Heart Failure Reviews

, Volume 18, Issue 6, pp 835–845 | Cite as

The immunological axis in heart failure: importance of the leukocyte differential

  • Muthiah Vaduganathan
  • Stephen J. Greene
  • Javed Butler
  • Hani N. Sabbah
  • Eduard Shantsila
  • Gregory Y. H. Lip
  • Mihai Gheorghiade


The important role of the immune system and inflammation in the pathophysiology of heart failure (HF) is becoming increasingly appreciated. We have reviewed the prognostic significance of under-recognized aspects of the leukocyte differential in HF, including lymphocytes, monocytes, eosinophils and mast cells. Studies to date evaluating lymphocyte counts in both chronic and hospitalized HF patients have consistently shown worse prognosis associated with low lymphocyte counts, despite widely heterogeneous study designs. Limited data suggest elevations in monocyte-derived cytokines and serum monocyte count may be predictive of poor outcomes in HF. Further data are required to better define the relationship between eosinophils, mast cells and HF. Leukocyte differentials are widely available, simple, inexpensive and appear to have independent prognostic significance, beyond traditional risk factors. Enhanced sympathetic activation and increased circulating cytokine levels (particularly tumor necrosis factor) have been implicated in the variability of leukocyte subpopulations. To date, immune-modulators targeting these mediators have been largely unsuccessful in improving cardiovascular outcomes in HF. Given the potential role of the immunological axis in HF, there may be an unmet need for novel therapeutic agents that can safely and effectively ameliorate these leukocyte derangements and perhaps improve the unacceptably high event rate in this population. Variations in leukocyte differentials may identify a high-risk subset of patients that may benefit from tailored immune therapies.


Heart failure Immune activation Inflammation Prognosis Outcomes 




Conflict of interest



  1. 1.
    Jencks SF, Williams MV, Coleman EA (2009) Rehospitalizations among patients in the Medicare fee-for-service program. New Engl J Med 360(14):1418–1428. doi: 10.1056/NEJMsa0803563 PubMedCrossRefGoogle Scholar
  2. 2.
    Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Soliman EZ, Sorlie PD, Sotoodehnia N, Turan TN, Virani SS, Wong ND, Woo D, Turner MB (2012) Heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation 125(1):e2–e220. doi: 10.1161/CIR.0b013e31823ac046 PubMedCrossRefGoogle Scholar
  3. 3.
    Ahmed A, Allman RM, Fonarow GC, Love TE, Zannad F, Dell’italia LJ, White M, Gheorghiade M (2008) Incident heart failure hospitalization and subsequent mortality in chronic heart failure: a propensity-matched study. J Card Fail 14(3):211–218. doi: 10.1016/j.cardfail.2007.12.001 PubMedCrossRefGoogle Scholar
  4. 4.
    Fonarow GC, Abraham WT, Albert NM, Stough WG, Gheorghiade M, Greenberg BH, O’Connor CM, Pieper K, Sun JL, Yancy C, Young JB (2007) Association between performance measures and clinical outcomes for patients hospitalized with heart failure. JAMA 297(1):61–70. doi: 10.1001/jama.297.1.61 PubMedCrossRefGoogle Scholar
  5. 5.
    Bueno H, Ross JS, Wang Y, Chen J, Vidan MT, Normand SL, Curtis JP, Drye EE, Lichtman JH, Keenan PS, Kosiborod M, Krumholz HM (2010) Trends in length of stay and short-term outcomes among Medicare patients hospitalized for heart failure, 1993–2006. J Am Med Assoc 303(21):2141–2147. doi: 10.1001/jama.2010.748 CrossRefGoogle Scholar
  6. 6.
    Gheorghiade M, Pang PS (2009) Acute heart failure syndromes. J Am Coll Cardiol 53(7):557–573. doi: 10.1016/j.jacc.2008.10.041 PubMedCrossRefGoogle Scholar
  7. 7.
    Gheorghiade M, Pang PS, Ambrosy AP, Lan G, Schmidt P, Filippatos G, Konstam M, Swedberg K, Cook T, Traver B, Maggioni A, Burnett J, Grinfeld L, Udelson J, Zannad F (2011) A comprehensive, longitudinal description of the in-hospital and post-discharge clinical, laboratory, and neurohormonal course of patients with heart failure who die or are re-hospitalized within 90 days: analysis from the EVEREST trial. Heart Fail Rev. doi: 10.1007/s10741-011-9280-0 Google Scholar
  8. 8.
    McDonagh TA, Komajda M, Maggioni AP, Zannad F, Gheorghiade M, Metra M, Dargie HJ (2011) Clinical trials in acute heart failure: simpler solutions to complex problems. Consensus document arising from a European Society of Cardiology cardiovascular round-table think tank on acute heart failure, 12 May 2009. Eur J Heart Fail 13(12):1253–1260. doi: 10.1093/eurjhf/hfr126 PubMedCrossRefGoogle Scholar
  9. 9.
    Nunez J, Minana G, Bodi V, Nunez E, Sanchis J, Husser O, Llacer A (2011) Low lymphocyte count and cardiovascular diseases. Curr Med Chem 18(21):3226–3233PubMedCrossRefGoogle Scholar
  10. 10.
    Wrigley BJ, Lip GY, Shantsila E (2011) The role of monocytes and inflammation in the pathophysiology of heart failure. Eur J Heart Fail 13(11):1161–1171. doi: 10.1093/eurjhf/hfr122 PubMedCrossRefGoogle Scholar
  11. 11.
    Novack V, Pencina M, Zahger D, Fuchs L, Nevzorov R, Jotkowitz A, Porath A (2010) Routine laboratory results and thirty day and one-year mortality risk following hospitalization with acute decompensated heart failure. PLoS ONE 5(8):e12184. doi: 10.1371/journal.pone.0012184 PubMedCrossRefGoogle Scholar
  12. 12.
    Milo-Cotter O, Felker GM, Uriel N, Kaluski E, Edwards C, Rund MM, Weatherley BD, Cotter G (2011) Patterns of leukocyte counts on admissions for acute heart failure–presentation and outcome–results from a community based registry. Int J Cardiol 148(1):17–22. doi: 10.1016/j.ijcard.2009.10.009 PubMedCrossRefGoogle Scholar
  13. 13.
    Cooper HA, Exner DV, Waclawiw MA, Domanski MJ (1999) White blood cell count and mortality in patients with ischemic and nonischemic left ventricular systolic dysfunction (an analysis of the studies of left ventricular dysfunction [SOLVD]). Am J Cardiol 84(3):252–257PubMedCrossRefGoogle Scholar
  14. 14.
    Arruda-Olson AM, Reeder GS, Bell MR, Weston SA, Roger VL (2009) Neutrophilia predicts death and heart failure after myocardial infarction: a community-based study. Circ Cardiovasc Qual Outcomes 2(6):656–662. doi: 10.1161/CIRCOUTCOMES.108.831024 PubMedCrossRefGoogle Scholar
  15. 15.
    Rashidi F, Rashidi A, Golmohamadi A, Hoseinzadeh E, Mohammadi B, Mirzajani H, Kheiri M, Jamshidi P (2008) Does absolute neutrophilia predict early congestive heart failure after acute myocardial infarction? A cross-sectional study. South Med J 101(1):19–23. doi: 10.1097/SMJ.0b013e31815d3e11 PubMedCrossRefGoogle Scholar
  16. 16.
    Kyne L, Hausdorff JM, Knight E, Dukas L, Azhar G, Wei JY (2000) Neutrophilia and congestive heart failure after acute myocardial infarction. Am Heart J 139(1 Pt 1):94–100PubMedCrossRefGoogle Scholar
  17. 17.
    Peschel T, Schonauer M, Thiele H, Anker SD, Schuler G, Niebauer J (2003) Invasive assessment of bacterial endotoxin and inflammatory cytokines in patients with acute heart failure. Eur J Heart Fail 5(5):609–614PubMedCrossRefGoogle Scholar
  18. 18.
    Krack A, Sharma R, Figulla HR, Anker SD (2005) The importance of the gastrointestinal system in the pathogenesis of heart failure. Eur Heart J 26(22):2368–2374. doi: 10.1093/eurheartj/ehi389 PubMedCrossRefGoogle Scholar
  19. 19.
    Niebauer J, Volk HD, Kemp M, Dominguez M, Schumann RR, Rauchhaus M, Poole-Wilson PA, Coats AJ, Anker SD (1999) Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet 353(9167):1838–1842. doi: 10.1016/S0140-6736(98)09286-1 PubMedCrossRefGoogle Scholar
  20. 20.
    von Haehling S, Schefold JC, Jankowska E, Doehner W, Springer J, Strohschein K, Genth-Zotz S, Volk HD, Poole-Wilson P, Anker SD (2009) Leukocyte redistribution: effects of beta blockers in patients with chronic heart failure. PLoS ONE 4(7):e6411. doi: 10.1371/journal.pone.0006411 CrossRefGoogle Scholar
  21. 21.
    Castro A, Bemer V, Nobrega A, Coutinho A, Truffa-Bachi P (1998) Administration to mouse of endotoxin from gram-negative bacteria leads to activation and apoptosis of T lymphocytes. Eur J Immunol 28(2):488–495. doi: 10.1002/(SICI)1521-4141(199802)28:02<488:AID-IMMU488>3.0.CO;2-R PubMedCrossRefGoogle Scholar
  22. 22.
    Maisel AS, Knowlton KU, Fowler P, Rearden A, Ziegler MG, Motulsky HJ, Insel PA, Michel MC (1990) Adrenergic control of circulating lymphocyte subpopulations. Effects of congestive heart failure, dynamic exercise, and terbutaline treatment. J Clin Investig 85(2):462–467. doi: 10.1172/JCI114460 PubMedCrossRefGoogle Scholar
  23. 23.
    Thomson SP, McMahon LJ, Nugent CA (1980) Endogenous cortisol: a regulator of the number of lymphocytes in peripheral blood. Clin Immunol Immunopathol 17(4):506–514PubMedCrossRefGoogle Scholar
  24. 24.
    Huehnergarth KV, Mozaffarian D, Sullivan MD, Crane BA, Wilkinson CW, Lawler RL, McDonald GB, Fishbein DP, Levy WC (2005) Usefulness of relative lymphocyte count as an independent predictor of death/urgent transplant in heart failure. Am J Cardiol 95(12):1492–1495. doi: 10.1016/j.amjcard.2005.02.022 PubMedCrossRefGoogle Scholar
  25. 25.
    Torre-Amione G (2005) Immune activation in chronic heart failure. Am J Cardiol 95(11A):3C-8C; discussion 38C-40C. doi: 10.1016/j.amjcard.2005.03.006
  26. 26.
    Battin DL, Ali S, Shahbaz AU, Massie JD, Munir A, Davis RC Jr, Newman KP, Weber KT (2010) Hypoalbuminemia and lymphocytopenia in patients with decompensated biventricular failure. Am J Med Sci 339(1):31–35. doi: 10.1097/MAJ.0b013e3181bfc83f PubMedCrossRefGoogle Scholar
  27. 27.
    Ali S, Shahbaz AU, Nelson MD, Shirwany A, Munir A, D’Cruz IC, Weber KT (2009) Reduced relative lymphocyte count in african-americans with decompensated heart failure. Am J Med Sci 337(3):156–160. doi: 10.1097/MAJ.0b013e318182198f PubMedCrossRefGoogle Scholar
  28. 28.
    Charach G, Grosskopf I, Roth A, Afek A, Wexler D, Sheps D, Weintraub M, Rabinovich A, Keren G, George J (2011) Usefulness of total lymphocyte count as predictor of outcome in patients with chronic heart failure. Am J Cardiol 107(9):1353–1356. doi: 10.1016/j.amjcard.2010.12.049 PubMedCrossRefGoogle Scholar
  29. 29.
    Sakatani T, Hadase M, Kawasaki T, Kamitani T, Kawasaki S, Sugihara H (2004) Usefulness of the percentage of plasma lymphocytes as a prognostic marker in patients with congestive heart failure. Jpn Heart J 45(2):275–284PubMedCrossRefGoogle Scholar
  30. 30.
    Ommen SR, Hodge DO, Rodeheffer RJ, McGregor CG, Thomson SP, Gibbons RJ (1998) Predictive power of the relative lymphocyte concentration in patients with advanced heart failure. Circulation 97(1):19–22PubMedCrossRefGoogle Scholar
  31. 31.
    Ommen SR, Hammill SC, Gibbons RJ (2002) The relative lymphocyte count predicts death in patients receiving implantable cardioverter defibrillators. Pacing Clin Electrophysiol PACE 25(10):1424–1428CrossRefGoogle Scholar
  32. 32.
    Acanfora D, Gheorghiade M, Trojano L, Furgi G, Pasini E, Picone C, Papa A, Iannuzzi GL, Bonow RO, Rengo F (2001) Relative lymphocyte count: a prognostic indicator of mortality in elderly patients with congestive heart failure. Am Heart J 142(1):167–173PubMedCrossRefGoogle Scholar
  33. 33.
    Rudiger A, Burckhardt OA, Harpes P, Muller SA, Follath F (2006) The relative lymphocyte count on hospital admission is a risk factor for long-term mortality in patients with acute heart failure. Am J Emerg Med 24(4):451–454. doi: 10.1016/j.ajem.2005.10.010 PubMedCrossRefGoogle Scholar
  34. 34.
    Nunez J, Nunez E, Minana G, Sanchis J, Bodi V, Rumiz E, Palau P, Olivares M, Merlos P, Bonanad C, Mainar L, Llacer A (2011) Effectiveness of the relative lymphocyte count to predict one-year mortality in patients with acute heart failure. Am J Cardiol 107(7):1034–1039. doi: 10.1016/j.amjcard.2010.11.029 PubMedCrossRefGoogle Scholar
  35. 35.
    Milo-Cotter O, Teerlink JR, Metra M, Felker GM, Ponikowski P, Voors AA, Edwards C, Weatherley BD, Greenberg B, Filippatos G, Unemori E, Teichman SL, Cotter G (2010) Low lymphocyte ratio as a novel prognostic factor in acute heart failure: results from the Pre-RELAX-AHF study. Cardiology 117(3):190–196. doi: 10.1159/000321416 PubMedCrossRefGoogle Scholar
  36. 36.
    Pfister R, Sharp SJ, Luben R, Wareham NJ, Khaw KT (2012) Differential white blood cell count and incident heart failure in men and women in the EPIC-Norfolk study. Eur Heart J 33(4):523–530. doi: 10.1093/eurheartj/ehr457 PubMedCrossRefGoogle Scholar
  37. 37.
    Bekwelem W, Lutsey PL, Loehr LR, Agarwal SK, Astor BC, Guild C, Ballantyne CM, Folsom AR (2011) White blood cell count, C-reactive protein, and incident heart failure in the atherosclerosis risk in communities (ARIC) study. Ann Epidemiol 21(10):739–748. doi: 10.1016/j.annepidem.2011.06.005 PubMedCrossRefGoogle Scholar
  38. 38.
    Apostolakis S, Lip GY, Shantsila E (2010) Monocytes in heart failure: relationship to a deteriorating immune overreaction or a desperate attempt for tissue repair? Cardiovasc Res 85(4):649–660. doi: 10.1093/cvr/cvp327 PubMedCrossRefGoogle Scholar
  39. 39.
    Baumgarten G, Knuefermann P, Kalra D, Gao F, Taffet GE, Michael L, Blackshear PJ, Carballo E, Sivasubramanian N, Mann DL (2002) Load-dependent and -independent regulation of proinflammatory cytokine and cytokine receptor gene expression in the adult mammalian heart. Circulation 105(18):2192–2197PubMedCrossRefGoogle Scholar
  40. 40.
