Heart and Vessels

, Volume 34, Issue 12, pp 1961–1968 | Cite as

Association between C-reactive protein levels at hospital admission and long-term mortality in patients with acute decompensated heart failure

  • Hiroki Matsumoto
  • Takatoshi KasaiEmail author
  • Akihiro Sato
  • Sayaki Ishiwata
  • Shoichiro Yatsu
  • Jun Shitara
  • Azusa Murata
  • Takao Kato
  • Shoko Suda
  • Yuya Matsue
  • Masaru Hiki
  • Atsutoshi Takagi
  • Hiroyuki Daida
Original Article


The C-reactive protein (CRP) levels obtained at hospital admission are associated with the prognosis of several cardiovascular diseases, including acute coronary syndrome. Although the admission CRP level is associated with in-hospital mortality in patients with acute decompensated heart failure (ADHF), there are limited data on the association between the admission CRP level and long-term mortality in patients with ADHF. This study included consecutive ADHF patients admitted to our institution from 2007 to 2011. Eligible patients were divided into four groups based on quartiles of admission CRP levels. The association between the admission CRP level and long-term mortality was assessed by multivariable Cox proportional analysis, including other independent variables with p values < 0.1 in the univariable analyses. Overall, 527 eligible patients were examined. There were 142 deaths (27%) during a median follow-up period of 2.0 years. In the multivariable analysis, the hazard ratio (HR) significantly increased with admission CRP levels in a dose-dependent manner for mortality (p for trend = 0.034). Multivariable analysis also showed a significant association between the admission CRP level, when treated as a natural logarithm-transformed continuous variable, and increased mortality (HR 1.16, p = 0.030). In patients with ADHF, the admission CRP level was associated with an increased risk of long-term mortality.


Heart failure Biomarker CRP Mortality 



A grant was awarded to The Intractable Respiratory Diseases and Pulmonary Hypertension Research Group, from the Ministry of Health, Labor and Welfare, Grant/Award Number: H29-027; Health, Labour and Welfare Sciences Research Grants, Research on Region Medical, Grant/Award Number: H30-iryou-ippan-009; MEXT-Supported Program for the Strategic Research Foundation at Private Universities, 2014–2018 (Ministry of Education, Culture, Sports, Science and Technology); JSPS KAKENHI, Grant/Award Number: JP17K09527.

Compliance with ethical standards

Conflict of interest

Drs. Hiroki Matsumoto, Takatoshi Kasai, Akihiro Sato, Sayaki Ishiwata, and Yuya Matsue are affiliated with a department endowed by Philips Respironics, ResMed, and Fukuda Denshi. Dr. Hiroyuki Daida received research grants from various pharmaceutical companies and payment for lectures, including service in speakers’ bureaus from Medtronic Japan, AstraZeneca K.K., MSD K.K., Ono Pharmaceutical Co. Ltd, GlaxoSmithKline K.K., Shionogi & Co. Ltd, Daiichi Sankyo Company, Takeda Pharmaceutical Co. Ltd, Nippon Boehringer Ingelheim Co. Ltd, Bayer Yakuhin, Ltd, Terumo Corporation, and Astellas Pharma Inc. The other authors report no conflicts of interest.


