- Email: [email protected]
Relation of C-reactive protein correlates with risk of thromboembolism in patients with atrial fibrillation
Relation of C-Reactive Protein Correlates With Risk of Thromboembolism in Patients With Atrial Fibrillation Senthil K. Thambidorai, MD, Kapil Parakh, MD, David O. Martin, MD, MPH, Tushar K. Shah, MD, Oussama Wazni, MD, Susan E. Jasper, BSN, David R. Van Wagoner, PhD, Mina K. Chung, MD, R. Daniel Murray, PhD, and Allan L. Klein, MD The relation between C-reactive protein, an inflammatory marker, and thromboembolic risk factors was investigated in 104 patients with atrial fibrillation. Tranesophageal echocardiography identified patients who had thromboembolic risk factors with greater C-reactive protein levels than those without (1.00 vs 0.302 mg/dl). C-reactive protein also correlated with clinical stroke risk factors. Increased C-reactive protein levels were also independently associated with transesophageal echocardiographic thromboembolic risk factors. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;94:805– 807)
trial fibrillation (AF), the most common sustained arrhythmia in clinical practice, is associated with A an increased risk for stroke. Increased C-reactive 1
protein (CRP), a marker for inflammation, is also associated with an increased risk for stroke and has been shown to be an independent predictor of the incidence of stroke.2,3 CRP is increased in patients with AF compared with controls4,5 and has recently been suggested as an independent predictor of the future development of AF.6 However, the relation between the inflammatory burden, as estimated by CRP, and thromboembolic risk in patients with AF has not previously been established. A greater risk for thromboembolism in patients with AF can be estimated by clinical characteristics7 and findings of left atrial (LA) thrombus, spontaneous echo contrast, or aortic atheroma by transesophageal echocardiography (TEE).8 We investigated the relation between CRP and thromboembolic risk factors in patients with AF. •••
The study patients were identified from a clinical registry of patients who underwent TEE at The Cleveland Clinic Foundation from January 2000 to May 2002. Eligible patients were those with AF with a duration ⬎2 days who had a TEE and had ultrasensitive CRP levels measured ⱕ1 week after TEE. Patients with rheumatoid arthritis or any infection were excluded. Patients who underwent surgery or had From the Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio. Dr. Klein’s address is: Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk F-15, Cleveland, Ohio 44195. E-mail: [email protected]. Manuscript received March 11, 2004; revised manuscript received and accepted June 7, 2004. ©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 94 September 15, 2004
acute coronary syndromes ⱕ60 days before CRP collection were also excluded. A cardiologist blinded to the CRP results reviewed the TEE studies. TEE thromboembolic risk was defined as the presence of a LA abnormality: (1) LA or LA appendage (LAA) thrombus, (2) LA or LAA severe spontaneous echo contrast, or (3) LAA peak emptying velocity ⱕ20 cm/s or complex aortic atheroma (⬎4 mm with mobile or protruding components).8 Mild spontaneous echo contrast was defined as being present if dynamic intracavitary microechos were seen only with high gain, whereas severe spontaneous echo contrast was present if spontaneous contrast was noted with low gain.9 LAA velocities were measured at end-diastole and averaged over 3 to 6 cardiac cycles. LAA shear rate was calculated as (2 ⫻ LAA peak velocity)/(LAA diameter/2).10 Chart review was done by a physician blinded to the CRP results to obtain information on demographics and clinical features, including hypertension, diabetes mellitus, previous thromboembolism, history of coronary artery disease, hypercholesterolemia, duration of AF (persistent AF defined as ⬎30 days in duration), the presence of structural heart disease, and medication use. According to the Stroke Prevention in Atrial Fibrillation (SPAF) risk criteria,7 high clinical risk was defined as a history of hypertension plus age ⬎75 years, systolic blood pressure ⬎160 mm Hg alone, previous thromboembolism (stroke, transient ischemic attack, or peripheral embolism) alone or women ⬎75 years. Moderate risk was defined as a history of hypertension plus age ⱕ75 years or diabetes mellitus. Low risk was defined as none of these features. CRP level was measured using an immunonephelometric assay according to the manufacturer’s instructions with reagents and instruments obtained from Beckman Coulter (Brea, California).11 The Cleveland Clinic Foundation institutional review board approved this study. Because the distribution of CRP was skewed to the right, univariate analysis was done using nonparametric tests, and log transformation of CRP was done for multivariate analysis. Comparison between groups was performed using the Mann-Whitney U statistic test or the Kruskal-Wallis test. To account for covariate imbalance, analysis of covariance was done using log-transformed CRP as the dependent variable. A p value of ⬍0.05 was considered statistically significant. Receiver-operator curves were plotted for the predictive value of CRP for TEE thromboembolic risk. All analyses were performed using SPSS 10.0 0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2004.06.011
805
Patients with TEE thromboembolic risk factors (n ⫽ 27), including CRP (mg/dl) those with thrombi by TEE (n ⫽ 7), had a significantly greater median Variable ⫹ O p Value CRP compared with those without Men 0.59 (0.39–1.12) 0.31 (0.097–0.79) 0.007 (1.00 [interquartile range 0.67 to Systemic hypertension 0.48 (0.30–1.09) 0.22 (0.076–0.72) 0.001 2.00] vs 0.302 [interquartile range Diabetes mellitus 0.67 (0.40–1.22) 0.36 (0.13–0.84) 0.130 0.097 to 0.57] mg/dl, p ⬍0.001). AlPrevious thromboembolism* 0.82 (0.16–3.55) 0.40 (0.13–0.83) 0.317 Coronary artery disease 0.78 (0.42–3.13) 0.28 (0.10–0.58) ⬍0.001 though greater CRP levels were Hypercholesterolemia† 0.42 (0.21–0.80) 0.41 (0.11–1.00) 0.633 found in patients with a history of ‡ Chronic AF 0.43 (0.21–1.00) 0.28 (0.098–0.72) 0.167 thromboembolism, they were not staStructural heart disease 0.67 (0.33–1.35) 0.21 (0.079–0.42) ⬍0.001 tistically significant. Figure 1 shows LA dilation 0.43 (0.19–0.89) 0.37 (0.12–0.82) 0.630 Severe mitral regurgitation 1.32 (0.59–1.71) 0.37 (0.13–0.84) 0.008 that patients with LA abnormalities (3⫹, 4⫹) (p ⬍0.001) or patients with aortic atheroma (p ⫽ 0.024) had signifiCRP represented as median (25th to 75th percentiles). *Previous stroke or transient ischemic attack or peripheral embolism. cantly elevated CRP compared with † Total cholesterol ⬎200 mg/dl and/or therapy for hypercholesterolemia. those without TEE risk factors. A ‡ AF ⬎30 days in duration. CRP value of 0.5 mg/dl yielded 82% sensitivity and 72% specificity for detecting TEE risk factors (area under curve 0.803, p ⬍0.001). CRP levels were elevated in proportion to the increased risk for stroke, as established by SPAF criteria (low risk 0.21 [0.082 to 0.68] vs intermediate risk 0.47 [0.27 to 0.76] vs high risk 1.21 [0.34 to 4.34] mg/dl, p ⫽ 0.001) (Figure 2). In multivariate analysis of covariance, which included age, gender, and clinical and echocardiographic characteristics, increased CRP levels were independently associated with the presence of coronary artery disease (mean CRP difference 0.410, 95% confidence interval 0.146 to 0.839, p ⬍0.001), lower LAA shear rate (p ⫽ 0.001), and the presence of TEE thromboembolic risk factors (mean CRP difference 0.316, 95% confidence interval 0.038 to 0.810, p ⫽ 0.02).
TABLE 1 Univariate Analysis of Baseline Characteristics and CRP Levels
•••
FIGURE 1. The correlation of CRP with TEE risk factors. Upper and lower limits represent 75th and 25th percentiles, respectively. Middle line indicates medians. A LA abnormality was defined as the presence of LA thrombus or severe spontaneous echo contrast or LAA peak emptying velocity <20 cm/s. Patients with LA abnormalities (thrombi) and complex aortic atheroma (n ⴝ 3, median CRP 4.26 mg/dl) were excluded, and the groups are mutually exclusive.
statistical software (SPSS, Inc., Chicago, Illinois). CRP was reported as median values with interquartile ranges (25th to 75th percentiles). The study population included 104 patients. Patient characteristics associated with elevated CRP levels are listed in Table 1. Of note, male patients and patients with hypertension, coronary artery disease, structural heart disease, or severe mitral regurgitation had significantly greater CRP levels compared with those without. Age (r ⫽ 0.392, p ⬍0.001), left ventricular ejection fraction (r ⫽ ⫺0.282, p ⫽ 0.004), LAA area (r ⫽ 0.302, p ⫽ 0.004), LAA peak emptying velocity (r ⫽ ⫺0.313, p ⫽ 0.003), and LAA shear rate (r ⫽ ⫺0.448, p ⬍0.001) were correlated with elevated CRP levels. 806 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 94
This is the first study to demonstrate the relation of CRP with the anatomic (LA thrombus, severe spontaneous echo contrast, and aortic atheroma) and physiologic (low LAA shear rate) surrogates of thromboembolism in patients with AF. CRP was associated with SPAF clinical risk factors for thromboembolism. It has also been associated with the presence4,5 and, more recently, with the future development of AF.6 Recently, there has been an increasing interest in the inflammatory mechanism of thromboembolism. This has prompted many studies linking inflammatory markers with specific thromboembolic events. Previous studies have reported increased CRP to be associated with deep vein thrombosis,12 elevated D-dimer in patients with ischemic heart disease,13 elevated D-dimer in patients with ischemic stroke,14 and elevated D-dimer in patients with AF.15 We now observe that in patients with AF, the presence of TEE thromboembolic risk factors (LA abnormality or aortic atheroma) correlates with the extent of CRP elevation. Although this study does not imply a causal relation, the association of CRP with LA abnormalities (thrombus, severe spontaneous echo contrast, and small LAA velocities) is novel. CRP may have a direct role in the production of a thromboembolic milieu in the atria. Severe mitral regurgitation was SEPTEMBER 15, 2004
are comparable to the largest quartile of CRP in the Framingham Study.3 This is not surprising, considering that this subgroup of patients were at high risk for stroke. Due to CRP being associated with the occurrence of future stroke,3 correlation with SPAF risk stratification was also expected. 1. Hart RG, Halperin JL. Atrial fibrillation and stroke: concepts and controver-
sies. Stroke 2001;32:803– 808. 2. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflamma-
FIGURE 2. The correlation of CRP with clinical risk for stroke using SPAF criteria. Upper and lower limits represent 75th and 25th percentiles, respectively. Middle line indicates medians.
associated with greater CRP levels but less incidence of LAA thrombus. Higher CRP levels in this subgroup reflect the inflammatory process and greater thrombogenic potential, but the smaller number of LAA thrombi reflects the “washing” mechanism of severe mitral regurgitation, preventing thrombus formation despite the risk. CRP can modify the procoagulant activity of inflammatory cells12 and, more important, can induce inflammatory cells to synthesize tissue factor.13 Tissue factor is a major regulator of thrombosis and has recently been suggested as an important mediator responsible for thrombotic complications associated in the presence of clinical risk factors.14 CRP, which is associated with the persistence of AF,4 could function as a link between clinical risk factors and increased tissue factor synthesis, resulting in a thromboembolic milieu, but this mechanism cannot be conclusively established from our study. The association of CRP with atherosclerosis has also been reported previously, with CRP involved in the recruitment of inflammatory cells15 and in the low-density lipoprotein uptake16 in the vascular endothelium. CRP levels in our study are comparable to previously reported levels of CRP in AF.4 CRP levels in the presence of TEE risk factors (approximately 1 mg/dl)
