if all US workplaces were to hours when the subjects were out of the smoking room, the be smoke-free by law, in the first year after law was heart rate variability returned to baseline. Similar reductions implemented, there would be 1500 myocardial infarctions in heart rate variability have also been noted in response to air prevented, yielding nearly $49 million in savings in direct pollution (ambient particulate matter); after all, SHS is air medical costs, because some people would stop smoking or pollution?1.92.'43 It is likely that the effects of SHS on heart consume fewer cigarettes.9 These benefits would grow over rate variability are mediated by the fine particles in SHS.The time. While providing health benefits, smoke-free policies reductions in heart rate variability reflect a decrease in the also reduce revenues and profits to tobacco companies; parasympathetic input to the heart, providing an important implementation of these policies in the remaining workplaces mechanistic link between SHS (and air pollution) and heart in the United States would reduce cigarette consumption by disease by promoting fatal tachyarrhythmias.2' an estimated 950 million packs a year, worth$2.3 billion to the tobacco industry in sales 9It is no surprise that the tobacco Insulin Resistance industry (often through surrogates148) continues cpntesting Increased insulin resistance is now recognized as increasing the evidence linking SHS with heart and other diseases and the risk of heart disease.144 The resulting compensatory continues fighting smoke-free policies around the world.'49-'5' hyperinsulinemia leads to a number of proatherogenic abnor- Physicians, public health advocates, and policy makers can malities known to as insulin resistance syndrome (hyperten- move forward in implementing these policies, secure in the sion, abdominal obesity, dyslipidemia, prothrombotic state, knowledge that implementing smoke-free environments to endothelial dysfunction, and chronic subclinical inflamma- rapidly and substantially improve cardiovascular health rests don). Insulin resistance per se is inadequate for identifying on a strong scientific foundation. people with the highest risk for heart disease; the entire syndrome best identifies these people.144 Cross-sectional data Acknowledgments from the Insulin Resistance Atherosclerosis Study (IRAS) This research was supported by the Flight Attendant Medical showed that exposure to SHS can lead to an increase in Research Institute. Dr Glantz holds a Cahan Distinguished Profes- insulin resistance, significantly in women(insulin sensitivity sorship from the Flight Attendant Medical Research Institute. We index in passive smokers, 1.07±0.07 [mean±SE]; in unex- thank Neal Benowitz and William Grossman for their criticisms of posed nonsmokers, 1.19±0.04;P=0.013)even after drafts of this manuscript control- ling for potentially confounding demographic and physiolog- References ical variables.145 In smokers, data are not yet conclusive; I. Taylor AE,Johnson DC,Kazemi H.Environmental tobacco smoke and there was no relationship with insulin sensitivity in IRAS,but cardiovascular disease:a position paper from the Council on Cardiopul- another study did find an increase in insulin resistance.146 monary and Critical Care, American Heart Association. Circulation. SHS might also lead to an increase in heart disease by 1992;86:1-4. 2. National Cancer Institute.Health Effects of Exposure to Environmental increasing insulin resistance. Tobacco Smoke:The Report of the California Environmental Protection Agency,Smoking and Tobacco Control.Bethesda,Md:Department of Conclusions Health and Human Services, National Institutes of Health, National The evidence that SHS causes heart disease has continued to Cancer Institute; 1999.Monograph 10. accumulate in terms of both the epidemiological evidence and 3. Glantz SA,Parmley WW.Passive smoking and heart disease:epidemi- ology,physiology,and biochemistry.Circulation. 1991;83:1-12. our understanding of mechanisms. Most important,this evi- 4. Glantz S,Parmley W.Passive smoking and heart disease:mechanisms dence shows consistently and from many dimensions that and risk.JAMA. 1995;273:1047-1053. 5. Law MR,Morris JK,Wald NJ.Environmental tobacco smoke exposure passive smoking has much larger effects on the cardiovascu lar system than would be expected from a comparison of the and ischaemic heart disease:an evaluation of the evidence.BMJ.1997; Y pe p 315:973-980. doses of toxins delivered to active and passive smokers. 