Differentiating heart failure phenotypes using sex-specific transcriptomic and proteomic biomarker panels

Mustafa Toma, George J Mak, Virginia Chen, Zsuzsanna Hollander, Casey P Shannon, Karen K Y Lam, Raymond T Ng, Scott J Tebbutt, Janet E Wilson-McManus, Andrew Ignaszewski, Todd Anderson, Jason R B Dyck, Jonathan Howlett, Justin Ezekowitz, Bruce M McManus, Gavin Y Oudit, Mustafa Toma, George J Mak, Virginia Chen, Zsuzsanna Hollander, Casey P Shannon, Karen K Y Lam, Raymond T Ng, Scott J Tebbutt, Janet E Wilson-McManus, Andrew Ignaszewski, Todd Anderson, Jason R B Dyck, Jonathan Howlett, Justin Ezekowitz, Bruce M McManus, Gavin Y Oudit

Abstract

Aims: Heart failure with preserved ejection fraction (HFpEF) accounts for 30-50% of patients with heart failure (HF). A major obstacle in HF management is the difficulty in differentiating between HFpEF and heart failure with reduced ejection fraction (HFrEF) using conventional clinical and laboratory investigations. The aim of this study is to develop robust transcriptomic and proteomic biomarker signatures that can differentiate HFpEF from HFrEF.

Methods and results: A total of 210 HF patients were recruited in participating institutions from the Alberta HEART study. An expert clinical adjudicating panel differentiated between patients with HFpEF and HFrEF. The discovery cohort consisted of 61 patients, and the replication cohort consisted of 70 patients. Transcriptomic and proteomic data were analysed to find panels of differentiating HFpEF from HFrEF. In the discovery cohort, a 22-transcript panel was found to differentiate HFpEF from HFrEF in male patients with a cross-validation AUC of 0.74, as compared with 0.70 for N-terminal pro-B-type natriuretic peptide (NT-proBNP) in those same patients. An ensemble of the transcript panel and NT-pro-BNP yielded a cross-validation AUC of 0.80. This performance improvement was also observed in the replication cohort. An ensemble of the transcriptomic panel with NT-proBNP produced a replication AUC of 0.90, as compared with 0.74 for NT-proBNP alone and 0.73 for the transcriptomic panel.

Conclusions: We have identified a male-specific transcriptomic biomarker panel that can differentiate between HFpEF and HFrEF. These biosignatures could be further replicated on other patients and potentially be developed into a blood test for better management of HF patients.

Keywords: Biomarkers; Heart failure; Heart failure with preserved ejection fraction; Heart failure with reduced ejection fraction; Proteomics; Transcriptomics.

© 2017 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.

Figures

Figure 1
Figure 1
The 10 most statistically significant pathway maps identified by MetaCore, based on all differentially expressed transcripts [false discovery rate 

Figure 2

The three pathway maps identified…

Figure 2

The three pathway maps identified as statistically significant (false discovery rate

Figure 2
The three pathway maps identified as statistically significant (false discovery rate 

Figure 3

Replication receiver operating characteristic curves…

Figure 3

Replication receiver operating characteristic curves of male‐specific classifiers. (A) Performance of the transcriptomic…

Figure 3
Replication receiver operating characteristic curves of male‐specific classifiers. (A) Performance of the transcriptomic panel, N‐terminal proBN (NT‐proBNP), and their ensemble; (B) Performance of the transcriptomic panel, cell proportion model, and their ensemble. HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.

Figure 4

Replication receiver operating characteristic curves…

Figure 4

Replication receiver operating characteristic curves of female‐specific classifiers. HFpEF, heart failure with preserved…

Figure 4
Replication receiver operating characteristic curves of female‐specific classifiers. HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; NT‐proBNP, N‐terminal proBN.
Similar articles
Cited by
References
    1. Writing Committee M , Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Jr. , Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL, American College of Cardiology Foundation/American Heart Association Task Force on Practice G . 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013; 128: e240–327. - PubMed
    1. Kaul P, Reed SD, Hernandez AF, Howlett JG, Ezekowitz JA, Li Y, Zheng Y, Rouleau JL, Starling RC, O'Connor CM, Califf RM, Armstrong PW. Differences in treatment, outcomes, and quality of life among patients with heart failure in Canada and the United States. JACC Heart Fail 2013; 1: 523–530. - PubMed
    1. Paulus WJ, Tschope C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, Marino P, Smiseth OA, De KG, Leite‐Moreira AF, Borbely A, Edes I, Handoko ML, Heymans S, Pezzali N, Pieske B, Dickstein K, Fraser AG, Brutsaert DL. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007; 28: 2539–2550. - PubMed
    1. Brouwers FP, de Boer RA, van der Harst P, Voors AA, Gansevoort RT, Bakker SJ, Hillege HL, van Veldhuisen DJ, van Gilst WH. Incidence and epidemiology of new onset heart failure with preserved vs. reduced ejection fraction in a community‐based cohort: 11‐year follow‐up of PREVEND. Eur Heart J 2013; 34: 1424–1431. - PubMed
    1. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006; 355: 251–259. - PubMed
Show all 31 references
Related information
Full text links [x]
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Figure 2
Figure 2
The three pathway maps identified as statistically significant (false discovery rate 

Figure 3

Replication receiver operating characteristic curves…

Figure 3

Replication receiver operating characteristic curves of male‐specific classifiers. (A) Performance of the transcriptomic…

Figure 3
Replication receiver operating characteristic curves of male‐specific classifiers. (A) Performance of the transcriptomic panel, N‐terminal proBN (NT‐proBNP), and their ensemble; (B) Performance of the transcriptomic panel, cell proportion model, and their ensemble. HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.

