10-Year Associations Between Tumor Necrosis Factor Receptors 1 and 2 and Cardiovascular Events in Patients With Stable Coronary Heart Disease: A CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) Trial Substudy

Axel C Carlsson, Toralph Ruge, Erik Kjøller, Jørgen Hilden, Hans Jørn Kolmos, Ahmad Sajadieh, Jens Kastrup, Gorm Boje Jensen, Anders Larsson, Christoph Nowak, Janus Christian Jakobsen, Per Winkel, Christian Gluud, Johan Ärnlöv, Axel C Carlsson, Toralph Ruge, Erik Kjøller, Jørgen Hilden, Hans Jørn Kolmos, Ahmad Sajadieh, Jens Kastrup, Gorm Boje Jensen, Anders Larsson, Christoph Nowak, Janus Christian Jakobsen, Per Winkel, Christian Gluud, Johan Ärnlöv

Abstract

Background: We aimed to assess the associations and predictive powers between the soluble receptors for tumor necrosis factor (TNF)-α (TNFR1 and TNFR2) and cardiovascular outcomes in patients with stable coronary heart disease.

Methods and results: CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) is a randomized clinical trial comparing clarithromycin with placebo in patients with stable coronary heart disease. The primary outcome was a composite of nonfatal acute myocardial infarction, unstable angina pectoris, cerebrovascular disease, and all-cause mortality. Patients were followed up for 10 years; discovery sample, those assigned placebo (1204 events in n=1998); and replication sample, those assigned clarithromycin (1220 events in n=1979). We used Cox regression adjusted for C-reactive protein level, established cardiovascular risk factors, kidney function, and cardiovascular drugs. After adjustments, higher serum levels of TNFR1 and TNFR2 were associated with the composite outcome in the discovery sample (hazard ratio per SD increase, 1.13; 95% confidence interval, 1.05-1.22; P=0.001 for TNFR1; hazard ratio, 1.16; 95% confidence interval, 1.08-1.24; P<0.001 for TNFR2). The associations were similar in the replication sample. The associations with the composite outcome were mainly driven by acute myocardial infarction, cardiovascular mortality, and noncardiovascular mortality. The addition of TNFR1 and TNFR2 to established cardiovascular risk factors improved prediction only modestly (<1%).

Conclusions: Increased concentrations of circulating TNFR1 and TNFR2 were associated with increased risks of cardiovascular events and mortality in patients with stable coronary heart disease. Yet, the utility of measuring TNFR1 and TNFR2 to improve risk prediction in these patients appears limited.

Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00121550.

Keywords: cohort study; coronary atherosclerosis; tumor necrosis factor‐α.

© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Figures

Figure 1
Figure 1
Spline curve of the association between the soluble receptor for tumor necrosis factor‐α 1 (sTNFR1) and the composite outcome as hazard ratio with 95% confidence intervals (dotted lines) in the discovery cohort (A) and the replication cohort (B). The mean level of sTNFR1 was 1776±836 pg/mL in the discovery cohort and 1770±797 pg/mL in the replication cohort.
Figure 2
Figure 2
Spline curve of the association between the soluble receptor for tumor necrosis factor‐α 2 (sTNFR2) and the composite outcome as hazard ratio with 95% confidence intervals (dotted lines) in the discovery cohort (A) and the replication cohort (B). The mean level of sTNFR2 was 5386±2011 pg/mL in the discovery cohort and 5416±2099 pg/mL in the replication cohort.

