Table Info

Table 2.

Univariate and multivariable Cox models for the prediction of subsequent new-onset AF by SUA quartiles using first quartile as reference

Variable	Number of events	Univariate			Multivariable
Variable	Number of events	2nd Quartile HR (95% CI)	3rd Quartile HR (95% CI)	4th Quartile HR (95% CI)	2nd Quartile HR (95% CI)	3rd Quartile HR (95% CI)	4th Quartile HR (95% CI)
Baseline	371	1.24 (0.94–1.65) P = 0.130	1.00 (0.75–1.35) P = 0.980	1.09 (0.81–1.46) P = 0.567	1.21 (0.91–1.61) P = 0.195	0.95 (0.70–1.29) P = 0.736	1.03 (0.75–1.40) P = 0.872
Year 1	294	1.95 (1.31–2.91) P = 0.001	1.70 (1.12–2.58) P = 0.012	1.92 (1.32–2.80) P = 0.001	1.58 (1.09–2.30) P = 0.016	1.67 (1.16–2.40) P = 0.006	1.63 (1.15–2.31) P = 0.007
Year 2	242	1.40 (0.94–2.07) P = 0.095	1.25 (0.83–1.90) P = 0.290	1.70 (1.17–2.46) P = 0.005	1.50 (1.07–2.11) P = 0.02	1.11 (0.77–1.59) P = 0.579	1.53 (1.09–2.13) P = 0.013
Year 3	186	1.81 (1.05–3.12) P = 0.033	1.82 (1.05–3.16) P = 0.033	2.56 (1.56–4.21) P < 0.0001	1.42 (0.95–2.10) P = 0.084	1.29 (0.86–1.92) P = 0.215	1.69 (1.17–2.43) P = 0.005
Year 4	130	1.89 (0.96–3.70) P = 0.064	1.75 (0.88–3.46) P = 0.110	2.18 (1.18–4.04) P = 0.013	1.07 (0.70–1.66) P = 0.748	1.29 (0.85–1.94) P = 0.228	1.54 (1.06–2.24) P = 0.025
Year 5	50	1.52 (0.38–6.09) P = 0.552	2.53 (0.70–9.19) P = 0.159	4.26 (1.30–13.93) P = 0.017	1.18 (0.67–2.07) P = 0.569	1.25 (0.74–2.13) P = 0.407	2.10 (1.31–3.38) P = 0.002

1st through 4th SUA quartiles at baseline using sex-specific ranges: < 309, 309–353, 354–408, and ≥ 409 μmol/L for men and < 255, 255–297, 298–345, and ≥ 346 μmol/L for women. 1st quartile n = 2,033, 2nd quartile n = 2,070, 3rd quartile n = 2,100, 4th quartile n = 2,040. Multivariable models included age, sex, time-varying Cornell voltage-duration product, time-varying BP, Framingham risk score, cerebrovascular disease, and treatment status

Declarations

Acknowledgments

The authors thank the 945 clinical centers who participated in the LIFE study.

Author contributions

ESZ, KW, PMO and RBD contributed to the conception and design of this LIFE sub-study. ESZ, IMS, KW and DAH performed the statistical analyses. ESZ wrote the first draft of the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.

Conflicts of interest

Sverre E. Kjeldsen has received ad-hoc lecture honoraria within the past 3 years from Getz, Merck Healthcare KGaA, Sanofi-Aventis and Vector-Intas. The other authors declare that they have no conflicts of interest.

Ethical approval

The trial protocol was approved by ethical committees in all countries with participating clinical centres and done in accordance with the Declaration of Helsinki.

Consent to participate

Written informed consent to participate in the study was obtained from all participants.

Consent to publication

Not applicable.

Availability of data and materials

The data that support the findings of this study are available from the corresponding author (RBD) upon dire need.

