Published online before print September 20, 2007, doi: 10.1161/STROKEAHA.106.481531
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(Stroke. 2007;38:2881.)
© 2007 American Heart Association, Inc.
Original Contributions |
High-Sensitivity C-Reactive Protein Is Independently Associated With Early Carotid Artery Progression in Women But Not in Men
The INVADE Study
From the INVADE Study Group, Department of Neurology, Technical University of Munich, Munich, Germany.
Correspondence to Dr Kerstin Sander, Department of Neurology, Technical University of Munich, Möhlstrasse 28, 81675 München, Germany. E-mail k.sander{at}neuro.med.tu-muenchen.de
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Abstract |
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Background and Purpose— High-sensitivity C-reactive protein (hsCRP) is known to be associated with atherosclerosis and cardiovascular events. Limited information exists regarding the importance of sex differences for the association between hsCRP and the progression of early stages of atherosclerosis. Therefore, we investigated the effect of hsCRP on early carotid atherosclerosis progression and major vascular risk factors in men and women.
Methods— We analyzed the data of INVADE (intervention project on cerebrovascular diseases and dementia in the community of Ebersberg, Bavaria), a prospective, population-based study. In addition to common risk factors, measurements of carotid intima-media-thickness and hsCRP were performed at baseline and after 2 years.
Results— Complete baseline data were available for 3387 subjects including 2001 women, and complete follow-up data were available for 2346 subjects. Within this study population, women were older and had higher systolic blood pressure and cholesterol levels. The prevalence of smoking and ischemic heart disease was more frequent in men. The baseline carotid intima-media-thickness was significantly higher in men compared with women (0.82 mm; 95% CI, 0.812 to 0.834 mm versus 0.77 mm; 95% CI, 0.763 to 0.779 mm; P<0.0001). Carotid intima-media-thickness progression after risk factor adjustment was significantly associated with hsCRP in women (P=0.006) but not in men (P=0.39).
Conclusions— The association between hsCRP and progression of early carotid atherosclerosis shows sex differences. In further studies analyzing the role of inflammation for cardiovascular diseases and atherosclerosis, these sex differences should be considered.
Key Words: atherosclerosis • Doppler ultrasound • inflammation • risk factors
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Introduction |
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Recent evidence suggests that high-sensitivity C-reactive protein (hsCRP) plays a direct role in all stages of the atherosclerotic process. Moreover, hsCRP predicts cardiovascular events like ischemic stroke and myocardial infarction in apparently healthy men and women,1–3 provides additional information on cardiovascular risk, and is positively correlated with atherosclerotic burden.4,5 High-resolution B-mode carotid ultrasonography and measurement of carotid intima-media thickness (IMT) are useful methods for an easy, noninvasive evaluation of early carotid atherosclerosis. Elevated hsCRP and increased IMT are known to be associated with prevalent coronary heart disease and cardiovascular risk factors and predict the risk of stroke and cardiovascular events.2,6,7 The association between hsCRP and carotid IMT was analyzed in various studies with different results.8–10 Recently, a close correlation between inflammation and morphological features of rapidly progressive carotid atherosclerosis was found.11 However, until now, limited data exist regarding the importance of sex differences in the association between hsCRP and the progression of early atherosclerosis. Recent clinical studies described a stronger relation between hsCRP and the development of the metabolic syndrome in women compared with men.12 and reported sex-based differences in the mechanisms of metabolic syndrome–induced atherosclerosis.13 Data from the Women’s Health Study14 indicated sex differences for the effect of low-dose aspirin in the primary prevention of vascular diseases. We therefore hypothesized that there are sex differences with respect to the effect of hsCRP on IMT progression. To examine this question, we analyzed data from a large, population-based sample of the INVADE (intervention project of cerebrovascular events and dementia in the community of Ebersberg) study.
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Methods |
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Subjects
This investigation is part of the INVADE study, a prospective and population-based cohort study in the elderly.15 All inhabitants of the community of Ebersberg, 30 km east of Munich, who were born before 1946 and were members of the health insurance company Allgemeine Ortskrankenkasse were identified in the Allgemeine Ortskrankenkasse database and were then invited to participate (n=10 325). In the community of Ebersberg, >40% of all inhabitants age >55 years were Allgemeine Ortskrankenkasse members. During a baseline phase (2001 to 2003), 3909 subjects accepted the invitation to participate. Complete baseline data were available for 3387 subjects. The remaining subjects were excluded owing to incomplete laboratory and/or medication data (n=346) or missing (n=95) or not analyzable (n=81) IMT. To rule out acute infection, another 241 subjects were excluded because of increased hsCRP levels (>10.0 mg/L). The baseline investigation was done by primary care physicians of the community of Ebersberg (n=65) and included a standardized questionnaire, physical examination, evaluation of several risk factors, medical and disease history, 12-lead ECG, and an overnight fasting venous blood sample drawn for analysis in a central laboratory. A duplex ultrasonographic examination of the carotid arteries was carried out in all subjects according to a standardized protocol at 8 local centers of excellence after training. All data were entered in a central database after plausibility checks for further evaluation. After the initial baseline investigation, the primary care physician investigated the participants every 3 months. Follow-up investigations were scheduled after 2 years. Complete data sets were available for 2346 of the 3146 participants. There were no significant differences in the baseline data between the initially recruited group and those who completed the follow-up. The local institutional review board approved this investigation. All subjects provided informed consent before entering the study.