6. He J,Vupputuri S,Allen K,Prerost MR,Hughes J,Whelton PK.Passive Indeed, the effects of SHS are, on average, 80% to 90% as smoking and the risk of coronary heart disease: a meta-analysis of large as those from active smoking (Table 2). The mecha epidemiologic studies.N Engl J Med. 1999;340:920-926. 7. Thun M, Henley J, Apicella L. Epidemiologic studies of fatal and nisms by which passive smoking increases the risk of heart nonfatal cardiovascular disease and ETS exposure from spousal disease are multiple and interact with each other (Table 1). smoking.Environ Health Perspect. 1999;107(suppl 6):841-846. These mechanisms include increase platelet aggregability, 8. Centers for Disease Control and Prevention. Annual smoking- attributable mortality,years of potential life lost,and economic costs: endothelial dysfunction,increased arterial stiffness,increased atherosclerosis, United States, 1995-1999. MMWR Morb Mortal Wkly Rep. 2002;51: increased oxidative stress and decreased an- 300-303. tioxidant defense,inflammation,decreased energy production 9. Ong MK, Glantz SA.Cardiovascular health and economic effects of in the heart muscle, and a decrease in the parasympathetic smoke-free workplaces.Am J Med.2004;117:32-38. 10. Fichtenberg CM, Glantz SA. Association of the California Tobacco output to the heart. Like outdoor air pollution,21 on a Control Program with declines in cigarette consumption and mortality population basis, the effects of SHS are rapid and large. from heart disease.N Engi J Med.2000;343:1772-1777. Implementation of smoke-free policies for the 30% of 11. Sargent RP,Shepard RM,Glantz SA.Reduced incidence of admissions Americans-and most of the world's population-who cur- for myocardial infarction associated with public smoking ban:before rend do not enjoy them would have substantial effects on and after study.BMJ.2004;328:977-980. Y j Y 12. Mitka M.Secondhand smoke an acute heart risk?Critics say smoking heart disease morbidity and mortality through a combination ban study inconclusive.JAMA.2004;291:2690. of reducing SHS exposure and providing an environment that 13. Duplicate reference deleted in proofs. Downloaded from http://circ.ahajournals.org/by guest on February 23,2016 I3arnoya and Glantz Cardiovascular Effects of Secondhand Smoke 2695 14. Steenland K. Passive smoking and the risk of heart disease. JAMA. 38. Iso H, Shimamoto T, Saw S, Koike K, lida M, Komachi Y. Passive 1992;267:94-99. smoking and plasma fibrinogen concentrations.Am J Epidemiol. 1996; 15. Kritz H,Schmid P,Sinzinger H.Passive smoking and cardiovascular 144:1151-1154. risk.Arch Intern Med. 1995;155:1942-194-8. 39. Stavroulakis GA, Makris TK, Hatzizacharias AN, Tsoukala C, 16. Pittilo M. Cigarette smoking, endothelial injury and cardiovascular Kyriakidis MK. Passive smoking adversely affects the haemostasis/ disease.Int J Exp Pathol.2000;81:219-230. fibrinolytic parameters in healthy non-smoker offspring of healthy 17. Glantz S,Parsley W. Even a little secondhand smoke is dangerous. smokers.Thromb Haemost.2000;84:923-924. JAMA.2001;286:462-463. 40. Schmid P,Karanikas G,Kritz H,Pinch C,Stamatopoulos Y,Peskar B, 18. Puranik R, Celermajer DS. Smoking and endothelial function. Prog Sinzinger H.Passive smoking and platelet thromboxane.Thromb Res. Cardiovasc Dis.2003;45:443-458. 1996;81:451-460. 19. Ambrose JA,Barua RS.The pathophysiology of cigarette smoking and 41. Kroll MH,Resendiz JC.Mechanisms of platelet activation.In:Loscalzo cardiovascular disease: an update. J Am Coll Cardiol. 2004;43: J,Schafer AI,eds.Thrombosis and Hemorrhage.3rd ed.Philadelphia, 1731-1737. Pa:Lippincott Williams&Wilkins;2003:187-205. 20. Pechacek TF,Babb S.How acute and reversible are the cardiovascular 42. Widlansky ME,Gokce N,Keaney JF Jr,Vita JA.The clinical impli- risks of secondhand smoke?BMJ.2004;328:980-983. cations of endothelial dysfunction. J Am Coll Cardiol. 2003;42: 21. Brook RD, Franklin B, Cascio W, Hong Y, Howard G, Upsets M, 1149-1160. Luepker R,Mitileman M,Samet 1,Smith SC Jr,Tager I.Air pollution 43. Otsuka R,Watanabe H, Hirata K,Tokai K,Muro T, Yoshiyama M, and cardiovascular disease: a statement for healthcare professionals Takeuchi K, Yoshikawa.1. Acute effects of passive smoking on the from the Expert Panel on Population and Prevention Science of the coronary circulation in healthy young adults. JAMA. 2001;286: American Heart Association.Circulation.2004;109:2655-2671. 