Clinical correlates of change in inflammatory biomarkers: The Framingham Heart Study



      Traditional clinical risk factors are associated with inflammation cross-sectionally, but associations of longitudinal variation in inflammatory biomarkers with corresponding changes in clinical risk factors are incompletely described. We sought to analyze clinical factors associated with change in inflammation in the community.


      We studied 3013 Framingham Offspring (n = 2735) and Omni Cohort (n = 278) participants (mean age 59 years, 55% women, 9% ethnic/racial minority) who attended two consecutive examination cycles (mean 6.7 years apart). We selected ten inflammatory biomarkers representing distinctive biological functions: C-reactive protein (CRP), intercellular adhesion molecule-1, interleukin-6, isoprostanes, lipoprotein-associated phospholipase-2 (Lp-PLA2) activity, Lp-PLA2-mass, monocyte chemoattractant protein-1, osteoprotegerin, P-selectin, and tumor necrosis factor receptor II (TNFRII). We constructed multivariable-adjusted regression models to assess the relations of baseline, follow-up and change in clinical risk factors with change in biomarker concentrations over time.


      Baseline, follow-up and change in clinical risk factors explain a moderate amount of the variation in biomarker concentrations across 2 consecutive examinations (ranging from r2 = 0.28 [TNFRII] up to 0.52 [Lp-PLA2-mass]). In multivariable models, increasing body-mass index, smoking initiation, worsening lipid profile, and increasing waist size were associated with increasing concentrations of several biomarkers. Conversely, hypercholesterolemia therapy and hormone replacement cessation were associated with decreasing concentrations of biomarkers such as CRP, Lp-PLA2-mass and activity.


      Cardiovascular risk factors have different patterns of association with longitudinal change in inflammatory biomarkers and explain modest amounts of variability in biomarker concentrations. Nevertheless, a substantial proportion of longitudinal change in inflammatory markers is not explained by traditional risk factors.


      • We examined baseline and follow-up clinical correlates of changes in concentrations of biomarkers representing different aspects of inflammation in association with changes in risk factors in 3013 Framingham participants over 2 consecutive examinations.
      • Baseline, follow-up and change in risk factors explained a moderate amount of variation in biomarker concentrations.
      • Weight, lipids and smoking were associated with increasing concentrations of several biomarkers.
      • Our study is a unique examination of factors associated with change in a broad panel of systemic inflammation in the community.


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        • Wilson P.W.
        • Nam B.H.
        • Pencina M.
        • et al.
        C-reactive protein and risk of cardiovascular disease in men and women from the Framingham Heart Study.
        Arch Intern Med. 2005; 165: 2473-2478
        • Wang T.J.
        • Gona P.
        • Larson M.G.
        • et al.
        Multiple biomarkers and the risk of incident hypertension.
        Hypertension. 2007; 49: 432-438
        • Libby P.
        Inflammation in atherosclerosis.
        Nature. 2002; 420: 868-874
        • Vasan R.S.
        Biomarkers of cardiovascular disease: molecular basis and practical considerations.
        Circulation. 2006; 113: 2335-2362
        • Koenig W.
        • Sund M.
        • Frohlich M.
        • et al.
        C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992.
        Circulation. 1999; 99: 237-242
        • Kugiyama K.
        • Ota Y.
        • Takazoe K.
        • et al.
        Circulating levels of secretory type II phospholipase A(2) predict coronary events in patients with coronary artery disease.
        Circulation. 1999; 100: 1280-1284
        • Pradhan A.D.
        • Rifai N.
        • Ridker P.M.
        Soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1, and the development of symptomatic peripheral arterial disease in men.
        Circulation. 2002; 106: 820-825
        • Chen T.H.
        • Gona P.
        • Sutherland P.A.
        • et al.
        Long-term C-reactive protein variability and prediction of metabolic risk.
        Am J Med. 2009; 122: 53-61
        • Farzadfar F.
        • Finucane M.M.
        • Danaei G.
        • et al.
        National, regional, and global trends in serum total cholesterol since 1980: systematic analysis of health examination surveys and epidemiological studies with 321 country-years and 3.0 million participants.
        Lancet. 2011; 377: 578-586
        • Danaei G.
        • Finucane M.M.
        • Lin J.K.
        • et al.
        National, regional, and global trends in systolic blood pressure since 1980: systematic analysis of health examination surveys and epidemiological studies with 786 country-years and 5.4 million participants.
        Lancet. 2011; 377: 568-577
        • Finucane M.M.
        • Stevens G.A.
        • Cowan M.J.
        • et al.
        National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants.
        Lancet. 2011; 377: 557-567
        • Kannel W.B.
        • Feinleib M.
        • McNamara P.M.
        • et al.
        An investigation of coronary heart disease in families. The Framingham Offspring Study.
        Am J Epidemiol. 1979; 110: 281-290
        • Splansky G.L.
        • Corey D.
        • Yang Q.
        • et al.
        The third generation cohort of the national heart, lung, and blood institute's Framingham heart study: design, recruitment, and initial examination.
        Am J Epidemiol. 2007; 165: 1328-1335
        • Schnabel R.
        • Larson M.G.
        • Dupuis J.
        • et al.
        Relations of inflammatory biomarkers and common genetic variants with arterial stiffness and wave reflection.
        Hypertension. 2008; 51: 1651-1657
        • Schnabel R.B.
        • Lunetta K.L.
        • Larson M.G.
        • et al.
        The relation of genetic and environmental factors to systemic inflammatory biomarker concentrations.
        Circ Cardiovasc Genet. 2009; 2: 229-237
        • Schnabel R.
        • Larson M.G.
        • Dupuis J.
        • et al.
        Relations of inflammatory biomarkers and common genetic variants with arterial stiffness and wave reflection.
        Hypertension. 2008;
        • Schnabel R.B.
        • Larson M.G.
        • Yamamoto J.F.
        • et al.
        Relation of multiple inflammatory biomarkers to incident atrial fibrillation.
        Am J Cardiol. 2009; 104: 92-96
        • Ridker P.M.
        • Rifai N.
        • Stampfer M.J.
        • et al.
        Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men.
        Circulation. 2000; 101: 1767-1772
        • Aviles R.J.
        • Martin D.O.
        • Apperson-Hansen C.
        • et al.
        Inflammation as a risk factor for atrial fibrillation.
        Circulation. 2003; 108: 3006-3010
        • Ridker P.M.
        • Cushman M.
        • Stampfer M.J.
        • et al.
        Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease.
        Circulation. 1998; 97: 425-428
        • Ridker P.M.
        • Hennekens C.H.
        • Buring J.E.
        • et al.
        C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women.
        N Engl J Med. 2000; 342: 836-843
        • Hwang S.J.
        • Ballantyne C.M.
        • Sharrett A.R.
        • et al.
        Circulating adhesion molecules VCAM-1, sICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk in Communities (ARIC) Study.
        Circulation. 1997; 96: 4219-4225
        • Schwedhelm E.
        • Bartling A.
        • Lenzen H.
        • et al.
        Urinary 8-iso-prostaglandin F2alpha as a risk marker in patients with coronary heart disease: a matched case-control study.
        Circulation. 2004; 109: 843-848
        • Packard C.J.
        • O'Reilly D.S.
        • Caslake M.J.
        • et al.
        Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group.
        N Engl J Med. 2000; 343: 1148-1155
        • Omland T.
        • Ueland T.
        • Jansson A.M.
        • et al.
        Circulating osteoprotegerin levels and long-term prognosis in patients with acute coronary syndromes.
        J Am Coll Cardiol. 2008; 51: 627-633
        • Ridker P.M.
        • Buring J.E.
        • Rifai N.
        Soluble P-selectin and the risk of future cardiovascular events.
        Circulation. 2001; 103: 491-495
        • Suzuki T.
        • Solomon C.
        • Jenny N.S.
        • et al.
        Lipoprotein-associated phospholipase A(2) and risk of congestive heart failure in older adults: the Cardiovascular Health Study.
        Circ Heart Fail. 2009; 2: 429-436
        • Ueland T.
        • Jemtland R.
        • Godang K.
        • et al.
        Prognostic value of osteoprotegerin in heart failure after acute myocardial infarction.
        J Am Coll Cardiol. 2004; 44: 1970-1976
        • Nambi V.
        • Hoogeveen R.C.
        • Chambless L.
        • et al.
        Lipoprotein-associated phospholipase A2 and high-sensitivity C-reactive protein improve the stratification of ischemic stroke risk in the Atherosclerosis Risk in Communities (ARIC) Study.
        Stroke. 2009; 40: 376-381
        • Vasan R.S.
        • Sullivan L.M.
        • Roubenoff R.
        • et al.
        Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham Heart Study.
        Circulation. 2003; 107: 1486-1491
        • Halvorsen B.
        • Lund Sagen E.
        • Ueland T.
        • et al.
        Effect of smoking cessation on markers of inflammation and endothelial cell activation among individuals with high risk for cardiovascular disease.
        Scand J Clin Lab Invest. 2007; 67: 604-611
        • Levitzky Y.S.
        • Guo C.Y.
        • Rong J.
        • et al.
        Relation of smoking status to a panel of inflammatory markers: the Framingham Offspring.
        Atherosclerosis. 2008; 201: 217-224
        • Pou K.M.
        • Massaro J.M.
        • Hoffmann U.
        • et al.
        Visceral and subcutaneous adipose tissue volumes are cross-sectionally related to markers of inflammation and oxidative stress: the Framingham Heart Study.
        Circulation. 2007; 116: 1234-1241
        • Park H.S.
        • Park J.Y.
        • Yu R.
        Relationship of obesity and visceral adiposity with serum concentrations of CRP, TNF-alpha and IL-6.
        Diabetes Res Clin Pract. 2005; 69: 29-35
        • Festa A.
        • D'Agostino Jr., R.
        • Williams K.
        • et al.
        The relation of body fat mass and distribution to markers of chronic inflammation.
        Int J Obes Relat Metab Disord. 2001; 25: 1407-1415
        • Robker R.L.
        • Collins R.G.
        • Beaudet A.L.
        • et al.
        Leukocyte migration in adipose tissue of mice null for sICAM-1 and Mac-1 adhesion receptors.
        Obes Res. 2004; 12: 936-940
        • Esposito K.
        • Pontillo A.
        • Di Palo C.
        • et al.
        Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial.
        J Am Med Assoc. 2003; 289: 1799-1804
        • Selvin E.
        • Paynter N.P.
        • Erlinger T.P.
        The effect of weight loss on C-reactive protein: a systematic review.
        Arch Intern Med. 2007; 167: 31-39
        • Sakai A.
        • Kume N.
        • Nishi E.
        • et al.
        P-selectin and vascular cell adhesion molecule-1 are focally expressed in aortas of hypercholesterolemic rabbits before intimal accumulation of macrophages and T lymphocytes.
        Arterioscler Thromb Vasc Biol. 1997; 17: 310-316
        • Ivandic B.
        • Castellani L.W.
        • Wang X.P.
        • et al.
        Role of group II secretory phospholipase A2 in atherosclerosis: 1. Increased atherogenesis and altered lipoproteins in transgenic mice expressing group IIa phospholipase A2.
        Arterioscler Thromb Vasc Biol. 1999; 19: 1284-1290
        • Li H.
        • Cybulsky M.I.
        • Gimbrone Jr., M.A.
        • et al.
        An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium.
        Arterioscler Thromb. 1993; 13: 197-204
        • Libby P.
        • Ridker P.M.
        • Maseri A.
        Inflammation and atherosclerosis.
        Circulation. 2002; 105: 1135-1143
        • Ridker P.M.
        • Danielson E.
        • Fonseca F.A.
        • et al.
        Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.
        N.Engl.J Med. 2008; 359: 2195-2207
        • Bautista L.E.
        Inflammation, endothelial dysfunction, and the risk of high blood pressure: epidemiologic and biological evidence.
        J Hum Hypertens. 2003; 17: 223-230
        • Ridker P.M.
        • Danielson E.
        • Rifai N.
        • et al.
        Valsartan, blood pressure reduction, and C-reactive protein: primary report of the Val-MARC trial.
        Hypertension. 2006; 48: 73-79
        • Dehghan A.
        • Dupuis J.
        • Barbalic M.
        • et al.
        Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels.
        Circulation. 2011; 123: 731-738
        • Ridker P.M.
        • Hennekens C.H.
        • Rifai N.
        • et al.
        Hormone replacement therapy and increased plasma concentration of C-reactive protein.
        Circulation. 1999; 100: 713-716
        • van der Vaart H.
        • Postma D.S.
        • Timens W.
        • et al.
        Acute effects of cigarette smoke on inflammation and oxidative stress: a review.
        Thorax. 2004; 59: 713-721
        • Keaney Jr., J.F.
        • Larson M.G.
        • Vasan R.S.
        • et al.
        Obesity and systemic oxidative stress: clinical correlates of oxidative stress in the Framingham Study.
        Arterioscler Thromb Vasc Biol. 2003; 23: 434-439
        • Murabito J.M.
        • Keyes M.J.
        • Guo C.Y.
        • et al.
        Cross-sectional relations of multiple inflammatory biomarkers to peripheral arterial disease: the Framingham Offspring Study.
        Atherosclerosis. 2009; 203: 509-514
        • Currie C.J.
        • Poole C.D.
        • Conway P.
        Evaluation of the association between the first observation and the longitudinal change in C-reactive protein, and all-cause mortality.
        Heart. 2008; 94: 457-462