tion, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973–979. 3. Rost NS, Wolf PA, Kase CS, Kelly-Hayes M, Silbershatz H, Massaro JM, D’Agostino RB, Franzblau C, Wilson PW. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham Study. Stroke 2001;32:2575–2579. 4. Chung MK, Martin DO, Sprecher D, Wazni O, Kanderian A, Carnes CA, Bauer JA, Tchou PJ, Niebauer MJ, Natale A, et al. C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation. Circulation 2001;104:2886 –2891. 5. Dernellis J, Panaretou M. C-reactive protein and paroxysmal atrial fibrillation: evidence of the implication of an inflammatory process in paroxysmal atrial fibrillation. Acta Cardiol 2001;56:375–380. 6. Aviles RJ, Martin DO, Apperson-Hansen C, Houghtaling PL, Rautaharju P, Kronmal RA, Tracy RP, Van Wagoner DR, Psaty BM, Lauer MS, et al. Inflammation as a risk factor for atrial fibrillation. Circulation 2003;108:3006 –3010. 7. Hart RG, Pearce LA, McBride R, Rothbart RM, Asinger RW. Factors associated with ischemic strike during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III clinical trials. The Stroke Prevention in Atrial Fibrillation (SPAF) Investigators. Stroke 1999;30:1223–1229. 8. Zabalgoitia M, Halperin JL, Pearce LA, Blackshear JL, Asinger RW, Hart RG. Transesophageal echocardiographic correlates of clinical risk of thromboembolism in nonvalvular atrial fibrillation. Stroke Prevention in Atrial Fibrillation III Investigators. J Am Coll Cardiol 1998;31:1622–1626. 9. Beppu S, Nimura Y, Sakakibara H, Nagata S, Park YD, Izumi S. Smoke-like echo in the left atrial cavity in mitral valve disease: its features and significance. J Am Coll Cardiol 1985;6:744 –749. 10. Grimm RA, Stewart WJ, Arheart K, Thomas JD, Klein AL. Left atrial appendage “stunning” after electrical cardioversion of atrial flutter: an attenuated response compared with atrial fibrillation as the mechanism for lower susceptibility to thromboembolic events. J Am Coll Cardiol 1997;29:582–589. 11. Rifai N, Tracy RP, Ridker PM. Clinical efficacy of an automated highsensitivity C-reactive protein assay. Clin Chem 1999;45:2136 –2141. 12. Whisler RL, Proctor VK, Downs EC, Mortensen RF. Modulation of human monocyte chemotaxis and procoagulant activity by human C-reactive protein (CRP). Lymphokine Res 1986;5:223–228. 13. Cermak J, Key NS, Bach RR, Balla J, Jacob HS, Vercellotti GM. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood 1993;82:513–520. 14. Sambola A, Osende J, Hathcock J, Degen M, Nemerson Y, Fuster V, Crandall J, Badimon JJ. Role of risk factors in the modulation of tissue factor activity and blood thrombogenicity. Circulation 2003;107:973–977. 15. Torzewski M, Rist C, Mortensen RF, Zwaka TP, Bienek M, Waltenberger J, Koenig W, Schmitz G, Hombach V, Torzewski J. C-reactive protein in the arterial intima: role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis. Arterioscler Thromb Vasc Biol 2000;20:2094 –2099. 16. Zwaka TP, Hombach V, Torzewski J. C-reactive protein-mediated low density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation 2001;103:1194 –1197.
BRIEF REPORTS
807
trial fibrillation (AF), the most common sustained arrhythmia in clinical practice, is associated with A an increased risk for stroke. Increased C-reactive 1
protein (CRP), a marker for inflammation, is also associated with an increased risk for stroke and has been shown to be an independent predictor of the incidence of stroke.2,3 CRP is increased in patients with AF compared with controls4,5 and has recently been suggested as an independent predictor of the future development of AF.6 However, the relation between the inflammatory burden, as estimated by CRP, and thromboembolic risk in patients with AF has not previously been established. A greater risk for thromboembolism in patients with AF can be estimated by clinical characteristics7 and findings of left atrial (LA) thrombus, spontaneous echo contrast, or aortic atheroma by transesophageal echocardiography (TEE).8 We investigated the relation between CRP and thromboembolic risk factors in patients with AF. •••
The study patients were identified from a clinical registry of patients who underwent TEE at The Cleveland Clinic Foundation from January 2000 to May 2002. Eligible patients were those with AF with a duration ⬎2 days who had a TEE and had ultrasensitive CRP levels measured ⱕ1 week after TEE. Patients with rheumatoid arthritis or any infection were excluded. Patients who underwent surgery or had From the Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio. Dr. Klein’s address is: Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk F-15, Cleveland, Ohio 44195. E-mail: [email protected]. Manuscript received March 11, 2004; revised manuscript received and accepted June 7, 2004. ©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 94 September 15, 2004
acute coronary syndromes ⱕ60 days before CRP collection were also excluded. A cardiologist blinded to the CRP results reviewed the TEE studies. TEE thromboembolic risk was defined as the presence of a LA abnormality: (1) LA or LA appendage (LAA) thrombus, (2) LA or LAA severe spontaneous echo contrast, or (3) LAA peak emptying velocity ⱕ20 cm/s or complex aortic atheroma (⬎4 mm with mobile or protruding components).8 Mild spontaneous echo contrast was defined as being present if dynamic intracavitary microechos were seen only with high gain, whereas severe spontaneous echo contrast was present if spontaneous contrast was noted with low gain.9 LAA velocities were measured at end-diastole and averaged over 3 to 6 cardiac cycles. LAA shear rate was calculated as (2 ⫻ LAA peak velocity)/(LAA diameter/2).10 Chart review was done by a physician blinded to the CRP results to obtain information on demographics and clinical features, including hypertension, diabetes mellitus, previous thromboembolism, history of coronary artery disease, hypercholesterolemia, duration of AF (persistent AF defined as ⬎30 days in duration), the presence of structural heart disease, and medication use. According to the Stroke Prevention in Atrial Fibrillation (SPAF) risk criteria,7 high clinical risk was defined as a history of hypertension plus age ⬎75 years, systolic blood pressure ⬎160 mm Hg alone, previous thromboembolism (stroke, transient ischemic attack, or peripheral embolism) alone or women ⬎75 years. Moderate risk was defined as a history of hypertension plus age ⱕ75 years or diabetes mellitus. Low risk was defined as none of these features. CRP level was measured using an immunonephelometric assay according to the manufacturer’s instructions with reagents and instruments obtained from Beckman Coulter (Brea, California).11 The Cleveland Clinic Foundation institutional review board approved this study. Because the distribution of CRP was skewed to the right, univariate analysis was done using nonparametric tests, and log transformation of CRP was done for multivariate analysis. Comparison between groups was performed using the Mann-Whitney U statistic test or the Kruskal-Wallis test. To account for covariate imbalance, analysis of covariance was done using log-transformed CRP as the dependent variable. A p value of ⬍0.05 was considered statistically significant. Receiver-operator curves were plotted for the predictive value of CRP for TEE thromboembolic risk. All analyses were performed using SPSS 10.0 0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2004.06.011
805
Patients with TEE thromboembolic risk factors (n ⫽ 27), including CRP (mg/dl) those with thrombi by TEE (n ⫽ 7), had a significantly greater median Variable ⫹ O p Value CRP compared with those without Men 0.59 (0.39–1.12) 0.31 (0.097–0.79) 0.007 (1.00 [interquartile range 0.67 to Systemic hypertension 0.48 (0.30–1.09) 0.22 (0.076–0.72) 0.001 2.00] vs 0.302 [interquartile range Diabetes mellitus 0.67 (0.40–1.22) 0.36 (0.13–0.84) 0.130 0.097 to 0.57] mg/dl, p ⬍0.001). AlPrevious thromboembolism* 0.82 (0.16–3.55) 0.40 (0.13–0.83) 0.317 Coronary artery disease 0.78 (0.42–3.13) 0.28 (0.10–0.58) ⬍0.001 though greater CRP levels were Hypercholesterolemia† 0.42 (0.21–0.80) 0.41 (0.11–1.00) 0.633 found in patients with a history of ‡ Chronic AF 0.43 (0.21–1.00) 0.28 (0.098–0.72) 0.167 thromboembolism, they were not staStructural heart disease 0.67 (0.33–1.35) 0.21 (0.079–0.42) ⬍0.001 tistically significant. Figure 1 shows LA dilation 0.43 (0.19–0.89) 0.37 (0.12–0.82) 0.630 Severe mitral regurgitation 1.32 (0.59–1.71) 0.37 (0.13–0.84) 0.008 that patients with LA abnormalities (3⫹, 4⫹) (p ⬍0.001) or patients with aortic atheroma (p ⫽ 0.024) had signifiCRP represented as median (25th to 75th percentiles). *Previous stroke or transient ischemic attack or peripheral embolism. cantly elevated CRP compared with † Total cholesterol ⬎200 mg/dl and/or therapy for hypercholesterolemia. those without TEE risk factors. A ‡ AF ⬎30 days in duration. CRP value of 0.5 mg/dl yielded 82% sensitivity and 72% specificity for detecting TEE risk factors (area under curve 0.803, p ⬍0.001). CRP levels were elevated in proportion to the increased risk for stroke, as established by SPAF criteria (low risk 0.21 [0.082 to 0.68] vs intermediate risk 0.47 [0.27 to 0.76] vs high risk 1.21 [0.34 to 4.34] mg/dl, p ⫽ 0.001) (Figure 2). In multivariate analysis of covariance, which included age, gender, and clinical and echocardiographic characteristics, increased CRP levels were independently associated with the presence of coronary artery disease (mean CRP difference 0.410, 95% confidence interval 0.146 to 0.839, p ⬍0.001), lower LAA shear rate (p ⫽ 0.001), and the presence of TEE thromboembolic risk factors (mean CRP difference 0.316, 95% confidence interval 0.038 to 0.810, p ⫽ 0.02).