  1. 1.
    Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, American College of Cardiology F and American Heart A (2009) Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines developed in collaboration with the International Society for Heart and Lung Transplantation. J Am Coll Cardiol 53:e1–e90PubMedGoogle Scholar
  2. 2.
    Gheorghiade M, Vaduganathan M, Fonarow GC, Bonow RO (2013) Rehospitalization for heart failure: problems and perspectives. J Am Coll Cardiol 61:391–403PubMedGoogle Scholar
  3. 3.
    Januzzi JL Jr, Rehman S, Mueller T, van Kimmenade RR, Lloyd-Jones DM (2010) Importance of biomarkers for long-term mortality prediction in acutely dyspneic patients. Clin Chem 56:1814–1821PubMedGoogle Scholar
  4. 4.
    Mentz RJ, Kelly JP, von Lueder TG, Voors AA, Lam CS, Cowie MR, Kjeldsen K, Jankowska EA, Atar D, Butler J, Fiuzat M, Zannad F, Pitt B, O′Connor CM (2014) Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol 64:2281–2293PubMedPubMedCentralGoogle Scholar
  5. 5.
    Sato Y, Takatsu Y, Kataoka K, Yamada T, Taniguchi R, Sasayama S, Matsumori A (1999) Serial circulating concentrations of C-reactive protein, interleukin (IL)-4, and IL-6 in patients with acute left heart decompensation. Clin Cardiol 22:811–813PubMedGoogle Scholar
  6. 6.
    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 5:609–614PubMedGoogle Scholar
  7. 7.
    Milo O, Cotter G, Kaluski E, Brill A, Blatt A, Krakover R, Vered Z, Hershkoviz R (2003) Comparison of inflammatory and neurohormonal activation in cardiogenic pulmonary edema secondary to ischemic versus nonischemic causes. Am J Cardiol 92:222–226PubMedGoogle Scholar
  8. 8.
    Tillett WS, Francis T (1930) Serological reactions in pneumonia with a non-protein somatic fraction of pneumococcus. J Exp Med 52:561–571PubMedPubMedCentralGoogle Scholar
  9. 9.
    Anand IS, Latini R, Florea VG, Kuskowski MA, Rector T, Masson S, Signorini S, Mocarelli P, Hester A, Glazer R, Cohn JN, Val-He FTI (2005) C-reactive protein in heart failure: prognostic value and the effect of valsartan. Circulation 112:1428–1434Google Scholar
  10. 10.
    Windram JD, Loh PH, Rigby AS, Hanning I, Clark AL, Cleland JG (2007) Relationship of high-sensitivity C-reactive protein to prognosis and other prognostic markers in outpatients with heart failure. Am Heart J 153:1048–1055PubMedGoogle Scholar
  11. 11.
    Tanner H, Mohacsi P, Fuller-Bicer GA, Rieben R, Meier B, Hess O, Hullin R (2007) Cytokine activation and disease progression in patients with stable moderate chronic heart failure. J Heart Lung Transpl 26:622–629Google Scholar
  12. 12.
    Ronnow BS, Reyna SP, Muhlestein JB, Horne BD, Allen Maycock CA, Bair TL, Carlquist JF, Kfoury AG, Anderson JL, Renlund DG, International Heart Collaborative Study G (2005) C-reactive protein predicts death in patients with non-ischemic cardiomyopathy. Cardiology 104:196–201PubMedGoogle Scholar
  13. 13.
    Ishikawa C, Tsutamoto T, Fujii M, Sakai H, Tanaka T, Horie M (2006) Prediction of mortality by high-sensitivity C-reactive protein and brain natriuretic peptide in patients with dilated cardiomyopathy. Circ J 70:857–863PubMedGoogle Scholar
  14. 14.
    McKee PA, Castelli WP, McNamara PM, Kannel WB (1971) The natural history of congestive heart failure: the Framingham Study. N Engl J Med 285:1441–1446PubMedGoogle Scholar
  15. 15.
    Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H, Hishida A, Collaborators developing the Japanese equation for estimated GFR (2009) Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 53:982–992PubMedGoogle Scholar
  16. 16.
    Packer M (1992) The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol 20:248–254PubMedPubMedCentralGoogle Scholar
  17. 17.
    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 323:236–241PubMedGoogle Scholar
  18. 18.
    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 92:1479–1486PubMedGoogle Scholar
  19. 19.
    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 102:3060–3067PubMedGoogle Scholar
  20. 20.
    Miettinen KH, Lassus J, Harjola VP, Siirila-Waris K, Melin J, Punnonen KR, Nieminen MS, Laakso M, Peuhkurinen KJ (2008) Prognostic role of pro- and anti-inflammatory cytokines and their polymorphisms in acute decompensated heart failure. Eur J Heart Fail 10:396–403PubMedGoogle Scholar
  21. 21.
    Vasan RS, Sullivan LM, Roubenoff R, Dinarello CA, Harris T, Benjamin EJ, Sawyer DB, Levy D, Wilson PW, D'Agostino RB, Framingham Heart S (2003) Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham Heart Study. Circulation 107:1486–1491Google Scholar
  22. 22.
    Van Linthout S, Tschope C (2017) Inflammation–cause or consequence of heart failure or both? Curr Heart Fail Rep 14:251–265PubMedPubMedCentralGoogle Scholar
  23. 23.
    Tian M, Yuan YC, Li JY, Gionfriddo MR, Huang RC (2015) Tumor necrosis factor-alpha and its role as a mediator in myocardial infarction: a brief review. Chronic Dis Transl Med 1:18–26PubMedPubMedCentralGoogle Scholar
  24. 24.
    Gabriel AS, Martinsson A, Wretlind B, Ahnve S (2004) IL-6 levels in acute and post myocardial infarction: their relation to CRP levels, infarction size, left ventricular systolic function, and heart failure. Eur J Intern Med 15:523–528PubMedGoogle Scholar
  25. 25.
    Toldo S, Van Tassell BW, Abbate A (2017) Interleukin-1 blockade in acute myocardial infarction and heart failure: getting closer and closer. JACC Basic Transl Sci 2:431–433PubMedPubMedCentralGoogle Scholar
  26. 26.
    Hu YF, Chen YJ, Lin YJ, Chen SA (2015) Inflammation and the pathogenesis of atrial fibrillation. Nat Rev Cardiol 12:230–243PubMedGoogle Scholar
  27. 27.
    Cote N, Mahmut A, Bosse Y, Couture C, Page S, Trahan S, Boulanger MC, Fournier D, Pibarot P, Mathieu P (2013) Inflammation is associated with the remodeling of calcific aortic valve disease. Inflammation 36:573–581PubMedGoogle Scholar
  28. 28.
    Wu CK, Lee JK, Chiang FT, Yang CH, Huang SW, Hwang JJ, Lin JL, Tseng CD, Chen JJ, Tsai CT (2011) Plasma levels of tumor necrosis factor-alpha and interleukin-6 are associated with diastolic heart failure through downregulation of sarcoplasmic reticulum Ca2+ ATPase. Crit Care Med 39:984–992PubMedGoogle Scholar
  29. 29.
    Thaik CM, Calderone A, Takahashi N, Colucci WS (1995) Interleukin-1 beta modulates the growth and phenotype of neonatal rat cardiac myocytes. J Clin Invest 96:1093–1099PubMedPubMedCentralGoogle Scholar
  30. 30.
    Yokoyama T, Vaca L, Rossen RD, Durante W, Hazarika P, Mann DL (1993) Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian heart. J Clin Invest 92:2303–2312PubMedPubMedCentralGoogle Scholar
  31. 31.
    Gurantz D, Cowling RT, Varki N, Frikovsky E, Moore CD, Greenberg BH (2005) IL-1beta and TNF-alpha upregulate angiotensin II type 1 (AT1) receptors on cardiac fibroblasts and are associated with increased AT1 density in the post-MI heart. J Mol Cell Cardiol 38:505–515PubMedGoogle Scholar
  32. 32.
