exposure locations plus age, sex, education, and employment status showed a stronger association between increased CAC + 1 and SHS exposure at home (34.1%; 95% CI: –5.0%, 89.3%) than exposure at work (7.1%; 95% CI: –22.8%, 48.7%) or at other places (–7.6%; 95% CI: –39.4%, 40.9%). We found no clear exposure–response relation- ship in the adjusted linear regression analy- sis. Compared with the reference group (no exposure), exposure to SHS only at home and exposure to SHS at home plus exposure at work led to increases in CAC + 1 of 52.1% (95% CI: –3.0%, 118.1%) and 17.9% (95% CI: –28.1%, 93.4%), respectively. Restricting the analysis to participants < 66 years of age did not substantially influence results (data not shown). We chose this cutoff because legal entitlement to a pension is 65 years in Germany. In logistic regression, SHS at home, at work, and at other places was associated with presence of CAC with ORs of 1.21 (95% CI: 0.82, 1.78), 1.24 (95% CI: 0.87, 1.76), and 1.53 (95% CI: 0.93, 2.49), respectively. We found no clear differences in asso- ciations according to age or sex, but point estimates were generally stronger among men than among women (Table 3). Figure 2, A and B, illustrates predicted CAC scores in men and women, respectively, according to age and exposure status. The pre- dicted CAC score for a 45- to 54-year-old man with SHS exposure is comparable to the pre- dicted CAC score for an unexposed man who is about 3 years older, whereas the predicted CAC score for an exposed man 65–74 years of age is comparable to the predicted score for an unexposed man who is about 1 year older. Women had much lower CAC scores than men at all ages, and we observed no clear association between SHS and predicted CAC score at any age. In sensitivity analyses, the association between SHS and CAC score remained positive when we used ln(CAC + 0.1) and ln(CAC + 10) as dependent variables in linear regression. The age- and sex-adjusted OR for the association of SHS with clinically mani- fested CHD was 1.48 (95% CI: 0.96, 2.26) and 1.43 (95% CI: 0.92, 2.22), respectively, with further adjustment for diabetes, BMI, physical activity, and LDL:HDL. Discussion This is the first study to examine exposure to SHS and CAC, a measure of subclinical ath- erosclerosis that is highly predictive of future cardiovascular events (Erbel et al. 2010; Folsom et al. 2008; van der Meer et al. 2004). We used CAC = 0 versus CAC > 0 as dichotomous clas- sification of coronary atherosclerosis in accor- dance with other studies (Detrano et al. 2008; Greenland et al. 2004). We found that expo- sure to SHS is associated with prevalence of CAC > 0 in never-smokers. This association is robust to the inclusion of a variety of cardio- vascular risk factors. Our results suggest that SHS may increase the risk of cardiovascular disease in part by influencing the underlying chronic process of coronary atherosclerosis, as has been suggested for ambient air pollution (Brook et al. 2010; U.S. Department of Health and Human Services 2006). The observed association between SHS and CAC is primarily based on the contrast between no calcification and any detectable calcification. Different biological mechanisms could be responsible for the development of plaque, which encompasses earlier stages of atherosclerotic disease, than those leading to the progression of already existing calcified plaque in advanced atherosclerotic disease. Animal experiments support the role of SHS in early stages of atherosclerosis, showing a causal role of SHS in the development of atherosclerotic lesions (Knight-Lozano et al. 2002). Exposure to SHS is associated with permanent inflammation and lipid accumu- lation in blood vessels in mice (Yuan et al. 2007) and in utero exposure results in an increased and earlier adult atherosclerotic lesion formation (Yang et al. 2007). Human studies have shown that the pathophysiology Table 3. Results of linear and logistic regression analysis.a SHS exposure and CAC among nonsmokers of SHS-induced cardiovascular toxicity includes arterial endothelial dysfunction, platelet activation, oxidation of low-density lipoprotein cholesterol, and increased insulin resistance, which are risk factors for athero- sclerosis at early stages of the disease (Barnoya and Glantz 2005). The association between exposure to SHS and atherosclerosis might be initiated as early as during gestation (Geerts et al. 2008). Increased thickening of the coro- nary walls has been observed in autopsies of fetuses of smoking mothers and of infants of smoking parents (Matturri et al. 2005). Our inability to observe a linear associa- tion of SHS with CAC in the subgroup of participants with more advanced coronary atherosclerosis, as manifested by presence of any CAC, might also be the result of an unfa- vorable signal-to-noise ratio, with the con- tribution of SHS to the progression of CAC being overshadowed by the increasing preva- lence of other risk factors. Atherosclerosis and hypertension are distinct but associated disease entities. The attenuation of associations between CAC and SHS after adjustment for blood pressure and antihypertensive medication is consistent with our assumption that high blood pressure may be an intermediate step in the causal pathway. Category Unadjusted model for exposure to any SHS Model 1 (age, sex) Model 2 (age, sex, SES) 45 to < 55 years of age 55 to < 65 years of age ≥ 65 years of age Men Women Model 3 (age, sex, SES, diabetes mellitus, BMI, physical activity, LDL:HDL) Model 4d (age, sex, SES) Model 5d (age, sex, SES, hypertension and antihypertensive therapy) Linear regression model Percent change in CAC+1b (95% CI) –18.6 (–38.0%, 7.0%) 22.3 (–4.1%, 56.1%) 21.1 (–5.5%, 55.2%) 28.3 (–10.6%, 84.1%) 8.1 (–26.6%, 59.2%) 21.4 (–29.4%, 108.6%) 27.8 (–16.5%, 95.7%) 16.0 (–14.6%, 57.6%) 15.4 (–9.6%, 47.2%) 21.1 (–6.5%, 56.8%) 10.6 (–14.3%, 42.7%) Logistic regression ORc (95% CI) 1.02 (0.80, 1.29) 1.46 (1.12, 1.92) 1.47 (1.11, 1.94) 1.59 (1.01, 2.49) 1.37 (0.89, 2.12) 1.41 (0.75, 2.64) 1.96 (1.11, 3.44) 1.33 (0.96, 1.85) 1.38 (1.03, 1.84) 1.41 (1.06, 1.89) 1.30 (0.97, 1.74) SES comprises two covariates: years of education and employment status. aAnalysis included 1,766 never-smokers without clinically manifested CHD for models 1–3 and 1,650 never-smokers for models 4 and 5. Manifested CHD includes previous myocardial infarction or coronary revascularization. bThe regression of ln(CAC + 1) can be converted to the percent change in CAC + 1 using the equation [(expβ – 1) × 100], where β is the change in ln(CAC + 1) associated with SHS exposure. cResponse variable of the logistic regression model: CAC > 0 (n = 1,150) versus CAC = 0 (n = 616). dSmaller sample size (n = 1,650) because of missing values for antihypertensive therapy; response variable of the logistic regression model: CAC > 0 (n = 1,084) versus CAC = 0 (n = 566). Unexposed men Exposed men Unexposed women Exposed women 250 200 150 C A C100 50 0 Men 60 Age 45 50 55 65 70 75 45 50 55 65 70 75 Figure 2. Predicted CAC from multivariable regression of ln(CAC+1) on age and sex: men (A) and women (B). The diamonds represent the estimated difference in vascular age between SHS-exposed participants and unexposed participants. Environmental Health Perspectives • volume 119 | number 11 | November 2011 1559 40 30 C CA20 10 0 Women 60 Age