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BRIEF cOMMUNICAT1O1V5 J Arterial Endothelial Dysfanction Related to Passive Smoking Is Potentially Reversible in. Healthy Young Adults Olli T. Raitakari, MD, PhD; . Mark R. -Adams, MB, BS, PhD, FRACP; Robyn 1. McCredie, BSc; Kaye A. t'irifiiths, DMU; and David S. Cefermajer, MB, BS, PhD, FRACP Background: Passive smoking is associated with early ar- terial damage, but the potential for reversibility of this damage is unknown. . . . Objective: To assess the reversibility of arterial endothe- fial dysfunction, a key marker of early atherosclerosis. Design: Cross-sectional study. Setting: Academic medical center. Participantsr-60 healthy persons 15 to 39 years of age: 20 with no exposure to active or passive smoking, 20 non- smoking passive smokers (exposure to environmental to- bacco smoke for z1 hour per day for ?2 years), and 20 former passive smokers. . . Measurements: Arteriall endothelial function measured by noninvasive ultrasonography. Results: Endothelium-dependent dilatation was signifi- cant/y better In former passive smokers (5.1%±-4.1% [range, -1.2% to 15.6°/a)) than in current passive-smokers (Z.3%:t 2.1% [range, -0.2%to.6.7°k]) (P= 0.01), al-though both groups were significantly impaired compared with nonsmoking controls (8.9% t3.246 [range, 2.1% to 16:7%])(Ps0:01forbothcomparisons). . Conclusions: In healthy young adults, arterial endothe- lial dysfunction related to passive smoking..seems too be partially reversible. This paper is also available at httpJ/vrnw.acponliae.org. .4nn Inton Med 1999;130578-581. From Royal Prince Alfred Hospitai, The Heart Research insti- mte, and University of Sydney, Sydney, Australia; aad University of TVrku, Turku, Finland. For current author addresses, see end of text. vtdence from several clinical, laboratory, and epidemiologic studies conducted over the past decade has clearly shown that regular exposure to environmental tobacco smoke is associated with early arterial injury (1, 2) and increases the risk for coronary disease in nonsmokers (3). The question of reversibility of the deleterious cardiovascular ef- fects of passive smoking may have important public health implications both for individuals and for in- stitutions determining policies for smoke-free envi- ronments (4). . We therefore compared arterial en- doth'elial responses in three matched groups of healthy young adults (nonsmokers, passive smokers, and former passive smokers). Methods Participants We studied 60 young adults 15 to 39 years of age (24 male participants and 36 female participants). Every participant had a blood pressure of 160/90 mm Hg or less, no history of dyslipidemia or dia- betes mellitus, and no family history of premature vascular disease. None was taking any regular car- diovascular or antioxidant medications. All partici- pants gave informed consent, and the study was approved by our institutional committee on ethical practice. The controls were 20 lifelong nonsmokers who had never been regularly exposed to tobacco smoke at home or in the workplace (self-reported). The passive smoking group consisted of 20 lifelong non- smokersw]th histories of exposureto envirotunental_ tobacco smoke at home, work, or both for at least 1 hour per day for 2 or more years. The former passive smoking group consisted of 20 consecutively studied nonsmokers who had been exposed to envi- ronmental tobacco smoke for at least 1 hour,per day for 2 or more years, and this exposure had ceased at least 1 year before their study visit. The duration and the average intensity of exposure to environmental tobacco smoke were assessed by questionnaire. The scale for the intensity score was 1= light (1 to 3 hours per day), 2 = moderate (4 to 6 hours per day), and 3 = heavy (>6 hours per day). The former passive smoking group and the passive smoking group were matched for the average inten- sity and lifetime duration of smoke exposure. 578 6 April 1999 •.4nuals of Intema! Medicine • Volume 130 • Number7 2505586013