TABLE 1 Univariate Analysis of Baseline Characteristics and CRP Levels
•••
FIGURE 1. The correlation of CRP with TEE risk factors. Upper and lower limits represent 75th and 25th percentiles, respectively. Middle line indicates medians. A LA abnormality was defined as the presence of LA thrombus or severe spontaneous echo contrast or LAA peak emptying velocity <20 cm/s. Patients with LA abnormalities (thrombi) and complex aortic atheroma (n ⴝ 3, median CRP 4.26 mg/dl) were excluded, and the groups are mutually exclusive.
statistical software (SPSS, Inc., Chicago, Illinois). CRP was reported as median values with interquartile ranges (25th to 75th percentiles). The study population included 104 patients. Patient characteristics associated with elevated CRP levels are listed in Table 1. Of note, male patients and patients with hypertension, coronary artery disease, structural heart disease, or severe mitral regurgitation had significantly greater CRP levels compared with those without. Age (r ⫽ 0.392, p ⬍0.001), left ventricular ejection fraction (r ⫽ ⫺0.282, p ⫽ 0.004), LAA area (r ⫽ 0.302, p ⫽ 0.004), LAA peak emptying velocity (r ⫽ ⫺0.313, p ⫽ 0.003), and LAA shear rate (r ⫽ ⫺0.448, p ⬍0.001) were correlated with elevated CRP levels. 806 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 94
This is the first study to demonstrate the relation of CRP with the anatomic (LA thrombus, severe spontaneous echo contrast, and aortic atheroma) and physiologic (low LAA shear rate) surrogates of thromboembolism in patients with AF. CRP was associated with SPAF clinical risk factors for thromboembolism. It has also been associated with the presence4,5 and, more recently, with the future development of AF.6 Recently, there has been an increasing interest in the inflammatory mechanism of thromboembolism. This has prompted many studies linking inflammatory markers with specific thromboembolic events. Previous studies have reported increased CRP to be associated with deep vein thrombosis,12 elevated D-dimer in patients with ischemic heart disease,13 elevated D-dimer in patients with ischemic stroke,14 and elevated D-dimer in patients with AF.15 We now observe that in patients with AF, the presence of TEE thromboembolic risk factors (LA abnormality or aortic atheroma) correlates with the extent of CRP elevation. Although this study does not imply a causal relation, the association of CRP with LA abnormalities (thrombus, severe spontaneous echo contrast, and small LAA velocities) is novel. CRP may have a direct role in the production of a thromboembolic milieu in the atria. Severe mitral regurgitation was SEPTEMBER 15, 2004
are comparable to the largest quartile of CRP in the Framingham Study.3 This is not surprising, considering that this subgroup of patients were at high risk for stroke. Due to CRP being associated with the occurrence of future stroke,3 correlation with SPAF risk stratification was also expected. 1. Hart RG, Halperin JL. Atrial fibrillation and stroke: concepts and controver-
sies. Stroke 2001;32:803– 808. 2. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflamma-
FIGURE 2. The correlation of CRP with clinical risk for stroke using SPAF criteria. Upper and lower limits represent 75th and 25th percentiles, respectively. Middle line indicates medians.
