a Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany
b Department of Internal Medicine VI-Clinical Pharmacology & Pharmacoepidemiology, University Hospital of Heidelberg, Heidelberg, Germany
c GSF-National Research Centre for Environment and Health, IGM-Institute, Neuherberg, Germany
d GSF-National Research Centre for Environment and Health, Institute of Epidemiology, Neuherberg, Germany
* Correspondence to: Prof. Wolfgang Koenig, Abteilung Innere Medizin II, Universität Ulm, Rbert-Koch-Straße 8, D-89081 Ulm, Germany. Tel. +49 731 500 24441; fax. +49 731 500 33872
E-mail address: wolfgang.koenig{at}medizin.uni-ulm.de
Received 16 October 2002; revised 15 April 2003; accepted 18 April 2003
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Abstract |
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Methods and results The effects of chronic smoking on white blood cell (WBC) count, fibrinogen, albumin, plasma viscosity (PV), and high-sensitivity C-reactive protein (CRP) were measured in 2305 men and 2211 women, age 2574 years, participating in the third MONICA Augsburg survey 1994/95. In men, current smokers showed statistically significantly higher values for WBC count, fibrinogen, PV, and CRP, compared to never smokers, with intermediate, but only slightly increased values for ex-smokers and for occasional smokers. No consistent associations were seen with albumin. Duration of smoking was positively associated with markers of inflammation as were pack-years of smoking. Conversely, duration of abstinence from smoking was inversely related to these markers. Except for WBC count, no such associations were found in women.
Conclusion Data from this large representative population show strong associations between smoking and various markers of systemic inflammation in men. They also show that cessation of smoking is associated with a decreased inflammatory response, which may represent one mechanism responsible for the reduced cardiovascular risk in these subjects.
Key Words: Smoking Inflammation C-reactive protein Fibrinogen Plasma viscosity White blood cell count
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1. Introduction |
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Mechanisms by which cigarette smoke may initiate or accelerate atherosclerosis and its complications are not fully understood. Smoking causes coagulation and lipid abnormalities,6and circulatory effects due to enhanced catecholaminerelease have been reported.7Recent work focuses on smoking-induced endothelial injury, and there is evidence that mainly free radicals, such as nitric oxide radicals, singlet oxygen and hydrogen peroxide, mediate cigarette-smoke induced endothelial damage.8Oxidative stress promotes a systemic acute phase response possibly by NF-B activation9and cytokine induction,10and an association of cigarette smoking with a variety of acute phase markers such as inflammatory cytokines,11,12cell adhesion molecules,12,13C-reactive protein (CRP),1423fibrinogen,18,2427plasma viscosity (PV),24,2830white blood cell (WBC)-count6,3133and albumin16,34,35has been reported. Therefore, markers of inflammation may directly indicate smoking-induced inflammatory responses. Additionally, the association of these markers of inflammation with smoking may modulate the smoking-associated risk, since several of them are by itself strong and independent risk factors for CHD.36
Some of the above mentioned studies merely investigated the association of solitary inflammatory markers with smoking status. Only incomplete data are available taking into account other smoking characteristics, such as duration of smoking, smoked pack-years, and duration of abstinence from smoking. Thus, in the present large population-based study we aimed to systematically investigate the association of the smoking status (never, ex, occasional, regular) with a variety of markers of systemic inflammation (CRP, fibrinogen, PV, WBC-count, albumin), and also to assess the association of various smoking characteristics with these markers.
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2. Methods |
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Routine laboratory tests, including blood cell counts, total cholesterol and HDL-cholesterol were subject to continuous internal and external quality control. Coefficients of variation for repeated measurements were 0.7% for PV, 5.0% for fibrinogen, 6.9% for albumin and 12% for CRP over all ranges.
2.1. Statistical analysis
Baseline characteristics and markers of inflammation of the study population are described as means and standard deviations, if not indicated otherwise. Values have been calculated separately for men and women. CRP, fibrinogen, PV, and WBC count values were transformed to natural logarithms for greater symmetry of the distribution. Numbers shown in the tables are back-transformed to the original scale by taking antilogs, thus representing geometric means. The following analyses were restricted to cigarette smokers because of the small numbers of cigar, cigarillo and pipe smokers. Relative frequencies of the smoking status were calculated separately for men and women and for different age groups. Medians and interquartile ranges of different smoking characteristics were calculated for the same categories. Adjusted means of different markers of inflammation (CRP, fibrinogen, PV, WBC count, albumin) were computed according to the smoking status (never, ex, occasional, regular smoke exposure) and in quintiles of different smoking characteristics (number of smoked cigarettes, duration of smoking, pack-years, duration of abstinence from smoking). Adjustment was performed for multiple possible confounding covariates such as BMI, total cholesterol, HDL-cholesterol, alcohol consumption,systolic and diastolic blood pressure, education, physical activity, diabetes, CHD and creatinine. The p-values represent probability values for testing the simultaneous equality of the means. All computations were performed with SAS software (SAS Windows 6.12). P-values <0.05 were considered statistically significant.
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3. Results |
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Smoking is more prevalent in men than in women (Table 2). In general, regular smoking is more common in younger individuals than in the older above age 55 years. There are also a large number of ex-smokers in this age group, particularly among men. Men are heavier smokers than women (Table 3), but there are no differences in smoking duration. The age at onset of smoking (derived from the duration of smoking) tends to be the same in both sexes, with a tendency to an earlier beginning (in the teenage years) in younger individuals.
The associations of smoking status and different smoking characteristics with markers of systemic inflammation are shown in Table 4. All means presented have been adjusted for a variety of potential confounders by multiple linear regression. In men, the positive acute phase markers CRP, fibrinogen, PV and WBC count are positively associated with smoking status, with highest plasma concentrations in regular smokers, slightly increased concentrations in occasional and ex-smokers, and lowest concentrations in never smokers. Comparing never smoking with regular smoking men, plasma concentrations of CRP are nearly doubled in regular smokers (1.03mg/l vs 1.92mg/l). In men, the number of smoked cigarettes and pack-years and duration of smoking are positively, whereas duration ofabstinence from smoking is inversely associated with these markers of systemic inflammation. This result is very consistent and statistically significant for all positive acute phase markers, except for the inverse association of fibrinogen and PV with the duration of abstinence from smoking and PV with the number of smoked cigarettes per day. There is no association of albuminan unspecific negative acute phase markerwith parameters of smoking. Furthermore, except for WBC count, there is no association of smoking with these markers of inflammation in women.
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4. Discussion |
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Several previous studies have reported anassociation of smoking with CRP,1423but only few analysed in detail the association of smokingcharacteristics, such as the number of smoked cigarettes,14pack-years17,19and abstinence from smoking,15,17,23with CRP in a large representative population-based sample. Comparing current smokers with never-smokers, the magnitude of the difference seems to be higher in men (e.g. 1.5mg/l in the Physicians Health Study14), compared to women (e.g. 0.08mg/l in the Women's Health Study12). This is in accordance with the missing difference in women reported here. All of the previously reported data were cross-sectional, except one.15In the course of this retrospective study, a non-significant decrease in CRP concentration (0.21mg/l) after smoking cessation of one year was reported. Conversely, in the present study reported smoking cessation covers a longer period (up to >30 years), and there was a greater difference in CRP concentration in men of 0.67mg/l, comparing smoking abstainers in the highest quintile (3055 years of abstinence) to current smokers.
Significantly higher fibrinogen concentrations in smokers24,26,27with a dose-response relationship have been shown by others.25In some reports PV values24,28,29parallel the changes in fibrinogen concentrations, as we also could show in the present analyses. This is not surprising, since fibrinogen is a major determinant of PV.44Again, smoking cessation was not associated with lower PV and fibrinogen concentrations in women, and this corresponds with data from a longitudinal study28in which men experienced a significant decrease in PV of 0.021mPa.s after 2 years of smoking cessation, and women did not (difference 0.009mPa·s, ns).
In the present study, WBC count represented the parameter most reliably associated with smoking in both men and women. The association of WBC count with smoking has been reported previously6,3133, showing a dose-response relationship31,32and an association with smokingduration.32Overall, the magnitude of the effect of smoking on WBC count (difference 1.52x103/µl) is comparable throughout the studies.
In contrast to other studies34,35we found an inverse association of the negative acute phase marker albumin with smoking in men only. Both, Das et al.16and Dales et al.34revealed significantly lower albumin levels in smokers, compared to non-smokers, but once more the difference was more prominent among men (men: 7.9g/l, women:4g/l16). A dose-response relationship and an association of albumin with abstinence from smoking was not observed in the present study, nor was it reported by others. The relatively weak association of albumin with smoking may be due to the fact that besides inflammation, serum albumin concentrations are mainly determined by other conditions such as nutritional status and liver function.
There are several possible mechanisms by which smoking may be associated with systemic markers of inflammation. First, acute phase proteins may be surrogates for smoking-induced chronic inflammatory processes such as periodontitis,45airwayinflammation46and atherosclerosis itself.47Second, certain compounds of smoke such as free radicals11and phenol-rich glycoproteins48directly exert an inflammatory stimulus on macrophages which may trigger the production of inflammatory cytokines such as TNF, IL-1, and IL-6.11And third, it is conceivable that there is an indirect effect by nicotine-induced catecholamine release7which modulates the systemic and local cytokinebalance.49
Although women are more sensitive to harmful effects of smoking,1in the present study except for WBC no association of smoking and smoking characteristics with markers of the acute phase response were observed in women, compared to men. Taking the above mentioned mechanisms into consideration, one may speculate that women experience less smoking-related inflammatory reactions, e.g. airway inflammation. This may be attributable to a different puffing behaviour in women. Generally, women use less untipped and more low-yield cigarettes,50and take smaller and shorter puffs.51However, the sex differences in self-reported inhaling habits disappear in pharmacological motivated heavy-smoking women (>20cigarettes/d).50This is in line with our observation of markedly elevated inflammatory parameters just in the 5th quintile (>21cigarettes/d) of cigarette consumption in women.
The major strength of the present analysis is the fact that data are based on a large representative sample (participation rate 74.9%) of the general population including both sexes and a large age range. However, the results may be limited due to the cross-sectional nature of the study which excludes establishing causal relationships. Furthermore, residual confounding for example by other lipid variables and homocysteine may represent a problem. However, this does not seem to be critical since age-adjusted values were not significantly altered in multivariate analyses. Finally, data may be biased by incorrect reporting of smoking habits, mainly because we did not perform objective measures of cigarette consumption, such as cotinine plasma concentrations.
In summary, we found a strong and consistent association of markers of systemic inflammation with smoking and various smoking characteristics, particularly in men. The low grade systemic acute phase response may contribute to the increased cardiovascular risk in smokers. Markers of systemic inflammation are inversely associated with years since cessation of smoking. Thus, our data provide further evidence that immediate smoking cessation should be strongly recommended in particular to those individuals with CHD. Different smoking patterns may explain the less consistent results in women.
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Acknowledgments |
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References |
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