Table. Baseline Characteristics and Arterial Reactivity Results` Variable Contmis Former Passive Smokers Passive Smokers P Valuet A9e,Y 22±4 2656 24±5 0.09 Males4emales, n/n 8/12 8/12 8/12 Environmental tobacco smoke intensity scores 0 2.420.7 2.2±0.8 >0.2§ Duration of exposure to environmental tobacco smoke, y 0 17;4 15}9 >01§ Blood pressure, mm Hg 85 m 7 89a9 85 7 7 >0.2 Total cholesterol level, mmol/L 469 z 0.75 4.37 031 1 4.92!0.76 0.09 Vessel size at rest, mm 337 w 0.53 3.63 x 0.43 - 3.46 i 0.59 >0.2 Blood flow at rest, mUmin 51 ~ 55 39 s 22 45 ~ 29 >0.2 Endothelium-dependent dilatation, % 8_9 ~ 3.2 5.1 -4.1 2.322.1 <0.001 Nitroglycerin-mediated dilatation, % 19.8 - 4.9 17.7 3 5 6 16.4 '_ 5.9 0.15 Hyperemia, % 578 t 228 590 S 232 437 ± 139 0.06 • Values with plue/minus signs are the mean z S0. t P values are for comparison of the three groups by analysis ot variance, except as noted belav. S Scale for intensity score: 1 = light, 2 = moderate, and 3= heavy. 4 P values for environmental oobaccv smoke exposure (intensity and duration) refer to the comparisons between former and current passive smokers. Study Design Each participant had one study visit, during - which a history was taken, supine resting blood pressure was measured, salivary cotinine was col- lected (for later analysis by rapid gas-liquid chro- matography) (5), and reactivity of the right brachial artery was analyzed. The ultrasonographic method for measuring arterial reactivity and flows, described elsewhere (1), relies on precise measurement of ar- terial diameter at rest, during reactive hyperemia (with increased flow producing endothelium-depen- dent dilatation), and after sublingual administration of nitroglycerin (leading to endothelium-indepen- dent~ dilatation). In the passive smoking group, time since last exposure to passive smoking was less than 24 hours in every case. Total cholesterol levels were measured in 55 of 60 participants (consent for vene- section was not obtained from the other 5 partici- pants) at the same time as or within 12 months of the arterial studies. A Hitachi 747 autoanalyzer was used for all cholesterol measurements (Hitachi In- struments, Inc., Tokyo, Japan). Data Analysis Vessel diameter was measured in every,case by two independent observers, as described elsewhere (1). Observers were blinded to the smoking status of each participant and the stage of the experiment. We have previously shown that this measurement method is accurate and reproducible for detection of small changes in arterial diameter (6), with low interobseiver error for measurement of flow-medi- ated endothelium-dependent dilatation (6, 7), Statistical Analysis Descriptive data are expressed as means t SDs. An analysis of variance for the three groups was performed, followed by the Scheffe method to allow pairwise significance testing. The duration and in- tensity of passive smoking were compared by using the Mann-Whitney U test. The determinants of endo- thelial function were assessed by multiple linear re- gression analysis, with age, sex, mean blood pres- sure, total cholesterol levels, vessel size, and the passive smoking group as the independent variables. Statistical significance was inferred at a two-tailed P value of 0.05 or less. Results The characteristics of the study groups are shown in the Table. The salivary cotinine level was less than 250 nmol/L in every participant, indicating no recent active smoking (8). In the former passive smoking group, exposure tq passive smoking had ceased 6:t 5 years before the study visit. Endothelium-dependent dilatation was signifi- cantly better in the former passive smokers than in the passive smokers (P = 0.01), although both groups were impaired compared with nonsmoking controls (P ~ 0.01 for both comparisons) (Table, Figure). The results remained essentially the samee e 20, ~ 15 0 5 0 w e I I P <0.01 P<0.001 I P=0.01 I _ Nonsmokers Former Passive Smokers Passive Smokers Figure. Flow-mediated, endotheltum-dependent dilatation in 20 nonsmokers, 20 former passive smokers, and 20 passlve smokers. For each study group, the box represents the interquartile range (between the 25th and 75th percentiles), with the median value shovm as a horizontal bar within each box. The bars outside each box show the range of 95% of values. 6 Apri1 1999 - Annals of Internal Medicine • Volume 130 - Number 7 579

