Table 2.12, Endothelial dysfunction in young smokers - Preventing Tobacco Use Among Youth and Young Adults

Table 2.12Endothelial dysfunction in young smokers

Study	Design/population	Vascular function assessment technique	Findings	Comments
Celermajer et al. 1993	Case-control study with assessment of chronic exposure to tobacco (pack-years^a) 200 English men and women 16–56 years of age with 80 nonsmokers, 40 former smokers, and 80 current smokers All subjects normotensive, cholesterol <240 mg/dl, nondiabetic, and no family history of cardiovascular disease Smoking status also assessed by cotinine levels	Brachial artery ultrasound and Doppler assessment of brachial artery flow at rest, after ischemia, and after sublingual glyceryl trinitrate	Flow-mediated dilation (%): nonsmokers 10.0 ± 3.3, smokers 4.0 ± 3.9, former smokers 5.1 ± 3.8; p <0.0001 smokers vs. nonsmokers, p <0.07 smokers vs. former smokers Flow-mediated dilation was dose dependent in a multivariate regression model including age, gender, cholesterol, cotinine, and pack- years; only pack-years significant, partial regression coefficient −0.33, p <0.05; cotinine nonsignificant No difference among groups in response to glyceryl trinitrate	First demonstration of effect of tobacco use on endothelial function; tightly controlled study with large sample size; demonstrates both dose- dependent effects of tobacco exposure and residual chronic effects in former smokers
Celermajer et al. 1996	Case-control study comparing nonsmokers, those exposed to smoke passively (>1 hour/day for 3 years), and current smokers All subjects normotensive, cholesterol <240 mg/dl, nondiabetic, and no family history of cardiovascular disease 78 healthy men and women, 15–30 years of age, 26 nonsmokers, 26 smoke exposed, and 26 current smokers	Brachial artery ultrasound and Doppler assessment of brachial artery flow at rest, after ischemia, and after sublingual glyceral trinitrate	Flow-mediated dilation (%): nonsmokers 8.2 ± 3.1, smokers 4.4 ± 3.1, smoke exposed 3.1 ± 2.7; p <0.0001 for smokers and smoke-exposed vs. nonsmokers In those passively exposed, flow-mediated dilation was inversely related to smoke exposure (hours/day/year); r = 0.67, p <0.0001 No difference among groups in response to glyceral trinitrate	First demonstration of effect of passive smoke exposure on endothelial function; effect similar to that of chronic exposure and also dose dependent
Leeson et al. 1997	Cross-sectional study of 333 British schoolchildren aged 9–11 years to assess the relationship of cardiovascular risk factors including low birth weight to endothelial dysfunction	Brachial artery ultrasound and Doppler assessment of brachial artery flow at rest and after ischemia Smoke exposure assessed by salivary cotinine	No relationship between smoke-exposed and nonexposed children	Negative study; smoke exposure measure is cotinine as opposed to self-report of exposure history
Raitakari et al. 1999	Case-control study conducted in Australia comparing nonsmokers (passive or active), those exposed to smoke passively (>1 hour/day for 2 years), and former passive smokers All subjects normotensive, cholesterol <240 mg/dl, nondiabetic, and no family history of cardiovascular disease 60 healthy men and women, 15–39 years of age, 20 nonsmokers, 20 smoke exposed, and 20 former smoke exposed (average of 5 years since last exposure)	Brachial artery ultrasound and Doppler assessment of brachial artery flow at rest, after ischemia, and after sublingual glyceral trinitrate	Flow-mediated dilation (%): nonsmokers 8.9 ± 3.2, passive smokers 2.3 ± 2.1, former smoke exposed 5.1 ± 4.1; p <0.01 vs. nonsmokers for both groups, p = 0.01 for passive smokers vs. former passive smokers (ANOVA, Scheffe) Flow-mediated dilation (%): subgroup comparison of those smoke exposed previously: >2 years 5.8 ± 4.0 vs. <2 years 1.2 ± 1.7; p <0.05 No difference among groups in response to glyceral trinitrate	Extends findings of Celermajer studies (1993 (1996) showing dose- dependent effect of passive smoke exposure; results are generally consistent for magnitude of effect across all 3 studies done by the same team
Woo et al. 2000	Case-control study comparing nonsmokers and those exposed to smoke passively in a casino Matched for other cardiovascular risk factors 20 men and women in each group, mean age 36.6 years Macao	Brachial artery ultrasound and Doppler assessment of brachial artery flow at rest, after ischemia, and after sublingual glyceral trinitrate	Flow-mediated dilation (%): nonsmokers 10.6 ± 2.3, passive smokers 6.6 ± 3.4; p <0.0001 Passive smoking was the strongest predictor of flow-mediated dilation in multivariate analysis; beta = −0.59, p <0.0001 for passive smoke exposure No difference among groups in response to glyceral trinitrate	Confirmation of effect of passive smoke exposure on endothelial dysfunction in a work environment
Leeson et al. 2001	Cross-sectional study conducted in England to assess the relationship of cardiovascular risk factors, including low birth weight, to endothelial dysfunction 315 men and women 20–28 years of age	Brachial artery ultrasound and Doppler assessment of brachial artery flow at rest and after ischemia	Smokers had lower flow-mediated dilation than did nonsmokers (mean difference 0.29); 95% CI, 0.07–0.51, p = 0.009 There was an inverse relation between flow- mediated dilation and number of smoking pack-years; coefficient −0.4 pack-years, 95% CI, −0.004 to −0.07, p = 0.03	Findings consistent with prior studies
Levent et al. 2004	Case-control study of smoking and nonsmoking adolescents 30 in each group, mean age of 16 years, cohort 90% male Duration of smoking 3.4 years, higher passive smoke exposure in the smoking group Turkey	Aortic stiffness assessed by calculation of aortic strain, pressure strain, and normalized pressure strain elastic modulus using transthoracic echocardiography and peripheral blood pressure measurement	Aortic strain: 0.262 ± 0.056 vs. 0.198 ± 0.042 (nonsmokers vs. smokers); p <0.0001 Elastic modulus: 152 ± 18 vs. 215 ± 17 (nonsmokers vs. smokers); p <0.0001 Elastic modulus normalized to aortic size: 2.2 ± 0.7 vs. 2.8 ± 0.4 (nonsmokers vs. smokers); p <0.001	Findings suggest tobacco use increases stiffness in large conduit arteries
Kato et al. 2006	Case-control study comparing smoking and nonsmoking healthy males; nonsmokers were then exposed to tobacco smoke for 30 minutes, 15 in each group, mean age 32 years, matched for cardiovascular risk factors Japan	Brachial artery ultrasound and Doppler assessment of brachial artery flow at rest, after ischemia, and after sublingual glyceral trinitrate Plasma 8-isoprostane measured at baseline and 30 minutes after smoke exposure	Flow-mediated dilation (%): nonsmokers 10.9 ± 3.1, smokers 4.3 ± 1.2; p <0.0001 Flow-mediated dilation after passive smoke exposure (%): nonsmokers 5.0 ± 1.9 (decreased), smokers 3.9 ± 1.0 (unchanged); p <0.003 for decrease in nonsmokers Plasma 8-isoprostane measured at baseline pg/ mL: nonsmokers 26.9 ± 5.4, smokers 41.5 ± 5.8; p <0.001 Plasma 8-isoprostane measured 30 minutes after baseline pg/mL: nonsmokers 37.8 ± 9.6 (increased), smokers 39.2 ± 9.0 (unchanged); p <0.001 for increase in nonsmokers Flow-mediated dilation was negatively correlated with plasma 8-isoprostane; r = −0.69, p <0.001	Confirms relationship of tobacco use and passive smoke exposure to flow- mediated dilation; correlates change in flow-mediated dilation with a measure of oxidative stress
Kallio et al. 2007	Longitudinal cohort study of boys and girls randomized to a low cholesterol/low saturated fat diet 402 children with cotinine measures from 8 to 11 years of age and stratified by cotinine concentration: nondetectable (n = 29), low (n = 134), top decile (n = 39) Finland	Brachial artery ultrasound and Doppler assessment of brachial artery flow at rest, after ischemia, and after sublingual glyceral trinitrate Annual cotinine measurements from 8 to 11 years of age (90% compliance in the cohort for the measurement) Controlled for cardiovascular risk factors and diet treatment group assignment	Flow-mediated dilation decreased as cotinine level increased across the three groups: nondetectable 9.10 ± 3.88, low 8.57 ± 3.78, top decile 7.73 ± 3.85; p <0.02 for trend (p = 0.008 for trend if analysis restricted to those with 4 cotinine measures)	Chronic passive smoke exposure contributes to endothelial dysfunction in children
Yufu et al. 2007	Case-control study comparing young adult men and women smokers and nonsmokers 26 smokers and 31 nonsmokers; mean age 30 years Japan	Brachial artery ultrasound and Doppler assessment of brachial artery flow at rest, after ischemia, and after sublingual glyceral trinitrate Pulse wave velocity assessed using a commercially available noninvasive automatic waveform analyzer	Flow-mediated dilation (%): nonsmokers 16.1 ± 6.6, smokers 12.4 ± 5.8; p <0.03 Pulse wave velocity (cm/s): nonsmokers 1,201 ± 161, smokers 1,232 ± 160; not significant In smokers only, flow-mediated dilation associated with pulse wave velocity; F = 8.108	Confirms effect of smoking on flow-mediated dilation in another country
