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Published in: BMC Cardiovascular Disorders 1/2021

Open Access 01-12-2021 | Heart Failure | Research article

Leukocyte count and the risk of adverse outcomes in patients with HFpEF

Authors: Zhaowei Zhu, Shenghua Zhou

Published in: BMC Cardiovascular Disorders | Issue 1/2021

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Abstract

Background

Inflammation is a key feature of heart failure including HFpEF. The leukocyte count is a marker of inflammation that is widely used in clinical practice. However, there is little available evidence for the relationship between leukocyte count and the outcomes of HFpEF.

Methods

We analyzed data from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial. The primary outcome was all-cause mortality, the secondary outcome was composite cardiovascular events and hospitalization for heart failure. Multivariable Cox proportional hazard models were used to compare the risk profiles of patients with leukocyte quartiles, subgroup study divided by sex was also analyzed.

Results

The present study included 2898 patients with HFpEF.429 deaths, 671 composite cardiovascular events and 386 hospitalization for heart failure occurred during a mean 3.4 years follow-up. The association between leukocyte count and adverse outcomes followed a U-shaped curve. After multivariable adjustment, the patients with the lowest leukocyte count (Q1) and the highest leukocyte count (Q4) faced higher risk of all-cause death(Q1 vs. Q2, adjusted HR: 1.439; 95% CI: 1.060–1.953, p = 0.020; Q4 vs. Q2, adjusted HR, 1.901; 95%CI: 1.424–2.539, p < 0.001). The subgroup analysis showed a consistent result in female but not male patients.