436-441. 22. Wells AJ. Passive smoking as a cause of heart disease. J Am Coll 44. Kato M,Roberts-Thomson P,Phillips BG,Narkiewicz K,Haynes WG, Cardiol. 1994;24:546-554. Pesek CA, Somers VK. The effects of short-term passive smoke 23. Panagiotakos D,Chrysohoou C,Pitsavo;C,Papaioannou I,Skoumas J, exposure on endothelium-dependent and independent vasodilation. Stefanadis C,Toutouzas P.The association between secondhand smoke J Hypertens. 1999;17:1395-1401. and the risk of developing acute coronary syndromes, among non- 45. Celermajer DS, Adams MR, Clarkson P, Robinson J, McCredie R, smokers,under the presence of several cardiovascular risk factors:the Donald A,Deanfield JE.Passive smoking and impaired endothelium- CARDIO2000 case-control study.BMC Public Health.2002;2:9. dependent arterial dilatation in healthy young adults. N Engl J Med. 24. Pitsavos C,Panagiotakos DB,Chrysohoou C,Skoumas J,Tzioumis K, 1996;334:150-154. Stefanadis C,Toutouzas P.Association between exposure to environ- 46. Sumida H,Watanabe H,Kugiyama K,Ohgushi M,Matsumura T,Yasue mental tobacco smoke and the development of acute coronary syn- H.Does passive smoking impair endothelium-dependent coronary artery dromes: the CARDIO2000 case-control study. Tob Control.2002;11: dilation in women?JAm Coll Cardiol. 1998;31:811-815. 220-225. 47. Zhu BQ,Parmley WW.Hemodynamic and vascular effects of active and 25. Pitsavos C,Panagiotakos DB,Chrysohoou C,Tzioumis K,Papaioannou passive smoking.Am Heart J. 1995;130:1270-1275. I, Stefanadis C, Toutouzas P. Association between passive cigarette 48. Hutchison SJ, Sudhir K, Chou TM, Sievers RE, Zhu BQ, Sun YP, smoking and the risk of developing acute coronary syndromes: the Deedwania PC,Glantz SA,Parmley WW,Chatterjee K.Testosterone CARDIO2000 study.Heart Vessels.2002;16:127-130. worsens endothelial dysfunction associated with hypercholesterolemia 26. Rosenlund M, Berglind N, Gustaysson A, Reuterwall C,Hallqvist J, and environmental tobacco smoke exposure in male rabbit aorta.JAm Nyberg F,Pershagen G.Environmental tobacco smoke and myocardial Coll Cardiol. 1997;29:800-807. infarction among never-smokers in the Stockholm Heart Epidemiology 49. Hutchison SJ,Glantz SA,Zhu B-Q,Sun Y-P,Chou TM,Chatterjee K, Program(SHEEP).Epidemiology.2001;12:558-564. Deedwania PC,Parmley WW,Sudhir K.In-utero and neonatal exposure 27. Enstrom JE, Kabat GC. Environmental tobacco smoke and tobacco to secondhand smoke causes vascular dysfunction in newborn rats.JAm related mortality in a prospective study of Californians,1960-98.BMJ. Coll Cardiol. 1998;32:1463-1467. 2003;326:1057-1060. 50. Barua RS,Ambrose IA, Eales-Reynolds LI,DeVoe MC,Zervas JG, 28. Whincup PH,Gilg JA,Emberson JR,Jarvis MJ,Feyerabend C,Bryant Saha DC.Dysfunctional endothelial nitric oxide biosynthesis in healthy A,Walker M,Cook DG.Passive smoking and risk of coronary heart smokers with impaired endothelium-dependent vasodilatation. Circu- disease and stroke:prospective study with cotinine measurement BMJ. lotion.2001;104:1905-1910. 2004;329:200-205. 51. Barua RS,Ambrose JA,Eales-Reynolds L-1,DeVoe MC,Zervas JG, 29. Thun MJ.Passive smoking:tobacco industry publishes disinformation. Saha DC.Heavy and light cigarette smokers have similar dysfunction of BMJ.2003;327:c502-e503. endothelial vasoregulatory activity:an in vivo and in vitro correlation. 30. Benowitz NL.Cotinine as a biomarker of environmental tobacco smoke JAm Coll Cardiol.2002;39:1758-1763. exposure.Epidemiol Rev. 1996;18:188-204. 52. Hutchison SJ, Sudhir K, Sievers RE, Zhu BQ, Sun YP, Chou TM, 31. Burghuber OC,Punzengruber C,Sinzinger H,Haber P,Silberbauer K. Chatterjee K, Deedwania PC, Cooke JP, Glantz SA, Parsley WW. Platelet sensitivity to prostacyclin in smokers and non-smokers. Chest. Effects of L-arginine on atherogenesis and endothelial dysfunction due 1986;90:34-38. to secondhand smoke.Hypertension. 1999;34:44-50. 32. Davis 1, Shelton L, Watanabe I, Arnold J. Passive smoking affects 53. Hutchison SJ,Reitz MS,Sudhir K,Sievers RE,Zhu BQ,Sun YP,Chou endothelium and platelets.Arch Intern Med. 1989;149:386-389. TM,Deedwania PC,Chatterjee K,Glantz SA,Parsley WW.Chronic 32a.Davis JW, Hartman CR, Lewis HD Jr, Shelton L, Eigenberg DA, dietary L-arginine prevents endothelial dysfunction secondary to envi- Hassanein KM,Hignite CE,Ruttinger HA.Cigarette smoking-induced ronmental tobacco smoke in normocholesterolemic rabbits. Hyper- enhancement of platelet function:lack of prevention by aspirin in men tension. 1997;29:1186-1191. with coronary artery disease.J Lab Clin Med. 1985;105:479-483. 54. Hutchison SJ, Sievers RE,Zhu B-Q, Sun Y-P, Stewart DJ, Parmley 33. Zhu BQ,Sun YP,Sievers RE,Isenberg WM,Glantz SA,Parsley WW. WW,Chatterjee K.Secondhand tobacco smoke impairs rabbit pulmo- Passive smoking increases experimental atherosclerosis in cholester- nary artery endothelium-dependent relaxation. Chest. 2001;120: of-fed rabbits.JAm Coll Cardiol 1993;21:225-232. 2004-2012. 34. Sun Y-p.Zhu B-q,SIevers RE,Glantz SA,Parsley WW.Metoprolol 55. Mullick AE, McDonald JM, Melkonian G,Talbot P, Pinkerton KE, does not attenuate atherosclerosis in lipid-fed rabbits exposed to envi- Rutledge IC.Reactive carbonyls from tobacco smoke increase arterial ronmental tobacco smoke.Circulation. 1994;89:2260-2265. endothelial layer injury.Am J Physiol Heart Circ Physiol.2002;283: 35. Zhu BQ,Sun YP,Sievers RE,Glantz SA,Parsley WW,Wolfe CL. H591-H597. Exposure to environmental tobacco smoke increases myocardial infarct 56. Lee TY,Gotlieb Al.Microfilaments and microtubules maintain endo- size in rats.Circulation. 1994;89:1282-1290. thelial integrity.Microsc Res Tech.2003;60:115-127. 36. Rubenstein D,Jesty J,Bluestein D.Differences between mainstream and 57. Cucina A,Sapienza P,Borrelli V,Corvino V.Foresi G, Randone B, sidestream cigarette smoke extracts and nicotine in the activation of Cavallaro A,Santoro-D'Angelo L.Nicotine reorganizes cytoskeleton of platelets under static and flow conditions.Circulation.2004;109:78-83. vascular endothelial cell through platelet-derived growth factor BB. 37. Rader DJ.Lipid disorders.In:Topol El,ed.Textbook of Cardiovascular J Surg Res.2000;92:233-238. Medicine. 2nd ed. Philadelphia, Pa: Lippincott Williams &Wilkins; 58. Cucina A, Sapienza P, Corvino V, Borrelli V, Randone B, Santoro- 2002. D'Angelo L, Cavallaro A. Nicotine induces platelet-derived growth Downloaded from http://circ.ahajournals.org/by guest on February 23,2016 2696 Circulation May 24, 2005 factor release and cytoskeletal alteration in aortic smooth muscle cells. smoking preadolescent children: the MCV Twin study. Circulation. Surgery.2000;127:72-78. 1990;81:586-592. 59. Raij L,DeMaster EG,Jaimes EA.Cigarette smoke-induced endothelium 81. Feldman J, Shenker IR, Etzel RA, Spierto FW, Lilienfield DE, dysfunction:role of superoxide anion.J Hypertens.2001;19:891-897. Nussbaum M,Jacobson MS. Passive smoking alters lipid profiles in 60. Jaimes EA, DeMaster EG, Tian RX, Raij L. Stable compounds of adolescents.Pediatrics. 1991;88:259-264. cigarette smoke induce endothelial superoxide anion production via 82. Neufeld EJ,Mietus-Snyder M,Beiser AS,Baker AL,Newburger JW. NADPH oxidase activation.Arterioscler Thromb Vasc Biol. 2004;24: Passive cigarette smoking and reduced HDL cholesterol levels in 1031-1036. children with high-risk lipid profiles.Circulation. 1997;96:1403-1407. 61. USDHHS.The Health Consequences of Involuntary Smoking:A Report 83. Libby P,Ridker PM,Maseri A.Inflammation and atherosclerosis.Cir- of the Surgeon General. Atlanta, Ga: US Department of Health and culation.2002;105:1135-1143. Human Services,Public Health Service,Centers for Disease Control; 84. Shims M,Adachi M.Effects of environmental tobacco smoke on serum 1986. levels of acute phase proteins in schoolchildren.Prey Med. 1996;25: 62. Raitakari OT,Adams MR,McCredie RJ,Griffiths KA,Celermajer DS. 617-624. Arterial endothelial dysfunction related to passive smoking is potentially 85. Nakata A,Tanigawa T,Araki S.Sakurai S,Iso H. Lymphocyte sub- . reversible in healthy young adults.Ann Intern Med.1999;130:578-581. populations among passive smokers.JAMA.2004;291:1699-1700. 63. Schwarzacher SP,Hutchison S,Chou TM,Sun YP,Zhu BQ,Chatterjee 86. Anderson R,Theron Al,Richards GA,Myer MS,van Rensburg AJ. K,Glantz SA,Deedwania PC,Parmley WW,Sudhir K.Antioxidant diet Passive smoking by humans sensitizes circulating neutrophils.Am Rev preserves endothelium-dependent vasodilatation in resistance arteries of Respir Dis. 1991;144:570-574. hypercholesterolemic rabbits exposed to environmental tobacco smoke. 87. Panagiotakos DB,Pitsavos C,Chrysohoou C,Skoumas J,Masoura C, J Cardiovasc Pharmacol. 