Canadian Journal of Cardiology 30 (2014) 1259e1261

Editorial

Serum Uric Acid Concentration and Left Atrial Thrombus: Biomarker, Pathophysiological Indicator, or Innocent Bystander? Stanley Nattel, MD Department of Medicine, Montreal Heart Institute, and Universite de Montre al, Montreal, Que bec, Canada

See article by Tang et al., pages 1415-1421 of this issue. Atrial fibrillation (AF) is estimated to affect approximately 1 of 4 individuals over the course of their lives.1 The most important complication of AF is thromboembolism.2 AF-related thromboembolism is a particularly significant contributor to stroke in elderly individuals,2 and unrecognized AF is an important contributor to cryptogenic stroke.3 Blood stasis in the fibrillating left atrial (LA) appendage is a major contributor to the thrombogenesis associated with AF, but altered coagulation factors and dysfunction of endocardial thrombosuppressant function likely also participate in LA thrombus formation.4 Biomarkers are of potential interest for their ability to provide insights into disease pathophysiology, prognosis, and risk of complications.4 In this issue of the Canadian Journal of Cardiology, Tang et al. evaluate the relationship between a variety of clinical variables and LA thrombus on echocardiography in 1359 AF patients subjected to transesophageal echocardiography before AF ablation.5 LA thrombus was noted in 61 patients (4.5% of the study population). On multivariate analysis, LA diameter and serum uric acid concentration (SUA) were associated with the presence of thrombus in a statistically significant way. The association with SUA was particularly strong among low-risk patents: for those with Congestive Heart Failure, Hypertension, Age  75 Years, Diabetes Mellitus, Stroke, Vascular Disease, Age 65 to 74 Years, Sex Category (CHA2DS2VASc) score ¼ 0, the relative risk for atrial thrombus among patients with elevated SUA was 7.2 (95% confidence interval, 1.7-30.9). Although the sensitivity of elevated SUA was limited, of the order of 70%-75%, its negative predictive value was high (98% in women and 97% in men). Possible Basis for the Association Between SUA and LA Thrombus There are several possible explanations for the relationship noted in this study between SUA and LA thrombus: (1) direct Received for publication July 22, 2014. Accepted July 22, 2014. Corresponding author: Dr Stanley Nattel, 5000 Belanger St E, Montreal, Quebec H1T 1C8, Canada. Tel.: þ1-514-376-3330; fax: þ1-514-376-1355. E-mail: [email protected] See page 1260 for disclosure information.

pathophysiological involvement; (2) an indirect link to underlying causality; (3) an association with other conditions closely related to AF; and (4) statistical chance. Most interesting would be a pathophysiological association. Evidence exists for direct adverse results of excess uric acid exposure,6,7 including proinflammatory effects and adverse consequences for endothelial function. Uric acid might thus promote tissue inflammation, believed to increase the likelihood of AF and thrombogenesis.8,9 SUA could also be a marker of profibrillatory/prothrombotic processes, without being itself a direct causative factor. Uric acid is a by-product of xanthine oxidase, which converts hypoxanthine to xanthine and xanthine to uric acid. Xanthine oxidase is an important source of oxidant stress molecules because it produces superoxide ions and results in the liberation of other oxygen free radicals. Inasmuch as increased SUA reflects increased xanthine oxidase activity, it might also indicate enhanced xanthine oxidaseinduced generation of oxidative stress. Because atrial oxidative stress and associated inflammation are believed to promote AF and accompanying LA thrombus formation,8,9 SUA might track the risk of AF-related LA thrombosis. A third possibility is that SUA is simply associated with cardiac conditions that promote LA thrombus formation, like congestive heart failure, hypertension, diabetes, and vascular disease.10,11 Finally, the observed relationship detected between SUA and LA thrombus could simply be a statistical quirk resulting from the retrospective search for correlations in a large database. Arguing against this possibility are previous publications that suggest that SUA is associated with stroke risk,12 and that SUA correlates with transesophageal echocardiography evidence of atrial thrombogenic risk.13 Of course, the most definitive way to confirm the independent contribution of SUA to prediction of LA thrombus risk would be with a prospective study in an independent sample of AF patients. Potential Value of Recognizing a Link Between SUA and LA Thrombus Confirmation of the association between increased SUA and likelihood of AF-related LA thrombus is potentially

http://dx.doi.org/10.1016/j.cjca.2014.07.730 0828-282X/Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