Conclusions

The association between leukocyte count and risk of adverse outcomes followed a U-shaped curve. Both higher and lower leukocyte count are associated with worse outcomes in patients with HFpEF, which may be attributed to the two sides of inflammation in cardiac remodeling.
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Literature
1.
go back to reference Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J. 2011;32(6):670–9.CrossRef Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J. 2011;32(6):670–9.CrossRef
2.
go back to reference Borlaug BA, Anstrom KJ, Lewis GD, Shah SJ, Levine JA, Koepp GA, Givertz MM, Felker GM, LeWinter MM, Mann DL, et al. Effect of inorganic nitrite vs placebo on exercise capacity among patients with heart failure with preserved ejection fraction: the INDIE-HFpEF randomized clinical trial. JAMA. 2018;320(17):1764–73.CrossRef Borlaug BA, Anstrom KJ, Lewis GD, Shah SJ, Levine JA, Koepp GA, Givertz MM, Felker GM, LeWinter MM, Mann DL, et al. Effect of inorganic nitrite vs placebo on exercise capacity among patients with heart failure with preserved ejection fraction: the INDIE-HFpEF randomized clinical trial. JAMA. 2018;320(17):1764–73.CrossRef
3.
go back to reference Upadhya B, Haykowsky MJ, Kitzman DW: Therapy for heart failure with preserved ejection fraction: current status, unique challenges, and future directions. Heart failure reviews 2018. Upadhya B, Haykowsky MJ, Kitzman DW: Therapy for heart failure with preserved ejection fraction: current status, unique challenges, and future directions. Heart failure reviews 2018.
4.
go back to reference Swirski FK, Nahrendorf M. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science. 2013;339(6116):161–6.CrossRef Swirski FK, Nahrendorf M. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science. 2013;339(6116):161–6.CrossRef
5.
go back to reference Kim S, Eliot M, Koestler DC, Wu WC, Kelsey KT. Association of neutrophil-to-lymphocyte ratio with mortality and cardiovascular disease in the Jackson heart study and modification by the Duffy antigen variant. JAMA Cardiol. 2018;3(6):455–62.CrossRef Kim S, Eliot M, Koestler DC, Wu WC, Kelsey KT. Association of neutrophil-to-lymphocyte ratio with mortality and cardiovascular disease in the Jackson heart study and modification by the Duffy antigen variant. JAMA Cardiol. 2018;3(6):455–62.CrossRef
6.
go back to reference Madjid M, Awan I, Willerson JT, Casscells SW. Leukocyte count and coronary heart disease: implications for risk assessment. J Am Coll Cardiol. 2004;44(10):1945–56.CrossRef Madjid M, Awan I, Willerson JT, Casscells SW. Leukocyte count and coronary heart disease: implications for risk assessment. J Am Coll Cardiol. 2004;44(10):1945–56.CrossRef
7.
go back to reference Mann DL. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ Res. 2002;91(11):988–98.CrossRef Mann DL. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ Res. 2002;91(11):988–98.CrossRef
8.
go back to reference Mann DL. Innate immunity and the failing heart: the cytokine hypothesis revisited. Circ Res. 2015;116(7):1254–68.CrossRef Mann DL. Innate immunity and the failing heart: the cytokine hypothesis revisited. Circ Res. 2015;116(7):1254–68.CrossRef
9.
go back to reference Nymo SH, Hulthe J, Ueland T, McMurray J, Wikstrand J, Askevold ET, Yndestad A, Gullestad L, Aukrust P. Inflammatory cytokines in chronic heart failure: interleukin-8 is associated with adverse outcome. Results from CORONA. Eur J Heart Fail. 2014;16(1):68–75.CrossRef Nymo SH, Hulthe J, Ueland T, McMurray J, Wikstrand J, Askevold ET, Yndestad A, Gullestad L, Aukrust P. Inflammatory cytokines in chronic heart failure: interleukin-8 is associated with adverse outcome. Results from CORONA. Eur J Heart Fail. 2014;16(1):68–75.CrossRef
10.
go back to reference Engstrom G, Melander O, Hedblad B. Leukocyte count and incidence of hospitalizations due to heart failure. Circ Heart Fail. 2009;2(3):217–22.CrossRef Engstrom G, Melander O, Hedblad B. Leukocyte count and incidence of hospitalizations due to heart failure. Circ Heart Fail. 2009;2(3):217–22.CrossRef
11.
go back to reference Hofmann U, Frantz S. How can we cure a heart “in flame”? A translational view on inflammation in heart failure. Basic Res Cardiol. 2013;108(4):356.CrossRef Hofmann U, Frantz S. How can we cure a heart “in flame”? A translational view on inflammation in heart failure. Basic Res Cardiol. 2013;108(4):356.CrossRef
12.
go back to reference Huehnergarth KV, Mozaffarian D, Sullivan MD, Crane BA, Wilkinson CW, Lawler RL, McDonald GB, Fishbein DP, Levy WC. Usefulness of relative lymphocyte count as an independent predictor of death/urgent transplant in heart failure. Am J Cardiol. 2005;95(12):1492–5.CrossRef Huehnergarth KV, Mozaffarian D, Sullivan MD, Crane BA, Wilkinson CW, Lawler RL, McDonald GB, Fishbein DP, Levy WC. Usefulness of relative lymphocyte count as an independent predictor of death/urgent transplant in heart failure. Am J Cardiol. 2005;95(12):1492–5.CrossRef
13.