\,w when the sexes were analyzed separately. On mul- tivariate analysis, endothelium-dependent dilatation was related to current passive smoking (P < 0.001) and was inversely related to total cholesterol level (P :s 0.05). Nitroglycerin-induced vasodilatation was similar in all three groups.,,In the former passive smoking group, endothelial function was most se- verely impaired in participants whose last exposure to environmental tobacco smoke was 2 years beforee the study visit or less (1.2% - 1.7%) compared with those whose exposure ended 2 or more years before the study visit (5.8% ±4.0%) (P s 0.05). Discussion In the current study, we have shown that endo- thelial function, a marker of arterial health, is sig- nificantly better in young adults who have.with- drawn from regular exposure to environmental tobacco smoke than in continuing passive smokers; despite a similar lifetime duration and intensity of smoke exposure. The maximum improvement in vascular function was only observed more than 2 years after cessation of passive smoking. Neither tobacco smoke-exposed group, however, had nor- mal endothelial function (as measured in a control group of persons who neither actively nor passively smoked), suggesting only partial-reversibility of pas- sive smoke-related arterial injury. The arterial endotheHum plays an important role in cardiovascular homeostasis, and the role of endo- thelium-derived nitric oxide seems pivotal in promot- ing vasodilatation and inhibiting platelet aggregation, monocyte adhesion, and smooth-muscle prolifera- tion (9). For these reasons, the observed recovery of the arteries' ability to produce nitric oxide after cessation of passive smoking (as assessed by our noninvasive method) (10) might have important pathophysiologic implications in terms of disease reversibility. Because our study examined the effects of passive smoking.cessation on arterial reactivity in a cross- sectional setting, the r0sults should be interpreted with caution. A more ideal approach would be serial prospective study of persons before and after they have withdrawn from environmental tobacco smoke exposure. Such a longitudinal study, however, would be logistically difficult because cessation of passive smoking at home or in the workplace often cannot be controlled voluntarily by the exposed person (for example, teenagers who continue to live at home with actively smoking parents). In the current study, the participants were carefully matched for the ab- sence of other potentially confounding vascular risk factors, for sex, and for the duration and intensity of exposure to passive smoking. Self-reporting of expo- sure to environmental tobacco smoke by question- naire was used because no methods are available to objectively quantify previous exposuree to tobacco smoke. Environmental tobacco smoke has numerous ad- verse effects on vascular biology; this may explain its relation to the increased risk for atherosclerotic events. Sidestream cigarette smoke (from the burn- ing ends of cigarettes) contains more than 4000 chemicals, many toxic or carcinogenic (11). Passive smoking reduces oxygen affinity for hemoglobin and decreases mitochondrial respiration; these effects in- crease the likelihood of ischemic episodes in per-sons with existing coronary artery disease (12). En- vironmental tobacco smoke in doses that are routinely encountered by persons in smoke-filled environments increases the percentage of the aorta covered by atheroma in cholesterol-fed rabbits (13), is.associ- ated with an increase in the size of aortic atheroma plaques in cockerels (14), and . may also increase platelet aggregation and thereby'predispose to acute thrombus formation (15). Passive smoke-related ar- terial damage may also be the consequence of en- hanced degradation of nitric oxide secondary to the formation of oxygen-derived free radicals (16). The potential for reversibility of these early pas- sive smoke-related changes is unknown. We previ- ously documented that active smoking-related endo- thelial dysfunction may be reversible with smoking cessation, but in this earlier study (17), no correla- tion was seen between time since cessation and endothelium-dependent dilatation. In the current study, most improvement in the former passive smokers was evident after 2 years of cessation of passive smoking. Epidemiologic studies of disease reversibility have also suggested that the risk for cardiovascular events is significantly lower in active . smokers who give up smoking (18) than in continu- ing smokers. This reduction in risk may be mediated by reversible effects of smoking on thrombogenesis with or without concomitant changes in. vascular .. structure or function. Whether similar clinical ben- efit from passive smoke withdrawal will be obtained requires further prospective study. . Passive smoking has been consistently linked to an increased risk for coronary heart disease and may be responsible for more than 30 cardiovascular deaths annually in the United States alone_ (19). In healthy young adults, we have now demonstrated that cessation of exposure to environmental tobacco smoke for more than 2 years is associated with improved arterial function. These data support in- dividual and public health policy initiatives to allow nonsmokers to avoid smoke-filled environments at home or in the workplace. 580 6 April 1999 - Annals of Internal Medicene - Volume 130 - Number 7 2505586015