1998;31:649-653. Toutouzas P,Stefanadis C.Effect of exposure to secondhand smoke on 64. Mack WJ, Islam T, Lee Z, Selzer RH, Hodis HN. Environmental markers of inflammation: the ATTICA study.Am J Med. 2004;116: tobacco smoke and carotid arterial stiffness. Prey Med. 2003;37: 145-150. 148-154. 88. Barnoya J,Glantz SA.Secondhand smoke:the evidence of danger keeps 65. Mahmud A,Feely J.Effects of passive smoking on blood pressure and growing.Am J Med.2004;116:201-202. aortic pressure waveform in healthy young adults:influence of gender. 89. Sobczak A,Wardas W,Zielinska-Danch W,Pawlicki K.The influence Br J Clin Pharmacol.2004;57:37-43. of smoking on plasma homocysteine and cysteine levels in passive and 66. Mahmud A,Feely J.Effect of smoking on arterial stiffness and pulse active smokers.Clin Chem lab Med.2004;42:408-414. pressure amplification.Hypertension.2003;41:183-187. 90. Zhang J,Jiang S,Watson RR. Antioxidant supplementation prevents 67. Stefanadis C, Vlachopoulos C, Tsiamis E, Diamantopoulos L, oxidation and inflammatory responses induced by sidestream cigarette Toutouzas K,Giatrakos N,Vaina S,Tsekoura D,Toutouzas P.Unfa- smoke in old mice.Environ Health Perspect.2001;109:1007-1009. vorable effects of passive smoking on aortic function in men.Ann Intern 91. Suwa T,Hogg.IC,Quinlan KB,Ohgami A,Vincent R,van Eeden SF. Med. 1998;128:426-434. Particulate air pollution induces progression of atherosclerosis.J Am 68. Stefanadis C, Tsiamis E, Vlachopoulos C, Stratos C, Toutouzas K, Coll Cardiol.2002;39:935-942. Pitsavos C,Marakas S,Boudoulas H,Toutouzas P.Unfavorable effect 92. Glantz SA.Air pollution as a cause of heart disease:Time for action. of smoking on the elastic properties of the human aorta. Circulation. J Am Coll Cardiol.2002;39:943-945. 1997;95:31-38. 93. Gupta S.Chronic infection in the aetiology of atherosclerosis:focus on 69. Howard G,Burke GL,Szklo M,Tell G,Eckfeldt J,Evans G,Heiss G. Chlamydia pneumoniae.Atherosclerosis. 1999;143:1-6. Active and passive smoking and are associated with increased carotid 94. Kiechl S,Werner P,Egger G,Oberhollenzer F,Mayr M,Xu Q.Poewe artery wall thickness:the Atherosclerosis Risk in Communities Study. W,Willeit J.Active and passive smoking,chronic infections,and the Arch Intern Med. 1994;154:1277-1282. risk of carotid atherosclerosis: prospective results from the Bruneck 70. Penn A, Snyder CA. Inhalation of sidestream cigarette smoke accel- Study.Stroke.2002;33:2170-2176. crates development of arteriosclerotic plaques. Circulation. 1993;88: 95. Zhang J,En-lie Du E,Watson RR.Side-stream cigarette smoke accen- 1820-1825. tuates immunomodulation during murine AIDS.Int Immunopharmacol. 71. Penn A, (len LC, Snyder CA. Inhalation of steady-state sidestream 2002;2:759-766. smoke from one cigarette promotes arteriosclerotic plaque development. 96. Feinstein SB, Voci P, Pizzuto F. Noninvasive surrogate markers of Circulation. 1994;90:1363-1367. atherosclerosis.Am J Cardiol.2002;89:31-43. 72. Sun YP,Zhu BQ,Browne AE,Sievers RE,Bekker JM,Chatterjee K, 97. Tani S,Dimayuga PC,Anazawa T,Chyu K-Y,Li H,Shah PK,Cercek Parmley WW, Glantz SA. Nicotine does not influence arterial lipid B.Aberrant antibody responses to oxidized LDL and increased intimal deposits in rabbits exposed to second-hand smoke. Circulation. 2001; thickening in apoE-/-mice exposed to cigarette smoke.Atherosclerosis. 104:810-814. 2004;175:7-14. 73. Gotto AM Jr, Brinton EA. Assessing low levels of high-density 98. Howard G, Wagenknecht LE, Burke GL, Diez-Roux A, Evans GW, lipoprotein cholesterol as a risk factor in coronary heart disease: a McGovern P,Nieto FJ,Tell GS.Cigarette smoking and progression of working group report and update.J Am Coll Cardiol.2004;43:717-724. atherosclerosis:the Atherosclerosis Risk in Communities(ARIC)Study. 74. Wang M,Briggs MR.HDL:the metabolism,function,and therapeutic JAMA. 1998;279:119-124. importance.Chem Rev.2004;104:119-137. 99. He Y,Lam T,Li LS,Du R,Jia G,Huang J,Zheng J.The number of 75. Azizi F,Raiszadeh F,Salehi P,Rahmani M,Emami H,Ghanbarian A, stenotic coronary arteries is associated with the amount of passive Hajipour R. Determinants of serum HDL-C level in a Tehran urban smoking exposure.Atherosclerosis. 1996;127:229-238. population: the Tehran Lipid and Glucose Study. Nutr Metab Car- 100. Griendling KK, FitzGerald GA. Oxidative stress and cardiovascular diovasc Dis.2002;12:80-89. injury:part i:basic mechanisms and in vivo monitoring of ROS.Cir- 76. Mizoue T, Ueda R, Hino Y, Yoshimura T. Workplace exposure to culation.2003;108:1912-1916. environmental tobacco smoke and high density lipoprotein cholesterol 101. Weissberg PL,Rudd JH.Atherosclerotic biology and epidemiology of among nonsmokers.Am J Epidemiol. 1999;150:1068-1072. disease.In:Topol EJ,ed.Textbook of Cardiovascular Medicine.2nd ed. 77. Moffatt RJ,Stamford BA,Biggerstaff KD.Influence of worksite envi- Philadelphia,Pa:Lippincott Williams&Wilkins;2002. ronmental tobacco smoke on serum lipoprotein profiles of female non- 102. Chait A, Wight TN. Interaction of native and modified low-density smokers.Metabolism. 1995;44:1536-1539. lipoproteins with extracellular matrix. Curr Opin Lipidol. 2000;11: 78. Moffatt RJ,Chelland SA,Pecott DL,Stamford BA.Acute exposure to 457-463. environmental tobacco smoke reduces HDL-C and HDL2-C.Preventive 103. Maehira F.Zaha F,Miyagi I,Tambora A,Noho A.Effects of passive Medicine.2004;38:637-641. smoking on the regulation of rat aortic cholesteryl ester hydrolases by 79. Moskowitz WB, Schwartz PF, Schieken RM. Childhood passive signal transduction.Lipids.2000;35:503-511. smoking,race,and coronary artery disease risk:the MCV Twin Study, 104. Wang S,Sun NN,Zhang J,Watson RR,Witten ML.Immunomodulatory Medical College of Virginia. Arch Pediatr Adolesc Med. 1999;153: effects of high-dose a-tocopherol aceta& on mice subjected to side- 446-453. stream cigarette smoke.Toxicology.2002;175:235-245. 80. Moskowitz W,Mosteller M,Schieken R,Bossano R,Hewitt J,Bodurtha 105. Valkonen MM, Kuusi T. Vitamin C prevents the acute atherogenic J, Segrest J. Lipoprotein and oxygen transport alterations in passive effects of passive smoking.Free Radical Biol Med.2000;28:428-436. Downloaded from http://circ.ahajournals.org/by guest on February 23,2016 Barnova and Glantz Cardiovascular Effects of Secondhand Smoke 2697 106. Valkonen M,Kuusi T.Passive smoking induces atherogenic changes in 129. Hu FB, Willett WC. Optimal diets for prevention of coronary heart low-density lipoprotein.Circulation. 1998;97:2012-2016. disease.JAMA.2002;288:2569-2578. 107. Roberts KA,Rezai AA,Pinkerton KE,Rutledge JC.Effect of environ- 130. Mannino DM, Mulinare J, Ford ES, Schwartz J. Tobacco smoke mental tobacco smoke on LDL accumulation in the artery wall.Circu- exposure and decreased serum and red blood cell folate levels:data from lation. 1996;94:2248-2253. the Third National Health and Nutrition Examination Survey.Nicotine 108. Gairola CG,Drawdy ML,Block AE,Daugherty A.Sidestream cigarette Tob Res.2003;5:357-362. smoke accelerates atherogenesis in apolipoprotein E-/- mice.Athero- 131. Jendryczko A, Szpyrka G, Gruszczynski J, Kozowicz M. Cigarette sclerosis.2001;156:49-55. smoke exposure of school children: effect of passive smoking and 109. Knight-Lozano CA, Young CG, Burow DL,Hu ZY, Uyeminami D, vitamin E supplementation on blood antioxidant status. Neoplasma. Pinkerton KE, ]schiropoulos H, Ballinger SW. Cigarette smoke 1993;40:199-203. exposure and hypercholesterolemia increase mitochondrial damage in 132. Visioli F,Galli C,Plasmati E,Viappiani S,Hemandez A,Colombo C, cardiovascular tissues.Circulation.2002;105:849-854. Sala A.Olive phenol hydroxytyrosol prevents passive smoking-induced 110. Galis ZS,Khatri JJ.Matrix metalloproteinases in vascular remodeling oxidative stress.Circulation.2000;102:2169-2171. and atherogenesis:the good,the bad,and the ugly.Circ Res.2002;90: 133. Zhang Z,Araghiniknam M,Inserra P,Jiang S.Lee J,Chow S,Breceda 251-262. V, Balagtas M, Witten M, Watson RR..Vitamin E supplementation 111. Szmitko PE, Wang C-H, Weisel RD, de Almeida JR, Anderson TJ, prevents lung dysfunction and lipid peroxidation in nude mice exposed Verma S.New markers of inflammation and endothelial cell activation: to side-stream cigarette smoke.Nutr Res. 1999;19.75-84. part I.Circulation.2003;108:1917-1923. 134. Dietrich M,Block G,Benowitz NL,Morrow JD,Hudes M,Jacob P 3rd, 112. Carty CS, Soloway PD, Kayastha S, Bauer J, Marsan B, Ricotta JJ, Norkus EP,Packer L.Vitamin C supplementation decreases oxidative Dryjski M.Nicotine and cotinine stimulate secretion of basic fibroblast stress biomarker f2-isoprostanes in plasma of nonsmokers exposed to growth factor and affect expression of matrix metalloproteinases in environmental tobacco smoke.Nutr Cancer.2003;45:176-184. cultured human smooth muscle cells.J Vasc Surg. 1996;24:927-934; 135. Howard DJ, Ota RB, Briggs LA,Hampton M,Pritsos CA.Environ- discussion 934-935. mental tobacco smoke in the workplace induces oxidative stress in 113. Zhu BQ,Sun YP,Sudhir K,Sievers RE,Browne AE,Gao L,Hutchison employees, including increased production of 8-hydroxy-2'- SJ,Chou TM,Deedwania PC,Chatterjee K,Glantz SA,Parmley WW. deoxyguanosine.Cancer Epidemiol Biomarkers Prey. 1998;7:141-146. Effects of second-hand smoke and gender on infarct size of young rats 136. Howard DJ,Ota RB,Briggs LA,Hampton M,Pritsos CA.Oxidative exposed in utero and in the neonatal to adolescent period.J Am Coll stress induced by environmental tobacco smoke in the workplace is Cardiol. 