Figure 4

Replication receiver operating characteristic curves…

Figure 4

Replication receiver operating characteristic curves of female‐specific classifiers. HFpEF, heart failure with preserved…

Figure 4
Replication receiver operating characteristic curves of female‐specific classifiers. HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; NT‐proBNP, N‐terminal proBN.
Figure 3
Figure 3
Replication receiver operating characteristic curves of male‐specific classifiers. (A) Performance of the transcriptomic panel, N‐terminal proBN (NT‐proBNP), and their ensemble; (B) Performance of the transcriptomic panel, cell proportion model, and their ensemble. HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.
Figure 4
Figure 4
Replication receiver operating characteristic curves of female‐specific classifiers. HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; NT‐proBNP, N‐terminal proBN.

References

    1. Writing Committee M , Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Jr. , Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL, American College of Cardiology Foundation/American Heart Association Task Force on Practice G . 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013; 128: e240–327.
    1. Kaul P, Reed SD, Hernandez AF, Howlett JG, Ezekowitz JA, Li Y, Zheng Y, Rouleau JL, Starling RC, O'Connor CM, Califf RM, Armstrong PW. Differences in treatment, outcomes, and quality of life among patients with heart failure in Canada and the United States. JACC Heart Fail 2013; 1: 523–530.
    1. Paulus WJ, Tschope C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, Marino P, Smiseth OA, De KG, Leite‐Moreira AF, Borbely A, Edes I, Handoko ML, Heymans S, Pezzali N, Pieske B, Dickstein K, Fraser AG, Brutsaert DL. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007; 28: 2539–2550.
    1. Brouwers FP, de Boer RA, van der Harst P, Voors AA, Gansevoort RT, Bakker SJ, Hillege HL, van Veldhuisen DJ, van Gilst WH. Incidence and epidemiology of new onset heart failure with preserved vs. reduced ejection fraction in a community‐based cohort: 11‐year follow‐up of PREVEND. Eur Heart J 2013; 34: 1424–1431.
    1. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006; 355: 251–259.
    1. Watson CJ, Gupta SK, O'Connell E, Thum S, Glezeva N, Fendrich J, Gallagher J, Ledwidge M, Grote‐Levi L, McDonald K, Thum T. MicroRNA signatures differentiate preserved from reduced ejection fraction heart failure. Eur J Heart Fail 2015; 17: 405–415.
    1. Krishnaswamy P, Lubien E, Clopton P, Koon J, Kazanegra R, Wanner E, Gardetto N, Garcia A, DeMaria A, Maisel AS. Utility of B‐natriuretic peptide levels in identifying patients with left ventricular systolic or diastolic dysfunction. Am J Med 2001; 111: 274–279.
    1. Sanders‐van Wijk S, van Empel V, Davarzani N, Maeder MT, Handschin R, Pfisterer ME, Brunner‐La Rocca HP, investigators T‐C. Circulating biomarkers of distinct pathophysiological pathways in heart failure with preserved vs. reduced left ventricular ejection fraction. Eur J Heart Fail 2015; 17: 1006–1014.
    1. Putko BN, Wang Z, Lo J, Anderson T, Becher H, Dyck JR, Kassiri Z, Oudit GY, Alberta HI. Circulating levels of tumor necrosis factor‐alpha receptor 2 are increased in heart failure with preserved ejection fraction relative to heart failure with reduced ejection fraction: evidence for a divergence in pathophysiology. PLoS One 2014; 9: e99495.
    1. Chan MM, Santhanakrishnan R, Chong JP, Chen Z, Tai BC, Liew OW, Ng TP, Ling LH, Sim D, Leong KT, Yeo PS, Ong HY, Jaufeerally F, Wong RC, Chai P, Low AF, Richards AM, Lam CS. Growth differentiation factor 15 in heart failure with preserved vs. reduced ejection fraction. Eur J Heart Fail 2016; 18: 81–88.
    1. Cheng ML, Wang CH, Shiao MS, Liu MH, Huang YY, Huang CY, Mao CT, Lin JF, Ho HY, Yang NI. Metabolic disturbances identified in plasma are associated with outcomes in patients with heart failure: diagnostic and prognostic value of metabolomics. J Am Coll Cardiol. 2015; 65: 1509–1520.
    1. Allen LA, Felker GM. Multi‐marker strategies in heart failure: clinical and statistical approaches. Heart Fail Rev 2010; 15: 343–349.