Cardiovascular Disease Status and Risk Factors
Information on current health status, medical history, lifestyle, cognitive status, mood disorders, drug use, and former cardiovascular risk factors was obtained by a computerized questionnaire at baseline and at follow-up. Risk factors included the following: body mass index (BMI, kg/m2), smoking status, pack-years of smoking, alcohol consumption, actual medication use (including statins and hormone replacement therapy [HRT]), social status, education status, arterial hypertension, diabetes mellitus, prevalent ischemic heart disease (IHD), and prevalent peripheral artery disease. The definitions were recently given in detail.15
Laboratory Examinations
Overnight fasting blood samples were drawn from each subject and transferred on ice to a central laboratory that performed all analyses. We used a high-sensitivity assay for measurement of serum hsCRP (N High Sensitivity CRP, Dade, Behring, Germany) with a lower detection level of 0.175 mg/L and a coefficient of variation of 7.6%. The intra-assay precision ranges from 3.1% for a CRP content of 0.5 mg/L and 4.0% for a CRP content of 15 mg/L; the interassay precision was 2.5% and 2.6%, respectively. In addition to these values, glycohemoglobin (hemoglobin A1c [HbA1c]), cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, creatinine, and fasting serum glucose were measured.
Ultrasound Imaging
Eight experienced investigators performed the duplex ultrasonography according to a standardized study protocol. The initial duplex sonography and the follow-up investigation were performed by the same investigator. The ultrasound data were stored on video or digital audiotapes, transferred to the neurovascular laboratory of the Department of Neurology, and digitized if necessary. The measurements of mean common carotid artery IMT were done in the neurovascular laboratory as previously described in detail16 with a computer-supported image analysis system (SigmascanPro 5.0, SPSS). To enhance the reproducibility of carotid measures, standardized interrogation angles were used according to the recommendations described previously.17 In every subject, the follow-up measurements were performed at the same location as in the initial measurement. The intrarater (
=0.93) and interrater (=0.83) variabilities were very good.
Statistical Analysis
All values are given as mean and 95% CIs, median and interquartile range (IQR), or counts and percentages. We used 
2 tests, independent t tests, Mann-Whitney U tests, and the Spearman rank correlation for univariate analysis, as appropriate. The relation between IMT and hsCRP was tested with multiple linear-regression techniques. To analyze the combined effect of sex and hsCRP on IMT, the interaction term hsCRPxsex was included in the regression models. In all models, the IMT data were entered as continuous values. All multiple analyses were adjusted for the same relevant covariates (baseline age; sex; pack-years of smoking; cholesterol; LDL cholesterol; BMI; HbA1c; diastolic and systolic blood pressures; prevalent IHD; and use of statins, antiplatelet drugs, antihypertensives, insulin, oral antidiabetic medications, and in women HRT). Calculations were performed with JMP 5.01 software (SPSS Inc). A calculated difference of P<005 was considered statistically significant.
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Results |
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Clinical Characteristics
The mean age of the included subjects (n=3146) was 69.3 years (95% CI, 69.0 to 69.6 years), 1281 (41%) were male, 21% (n=652) had a history of diabetes mellitus, 76% (n=2383) had a history of hypertension, 55% (n=1746) had a history of hyperlipidemia, 12% (n=365) had a history of IHD, and 16% (n=510) of the subjects were being treated with statins. The mean IMT at baseline was 0.79 mm (95% CI, 0.79 to 0.80 mm). The median hsCRP was 2.0 mg/L (IQR, 1.0 to 3.5 mg/L). There was a significant correlation between baseline hsCRP and baseline carotid IMT (P=0.0005), BMI (P<0.0001), HbA1c level (P<0.0001), systolic blood pressure (P<0.0001), HDL cholesterol (P<0.0001), LDL cholesterol (P=0.04), and pack-years of smoking (P=0.001) in univariate analysis.