    Ferrari R, Bachetti T, Confortini R, Opasich C, Febo O, Corti A, Cassani G, Visioli O (1995) Tumor necrosis factor soluble receptors in patients with various degrees of congestive heart failure. Circulation 92(6):1479–1486PubMedCrossRefGoogle Scholar
  41. 41.
    Gu L, Tseng SC, Rollins BJ (1999) Monocyte chemoattractant protein-1. Chem Immunol 72:7–29PubMedCrossRefGoogle Scholar
  42. 42.
    Aukrust P, Ueland T, Muller F, Andreassen AK, Nordoy I, Aas H, Kjekshus J, Simonsen S, Froland SS, Gullestad L (1998) Elevated circulating levels of C–C chemokines in patients with congestive heart failure. Circulation 97(12):1136–1143PubMedCrossRefGoogle Scholar
  43. 43.
    Torre-Amione G (2005) Immune activation in chronic heart failure. Am J Cardiol 95(11A):3C–8C; discussion 38C–40C. doi: 10.1016/j.amjcard.2005.03.006 Google Scholar
  44. 44.
    Aukrust P, Ueland T, Lien E, Bendtzen K, Muller F, Andreassen AK, Nordoy I, Aass H, Espevik T, Simonsen S, Froland SS, Gullestad L (1999) Cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 83(3):376–382PubMedCrossRefGoogle Scholar
  45. 45.
    Comini L, Bachetti T, Agnoletti L, Gaia G, Curello S, Milanesi B, Volterrani M, Parrinello G, Ceconi C, Giordano A, Corti A, Ferrari R (1999) Induction of functional inducible nitric oxide synthase in monocytes of patients with congestive heart failure. Link with tumour necrosis factor-alpha. Eur Heart J 20(20):1503–1513. doi: 10.1053/euhj.1999.1580 PubMedCrossRefGoogle Scholar
  46. 46.
    Conraads VM, Bosmans JM, Schuerwegh AJ, Goovaerts I, De Clerck LS, Stevens WJ, Bridts CH, Vrints CJ (2005) Intracellular monocyte cytokine production and CD 14 expression are up-regulated in severe vs mild chronic heart failure. J Heart Lung Transpl Off Publ Int Soc Heart Transpl 24(7):854–859. doi: 10.1016/j.healun.2004.04.017 CrossRefGoogle Scholar
  47. 47.
    Vonhof S, Brost B, Stille-Siegener M, Grumbach IM, Kreuzer H, Figulla HR (1998) Monocyte activation in congestive heart failure due to coronary artery disease and idiopathic dilated cardiomyopathy. Int J Cardiol 63(3):237–244PubMedCrossRefGoogle Scholar
  48. 48.
    von Haehling S, Jankowska EA, Anker SD (2004) Tumour necrosis factor-alpha and the failing heart–pathophysiology and therapeutic implications. Basic Res Cardiol 99(1):18–28. doi: 10.1007/s00395-003-0433-8 CrossRefGoogle Scholar
  49. 49.
    Fredj S, Bescond J, Louault C, Delwail A, Lecron JC, Potreau D (2005) Role of interleukin-6 in cardiomyocyte/cardiac fibroblast interactions during myocyte hypertrophy and fibroblast proliferation. J Cell Physiol 204(2):428–436. doi: 10.1002/jcp.20307 PubMedCrossRefGoogle Scholar
  50. 50.
    Levine B, Kalman J, Mayer L, Fillit HM, Packer M (1990) Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 323(4):236–241. doi: 10.1056/NEJM199007263230405 PubMedCrossRefGoogle Scholar
  51. 51.
    Torre-Amione G, Kapadia S, Benedict C, Oral H, Young JB, Mann DL (1996) Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the studies of left ventricular dysfunction (SOLVD). J Am Coll Cardiol 27(5):1201–1206. doi: 10.1016/0735-1097(95)00589-7 PubMedCrossRefGoogle Scholar
  52. 52.
