Canadian Journal of Cardiology 30 (2014) 1415e1421
Clinical Research
Serum Uric Acid and Risk of Left Atrial Thrombus in Patients With Nonvalvular Atrial Fibrillation Ri-Bo Tang, MD, Jian-Zeng Dong, MD, Xian-Liang Yan, MD, Xin Du, MD, Jun-Ping Kang, MD, Jia-Hui Wu, MD, Rong-Hui Yu, MD, De-Yong Long, MD, Man Ning, MD, Cai-Hua Sang, MD, Chen-Xi Jiang, MD, Mohamed Salim, MD, Rong Bai, MD, Yan Yao, MD, and Chang-Sheng Ma, MD Department of Cardiology, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China
See editorial by Stanley Nattel, pages 1259-1261 of this issue. ABSTRACT
RESUM E
Background: Serum uric acid (SUA) is a simple and independent marker of morbidity and mortality in a variety of cardiovascular diseases. In this study we aimed to investigate SUA and the risk of left atrial (LA) thrombus in patients with nonvalvular atrial fibrillation (AF). Methods: In this retrospective study, 1359 consecutive patients undergoing transesophageal echocardiography before catheter ablation of AF were enrolled. Sixty-one of the 1359 patients (4.5%) had LA thrombus. Results: SUA levels in patients with LA thrombus were significantly greater (413.5 98.8 mmol/L vs 366.7 94.3 mmol/L; P < 0.001). Hyperuricemia was defined as SUA 359.8 mmol/L in women and 445.6 mmol/L in men determined according to receiver operating characteristic curve. The incidence of LA thrombus was significantly greater in patients with hyperuricemia than in those with a normal SUA level in women (12.1% vs 1.9%; P < 0.001) and in men (8.5% vs 2.8%;
rique (AUS) est un marqueur simple et Introduction : L’acide urique se pendant de la morbidite et de la mortalite des nombreuses mainde tude, l’objectif e tait d’examiner ladies cardiovasculaires. Dans cette e l’AUS et le risque de thrombus de l’oreillette gauche (OG) chez les patients souffrant de fibrillation auriculaire (FA) non valvulaire. thodes : Dans cette e tude re trospective, 1359 patients conse cutifs Me chocardiographie transœsophagienne avant l’ablation subissant une e ter de la FA ont e te inscrits. Soixante-et-un (61) des 1359 par cathe patients (4,5 %) avaient un thrombus de l’OD. sultats : Les concentrations se riques de l’acide urique chez les Re taient significativement plus patients ayant un thrombus de l’OD e grandes (413,5 98,8 mmol/l vs 366,7 94,3 mmol/l; P < 0,001). mie a e te de finie par une AUS 359,8 mmol/l chez les L’hyperurice termine e femmes et une AUS 445,6 mmol/l chez les hommes de ristique d’efficacite du re cepteur. L’incidence selon la courbe caracte
Atrial fibrillation (AF) is the most common persistent heart rhythm disturbance in clinical practice. It affects more than 2 million patients in United States, over 6 million patients in Europe, and approximately 8 million patients in China.1-3 The increased incidence of AF might result in a worldwide public health crisis. AF is independently associated with a 5-fold increased risk of stroke and accounts for more than 140,000 cases of ischemic stroke per year in the United States.4,5 Left atrial (LA) thrombus is a risk factor for stroke in patients with AF. It is estimated that at least 2 thirds of stroke
in patients with nonvalvular AF occur because of LA thrombus drop-off.6 Serum uric acid (SUA) is a simple and independent marker of morbidity and mortality in a variety of cardiovascular diseases.7,8 It has been recently reported that SUA is independently associated with AF.9-13 In addition to that, SUA has been clearly associated with oxidative stress and inflammation in several pathological conditions.14,15 SUA is also an independent risk factor for thromboembolic events such as ischemic stroke and myocardial infarction.16 Because oxidative stress and inflammation is associated with thromboembolic complications,17 we hypothesized that SUA is associated with a greater risk of LA thrombus in patients with AF.
Received for publication May 8, 2014. Accepted June 11, 2014.
Methods
Corresponding author: Dr Chang-Sheng Ma, Department of Cardiology, Beijing An Zhen Hospital, Capital Medical University, Chaoyang District, Beijing, China 100029. Tel.: þ86-10-84005361; fax: þ86-10-64456078. E-mail: [email protected] See page 1420 for disclosure information.
