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Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:577-582
Published online before print January 15, 2004, doi: 10.1161/01.ATV.0000116863.37311.82
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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:577.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoprotein

Risk of Myocardial Infarction and Stroke in Smokers Is Related to Plasma Levels of Inflammation-Sensitive Proteins

P. Lind; G. Engström; L. Stavenow; L. Janzon; F. Lindgärde; B. Hedblad

From the Departments of Internal Medicine (P.L., L.S.), Community Medicine (G.E., L.J., B.H.), and Vascular Diseases (F.L.), Malmö University Hospital, Malmö, Sweden.

Correspondence to Dr Peter Lind, Department of Internal Medicine, Malmö University Hospital, S-20502 Malmö, Sweden. E-mail Peter.C.Lind{at}skane.se


*    Abstract
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Background— The extent to which differences in cardiovascular risk between smokers with similar daily tobacco consumption may be related to plasma levels of inflammation-sensitive proteins (ISP) and whether these proteins are associated with levels of carboxyhemoglobin (COHb%) have not been clarified.

Methods and Results— In a population-based cohort of 1489 never smokers, 1685 former smokers, and 2901 current smokers, aged 28 to 61 years, plasma levels of orosomucoid ({alpha}1-acid glycoprotein), {alpha}1-antitrypsin, haptoglobin, fibrinogen, and ceruloplasmin were measured. COHb% levels were available for 2098 of them. Incidence of myocardial infarction, stroke, and death were monitored over 18.7±4.7 years. The proportion with high ISP levels (ie, >=2 ISP in the top quartile) increased progressively with daily tobacco consumption (P<0.01) and COHb% (P<0.01). In all smoking categories, the incidence of stroke, cardiac events, and death was related to ISP. In heavy smokers, high ISP levels were associated with adjusted relative risks of 1.57 (1.05 to 2.35) and 1.50 (1.11 to 2.03) for cardiac events and death, respectively. Corresponding figures for moderate and light smokers were 1.59 (1.13 to 2.24) and 1.14 (0.87 to 1.49), respectively, and 1.32 (0.95 to 1.85) and 1.48 (1.10 to 1.98), respectively.

Conclusion— ISP levels are related to COHb% in smokers. High levels are associated with an increased cardiovascular risk.


Key Words: stroke • myocardial infarction • smoking • inflammation • plasma proteins • epidemiology


*    Introduction
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Smoking is one of the major risk factors for arteriosclerosis and its complications.1–3 Yet how smoking harms the vessel wall remains controversial. The biological mechanism linking smoking and atherothrombosis is complex and not fully understood4 and include vascular endothelial dysfunction,5 systemic coagulation disturbances,6 and lipid disorders.7 It has been demonstrated in several cohort studies that the incidence of myocardial infarction and stroke are associated with plasma level of interleukin-6 (IL-6),8 tumor necrosis factor-{alpha} (TNF-{alpha}),9 soluble intracellular adhesion molecule type 1 (ICAM-1),10 E-selectin,11 P-selectin,12 high sensitive C-reactive protein (CRP),13,14 and other inflammatory-sensitive proteins (ISP), eg, fibrinogen, orosomucoid ({alpha}1-acid glycoprotein), {alpha}1-antitrypsin, haptoglobin, and ceruloplasmin.15,16 Plasma levels of inflammatory markers are generally higher in smokers compared with nonsmokers.17,18

Between smokers with equal tobacco consumption there are, however, great variations of the cardiovascular risk. This may be related to the amount of harmful components in the tobacco smoke that is absorbed into the blood. Carboxyhemoglobin (COHb%), which in prospective studies has been identified as a predictor of cardiovascular disease in smokers,19 may vary substantially within categories defined in terms of daily consumption. Whether and how the cardiovascular risk in smokers is related to the plasma levels of ISP and whether the amount of these proteins has any relationship with the level of COHb% is largely unknown.20

The objectives in this prospective cohort study have been to assess the extent to which differences in cardiovascular risk between smokers with equal daily tobacco consumption may be related to plasma levels of ISP and whether these proteins have any relationship with COHb% level.


*    Methods
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The Malmö Preventive Project (MPP) was organized and performed by the Department of Medicine at Malmö University Hospital, Malmö, Sweden. The project, participation rate, and information on nonparticipation have been described in detail previously.21 In summary, the aim of the project, which started in 1974, was to invite the adult population to screening to identify individuals at high risk for cardiovascular disease (CVD). All male subjects living in the city of Malmö and born 1921, 1926 to 1942, 1944, 1946, 1948, and 1949 were invited by letter to participate in a broad health-screening program, including a physical examination and a panel of laboratory tests. When the unit was closed for men in 1984, 22 444 men had attended the examination, with an overall attendance rate of 71%. Determination of plasma ISP was part of the program for men only, ie, 6193 subjects aged 28 to 61 years at the time of the screening examination, selected at random, and corresponding to 30% of the cohort.15 After excluding those with a history of myocardial infarction, stroke, or cancer (according to questionnaire), 6075 men remained. The Health Service Authority of Malmö approved the screening program and all participants have given their written consent.