associated with greater CRP levels but less incidence of LAA thrombus. Higher CRP levels in this subgroup reflect the inflammatory process and greater thrombogenic potential, but the smaller number of LAA thrombi reflects the “washing” mechanism of severe mitral regurgitation, preventing thrombus formation despite the risk. CRP can modify the procoagulant activity of inflammatory cells12 and, more important, can induce inflammatory cells to synthesize tissue factor.13 Tissue factor is a major regulator of thrombosis and has recently been suggested as an important mediator responsible for thrombotic complications associated in the presence of clinical risk factors.14 CRP, which is associated with the persistence of AF,4 could function as a link between clinical risk factors and increased tissue factor synthesis, resulting in a thromboembolic milieu, but this mechanism cannot be conclusively established from our study. The association of CRP with atherosclerosis has also been reported previously, with CRP involved in the recruitment of inflammatory cells15 and in the low-density lipoprotein uptake16 in the vascular endothelium. CRP levels in our study are comparable to previously reported levels of CRP in AF.4 CRP levels in the presence of TEE risk factors (approximately 1 mg/dl)
tion, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973–979. 3. Rost NS, Wolf PA, Kase CS, Kelly-Hayes M, Silbershatz H, Massaro JM, D’Agostino RB, Franzblau C, Wilson PW. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham Study. Stroke 2001;32:2575–2579. 4. Chung MK, Martin DO, Sprecher D, Wazni O, Kanderian A, Carnes CA, Bauer JA, Tchou PJ, Niebauer MJ, Natale A, et al. C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation. Circulation 2001;104:2886 –2891. 5. Dernellis J, Panaretou M. C-reactive protein and paroxysmal atrial fibrillation: evidence of the implication of an inflammatory process in paroxysmal atrial fibrillation. Acta Cardiol 2001;56:375–380. 6. Aviles RJ, Martin DO, Apperson-Hansen C, Houghtaling PL, Rautaharju P, Kronmal RA, Tracy RP, Van Wagoner DR, Psaty BM, Lauer MS, et al. Inflammation as a risk factor for atrial fibrillation. Circulation 2003;108:3006 –3010. 7. Hart RG, Pearce LA, McBride R, Rothbart RM, Asinger RW. Factors associated with ischemic strike during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III clinical trials. The Stroke Prevention in Atrial Fibrillation (SPAF) Investigators. Stroke 1999;30:1223–1229. 8. Zabalgoitia M, Halperin JL, Pearce LA, Blackshear JL, Asinger RW, Hart RG. Transesophageal echocardiographic correlates of clinical risk of thromboembolism in nonvalvular atrial fibrillation. Stroke Prevention in Atrial Fibrillation III Investigators. J Am Coll Cardiol 1998;31:1622–1626. 9. Beppu S, Nimura Y, Sakakibara H, Nagata S, Park YD, Izumi S. Smoke-like echo in the left atrial cavity in mitral valve disease: its features and significance. J Am Coll Cardiol 1985;6:744 –749. 10. Grimm RA, Stewart WJ, Arheart K, Thomas JD, Klein AL. Left atrial appendage “stunning” after electrical cardioversion of atrial flutter: an attenuated response compared with atrial fibrillation as the mechanism for lower susceptibility to thromboembolic events. J Am Coll Cardiol 1997;29:582–589. 11. Rifai N, Tracy RP, Ridker PM. Clinical efficacy of an automated highsensitivity C-reactive protein assay. Clin Chem 1999;45:2136 –2141. 12. Whisler RL, Proctor VK, Downs EC, Mortensen RF. Modulation of human monocyte chemotaxis and procoagulant activity by human C-reactive protein (CRP). Lymphokine Res 1986;5:223–228. 13. Cermak J, Key NS, Bach RR, Balla J, Jacob HS, Vercellotti GM. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood 1993;82:513–520. 14. Sambola A, Osende J, Hathcock J, Degen M, Nemerson Y, Fuster V, Crandall J, Badimon JJ. Role of risk factors in the modulation of tissue factor activity and blood thrombogenicity. Circulation 2003;107:973–977. 15. Torzewski M, Rist C, Mortensen RF, Zwaka TP, Bienek M, Waltenberger J, Koenig W, Schmitz G, Hombach V, Torzewski J. C-reactive protein in the arterial intima: role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis. Arterioscler Thromb Vasc Biol 2000;20:2094 –2099. 16. Zwaka TP, Hombach V, Torzewski J. C-reactive protein-mediated low density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation 2001;103:1194 –1197.
BRIEF REPORTS
807