Study population From January 2007 to June 2010, 1524 consecutive patients referred to Beijing An Zhen Hospital with refractory AF
http://dx.doi.org/10.1016/j.cjca.2014.06.009 0828-282X/Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
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Canadian Journal of Cardiology Volume 30 2014
P < 0.001). Hyperuricemia had a negative predictive value of 98.1% in women and 97.1% in men for identifying LA thrombus. Hyperuricemia was associated with significantly greater risk of LA thrombus among Congestive Heart Failure, Hypertension, Age 75 Years, Diabetes Mellitus, Stroke, Vascular Disease, Age 65 to 74 Years, Sex Category (CHA2DS2-VASc) score ¼ 0, 1, and 2 groups with odds ratios of 7.19, 4.05, and 3.25, respectively. In multivariable analysis, SUA was an independent risk factor of LA thrombus (odds ratio, 1.004; 95% confidence interval, 1.000-1.008; P ¼ 0.028). Conclusions: Hyperuricemia was a modest risk factor for LA thrombus, which might refine stratification of LA thrombus in patients with nonvalvular AF.
tait significativement plus grande chez les padu thrombus de l’OD e sentant une hyperurice mie que chez les femmes (12,1 % vs tients pre 1,9 %; P < 0,001) et chez les hommes (8,5 % vs 2,8 %; P < 0,001) tait normale. L’hyperurice mie avait une dont la concentration d’AUS e gative pre dictive du thrombus de l’OD de 98,1 % chez les valeur ne mie e tait femmes et de 97,1 % chez les hommes. L’hyperurice e à un risque significativement plus grand de thrombus de l’OD associe chez les groupes dont le score CHA2DS2-VASc (Congestive Heart Failure, Hypertension, Age 75 Years, Diabetes Mellitus, Stroke, Vascular Disease, Age 65 to 74 Years, Sex Category, soit l’insuffisance cardiaque congestive, l’hypertension, l’âge 75 ans, le diabète, l’accire bral, la maladie vasculaire, l’âge situe entre 65 et dent vasculaire ce gorie du sexe) ¼ 0, 1 et 2 montrait respectivement 74 ans, la cate s de 7,19, 4,05 et 3,25. Dans l’analyse des ratios d’incidence approche e, l’AUS e tait un facteur de risque inde pendant de thrombus multivarie , 1,004; intervalle de confiance à de l’OD (ratio d’incidence approche 95 %, 1,000-1,008; P ¼ 0,028). mie e tait un facteur de risque modeste de Conclusions : L’hyperurice thrombus de l’OD qui affinerait la stratification de thrombus de l’OD chez les patients souffrant d’une FA non valvulaire.
underwent transesophageal echocardiography (TEE) before the first-time catheter ablation of AF were screened in a prospectively established database. Patients with valvular heart disease, deep venous thrombosis, pulmonary embolism, hypertrophic cardiomyopathy, and taking drugs that significantly affect SUA metabolism (ie, allopurinol, diuretics) were excluded. In total, 1359 patients were included in this retrospective study. After admission, warfarin and antiplatelet medications were discontinued, and all the patients received subcutaneous low-molecular weight heparin (enoxaparin; Sanofi-Aventis, France) twice per day as bridge therapy. Venous blood samples were obtained using sterile antecubital vein puncture after overnight fasting on the morning of first hospitalization. Laboratory data, including SUA, serum creatinine, and fibrinogen were analyzed. SUA levels were arrayed using the uricase enzymatic test (Olympus AU 5400 automatic biochemical analyzer; Olympus, Tokyo, Japan). As a measure of renal function, the baseline glomerular filtration rate (GFR) was estimated using the abbreviated Modification of Diet in Renal Disease (MDRD) study equation: GFR (mL/min/1.73 m2 of body surface area) ¼ 186 (serum creatinine in mg/dL)1.154 (age in years)0.203 ( 0.742 in female subjects).18 Paroxysmal AF was defined as recurrent AF that terminates spontaneously within 7 days according to the published guideline,2 and the other AF presentations, including persistent and long-standing AF, were categorized as nonparoxysmal AF. Stroke risk was then evaluated according to the Congestive Heart Failure, Hypertension, Age 75 Years, Diabetes Mellitus, Stroke, Vascular Disease, Age 65 to 74 Years, Sex Category (CHA2DS2-VASc) score, which was calculated as follows: 2 points were assigned for a history of stroke or transient ischemic attack, or age 75 years; and 1 point was assigned for age 65-74 years, history of hypertension, diabetes, recent cardiac failure, vascular disease, and female sex.19 This study was approved by the institutional review board and all patients provided written informed consent.