Baseline Examinations
Information on smoking habits and leisure-time physical activity and history of angina pectoris was assessed from a self-administered questionnaire. The following smoking categories were used: those who had never smoked, former smokers (smokers who had quit smoking at least 1 year before the examination), and current smokers, eg, daily consumers of at least 1 gram of tobacco. Smokers were then divided according to the daily tobacco consumption, whether they smoked <10, 10 to 19, or >=20 cigarettes per day. In former smokers, the time since they stopped smoking was assessed in the questionnaire by the question, "Have you stopped smoking within the past 5 years?" In smokers, the duration of smoking was assessed by the question, "Have you smoked longer than 10 years?" Two categories were used for the classification of leisure-time physical activity, ie, sedentary or not. Angina pectoris was recorded if the participant confirmed that this diagnose was determined by a physician or if they reported treatment with nitroglycerine. The prevalence of problematic drinking behavior was based on a modified version of the Michigan Alcoholism Screening Test (Mm-Mast).22 Information on occupational level and civil status in the MPP has been reported in detail previously.23 Classification into socio-economic index (SEI) groups was in accordance with methods used by the Swedish National Bureau of Statistics.24 In this study, the different SEI categories have been combined into three occupational groups: non-manual workers, manual workers, and other SEI positions.

Blood pressure (mm Hg) was measured twice in the right arm after a 10-minute rest. The average value of these two measurements was used. A sphygmomanometer and a rubber cuff of appropriate size were used. Men with systolic blood pressure >=160 mm Hg and/or diastolic >=95 mm Hg or with ongoing pharmacological antihypertensive treatment were considered to have hypertension.

Blood samples were taken after an overnight fast and analyzed at the Department of Clinical Chemistry at Malmö University Hospital, which uses a recurrent standardization system. Serum cholesterol, triglycerides, and blood glucose concentrations were analyzed with standard methods at the laboratory. Diabetes mellitus was recorded when venous blood glucose was >=6.70 mmol/L measured in whole blood and in those using anti-diabetic medication. Body mass index (BMI) was calculated as weight/height2 (kg/m2).

COHb%
In the mailed invitation were instructions to abstain from food, alcohol, and tobacco for 12 hours before the examination. Questioning checked the compliance. The carboxyhemoglobin concentration (in percent) was analyzed in venous blood by gas chromatography in 2098 men according to the method described by Collinson et al.25,26

ISP
An electroimmunoassay method was used to assess plasma levels of 5 ISP.28 The coefficient of variation of this method is considered to be <5%.28 We have previously shown that these proteins are highly correlated and that the cardiovascular risk increases with the number of ISP in the top quartile.15,16 The sample was therefore categorized into those who had 2 to 5 ISP in the top quartile (high ISP levels) and those with 0 to 1 ISP in the top quartile (low ISP levels).15 High ISP levels were thus defined as at least two of the following criteria: fibrinogen >4.0 g/L, orosomucoid ({alpha}1-acid glycoprotein) >0.93 g/L, {alpha}1-acid antitrypsin >1.42 g/L, haptoglobin >1.76 g/L, and ceruloplasmin >0.36 g/L. Analyses of these proteins at the time were for the screening examination usually used in Swedish routine clinical practice to reflect inflammatory activity. The relationships between ISP and other cardiovascular risk factors from the MPP have been published previously.15,16,28–31

Follow-Up
Information on case retrieval, validity, and ascertainment of cases in the MPP has been described in detail previously.16,23 In summary, all cases were followed-up from the baseline examination until death, date of emigration, or December 31, 1997. A cardiac event was defined as fatal or non-fatal myocardial infarction (code 410 according to the International Classification of Diseases, ICD, 8th and 9th revisions) or death caused by chronic ischemic heart disease (ie, ICD codes 412 to 414). In men with more than one cardiac event, only the first event was used for the analyses. Stroke was defined as cases coded 430 (subarachnoid hemorrhage), 431 (intracerebral hemorrhage), 434 (ischemic stroke), or 436 (unspecified stroke) according the ICD.

Statistics
SPSS (version 10.0) was used for all statistical analyses. A general linear model (for continuous variables) and logistic regression (for dichotomous variables) were used to study the covariate-adjusted relationships (by test for linear trends) between smoking habits and COHb% and ISP levels. Spearman correlation coefficients were computed for all 5 ISP and COHb%. ANOVA was used to compare the number of ISP in the top quartile by quartiles of the COHb% concentration in light, moderate, and heavy smokers. Cox proportional hazards model was used for the analysis of the event rates in categories of smoking habits and ISP with adjustment for potential confounders. Survival plots of the different risk factor categories confirmed the fit of the proportional hazards model. Emigrants (n=72) were followed-up until date of emigration and were thereafter censored in the analyses.


*    Results
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Study Cohort
A total of 1489 men were never smokers, 1685 were former smokers, 1048 were light smokers (<10 cigarettes/d), 1130 were moderate smokers (10 to 19 cigarettes/d), and 723 were heavy smokers (>=20 cigarettes/d) (Table I, available online at http://atvb.ahajournals.org).

Smoking in Relation to COHb% and ISP
The distribution of the COHb% concentrations in different categories is shown in Table 1. The mean concentration was similar in smokers and former smokers. With increasing cigarette consumption, the COHb% concentration and all measured ISP levels increased significantly. Prevalence of 2 to 5 ISP in the top quartile increased by smoking habits and was 19.5% in non-smokers and 56% among heavy smokers. This trend remained significant after adjustment for age, BMI, diabetes, cholesterol, triglycerides, systolic blood pressure, use of blood pressure-lowering medication, history of angina pectoris, history of problematic drinking behavior, leisure-time physical activity, cohabiting status, and occupational level. In smokers, the COHb% was moderately but significantly correlated with all 5 ISP (Table II and Figure I, available online at http://atvb.ahajournals.org). In smokers, the COHb% concentration was significantly higher in men with 2 to 5 ISP in the top quartile than in smokers with low ISP (Figure 1). In never smokers and former smokers, no significant differences in COHb% was found between men with and without high ISP (data not shown).


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  		TABLE 1. Smoking Habits, Carboxyhemoglobin (COHb%) in Relation to ISP Levels



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  		Figure 1. Mean carboxyhemoglobin (COHb%) with 95% confidence interval in light smokers (LS) (1 to 9 cigarettes/d), moderate smokers (MS) (10 to 19 cigarettes/d), and heavy smokers (HS) (>=20 cigarettes/d) with and without 2 to 5 inflammation-sensitive proteins (ISP) in the top quartile.

Mortality, Stroke, and Cardiac Events
A total of 919 men (15.1%) died during the follow-up, 378 (41%) of them from cardiovascular diseases (ICD-9 codes 390 to 440). Six hundred thirteen men (10.1%) had a coronary event. Two hundred thirty-eight (3.9%) men had a stroke, 9 had a subarachnoid hemorrhage, 29 had an intracerebral hemorrhage, 170 had an ischemic stroke, and 30 cases were unspecified.

Event Rates in Relation to Smoking Habits, COHb%, and ISP Levels
The cardiac event-free survival associated with low and high COHb% (ie, above the median concentration, 2.24%) in 1097 smokers with light and moderate to heavy tobacco consumption is presented in Figure 2. The age-adjusted relative risk was 1.46-times (0.98 to 2.18, P=0.063) higher in moderate and heavy smokers with a high concentration in comparison to a low COHb% concentration. The mean number of ISP in the top quartile increased significantly by level of COHb% concentration in light, moderate, and heavy smokers as presented in Figure II (available online at http://atvb.ahajournals.org) (P<0.001 for trend). The prevalence of major cardiovascular risk factors in the different groups is presented in Table I.



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  		Figure 2. Age-adjusted cardiac event rates in relation to smoking habits in 2098 men with COHb% measurements; ie, never smokers, former smokers, light smokers (1 to 9 cigarettes/d), and moderate/heavy smokers (>=10 cigarettes/d) with and without high (above the median) concentration of COHb%.

In each smoking category, the incidence of cardiac events, stroke, and deaths was higher in those with high ISP (Table 2). The highest incidence of stroke, cardiac events, and cardiovascular deaths was found among heavy smokers with high ISP. The increased risk in that group remained statistically significant after adjustments for several potential confounders. The incidence of cardiac events and deaths in heavy smokers with high ISP was, after adjustment for potential confounders, 1.57-times higher (1.05 to 2.35) and 1.50-times higher (1.11 to 2.03), respectively, than it was in the heavy smoker group with low ISP. The corresponding figure for moderate smokers were 1.59 (1.13 to 2.24) and 1.14 (0.87 to 1.49), and for light smokers were 1.32 (0.95 to 1.85) and 1.48 (1.10 to 1.98), respectively.