    Tsutamoto T, Hisanaga T, Wada A, Maeda K, Ohnishi M, Fukai D, Mabuchi N, Sawaki M, Kinoshita M (1998) Interleukin-6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukin-6 is an important prognostic predictor in patients with congestive heart failure. J Am Coll Cardiol 31(2):391–398PubMedCrossRefGoogle Scholar
  53. 53.
    Rauchhaus M, Doehner W, Francis DP, Davos C, Kemp M, Liebenthal C, Niebauer J, Hooper J, Volk HD, Coats AJ, Anker SD (2000) Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation 102(25):3060–3067PubMedCrossRefGoogle Scholar
  54. 54.
    Deswal A, Petersen NJ, Feldman AM, Young JB, White BG, Mann DL (2001) Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST). Circulation 103(16):2055–2059PubMedCrossRefGoogle Scholar
  55. 55.
    Maekawa Y, Anzai T, Yoshikawa T, Asakura Y, Takahashi T, Ishikawa S, Mitamura H, Ogawa S (2002) Prognostic significance of peripheral monocytosis after reperfused acute myocardial infarction:a possible role for left ventricular remodeling. J Am Coll Cardiol 39(2):241–246PubMedCrossRefGoogle Scholar
  56. 56.
    Hong YJ, Jeong MH, Ahn Y, Yoon NS, Lee SR, Hong SN, Moon JY, Kim KH, Park HW, Kim JH, Cho JG, Park JC, Kang JC (2007) Relationship between peripheral monocytosis and nonrecovery of left ventricular function in patients with left ventricular dysfunction complicated with acute myocardial infarction. Circ J 71(8):1219–1224PubMedCrossRefGoogle Scholar
  57. 57.
    Dixon DL, Griggs KM, Bersten AD, De Pasquale CG (2011) Systemic inflammation and cell activation reflects morbidity in chronic heart failure. Cytokine 56(3):593–599. doi: 10.1016/j.cyto.2011.08.029 PubMedCrossRefGoogle Scholar
  58. 58.
    Shantsila E, Bialiuk N, Navitski D, Pyrochkin A, Gill PS, Pyrochkin V, Snezhitskiy V, Lip GY (2012) Blood leukocytes in heart failure with preserved ejection fraction: impact on prognosis. Int J Cardiol 155(2):337–338. doi: 10.1016/j.ijcard.2011.12.048 PubMedCrossRefGoogle Scholar
  59. 59.
    Gleich GJ, Adolphson CR (1986) The eosinophilic leukocyte: structure and function. Adv Immunol 39:177–253PubMedCrossRefGoogle Scholar
  60. 60.
    Klion AD, Bochner BS, Gleich GJ, Nutman TB, Rothenberg ME, Simon HU, Wechsler ME, Weller PF, The Hypereosinophilic Syndromes Working G (2006) Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report. J Allergy Clin Immunol 117(6):1292–1302. doi: 10.1016/j.jaci.2006.02.042 Google Scholar
  61. 61.
    Weller PF, Bubley GJ (1994) The idiopathic hypereosinophilic syndrome. Blood 83(10):2759–2779PubMedGoogle Scholar
  62. 62.
    Tai PC, Ackerman SJ, Spry CJ, Dunnette S, Olsen EG, Gleich GJ (1987) Deposits of eosinophil granule proteins in cardiac tissues of patients with eosinophilic endomyocardial disease. Lancet 1(8534):643–647PubMedCrossRefGoogle Scholar
  63. 63.
    Cikrikcioglu MA, Soysal P, Dikerdem D, Cakirca M, Kazancioglu R, Yolbas S, Erkal H, Hursitoglu M, Karakose TK, Kiskac M, Akkaya M, Zorlu M, Akkoyunlu ME, Tukek T (2011) Absolute blood eosinophil count and 1-year mortality risk following hospitalization with acute heart failure. Eur J Emerg Med Off J Eur Soc Emerg Med. doi: 10.1097/MEJ.0b013e32834c67eb Google Scholar
  64. 64.
