High-sensitivity C-reactive protein in heart failure with preserved ejection fraction

Hilary M DuBrock, Omar F AbouEzzeddine, Margaret M Redfield, Hilary M DuBrock, Omar F AbouEzzeddine, Margaret M Redfield

Abstract

Background: Microvascular inflammation may contribute to the pathogenesis of both heart failure with preserved ejection fraction (HFpEF) and pulmonary hypertension (PH). We investigated whether the inflammation biomarker C-reactive protein (CRP) was associated with clinical characteristics, disease severity or PH in HFpEF.

Methods: Patients in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart failure (RELAX) trial had baseline high-sensitivity CRP levels measured (n = 214). Clinical characteristics, exercise performance, echocardiographic variables and biomarkers of neurohumoral activation, fibrosis and myocardial necrosis were assessed. Patients with normal (≤3mg/L) versus high (>3mg/L) CRP levels were compared.

Results: The median CRP level was 3.69mg/L. CRP was elevated in 57% of patients. High CRP levels were associated with younger age, higher body mass index (BMI), chronic obstructive pulmonary disease (COPD), lower peak oxygen consumption and higher endothelin-1 and aldosterone levels. CRP increased progressively with the number of comorbidities (0.7mg/L per increment in comorbidity number, P = 0.02). Adjusting for age, BMI and statin use, high CRP levels were additionally associated with atrial fibrillation, right ventricular dysfunction, and higher N-terminal pro-B-type natriuretic peptide levels (P<0.05 for all). CRP was not associated with PH or left ventricular function. CRP did not identify responders to sildenafil(P-value for interaction 0.13).

Conclusions: In HFpEF, high CRP is associated with greater comorbidity burden and some markers of disease severity but CRP was normal in 40% of patients. These findings support the presence of comorbidity-driven systemic inflammation in HFpEF but also the need to study other biomarkers which may better reflect the presence of systemic inflammation.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Frequency distribution of high-sensitivity C-reactive…
Fig 1. Frequency distribution of high-sensitivity C-reactive protein (CRP) levels in heart failure with preserved ejection fraction.
Overall, median CRP levels were 3.69mg/L (interquartile range 1.83–8.12 mg/L with a range of 0.16 to 44.0 mg/L).
Fig 2. The relationship between C-reactive protein…
Fig 2. The relationship between C-reactive protein (CRP) and endothelin-1 and aldosterone in heart failure with preserved ejection fraction.
CRP was significantly associated with endothelin-1 and aldosterone. Ln indicates log transformed. *Adjusted for age, BMI and statin use.

References

    1. 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. Journal of the American College of Cardiology. 2013;62(4):263–71. 10.1016/j.jacc.2013.02.092 .
    1. Reilly SM, Saltiel AR. Adapting to obesity with adipose tissue inflammation. Nat Rev Endocrinol. 2017;13(11):633–43. 10.1038/nrendo.2017.90 .
    1. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003;111(12):1805–12. 10.1172/JCI18921 ; PubMed Central PMCID: PMCPMC161431.
    1. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352(16):1685–95. 10.1056/NEJMra043430 .
    1. Ridker PM. From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving Upstream To Identify Novel Targets for Atheroprotection. Circ Res. 2016;118(1):145–56. 10.1161/CIRCRESAHA.115.306656 ; PubMed Central PMCID: PMCPMC4793711.
    1. Williams ES, Shah SJ, Ali S, Na BY, Schiller NB, Whooley MA. C-reactive protein, diastolic dysfunction, and risk of heart failure in patients with coronary disease: Heart and Soul Study. Eur J Heart Fail. 2008;10(1):63–9. 10.1016/j.ejheart.2007.11.003 ; PubMed Central PMCID: PMCPMC2789557.
    1. Shah SJ, Marcus GM, Gerber IL, McKeown BH, Vessey JC, Jordan MV, et al. High-sensitivity C-reactive protein and parameters of left ventricular dysfunction. J Card Fail. 2006;12(1):61–5. 10.1016/j.cardfail.2005.08.003 .
    1. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. The New England journal of medicine. 2017;377(12):1119–31. 10.1056/NEJMoa1707914 .
    1. Ridker PM, MacFadyen JG, Everett BM, Libby P, Thuren T, Glynn RJ. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet. 2017. In press.
    1. Koller L, Kleber M, Goliasch G, Sulzgruber P, Scharnagl H, Silbernagel G, et al. C-reactive protein predicts mortality in patients referred for coronary angiography and symptoms of heart failure with preserved ejection fraction. Eur J Heart Fail. 2014;16(7):758–66. 10.1002/ejhf.104 .
    1. Van Tassell BW, Arena R, Biondi-Zoccai G, Canada JM, Oddi C, Abouzaki NA, et al. Effects of interleukin-1 blockade with anakinra on aerobic exercise capacity in patients with heart failure and preserved ejection fraction (from the D-HART pilot study). The American journal of cardiology. 2014;113(2):321–7. 10.1016/j.amjcard.2013.08.047 ; PubMed Central PMCID: PMCPMC4899612.
    1. Rabinovitch M, Guignabert C, Humbert M, Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res. 2014;115(1):165–75. 10.1161/CIRCRESAHA.113.301141 ; PubMed Central PMCID: PMCPMC4097142.
    1. Quarck R, Nawrot T, Meyns B, Delcroix M. C-reactive protein: a new predictor of adverse outcome in pulmonary arterial hypertension. Journal of the American College of Cardiology. 2009;53(14):1211–8. 10.1016/j.jacc.2008.12.038 .
    1. Chatterjee NA, Steiner J, Lewis GD. It is time to look at heart failure with preserved ejection fraction from the right side. Circulation. 2014;130(25):2272–7. 10.1161/CIRCULATIONAHA.114.013536 ; PubMed Central PMCID: PMCPMC4947936.
    1. Mohammed SF, Hussain I, AbouEzzeddine OF, Takahama H, Kwon SH, Forfia P, et al. Right ventricular function in heart failure with preserved ejection fraction: a community-based study. Circulation. 2014;130(25):2310–20. 10.1161/CIRCULATIONAHA.113.008461 ; PubMed Central PMCID: PMCPMC4276536.
    1. Fayyaz AU, Edwards WD, Maleszewski JJ, Konik EA, DuBrock HM, Borlaug BA, et al. Global Pulmonary Vascular Remodeling in Pulmonary Hypertension Associated With Heart Failure and Preserved or Reduced Ejection Fraction. Circulation. 2018;137(17):1796–810. 10.1161/CIRCULATIONAHA.117.031608 ; PubMed Central PMCID: PMCPMC5915920.
    1. Redfield MM, Chen HH, Borlaug BA, Semigran MJ, Lee KL, Lewis G, et al. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013;309(12):1268–77. 10.1001/jama.2013.2024 ; PubMed Central PMCID: PMCPMC3835156.
    1. Redfield MM, Borlaug BA, Lewis GD, Mohammed SF, Semigran MJ, Lewinter MM, et al. PhosphdiesteRasE-5 Inhibition to Improve CLinical Status and EXercise Capacity in Diastolic Heart Failure (RELAX) trial: rationale and design. Circ Heart Fail. 2012;5(5):653–9. 10.1161/CIRCHEARTFAILURE.112.969071 ; PubMed Central PMCID: PMCPMC3530955.
    1. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18(12):1440–63. 10.1016/j.echo.2005.10.005 .
    1. Zakeri R, Borlaug BA, McNulty SE, Mohammed SF, Lewis GD, Semigran MJ, et al. Impact of atrial fibrillation on exercise capacity in heart failure with preserved ejection fraction: a RELAX trial ancillary study. Circ Heart Fail. 2014;7(1):123–30. 10.1161/CIRCHEARTFAILURE.113.000568 ; PubMed Central PMCID: PMCPMC3972021.
    1. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107(3):499–511. .
    1. Kalogeropoulos A, Georgiopoulou V, Psaty BM, Rodondi N, Smith AL, Harrison DG, et al. Inflammatory markers and incident heart failure risk in older adults: the Health ABC (Health, Aging, and Body Composition) study. Journal of the American College of Cardiology. 2010;55(19):2129–37. 10.1016/j.jacc.2009.12.045 ; PubMed Central PMCID: PMCPMC3267799.
    1. McMurray JJ, Kjekshus J, Gullestad L, Dunselman P, Hjalmarson A, Wedel H, et al. Effects of statin therapy according to plasma high-sensitivity C-reactive protein concentration in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA): a retrospective analysis. Circulation. 2009;120(22):2188–96. 10.1161/CIRCULATIONAHA.109.849117 .
    1. AbouEzzeddine OF, McKie PM, Dunlay SM, Stevens SR, Felker GM, Borlaug BA, et al. Suppression of Tumorigenicity 2 in Heart Failure With Preserved Ejection Fraction. J Am Heart Assoc. 2017;6(2). 10.1161/JAHA.116.004382 ; PubMed Central PMCID: PMCPMC5523750.
    1. AbouEzzeddine OF, Haines P, Stevens S, Nativi-Nicolau J, Felker GM, Borlaug BA, et al. Galectin-3 in heart failure with preserved ejection fraction. A RELAX trial substudy (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure). JACC Heart failure. 2015;3(3):245–52. 10.1016/j.jchf.2014.10.009 ; PubMed Central PMCID: PMCPMC4369675.
    1. Pandey A, Golwala H, Sheng S, DeVore AD, Hernandez AF, Bhatt DL, et al. Factors Associated With and Prognostic Implications of Cardiac Troponin Elevation in Decompensated Heart Failure With Preserved Ejection Fraction: Findings From the American Heart Association Get With The Guidelines-Heart Failure Program. JAMA Cardiol. 2017;2(2):136–45. 10.1001/jamacardio.2016.4726 .
    1. Anand IS, Rector TS, Cleland JG, Kuskowski M, McKelvie RS, Persson H, et al. Prognostic value of baseline plasma amino-terminal pro-brain natriuretic peptide and its interactions with irbesartan treatment effects in patients with heart failure and preserved ejection fraction: findings from the I-PRESERVE trial. Circulation Heart failure. 2011;4(5):569–77. 10.1161/CIRCHEARTFAILURE.111.962654 .
    1. van Veldhuisen DJ, Linssen GC, Jaarsma T, van Gilst WH, Hoes AW, Tijssen JG, et al. B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction. Journal of the American College of Cardiology. 2013;61(14):1498–506. 10.1016/j.jacc.2012.12.044 .
    1. Anand IS, Latini R, Florea VG, Kuskowski MA, Rector T, Masson S, et al. C-reactive protein in heart failure: prognostic value and the effect of valsartan. Circulation. 2005;112(10):1428–34. 10.1161/CIRCULATIONAHA.104.508465 .
    1. Sinning C, Kempf T, Schwarzl M, Lanfermann S, Ojeda F, Schnabel RB, et al. Biomarkers for characterization of heart failure—Distinction of heart failure with preserved and reduced ejection fraction. Int J Cardiol. 2017;227:272–7. 10.1016/j.ijcard.2016.11.110 .
    1. Dupuy AM, Curinier C, Kuster N, Huet F, Leclercq F, Davy JM, et al. Multi-Marker Strategy in Heart Failure: Combination of ST2 and CRP Predicts Poor Outcome. PLoS One. 2016;11(6):e0157159 10.1371/journal.pone.0157159 ; PubMed Central PMCID: PMCPMC4911159.
    1. Westermann D, Lindner D, Kasner M, Zietsch C, Savvatis K, Escher F, et al. Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction. Circ Heart Fail. 2011;4(1):44–52. 10.1161/CIRCHEARTFAILURE.109.931451 .
    1. Aviles RJ, Martin DO, Apperson-Hansen C, Houghtaling PL, Rautaharju P, Kronmal RA, et al. Inflammation as a risk factor for atrial fibrillation. Circulation. 2003;108(24):3006–10. 10.1161/01.CIR.0000103131.70301.4F .
    1. Dahl M, Vestbo J, Lange P, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. American journal of respiratory and critical care medicine. 2007;175(3):250–5. 10.1164/rccm.200605-713OC .
    1. Cody RJ, Haas GJ, Binkley PF, Capers Q, Kelley R. Plasma endothelin correlates with the extent of pulmonary hypertension in patients with chronic congestive heart failure. Circulation. 1992;85(2):504–9. .
    1. Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. New England Journal of Medicine. 1993;328(24):1732–9. 10.1056/NEJM199306173282402
    1. Januzzi JL, van Kimmenade R, Lainchbury J, Bayes-Genis A, Ordonez-Llanos J, Santalo-Bel M, et al. NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: the International Collaborative of NT-proBNP Study. Eur Heart J. 2006;27(3):330–7. 10.1093/eurheartj/ehi631 .
    1. Safdar Z, Thakur A, Singh S, Ji Y, Guffey D, Minard CG, et al. Circulating Aldosterone Levels and Disease Severity in Pulmonary Arterial Hypertension. J Pulm Respir Med. 2015;5(5). 10.4172/2161-105X.1000295 ; PubMed Central PMCID: PMCPMC4861074.
    1. Krauser DG, Lloyd-Jones DM, Chae CU, Cameron R, Anwaruddin S, Baggish AL, et al. Effect of body mass index on natriuretic peptide levels in patients with acute congestive heart failure: a ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) substudy. Am Heart J. 2005;149(4):744–50. 10.1016/j.ahj.2004.07.010 .
    1. Canada JM, Fronk DT, Cei LF, Carbone S, Erdle CO, Abouzaki NA, et al. Usefulness of C-Reactive Protein Plasma Levels to Predict Exercise Intolerance in Patients With Chronic Systolic Heart Failure. Am J Cardiol. 2016;117(1):116–20. 10.1016/j.amjcard.2015.10.020 .
    1. Windram JD, Loh PH, Rigby AS, Hanning I, Clark AL, Cleland JG. Relationship of high-sensitivity C-reactive protein to prognosis and other prognostic markers in outpatients with heart failure. Am Heart J. 2007;153(6):1048–55. 10.1016/j.ahj.2007.03.044 .
    1. Harhay MO, Tracy RP, Bagiella E, Barr RG, Pinder D, Hundley WG, et al. Relationship of CRP, IL-6, and fibrinogen with right ventricular structure and function: the MESA-Right Ventricle Study. International journal of cardiology. 2013;168(4):3818–24. 10.1016/j.ijcard.2013.06.028 ; PubMed Central PMCID: PMCPMC3805818.
    1. Gan CT, McCann GP, Marcus JT, van Wolferen SA, Twisk JW, Boonstra A, et al. NT-proBNP reflects right ventricular structure and function in pulmonary hypertension. The European respiratory journal. 2006;28(6):1190–4. 10.1183/09031936.00016006 .
    1. Fijalkowska A, Kurzyna M, Torbicki A, Szewczyk G, Florczyk M, Pruszczyk P, et al. Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension. Chest. 2006;129(5):1313–21. 10.1378/chest.129.5.1313 .

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir