The impact of CD4⁺CD28^null T-lymphocytes on atrial fibrillation and mortality in patients with chronic heart failure

Summary

Atrial fibrillation (AF) represents the most common cardiac arrhythmia. Especially in patients with chronic heart failure (CHF) the development of AF represents a severe complication resulting in haemodynamic deterioration. While pro-inflammatory cytokines proved to have a pivotal role in the development and progression of both AF and CHF, less attention has been paid to the cellular immunity. Therefore we prospectively enrolled 112 patients with CHF and performed fluorescein-activated cell sorting (FACS). Patients were stratified in two subgroups according to patients presenting with AF (n=56) and patients free of AF (n=56). Comparing AF to non-AF patients we found a significantly lower fraction of regulatory T cells (p<0.001) in patients presenting with AF. However there was a higher fraction of CD4⁺ cells (p=0.007) and more specifically a significantly higher number of cytotoxic T cells characterised by the loss of CD28 within CD4 T cells (CD4+CD28^null; p=0.035) in individuals with AF. After a mean follow-up time of 4.5 years 32 (28.6 %) patients died due to cardiovascular causes. CD4+CD28^null cells were significantly associated with cardiovascular mortality in patients presenting with AF, with an adjusted HR per one standard deviation (1-SD) of 1.59 (95 % CI 1.13–2.24; p=0.008), but not in patients free of AF with an adjusted HR per 1-SD of 1.27 (95 % CI 0.86–1.87; p=0.216). We found that the fraction of CD4+CD28^null cells proved to be predictive on outcome in CHF-patients presenting with AF. Our results might indicate a potential role of CD4+CD28^null cells in the pathogenesis of AF which needs to be confirmed in future studies.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

CD4⁺CD28^null cells - atrial fibrillation - mortality - heart failure

• References

• 1 Lip GY. The prothrombotic state in atrial fibrillation: the atrium, the endothelium and tissue factor?. Thrombos Res 2003; 111: 133-135.
• 2 Conway DS, Buggins P, Hughes E, Lip GY. Relationship of interleukin-6 and C-reactive protein to the prothrombotic state in chronic atrial fibrillation. J Am Coll Cardiol 2004; 43: 2075-2082.
• 3 Johnson LS, Juhlin T, Engström G, Nilsson PM. Risk factor changes and incident atrial fibrillation among middle-aged men in the Malmö Preventive Project cohort. Eur Heart J Cardiovasc Pharmacother 2016; 02: 81-87.
• 4 Chung MK, Martin DO, Sprecher D. et al. C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation.. Circulation 2001; 104: 2886-2891.
• 5 Aviles RJ, Martin DO, Apperson-Hansen C. et al. Inflammation as a risk factor for atrial fibrillation.. Circulation 2003; 108: 3006-3010.
• 6 Dernellis J, Panaretou M. Effects of C-reactive protein and the third and fourth components of complement (C3 and C4) on incidence of atrial fibrillation. Am J Cardiol 2006; 97: 245-248.
• 7 Acuto O, Michel F. CD28-mediated co-stimulation: a quantitative support for TCR signaling. Nat Rev Immunol 2003; 03: 939-951.
• 8 Liuzzo G, Goronzy JJ, Yang H. et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes.. Circulation 2000; 101: 2883-2888.
• 9 Thewissen M, Somers V, Hellings N. et al. CD4+CD28null T cells in autoimmune disease: pathogenic features and decreased susceptibility to immunoregulation.. J Immunol 2007; 179: 6514-6523.
• 10 Sakaguchi S, Yamaguchi T, Nomura T. Ono M. Regulatory T cells and immune tolerance. Cell 2008; 133: 775-787.
• 11 Weyand CM, Brandes JC, Schmidt D. et al. Functional properties of CD4+ CD28-T cells in the aging immune system.. Mech Age Dev 1998; 102: 131-147.
• 12 Schmidt D, Goronzy JJ, Weyand CM. CD4+ CD7- CD28- T cells are expanded in rheumatoid arthritis and are characterized by autoreactivity. J Clin Invest 1996; 97: 2027-2037.
• 13 Liuzzo G, Kopecky SL, Frye RL. et al. Perturbation of the T-cell repertoire in patients with unstable angina.. Circulation 1999; 100: 2135-2139.
• 14 Daugherty A, Rateri DL. T lymphocytes in atherosclerosis: the yin-yang of Th1 and Th2 influence on lesion formation. Circ Res 2002; 90: 1039-1040.
• 15 Nadareishvili ZG, Li H, Wright V. et al. Elevated pro-inflammatory CD4+CD28- lymphocytes and stroke recurrence and death.. Neurology 2004; 63: 1446-1451.
• 16 Tuttolomondo A, Pecoraro R, Casuccio A. et al. Peripheral frequency of CD4+ CD28- cells in acute ischemic stroke: relationship with stroke subtype and severity markers.. Medicine 2015; 94: e813.
• 17 McMurray JJ, Adamopoulos S, Anker SD. et al. ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC.. Eur Heart J 2012; 33: 1787-1847.
• 18 Ponikowski P, Voors AA, Anker SD. et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart FailureAssociation (HFA) of the ESC.. Eur J Heart Fail 2016; 18: 891-975.
• 19 Kirchhof P, Benussi S, Kotecha D. et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS: The Task Force for the management of atrial fibrillation of the European Society of Cardiology (ESC)Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESCEndorsed by the European Stroke Organisation (ESO).. Eur Heart J 2016; Pii: ehw210.
• 20 http://apps.who.int/classifications/icd/icd10updates/en/index.html. Accessed February1, 2016.
• 21 Koller L, Richter B, Goliasch G. et al. CD4+ CD28(null) cells are an independent predictor of mortality in patients with heart failure.. Atherosclerosis 2013; 230: 414-416.
• 22 Liuzzo G, Biasucci LM, Trotta G. et al. Unusual CD4+CD28null T lymphocytes and recurrence of acute coronary events.. J Am Coll Cardiol 2007; 50: 1450-1458.
• 23 Weber C, Shantsila E, Hristov M. et al. Role and analysis of monocyte subsets in cardiovascular disease. Joint consensus document of the European Society of Cardiology (ESC) Working Groups "Atherosclerosis & Vascular Biology" and "Thrombosis".. Thromb Haemost 2016; 116: 626-637.
• 24 Banham AH, Powrie FM, Suri-Payer E. FOXP3+ regulatory T cells: Current controversies and future perspectives. Eur J Immunol 2006; 36: 2832-2836.
• 25 Salazar-Fontana LI, Sanz E, Mérida I. et al. Cell surface CD28 levels define four CD4+ T cell subsets: abnormal expression in rheumatoid arthritis.. Clin Immunol 2001; 99: 253-265.
• 26 Rauchhaus M, Doehner W, Francis DP. et al. Plasma cytokine parameters and mortality in patients with chronic heart failure.. Circulation 2000; 102: 3060-3067.
• 27 Vallejo AN, Weyand CM, Goronzy JJ. T-cell senescence: a culprit of immune abnormalities in chronic inflammation and persistent infection. Trends Mol Med 2004; 10: 119-124.
• 28 Heymans S, Hirsch E, Anker SD. et al. Inflammation as a therapeutic target in heart failure? A scientific statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology.. Eur J Heart Fail 2009; 11: 119-129.
• 29 Qu YC, Du YM, Wu SL. et al. Activated nuclear factor-kappaB and increased tumor necrosis factor-alpha in atrial tissue of atrial fibrillation.. Scand Cardiovasc J 2009; 43: 292-297.
• 30 Deng H, Xue YM, Zhan XZ. et al. Role of tumor necrosis factor-alpha in the pathogenesis of atrial fibrillation.. Chin Med J 2011; 124: 1976-1982.
• 31 Li J, Solus J, Chen Q. et al. Role of inflammation and oxidative stress in atrial fibrillation.. Heart Rhythm 2010; 07: 438-444.
• 32 Liuzzo G, Goronzy JJ, Yang H. et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes.. Circulation 2000; 101: 2883-2888.
• 33 Schmidt D, Martens PB, Weyand CM, Goronzy JJ. The repertoire of CD4+ CD28- T cells in rheumatoid arthritis. Mol Med 1996; 02: 608-618.
• 34 Namekawa T, Wagner UG, Goronzy JJ, Weyand CM. Functional subsets of CD4 T cells in rheumatoid synovitis. Arthritis Rheum 1998; 41: 2108-2116.
• 35 Warrington KJ, Takemura S, Goronzy JJ, Weyand CM. CD4+,CD28- T cells in rheumatoid arthritis patients combine features of the innate and adaptive immune systems. Arthritis Rheum 2001; 44: 13-20.
• 36 Nakajima T, Schulte S, Warrington KJ. et al. T-cell-mediated lysis of endothelial cells in acute coronary syndromes.. Circulation 2002; 105: 570-575.
• 37 Pryshchep S, Sato K, Goronzy JJ, Weyand CM. T cell recognition and killing of vascular smooth muscle cells in acute coronary syndrome. Circ Res 2006; 98: 1168-1176.
• 38 Sato K, Niessner A, Kopecky SL. et al. TRAIL-expressing T cells induce apoptosis of vascular smooth muscle cells in the atherosclerotic plaque.. J Exp Med 2006; 203: 239-250.
• 39 Rotter M, Jaïs P, Vergnes MC. et al. Decline in C-reactive protein after successful ablation of long-lasting persistent atrial fibrillation.. J Am Coll Cardiol 2006; 47: 1231-1233.
• 40 Acevedo M, Corbalán R, Braun S. et al. C-reactive protein and atrial fibrillation: „evidence for the presence of inflammation in the perpetuation of the arrhythmia“.. Int J Cardiol 2006; 108: 326-331.
• 41 Warrington KJ, Vallejo AN, Weyand CM, Goronzy JJ. CD28 loss in senescent CD4+ T cells: reversal by interleukin-12 stimulation. Blood 2003; 101: 3543-3549.
• 42 Bryl E, Vallejo AN, Matteson EL. et al. Modulation of CD28 expression with anti-tumor necrosis factor alpha therapy in rheumatoid arthritis.. Arthritis Rheum 2005; 52: 2996-3003.