go back to reference Everett BM, Cornel JH, Lainscak M, Anker SD, Abbate A, Thuren T, Libby P, Glynn RJ, Ridker PM. Anti-Inflammatory therapy with canakinumab for the prevention of hospitalization for heart failure. Circulation. 2019;139(10):1289–99.CrossRef Everett BM, Cornel JH, Lainscak M, Anker SD, Abbate A, Thuren T, Libby P, Glynn RJ, Ridker PM. Anti-Inflammatory therapy with canakinumab for the prevention of hospitalization for heart failure. Circulation. 2019;139(10):1289–99.CrossRef
14.
go back to reference de Boer RA, Nayor M, deFilippi CR, Enserro D, Bhambhani V, Kizer JR, Blaha MJ, Brouwers FP, Cushman M, Lima JAC, et al. Association of cardiovascular biomarkers with incident heart failure with preserved and reduced ejection fraction. JAMA Cardiol. 2018;3(3):215–24.CrossRef de Boer RA, Nayor M, deFilippi CR, Enserro D, Bhambhani V, Kizer JR, Blaha MJ, Brouwers FP, Cushman M, Lima JAC, et al. Association of cardiovascular biomarkers with incident heart failure with preserved and reduced ejection fraction. JAMA Cardiol. 2018;3(3):215–24.CrossRef
15.
go back to reference Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013;62(4):263–71.CrossRef Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013;62(4):263–71.CrossRef
16.
go back to reference Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370(15):1383–92.CrossRef Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370(15):1383–92.CrossRef
17.
go back to reference Desai AS, Lewis EF, Li R, Solomon SD, Assmann SF, Boineau R, Clausell N, Diaz R, Fleg JL, Gordeev I, et al. Rationale and design of the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial: a randomized, controlled study of spironolactone in patients with symptomatic heart failure and preserved ejection fraction. Am Heart J. 2011;162(6):966–72.CrossRef Desai AS, Lewis EF, Li R, Solomon SD, Assmann SF, Boineau R, Clausell N, Diaz R, Fleg JL, Gordeev I, et al. Rationale and design of the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial: a randomized, controlled study of spironolactone in patients with symptomatic heart failure and preserved ejection fraction. Am Heart J. 2011;162(6):966–72.CrossRef
18.
go back to reference Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, 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 Failure Association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129–200.CrossRef Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, 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 Failure Association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129–200.CrossRef
19.
go back to reference Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–12.CrossRef Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–12.CrossRef
20.
go back to reference Cheng JM, Akkerhuis KM, Battes LC, van Vark LC, Hillege HL, Paulus WJ, Boersma E, Kardys I. Biomarkers of heart failure with normal ejection fraction: a systematic review. Eur J Heart Fail. 2013;15(12):1350–62.CrossRef Cheng JM, Akkerhuis KM, Battes LC, van Vark LC, Hillege HL, Paulus WJ, Boersma E, Kardys I. Biomarkers of heart failure with normal ejection fraction: a systematic review. Eur J Heart Fail. 2013;15(12):1350–62.CrossRef
21.
go back to reference D’Elia E, Vaduganathan M, Gori M, Gavazzi A, Butler J, Senni M. Role of biomarkers in cardiac structure phenotyping in heart failure with preserved ejection fraction: critical appraisal and practical use. Eur J Heart Fail. 2015;17(12):1231–9.CrossRef D’Elia E, Vaduganathan M, Gori M, Gavazzi A, Butler J, Senni M. Role of biomarkers in cardiac structure phenotyping in heart failure with preserved ejection fraction: critical appraisal and practical use. Eur J Heart Fail. 2015;17(12):1231–9.CrossRef
22.
go back to reference Collier P, Watson CJ, Voon V, Phelan D, Jan A, Mak G, Martos R, Baugh JA, Ledwidge MT, McDonald KM. Can emerging biomarkers of myocardial remodelling identify asymptomatic hypertensive patients at risk for diastolic dysfunction and diastolic heart failure? Eur J Heart Fail. 2011;13(10):1087–95.CrossRef Collier P, Watson CJ, Voon V, Phelan D, Jan A, Mak G, Martos R, Baugh JA, Ledwidge MT, McDonald KM. Can emerging biomarkers of myocardial remodelling identify asymptomatic hypertensive patients at risk for diastolic dysfunction and diastolic heart failure? Eur J Heart Fail. 2011;13(10):1087–95.CrossRef
23.
go back to reference Glezeva N, Baugh JA. Role of inflammation in the pathogenesis of heart failure with preserved ejection fraction and its potential as a therapeutic target. Heart Fail Rev. 2014;19(5):681–94.CrossRef Glezeva N, Baugh JA. Role of inflammation in the pathogenesis of heart failure with preserved ejection fraction and its potential as a therapeutic target. Heart Fail Rev. 2014;19(5):681–94.CrossRef
24.
go back to reference Ommen SR, Hodge DO, Rodeheffer RJ, McGregor CG, Thomson SP, Gibbons RJ. Predictive power of the relative lymphocyte concentration in patients with advanced heart failure. Circulation. 1998;97(1):19–22.CrossRef Ommen SR, Hodge DO, Rodeheffer RJ, McGregor CG, Thomson SP, Gibbons RJ. Predictive power of the relative lymphocyte concentration in patients with advanced heart failure. Circulation. 1998;97(1):19–22.CrossRef
25.
go back to reference Acanfora D, Gheorghiade M, Trojano L, Furgi G, Pasini E, Picone C, Papa A, Iannuzzi GL, Bonow RO, Rengo F. Relative lymphocyte count: a prognostic indicator of mortality in elderly patients with congestive heart failure. Am Heart J. 2001;142(1):167–73.CrossRef Acanfora D, Gheorghiade M, Trojano L, Furgi G, Pasini E, Picone C, Papa A, Iannuzzi GL, Bonow RO, Rengo F. Relative lymphocyte count: a prognostic indicator of mortality in elderly patients with congestive heart failure. Am Heart J. 2001;142(1):167–73.CrossRef
26.
go back to reference Strassheim D, Dempsey EC, Gerasimovskaya E, Stenmark K, Karoor V. Role of inflammatory cell subtypes in heart failure. J Immunol Res. 2019;2019:2164017.CrossRef Strassheim D, Dempsey EC, Gerasimovskaya E, Stenmark K, Karoor V. Role of inflammatory cell subtypes in heart failure. J Immunol Res. 2019;2019:2164017.CrossRef
27.
go back to reference Bajaj NS, Kalra R, Gupta K, Aryal S, Rajapreyar I, Lloyd SG, McConathy J, Shah SJ, Prabhu SD. Leucocyte count predicts cardiovascular risk in heart failure with preserved ejection fraction: insights from TOPCAT Americas. ESC Heart Fail. 2020;7(4):1676–87.CrossRef Bajaj NS, Kalra R, Gupta K, Aryal S, Rajapreyar I, Lloyd SG, McConathy J, Shah SJ, Prabhu SD. Leucocyte count predicts cardiovascular risk in heart failure with preserved ejection fraction: insights from TOPCAT Americas. ESC Heart Fail. 2020;7(4):1676–87.CrossRef
28.
go back to reference Redfield MM. Heart failure with preserved ejection fraction. N Engl J Med. 2016;375(19):1868–77.CrossRef Redfield MM. Heart failure with preserved ejection fraction. N Engl J Med. 2016;375(19):1868–77.CrossRef
29.
go back to reference Hulsmans M, Sager HB, Roh JD, Valero-Munoz M, Houstis NE, Iwamoto Y, Sun Y, Wilson RM, Wojtkiewicz G, Tricot B, et al. Cardiac macrophages promote diastolic dysfunction. J Exp Med. 2018;215(2):423–40.CrossRef Hulsmans M, Sager HB, Roh JD, Valero-Munoz M, Houstis NE, Iwamoto Y, Sun Y, Wilson RM, Wojtkiewicz G, Tricot B, et al. Cardiac macrophages promote diastolic dysfunction. J Exp Med. 2018;215(2):423–40.CrossRef
30.
go back to reference Kallikourdis M, Martini E, Carullo P, Sardi C, Roselli G, Greco CM, Vignali D, Riva F, Ormbostad Berre AM, Stolen TO, et al. T cell costimulation blockade blunts pressure overload-induced heart failure. Nat Commun. 2017;8:14680.CrossRef Kallikourdis M, Martini E, Carullo P, Sardi C, Roselli G, Greco CM, Vignali D, Riva F, Ormbostad Berre AM, Stolen TO, et al. T cell costimulation blockade blunts pressure overload-induced heart failure. Nat Commun. 2017;8:14680.CrossRef
31.
go back to reference Everett BM, Cornel J, Lainscak M, Anker SD, Abbate A, Thuren T, Libby P, Glynn RJ, Ridker PM: Anti-Inflammatory Therapy with Canakinumab for the Prevention of Hospitalization for Heart Failure. Circulation 2018. Everett BM, Cornel J, Lainscak M, Anker SD, Abbate A, Thuren T, Libby P, Glynn RJ, Ridker PM: Anti-Inflammatory Therapy with Canakinumab for the Prevention of Hospitalization for Heart Failure. Circulation 2018.
32.
go back to reference Currie CJ, Peters JR, Tynan A, Evans M, Heine RJ, Bracco OL, Zagar T, Poole CD. Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study. Lancet. 2010;375(9713):481–9.CrossRef Currie CJ, Peters JR, Tynan A, Evans M, Heine RJ, Bracco OL, Zagar T, Poole CD. Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study. Lancet. 2010;375(9713):481–9.CrossRef
33.
go back to reference Strandberg TE, Strandberg AY, Salomaa VV, Pitkala KH, Tilvis RS, Sirola J, Miettinen TA. Explaining the obesity paradox: cardiovascular risk, weight change, and mortality during long-term follow-up in men. Eur Heart J. 2009;30(14):1720–7.CrossRef Strandberg TE, Strandberg AY, Salomaa VV, Pitkala KH, Tilvis RS, Sirola J, Miettinen TA. Explaining the obesity paradox: cardiovascular risk, weight change, and mortality during long-term follow-up in men. Eur Heart J. 2009;30(14):1720–7.CrossRef
34.
go back to reference Bangalore S, Qin J, Sloan S, Murphy SA, Cannon CP. Investigators PI-TT: What is the optimal blood pressure in patients after acute coronary syndromes? Relationship of blood pressure and cardiovascular events in the PRavastatin OR atorVastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction (PROVE IT-TIMI) 22 trial. Circulation. 2010;122(21):2142–51.CrossRef Bangalore S, Qin J, Sloan S, Murphy SA, Cannon CP. Investigators PI-TT: What is the optimal blood pressure in patients after acute coronary syndromes? Relationship of blood pressure and cardiovascular events in the PRavastatin OR atorVastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction (PROVE IT-TIMI) 22 trial. Circulation. 2010;122(21):2142–51.CrossRef
35.
go back to reference Vilaro JR, Ahmed M, Aranda JM. Heart failure with preserved ejection fraction: time to revisit the stiff heart. Cardiovascular Innovations and Applications. 2019;3(4):409–20.CrossRef Vilaro JR, Ahmed M, Aranda JM. Heart failure with preserved ejection fraction: time to revisit the stiff heart. Cardiovascular Innovations and Applications. 2019;3(4):409–20.CrossRef
Metadata
Title
Leukocyte count and the risk of adverse outcomes in patients with HFpEF
Authors
Zhaowei Zhu
Shenghua Zhou
Publication date
01-12-2021
Publisher
BioMed Central
Keyword
Heart Failure
Published in
BMC Cardiovascular Disorders / Issue 1/2021
Electronic ISSN: 1471-2261
DOI
https://doi.org/10.1186/s12872-021-02142-y

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