Published online before print March 1, 2007, doi: 10.1161/01.STR.0000260090.90508.3e
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(Stroke. 2007;38:1229.)
© 2007 American Heart Association, Inc.
Original Contributions |
High-Sensitivity C-Reactive Protein and Soluble CD40 Ligand as Indices of Inflammation and Platelet Activation in 880 Patients With Nonvalvular Atrial Fibrillation
Relationship to Stroke Risk Factors, Stroke Risk Stratification Schema, and Prognosis
From Haemostasis Thrombosis and Vascular Biology Unit (G.Y.H.L., J.V.P., E.H.), University Department of Medicine, City Hospital, Birmingham, England, UK; University of Texas Health Science Center (R.G.H.), San Antonio, Tex.
Correspondence to Professor G.Y.H. Lip, University Department of Medicine, City Hospital, Birmingham, England, UK. E-mail g.y.h.lip{at}bham.ac.uk
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Abstract |
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Background and Purpose— There is now considerable evidence that atrial fibrillation is associated with an inflammatory state. We tested the hypothesis that plasma levels of C-reactive protein (CRP; an index of inflammation) and soluble CD40 ligand (an index of platelet activation, with links to inflammation) could be related to 3 established stroke risk stratification schema (SPAF, CHADS2, and NICE), recognized stroke risk factors or other cardiovascular disease, and prognosis.
Methods— We studied 880 subjects with atrial fibrillation recruited from subjects receiving aspirin 325 mg/d (alone or combined with fixed inefficacious doses of warfarin) from the Stroke Prevention in Atrial Fibrillation (SPAF) III clinical trial. CRP and soluble CD40 ligand were measured by enzyme-linked immunosorbent assay.
Results— With respect to the SPAF III stroke risk stratification criteria, those with moderate to high risk had the highest levels of CRP (Kruskal Wallis test, P<0.001), but those with the highest risk had the lowest levels of soluble CD40 ligand (P=0.01). Similarly, CRP levels increased in a positive fashion with increasing stroke risk with respect to the CHADS2 and NICE risk stratification criteria, whereas soluble CD40 ligand levels were negatively associated with stroke risk. CRP levels were higher among those patients with raised body mass index, diabetes, hypertension, ischemic heart disease, peripheral vascular disease, and recent heart failure, but not those with thromboembolism. Patients were followed-up for a mean time of 453 (standard deviation, 229) days, and all-cause mortality (log rank test, P=0.001), and vascular events (P=0.05), but not stroke, were more common in patients with high CRP levels. Soluble CD40 ligand levels were not related to stroke, vascular events, or all-cause mortality.
Conclusion— Among atrial fibrillation patients, CRP was positively correlated to stroke risk and related to stroke risk factors and prognosis (mortality, vascular events). Soluble CD40 ligand levels were lowest in those at moderate to high risk of stroke and not related to prognosis. The use of CRP in risk stratification for atrial fibrillation merits further study.