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significant in a number of ways. Biomarkers can be used to predict disease occurrence and complications, and as surrogates to follow therapeutic interventions. A number of biomarkers have been described in AF.4 Factors associated with thromboembolic events include D-dimers, P-selectin, and brain natriuretic peptide.4 In addition, b-thromboglobulin, von Willebrand factor, and d-dimer concentrations have been related to the presence of LA thrombus.14,15 If a pathophysiological link between SUA and thrombotic risk in AF were supported, SUA could be used as a surrogate for the activity of treatments (eg, xanthine oxidase inhibitors like allopurinol) used in prospective randomized intervention trials aiming to confirm value in the prevention of LA thrombus; if these trial results were positive, SUA measurements could then be applied as a surrogate to assess clinical efficacy. A potential application that does not require direct pathophysiological involvement would be the use of SUA to identify patients at increased risk of LA thrombus for therapeutic decisionmaking (eg, choice of antithrombotic intervention, risk of cardioversion, etc). Interesting in this regard was the particularly strong association between SUA and LA thrombus in patients with low CHA2DS2-VASc scores and the strong negative predictive value of low SUA, raising the possibility that SUA might help to distinguish among patients requiring an oral anticoagulant vs an antiplatelet drug vs no antithrombotic drug. Actual clinical application of any biomarker for AF or its complications would require prospective assessment in patients guided by the use of that biomarker vs a “usual care” groupdto my knowledge that has yet to be achieved for any potential AF biomarker. Limitations of the Study The study by Tang et al.5 has some limitations that should be noted. The analysis was performed retrospectively, so all references to “prediction,” “predictive value,” etc, should be understood as descriptive only, and really referring to observed relationships rather than prediction per se. The term “prediction” properly refers to a priori criteria that are applied prospectively. The overall number of thrombi was relatively small in the study, and for some subgroup analyses, is so small that the results should be considered only exploratory (eg, for the risk ratio calculations for CHA2DS2-VASc of 0 and 1, the total number of patients with thrombi was 8 and 15, respectively). Although the negative predictive value of low SUA was > 97%, this must be considered in relation to the fact that 95.5% of the population lacked LA thrombus. Finally, the study population was drawn from a Beijing hospital, and the characteristics of the sample have some peculiarities that raise questions about generalizability. Most importantly, only a small percentage of the sample (12.5%) was taking oral anticoagulants: for the overall sample, approximately half of the individuals had a CHA2DS2-VASc score  2. The overall incidence of thrombus might thus have been increased by underuse of anticoagulation therapy and the results might not apply to populations with more extensive anticoagulation therapy, as recommended in recent guidelines.16

Canadian Journal of Cardiology Volume 30 2014

The Study in Context The study by Tang et al.5 provides interesting new information of primarily hypothesis-forming value. It raises a number of important questions about the relationship between SUA and LA thrombus. Is uric acid a pathophysiological contributor to LA thrombus formation? Is oxidative stress involved and, if so, can antioxidant interventions be used to reduce thromboembolic risk in AF? Are xanthine oxidase inhibitors of potential antithrombotic value? Can uric acid, or for that matter, other biomarkers of thrombogenic risk in AF, be used to guide antithrombotic therapy? Like any good piece of research, this study raises many more questions than it answersdwe look forward to seeing further investigation that pursues these interesting issues. Acknowledgements Dr Nattel thanks France Theriault for expert secretarial assistance. Funding Sources Supported by the Canadian Institutes of Health Research (#6957) and Heart and Stroke Foundation of Canada. Disclosures The author has no conflicts of interest to disclose. References 1. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004;110: 1042-6. 2. Wolf PA, Mitchell JB, Baker CS, Kannel WB, D’Agostino RB. Impact of atrial fibrillation on mortality, stroke, and medical costs. Arch Intern Med 1998;158:229-34. 3. Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014;370:2478-86. 4. Kornej J, Apostolakis S, Bollmann A, Lip GY. The emerging role of biomarkers in atrial fibrillation. Can J Cardiol 2013;29:1181-93. 5. Tang RT, Dong JZ, Yan XL, et al. Serum uric acid and risk of left atrial thrombus in patients with nonvalvular atrial fibrillation. Can J Cardiol 2014;30:1415-21. 6. Johnson RJ, Kang DH, Feig D, et al. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 2003;416:1183-90. 7. 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;416:1287-93. 8. Van Wagoner DR. Oxidative stress and inflammation in atrial fibrillation: role in pathogenesis and potential as a therapeutic target. J Cardiovasc Pharmacol 2008;52:306-13. 9. Nishida K, Chiba K, Iwasaki YK, et al. Atrial fibrillation-associated remodeling does not promote atrial thrombus formation in canine models. Circ Arrhythm Electrophysiol 2012;5:1168-75. 10. Erdogan D, Tayyar S, Uysal BA, et al. Effects of allopurinol on coronary microvascular and left ventricular function in patients with idiopathic dilated cardiomyopathy. Can J Cardiol 2012;28:721-7.

Stanley Nattel Serum Uric Acid as an AF Biomarker 11. Ruggiero C, Cherubini A, Ble A, et al. Uric acid and inflammatory markers. Eur Heart J 2006;27:1174-81. 12. Chao TF, Liu CJ, Chen SJ, et al. Hyperuricemia and the risk of ischemic stroke in patients with atrial fibrillationecould it refine clinical risk stratification in AF? Int J Cardiol 2014;170:344-9. 13. Numa S, Hirai T, Nakagawa K, et al. Hyperuricemia and transesophageal echocardiographic thromboembolic risk in patients with atrial fibrillation at clinically low-intermediate risk. Circ J 2014;78: 1600-5.

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14. Heppell RM, Berkin KE, McLenachan JM, Davies JA. Haemostatic and haemodynamic abnormalities associated with left atrial thrombosis in non-rheumatic atrial fibrillation. Heart 1997;77:407-11. 15. Sugiura S, Fujii E, Senga M, et al. Clinical features of patients with left atrial thrombus undergoing anticoagulant therapy. J Interv Card Electrophysiol 2012;34:59-63. 16. Skanes AC, Healey JS, Cairns JA, et al. Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control. Can J Cardiol 2012;28:125-36.

Serum uric acid concentration and left atrial thrombus: biomarker, pathophysiological indicator, or innocent bystander?

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