Heiss et al. 2008	Nonsmokers exposed to tobacco smoke for 30 minutes and compared with clean air exposure 10 men and women, 30 years of age United States	Brachial artery ultrasound and Doppler assessment of brachial artery flow at rest, after ischemia Cotinine measured to confirm absence of tobacco use at baseline and amount of exposure Measurement of endothelial progenitor cells, plasma vascular endothelial growth factor, endothelial microparticles, and progenitor cell chemotaxis Plasma from smoke- exposed individuals used in in vitro experiments with unexposed endothelial progenitor cells	Flow-mediated dilation decreased by 3% and returned to normal 2 hours after exposure; p <0.05 compared with baseline state and clean air exposure for all findings presented Increase in appearance of endothelial progenitor cells at 1 hour after exposure with sustained increase for 24 hours Chemotaxis to vascular endothelial growth factor of endothelial progenitor cells abolished immediately after smoke exposure, effect persisted for 24 hours Vascular endothelial growth factor concentrations increased immediately after exposure Linear relationships between cotinine levels after exposure and measured biological parameters Incubation of unexposed endothelial progenitor cells with exposed plasma leads to in vitro decreased nitric oxide production, decreased chemotaxis, and increased proliferation	Establishes a mechanistic link between decrease in endothelial function as assessed by brachial ultrasound after passive smoke exposure and endothelial cell dysfunction including nitric-oxide- mediated processes; effect seen in a relatively small sample
Quinton et al. 2008	Smoking (n = 21) and nonsmoking (n = 20) pregnant women compared for flow- mediated dilation Birth weight in the offspring of smoking women assessed and compared with flow-mediated dilation results	Brachial artery ultrasound and Doppler assessment of brachial artery flow at rest and a second time at 28– 32 weeks gestation (after smoking in the smokers and after no intervention in the nonsmokers) Birth weight measured in g for all offspring	Smokers had lower flow-mediated dilation compared with nonsmokers (4.0 ± 2.3 vs. 9.7 ± 4.0); p <0.001 No change in flow-mediated dilation values after active smoking; no change in the nonsmokers; reproducibility of the test demonstrated Smoking women had infants of lower birth weight (3,090 g ± 596 vs. 3,501 g ± 396); no small-for-gestational-age infants in the nonsmoking group; p = 0.014 In all women, those with infants less than the 10th percentile for weight had lower flow- mediated dilation than those with normal birth weight infants (4.7 ± 2.2 vs. 7.3 ± 4.6); p <0.03	Confirms impact of tobacco use on endothelial function, confirms that regular smokers have chronic endothelial dysfunction (i.e., smoking an additional cigarette after a 9-hour abstinence does not change findings); relates endothelial dysfunction to poorer pregnancy outcome with respect to birth weight
Thomas et al. 2008	Total of 616 subjects from urban and rural sites Aged 18–75 years (152 smokers) China and United States	Brachial artery ultrasound and Doppler assessment of brachial artery flow at rest, after ischemia, and after sublingual glyceral trinitrate Measurement of carotid intima-media thickness and other cardiovascular risk factors	Smokers had impaired flow-mediated dilation vs. nonsmokers (7.0 ± 2.3 vs. 8.2 ± 2.5%); p <0.001 Additional factors related to flow-mediated dilation included urban location, triglycerides, age, diastolic blood pressure, and glucose; total r² = 0.18 Smokers had higher carotid intima-media thickness vs. nonsmokers (0.61 ± 0.13 vs. 0.58 ± 0.12 mm); p = 0.25	Confirms findings in prior studies of individuals of Chinese ancestry, controlling for work environment, geographic location, and other cardiovascular risk factors

: Note: ANOVA = analysis of variance; cm/s = centimeters per second; dl = deciliter; g = grams; mg = milligrams; mL = milliliters; mm = millimeters; pg = picograms.
a: Pack-years = the number of years of smoking multiplied by the number of packs of cigarettes smoked per day.

From: 2, The Health Consequences of Tobacco Use Among Young People

Cover of Preventing Tobacco Use Among Youth and Young Adults

Preventing Tobacco Use Among Youth and Young Adults: A Report of the Surgeon General.

National Center for Chronic Disease Prevention and Health Promotion (US) Office on Smoking and Health.

Atlanta (GA): Centers for Disease Control and Prevention (US); 2012.

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