Ultrasound exam All patients underwent transthoracic echocardiography and TEE before catheter ablation of AF after admission. Before the TEE study, the procedure was explained in detail, and written informed consent was obtained. Lidocaine hydrochloride spray was routinely used for local anaesthesia; sedation or anaesthesia was not applied. TEE was performed with a 5MHz multiplane probe (Sonos 4500 or 5500; Philips Medical Systems, Andover, MA) and live images were interpreted by experienced physicians. Images of the left atrium including the LA appendage were evaluated in the horizontal plane (0 ) and in contiguous planes obtained using rotation of the imaging sector from 0 to 180 during continuous visualization of the left atrium and LA appendage. LA thrombus was defined as a well-circumscribed echogenic mass with a unique echotexture contrasting with the adjacent or underlying myocardium. The presence of spontaneous echocardiographic contrast (SEC) within the atrial blood pool, which might be seen in slow turbulent blood flow, was also characterized. Statistical analysis All analyses were performed with SPSS software version 13.0. Continuous data were presented as mean standard deviation and were compared using Student t test or 1-way analysis of variance. If variables were not in normal distribution, Mann-Whitney U test was performed. Categorical variables were compared using c2 test or Fisher exact test if necessary. The receiver operating characteristic (ROC) curve analysis was used to evaluate the efficiency of SUA in predicting LA thrombus. The optimal cutoff points for the variables predicting LA thrombus were determined according to the ROC curve. The ROC curve was constructed by plotting sensitivity vs specificity. Multivariable logistic regression was used to examine the risks of LA thrombus. We entered in the multivariable model AF type, CHA2DS2-VASc score, LA diameter, high-sensitivity C-reactive protein (hs-CRP), fibrinogen GFR, warfarin therapy, aspirin therapy, and SUA. A
Tang et al. Uric Acid and Left Atrial Thrombus
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Table 1. Characteristics of patients with and without left atrial thrombus Characteristic Age, years Male sex, n (%) Atrial fibrillation history, years Paroxysmal atrial fibrillation, n (%) Type 2 diabetes mellitus, n (%) Hypertension, n (%) Previous embolic events, n (%) Heart failure, n (%) Coronary artery disease, n (%) CHA2DS2-VASc, n (%) 0 1 2 Body mass index Left atrial diameter, mm Left ventricular end diastolic diameter, mm Left ventricular end systolic diameter, mm Ejection fraction, % Uric acid, mmol/L Creatinine, mmol/L Glomerular filtration rate, mL/min/1.73 m2 Median high-sensitivity C-reactive protein (25th percentile-75th percentile), mg/L Fibrinogen, g/L Warfarin, n (%) Aspirin, n (%)
Nonthrombus (n ¼ 1298)
Thrombus (n ¼ 61)
P
58.1 11.2 922 (71.0) 6.1 5.9 864 (66.6) 173 (13.3) 658 (50.7) 95 (7.3) 19 (1.5) 92 (7.1)
59.8 11.6 40 (65.6) 6.1 6.7 21 (34.4) 9 (14.8) 44 (72.1) 7 (11.5) 2 (3.3) 3 (4.9)
0.262 0.360 0.991 < 0.001 0.749 0.001 0.229 0.261 0.650 0.026
324 (25.0) 382 (29.4) 592 (45.6) 26.1 3.8 38.7 6.1 48.2 4.9 31.4 5.0 63.7 7.8 366.7 94.3 83.4 18.5 85.0 20.7 0.90 (0.45-1.95)
8 (13.1) 15 (24.6) 38 (62.3) 27.5 3.2 44.3 6.0 50.6 5.2 37.0 12.3 57.9 10.0 413.5 98.8 87.2 21.4 80.1 22.0 1.60 (0.77-4.03)
2.71 0.61 160 (12.3) 288 (22.2)
2.96 0.66 11 (18.0) 10 (16.4)
< < < <
97% in women and in men. Approximately 46.4% of the study population had CHA2DS2-VASc scores 2, however, only 12.6% of the study population was using anticoagulation therapy. This reflects the real world status of anticoagulation therapy for patients with AF in China. Only < 10% of patients with AF were using anticoagulation therapy.3 There is a large gap between clinical practice and the guidelines with regard to the issue of antithrombotic therapy in China. More attention has been paid to the upstream therapy for primary and secondary prevention of AF. A recent animal experiment provided evidence that allopurinol, when used as an upstream therapy, can prevent AF associated with heart failure.22 Whether allopurinol, which can decrease SUA, can serve as complementary therapy to decrease the formation of LA thrombus and prevent stroke in hyperuricemia patients with AF needs further study. There are several limitations of this study. The mechanism of SUA levels linking LA thrombus was not well explored. Fibrinogen, a prothrombotic factor, was significantly correlated with SUA in women, which might in part, explain the correlation between SUA levels and LA thrombus in women. However, more inflammatory prothrombotic factors, oxidative stress factors, and endothelial damage markers should be studied in the future. In addition to that, we did not determine if SUA is an innocent marker or a mediator of LA thrombus in patients with AF. Second, the patients in this study were referred for catheter ablation of AF. The population in this study might not reflect the general AF population.
Funding Sources This work was supported by High Levels Talent in Health in Beijing (Project 215, No. 2013-3-007), the National Science Foundation Council of China (No. 30900628, 81070147, 81241005), Beijing Natural Science Foundation (No. 7102048), Beijing Nova Program (No. 2009B32), Training Program for Excellent Talent of Beijing (2010D003034000025) and Beijing Municipal Science & Technology Commission (No.D11110700300000).
Canadian Journal of Cardiology Volume 30 2014
Disclosures The authors have no conflicts of interest to disclose. References 1. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. JAMA 2001;285:2370-5. 2. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the task force for the management of atrial fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31: 2369-429. 3. Hu D, Sun Y. Epidemiology, risk factors for stroke, and management of atrial fibrillation in China. J Am Coll Cardiol 2008;52:865-8. 4. Marini C, De Santis F, Sacco S, et al. Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a populationbased study. Stroke 2005;36:1115-9. 5. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statisticse2012 update: a report from the American Heart Association. Circulation 2012;125:e2-220. 6. Miller VT, Rothrock JF, Pearce LA, et al. Ischemic stroke in patients with atrial fibrillation: effect of aspirin according to stroke mechanism. Stroke prevention in atrial fibrillation investigators. Neurology 1993;43:32-6. 7. Bae MH, Lee JH, Lee SH, et al. Serum uric acid as an independent and incremental prognostic marker in addition to n-terminal pro-b-type natriuretic peptide in patients with acute myocardial infarction. Circ J 2011;75:1440-7. 8. Alderman M. Uric acid in hypertension and cardiovascular disease. Can J Cardiol 1999;15(suppl F):20F-2F. 9. Tamariz L, Agarwal S, Soliman EZ, et al. Association of serum uric acid with incident atrial fibrillation (from the atherosclerosis risk in communities [ARIC] study). Am J Cardiol 2011;108:1272-6. 10. Letsas KP, Korantzopoulos P, Filippatos GS, et al. Uric acid elevation in atrial fibrillation. Hellenic J Cardiol 2010;51:209-13. 11. Valbusa F, Bertolini L, Bonapace S, et al. Relation of elevated serum uric acid levels to incidence of atrial fibrillation in patients with type 2 diabetes mellitus. Am J Cardiol 2013;112:499-504. 12. Liu T, Zhang X, Korantzopoulos P, Wang S, Li G. Uric acid levels and atrial fibrillation in hypertensive patients. Intern Med 2011;50:799-803. 13. Suzuki S, Sagara K, Otsuka T, et al. Gender-specific relationship between serum uric acid level and atrial fibrillation prevalence. Circ J 2012;76: 607-11. 14. Shi Y. Caught red-handed: uric acid is an agent of inflammation. J Clin Invest 2010;120:1809-11. 15. Kanellis J, Watanabe S, Li JH, et al. Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension 2003;41:1287-93. 16. Bos MJ, Koudstaal PJ, Hofman A, Witteman JC, Breteler MM. Uric acid is a risk factor for myocardial infarction and stroke: the Rotterdam study. Stroke 2006;37:1503-7. 17. Dudley SC Jr, Hoch NE, McCann LA, et al. Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage: role of the NADPH and xanthine oxidases. Circulation 2005;112:1266-73.
Tang et al. Uric Acid and Left Atrial Thrombus 18. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in renal disease study group. Ann Intern Med 1999;130:461-70. 19. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010;137:263-72. 20. Lenaerts I, Driesen RB, Blanco NH, et al. Role of nitric oxide and oxidative stress in a sheep model of persistent atrial fibrillation. Europace 2013;15:754-60. 21. Adamsson Eryd S, Smith JG, Melander O, Hedblad B, Engstrom G. Inflammation-sensitive proteins and risk of atrial fibrillation: a population-based cohort study. Eur J Epidemiol 2011;26:449-55. 22. Sakabe M, Fujiki A, Sakamoto T, et al. Xanthine oxidase inhibition prevents atrial fibrillation in a canine model of atrial pacing-induced left ventricular dysfunction. J Cardiovasc Electrophysiol 2012;23:1130-5. 23. Lehto S, Niskanen L, Ronnemaa T, Laakso M. Serum uric acid is a strong predictor of stroke in patients with non-insulin-dependent diabetes mellitus. Stroke 1998;29:635-9.
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24. Mazza A, Pessina AC, Pavei A, et al. Predictors of stroke mortality in elderly people from the general population. The cardiovascular study in the elderly. Eur J Epidemiol 2001;17:1097-104. 25. Kim SY, Guevara JP, Kim KM, et al. Hyperuricemia and risk of stroke: a systematic review and meta-analysis. Arthritis Rheum 2009;61:885-92. 26. Chao TF, Liu CJ, Chen SJ, et al. Hyperuricemia and the risk of ischemic stroke in patients with atrial fibrillation - could it refine clinical risk stratification in AF? Int J Cardiol 2014;170:344-9. 27. Zapolski T, Wacinski P, Kondracki B, et al. Uric acid as a link between renal dysfunction and both pro-inflammatory and prothrombotic state in patients with metabolic syndrome and coronary artery disease. Kardiol Pol 2011;69:319-26. 28. Yu MA, Sanchez-Lozada LG, Johnson RJ, Kang DH. Oxidative stress with an activation of the renin-angiotensin system in human vascular endothelial cells as a novel mechanism of uric acid-induced endothelial dysfunction. J Hypertens 2010;28:1234-42. 29. Habara S, Dote K, Kato M, et al. Prediction of left atrial appendage thrombi in non-valvular atrial fibrillation. Eur Heart J 2007;28:2217-22. 30. Tang RB, Dong JZ, Liu XP, et al. Is CHA2DS2-Vasc score a predictor of left atrial thrombus in patients with paroxysmal atrial fibrillation? Thromb Haemost 2011;105:1107-9.
