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Impact of Chronic Inflammation, Assessed by hs-CRP, on the Association between Red Cell Distribution Width and Arterial Cardiovascular Disease: The Tromsø StudyFunding K.G. Jebsen Thrombosis Research and Expertise Centre (TREC) is supported by an independent grant from Stiftelsen Kristian Gerhard Jebsen. S.K.B. and J-B.H. have received research grants from the Northern Norway Regional Health Authority (URL: http://www.helse-nord.no/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
31 January 2018
10 April 2018
16 May 2018 (online)
Red cell distribution width (RDW), a measure of variability in size of circulating erythrocytes, is associated with arterial cardiovascular disease (CVD), but the underlying mechanism remains unclear. We aimed to investigate the impact of chronic inflammation as measured by high-sensitivity C-reactive protein (hs-CRP) on this relationship, and explore whether RDW could be a mediator in the causal pathway between inflammation and arterial CVD. Baseline characteristics, including RDW and hs-CRP, were obtained from 5,765 individuals attending a population-based cohort study. We followed up participants from inclusion in the fourth survey of the Tromsø Study (1994/1995) until December 31, 2012. Multivariable Cox-regression models were used to calculate hazard ratios (HR) with 95% confidence intervals (CI) for incident myocardial infarction (MI) and ischemic stroke across quintiles of hs-CRP and RDW. Subjects with hs-CRP in the highest quintile had 44% higher risk of MI (HR: 1.44, 95% CI: 1.14–1.80), and 64% higher risk of ischemic stroke (HR: 1.64, 95% CI: 1.20–2.24) compared with subjects in the lowest quintile. RDW mediated 7.2% (95% CI: 4.0–30.8%) of the association between hs-CRP and ischemic stroke. Subjects with RDW in the highest quintile had 22% higher risk of MI (HR: 1.22, 95% CI: 0.98–1.54) and 44% higher risk of ischemic stroke (HR: 1.44, 95% CI: 1.06–1.97) compared with subjects in the lowest quintile. These risk estimates were slightly attenuated after adjustments for hs-CRP. Our findings suggest that chronic inflammation is not a primary mechanism underlying the relationship between RDW and arterial CVD.
J.L.—analyzed the data and drafted the manuscript.
T.S.E.—interpreted the results and revised the manuscript.
K.H.—provided statistical support, interpreted the results, and revised the manuscript.
E.B.M.—collected data, interpreted the results, and revised the manuscript.
I.N.—collected data, interpreted the results, and revised the manuscript.
T.W.—collected data and revised the manuscript.
M-L.L.—collected data, interpreted the results, and revised the manuscript.
S.K.B.—designed the study, interpreted the results, and revised the manuscript.
J-B.H.—designed the study, interpreted the results, and revised the manuscript.
- 1 Simel DL, DeLong ER, Feussner JR, Weinberg JB, Crawford J. Erythrocyte anisocytosis. Visual inspection of blood films vs automated analysis of red blood cell distribution width. Arch Intern Med 1988; 148 (04) 822-824
- 2 Bessman JD, Gilmer Jr PR, Gardner FH. Improved classification of anemias by MCV and RDW. Am J Clin Pathol 1983; 80 (03) 322-326
- 3 Rodak BF, Fritsma GA, Doig K. Hematology: Clinical Principles and Applications. Philadelphia, PA: Saunders Elsevier; 2007
- 4 Monzon CM, Beaver BD, Dillon TD. Evaluation of erythrocyte disorders with mean corpuscular volume (MCV) and red cell distribution width (RDW). Clin Pediatr (Phila) 1987; 26 (12) 632-638
- 5 Nagajothi N, Braverman A. Elevated red cell distribution width in the diagnosis of thrombotic thrombocytopenic purpura in patients presenting with anemia and thrombocytopenia. South Med J 2007; 100 (03) 257-259
- 6 Skjelbakken T, Lappegård J, Ellingsen TS. , et al. Red cell distribution width is associated with incident myocardial infarction in a general population: the Tromsø Study. J Am Heart Assoc 2014; 3 (04) e001109
- 7 Borné Y, Smith JG, Melander O, Engström G. Red cell distribution width in relation to incidence of coronary events and case fatality rates: a population-based cohort study. Heart 2014; 100 (14) 1119-1124
- 8 Söderholm M, Borné Y, Hedblad B, Persson M, Engström G. Red cell distribution width in relation to incidence of stroke and carotid atherosclerosis: a population-based cohort study. PLoS One 2015; 10 (05) e0124957
- 9 Lappegård J, Ellingsen TS, Skjelbakken T. , et al. Red cell distribution width is associated with future risk of incident stroke. The Tromsø Study. Thromb Haemost 2016; 115 (01) 126-134
- 10 Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation 2001; 104 (03) 365-372
- 11 Libby P. Inflammation in atherosclerosis. Nature 2002; 420 (6917): 868-874
- 12 Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med 1999; 340 (02) 115-126
- 13 Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999; 340 (06) 448-454
- 14 Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336 (14) 973-979
- 15 Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 1998; 97 (20) 2007-2011
- 16 Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA 1998; 279 (18) 1477-1482
- 17 Kaptoge S, Di Angelantonio E, Lowe G. , et al; Emerging Risk Factors Collaboration. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 2010; 375 (9709): 132-140
- 18 Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005; 352 (10) 1011-1023
- 19 Lippi G, Targher G, Montagnana M, Salvagno GL, Zoppini G, Guidi GC. Relation between red blood cell distribution width and inflammatory biomarkers in a large cohort of unselected outpatients. Arch Pathol Lab Med 2009; 133 (04) 628-632
- 20 Förhécz Z, Gombos T, Borgulya G, Pozsonyi Z, Prohászka Z, Jánoskuti L. Red cell distribution width in heart failure: prediction of clinical events and relationship with markers of ineffective erythropoiesis, inflammation, renal function, and nutritional state. Am Heart J 2009; 158 (04) 659-666
- 21 Miyamoto K, Inai K, Takeuchi D, Shinohara T, Nakanishi T. Relationships among red cell distribution width, anemia, and interleukin-6 in adult congenital heart disease. Circ J 2015; 79 (05) 1100-1106
- 22 Lappé JM, Horne BD, Shah SH. , et al. Red cell distribution width, C-reactive protein, the complete blood count, and mortality in patients with coronary disease and a normal comparison population. Clin Chim Acta 2011; 412 (23-24): 2094-2099
- 23 Jacobsen BK, Eggen AE, Mathiesen EB, Wilsgaard T, Njølstad I. Cohort profile: the Tromso Study. Int J Epidemiol 2012; 41 (04) 961-967
- 24 Caporal FA, Comar SR. Evaluation of RDW-CV, RDW-SD, and MATH-1SD for the detection of erythrocyte anisocytosis observed by optical microscopy. J Bras Patol Med Lab 2013; 49: 324-331
- 25 Hicks R, Tingley D. Causal mediation analysis. Stata J 2011; 11: 605-619
- 26 Chen P-C, Sung F-C, Chien K-L, Hsu H-C, Su T-C, Lee Y-T. Red blood cell distribution width and risk of cardiovascular events and mortality in a community cohort in Taiwan. Am J Epidemiol 2010; 171 (02) 214-220
- 27 Özcan F, Turak O, Durak A. , et al. Red cell distribution width and inflammation in patients with non-dipper hypertension. Blood Press 2013; 22 (02) 80-85
- 28 Fujita B, Strodthoff D, Fritzenwanger M. , et al. Altered red blood cell distribution width in overweight adolescents and its association with markers of inflammation. Pediatr Obes 2013; 8 (05) 385-391
- 29 Öztürk ZA, Ünal A, Yiğiter R. , et al. Is increased red cell distribution width (RDW) indicating the inflammation in Alzheimer's disease (AD)?. Arch Gerontol Geriatr 2013; 56 (01) 50-54
- 30 Emans ME, Gaillard CA, Pfister R. , et al. Red cell distribution width is associated with physical inactivity and heart failure, independent of established risk factors, inflammation or iron metabolism; the EPIC-Norfolk study. Int J Cardiol 2013; 168 (04) 3550-3555
- 31 Horne BD, Muhlestein JB, Bennett ST, Anderson JL. The red cell distribution width predicts mortality among patients free from systemic inflammation. Circulation 2014; 130: A14819
- 32 Vogiatzi G, Tousoulis D, Stefanadis C. The role of oxidative stress in atherosclerosis. Hellenic J Cardiol 2009; 50 (05) 402-409
- 33 Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation 2007; 115 (10) 1285-1295
- 34 Ghaffari S. Oxidative stress in the regulation of normal and neoplastic hematopoiesis. Antioxid Redox Signal 2008; 10 (11) 1923-1940
- 35 Sarnak MJ, Tighiouart H, Manjunath G. , et al. Anemia as a risk factor for cardiovascular disease in The Atherosclerosis Risk in Communities (ARIC) study. J Am Coll Cardiol 2002; 40 (01) 27-33
- 36 Lappegård J, Ellingsen TS, Vik A. , et al. Red cell distribution width and carotid atherosclerosis progression. The Tromsø Study. Thromb Haemost 2015; 113 (03) 649-654
- 37 Kolodgie FD, Gold HK, Burke AP. , et al. Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med 2003; 349 (24) 2316-2325
- 38 Kolodgie FD, Burke AP, Nakazawa G, Cheng Q, Xu X, Virmani R. Free cholesterol in atherosclerotic plaques: where does it come from?. Curr Opin Lipidol 2007; 18 (05) 500-507
- 39 Felton CV, Crook D, Davies MJ, Oliver MF. Relation of plaque lipid composition and morphology to the stability of human aortic plaques. Arterioscler Thromb Vasc Biol 1997; 17 (07) 1337-1345
- 40 Tziakas D, Chalikias G, Grapsa A, Gioka T, Tentes I, Konstantinides S. Red blood cell distribution width: a strong prognostic marker in cardiovascular disease: is associated with cholesterol content of erythrocyte membrane. Clin Hemorheol Microcirc 2012; 51 (04) 243-254
- 41 Patel K, Mohanty J, Kanapuru B, Hesdorffer C, Ershler W, Rifkind J. Association of the red cell distribution width with red blood cell deformability. In: Welch WJ, Palm F, Bruley DF, Harrison DK. , eds. Oxygen Transport to Tissue XXXIV. New York: Springer; 2013: 211-216
- 42 Simchon S, Jan K-M, Chien S. Influence of reduced red cell deformability on regional blood flow. Am J Physiol 1987; 253 (4, Pt 2): H898-H903
- 43 Chien S. Rheology in the microcirculation in normal and low flow states. Adv Shock Res 1982; 8: 71-80
- 44 Maeda N. Erythrocyte rheology in microcirculation. Jpn J Physiol 1996; 46 (01) 1-14
- 45 Maino A, Rosendaal FR, Algra A, Peyvandi F, Siegerink B. Hypercoagulability is a stronger risk factor for ischaemic stroke than for myocardial infarction: a systematic review. PLoS One 2015; 10 (08) e0133523
- 46 Kolominsky-Rabas PL, Weber M, Gefeller O, Neundoerfer B, Heuschmann PU. Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study. Stroke 2001; 32 (12) 2735-2740
- 47 Hutcheon JA, Chiolero A, Hanley JA. Random measurement error and regression dilution bias. BMJ 2010; 340: c2289
- 48 Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest 2003; 111 (12) 1805-1812