Association of White Blood Cell Count and Differential with the Incidence of Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study

Jeffrey R Misialek, Wobo Bekwelem, Lin Y Chen, Laura R Loehr, Sunil K Agarwal, Elsayed Z Soliman, Faye L Norby, Alvaro Alonso, Jeffrey R Misialek, Wobo Bekwelem, Lin Y Chen, Laura R Loehr, Sunil K Agarwal, Elsayed Z Soliman, Faye L Norby, Alvaro Alonso

Abstract

Background: Although inflammation is involved in the development of atrial fibrillation (AF), the association of white blood cell (WBC) count and differential with AF has not been thoroughly examined in large cohorts with extended follow-up.

Methods: We studied 14,500 men and women (25% blacks, 55% women, mean age 54) free of AF at baseline (1987-89) from the Atherosclerosis Risk in Communities (ARIC) study, a community-based cohort in the United States. Incident AF cases through 2010 were identified from study electrocardiograms, hospital discharge records and death certificates. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for AF associated with WBC count and differential.

Results: Over a median follow-up time of 21.5 years for the entire cohort, 1928 participants had incident AF. Higher total WBC count was associated with higher AF risk independent of AF risk factors and potential confounders (HR 1.09, 95% CI 1.04-1.15 per 1-standard deviation [SD] increase). Higher neutrophil and monocyte counts were positively associated with AF risk, while an inverse association was identified between lymphocyte count and AF (multivariable adjusted HRs 1.16, 95% CI 1.09-1.23; 1.05, 95% CI 1.00-1.11; 0.91, 95% CI 0.86-0.97 per 1-SD, respectively). No significant association was identified between eosinophils or basophils and AF.

Conclusions: High total WBC, neutrophil, and monocyte counts were each associated with higher AF risk while lymphocyte count was inversely associated with AF risk. Systemic inflammation may underlie this association and requires further investigation for strategies to prevent AF.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Flow chart of participants excluded…
Fig 1. Flow chart of participants excluded at baseline, Atherosclerosis Risk in Communities Study, 1987 to 1989.
ECG = electrocardiogram. WBC = White Blood Cell.
Fig 2. Association between total white blood…
Fig 2. Association between total white blood cell count and incident atrial fibrillation presented as hazard ratio (solid line) and 95% confidence intervals (shaded area), Atherosclerosis Risk in Communities Study, 1987 to 2010.
*Cox proportional hazards model using restricted cubic splines with knots at the 5th, 27.5th, 50th, 72.5th and 95th percentiles and adjustment for age, race, and sex. The reference is the median value of the total white blood cell count (hazard ratio = 1), and the histogram represents the frequency distribution of the total white blood cell count in the study sample.
Fig 3. Association between each white blood…
Fig 3. Association between each white blood cell differential count and incident atrial fibrillation presented as hazard ratio (solid line) and 95% confidence intervals (shaded area), Atherosclerosis Risk in Communities Study, 1987 to 2010.
(A) Neutrophil Count; (B) Lymphocyte Count; (C) Neutrophil Count/Lymphocyte Count Ratio; (D) Monocyte Count; (E) Eosinophil Count. *Cox proportional hazards model using restricted cubic splines with knots at the 5th, 27.5th, 50th, 72.5th and 95th percentiles and adjustment for age, race, and sex. The reference is the median value of each white blood cell differential count (hazard ratio = 1), and the histogram represents the frequency distribution of each white blood cell differential count in the study sample.

References

    1. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, et al. (2001) 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 285: 2370–2375.
    1. Benjamin EJ, Levy D, Vaziri SM, D'Agostino RB, Belanger AJ, Wolf PA (1994) Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. JAMA 271: 840–844.
    1. Wolf PA, Abbott RD, Kannel WB (1991) Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 22: 983–988.
    1. Benjamin EJ, Wolf PA, D'Agostino RB, Silbershatz H, Kannel WB, Levy D (1998) Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 98: 946–952.
    1. Soliman EZ, Safford MM, Muntner P, Khodneva Y, Dawood FZ, Zakai NA, et al. (2014) Atrial fibrillation and the risk of myocardial infarction. JAMA Intern Med 174: 107–114. 10.1001/jamainternmed.2013.11912
    1. Huxley RR, Lopez FL, Folsom AR, Agarwal SK, Loehr LR, Soliman EZ, et al. (2011) Absolute and attributable risks of atrial fibrillation in relation to optimal and borderline risk factors: the Atherosclerosis Risk in Communities (ARIC) study. Circulation 123: 1501–1508. 10.1161/CIRCULATIONAHA.110.009035
    1. Aviles RJ, Martin DO, Apperson-Hansen C, Houghtaling PL, Rautaharju P, Kronmal RA, et al. (2003) Inflammation as a risk factor for atrial fibrillation. Circulation 108: 3006–3010.
    1. Sinner MF, Stepas KA, Moser CB, Krijthe BP, Aspelund T, Sotoodehnia N, et al. (2014) B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies. Europace 16: 1426–1433. 10.1093/europace/euu175
    1. Lamm G, Auer J, Weber T, Berent R, Ng C, Eber B (2006) Postoperative white blood cell count predicts atrial fibrillation after cardiac surgery. J Cardiothorac Vasc Anesth 20: 51–56.
    1. Amar D, Goenka A, Zhang H, Park B, Thaler HT (2006) Leukocytosis and increased risk of atrial fibrillation after general thoracic surgery. Ann Thorac Surg 82: 1057–1061.
    1. Sood N, Coleman CI, Kluger J, White CM, Padala A, Baker WL (2009) The association among blood transfusions, white blood cell count, and the frequency of post-cardiothoracic surgery atrial fibrillation: a nested cohort study from the Atrial Fibrillation Suppression Trials I, II, and III. J Cardiothorac Vasc Anesth 23: 22–27. 10.1053/j.jvca.2008.06.009
    1. Fontes ML, Amar D, Kulak A, Koval K, Zhang H, Shi W, et al. (2009) Increased preoperative white blood cell count predicts postoperative atrial fibrillation after coronary artery bypass surgery. J Cardiothorac Vasc Anesth 23: 484–487. 10.1053/j.jvca.2009.01.030
    1. Letsas KP, Weber R, Burkle G, Mihas CC, Minners J, Kalusche D, et al. (2009) Pre-ablative predictors of atrial fibrillation recurrence following pulmonary vein isolation: the potential role of inflammation. Europace 11: 158–163. 10.1093/europace/eun309
    1. Rienstra M, Sun JX, Magnani JW, Sinner MF, Lubitz SA, Sullivan LM, et al. (2012) White blood cell count and risk of incident atrial fibrillation (from the Framingham Heart Study). Am J Cardiol 109: 533–537. 10.1016/j.amjcard.2011.09.049
    1. Nyrnes A, Njolstad I, Mathiesen EB, Wilsgaard T, Hansen JB, Skjelbakken T, et al. (2012) Inflammatory biomarkers as risk factors for future atrial fibrillation. An eleven-year follow-up of 6315 men and women: the Tromso study. Gend Med 9: 536–547 e532. 10.1016/j.genm.2012.09.001
    1. Bekwelem W, Lutsey PL, Loehr LR, Agarwal SK, Astor BC, Guild C, et al. (2011) White blood cell count, C-reactive protein, and incident heart failure in the Atherosclerosis Risk in Communities (ARIC) Study. Ann Epidemiol 21: 739–748. 10.1016/j.annepidem.2011.06.005
    1. Wheeler JG, Mussolino ME, Gillum RF, Danesh J (2004) Associations between differential leucocyte count and incident coronary heart disease: 1764 incident cases from seven prospective studies of 30,374 individuals. Eur Heart J 25: 1287–1292.
    1. Rudolph V, Andrie RP, Rudolph TK, Friedrichs K, Klinke A, Hirsch-Hoffmann B, et al. (2010) Myeloperoxidase acts as a profibrotic mediator of atrial fibrillation. Nat Med 16: 470–474. 10.1038/nm.2124
    1. Friedrichs K, Baldus S, Klinke A (2012) Fibrosis in Atrial Fibrillation—Role of Reactive Species and MPO. Front Physiol 3: 214 10.3389/fphys.2012.00214
    1. (1989) The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. The ARIC investigators. Am J Epidemiol 129: 687–702.
    1. Nieto FJ, Szklo M, Folsom AR, Rock R, Mercuri M (1992) Leukocyte count correlates in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Epidemiol 136: 525–537.