References

    1. Cabal‐Hierro L, Lazo PS. Signal transduction by tumor necrosis factor receptors. Cell Signal. 2012;24:1297–1305.
    1. Pass HI, Mew D, Pass HA, Temeck BK. The macrophage, TNF, and other cytokines. Chest Surg Clin N Am. 1995;5:73–90.
    1. Carlsson AC, Juhlin CC, Larsson TE, Larsson A, Ingelsson E, Sundstrom J, Lind L, Arnlov J. Soluble tumor necrosis factor receptor 1 (sTNFR1) is associated with increased total mortality due to cancer and cardiovascular causes: findings from two community based cohorts of elderly. Atherosclerosis. 2014;237:236–242.
    1. Carlsson AC, Bandstein N, Roos A, Hammarsten O, Holzmann MJ. High‐sensitivity cardiac troponin T levels in the emergency department in patients with chest pain but no myocardial infarction. Int J Cardiol. 2017;228:253–259.
    1. Luna JM, Moon Y, Liu K, Spitalnik S, Paik M, Sacco R, Elkind MS. Tumour necrosis factor receptor 1 and mortality in a multi‐ethnic cohort: the Northern Manhattan Study. Age Ageing. 2013;42:385–390.
    1. Mattey DL, Glossop JR, Nixon NB, Dawes PT. Circulating levels of tumor necrosis factor receptors are highly predictive of mortality in patients with rheumatoid arthritis. Arthritis Rheum. 2007;56:3940–3948.
    1. Pai JK, Pischon T, Ma J, Manson JE, Hankinson SE, Joshipura K, Curhan GC, Rifai N, Cannuscio CC, Stampfer MJ, Rimm EB. Inflammatory markers and the risk of coronary heart disease in men and women. N Engl J Med. 2004;351:2599–2610.
    1. Saulnier PJ, Gand E, Ragot S, Ducrocq G, Halimi JM, Hulin‐Delmotte C, Llaty P, Montaigne D, Rigalleau V, Roussel R, Velho G, Sosner P, Zaoui P, Hadjadj S. Association of serum concentration of TNFR1 with all‐cause mortality in patients with type 2 diabetes and chronic kidney disease: follow‐up of the SURDIAGENE cohort. Diabetes Care. 2014;37:1425–1431.
    1. Schnabel RB, Yin X, Larson MG, Yamamoto JF, Fontes JD, Kathiresan S, Rong J, Levy D, Keaney JF Jr, Wang TJ, Murabito JM, Vasan RS, Benjamin EJ. Multiple inflammatory biomarkers in relation to cardiovascular events and mortality in the community. Arterioscler Thromb Vasc Biol. 2013;33:1728–1733.
    1. Shai I, Schulze MB, Manson JE, Rexrode KM, Stampfer MJ, Mantzoros C, Hu FB. A prospective study of soluble tumor necrosis factor‐alpha receptor ii (sTNF‐RII) and risk of coronary heart disease among women with type 2 diabetes. Diabetes Care. 2005;28:1376–1382.
    1. Winkel P, Hilden J, Hansen JF, Kastrup J, Kolmos HJ, Kjoller E, Jensen GB, Skoog M, Lindschou J, Gluud C. Clarithromycin for stable coronary heart disease increases all‐cause and cardiovascular mortality and cerebrovascular morbidity over 10 years in the CLARICOR randomised, blinded clinical trial. Int J Cardiol. 2015;182:459–465.
    1. Jespersen CM, Als‐Nielsen B, Damgaard M, Hansen JF, Hansen S, Helo OH, Hildebrandt P, Hilden J, Jensen GB, Kastrup J, Kolmos HJ, Kjoller E, Lind I, Nielsen H, Petersen L, Gluud C; CLARICOR Trial Group . Randomised placebo controlled multicentre trial to assess short term clarithromycin for patients with stable coronary heart disease: CLARICOR trial. BMJ. 2006;332:22–27.
    1. Gluud C, Als‐Nielsen B, Damgaard M, Fischer Hansen J, Hansen S, Helo OH, Hildebrandt P, Hilden J, Jensen GB, Kastrup J, Kolmos HJ, Kjoller E, Lind I, Nielsen H, Petersen L, Jespersen CM; CLARICOR Trial Group . Clarithromycin for 2 weeks for stable coronary heart disease: 6‐year follow‐up of the CLARICOR randomized trial and updated meta‐analysis of antibiotics for coronary heart disease. Cardiology. 2008;111:280–287.
    1. Hilden J, Lind I, Kolmos HJ, Als‐Nielsen B, Damgaard M, Hansen JF, Hansen S, Helo OH, Hildebrandt P, Jensen GB, Kastrup J, Kjoller E, Nielsen H, Petersen L, Jespersen CM, Gluud C; CLARICOR Trial Group . Chlamydia pneumoniae IgG and IgA antibody titers and prognosis in patients with coronary heart disease: results from the CLARICOR trial. Diagn Microbiol Infect Dis. 2010;66:385–392.
    1. Jespersen CM, Kolmos HJ, Frydendall N, Hilden J, Gluud C, Hansen JF; CLARICOR Trial Group . Compliance with and short‐term adverse events from clarithromycin versus placebo in patients with stable coronary heart disease: the CLARICOR trial. J Antimicrob Chemother. 2009;64:411–415.
    1. Winkel P, Jakobsen JC, Hilden J, Lange T, Jensen GB, Kjoller E, Sajadieh A, Kastrup J, Kolmos HJ, Larsson A, Arnlov J, Gluud C. Predictors for major cardiovascular outcomes in stable ischaemic heart disease (PREMAC): statistical analysis plan for data originating from the CLARICOR (clarithromycin for patients with stable coronary heart disease) trial. Diagn Progn Res. 2017;1:10.
    1. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF III, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604–612.
    1. Kjoller E, Hilden J, Winkel P, Frandsen NJ, Galatius S, Jensen G, Kastrup J, Hansen JF, Kolmos HJ, Jespersen CM, Hildebrandt P, Gluud C; CLARICOR Trial Group . Good interobserver agreement was attainable on outcome adjudication in patients with stable coronary heart disease. J Clin Epidemiol. 2012;65:444–453.
    1. Greenland P, Knoll MD, Stamler J, Neaton JD, Dyer AR, Garside DB, Wilson PW. Major risk factors as antecedents of fatal and nonfatal coronary heart disease events. JAMA. 2003;290:891–897.
    1. Khot UN, Khot MB, Bajzer CT, Sapp SK, Ohman EM, Brener SJ, Ellis SG, Lincoff AM, Topol EJ. Prevalence of conventional risk factors in patients with coronary heart disease. JAMA. 2003;290:898–904.
    1. Carlsson AC, Larsson TE, Helmersson‐Karlqvist J, Larsson A, Lind L, Arnlov J. Soluble TNF receptors and kidney dysfunction in the elderly. J Am Soc Nephrol. 2014;25:1313–1320.
    1. Carlsson AC, Nordquist L, Larsson TE, Carrero JJ, Larsson A, Lind L, Arnlov J. Soluble tumor necrosis factor receptor 1 is associated with glomerular filtration rate progression and incidence of chronic kidney disease in two community‐based cohorts of elderly individuals. Cardiorenal Med. 2015;5:278–288.
    1. Bottai M, Zhang J. Laplace regression with censored data. Biom J. 2010;52:487–503.
    1. Kjoller E, Hilden J, Winkel P, Galatius S, Frandsen NJ, Jensen GB, Fischer Hansen J, Kastrup J, Jespersen CM, Hildebrandt P, Kolmos HJ, Gluud C; CLARICOR Trial Group . Agreement between public register and adjudication committee outcome in a cardiovascular randomized clinical trial. Am Heart J. 2014;168:197–204.e191–194.
    1. Nilsson L, Szymanowski A, Swahn E, Jonasson L. Soluble TNF receptors are associated with infarct size and ventricular dysfunction in ST‐elevation myocardial infarction. PLoS One. 2013;8:e55477.
    1. Mizia‐Stec K, Gasior Z, Zahorska‐Markiewicz B, Holecki M, Kumor P. Inflammatory markers in a 2‐year follow‐up of coronary artery disease. Heart Vessels. 2006;21:302–308.
    1. Safranow K, Dziedziejko V, Rzeuski R, Czyzycka E, Wojtarowicz A, Binczak‐Kuleta A, Jakubowska K, Olszewska M, Ciechanowicz A, Kornacewicz‐Jach Z, Machalinski B, Pawlik A, Chlubek D. Plasma concentrations of TNF‐alpha and its soluble receptors sTNFR1 and sTNFR2 in patients with coronary artery disease. Tissue Antigens. 2009;74:386–392.
    1. Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32:2045–2051.
    1. Ferreira GA, Teixeira AL, Calderaro DC, Sato EI. Atorvastatin reduced soluble receptors of TNF‐alpha in systemic lupus erythematosus. Clin Exp Rheumatol. 2016;34:42–48.
    1. Ridker PM. C‐reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus. J Am Coll Cardiol. 2007;49:2129–2138.
    1. Esposito K, Nappo F, Marfella R, Giugliano G, Giugliano F, Ciotola M, Quagliaro L, Ceriello A, Giugliano D. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation. 2002;106:2067–2072.
    1. Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Oxidative stress and stress‐activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr Rev. 2002;23:599–622.
    1. Fernandez‐Real JM, Broch M, Ricart W, Casamitjana R, Gutierrez C, Vendrell J, Richart C. Plasma levels of the soluble fraction of tumor necrosis factor receptor 2 and insulin resistance. Diabetes. 1998;47:1757–1762.
    1. Ohgushi M, Taniguchi A, Fukushima M, Nakai Y, Kuroe A, Ohya M, Nagasaka S, Taki Y, Yoshii S, Matsumoto K, Yamada Y, Inagaki N, Seino Y. Soluble tumor necrosis factor receptor 2 is independently associated with pulse wave velocity in nonobese Japanese patients with type 2 diabetes mellitus. Metabolism. 2007;56:571–577.
    1. Kim HL, Lee JP, An JN, Kim JH, Lim WH, Seo JB, Chung WY, Oh YK, Kim YS, Lim CS, Zo JH, Kim MA, Kim SH. Soluble tumor necrosis factor receptors and arterial stiffness in patients with coronary atherosclerosis. Am J Hypertens. 2017;30:313–318.
    1. Morange PE, Alessi MC. Thrombosis in central obesity and metabolic syndrome: mechanisms and epidemiology. Thromb Haemost. 2013;110:669–680.
    1. Sugano M, Tsuchida K, Makino N. Intramuscular gene transfer of soluble tumor necrosis factor‐alpha receptor 1 activates vascular endothelial growth factor receptor and accelerates angiogenesis in a rat model of hindlimb ischemia. Circulation. 2004;109:797–802.
    1. Gohda T, Niewczas MA, Ficociello LH, Walker WH, Skupien J, Rosetti F, Cullere X, Johnson AC, Crabtree G, Smiles AM, Mayadas TN, Warram JH, Krolewski AS. Circulating TNF receptors 1 and 2 predict stage 3 CKD in type 1 diabetes. J Am Soc Nephrol. 2012;23:516–524.
    1. Niewczas MA, Gohda T, Skupien J, Smiles AM, Walker WH, Rosetti F, Cullere X, Eckfeldt JH, Doria A, Mayadas TN, Warram JH, Krolewski AS. Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes. J Am Soc Nephrol. 2012;23:507–515.
    1. Bae E, Cha RH, Kim YC, An JN, Kim DK, Yoo KD, Lee SM, Kim MH, Park JT, Kang SW, Park JY, Lim CS, Kim YS, Yang SH, Lee JP. Circulating TNF receptors predict cardiovascular disease in patients with chronic kidney disease. Medicine (Baltimore). 2017;96:e6666.
    1. Knight EL, Rimm EB, Pai JK, Rexrode KM, Cannuscio CC, Manson JE, Stampfer MJ, Curhan GC. Kidney dysfunction, inflammation, and coronary events: a prospective study. J Am Soc Nephrol. 2004;15:1897–1903.
    1. Feldman AM, Mann DL, She L, Bristow MR, Maisel AS, McNamara DM, Walsh R, Lee DL, Wos S, Lang I, Wells G, Drazner MH, Schmedtje JF Jr, Pauly DF, Sueta CA, Di Maio M, Kron IL, Velazquez EJ, Lee KL. Prognostic significance of biomarkers in predicting outcome in patients with coronary artery disease and left ventricular dysfunction: results of the biomarker substudy of the Surgical Treatment for Ischemic Heart Failure trials. Circ Heart Fail. 2013;6:461–472.
    1. Ueland T, Kjekshus J, Froland SS, Omland T, Squire IB, Gullestad L, Dickstein K, Aukrust P. Plasma levels of soluble tumor necrosis factor receptor type i during the acute phase following complicated myocardial infarction predicts survival in high‐risk patients. J Am Coll Cardiol. 2005;46:2018–2021.
    1. Valgimigli M, Ceconi C, Malagutti P, Merli E, Soukhomovskaia O, Francolini G, Cicchitelli G, Olivares A, Parrinello G, Percoco G, Guardigli G, Mele D, Pirani R, Ferrari R. Tumor necrosis factor‐alpha receptor 1 is a major predictor of mortality and new‐onset heart failure in patients with acute myocardial infarction: the Cytokine‐Activation and Long‐Term Prognosis in Myocardial Infarction (C‐ALPHA) study. Circulation. 2005;111:863–870.
    1. Carlsson AC, Carrero JJ, Stenvinkel P, Bottai M, Barany P, Larsson A, Arnlov J. High levels of soluble tumor necrosis factor receptors 1 and 2 and their association with mortality in patients undergoing hemodialysis. Cardiorenal Med. 2015;5:89–95.
    1. Thalayasingam N, Isaacs JD. Anti‐TNF therapy. Best Pract Res Clin Rheumatol. 2011;25:549–567.
    1. Bozkurt B, Torre‐Amione G, Warren MS, Whitmore J, Soran OZ, Feldman AM, Mann DL. Results of targeted anti‐tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure. Circulation. 2001;103:1044–1047.
    1. Monden Y, Kubota T, Tsutsumi T, Inoue T, Kawano S, Kawamura N, Ide T, Egashira K, Tsutsui H, Sunagawa K. Soluble TNF receptors prevent apoptosis in infiltrating cells and promote ventricular rupture and remodeling after myocardial infarction. Cardiovasc Res. 2007;73:794–805.

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