Clinical Research
Serum Uric Acid and Risk of Left Atrial Thrombus in Patients With Nonvalvular Atrial Fibrillation Ri-Bo Tang, MD, Jian-Zeng Dong, MD, Xian-Liang Yan, MD, Xin Du, MD, Jun-Ping Kang, MD, Jia-Hui Wu, MD, Rong-Hui Yu, MD, De-Yong Long, MD, Man Ning, MD, Cai-Hua Sang, MD, Chen-Xi Jiang, MD, Mohamed Salim, MD, Rong Bai, MD, Yan Yao, MD, and Chang-Sheng Ma, MD Department of Cardiology, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China
See editorial by Stanley Nattel, pages 1259-1261 of this issue. ABSTRACT
RESUM E
Background: Serum uric acid (SUA) is a simple and independent marker of morbidity and mortality in a variety of cardiovascular diseases. In this study we aimed to investigate SUA and the risk of left atrial (LA) thrombus in patients with nonvalvular atrial fibrillation (AF). Methods: In this retrospective study, 1359 consecutive patients undergoing transesophageal echocardiography before catheter ablation of AF were enrolled. Sixty-one of the 1359 patients (4.5%) had LA thrombus. Results: SUA levels in patients with LA thrombus were significantly greater (413.5 98.8 mmol/L vs 366.7 94.3 mmol/L; P < 0.001). Hyperuricemia was defined as SUA 359.8 mmol/L in women and 445.6 mmol/L in men determined according to receiver operating characteristic curve. The incidence of LA thrombus was significantly greater in patients with hyperuricemia than in those with a normal SUA level in women (12.1% vs 1.9%; P < 0.001) and in men (8.5% vs 2.8%;
rique (AUS) est un marqueur simple et Introduction : L’acide urique se pendant de la morbidite et de la mortalite des nombreuses mainde tude, l’objectif e tait d’examiner ladies cardiovasculaires. Dans cette e l’AUS et le risque de thrombus de l’oreillette gauche (OG) chez les patients souffrant de fibrillation auriculaire (FA) non valvulaire. thodes : Dans cette e tude re trospective, 1359 patients conse cutifs Me chocardiographie transœsophagienne avant l’ablation subissant une e ter de la FA ont e te inscrits. Soixante-et-un (61) des 1359 par cathe patients (4,5 %) avaient un thrombus de l’OD. sultats : Les concentrations se riques de l’acide urique chez les Re taient significativement plus patients ayant un thrombus de l’OD e grandes (413,5 98,8 mmol/l vs 366,7 94,3 mmol/l; P < 0,001). mie a e te de finie par une AUS 359,8 mmol/l chez les L’hyperurice termine e femmes et une AUS 445,6 mmol/l chez les hommes de ristique d’efficacite du re cepteur. L’incidence selon la courbe caracte
Atrial fibrillation (AF) is the most common persistent heart rhythm disturbance in clinical practice. It affects more than 2 million patients in United States, over 6 million patients in Europe, and approximately 8 million patients in China.1-3 The increased incidence of AF might result in a worldwide public health crisis. AF is independently associated with a 5-fold increased risk of stroke and accounts for more than 140,000 cases of ischemic stroke per year in the United States.4,5 Left atrial (LA) thrombus is a risk factor for stroke in patients with AF. It is estimated that at least 2 thirds of stroke
in patients with nonvalvular AF occur because of LA thrombus drop-off.6 Serum uric acid (SUA) is a simple and independent marker of morbidity and mortality in a variety of cardiovascular diseases.7,8 It has been recently reported that SUA is independently associated with AF.9-13 In addition to that, SUA has been clearly associated with oxidative stress and inflammation in several pathological conditions.14,15 SUA is also an independent risk factor for thromboembolic events such as ischemic stroke and myocardial infarction.16 Because oxidative stress and inflammation is associated with thromboembolic complications,17 we hypothesized that SUA is associated with a greater risk of LA thrombus in patients with AF.
Received for publication May 8, 2014. Accepted June 11, 2014.
Methods
Corresponding author: Dr Chang-Sheng Ma, Department of Cardiology, Beijing An Zhen Hospital, Capital Medical University, Chaoyang District, Beijing, China 100029. Tel.: þ86-10-84005361; fax: þ86-10-64456078. E-mail: [email protected] See page 1420 for disclosure information.
