Arterial Endothelial Dysfunction Related to Passive Smoking Is Potentially Reversible in Healthy Young Adults

Evidence 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 effects of passive smoking may have important public health implications both for individuals and for institutions determining policies for smoke-free environments (4). We therefore compared arterial endothelial 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 diabetes mellitus, and no family history of premature vascular disease. None was taking any regular cardiovascular or antioxidant medications. All participants 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 nonsmokers with histories of exposure to environmental 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 environmental 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 intensity and lifetime duration of smoke exposure. Study Design Each participant had one study visit, during which a history was taken, supine resting blood pressure was measured, salivary cotinine was collected (for later analysis by rapid gas-liquid chromatography) (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 arterial diameter at rest, during reactive hyperemia (with increased flow producing endothelium-dependent dilatation), and after sublingual administration of nitroglycerin (leading to endothelium-independent 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 venesection was not obtained from the other 5 participants) at the same time as or within 12 months of the arterial studies. A Hitachi 747 autoanalyzer was used for all cholesterol measurements (Hitachi Instruments, 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 interobserver error for measurement of flow-mediated endothelium-dependent dilatation (6, 7). Statistical Analysis Descriptive data are expressed as means SDs. An analysis of variance for the three groups was performed, followed by the Scheffe method to allow pairwise significance testing. The duration and intensity of passive smoking were compared by using the Mann-Whitney U test. The determinants of endothelial function were assessed by multiple linear regression analysis, with age, sex, mean blood pressure, 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 to passive smoking had ceased 6 5 years before the study visit. Table. Baseline Characteristics and Arterial Reactivity Results Endothelium-dependent dilatation was significantly 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 same when the sexes were analyzed separately. On multivariate analysis, endothelium-dependent dilatation was related to current passive smoking (P 0.001) and was inversely related to total cholesterol level (P 0.05). Nitroglycerin-induced vasodilatation was similar in all three groups. In the former passive smoking group, endothelial function was most severely impaired in participants whose last exposure to environmental tobacco smoke was 2 years before 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 0.05). Figure. Flow-mediated, endothelium-dependent dilatation in 20 nonsmokers, 20 former passive smokers, and 20 passive smokers. Discussion In the current study, we have shown that endothelial function, a marker of arterial health, is significantly better in young adults who have withdrawn 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 normal endothelial function (as measured in a control group of persons who neither actively nor passively smoked), suggesting only partial reversibility of passive smoke-related arterial injury. The arterial endothelium plays an important role in cardiovascular homeostasis, and the role of endothelium-derived nitric oxide seems pivotal in promoting vasodilatation and inhibiting platelet aggregation, monocyte adhesion, and smooth-muscle proliferation (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 results 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 absence of other potentially confounding vascular risk factors, for sex, and for the duration and intensity of exposure to passive smoking. Self-reporting of exposure to environmental tobacco smoke by questionnaire was used because no methods are available to objectively quantify previous exposure to tobacco smoke. Environmental tobacco smoke has numerous adverse effects on vascular biology; this may explain its relation to the increased risk for atherosclerotic events. Sidestream cigarette smoke (from the burning 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 increase the likelihood of ischemic episodes in persons with existing coronary artery disease (12). Environmental 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 associated 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 arterial damage may also be the consequence of enhanced degradation of nitric oxide secondary to the formation of oxygen-derived free radicals (16). The potential for reversibility of these early passive smoke-related changes is unknown. We previously documented that active smoking-related endothelial dysfunction may be reversible with smoking cessation, but in this earlier study (17), no correlation 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 continuing 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 benefit 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 you