    Sullivan DE, Ferris M, Nguyen H, Abboud E, Brody AR (2009) TNF-alpha induces TGF-beta1 expression in lung fibroblasts at the transcriptional level via AP-1 activation. J Cell Mol Med 13:1866–1876PubMedPubMedCentralGoogle Scholar
  33. 33.
    Voloshenyuk TG, Hart AD, Khoutorova E, Gardner JD (2011) TNF-alpha increases cardiac fibroblast lysyl oxidase expression through TGF-beta and PI3Kinase signaling pathways. Biochem Biophys Res Commun 413:370–375PubMedGoogle Scholar
  34. 34.
    Yoshida T, Friehs I, Mummidi S, del Nido PJ, Addulnour-Nakhoul S, Delafontaine P, Valente AJ, Chandrasekar B (2014) Pressure overload induces IL-18 and IL-18R expression, but markedly suppresses IL-18BP expression in a rabbit model. IL-18 potentiates TNF-alpha-induced cardiomyocyte death. J Mol Cell Cardiol 75:141–151PubMedPubMedCentralGoogle Scholar
  35. 35.
    Sager HB, Heidt T, Hulsmans M, Dutta P, Courties G, Sebas M, Wojtkiewicz GR, Tricot B, Iwamoto Y, Sun Y, Weissleder R, Libby P, Swirski FK, Nahrendorf M (2015) Targeting Interleukin-1beta reduces leukocyte production after acute myocardial infarction. Circulation 132:1880–1890PubMedPubMedCentralGoogle Scholar
  36. 36.
    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 353:1838–1842PubMedGoogle Scholar
  37. 37.
    Wang W, Zhang X, Ge N, Liu J, Yuan H, Zhang P, Liu W, Wen D (2014) Procalcitonin testing for diagnosis and short-term prognosis in bacterial infection complicated by congestive heart failure: a multicenter analysis of 4698 cases. Crit Care 18:R4PubMedPubMedCentralGoogle Scholar
  38. 38.
    Mockel M, Searle J, Maisel A (2017) The role of procalcitonin in acute heart failure patients. ESC Heart Fail 4:203–208PubMedPubMedCentralGoogle Scholar
  39. 39.
    Maisel A, Neath SX, Landsberg J, Mueller C, Nowak RM, Peacock WF, Ponikowski P, Mockel M, Hogan C, Wu AH, Richards M, Clopton P, Filippatos GS, Di Somma S, Anand I, Ng LL, Daniels LB, Christenson RH, Potocki M, McCord J, Terracciano G, Hartmann O, Bergmann A, Morgenthaler NG, Anker SD (2012) Use of procalcitonin for the diagnosis of pneumonia in patients presenting with a chief complaint of dyspnoea: results from the BACH (Biomarkers in Acute Heart Failure) trial. Eur J Heart Fail 14:278–286PubMedPubMedCentralGoogle Scholar
  40. 40.
    Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P, Group ESCSD (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 Failure Association (HFA) of the ESC. Eur Heart J 37:2129–2200Google Scholar
  41. 41.
    Alonso-Martinez JL, Llorente-Diez B, Echegaray-Agara M, Olaz-Preciado F, Urbieta-Echezarreta M, Gonzalez-Arencibia C (2002) C-reactive protein as a predictor of improvement and readmission in heart failure. Eur J Heart Fail 4:331–336PubMedGoogle Scholar
  42. 42.
    Siirila-Waris K, Lassus J, Melin J, Peuhkurinen K, Nieminen MS, Harjola VP, Group F-AS (2006) Characteristics, outcomes, and predictors of 1-year mortality in patients hospitalized for acute heart failure. Eur Heart J 27:3011–3017Google Scholar
  43. 43.
    Minami Y, Kajimoto K, Sato N, Hagiwara N, Takano T, Investigators AS (2017) C-reactive protein level on admission and time to and cause of death in patients hospitalized for acute heart failure. Eur Heart J Qual Care Clin Outcomes 3:148–156PubMedGoogle Scholar
  44. 44.
    Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH (1997) Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 336:973–979PubMedGoogle Scholar
  45. 45.