Key Words: atrial fibrillation • C-reactive protein • soluble CD40 ligand • stroke
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Introduction |
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Atrial fibrillation (AF) is the commonest sustained cardiac rhythm disorder that has been associated with an increased mortality and morbidity from stroke and thromboembolism.1 Greater understanding of the pathophysiology of AF leading to this increased risk of thrombogenesis in AF may inform our clinical management, given that prothrombotic indices in AF may have prognostic implications2–5 and may complement clinical risk stratification for stroke and vascular events.5
Thrombosis appears to be intimately related to inflammation, and there is now considerable evidence that AF is associated with an inflammatory state.6 For example, abnormal levels of C-reactive protein (CRP) and IL-6 (both indices of inflammation) have shown to be raised in patients with nonvalvular AF, independently of other cardiovascular risk factors.7–10 The abnormal inflammatory state may "drive" the prothrombotic state in AF, which may contribute to the increased risk of thrombogenesis and, subsequently, thromboembolism.11
CD40 and CD40 ligand (CD40L or alternatively termed CD154) interactions were initially described in antigen presentation and B and T lymphocyte biology.12 The CD40–CD40L system has been implicated in the pathophysiology of atherothrombotic complications (and prognosis) in cardiovascular disease (CVD), as well as in the processes of inflammation and thrombosis.13,14 On exposure to CD40 expressing vascular cells (including endothelial cells), platelet-associated CD40L induces the expression of adhesion molecules, the release of inflammatory cytokines (eg, IL-6), and the pro-coagulant tissue factor.15,16 Surface expressed CD40L may be subsequently cleaved to generate a soluble fragment (ie, soluble CD40 ligand [sCD40L]), which retains biological activity by binding to glycoprotein IIb/IIIa and formation of platelet microparticles, as well as the induction of signaling reactions when bound to receptors.17 Like soluble P-selectin, circulating sCD40L is believed to derive predominantly from activated platelets and, hence, may reflect platelet activation.18 Increased sCD40L levels have also been found in a range of vascular diseases, such as diabetes, hypertension, and unstable angina.14,19–22 Also, sCD40L levels are higher in patients with acute cerebral ischemia.23
However, there are no data on the associates of sCD40L levels in AF, or the relationship of this marker to the risk factors associated with AF. Intuitively, because of its potential role as a marker of platelet activation and plaque dynamics, which may mediate prothrombotic dynamics during plaque development and angiogenesis, sCD40L may serve as another inflammatory marker involved in the pathophysiology of thrombogenesis and the risk of stroke or vascular events in AF.22,24
We hypothesized that plasma levels of CRP and sCD40L could be related to 3 established clinical stroke risk stratification schema (SPAF, CHADS2, and NICE), recognized stroke risk factors, or other CVD. To test these hypotheses, we measured plasma levels of CRP and sCD40L in 880 participants in the Stroke Prevention in Atrial Fibrillation (SPAF) III study and related levels to the presence of stroke risk factors and cardiovascular disease among this large AF cohort. Second, baseline plasma levels of CRP and sCD40L were analyzed for their association with the risk of subsequent stroke, vascular events, and death.
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Methods |
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All patients were participants in the SPAF III study, which was performed at 20 clinical sites in the United States and Canada between 1993 and 1997; the design and main results have been reported previously.25 Briefly, AF patients were stratified as having either a low, moderate, or high risk of stroke based on clinical and echocardiographic features found to be predictive of thromboembolic risk.
For the SPAF risk stratification criteria, high risk was used to describe those patients those with any of the high-risk criteria: (1) women older than 75 years of age; (2) systolic hypertension >160 mm Hg; (3) impaired left ventricular function (clinical heart failure within 100 days of entry or M-mode fractional shortening 
25%); or (4) previous thromboembolism. Participants without any of these 4 specific risk factors were classified as having low or moderate risk, depending on the absence or presence of hypertension, respectively. We also related CRP and sCD40L levels to the CHADS2 score and UK National Institute for Health and Clinical Excellence (NICE) AF stroke risk stratification schema (which is based on the Birmingham risk stratification schema).1,5,26 The NICE clinical risk stratification defines subjects into low, moderate, and high risk categories, and this clinical risk stratification scheme was broadly similar to CHADS2 for predicting stroke and vascular event rates.5 The CHADS2 acronym is derived from the individual stroke risk factors: congestive heart failure, hypertension, age older than 75 years, diabetes mellitus, and previous stroke or transient ischemic attack. One point was assigned for each of the risk factors, except for previous stroke or transient ischemic attack, which was assigned 2 points (hence, the subscripted "2").26 In a recent analysis, CHADS2 successfully identified primary prevention patients who were at high risk for stroke (5.3 strokes per 100 patient-years); in contrast, patients identified as high risk by other schemes (the original AF Investigators, SPAF, Framingham, ACCP risk stratification schemes) had 3.0 to 4.2 strokes per 100 patient-years.26 The CHADS2 scheme also successfully stratified a large outpatient cohort of AF patients who were not anticoagulated.27