Study population From January 2007 to June 2010, 1524 consecutive patients referred to Beijing An Zhen Hospital with refractory AF
http://dx.doi.org/10.1016/j.cjca.2014.06.009 0828-282X/Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
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Canadian Journal of Cardiology Volume 30 2014
P < 0.001). Hyperuricemia had a negative predictive value of 98.1% in women and 97.1% in men for identifying LA thrombus. Hyperuricemia was associated with significantly greater risk of LA thrombus among Congestive Heart Failure, Hypertension, Age 75 Years, Diabetes Mellitus, Stroke, Vascular Disease, Age 65 to 74 Years, Sex Category (CHA2DS2-VASc) score ¼ 0, 1, and 2 groups with odds ratios of 7.19, 4.05, and 3.25, respectively. In multivariable analysis, SUA was an independent risk factor of LA thrombus (odds ratio, 1.004; 95% confidence interval, 1.000-1.008; P ¼ 0.028). Conclusions: Hyperuricemia was a modest risk factor for LA thrombus, which might refine stratification of LA thrombus in patients with nonvalvular AF.
tait significativement plus grande chez les padu thrombus de l’OD e sentant une hyperurice mie que chez les femmes (12,1 % vs tients pre 1,9 %; P < 0,001) et chez les hommes (8,5 % vs 2,8 %; P < 0,001) tait normale. L’hyperurice mie avait une dont la concentration d’AUS e gative pre dictive du thrombus de l’OD de 98,1 % chez les valeur ne mie e tait femmes et de 97,1 % chez les hommes. L’hyperurice e à un risque significativement plus grand de thrombus de l’OD associe chez les groupes dont le score CHA2DS2-VASc (Congestive Heart Failure, Hypertension, Age 75 Years, Diabetes Mellitus, Stroke, Vascular Disease, Age 65 to 74 Years, Sex Category, soit l’insuffisance cardiaque congestive, l’hypertension, l’âge 75 ans, le diabète, l’accire bral, la maladie vasculaire, l’âge situe entre 65 et dent vasculaire ce gorie du sexe) ¼ 0, 1 et 2 montrait respectivement 74 ans, la cate s de 7,19, 4,05 et 3,25. Dans l’analyse des ratios d’incidence approche e, l’AUS e tait un facteur de risque inde pendant de thrombus multivarie , 1,004; intervalle de confiance à de l’OD (ratio d’incidence approche 95 %, 1,000-1,008; P ¼ 0,028). mie e tait un facteur de risque modeste de Conclusions : L’hyperurice thrombus de l’OD qui affinerait la stratification de thrombus de l’OD chez les patients souffrant d’une FA non valvulaire.
underwent transesophageal echocardiography (TEE) before the first-time catheter ablation of AF were screened in a prospectively established database. Patients with valvular heart disease, deep venous thrombosis, pulmonary embolism, hypertrophic cardiomyopathy, and taking drugs that significantly affect SUA metabolism (ie, allopurinol, diuretics) were excluded. In total, 1359 patients were included in this retrospective study. After admission, warfarin and antiplatelet medications were discontinued, and all the patients received subcutaneous low-molecular weight heparin (enoxaparin; Sanofi-Aventis, France) twice per day as bridge therapy. Venous blood samples were obtained using sterile antecubital vein puncture after overnight fasting on the morning of first hospitalization. Laboratory data, including SUA, serum creatinine, and fibrinogen were analyzed. SUA levels were arrayed using the uricase enzymatic test (Olympus AU 5400 automatic biochemical analyzer; Olympus, Tokyo, Japan). As a measure of renal function, the baseline glomerular filtration rate (GFR) was estimated using the abbreviated Modification of Diet in Renal Disease (MDRD) study equation: GFR (mL/min/1.73 m2 of body surface area) ¼ 186 (serum creatinine in mg/dL)1.154 (age in years)0.203 ( 0.742 in female subjects).18 Paroxysmal AF was defined as recurrent AF that terminates spontaneously within 7 days according to the published guideline,2 and the other AF presentations, including persistent and long-standing AF, were categorized as nonparoxysmal AF. Stroke risk was then evaluated according to the Congestive Heart Failure, Hypertension, Age 75 Years, Diabetes Mellitus, Stroke, Vascular Disease, Age 65 to 74 Years, Sex Category (CHA2DS2-VASc) score, which was calculated as follows: 2 points were assigned for a history of stroke or transient ischemic attack, or age 75 years; and 1 point was assigned for age 65-74 years, history of hypertension, diabetes, recent cardiac failure, vascular disease, and female sex.19 This study was approved by the institutional review board and all patients provided written informed consent.