1997;30:1878-1885. mitigated by antioxidant supplementation. Cancer Epidemiol 114. Antman EM,Braunwald E.Acute myocardial infarction.In:Braunwald Biomarkers Prey. 1998;7:981-988. E, Zipes DP, Libby P, eds. Heart Diseases:A Textbook of Cardia 137. Gvozdjak J.Gvozdjakova A,Kucharska,Bada V.The effect of smoking vascular Medicine. Philadelphia, Pa: WB Saunders Co; 2001: on myocardial metabolism.Czech Med. 1987.10:47-53. 1114-1231. 138. Gvozdjakova A, Kucharska J, Gvozdjak J.Effect of smoking on the 115. Ganz LI. Approach to the patient with asymptomatic electrocardio- oxidative processes of cardiomyocytes.Cardiology. 1992;1992:81-84. graphic abnormalities. In: Braunwald E, Goldman L, eds. Primary 139. Gvozdjakova A, Simko F, Kucharska J, Braunova Z, Psenek P, Cardiology.2nd ed.Philadelphia,Pa WB Saunders Co;2003:169-192. Kyselovic J.Captopril increased mitochondrial coenzyme Q(10)level, 116. Torok J,Gvozdjakova A,Kucharska J,Balazovjech I,Kysela S.Simko improved respiratory chain function and energy production in the left F, Gvozdjak J. Passive smoking impairs endothelium-dependent ventricle in rabbits with smoke mitochondrial cardiomyopathy. Bio- relaxation of isolated rabbit arteries.Physiol Res.2000;49:135-141. factors. 1999;10:61-65. 117. Harrison D,Griendling KK,Landmesser U,Hornig B,Drexler H.Role 140. McMurray RG,Hicks LL,Thompson DL.The effects of passive inha- of oxidative stress in atherosclerosis.Am J Cardiol.2003;91:7A-11A. lation of cigarette smoke on exercise performance.Eur J Appl Physiol. 118. Burke A, FitzGerald GA. Oxidative stress and smoking-induced 1985;54:196-200. vascular injury.Prog Cardiovasc Dis.2003;46:79-90. 141. Pope CA,3rd,Eatough DJ,Gold DR,Pang Y, Nielsen KR,Nath P. 119. Shekelle PG,Morton SC,Jungvig LK Udani J,Spar M,Tu W,J Suttorp Verner RI., Kanner RE. Acute exposure to environmental tobacco M,Coulter I,Newberry Si.Hardy M.Effect of Supplemental Vitamin E for the Prevention and Treatment of Cardiovascular Disease. J Gen smoke and heart rate variability.Environ Health Perspect.2001;109: • Intern Med.2004;19:380-389. 711-716. 120. Tribble DL,Giuliano U,Forman SP.Reduced plasma ascorbic acid 142. Cole CR Lauer MS,Bigger IT.Clinical assessment of the autonomic concentrations in nonsmokers regularly exposed to environmental nervous system.In:Topol EJ,ed.Textbook of Cardiovascular Medicine. tobacco smoke.Am J Clin Nutr. 1993;58:886-890. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2002: • 121. Jacob RA. Passive smoking induces oxidant damage preventable by 1615-1632. vitamin C.Nutr Rev.2000;58:239-241. 143. Jo W-K,Oh J-W,Dong J-I.Evaluation of exposure to carbon monoxide 122. Ayaori M,Hisada T,Suzukawa M, Yoshida H,Nishiwaki M, Ito T, associated with passive smoking.Environ Res.2004;94:309-318. Nakajima K,Higashi K,Yonemura A,Ishikawa T,Ohsuzu F,Nakamura 144. Kendall DM,Sobel BE Coulston AM,Peters Harmel AL,McLean BK, H.Plasma levels and redox status of ascorbic acid and levels of lipid Peragallo-Dittko V,Buse JB,Fonseca VA,Hill JO,Nesto RW,Sunyer peroxidation products in active and passive smokers.Environ Health FX.The insulin resistance syndrome and coronary artery disease.Coron Perspect.2000;108:105-108. Artery Dis.2003;14:335-348. 123. Strauss RS.Environmental tobacco smoke and serum vitamin C levels 145. Henkin L,Zaccaro D, Haffner S, Karter A, Rewers M, Sholinsky P, in children.Pediatrics.2001;107.540-542. Wagenknecht L. Cigarette smoking, environmental tobacco smoke 124. Preston AM,Rodriguez C,Rivera CE,Sahai H.Influence of environ- exposure and insulin sensitivity:the Insulin Resistance Atherosclerosis mental tobacco smoke on vitamin C status in children.Am J Clin Nutr. Study.Ann Epidemiol. 1999;9:290-296. 2003;77:167-172. 