    Vogiatzi G, Oikonomou E, Siasos G, Tsalamandris S, Briasoulis A, Androulakis E, Latsios G, Papaioannou S, Tsioufis K, Tousoulis D (2017) Statins and inflammation in cardiovascular disease. Curr Pharm Des. CrossRefPubMedGoogle Scholar
  46. 46.
    Calo LA, Semplicini A, Davis PA (2005) Antioxidant and antiinflammatory effect of carvedilol in mononuclear cells of hypertensive patients. Am J Med 118:201–202PubMedGoogle Scholar
  47. 47.
    Kurum T, Tatli E, Yuksel M (2007) Effects of carvedilol on plasma levels of pro-inflammatory cytokines in patients with ischemic and nonischemic dilated cardiomyopathy. Tex Heart Inst J 34:52–59PubMedPubMedCentralGoogle Scholar
  48. 48.
    Bozkurt B, Torre-Amione G, Warren MS, Whitmore J, Soran OZ, Feldman AM, Mann DL (2001) Results of targeted anti-tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure. Circulation 103:1044–1047Google Scholar
  49. 49.
    Anker SD, Coats AJ (2002) How to recover from renaissance? The significance of the results of recover, renaissance, renewal and attach. Int J Cardiol 86:123–130PubMedGoogle Scholar
  50. 50.
    Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ, Group CT (2017) Antiinflammatory therapy with Canakinumab for atherosclerotic disease. N Engl J Med 377:1119–1131Google Scholar
  51. 51.
    Trankle CR, Canada JM, Cei L, Abouzaki N, Oddi-Erdle C, Kadariya D, Christopher S, Viscusi M, Del Buono M, Kontos MC, Arena R, Van Tassell B, Abbate A (2018) Usefulness of Canakinumab to improve exercise capacity in patients with long-term systolic heart failure and elevated C-reactive protein. Am J Cardiol 122:1366–1370PubMedPubMedCentralGoogle Scholar
  52. 52.
    Van Tassell BW, Abouzaki NA, Oddi Erdle C, Carbone S, Trankle CR, Melchior RD, Turlington JS, Thurber CJ, Christopher S, Dixon DL, Fronk DT, Thomas CS, Rose SW, Buckley LF, Dinarello CA, Biondi-Zoccai G, Abbate A (2016) Interleukin-1 blockade in acute decompensated heart failure: a randomized, double-blinded, Placebo-Controlled Pilot Study. J Cardiovasc Pharmacol 67:544–551PubMedPubMedCentralGoogle Scholar
  53. 53.
    Van Tassell BW, Canada J, Carbone S, Trankle C, Buckley L, Oddi Erdle C, Abouzaki NA, Dixon D, Kadariya D, Christopher S, Schatz A, Regan J, Viscusi M, Del Buono M, Melchior R, Mankad P, Lu J, Sculthorpe R, Biondi-Zoccai G, Lesnefsky E, Arena R, Abbate A (2017) Interleukin-1 blockade in recently decompensated systolic heart failure: results from REDHART (recently decompensated heart failure anakinra response trial). Circ Heart Fail 10:e004373PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Japan KK, part of Springer Nature 2019

Authors and Affiliations

  • Hiroki Matsumoto
    • 1
    • 2
  • Takatoshi Kasai
    • 1
    • 2
    • 3
    Email author
  • Akihiro Sato
    • 1
    • 2
  • Sayaki Ishiwata
    • 1
    • 2
  • Shoichiro Yatsu
    • 1
  • Jun Shitara
    • 1
  • Azusa Murata
    • 1
  • Takao Kato
    • 1
  • Shoko Suda
    • 1
  • Yuya Matsue
    • 1
    • 2
  • Masaru Hiki
    • 1
  • Atsutoshi Takagi
    • 1
    • 4
  • Hiroyuki Daida
    • 1
  1. 1.Department of Cardiovascular MedicineJuntendo University School of MedicineTokyoJapan
  2. 2.Cardiovascular Respiratory Sleep MedicineJuntendo University Graduate School of MedicineTokyoJapan
  3. 3.Sleep and Sleep-Disordered Breathing CenterJuntendo University HospitalTokyoJapan
  4. 4.Department of CardiologyKoshigaya Municipal HospitalSaitamaJapan

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