Ultrasound exam All patients underwent transthoracic echocardiography and TEE before catheter ablation of AF after admission. Before the TEE study, the procedure was explained in detail, and written informed consent was obtained. Lidocaine hydrochloride spray was routinely used for local anaesthesia; sedation or anaesthesia was not applied. TEE was performed with a 5MHz multiplane probe (Sonos 4500 or 5500; Philips Medical Systems, Andover, MA) and live images were interpreted by experienced physicians. Images of the left atrium including the LA appendage were evaluated in the horizontal plane (0 ) and in contiguous planes obtained using rotation of the imaging sector from 0 to 180 during continuous visualization of the left atrium and LA appendage. LA thrombus was defined as a well-circumscribed echogenic mass with a unique echotexture contrasting with the adjacent or underlying myocardium. The presence of spontaneous echocardiographic contrast (SEC) within the atrial blood pool, which might be seen in slow turbulent blood flow, was also characterized. Statistical analysis All analyses were performed with SPSS software version 13.0. Continuous data were presented as mean standard deviation and were compared using Student t test or 1-way analysis of variance. If variables were not in normal distribution, Mann-Whitney U test was performed. Categorical variables were compared using c2 test or Fisher exact test if necessary. The receiver operating characteristic (ROC) curve analysis was used to evaluate the efficiency of SUA in predicting LA thrombus. The optimal cutoff points for the variables predicting LA thrombus were determined according to the ROC curve. The ROC curve was constructed by plotting sensitivity vs specificity. Multivariable logistic regression was used to examine the risks of LA thrombus. We entered in the multivariable model AF type, CHA2DS2-VASc score, LA diameter, high-sensitivity C-reactive protein (hs-CRP), fibrinogen GFR, warfarin therapy, aspirin therapy, and SUA. A
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Table 1. Characteristics of patients with and without left atrial thrombus Characteristic Age, years Male sex, n (%) Atrial fibrillation history, years Paroxysmal atrial fibrillation, n (%) Type 2 diabetes mellitus, n (%) Hypertension, n (%) Previous embolic events, n (%) Heart failure, n (%) Coronary artery disease, n (%) CHA2DS2-VASc, n (%) 0 1 2 Body mass index Left atrial diameter, mm Left ventricular end diastolic diameter, mm Left ventricular end systolic diameter, mm Ejection fraction, % Uric acid, mmol/L Creatinine, mmol/L Glomerular filtration rate, mL/min/1.73 m2 Median high-sensitivity C-reactive protein (25th percentile-75th percentile), mg/L Fibrinogen, g/L Warfarin, n (%) Aspirin, n (%)
Nonthrombus (n ¼ 1298)
Thrombus (n ¼ 61)
P
58.1 11.2 922 (71.0) 6.1 5.9 864 (66.6) 173 (13.3) 658 (50.7) 95 (7.3) 19 (1.5) 92 (7.1)
59.8 11.6 40 (65.6) 6.1 6.7 21 (34.4) 9 (14.8) 44 (72.1) 7 (11.5) 2 (3.3) 3 (4.9)
0.262 0.360 0.991 < 0.001 0.749 0.001 0.229 0.261 0.650 0.026
324 (25.0) 382 (29.4) 592 (45.6) 26.1 3.8 38.7 6.1 48.2 4.9 31.4 5.0 63.7 7.8 366.7 94.3 83.4 18.5 85.0 20.7 0.90 (0.45-1.95)
8 (13.1) 15 (24.6) 38 (62.3) 27.5 3.2 44.3 6.0 50.6 5.2 37.0 12.3 57.9 10.0 413.5 98.8 87.2 21.4 80.1 22.0 1.60 (0.77-4.03)
2.71 0.61 160 (12.3) 288 (22.2)
2.96 0.66 11 (18.0) 10 (16.4)
< < < <
97% in women and in men. Approximately 46.4% of the study population had CHA2DS2-VASc scores 2, however, only 12.6% of the study population was using anticoagulation therapy. This reflects the real world status of anticoagulation therapy for patients with AF in China. Only < 10% of patients with AF were using anticoagulation therapy.3 There is a large gap between clinical practice and the guidelines with regard to the issue of antithrombotic therapy in China. More attention has been paid to the upstream therapy for primary and secondary prevention of AF. A recent animal experiment provided evidence that allopurinol, when used as an upstream therapy, can prevent AF associated with heart failure.22 Whether allopurinol, which can decrease SUA, can serve as complementary therapy to decrease the formation of LA thrombus and prevent stroke in hyperuricemia patients with AF needs further study. There are several limitations of this study. The mechanism of SUA levels linking LA thrombus was not well explored. Fibrinogen, a prothrombotic factor, was significantly correlated with SUA in women, which might in part, explain the correlation between SUA levels and LA thrombus in women. However, more inflammatory prothrombotic factors, oxidative stress factors, and endothelial damage markers should be studied in the future. In addition to that, we did not determine if SUA is an innocent marker or a mediator of LA thrombus in patients with AF. Second, the patients in this study were referred for catheter ablation of AF. The population in this study might not reflect the general AF population.
Funding Sources This work was supported by High Levels Talent in Health in Beijing (Project 215, No. 2013-3-007), the National Science Foundation Council of China (No. 30900628, 81070147, 81241005), Beijing Natural Science Foundation (No. 7102048), Beijing Nova Program (No. 2009B32), Training Program for Excellent Talent of Beijing (2010D003034000025) and Beijing Municipal Science & Technology Commission (No.D11110700300000).