Sex Differences at Baseline
Baseline data of both subgroups are given in Table 1. There were significant differences in the vascular risk factors and age between men and women. As expected, in men the number of pack-years of smoking and the incidence of IHD were significantly higher. Diabetes mellitus was more frequent in men compared with women (21% versus 16%, P=0.001). However, HbA1c values did not differ significantly (Table 1). Oral antidiabetic and antiplatelet agents were significantly more often used in men compared with women. Statin administration was comparable between men and women (Table 1). Baseline IMT was significantly higher in men compared with women (0.82 versus 0.77 mm, P<0.0001; Table 2). In both sexes, age was significantly associated with baseline IMT. Median hsCRP levels were higher in women (2.0 versus 1.9 mg/L, P=0.02). This relation persisted (P=0.02) when women with HRT were excluded from analysis. The association between hsCRPxsex and baseline carotid IMT was highly significant (F=6.54, P=0.01) and remained statistically significant even after adjustment for the other risk factors (F=4.04, P=0.04).
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Nineteen percent (n=348) of women received HRT with estrogens. Women with HRT were significantly younger (65.7 versus 72.5 years, P<0.0001) and had a lower vascular risk profile with a significantly lower BMI (26.9 versus 27.5 kg/m2, P=0.03), baseline carotid IMT (0.73 versus 0.78 mm, P<0.0001, HbA1c (5.63% versus 5.85%, P<0.0001), and systolic blood pressure (139 versus 142 mm Hg, P=0.02). Moreover, the prevalence of IHD was significantly lower in women receiving HRT (3.7% versus 10%, P=0.002).
Sex Differences at Follow-Up
Two thousand three hundred forty-six subjects were included in the follow-up analysis, including 1393 women. At follow-up, vascular risk factors and laboratory data had improved in men and women. In addition to a significantly higher cholesterol reduction in men and a higher HDL cholesterol increase in women, the differences were comparable. Moreover, the changes in concomitant medications after 2 years did not differ significantly (Table 2). IMT progression was observed at a similar frequency in women and men (Table 1). The overall median IMT progression per year was 0.013 mm (IQR, –0.025, 0.052), without a significant sex difference (men=0.015 mm; IQR, –0.025, 0.056 versus women=0.011; IQR –0.024, 0.05; P=0.28). The median IMT increase was significantly associated with hsCRP in women (F=3.29, P=0.02) but not in men (F=0.59, P=0.62) in a univariate analysis (the Figure). In men, median IMT progression was stable across CRP quartiles, whereas in women IMT progression increased over the CRP quartiles. Hence, IMT progression was higher in men in the first CRP quartile, whereas IMT progression was greater in women compared with men in the fourth quartile. In a multiple linear-regression analysis, IMT progression was independently associated with age, baseline carotid IMT, sex, and LDL cholesterol for all subjects. In men, IMT progression was significantly associated with BMI and baseline IMT. In contrast, in women, hsCRP remained an independent predictor of IMT progression even after adjustment for HRT (Table 3). The model accounted jointly for 12% of the variation in IMT progression in men and for 21% of the variation in women (multiple r=0.35, P<0.0001 and r=0.45, P<0.0001, respectively).
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Discussion |
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This large, prospective, and population-based cohort study demonstrates several interesting findings regarding the effect of hsCRP on the progression of early carotid atherosclerosis in men compared with women. Until now, conflicting findings have been published concerning the impact of hsCRP on early atherosclerosis. Some cross-sectional studies demonstrated that hsCRP was associated with IMT.8,18 In our study, we confirmed the results of other broad-based community cohort studies,19–21 which suggested that after correction for various risk factors and statin treatment, hsCRP failed to be an independent risk factor for early carotid atherosclerosis. In addition, the present investigation is the largest study to evaluate the effect of hsCRP on IMT progression, and we did not observe an independent association between hsCRP and IMT progression for the whole study population. However, the most important result was the significant sex difference concerning the impact of hsCRP on early atherosclerosis progression. In men, hsCRP failed to be associated with IMT progression, whereas in women, a significant association between IMT progression and hsCRP remained, even after adjustment for several traditional risk factors including statin treatment and HRT. The median IMT progression was similar across CRP quartiles in men, whereas women showed a nearly 3-fold higher median IMT progression when CRP was in the fourth quartile compared with the first quartile. In the Framingham Heart Study, Wang et al10 observed an association between the internal carotid IMT measured 4 years after hsCRP determination in women only.