146. Reaven G,Tsao PS.Insulin resistance and compensatory hyperinsulin- 125. Alberg AJ,Chen JC,Zhao H,Hoffman SC,Comstock GW,Helzlsouer . emia: the key player between cigarette smoking and cardiovascular KJ.Household exposure to passive cigarette smoking and serum micro- disease?J Am Coll Cardiol.2003;41:1044-1047. nutrient concentrations.Am J Clin Nutr.2000;72:1576-1582. 147. Fichtenberg CM, Glantz SA. Effect of smoke-free workplaces on 126. van der Vliet A. Cigarettes, cancer, and carotenoids: a continuing, smoking behaviour:systematic review.BMJ.2002;325:188. unresolved antioxidant paradox.Am J Clin Nutr.2000;72:1421-1423. 148. Ong EK,Glantz SA.Constructing"sound science"and"good epidemi- 127. Dietrich M, Block G, Norkus EP, Hudes M,Traber MG,Cross CE, ology": tobacco, lawyers, and public relations firms. Am J Public Packer L. Smoking and exposure to environmental tobacco smoke Health.2001;91:1749-1757. decrease some plasma antioxidants and increase y-tocopherol in vivo 149. Muggli ME,Forster JL,Hurt RD,Repace JL.The smoke you don't see: after adjustment for dietary antioxidant intakes.Am J Clin Nutr.2003; uncovering tobacco industry scientific strategies aimed against environ- 77:160-166. mental tobacco smoke policies. Am J Public Health. 2001;91: 128. Farchi S,Forastiere F,Pistelli R,Baldacci S.Simoni M,Perucci CA, 1419-1423. Viegi G.Exposure to environmental tobacco smoke is associated with 150. Muggli ME,Hurt RD,Blanke DD.Science for hire:a tobacco industry lower plasma beta-carotene levels among nonsmoking women married strategy to influence public opinion on secondhand smoke.Nicotine Tob to a smoker.Cancer Epidemiol Biomarkers Prey.2001;10:907-909. Res.2003;5:303-314. Downloaded from http://circ.ahajotunals.org/by guest on February 23,2016 2698 Circulation May 24, 2005 151. Bamoya J,Glantz S.Tobacco industry success in preventing regulation 159. Sandler DP,Comstock GW, Helsing KJ, Shore DL.Deaths from all of secondhand smoke in Latin America: the "Latin Project". Tob causes in nonsmokers who lived with smokers.Am J Public Health. Control.2002;11:305-314. 1989;79:163-167. 152. Steenland K,Thun M,Lally C,Heath CJ.Environmental tobacco smoke 160. Svendsen KH, Kuller LH,Martin MJ,Ockene JK.Effects of passive and coronary heart disease in the American Cancer Society CPS-H smoking in the Multiple Risk Factor Intervention Trial.Am J Epidemiol. cohort.Circulation. 1996;94:622-628. 1987;126:783-795. 161. McElduff Kawachi I,Colditz G, Speizer F,Manson J,Stampfer M,Willett W, P.Dobson AJ,Jackson R.Beaglehole R,Heller RF,Lay-Yee R.Coronary events and exposure to environmental tobacco smoke: a Hennekens C. A prospective study of passive smoking and coronary case-control study from Australia and New Zealand.Tob Control.1998; heart disease.Circulation. 1997;95:2374-2379. 7:41-46. 154. Humble C,Croft J,Gerber A,Casper M,Hames C,Tyroler H.Passive 162. Ciruzzi M,Pramparo P,Esteban 0,Rozlosnik J,Tartaglione J,Abecasis smoking and twenty year cardiovascular disease mortality among non- B,Cesar J,De Rosa J,Paterno C,Schargrodsky H.Case-control study smoking wives in Evans County,Georgia.Am J Public Health. 1990; of passive smoking at home and risk of acute myocardial infarction. 80:599-601. JAm Coll Cardiol. 1998;31:797-803. 155. Hole DJ,Gillis CR,Chopra C,Hawthorne VM.Passive smoking and 163. LaVecchia C,D'Avanzo B,Franzosi MG,Tognoni G.Passive smoking cardiorespiratory health in a general population in the west of Scotland. and the risk of acute myocardial infarction.Lancet. 1993;341:505-506. BMJ. 1989;299:423-427. Letter. 156. Garland C,Barrett-Connor E,Suarez L,Criqui M,Wingard D.Effects 164. Lee P,Chamberlain J,Alderson M.Relationship of passive smoking to of passive smoking on ischemic heart disease mortality of nonsmokers. risk of lung cancer and other smoking-associated diseases.Br J Cancer. 1986;54: Am J Epidemiol. 1985;121:645-650. 165. Muscat J,,Wynder 105. WE.Exposure to environmental tobacco smoke and risk 157. Hirayama T.Lung Cancer in Japan:Effects of Nutrition and Passive of heart attack.Int J Epidemiol. 1995;24:715-719. Smoking.New York,NY:Verlag Chemie International; 1984. 166. Jackson RT.The Auckland Heart Study.Auckland,New Zealand:UM- 158. Butler TL. The Relationship of Passive Smoking to Various Health versity of Auckland; 1989. Outcomes Among Seventh Day Adventists in California.Los Angeles, 167. Dobson Al,Alexander HM,Heller RF,Lloyd DM.Passive smoking and Calif:University of California; 1988. the risk of heart attack or coronary death.Med JAustr.1991;154:793-797. 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