    Levick SP, Melendez GC, Plante E, McLarty JL, Brower GL, Janicki JS (2011) Cardiac mast cells: the centrepiece in adverse myocardial remodelling. Cardiovasc Res 89(1):12–19. doi: 10.1093/cvr/cvq272 PubMedCrossRefGoogle Scholar
  65. 65.
    Kolck UW, Alfter K, Homann J, von Kugelgen I, Molderings GJ (2007) Cardiac mast cells: implications for heart failure. J Am Coll Cardiol 49(10):1107; author reply 1107–1108. doi: 10.1016/j.jacc.2006.12.018 Google Scholar
  66. 66.
    Levy WC, Mozaffarian D, Linker DT, Sutradhar SC, Anker SD, Cropp AB, Anand I, Maggioni A, Burton P, Sullivan MD, Pitt B, Poole-Wilson PA, Mann DL, Packer M (2006) The seattle heart failure model: prediction of survival in heart failure. Circulation 113(11):1424–1433. doi: 10.1161/CIRCULATIONAHA.105.584102 PubMedCrossRefGoogle Scholar
  67. 67.
    Barisione C, Garibaldi S, Ghigliotti G, Fabbi P, Altieri P, Casale MC, Spallarossa P, Bertero G, Balbi M, Corsiglia L, Brunelli C (2010) CD14CD16 monocyte subset levels in heart failure patients. Dis Markers 28(2):115–124. doi: 10.3233/DMA-2010-0691 PubMedCrossRefGoogle Scholar
  68. 68.
    Li N, Bian H, Zhang J, Li X, Ji X, Zhang Y (2010) The Th17/Treg imbalance exists in patients with heart failure with normal ejection fraction and heart failure with reduced ejection fraction. Clin Chim Acta 411(23–24):1963–1968. doi: 10.1016/j.cca.2010.08.013 PubMedCrossRefGoogle Scholar
  69. 69.
    Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT (2003) Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF therapy against congestive heart failure (ATTACH) trial. Circulation 107(25):3133–3140. doi: 10.1161/01.CIR.0000077913.60364.D2 PubMedCrossRefGoogle Scholar
  70. 70.
    Mann DL, McMurray JJ, Packer M, Swedberg K, Borer JS, Colucci WS, Djian J, Drexler H, Feldman A, Kober L, Krum H, Liu P, Nieminen M, Tavazzi L, van Veldhuisen DJ, Waldenstrom A, Warren M, Westheim A, Zannad F, Fleming T (2004) Targeted anticytokine therapy in patients with chronic heart failure: results of the randomized etanercept worldwide evaluation (RENEWAL). Circulation 109(13):1594–1602. doi: 10.1161/01.CIR.0000124490.27666.B2 PubMedCrossRefGoogle Scholar
  71. 71.
    Uthamalingam S, Patvardhan EA, Subramanian S, Ahmed W, Martin W, Daley M, Capodilupo R (2011) Utility of the neutrophil to lymphocyte ratio in predicting long-term outcomes in acute decompensated heart failure. Am J Cardiol 107(3):433–438. doi: 10.1016/j.amjcard.2010.09.039 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Muthiah Vaduganathan
    • 1
  • Stephen J. Greene
    • 2
  • Javed Butler
    • 3
  • Hani N. Sabbah
    • 4
  • Eduard Shantsila
    • 5
  • Gregory Y. H. Lip
    • 5
  • Mihai Gheorghiade
    • 2
  1. 1.Department of MedicineMassachusetts General HospitalBostonUSA
  2. 2.Center for Cardiovascular InnovationNorthwestern University Feinberg School of MedicineChicagoUSA
  3. 3.Division of CardiologyEmory University School of MedicineAtlantaUSA
  4. 4.Department of MedicineHenry Ford HospitalDetroitUSA
  5. 5.Centre for Cardiovascular Sciences, City HospitalUniversity of BirminghamBirminghamUK

Personalised recommendations