    1. 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: 1231–1239.
    1. Liew CC. Expressed genome molecular signatures of heart failure. Clin Chem Lab Med 2005; 43: 462–469.
    1. Liew CC, Ma J, Tang HC, Zheng R, Dempsey AA. The peripheral blood transcriptome dynamically reflects system wide biology: a potential diagnostic tool. J Lab Clin Med 2006; 147: 126–132.
    1. Ezekowitz JA, Becher H, Belenkie I, Clark AM, Duff HJ, Friedrich MG, Haykowsky MJ, Howlett JG, Kassiri Z, Kaul P, Kim DH, Knudtson ML, Light PE, Lopaschuk GD, McAlister FA, Noga ML, Oudit GY, Paterson DI, Quan H, Schulz R, Thompson RB, Weeks SG, Anderson TJ, Dyck JR. The Alberta Heart Failure Etiology and Analysis Research Team (HEART) study. BMC Cardiovasc Disord 2014; 14: 91.
    1. Cohen Freue GV, Meredith A, Smith D, Bergman A, Sasaki M, Lam KK, Hollander Z, Opushneva N, Takhar M, Lin D, Wilson‐McManus J, Balshaw R, Keown PA, Borchers CH, McManus B, Ng RT, McMaster WR. Computational biomarker pipeline from discovery to clinical implementation: plasma proteomic biomarkers for cardiac transplantation. PLoS Comput Biol 2013; 9: e1002963.
    1. Lee‐Lewandrowski E, Januzzi JL, Green SM, Tannous B, Wu AH, Smith A, Wong A, Murakami MM, Kaczmarek J, Apple FS, Miller WL, Hartman K, Jaffe AS. Multi‐center validation of the Response Biomedical Corporation RAMP NT‐proBNP assay with comparison to the Roche Diagnostics GmbH Elecsys proBNP assay. Clin Chim Acta 2007; 386: 20–24.
    1. Gunther OP, Chen V, Freue GC, Balshaw RF, Tebbutt SJ, Hollander Z, Takhar M, McMaster WR, McManus BM, Keown PA, Ng RT. A computational pipeline for the development of multi‐marker bio‐signature panels and ensemble classifiers. BMC Bioinformatics 2012; 13: 326.
    1. Xu Q, Ni S, Wu F, Liu F, Ye X, Mougin B, Meng X, Du X. Investigation of variation in gene expression profiling of human blood by extended principle component analysis. PLoS One 2011; 6: e26905.
    1. Benita Y, Cao Z, Giallourakis C, Li C, Gardet A, Xavier RJ. Gene enrichment profiles reveal T‐cell development, differentiation, and lineage‐specific transcription factors including ZBTB25 as a novel NF‐AT repressor. Blood 2010; 115: 5376–5384.
    1. Frey A, Ertl G, Angermann CE, Hofmann U, Stork S, Frantz S. Complement c3c as a biomarker in heart failure. MediatorsInflamm 2013; 2013: 716902.
    1. Heymans S, Hirsch E, Anker SD, Aukrust P, Balligand JL, Cohen‐Tervaert JW, Drexler H, Filippatos G, Felix SB, Gullestad L, Hilfiker‐Kleiner D, Janssens S, Latini R, Neubauer G, Paulus WJ, Pieske B, Ponikowski P, Schroen B, Schultheiss HP, Tschope C, Van Bilsen M, Zannad F, McMurray J, Shah AM. 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.
    1. Carter AM. Complement activation: an emerging player in the pathogenesis of cardiovascular disease. Scientifica(Cairo) 2012; 2012: 402783.
    1. de Boer RA, Edelmann F, Cohen‐Solal A, Mamas MA, Maisel A, Pieske B. Galectin‐3 in heart failure with preserved ejection fraction. Eur J Heart Fail 2013; 15: 1095–1101.
    1. Hollander Z, Dai DL, Putko BN, Yogasundaram H, Wilson‐McManus JE, Thompson RB, Khan A, West ML, McManus BM, Oudit GY. Gender‐specific plasma proteomic biomarkers in patients with Anderson‐Fabry disease. Eur J Heart Fail 2015; 17: 291–300.
    1. Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett JC Jr. Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll Cardiol 2002; 40: 976–982.
    1. Motiwala SR, Sarma A, Januzzi JL, O'Donoghue ML. Biomarkers in ACS and heart failure: should men and women be interpreted differently? Clin Chem 2014; 60: 35–43.
    1. Xiao L, Zhang L, Han W, Wang Z, Nattel S. Sex‐based transmural differences in cardiac repolarization and ionic‐current properties in canine left ventricles. Am J Physiol Heart Circ Physiol 2006; 291: H570–HH80.
    1. Furukawa T, Kurokawa J. Regulation of cardiac ion channels via non‐genomic action of sex steroid hormones: implication for the gender difference in cardiac arrhythmias. Pharmacol Ther 2007; 115: 106–115.
    1. Kaminsky Z, Wang SC, Petronis A. Complex disease, gender and epigenetics. Ann Med 2006; 38: 530–544.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever