Environmental tobacco smoke and cardiometabolic ...

6 downloads 0 Views 185KB Size Report
from a survey in south-west Germany. Gabriele Nagel1*, Frank J. Arnold4, Manfred Wilhelm2, Bernhard Link3, Iris Zoellner3, and Wolfgang Koenig4. 1Institute of ...
CLINICAL RESEARCH

European Heart Journal (2009) 30, 1885–1893 doi:10.1093/eurheartj/ehp180

Prevention and epidemiology

Environmental tobacco smoke and cardiometabolic risk in young children: results from a survey in south-west Germany Gabriele Nagel1*, Frank J. Arnold4, Manfred Wilhelm2, Bernhard Link3, Iris Zoellner3, and Wolfgang Koenig4 1 Institute of Epidemiology, Ulm University, Helmholtzstr.22, 89081 Ulm, Germany; 2Institute of Informatics (Medical Documentation and Statistics), Ulm University of Applied Sciences, Ulm, Germany; 3Baden-Wu¨rttemberg State Health Office, Stuttgart, Germany; and 4Department of Internal Medicine II –Cardiology, Ulm University Medical Center, Ulm, Germany

Received 22 October 2008; revised 20 March 2009; accepted 21 April 2009; online publish-ahead-of-print 24 May 2009

We explored the association between exposure to environmental tobacco smoke (ETS) and various cardiometabolic biomarkers in 10-year-old children. ..................................................................................................................................................................................... Methods A population-based cross-sectional study was carried out. Data on ETS exposure and potential confounders were and results collected by parental questionnaire. Adiponectin, leptin, markers of inflammation, apolipoproteins (apo) AI and B, and lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured. Linear and logistic regression models were applied using the 90th percentile as a cut-off point except for adiponectin and apoAI (10th percentile). In linear models, ETS exposure was significantly associated with increasing plasma concentrations of leptin, C-reactive protein, fibrinogen, interleukin (IL)-6, and Lp-PLA2. When compared with none, ETS exposure of more than 10 cigarettes per day was associated with elevated concentrations of leptin (OR 6.40; 95% CI, 2.67–15.39), C-reactive protein (OR 3.17; 95% CI, 1.31–7.68), Lp-PLA2 (OR 2.97 95% CI, 1.32 –6.68), low adiponectin (OR 2.69; 95% CI, 1.10 –6.57), and low apoAI (OR 4.48; 95% CI, 2.16–10.85). Increasing dose of ETS exposure was related to an increasing number of abnormal cardiometabolic markers. ..................................................................................................................................................................................... Conclusion Among children, ETS exposure was associated with a low-grade inflammatory response and altered markers of lipid metabolism, which may initiate atherosclerosis in early life. However, longitudinal studies are necessary to determine the potential causal relevance of these associations.

----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords

Leptin † Adiponectin † Apolipoproteins † Inflammation † Environmental tobacco smoke † Children

Introduction Exposure to environmental tobacco smoke (ETS) increases the risk of coronary heart disease (CHD) and mortality in adults.1,2 Observational studies in adults provide evidence for an association between ETS and endothelial dysfunction, platelet aggregation, acceleration of lipid peroxidation,3 and an increase in systemically measurable inflammatory markers.4 Recent evidence also suggests that exposure to ETS carries adverse health effects in children.5,6 Exposure to ETS is associated with childhood obesity7,8 and the metabolic syndrome in adolescents including high triglycerides.9 ETS exposure was associated with impaired endothelial function

an established precursor of CHD among 11-year-old children in a prospective study in Finland10 and higher levels of fibrinogen but not of C-reactive protein in 10- to 11-year-old children11 and in never smoking adults.12 In adults, markers of low-grade inflammation such as interleukin (IL)-613 and, in particular, C-reactive protein are considered as risk factors for the metabolic syndrome14 and cardiovascular disease (CVD).15 In addition, markers of the lipid metabolism including apolipoprotein AI (apoAI), apolipoprotein B (apoB), and lipoprotein-associated phospholipase A2 (Lp-PLA2) have been shown to predict CVD.16,17 Leptin correlates with body mass index (BMI) by regulating food intake and basal metabolism, and is linked to CHD.18 Adiponectin

* Corresponding author. Tel: þ49 731 50 31073, Fax: þ49 731 50 31069, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2009. For permissions please email: [email protected].

Downloaded from eurheartj.oxfordjournals.org by guest on May 16, 2011

Aims

1886 is inversely related to BMI and plays a role in the regulation of insulin sensitivity and fatty acid metabolism19. To date, little is known about the relationship between exposure to ETS and biomarkers of cardiometabolic risk in children. The purpose of this study therefore was (i) to explore the association between ETS and plasma concentrations of cardiometabolic markers and (ii) to cluster abnormal levels of cardiometabolic biomarkers according to ETS in a representative large group of 10-year-old children.

Methods Study population

Laboratory methods Among 450 children non-fasting EDTA blood was drawn. After centrifugation, samples were aliquoted and stored at 2808C until analysis. All laboratory analyses were performed in a single laboratory at the Department of Internal Medicine II-Cardiology, Ulm University Medical Centre. Leptin (ng/mL), adiponectin (mg/mL), and IL-6 (pg/mL) were measured by ELISA (R&D Systems, Wiesbaden, Germany) in EDTA plasma samples. The lower detection limits were 0.057 ng/mL for leptin, 0.246 ng/mL for adiponectin, and 0.039 pg/mL for IL-6. Inter-assay coefficients of variation (CV) were 3.9% for leptin, 5.8% for adiponectin, and 7.7% for IL-6. Lipoprotein-associated phospholipase A2 (ng/mL) was also determined by ELISA (PLAC test, diaDexus, South San Francisco, USA). Detection limit was 1.3 mg/L and the inter-assay CV was 5.8%. C-reactive protein (mg/L), fibrinogen (g/L), and apoAI (g/L) and apoB (g/L) were measured by immunonephelometry on a BN II analyser (Dade Behring, Marburg, Germany). Detection limits were 0.16 mg/L for C-reactive protein and 0.15 g/L for fibrinogen. The inter-assay CVs were 4.7% for C-reactive protein, and 1.1% for Fibrinogen. The inter-assay CV for apoAI was 6.7% and the corresponding CV for apoB was 4.6%. For most of the analyzed biomarkers, no accepted external cut-off point was available to define increased concentrations in children. Therefore, we used values above the 90th percentile of the biomarker distribution in our population, except for apoAI and adiponectin, for which the 10th percentile were biologically plausible cut-off points. Sex-specific increased concentrations were calculated separately for boys and girls: C-reactive protein ( 1.65 mg/L for boys and  1.99 mg/L for girls), IL-6 ( 0.28 pg/mL for boys and  0.28 pg/mL for girls), fibrinogen ( 2.82 g/L for boys and  2.92 g/L

for girls), apoB ( 0.88 g/L for boys and  0.88 g/L for girls), leptin ( 13.89 ng/mL for boys and  20.16 ng/mL for girls), and Lp-PLA2 ( 193 ng/mL for boys and  0.192 ng/mL for girls). For adiponectin ( 4.63 mg/mL for boys and  5.17 mg/mL for girls) and apoAI ( 1.29 g/L for boys and  1.27 g/L for girls), elevated levels were defined as values below the 10th percentile.

Exposure Parental questionnaires were used to collect data on environmental and lifestyle factors. The question ‘Is a smoker living in your child’s home?’ (yes, no) was applied to determine exposure to ETS. And the question ‘How many cigarettes are in average per day smoked in your home?’ in order to collect information on the dose (none, 1 – 10 cigarettes per day, . 10 cigarettes per day). Smoking during the child’s first year (yes, no) was assessed with the question: ‘Did the child’s mother smoke during the child’s first year of life?’.

Covariates The following variables were considered as potential confounders in the analyses: time of breastfeeding (none, 1 – 6 months, . 6 months), birth weight (, 2500 g,  2500 g), and educational attainment, which summarizes the highest achieved level of paternal or maternal school education and which was classified in primary school or less (low), secondary school (middle), and grammar school (high). During a physical examination, height and weight was measured in a standardized manner. Body mass index was calculated as weight (kg)/ height2 (m).

Statistical analysis Descriptive analyses were carried out separately for each gender and exposure levels to ETS. P-values were calculated using x2 test or Fisher’s exact test for categorical data and Kruskal – Wallis test for continuous data in order to test differences among ETS levels. Median and interquartile range (IQR, 25th to 75th percentile) were computed for each biomarker using the same subgroups. Except for C-reactive protein, apoAI, and Lp-PLA2, no major sex differences were seen, therefore, boys and girls were pooled for application of regression models. Linear regression models for continuous response variables (log-transformed if not normally distributed) as well as logistic regression models for binary response variables were applied using the non-passive smokers as reference. We determined three adjustments for the linear and logistic regression models during the model-building process23 in order to calculate b-coefficients and odds ratios and 95% confidence intervals (CIs) for biomarker concentrations (continuous) and abnormal biomarker levels (binary). Model 1 was adjusted only for age (continuous); in Model 2, adjustment for age and maternal smoking during child’s first year of life (yes/no) was performed, and Model 3 was additionally adjusted for BMI. Since sex-specific cut-off points for the biomarkers were applied, no further adjustment for sex was performed. In addition, clustering of elevated levels by number of cigarettes smoked was determined using all biomarkers. For all statistical analyses, P-values , 0.05 from two-sided tests were considered to be statistically significant. All analyses were performed with the statistical software package SAS release 9.1 (SAS Institute, Cary, NC, USA).

Results In 127 (33.2%) of 383 children, exposure to ETS has been reported. In both boys and girls, ETS exposure was significantly

Downloaded from eurheartj.oxfordjournals.org by guest on May 16, 2011

A cross-sectional study on body weight was undertaken within the framework of a health surveillance program in children.20,21 The investigation was coordinated by the Baden-Wu¨rttemberg State Health Office and approved by the local Ethics Committee.22 In the state of Baden-Wu¨rttemberg, six schools were randomly selected, from which 934 children were invited to participate in the study. After written informed consent had been obtained from the parents 536 (47% boys, 53% girls) fourth grade schoolchildren were recruited (October 2004 to March 2005). Data from 450 children (84%) with a complete set of anthropometric and laboratory parameters were available for analysis (47% boys, 27% with low and 34% with high parental education). Information on ETS exposure (yes, no) was available in 439 children. Data of 383 of them with information on the dose of ETS (cigarettes/day) formed the basis of the present analyses (46% boys, 27% with low and 34% with high parental education).

G. Nagel et al.

1887

ETS and cardiometabolic risk in young children

Discussion There is growing evidence of an association between ETS exposure and obesity in childhood. To date, studies including biomarkers to elucidate such relationship are scarce. The present study provides information on the association between ETS exposure and biochemical markers of metabolism and CVD in children. Both linear and logistic regression models revealed associations between exposure to ETS and cardiometabolic markers

including elevated plasma leptin, C-reactive protein, fibrinogen, Lp-PLA2, and low apoAI concentrations. Dose-dependent relationships were apparent between ETS exposure and cardiometabolic markers. Our observations indicate a link between exposure to ETS and unfavourable concentrations of cardiometabolic biomarkers in 10-year-old children, which may contribute to CVD risk in later life.2 Our findings are consistent with previous research showing associations between cigarette smoking and increased prevalence of an inflammatory response, insulin resistance, and dyslipidaemia in adults.24 – 26 Among children, exposure to ETS was related to increased C-reactive protein concentrations, endothelial dysfunction,10 and the metabolic syndrome.9,27 In agreement with these results, we observed a clustering of cardiometabolic markers according to ETS exposure level.28

Adipokines Our observation that ETS exposure is associated with elevated leptin levels is in line with research on childhood obesity.27,29 Research in adults revealed inconsistent results. However, it is well established that among adults smoking results in a loss of body weight and changes in body composition.30 In contrast, our study in children revealed a statistically significant association in the opposite direction, which, however, was attenuated after further adjustment for BMI. Consistent with our observation of an association between ETS exposure and low adiponectin concentrations, lower adiponectin levels were found in adult Japanese smokers compared with never smokers.31,32 Thus, low adiponectin concentrations may link smoking with adiposity and insulin resistance.

Markers of inflammation In line with the literature on active and passive smoking in adults4,26 and on ETS exposure in children,33 we found associations between ETS exposure and higher levels of circulating inflammatory markers in the linear models. In the dichotomized models, only high C-reactive protein concentrations remained significantly associated with ETS exposure, whereas for fibrinogen and IL-6 positive trends were observed. C-reactive protein concentrations were positively associated with IL-6, fibrinogen, and leptin levels.34 Constituents of ETS may cause a systemic inflammatory response through activation of immune cells,2,35 which subsequently may result in vascular damage.10

Lipid metabolism In adults, cigarette smoking is associated with lower HDL and elevated LDL concentrations indicating a more atherogenic lipid profile.36 Our observation of an association between ETS exposure and low apoAI concentrations is consistent with these findings. Exposure to ETS induces oxidative stress, converting LDL to oxidized LDL (oxLDL).2 Lipoprotein-associated phospholipase A2 is involved in the generation of inflammatory mediators from oxLDL. The association between exposure to ETS and high Lp-PLA2 concentrations in the logistic regression model are consistent with this mechanism37 and further supported by findings in 3-month-old children.38

Downloaded from eurheartj.oxfordjournals.org by guest on May 16, 2011

associated with the duration of breastfeeding, parental education, German nationality, and maternal smoking during the first year of life (Table 1). Children’s age was only associated with ETS exposure in boys, whereas BMI was only associated with ETS exposure in girls. In our data, no relationship between birth weight and ETS exposure was seen. Table 2 shows the distribution of cardiometabolic markers by ETS exposure and sex. In boys, exposure to increasing levels of ETS was associated with differences in C-reactive protein, IL-6, and leptin. In girls, significant differences between levels of ETS exposure were observed for IL-6, leptin, apoAI, and Lp-PLA2 concentrations. Table 3 shows the b-coefficients and 95% CI of the cardiometabolic markers according to ETS exposure levels. In the adjusted model (Model 2), ETS exposure to more than 10 cigarettes per day was positively associated with increased leptin, C-reactive protein, IL-6, Lp-PLA2, and a trend was seen for increased fibrinogen concentrations. Between plasma adiponectin, apoAI, and apoB concentrations and ETS exposure, no statistically significant association was observed. With increasing dose of cigarette smoke (1– 10 and . 10 cigarettes per day), the associations became stronger, indicating a dose-dependent relationship between ETS exposure and cardiometabolic markers. No substantial changes in the associations between ETS exposure and cardiometabolic markers were found after additional adjustment of Model 1 for breastfeeding, German nationality, parental education, or playing outdoor (data not shown). As expected, further adjustment for BMI attenuated the relationships (Model 3). Only the association with Lp-PLA2 concentrations remained statistically significant. The results for the 90th percentile or 10th percentile, respectively, of cardiometabolic marker as outcome variable are presented in Table 4. When compared with no exposure, exposure to more than 10 cigarettes of ETS per day was associated with elevated plasma concentrations of leptin, C-reactive protein, and Lp-PLA2. Environmental tobacco smoke exposure was also associated with low plasma concentrations of adiponectin and apoAI. Further adjustment for BMI (Model 3) again attenuated the relationships, except for Lp-PLA2. Figure 1 shows the clustering of abnormal cardiometabolic marker concentrations by exposure level to ETS. With increasing exposure to ETS, the number of abnormal cardiometabolic markers increased: among children exposed to 1–10 cigarettes per day 50% revealed at least one abnormal marker, and among children exposed to 10 or more cigarettes per day 70% had at least one abnormal marker.

1888

Table 1 Baseline characteristics of the participants in groups of environmental tobacco smoke exposure (n 5 383) Environmental tobacco smoke

............................................................................................................................................................................................................................................. Boys

.................................................................................

Non-exposed

1 –10 Cig/day

>10 Cig/day

P-value

Girls

.................................................................................

Non-exposed

1 –10 Cig/day

>10 Cig/day

P-value

............................................................................................................................................................................................................................................. n

(%)

Age (years)

Mean (SD)

BMI (kg/m2) German nationality

Mean (SD) No

116 (65.9%) 9.5 (0.6)

33 (18.8%)

27 (15.3%)

9.8 (0.7)

9.9 (0.7)

17.4 (2.7) 12 (11.3%)

17.9 (3.1) 12 (46.2%)

19.3 (4.5) 3 (12.0%)

Yes

94 (88.7%)

14 (53.9%)

22 (88.0%)

None

15 (13.6%)

5 (17.2%)

12 (48.0%)

6 months .6 months

47 (42.7%) 48 (43.6%)

20 (69.0%) 4 (13.8%)

7 (28.0%) 6 (24.0%)

140 (67.6%) ,0.001 0.134 ,0.001

9.5 (0.6)

41 (19.8%)

26 (12.6%)

9.6 (0.7)

9.7 (0.7)

17.1 (2.6) 14 (10.7%)

18.4 (3.4) 14 (41.2%)

19.9 (3.8) 13 (56.5%)

117 (89.3%)

20 (58.8%)

10 (43.5%)

0.185 ,0.001 ,0.001

............................................................................................................................................................................................................................................. Breast feeding time

,0.001

14 (10.3%)

8 (23.5%)

5 (20.8%)

59 (10.3%) 63 (46.3%)

19 (55.9%) 7 (20.6%)

16 (66.7%) 3 (12.5%)

0.012

............................................................................................................................................................................................................................................. Birth weight

,2500 g

13 (11.5%)

5 (16.1%)

4 (14.8%)

2500 g

100 (88.5%)

26 (83.9%)

23 (85.2%)

Low Medium

20 (18.7%) 40 (37.4%)

12 (46.2%) 11 (42.3%)

11 (45.8%) 9 (37.5%)

High

47 (43.9%)

3 (11.5%)

4 (16.7%)

No

104 (89.7%)

26 (78.8%)

13 (48.2%)

Yes

12 (10.3%)

7 (21.2%)

14 (51.9%)

0.702

17 (12.4%)

3 (7.7%)

6 (23.1%)

120 (87.6%)

36 (92.3%)

20 (76.9%)

26 (20.2%) 49 (38.0%)

15 (41.7%) 14 (38.9%)

10 (43.5%) 12 (52.2%)

54 (41.9%)

7 (19.4%)

1 (4.4%)

119 (85.0%)

25 (61.0%)

15 (57.7%)

21 (15.0%)

16 (39.0%)

11 (42.3%)

0.196

............................................................................................................................................................................................................................................. Parent’s education

0.001

,0.001

............................................................................................................................................................................................................................................. ,0.001

, 0.001

G. Nagel et al.

Downloaded from eurheartj.oxfordjournals.org by guest on May 16, 2011

Maternal smoking in first year of life

1889

,0.001

0.150 0.409

0.039

173 (47)

0.74 (1.15) 2.36 (0.74)

1.94 (1.59)

.............................................................................................................................................................................................................................................

0.025 0.962 1.40 (0.32) 0.68 (0.18)

0.32 (0.82) 2.16 (0.64)

0.84 (0.63)

0.26 (0.63) 2.18 (0.57)

0.92 (1.12) 1.20 (0.92) 0.79 (0.85) IL-6 (pg/mL)

0.88 (1.25)

0.025 0.100 0.62 (1.46) 2.41 (0.74) 0.20 (0.56) 2.28 (0.76) 0.20 (0.40) 2.09 (0.55) C-reactive protein (mg/L) Fibrinogen (g/L)

Inflammatory markers

148 (48)

Lp-PLA2 (ng/mL)

0.041

145 (30) 145 (43) 0.247 156 (53)

1.48 (0.28) 0.63 (0.16) 1.47 (0.20) 0.64 (0.15) 1.50 (0.24) 0.67 (0.19) ApoA (g/L) ApoB (g/L)

Lipoproteins

Biological plausibility

140 (44)

1.43 (0.24) 0.66 (0.20) 0.575 0.377

1.51 (0.23) 0.69 (0.19)

,0.001

.............................................................................................................................................................................................................................................

0.513 8.73 (4.49)

12.53 (14.13)

9.80 (5.80)

5.67 (13.27)

9.06 (5.57)

3.93 (6.74) 0.031

0.496 7.87 (9.20)

5.18 (12.48) 3.60 (5.55)

10.50 (7.69) 9.25 (4.73)

2.26 (3.84)

27

Adipokines Adiponectin (mg/mL)

33 116 n

Leptin (ng/mL)

41 140

26

P-value 1 –10 Cig/day

>10 Cig/day

.............................................................................................................................................................................................................................................

............................................................................................

Non-exposed P-value >10 Cig/day 1 –10 Cig/day Non-exposed

Girls

............................................................................................

Boys

In our study, further adjustment for duration of breastfeeding attenuated the relationships between ETS exposure and elevated plasma leptin levels. By exclusion of children with low birth weight (, 2500 g) in the logistic regression models, the strength of the associations was attenuated, but except for Lp-PLA2, associations remained statistically significant. After further adjustment for education, the association pattern between ETS and cardiometabolic markers did not change substantially.

Various mechanisms have been suggested to link smoking to body weight and body fat distribution.39 Among young adults, active and passive smoking were both associated with the development of glucose intolerance over 15 years in a dose–response relationship.25 Recent results in a mouse model have shown a decrease in adiponectin concentrations, enhancement of Th1 response, and a decrease of the HDL/LDL ratio.40

Limitations and strengths of the study The association between ETS exposure and cardiometabolic markers may be attributed, at least in part, to residual confounding due to other environmental and lifestyle factors that could not be adjusted for. Other sources of ETS outside the children’s homes or even active smoking cannot be excluded. However, in these young children, the latter is unlikely. Smoking variables on exposure time are likely to be correlated, which complicates the detection of associations of ETS and cardiometabolic risk. Other studies revealed a link between socioeconomic factors and ETS exposure.41 In our study, further adjustment for parental education did not substantially influence the estimates. Similarly, the adjustment for playing outside as an indicator for physical activity, breastfeeding, and German nationality did not appreciably change the pattern of associations between ETS exposure and cardiometabolic markers. Body mass index is a well-established measure to define obesity in population studies, but it should be acknowledged that BMI does not reflect body fat distribution.42 Furthermore, the application of data on ETS exposure collected by questionnaire instead of cotinine as an objective marker of inhaled smoke may have introduced some bias. However, good correlations between questionnaire data and cotinine levels have been reported.43 Finally, the cross-sectional study design limits a causal interpretation of our results. The strengths of our study are the measurement of intermediate biomarkers of cardiometabolic diseases, the population-based approach of the survey, and the homogeneous age of the analysed study sample as well as the measurements of the anthropometric variables according to a standardized protocol. In summary, ETS was associated with several cardiometabolic biomarkers in 10-year-old children, suggesting an adverse effect on the vascular wall very early in life. The clustering of multiple unfavourable biomarkers indicates a dose-dependent relationship. Most importantly from a public health perspective, avoidance of ETS exposure during childhood may reduce risk of cardiometabolic diseases in later life. However, prospective studies will be needed to clarify this relationship.

Downloaded from eurheartj.oxfordjournals.org by guest on May 16, 2011

Table 2 Median (interquartile range) of cardiovascular biomarkers by environmental tobacco smoke exposure and gender (n 5 383)

ETS and cardiometabolic risk in young children

1890

Table 3 b-Coefficient estimates and 95% confidence interval of concentrations of adipokines, lipoproteins, and inflammatory markers by environmental tobacco smoke exposure Environmental tobacco smoke

............................................................................................................................................................................................................................................. Model 1

...................................................................

Model 2

.................................................................

Model 3

.................................................................

Non-exposed

1– 10 Cig/day

>10 Cig/day

Non-exposed

1– 10 Cig/day

>10 Cig/day

Non-exposed

1 –10 Cig/day

>10 Cig/day

256

74

53

256

74

53

256

74

53

1Ref

1.00 20.07 to 2.07

20.19 21.42 to 1.04

1Ref

0.88 20.21 to 1.96

20.44 21.71 to 0.84

1Ref

1.09 0.01– 2.16

0.11 21.19 to 1.40

1Ref

0.46 0.16– 0.77

0.72 0.37 –1.07

1Ref

0.44 0.13 –0.75

0.67 0.31 –1.04

1Ref

0.18 20.03 to 0.38

0.003 20.24 to 0.25

1Ref

20.04 20.09 to 0.01

20.08 20.14 to 20.02

1Ref

20.04 20.09 to 0.01

20.08 20.14 to 0.02

1Ref

20.02 20.07 to 0.03

20.04 20.10 to 0.02

1Ref

0.002 20.04 to 0.04

20.02 20.06 to 0.03

1Ref

20.0001 20.04 to 0.04

20.02 20.06 to 0.03

1Ref

20.01 20.05 to 0.03

20.03 20.08 to 0.01

1Ref

23.55 211.84 to 4.74

17.27 7.76 to 26.78

1Ref

23.53 211.95 to 4.89

17.31 7.40 –27.22

1Ref

24.23 212.67 to 4.22

15.54 5.38– 25.70

1Ref

0.16 20.14 to 0.45

0.61 0.27 –0.95

1Ref

0.13 20.17 to 0.43

0.56 0.21 –0.91

1Ref

0.01 20.27 to 0.29

0.24 20.09 to 0.58

1Ref

0.05 20.08 to 0.19

0.17 0.01 –0.32

1Ref

0.05 20.09 to 0.19

0.16 0.00 –0.33

1Ref

0.02 20.12 to 0.15

0.07 20.09 to 0.23

1Ref

0.02 20.36 to 0.40

0.55 0.11 –0.99

1Ref

0.01 20.38 to 0.39

0.52 0.07 –0.98

1Ref

20.04 20.43 to 0.35

0.41 20.06 to 0.87

............................................................................................................................................................................................................................................. n Adipokines Adiponectina b-Coefficient 95% CI Leptina b-Coefficient 95% CI

............................................................................................................................................................................................................................................. Lipoproteins ApoA1a b-Coefficient 95% CI ApoBa b-Coefficient 95% CI Lp-PLAa2 b-Coefficient 95% CI

............................................................................................................................................................................................................................................. Inflammatory markers C-reactive proteina b-Coefficient 95% CI Fibrinogena b-Coefficient 95% CI IL-6a b-Coefficient 95% CI

G. Nagel et al.

Model 1: adjusted for age; Model 2: adjusted for age and maternal smoking in child’s first year of life; Model 3: additional adjustment for BMI (continuous). a Abnormal concentrations are defined as 90th percentile (leptin, C-reactive protein, fibrinogen, IL-6, apoB, Lp-PLA2) or 10th percentile (adiponectin, apoA1).

Downloaded from eurheartj.oxfordjournals.org by guest on May 16, 2011

Environmental tobacco smoke

............................................................................................................................................................................................................................................. Model 1

................................................................

Model 2

................................................................

Model 3

................................................................

Non-exposed

1– 10 Cig/day

>10 Cig/day

Non-exposed

1–10 Cig/day

>10 Cig/day

Non-exposed

1 –10 Cig/day

>10 Cig/day

256

74

53

256

74

53

256

74

53

1Ref

1.33

1.97

1Ref

1.55

2.69

1Ref

1.41

2.01

0.59 –3.04

0.84 –4.59

0.67 –3.58

1.10– 6.57

0.60– 3.29

0.78 –5.16

2.86

6.34

2.87

6.40

2.82

3.67

1.20 –6.77

2.76 –14.59

1.20 –6.86

2.67– 15.39

0.82– 9.64

1.11 –12.16

0.74

4.14

0.80

4.84

0.74

4.01

0.27 –2.03

1.95 –8.81

0.29 –2.22

2.16– 10.85

0.27– 2.07

1.73 –9.32

1.50

1.19

1.46

1.15

1.27

0.82

0.66 –3.42

0.43 –3.34

0.63 –3.40

0.39– 3.34

0.54– 3.03

0.27 –2.51

0.48

2.67

0.50

2.97

0.49

2.89

0.16 –1.42

1.25 –5.72

0.17 –1.50

1.32– 6.68

0.16– 1.49

1.24 –6.75

1.90

2.91

1.99

3.17

1.61

1.87

0.84 –4.28

1.25 –6.74

0.87 –4.56

1.31– 7.68

0.68– 3.81

0.73 –4.80

1.38

1.78

1.33

1.65

1.21

1.32

0.62 –3.05

0.77 –4.13

0.59 –2.97

0.68– 4.00

0.54– 2.74

0.53 –3.29

1.42

1.81

1.43

1.85

1.29

1.39

0.63 –3.18

0.77 –4.25

0.63 –3.24

0.75– 4.52

0.57– 2.95

0.55 –3.51

............................................................................................................................................................................................................................................. N Adipokines Adiponectin: ,10%ile OR 95% CI Leptin: .90%ile OR

1Ref

95% CI

1Ref

1Ref

ETS and cardiometabolic risk in young children

Table 4 Odds ratio and 95% confidence interval of abnormala concentrations of adipokines, lipoproteins, and inflammatory markers by environmental tobacco smoke exposure

............................................................................................................................................................................................................................................. Lipoproteins ApoA1: ,10%ile OR

1Ref

95% CI ApoB: .90%ile OR

1Ref

95% CI Lp-PLA2: .90%ile OR

1Ref

95% CI

1Ref

1Ref

1Ref

1Ref

1Ref

1Ref

............................................................................................................................................................................................................................................. Inflammatory markers C-reactive protein: .90%ile OR

1Ref

95% CI Fibrinogen: .90%ile OR

1Ref

95% CI IL-6: .90%ile OR 95% CI

1Ref

1Ref

1Ref

1Ref

1Ref

1Ref

1891

OR, odds ratio; 95% CI, 95% confidence interval. a Abnormal concentrations are defined as 90th percentile (leptin, C-reactive protein, fibrinogen, IL-6, apoB, Lp-PLA2) or 10th percentile (adiponectin, apoA1).

1Ref

Downloaded from eurheartj.oxfordjournals.org by guest on May 16, 2011

1892

Figure 1 Percentage of children with clustering of abnormal cardiometabolic markers by ETS exposure (n ¼ 383). Abnormal concentrations are defined as 90th percentile (leptin, C-reactive protein, fibrinogen, IL-6, apoB, Lp-PLA2) or 10th percentile (adiponectin, apoA1).

Acknowledgements

Funding Additional funds for the measurement of the cardio-metabolic markers at the Department of Internal Medicine II came from the Ulm university.

Conflict of interest: none declared.

References 1. He J, Vupputuri S, Allen K, Prerost MR, Hughes J, Whelton PK. Passive smoking and the risk of coronary heart disease—a meta-analysis of epidemiologic studies. N Engl J Med 1999;340:920 –926. 2. Raupach T, Schafer K, Konstantinides S, Andreas S. Secondhand smoke as an acute threat for the cardiovascular system: a change in paradigm. Eur Heart J 2006;27:386 –392. 3. Barnoya J, Glantz SA. Cardiovascular effects of secondhand smoke: nearly as large as smoking. Circulation 2005;111:2684 –2698. 4. Panagiotakos DB, Pitsavos C, Chrysohoou C, Skoumas J, Masoura C, Toutouzas P, Stefanadis C. Effect of exposure to secondhand smoke on markers of inflammation: the ATTICA study. Am J Med 2004;116:145 –150. 5. Hofhuis W, de Jongste JC, Merkus PJ. Adverse health effects of prenatal and postnatal tobacco smoke exposure on children. Arch Dis Child 2003;88:1086 –1090. 6. Braun JM, Froehlich TE, Daniels JL, Dietrich KN, Hornung R, Auinger P, Lanphear BP. Association of environmental toxicants and conduct disorder in U.S. children: NHANES 2001– 2004. Environ Health Perspect 2008;116:956 – 962. 7. von Kries R, Bolte G, Baghi L, Toschke AM. Parental smoking and childhood obesity—is maternal smoking in pregnancy the critical exposure? Int J Epidemiol 2008;37:210 –216. 8. Leary SD, Smith GD, Rogers IS, Reilly JJ, Wells JC, Ness AR. Smoking during pregnancy and offspring fat and lean mass in childhood. Obesity (Silver Spring) 2006; 14:2284 –2293. 9. Weitzman M, Cook S, Auinger P, Florin TA, Daniels S, Nguyen M, Winickoff JP. Tobacco smoke exposure is associated with the metabolic syndrome in adolescents. Circulation 2005;112:862 –869. 10. Kallio K, Jokinen E, Raitakari OT, Hamalainen M, Siltala M, Volanen I, Kaitosaari T, Viikari J, Ronnemaa T, Simell O. Tobacco smoke exposure is associated with attenuated endothelial function in 11-year-old healthy children. Circulation 2007;115: 3205 –3212.

11. Cook DG, Mendall MA, Whincup PH, Carey IM, Ballam L, Morris JE, Miller GJ, Strachan DP. C-reactive protein concentration in children: relationship to adiposity and other cardiovascular risk factors. Atherosclerosis 2000;149:139–150. 12. Venn A, Britton J. Exposure to secondhand smoke and biomarkers of cardiovascular disease risk in never-smoking adults. Circulation 2007;115:990 –995. 13. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999;340:448 –454. 14. de Ferranti SD, Gauvreau K, Ludwig DS, Newburger JW, Rifai N. Inflammation and changes in metabolic syndrome abnormalities in US adolescents: findings from the 1988 –1994 and 1999– 2000 National Health and Nutrition Examination Surveys. Clin Chem 2006;52:1325 –1330. 15. Ridker PM, Morrow DA. C-reactive protein, inflammation, and coronary risk. Cardiol Clin 2003;21:315 – 325. 16. Thompson A, Danesh J. Associations between apolipoprotein B, apolipoprotein AI, the apolipoprotein B/AI ratio and coronary heart disease: a literature-based meta-analysis of prospective studies. J Intern Med 2006;259:481 –492. 17. Koenig W, Twardella D, Brenner H, Rothenbacher D. Lipoprotein-associated phospholipase A2 predicts future cardiovascular events in patients with coronary heart disease independently of traditional risk factors, markers of inflammation, renal function, and hemodynamic stress. Arterioscler Thromb Vasc Biol 2006;26: 1586 –1593. 18. Singhal A, Farooqi IS, Cole TJ, O’Rahilly S, Fewtrell M, Kattenhorn M, Lucas A, Deanfield J. Influence of leptin on arterial distensibility: a novel link between obesity and cardiovascular disease? Circulation 2002;106:1919 –1924. 19. Asayama K, Hayashibe H, Dobashi K, Uchida N, Nakane T, Kodera K, Shirahata A, Taniyama M. Decrease in serum adiponectin level due to obesity and visceral fat accumulation in children. Obes Res 2003;11:1072 –1079. 20. Link B, Gabrio T, Piechotowski I, Zollner I, Schwenk M. Baden-Wuerttemberg Environmental Health Survey (BW-EHS) from 1996 to 2003: toxic metals in blood and urine of children. Int J Hyg Environ Health 2007;210:357 –371. 21. Link B, Gabrio T, Zollner I, Piechotowski I, Kouros B. Sentinel health department project in Baden-Wuerttemberg (Germany)—a useful tool for monitoring children’s health and environment. Int J Hyg Environ Health 2007;210: 351 –355. 22. Zollner IK, Weiland SK, Piechotowski I, Gabrio T, von Mutius E, Link B, Pfaff G, Kouros B, Wuthe J. No increase in the prevalence of asthma, allergies, and atopic sensitisation among children in Germany: 1992 –2001. Thorax 2005;60: 545 –548. 23. Hosmer DW, Lemeshow S. Applied Logistic Regression. 2nd ed. New York: John Wiley & Sons. 2008. 24. Facchini FS, Hollenbeck CB, Jeppesen J, Chen YD, Reaven GM. Insulin resistance and cigarette smoking. Lancet 1992;339:1128 –1130. 25. Houston TK, Person SD, Pletcher MJ, Liu K, Iribarren C, Kiefe CI. Active and passive smoking and development of glucose intolerance among young adults in a prospective cohort: CARDIA study. Br Med J 2006;332:1064 – 1069. 26. Frohlich M, Sund M, Lowel H, Imhof A, Hoffmeister A, Koenig W. Independent association of various smoking characteristics with markers of systemic inflammation in men. Results from a representative sample of the general population (MONICA Augsburg Survey 1994/95). Eur Heart J 2003;24:1365 – 1372. 27. Apfelbacher CJ, Loerbroks A, Cairns J, Behrendt H, Ring J, Kraemer U. Predictors of overweight and obesity in five to seven-year-old children in Germany: results from cross-sectional studies. BMC Public Health 2008;8:171. 28. Freedman DS, Mei Z, Srinivasan SR, Berenson GS, Dietz WH. Cardiovascular risk factors and excess adiposity among overweight children and adolescents: the Bogalusa Heart Study. J Pediatr 2007;150:12 –17. 29. von Kries R, Toschke AM, Koletzko B, Slikker W Jr. Maternal smoking during pregnancy and childhood obesity. Am J Epidemiol 2002;156:954 –961. 30. Law MR, Wald NJ. Environmental tobacco smoke and ischemic heart disease. Prog Cardiovasc Dis 2003;46:31– 38. 31. Takefuji S, Yatsuya H, Tamakoshi K, Otsuka R, Wada K, Matsushita K, Sugiura K, Hotta Y, Mitsuhashi H, Oiso Y, Toyoshima H. Smoking status and adiponectin in healthy Japanese men and women. Prev Med 2007;45:471–475. 32. Iwashima Y, Katsuya T, Ishikawa K, Kida I, Ohishi M, Horio T, Ouchi N, Ohashi K, Kihara S, Funahashi T, Rakugi H, Ogihara T. Association of hypoadiponectinemia with smoking habit in men. Hypertension 2005;45:1094 –1100. 33. Wilkinson JD, Lee DJ, Arheart KL. Secondhand smoke exposure and C-reactive protein levels in youth. Nicotine Tob Res 2007;9:305 –307. 34. Nagel G, Rapp K, Wabitsch M, Buchele G, Kroke A, Zollner I, Weiland SK, Koenig W. Prevalence and cluster of cardiometabolic biomarkers in overweight and obese schoolchildren: results from a large survey in southwest Germany. Clin Chem 2008;54:317 –325. 35. Benowitz NL. Cigarette smoking and cardiovascular disease: pathophysiology and implications for treatment. Prog Cardiovasc Dis 2003;46:91 –111.

Downloaded from eurheartj.oxfordjournals.org by guest on May 16, 2011

The authors would like to thank Gerlinde Trischler for excellent technical assistance and Holger Knebel for documentation and data management. Finally, we thank all study participants.

G. Nagel et al.

1893

ETS and cardiometabolic risk in young children

36. Craig WY, Palomaki GE, Haddow JE. Cigarette smoking and serum lipid and lipoprotein concentrations: an analysis of published data. Br Med J 1989;298: 784 –788. 37. Tsimikas S. In vivo markers of oxidative stress and therapeutic interventions. Am J Cardiol 2008;101:34D – 42D. 38. Noakes PS, Thomas R, Lane C, Mori TA, Barden AE, Devadason SG, Prescott SL. Association of maternal smoking with increased infant oxidative stress at 3 months of age. Thorax 2007;62:714 –717. 39. Chiolero A, Faeh D, Paccaud F, Cornuz J. Consequences of smoking for body weight, body fat distribution, and insulin resistance. Am J Clin Nutr 2008;87: 801 –809.

40. Yuan H, Wong LS, Bhattacharya M, Ma C, Zafarani M, Yao M, Schneider M, Pitas RE, Martins-Green M. The effects of second-hand smoke on biological processes important in atherogenesis. BMC Cardiovasc Disord 2007;7:1. 41. Bolte G, Fromme H. Socioeconomic determinants of children’s environmental tobacco smoke exposure and family’s home smoking policy. Eur J Public Health 2009;19:52 –58. 42. Must A, Anderson SE. Body mass index in children and adolescents: considerations for population-based applications. Int J Obes (Lond) 2006;30: 590 –594. 43. Thaqi A, Franke K, Merkel G, Wichmann HE, Heinrich J. Biomarkers of exposure to passive smoking of school children: frequency and determinants. Indoor Air 2005;15:302 –310.

CARDIOVASCULAR FLASHLIGHT

doi:10.1093/eurheartj/ehp079 Online publish-ahead-of-print 20 March 2009

.............................................................................................................................................................................

An innocent bystander in the coronary tree Andrew S.P. Sharp* and Antonio Colombo Centro Cuore, Columbus Hospital and San Raffaele Scientific Institute, Milan, Italy

* Corresponding author. Tel: þ39 02 4812920, Fax: þ39 02 48193433, Email: [email protected]

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2009. For permissions please email: [email protected].

Downloaded from eurheartj.oxfordjournals.org by guest on May 16, 2011

A 58-year-old man presented to his local doctor with 30 min of chest pain and inferior ST-segment elevation on his ECG (Panel A). He was transferred immediately for primary angioplasty. On arrival, his ECG became normal and pain had eased (Panel B). Left coronary injection (Panel C) showed a 70% stenosis of the posterolateral branch of the circumflex (arrow). Right coronary injection showed only minor atheroma (Panel D). The diagnosis was presumed to be ischaemia due to the stenosis involving the posterolateral circumflex branch and therefore a guiding catheter was taken in order to perform angioplasty to this lesion. After first injection into the left coronary artery with the guide, the patient developed chest pain and ST elevation (Panel E). However, the circumflex appearance was identical to that seen in Panel C, with TIMI 3 flow. The right coronary was accessed again and this time showed three areas of significant coronary artery vasospasm (Panel G). Intracoronary nitroglycerin was administered and the chest pain abated with resolution of the ECG and angiographic changes (Panels F and H ). The following day, blood tests showed no enzyme rise and he was discharged uneventfully on vasodilators. At 1 month clinical follow-up, the patient has been entirely asymptomatic on aspirin and calcium-channel blocker. In this case, the operator almost succumbed to the ‘oculo-stenotic reflex’. Only coincidental chest pain with new ECG changes alerted him to the fact that the acute problem lay elsewhere, sparing this patient an unnecessary procedure. This case serves as a useful reminder that a ‘culprit lesion’ may occasionally have a very respectable appearance on coronary angiography, while the apparently attractive target may simply be an innocent bystander with respect to the acute presentation.