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  		TABLE 2. Incidence Rates and Relative Risk (RR) of Deaths, Cardiac Events, and Stroke in Relation to Inflammation-Sensitive Proteins (ISP) and Smoking Habits


*    Discussion
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In agreement with previous publications, plasma levels of ISP and number of elevated ISP were significantly associated with the prevalence of smoking and tobacco consumption,17,20 and this association was independent of other known cardiovascular risk factors.18 Eighteen years after the baseline examination, 612 (21.1%) of the smokers were no longer alive. Two hundred seventy-eight (41.1%) of these deaths were caused by cardiovascular disease. The morbidity and mortality patterns associated with smoking in this cohort study are similar to what has been reported by many others.2,3 Yet for each smoker dead because of cardiovascular disease, there were 10 who were alive by the end of follow-up. It is the conclusion in this study that heterogeneity in risk between smokers is related to plasma levels of ISP.

A continuous and linear relationship between tobacco consumption and atherosclerosis has been demonstrated.32 Furthermore, the interaction between cigarette smoking and chronic infections on the development of carotid atherosclerosis has been demonstrated.33 In this study, the incidence of cardiac events tended to be higher in smokers with high concentration of COHb%, which can be considered a marker of the amount of potentially vessel wall-damaging components in tobacco smoke that are absorbed into the blood.34

In this study, there was a relationship between COHb% and plasma levels of ISP. In a study of Swedish 58-year-old men, tobacco smoking, but not oral moist snuff use, was associated with carotid and femoral artery intima-media thickness and increased levels of C-reactive protein indicating, as the authors suggests, that inhaled smoke from the combustion of tobacco, and not nicotine, may be the most important causative factor in the atherosclerotic process.35 There are several possible pathways linking inhaled tobacco smoke, which is reflected by the amount of COHb%, to atherosclerosis. The toxicity of inhaled tobacco could by caused by a variety of compounds including reactive oxygen species, eg, causing DNA damage,36 inhibition of the transcription nuclear factor kappa B (NF{kappa}B) in human monocytes37 and production of platelet activator factor,38 nitric oxide modified substances,39 glycotoxines,40 endotoxins,41 and substances stimulating the production of isoeicosanoids.42 Smokers with reduced lung function comprise another group at risk for cardiovascular disease. It has been documented in prospective studies that ISP influences this risk.43,44

The 5 ISP in the present study are strongly correlated and can all be regarded as non-specific markers of inflammation and the actions of pro-inflammatory cytokines.45 Previous studies from the present cohort have shown that the association with incidence of cardiovascular diseases is similar for the 5 proteins and that the relationship is further increased if the number of ISP in the top quartile is used.15,29

Some methodological issues need to be considered. Local and national registers were used for case retrieval. A validation study from the National Hospital Discharge Register showed that the diagnosis of myocardial infarction was false in only 5% of the cases.46 Thus, based on the experience from the Swedish National Board of Welfare, the Malmö Heart Infarction register,47 and several other follow-up studies of this cohort, there should be no reason to believe that observed associations could have been confounded by biased retrieval and validation of endpoints.21,23

Change in exposure is an inherent problem in long-term cohort studies. We do not know whether cardiovascular risk factors and treatment of diabetes, hypertension, and hyperlipidemia differed during the follow-up. All with hypertension, lipid disorders, or diabetes diagnosed were referred for further evaluation and treatment. Smokers were advised to quit but received no help in doing so. Intervention against overweight and obesity was not part of the preventive program. Because the prevalence of these risk factors were more common among men with high ISP levels, they should benefit most from the interventions, and this would, if anything, tend to dilute existing associations. We have previously reported that cholesterol increases with the number of elevated ISP and with increasing concentrations of the individual ISP.16 However, another limitation is that we do not know whether the subfractions of cholesterol, eg, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and lipoprotein(a) differed between the groups. From previous experience, it is known that the LDL-to-HDL ratio is strongly correlated to levels of triglycerides and the results were adjusted for triglyceride levels as a proxy for dyslipidemia. Furthermore, in a substudy of 1035 middle-aged men from the MPP, the relationship between COHb% and cholesterol and triglyceride and apolipoprotein A1 (Apo-A1) were studied.48 The conclusion from that study was that although statistically significant, the influence of smoking, eg, COHb%, on blood lipid variability was found to be clinically insignificant. Another limitation of the present study was that only men were studied. However, circulating biochemical markers of inflammation such as high sensitive CRP, ICAM-1, and IL-6 have also been demonstrated as predictors of cardiovascular events in apparently healthy postmenopausal women.49

It is the conclusion that plasma levels of ISP in smokers are related to COHb% and that smokers with high levels of these proteins are exposed to increased cardiovascular risk.


*    Acknowledgments
 
Acknowledgments

Supported by grants from the Swedish Medical Research Council, the Swedish Heart and Lung Foundation, the Swedish Council for Work-Life and Social Research, the Swedish Society of Medicine, the Apotekare Hedberg Foundation, and the Åke Wiberg Foundation.

Received August 19, 2003; accepted November 11, 2003.


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