Gmnr Supporr: By thc Academy of Finland and Turku Univcrsity Central Hospital, Finland (Dr. Raitakari); the Medical Founda- iion of Sydney University, Australia (Ms. McCredie and Dr. Cclermajer); and the National Heart Foundation of Australia (Ms. Griffiths)- Requetf for Reprin[s.' David S. Celermajer, MB, BS, PhD, FRACP, Department of Cardiology, Royal Prince Alfred Hospi- tal, Missenden Road, Camperdown NSW 2050, Sydney, Australia. Cruren( Author Address: Drs. Raitakari, Adams, and Celermajer, Ms. Griffiths, and Ms. McCredie: Department of Cardiology, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Sydney, Australia. References 1. Celermajer 05. Adams MR. Clarkson P, Rabinson J, McCredie R, Donald A, et a]. Passlve smoking and impaired endotheliumdependent arterial dilatation in healthy young adults. N Engl / Med. 1996;334:150-4. 2. 5tefanadis C, Vlachopoulas C. Tsiamis E, Diamantapoulos L, Toutou- zas R, Giatrakos N, at al. Unfavorable eHects of passive smoking on aortic function in men. Ann Intern Med. 1998;128:426-34. 3. Glaniz SA, Parrnley W W. Passive smoking and heart disease. Mechanisms and dsk. JAMA. 1995;273:1047-53. 4. Brownson RC. Eriksen MP, Davis RM, Wanrer KE Environmental tobacco smoke: health effects and polides to reduce eaposure. Annu Re+ Public Health. 1997:18:163-85. 5. Peyerabend C, Russel MA. A rapid gas-liquid dlrtxnatographic method for the determination of cotinine and nrcotine in biological fluids. I Pham, Phar- maco1.1990;42:450-2. 6. Sorensen KE, Celennajer DS, Splegelhaher DJ, Georgakopoulos D, Robinson l. Thomas Q, et al. Non-invasive measurement of endothelium- dependent arterial responsesaccuracy and reproducibility. Br Heart 1. 1995; 74247-53 ' 7. Celermajer D5, Sorensen KE. Gooch VM. Spiegelhalter D1, Miller OL Sullivan ID, at al. Norvlnvaslve detenlon of endothellal dysfunction in chil- dren and adults at risk of atherosckrosu. Lancec 1992;340:1111-5. 8. Pierce JP. Dwyer T, DiGiusta E. Carpenter T, Hannam C Amin A, ei al. Cotinine validation of self-reported smoking in commercially run communiry surveys. I Chronic Ois. 1987;40:689-95. A Celermajer O5. Endothelial dysfunction: does it matter? Is it resyrgble? I Gio Coll Cardiol. 1997;30:325-33. 10. loxnnides R, Haefeli WE, Linder L Richard V, Bakkati EH. Thuillez C et at Nitric oxitle is responsible for Flax-dependent dilatation ot human periph- eral conduit aatenes in vivo. CirculaGon. 1995;91:13i4-9. 11. Taylor AE, Johnson DC, Kazerni H. Envlromental tobacco smoke and cardiovascular disease. A position paper from the Council of Cardloputmonary and Cdtical Care, American Neart Attodation. Circulation, 1992;86:699-7g2. 12. Dwyer EM lr, Turino GM.'Carbon monodde and card'wvascnlar disease (Editoriap- N Engl l Med_ 1989;321:1474-5. 13. Zhu BQ, Sun YP, Sievers RE, Isenberg WM, Gfantz SA, Parmley WW- Passive smoking increases experimental athe.osderosis in cholesterol-fed rab- bits. I Am Coll Cardiol. 1993;21:225-32. 14. Penn A, Snyder CA. Inhalation of sidestream cigarette smoke accelerates development of zrteriosderotic plaques. Circulation. 1993;88(4 Pt 1):1820-5. 15. Steinberg D, Parthasarathy 5, Carew TE, Khoo IC, Wit¢tum IL Beyond chohsteroi. Modifications of Iow-densiry lipoprotein that increase its athero- genicity N Engl J Med. 1989;320:915-24. 16. Duthie GG, Arthur JR, James WP. Effects of smoking and vitamin E on blood antioxidant status. Am J Clin Nutr, 1991:53(4 SuppIk10615-3S. 17, Celermajer O5, Sorensen KE, Georgakopoulos D, Bull C Thomas o, Robinson l, et al. Ci9arette smoking is associated with tlose-related and potentially re.essibk impairment of endothelium-dependent dilauon in healthy young adults. Circulation. 1993;88:2149-55_ 18. Rosenberg L Kaufmann DW, Helmrich SP, Shapiro S. The risk of myo- -cardiat infarction after quittin9 smoking in men under 55 years of age. N Engl I Med. 1985:313:15I t~. 19. Giant¢ SA. Parmley WW. Passive smoking and heart disease. Epidemiotogy, physiology, and biochemistry. Circolation. 1991;83'1-12. ® 1999 American College of Physicians-American Sodety of Interna) Medieine 6 April 1999 • Annals of Internal Medicine • Volume 130 • Number 7 581 /