Blood Collection and Laboratory Analysis
Blood samples were collected within 30 days of enrollment or after 3 months in the study. Blood collection materials were prepared at the Laboratory for Clinical Biochemistry Research, Department of Pathology, University of Vermont. Blood samples were drawn from an antecubital vein blood tubes with 3.8% sodium citrate, mixed by gentle inversion, and stored on melting ice. Plasma fractions were separated by centrifugation at 4°C for 30,000g-minutes within 1 hour of collection. Aliquots were stored at –70°C until batch analysis. Our group has previously reported indices of endothelial damage and platelet activation in 1321 patients from the SPAF study,2 but for the present analysis, sufficient specimen volumes were only available for both CRP and sCD40L analysis in only 880 patients because of natural sample wastage and usage. To avoid confounding effects of anticoagulation on prognosis (stroke, vascular events), this analysis was confined to those subjects receiving aspirin 325 mg/d (alone or combined with fixed inefficacious doses of warfarin). There were no significant differences in the demography of patients in this substudy, compared with those in the main SPAF clinical trial.2
Measurement of sCD40L levels was performed by 2-site enzyme-linked immunosorbent assay, with commercially available antibodies from R&D systems. The lower limit of detection for the sCD40L assay was 0.016 ng/mL, and the intra-assay and inter-assay coefficients of variation were 7.0% and 9.6%, respectively. Plasma CRP was measured with ultra sensitive reagents from Biokit, S.A. by assay using auto analyser IL600 (Instrument Laboratories). The lower limit of sensitivity of CRP measurement was 1 µg/dL, and the inter-assay and intra-assay coefficient of variation were 8% and 5%, respectively.
Data Analysis
Data were analyzed in SPSS v11.5 (SPSS Inc) using standard and nonparametric tests as appropriate. CRP and sCD40L were of nonparametric distribution, as determined by normality plots (Kolmorov-Smirnov). Differences between patients with and without SPAF risk factors (dichotomous variables) were determined using the Mann-Whitney t test equivalent, where central tendencies were reported as medians, and variation by interquartile range. Similarly, for normally distributed variables, the t test was used, and mean 95% confidence intervals were reported. The 
2 test was used for hypothesis testing among categorical variables. Spearman rank correlation method was used to determine statistical correlations between CRP or sCD40L and age, blood pressure, etc. Multivariate linear regression was used to determine the contribution of various risk factors to the variation of log transformed CRP or sCD40L using a stepwise method. Differences between low- to high-risk groups in CRP and sCD40L were determined using the Kruskal-Wallis test. For the correlation analysis of ordinal variables, PLUM ordinal regression analysis was used, where the Cox and Snell pseudo R Square (pseudo r2) values are reported to estimate the proportion of the total variation of an ordinal response that is explained by variables included in the model.
Kaplan-Meier curves were used to estimate time-to-event models (stroke, composite vascular events, and composite death). The mean survival time (95% confidence interval) for ordinal cohorts of inflammatory indices were generated and the log rank statistic was used to determine equality of the survival distributions therein. Receiver operator characteristic curves were use to evaluate the performance of inflammatory indices, depicted by the mean area under the curve with 95% confidence interval. Risk factors (continuous data were possible) and inflammatory indices were entered into a logistic regression model to calculate the odds ratio (95% confidence interval) for independent predictors of stroke, vascular events, and composite death. P<0.05 was considered as statistically significant.
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Results |
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Levels of CRP for the 880 participants were nonparametrically distributed, with a median value of 337 mg/dL (interquartile range, 163 to 767). Levels of sCD40L were similarly nonparametrically distributed, with a median value of 2.2 ng/L (3.9 to 16.6).
Relationship to Clinical Demography and Associated Comorbidities
CRP levels were higher among females (P=0.002), as well as those patients with raised body mass index (P<0.001), diabetes (P=0.006), and history of hypertension (P=0.009). CRP was also higher among those patients with comorbidities of ischemic heart disease (P=0.002), peripheral vascular disease (P=0.015), and recent heart failure (P<0.001), but not those with thromboembolism (P=0.07). CRP levels were higher among those patients with low fractional shortening (P<0.001) and left ventricular dysfunction (P=0.01). Other differences in CRP levels according to clinical features (age, smoking status, systolic blood pressure, serum cholesterol) did not reach significance. Levels of sCD40L were only higher among patients with heart failure (P=0.042) and those aged younger than 75 years (P=0.035; Table 1).
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Among the male patients with AF, those with CVD were reasonably matched for age, body mass index, diabetes, systolic and diastolic blood pressures, and serum cholesterol, when compared with those with no CVD (P=not significant; Table 2). Smoking and the presence of hypertension was more common in the CVD group. Levels of CRP were significantly higher among men with a history of CVD (P<0.001), whereas sCD40L was lower (P=0.02; Table 2). Among women, there were no significant differences in CRP or sCD40L levels between those with and without CVD (Table 2).
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Relationship to Risk Stratification Schema
With respect to the SPAF III risk stratification criteria, those with moderate to high risk had the highest levels of CRP (Kruskal Wallis test, P<0.001), but those with the highest risk had the lowest levels of sCD40L (P=0.01; Figure 1). Patients at low risk had significantly lower CRP levels than those at moderate (P=0.002) and high risk (P<0.001), but there were no differences between the latter 2 categories (P=0.36). Similarly, sCD40L was significantly lower in patients in the high-risk group, when compared with those at moderate (P=0.04) and low risk (P=0.014), but there were no significant differences between low versus moderate groups (P=0.91). The SPAF III risk stratification is an ordinal variable, and on "ordinal regression" analysis, CRP increased in an ordinal fashion (pseudo r2=0.013, P<0.001) with stroke risk, whereas sCD40L decreased (P=0.09).
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With respect to the CHADS2 risk stratification criteria, CRP levels increased in a positive fashion with increasing CHADS2 score (Spearman r=0.147, P<0.001); those with low risk had significantly lower CRP levels than those at moderate (P=0.05) or high risk (P=0.003), with no significant difference between the moderate versus high-risk subjects (P=0.98). sCD40L levels were negatively associated with CHADS2 risk (r=–0.096, P=0.02), where those patients classified as low risk had higher levels than those deemed to be high risk (P=0.003).
With respect to the UK NICE risk stratification criteria, CRP levels increased in a positive fashion with increasing risk (P<0.001); those at low risk had significantly lower levels than those with moderate (P=0.002) or high risk (pseudo r2=0.016, P<0.001), but there were no significant differences between the moderate or high risk groups (P=0.16). Concentrations of sCD40L were also negatively associated with NICE risk strata (pseudo r2=0.007; P=0.02).
Correlations and Multivariable Regression
On univariate analysis there was a negative association between CRP and sCD40L (spearman correlation coefficient: –0.11, P=0.002). CRP was also associated positively with body mass index (0.18, P<0.001) and serum cholesterol (0.08, P=0.02), and negatively with fractional shortening (0.08, P=0.02). sCD40L was negatively associated with age (–0.08, P=0.02).
In multivariate regression analysis, excluding known diabetes and after adjusting for age, smoking habit, serum cholesterol, heart failure, previous cardiovascular morbidity (stroke, peripheral vascular disease, ischemic heart disease), and systolic blood pressure, CRP was positively associated with increasing body mass index (P<0.001), female gender (P<0.001), and diabetes (P=0.01; Table 3). On similar analysis, sCD40L was associated with age (P=0.011), diabetes (P=0.017), and smoking (P=0.004).
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Relationship to Prognosis
Patients were followed-up for a mean time of 453 (standard deviation, 229) days, and there were 28 cases of stroke (2.53% per patient year), 54 vascular events (4.90% per patient year), and a total of 34 deaths (3.02% per patient year). All-cause mortality (log rank test, P=0.001) and vascular events (P=0.05) were more common in patients with CRP within the upper tertile at baseline, but CRP levels were not associated with stroke (Figure 2). Tertiles of sCD40L levels were not related to stroke (P=0.57), vascular events (P=0.23), or all-cause mortality (P=0.9; Figure 2). A comparison of mortality across SPAF risk score groups by CRP levels is shown in Figure 3, where high (>3g/L) CRP levels were associated with higher mortality across all 3 risk strata. On a Cox proportional hazards analysis, independent predictors for stroke were age, warfarin therapy, and smoking, whereas predictors for vascular events were smoking, history of stroke, and fractional shortening (Table 4). Independent predictors for mortality were fractional shortening and CRP levels. Receiver operator characteristic curve analysis of baseline characteristics in AF patients and all-cause mortality only show CRP to be the most useful variable in this population (Table 5).