Funding

Merck & Co., Inc. supported the LIFE study with an unrestricted grant from 1993. Merck had a non-voting member of the Steering Committee, which designed the study and wrote the protocol. Merck did monitoring, and data was accumulated in a Merck database until study ended in 2002. Merck provided the study steering committee with free access to blinded data until 2002 and then un-blinded data after the database was cleared for queries and frozen. The steering committee including a committee statistician validated independently the main outcomes. The steering committee has always been free to analyze and interpret the data, make decisions to publish and write the papers. Merck has not had any formal role after 2002 except for sporadically provided expert statistical assistance.

Copyright

References

Wachtell K, Hornestam B, Lehto M, Slotwiner DJ, Gerdts E, Olsen MH, et al. Cardiovascular morbidity and mortality in hypertensive patients with a history of atrial fibrillation: the Losartan Intervention For End Point Reduction in Hypertension (LIFE) study. J Am Coll Cardiol. 2005;45:705–11. [DOI] [PubMed]

Tsang TS, Petty GW, Barnes ME, O’Fallon WM, Bailey KR, Wiebers DO, et al. The prevalence of atrial fibrillation in incident stroke cases and matched population controls in Rochester, Minnesota: changes over three decades. J Am Coll Cardiol. 2003;42:93–100. [DOI] [PubMed]

Healey JS, Connolly SJ. Atrial fibrillation: hypertension as a causative agent, risk factor for complications, and potential therapeutic target. Am J Cardiol. 2003;91:9–14. [DOI] [PubMed]

L’Allier PL, Ducharme A, Keller PF, Yu H, Guertin MC, Tardif JC. Angiotensin-converting enzyme inhibition in hypertensive patients is associated with a reduction in the occurrence of atrial fibrillation. J Am Coll Cardiol. 2004;44:159–64. [DOI] [PubMed]

Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial fibrillation-Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet. 2000;356:1789–94. [DOI] [PubMed]

Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, et al.; Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347:1825–33. [DOI] [PubMed]

Pedersen OD, Bagger H, Køber L, Torp-Pedersen C. Trandolapril reduces the incidence of atrial fibrillation after acute myocardial infarction in patients with left ventricular dysfunction. Circulation. 1999;100:376–80. [DOI] [PubMed]

Saito I, Saruta T, Kondo K, Nakamura R, Oguro T, Yamagami K, et al. Serum uric acid and the renin-angiotensin system in hypertension. J Am Geriatr Soc. 1978;26:241–7. [DOI] [PubMed]

Perlstein TS, Gumieniak O, Hopkins PN, Murphy LJ, Brown NJ, Williams GH, et al. Uric acid and the state of the intrarenal renin-angiotensin system in humans. Kidney Int. 2004;66:1465–70. [DOI] [PubMed]

10.

Fogari R, Mugellini A, Destro M, Corradi L, Zoppi A, Fogari E, et al. Losartan and prevention of atrial fibrillation recurrence in hypertensive patients. J Cardiovasc Pharmacol. 2006;47:46–50. [DOI] [PubMed]

11.

Wachtell K, Lehto M, Gerdts E, Olsen MH, Hornestam B, Dahlöf B, et al. Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol: the Losartan Intervention For End Point Reduction in Hypertension (LIFE) study. J Am Coll Cardiol. 2005;45:712–9. [DOI] [PubMed]

12.

Devereux RB, Wachtell K, Gerdts E, Boman K, Nieminen MS, Papademetriou V, et al. Prognostic significance of left ventricular mass change during treatment of hypertension. JAMA. 2004;292:2350–6. [DOI] [PubMed]

13.

Wachtell K, Gerdts E, Aurigemma G, Boman K, Dahlöf B, Kjeldsen SE, et al. Does reduction in left atrial diameter during antihypertensive treatment reduce new-onset atrial fibrillation in hypertensive patients with left ventricular hypertrophy: the LIFE study [abstract]. J Am Coll Cardiol. 2006;47:9A. [DOI]

14.