    1. Papp AC, Hatzakis H, Bracey A, Wu KK (1989) ARIC hemostasis study—I. Development of a blood collection and processing system suitable for multicenter hemostatic studies. Thromb Haemost 61: 15–19.
    1. Chambless LE, McMahon R, Wu K, Folsom A, Finch A, Shen YL (1992) Short-term intraindividual variability in hemostasis factors. The ARIC Study. Atherosclerosis Risk in Communities Intraindividual Variability Study. Ann Epidemiol 2: 723–733.
    1. Doumas BT, Watson WA, Biggs HG (1971) Albumin standards and the measurement of serum albumin with bromcresol green. Clin Chim Acta 31: 87–96.
    1. Eckfeldt JH, Chambless LE, Shen YL (1994) Short-term, within-person variability in clinical chemistry test results. Experience from the Atherosclerosis Risk in Communities Study. Arch Pathol Lab Med 118: 496–500.
    1. Eriksson H, Caidahl K, Larsson B, Ohlson LO, Welin L, Wilhelmsen L, et al. (1987) Cardiac and pulmonary causes of dyspnoea—validation of a scoring test for clinical-epidemiological use: the Study of Men Born in 1913. Eur Heart J 8: 1007–1014.
    1. Alonso A, Agarwal SK, Soliman EZ, Ambrose M, Chamberlain AM, Prineas RJ, et al. (2009) Incidence of atrial fibrillation in whites and African-Americans: The Atherosclerosis Risk in Communities (ARIC) study. American Heart Journal 158: 111–117. 10.1016/j.ahj.2009.05.010
    1. Chamberlain AM, Agarwal SK, Ambrose M, Folsom AR, Soliman EZ, Alonso A (2010) Metabolic syndrome and incidence of atrial fibrillation among blacks and whites in the Atherosclerosis Risk in Communities (ARIC) Study. American Heart Journal 159: 850–856. 10.1016/j.ahj.2010.02.005
    1. Soliman EZ, Prineas RJ, Case LD, Zhang ZM, Goff DC Jr (2009) Ethnic distribution of ECG predictors of atrial fibrillation and its impact on understanding the ethnic distribution of ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study. Stroke 40: 1204–1211. 10.1161/STROKEAHA.108.534735
    1. Fine JP, Gray RJ (1999) A Proportional Hazards Model for the Subdistribution of a Competing Risk. Journal of the American Statistical Association 94: 496–509.
    1. Verheule S, Sato T, Everett T IV, Engle SK, Otten D, Rubart-von der Lohe M, et al. (2004) Increased vulnerability to atrial fibrillation in transgenic mice with selective atrial fibrosis caused by overexpression of TGF-beta1. Circ Res 94: 1458–1465.
    1. Burstein B, Qi XY, Yeh YH, Calderone A, Nattel S (2007) Atrial cardiomyocyte tachycardia alters cardiac fibroblast function: a novel consideration in atrial remodeling. Cardiovasc Res 76: 442–452.
    1. Polyakova V, Miyagawa S, Szalay Z, Risteli J, Kostin S (2008) Atrial extracellular matrix remodelling in patients with atrial fibrillation. J Cell Mol Med 12: 189–208. 10.1111/j.1582-4934.2008.00219.x
    1. Rossi MA (1998) Pathologic fibrosis and connective tissue matrix in left ventricular hypertrophy due to chronic arterial hypertension in humans. J Hypertens 16: 1031–1041.
    1. Chen CL, Huang SK, Lin JL, Lai LP, Lai SC, Liu CW, et al. (2008) Upregulation of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases in rapid atrial pacing-induced atrial fibrillation. J Mol Cell Cardiol 45: 742–753. 10.1016/j.yjmcc.2008.07.007
    1. Huxley RR, Lopez FL, MacLehose RF, Eckfeldt JH, Couper D, Leiendecker-Foster C, et al. (2013) Novel association between plasma matrix metalloproteinase-9 and risk of incident atrial fibrillation in a case-cohort study: the Atherosclerosis Risk in Communities study. PLoS One 8: e59052 10.1371/journal.pone.0059052
    1. Fu X, Kassim SY, Parks WC, Heinecke JW (2001) Hypochlorous acid oxygenates the cysteine switch domain of pro-matrilysin (MMP-7). A mechanism for matrix metalloproteinase activation and atherosclerotic plaque rupture by myeloperoxidase. J Biol Chem 276: 41279–41287.
    1. Fu X, Kassim SY, Parks WC, Heinecke JW (2003) Hypochlorous acid generated by myeloperoxidase modifies adjacent tryptophan and glycine residues in the catalytic domain of matrix metalloproteinase-7 (matrilysin): an oxidative mechanism for restraining proteolytic activity during inflammation. J Biol Chem 278: 28403–28409.
    1. Jensen PN, Johnson K, Floyd J, Heckbert SR, Carnahan R, Dublin S (2012) A systematic review of validated methods for identifying atrial fibrillation using administrative data. Pharmacoepidemiol Drug Saf 21 Suppl 1: 141–147. 10.1002/pds.2317

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