Canadian Journal of Cardiology Volume 30 2014
Disclosures The authors have no conflicts of interest to disclose. References 1. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. JAMA 2001;285:2370-5. 2. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the task force for the management of atrial fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31: 2369-429. 3. Hu D, Sun Y. Epidemiology, risk factors for stroke, and management of atrial fibrillation in China. J Am Coll Cardiol 2008;52:865-8. 4. Marini C, De Santis F, Sacco S, et al. Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a populationbased study. Stroke 2005;36:1115-9. 5. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statisticse2012 update: a report from the American Heart Association. Circulation 2012;125:e2-220. 6. Miller VT, Rothrock JF, Pearce LA, et al. Ischemic stroke in patients with atrial fibrillation: effect of aspirin according to stroke mechanism. Stroke prevention in atrial fibrillation investigators. Neurology 1993;43:32-6. 7. Bae MH, Lee JH, Lee SH, et al. Serum uric acid as an independent and incremental prognostic marker in addition to n-terminal pro-b-type natriuretic peptide in patients with acute myocardial infarction. Circ J 2011;75:1440-7. 8. Alderman M. Uric acid in hypertension and cardiovascular disease. Can J Cardiol 1999;15(suppl F):20F-2F. 9. Tamariz L, Agarwal S, Soliman EZ, et al. Association of serum uric acid with incident atrial fibrillation (from the atherosclerosis risk in communities [ARIC] study). Am J Cardiol 2011;108:1272-6. 10. Letsas KP, Korantzopoulos P, Filippatos GS, et al. Uric acid elevation in atrial fibrillation. Hellenic J Cardiol 2010;51:209-13. 11. Valbusa F, Bertolini L, Bonapace S, et al. Relation of elevated serum uric acid levels to incidence of atrial fibrillation in patients with type 2 diabetes mellitus. Am J Cardiol 2013;112:499-504. 12. Liu T, Zhang X, Korantzopoulos P, Wang S, Li G. Uric acid levels and atrial fibrillation in hypertensive patients. Intern Med 2011;50:799-803. 13. Suzuki S, Sagara K, Otsuka T, et al. Gender-specific relationship between serum uric acid level and atrial fibrillation prevalence. Circ J 2012;76: 607-11. 14. Shi Y. Caught red-handed: uric acid is an agent of inflammation. J Clin Invest 2010;120:1809-11. 15. Kanellis J, Watanabe S, Li JH, et al. Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension 2003;41:1287-93. 16. Bos MJ, Koudstaal PJ, Hofman A, Witteman JC, Breteler MM. Uric acid is a risk factor for myocardial infarction and stroke: the Rotterdam study. Stroke 2006;37:1503-7. 17. Dudley SC Jr, Hoch NE, McCann LA, et al. Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage: role of the NADPH and xanthine oxidases. Circulation 2005;112:1266-73.
Tang et al. Uric Acid and Left Atrial Thrombus 18. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in renal disease study group. Ann Intern Med 1999;130:461-70. 19. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010;137:263-72. 20. Lenaerts I, Driesen RB, Blanco NH, et al. Role of nitric oxide and oxidative stress in a sheep model of persistent atrial fibrillation. Europace 2013;15:754-60. 21. Adamsson Eryd S, Smith JG, Melander O, Hedblad B, Engstrom G. Inflammation-sensitive proteins and risk of atrial fibrillation: a population-based cohort study. Eur J Epidemiol 2011;26:449-55. 22. Sakabe M, Fujiki A, Sakamoto T, et al. Xanthine oxidase inhibition prevents atrial fibrillation in a canine model of atrial pacing-induced left ventricular dysfunction. J Cardiovasc Electrophysiol 2012;23:1130-5. 23. Lehto S, Niskanen L, Ronnemaa T, Laakso M. Serum uric acid is a strong predictor of stroke in patients with non-insulin-dependent diabetes mellitus. Stroke 1998;29:635-9.
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24. Mazza A, Pessina AC, Pavei A, et al. Predictors of stroke mortality in elderly people from the general population. The cardiovascular study in the elderly. Eur J Epidemiol 2001;17:1097-104. 25. Kim SY, Guevara JP, Kim KM, et al. Hyperuricemia and risk of stroke: a systematic review and meta-analysis. Arthritis Rheum 2009;61:885-92. 26. Chao TF, Liu CJ, Chen SJ, et al. Hyperuricemia and the risk of ischemic stroke in patients with atrial fibrillation - could it refine clinical risk stratification in AF? Int J Cardiol 2014;170:344-9. 27. Zapolski T, Wacinski P, Kondracki B, et al. Uric acid as a link between renal dysfunction and both pro-inflammatory and prothrombotic state in patients with metabolic syndrome and coronary artery disease. Kardiol Pol 2011;69:319-26. 28. Yu MA, Sanchez-Lozada LG, Johnson RJ, Kang DH. Oxidative stress with an activation of the renin-angiotensin system in human vascular endothelial cells as a novel mechanism of uric acid-induced endothelial dysfunction. J Hypertens 2010;28:1234-42. 29. Habara S, Dote K, Kato M, et al. Prediction of left atrial appendage thrombi in non-valvular atrial fibrillation. Eur Heart J 2007;28:2217-22. 30. Tang RB, Dong JZ, Liu XP, et al. Is CHA2DS2-Vasc score a predictor of left atrial thrombus in patients with paroxysmal atrial fibrillation? Thromb Haemost 2011;105:1107-9.