Freedman DS, Williamson DF, Gunter EW, Byers T. Relation of serum uric acid to mortality and ischemic heart disease: the NHANES I epidemiologic follow-up study. Am J Epidemiol. 1995;141:637–44. [DOI] [PubMed]

15.

Levine W, Dyer AR, Shekelle RB, Schoenberger JA, Stamler J. Serum uric acid and 11.5-year mortality of middle-aged women: findings of the Chicago Heart Association Detection Project in Industry. J Clin Epidemiol. 1989;42:257–67. [DOI] [PubMed]

16.

Fang J, Alderman MH. Serum uric acid and cardiovascular mortality: the NHANES I epidemiologic follow-up study, 1971–1992. JAMA. 2000;283:2404–10. [DOI] [PubMed]

17.

Choi HK, Curhan G. Independent impact of gout on mortality and risk for coronary heart disease. Circulation. 2007;116:894–900. [DOI] [PubMed]

18.

Jossa F, Farinaro E, Panico S, Krogh V, Celentano E, Galasso R, et al. Serum uric acid and hypertension: the Olivetti heart study. J Hum Hypertens. 1994;8:677–81. [PubMed]

19.

Alderman MH, Cohen H, Madhavan S, Kivlighn S. Serum uric acid and cardiovascular events in successfully treated hypertensive patients. Hypertension. 1999;34:144–50. [DOI] [PubMed]

20.

Verdecchia P, Schillaci G, Reboldi G, Santeusanio F, Porcellati C, Brunetti P. Relation between serum uric acid and risk of cardiovascular disease in essential hypertension. The PIUMA study. Hypertension. 2000;36:1072–8. [DOI] [PubMed]

21.

Lehto S, Niskanen L, Rönnemaa 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. [DOI] [PubMed]

22.

Weir CJ, Muir SW, Walters MR, Lees KR. Serum urate is an independent predictor of poor outcome and future vascular events after acute stroke. Stroke. 2003;34:1951–6. [DOI] [PubMed]

23.

Anker SD, Doehner W, Rauchhaus M, Sharma R, Francis D, Knosalla C, et al. Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging. Circulation. 2003;107:1991–7. [DOI] [PubMed]

24.

Doehner W, Schoene N, Rauchhaus M, Leyva-Leon F, Pavitt DV, Reaveley DA, et al. Effects ofxanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies. Circulation. 2002;105:2619–24. [DOI] [PubMed]

25.

Borghi C, Agabiti-Rosei E, Johnson RJ, Kielstein JT, Lurbe E, Mancia G, et al. Hyperuricaemia and gout in cardiovascular, metabolic and kidney disease. Eur J Intern Med. 2020;80:1–11. [DOI] [PubMed]

26.

Memetoglu ME, Kehlibar T, Yılmaz M, Günay R, Arslan Y, Tuygun A, et al. Serum uric acid level predicts new-onset atrial fibrillation after coronary artery bypass graft operation. Eur Rev Med Pharmacol Sci. 2015;19:784–9. [PubMed]

27.

Chao TF, Hung CL, Chen SJ, Wang KL, Chen TJ, Lin YJ, et al. The association between hyperuricemia, left atrial size and new-onset atrial fibrillation. Int J Cardiol. 2013;168:4027–32. [DOI] [PubMed]

28.

Wang X, Hou Y, Wang X, Li Z, Wang X, Li H, et al. Relationship between serum uric acid levels and different types of atrial fibrillation: an updated meta-analysis. Nutr Metab Cardiovasc Dis. 2021;31:2756–65. [DOI] [PubMed]

29.

Kawasoe S, Kubozono T, Yoshifuku S, Ojima S, Miyata M, Miyahara H, et al. Uric acid level and new-onset atrial fibrillation in the Japanese general population-longitudinal study. Circ J. 2018;83:156–63. [DOI] [PubMed]

30.

Høieggen A, Alderman M, Kjeldsen SE, Julius S, Devereux RB, de Faire U, et al. The impact of serum uric acid on cardiovascular outcomes in the LIFE study. Kidney Int. 2004;65:1041–9. [DOI] [PubMed]

31.

Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995–1003. [DOI] [PubMed]

32.

Dahlöf B, Devereux R, de Faire U, Fyhrquist F, Hedner T, Ibsen H, et al. The Losartan Intervention For Endpoint reduction (LIFE) in Hypertension study: rationale, design, and methods. Am J Hypertens. 1997;10:705–13. [PubMed]

33.

Prineas RJ, Crow RS, Blackburn H. The Minnesota Code manual of electrocardiographic finding. 1st ed. Bristol: John Wright & Sons; 1982.

34.

Snapinn SM, Jiang Q, Iglewicz B. Illustrating the impact of a time-varying covariate with an extended Kaplan-Meier estimator. Am Statistician. 2005;59:301–7. [DOI]

35.

Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S, et al. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension. 2003;41:1183–90. [DOI] [PubMed]

36.

Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension. 2001;38:1101–6. [DOI] [PubMed]

37.

Mazzali M, Kanellis J, Han L, Feng L, Xia YY, Chen Q, et al. Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism. Am J Physiol Renal Physiol. 2002;282:F991–7. [DOI] [PubMed]

38.

Kang DH, Nakagawa T, Feng L, Watanabe S, Han L, Mazzali M, et al. A role for uric acid in the progression of renal disease. J Am Soc Nephrol. 2002;13:2888–97. [DOI] [PubMed]

39.

Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA. 2008;300:924–32. [DOI] [PubMed] [PMC]

40.

Mustard JF, Murphy EA, Ogrzylo MA, Smythe HA. Blood coagulation and platelet economy in subjects with primary gout. Can Med Assoc J. 1963;89:1207–11. [PubMed] [PMC]

41.

Høieggen A, Fossum E, Reims H, Kjeldsen SE. Serum uric acid and hemorheology in borderline hypertensives and in subjects with established hypertension and left ventricular hypertrophy. Blood Press. 2003;12:104–10. [DOI] [PubMed]

42.

Guthikonda S, Sinkey C, Barenz T, Haynes WG. Xanthine oxidase inhibition reverses endothelial dysfunction in heavy smokers. Circulation. 2003;107:416–21. [DOI] [PubMed]

43.

Coghlan JG, Flitter WD, Clutton SM, Panda R, Daly R, Wright G, et al. Allopurinol pretreatment improves postoperative recovery and reduces lipid peroxydation in patients undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg. 1994;107:248–56. [DOI] [PubMed]

44.

Abuja PM. Ascorbate prevents prooxidant effects of urate in oxidation of human low density lipoprotein. FEBS Lett. 1999;446:305–8. [DOI] [PubMed]

45.

Bickel C, Rupprecht HJ, Blandkenberg S, Rippin G, Hafner G, Daunhauer A, et al. Serum uric acid as an independent predictor of mortality in patients with angiographically proven coronary artery disease. Am J Cardiol. 2002;89:12–7. [DOI] [PubMed]

46.

Baker JF, Krishnan E, Chen L, Schumacher HR. Serum uric acid and cardiovascular disease: recent developments, and where do they leave us? Am J Med. 2005;118:816–26. [DOI] [PubMed]

47.

Iwashima Y, Horio T, Kamide K, Rakugi H, Ogihara T, Kawano Y. Uric acid, left ventricular mass index, and risk of cardiovascular disease in essential hypertension. Hypertension. 2006;47:195–202. [DOI] [PubMed]

48.

Virdis A, Masi S, Casiglia E, Tikhonoff V, Cicero AFG, Ungar A, et al. Identification of the uric acid thresholds predicting an increased total and cardiovascular mortality over 20 years. Hypertension. 2020;75:302–8. [DOI] [PubMed]