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Discussion |
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Circulating levels of CRP are associated with all risk factors associated with thromboembolic stroke, as well as adverse outcomes (mortality and vascular events, but not stroke) among patients with nonvalvular AF, whereas sCD40L is a poor marker of increased risk. The implication is that CRP concentrations may provide insight into the increased cardiovascular risk in AF, although this may reflect the prognostic value of CRP in CVD.28 Indeed, it is unlikely that either of these markers are sensitive to an increased stroke and thromboembolic risk from AF in the absence of conventional CVD risk factors.
Raised plasma markers of inflammation have been shown to predict increased risk of cardiovascular events in AF. While raised CRP levels have been reported previously,7,8,11 there are no data on sCD40L levels in patients with AF. The lack of consistency between these 2 markers of inflammation with cardiovascular risk factors adds further support for the view that CRP and sCD40L reflect independent information on low-level chronic inflammatory processes.24 Aggarwal et al29 have reported an increasing sCD40L gradient between peripheral arterial and ostial blood sampled from a culprit coronary artery proximal to an atherosclerotic plaque, but no differences in CRP levels. Hence, our data suggest that sCD40L may be more indicative of "symptomatic" atherosclerotic plaques, while CRP represents "pan-vascular" inflammation.29,30 Given that thrombogenesis in AF may be more coagulation factor-related, rather than platelet-related, the more limited relationship of sCD40L to stroke risk in AF seems plausible. Our previous analysis also suggested that soluble P-selectin, a marker of platelet activation, was more related to atherosclerosis risk factors, and was not prognostically related to stroke or vascular events.2,31
CRP was comprehensively related to excessive CVD risk, mortality, and vascular events in these AF patients, and our findings support a risk stratification role of CRP in AF. Of note, CRP is well-recognized to predict adverse outcomes in many studies of healthy subjects and those with vascular disease.28,32,33 Current guidelines also suggest measuring high-sensitivity CRP as an aid to coronary risk assessment in adults without CVD.34 A linear relationship between stroke risk factors and CRP levels has been reported in small studies.35,36 While levels of CRP were similar in this larger population of AF patients, the relation between increasing risk and CRP diminishes in high-risk individuals. The reason for this disparity at high CRP concentrations is likely to relate to other acute inflammatory conditions that are associated with the development of AF, such as pericarditis.37 With respect to AF, CRP has already been associated with its incidence6 and the propensity to its persistence and recurrence.38,39 The cardiovascular basis for raised CRP may relate to oxidative injury40 that perpetuates contractile dysfunction, as well as cardiac41 and electrical42 remodeling in AF.
This study is limited by its reliance on a clinical trial cohort, and the results may not be generalizable to the general AF population. Also, Roldan et al43 reported high levels of IL-6 in AF, but this appears to be more related to clinical variables of the patients rather than to the presence of AF per se. Thus, the inflammatory state in AF may simply reflect associated vascular disease in AF, as implied by the associations to many vascular risk factors in the present study. Drug therapies that influence inflammation (eg, statins, angiotensin-converting enzyme inhibitors, etc) may also influence AF, as reviewed in detail by Boos et al,6 and our follow-up analysis cannot fully account for all possible confounders from multiple changes in these drugs (and doses) over the follow-up period.
In conclusion, among AF patients, CRP was positively correlated to stroke risk and related to stroke risk factors and prognosis (mortality, vascular events), with the highest CRP levels seen among those at moderate to high risk for stroke. Relationships were less clear with sCD40L, perhaps reflecting the more limited role of platelet activation in thrombogenesis in AF.31 The use of CRP in risk stratification for AF merits further study.
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Acknowledgments |
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The SPAF-III investigators are listed in reference.25 We thank Drs Dwayne Conway and Bernard Chin for help with data collection.
Sources of Funding
The authors acknowledge the support of the Dowager Countess Eleanor Peel Trust and the Sandwell & West Birmingham Hospitals NHS Trust Research and Development program.
Disclosures
None.
Received October 18, 2006; accepted November 23, 2006.
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References |
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