The role of hsCRP as an acute-phase reactant on the progression of early atherosclerosis has not been clarified in detail. hsCRP levels might express the inflammatory activity of the atherosclerotic lesion, but hsCRP per se could also promote endothelial cell activation, leading to endothelial dysfunction and progression of atherosclerosis.11,22,23 The influence of sex on the atherosclerotic response to inflammation has so far not been characterized. Previously, hsCRP levels were thought to be similar between the sexes, despite the fact that only limited data were available comparing the distribution of CRP levels between men and women within the same study population. In our investigation, women had significantly higher hsCRP levels than men, although in men cardiovascular risk factors and the incidence of smoking were more frequent. One might argue that higher CRP levels in women could be explained by exogenous estrogen medication. However, in our study, the differences in CRP levels between men and women remained after excluding women with HRT. These findings are in accordance with the results of recent investigations reporting higher levels of hsCRP in women compared with men.24,25 The increased carotid IMT progression in the fourth CRP quartile in women, which was even greater than in men, might indicate that women with pronounced chronic inflammation might be at higher risk than men for vascular events due to increased atherosclerosis progression. These findings are in accordance with recent clinical studies that described sex differences for the impact of chronic inflammation on the occurrence of the metabolic syndrome. Those investigations documented a stronger relation between hsCRP and the development of the metabolic syndrome in women compared with men.24,26 The authors discussed that endogenous estrogen or a greater effect of chronic inflammation on insulin resistance in women might explain the findings. Additionally, the metabolic syndrome is a stronger risk factor for early carotid atherosclerosis in women.12 Interestingly, Kawamoto et al27 found that the metabolic syndrome is an independent risk factor for early carotid atherosclerosis in women only. On the basis of this finding, one might hypothesize that hsCRP levels and the close correlation between hsCRP and IMT progression in women might be partly explained by a higher prevalence of metabolic factors or insulin resistance.
A meta-analysis of >3440 subjects suggested that statin treatment is effective in decreasing the rate of carotid atherosclerosis progression.28 Therefore, it might be argued that a sex-specific difference in statin prescriptions could have influenced our data. However, in our investigation, statin administration was independently associated with baseline carotid IMT, but not with the progression of early atherosclerosis after adjustment for various risk factors in both sexes. Other concomitant medications, like antihypertensive and antidiabetic agents, as well as antiplatelet drugs, are known to influence IMT progression. However, these agents failed to demonstrate an independent effect on IMT progression in our study in multivariate analysis. Moreover, concomitant medication use after follow-up was comparable between men and women.
Because atheroprotective effects of HRT via different mechanisms have been described,29,30 one might argue that different serum hormone levels might explain the differences in IMT progression. However, in clinical studies, the effect of HRT on the progression of atherosclerosis is controversial. Some investigators could not find an association between HRT and atherosclerosis,31,32 whereas others described a protective effect of estrogen administration on age-related IMT progression in apparently healthy women without cardiovascular risk factors.33,34 Although women with HRT in our study had lower BMI, HbA1c levels, systolic blood pressure, and baseline carotid IMT, multiple-regression analysis including HRT failed to detect an independent association between estrogen use and IMT progression in women. Moreover, hsCRP levels in women with and without HRT therapy did not differ significantly in our study population.
In addition to sex hormone levels and differences in vascular risk factors between men and women, the vascular anatomy of the carotid arteries may also in part account for the observed sex differences in our investigation. Schulz et al35 recently reported sex differences in carotid anatomy as well as in carotid outflow and inflow areas.
Strengths and Limitations
This is the largest population-based study to date in which the relation of hsCRP to IMT progression was analyzed with respect to sex. However, some methodologic issues need to be addressed. First, complete follow-up data were available for only 70% of the baseline study population. However, because there were no significant differences between the follow-up group compared with the initially recruited group with respect to all biologic variables and risk factors, the follow-up subgroup is a valid representative sample of the overall group, and our main results should not be biased owing to the smaller size of the follow-up group. Secondly, there were several significant differences in baseline variables between men and women. Although we adjusted for these differences in the multivariate regression models, we could not fully exclude the possibility that a sex-specific impact of hsCRP on IMT progression might be biased to some degree by these baseline differences. However, because several of these differences were sex related, it seems difficult to fully account for these parameters.
Summary
In summary, in this large, prospective, and population-based study, we observed a significant interaction between hsCRPxsex and baseline IMT, even after adjustment for various other risk factors. Additionally, hsCRP was an independent predictor of early carotid atherosclerosis progression in women but not in men. In women, there was a steady increase of IMT with increasing CRP quartiles. Therefore, one might hypothesize that an elevated inflammatory response is associated with enhanced atherosclerosis development in women compared with men. However, the clinical importance of these sex differences and the role of hsCRP regarding the incidence of new vascular events must be analyzed in further dedicated and prospective studies.
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Acknowledgments |
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Disclosures
None.
Received January 3, 2007; revision received April 3, 2007; accepted April 23, 2007.
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