Advertisement
Heart, Lung and Circulation

Biomarkers in Heart Failure With Preserved Ejection Fraction: An Update on Progress and Future Challenges

      Heart failure with preserved ejection fraction (HFpEF) is a major health care problem, with no treatment available that significantly reduces mortality. HFpEF is a phenotypically diverse syndrome, which creates difficulties in establishing an accurate diagnosis, determining prognosis, and developing effective management strategies. The number of serum biomarkers being investigated to further our understanding of HFpEF is rapidly expanding. In this review, we critically appraise the current clinical utility of biomarkers in HFpEF, particularly for pathophysiological pathways involving cardiomyocyte stretch, injury, fibrosis, remodelling, systemic inflammation, and renal dysfunction. Guideline-based clinical indications for biomarker testing in HFpEF and their limitations are discussed. Investigative strategies including the use of multi-biomarker panels and standardisation of research methodologies may prove useful in developing biomarkers for HFpEF in the future.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Heart, Lung and Circulation
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Owan T.E.
        • Hodge D.O.
        • Herges R.M.
        • Jacobsen S.J.
        • Roger V.L.
        • Redfield M.M.
        Trends in prevalence and outcome of heart failure with preserved ejection fraction.
        N Engl J Med. 2006; 355: 251-259
        • Steinberg B.A.
        • Zhao X.
        • Heidenreich P.A.
        • Peterson E.D.
        • Bhatt D.L.
        • Cannon C.P.
        • et al.
        Trends in patients hospitalized with heart failure and preserved left ventricular ejection fraction: prevalence, therapies, and outcomes.
        Circulation. 2012; 126: 65-75
        • Senni M.
        • Gavazzi A.
        • Oliva F.
        • Mortara A.
        • Urso R.
        • Pozzoli M.
        • et al.
        In-hospital and 1-year outcomes of acute heart failure patients according to presentation (de novo vs. worsening) and ejection fraction. Results from IN-HF Outcome Registry.
        Int J Cardiol. 2014; 173: 163-169
        • Shah K.S.
        • Xu H.
        • Matsouaka R.A.
        • Bhatt D.L.
        • Heidenreich P.A.
        • Hernandez A.F.
        • et al.
        Heart failure with preserved, borderline, and reduced ejection fraction: 5-year outcomes.
        J Am Coll Cardiol. 2017; 70: 2476-2486
        • Ather S.
        • Chan W.
        • Bozkurt B.
        • Aguilar D.
        • Ramasubbu K.
        • Zachariah A.A.
        • et al.
        Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction.
        J Am Coll Cardiol. 2012; 59: 998-1005
        • Seferović P.M.
        • Polovina M.
        • Bauersachs J.
        • Arad M.
        • Gal T.B.
        • Lund L.H.
        • et al.
        Heart failure in cardiomyopathies: a position paper from the Heart Failure Association of the European Society of Cardiology.
        Eur J Heart Fail. 2019; 21: 553-576
        • Chen X.
        • Savarese G.
        • Dahlström U.
        • Lund L.H.
        • Fu M.
        Age-dependent differences in clinical phenotype and prognosis in heart failure with mid-range ejection compared with heart failure with reduced or preserved ejection fraction.
        Clin Res Cardiol. 2019; ([Epub ahead of print])https://doi.org/10.1007/s00392-019-01477-z
        • Mentz R.J.
        • Kelly J.P.
        • von Lueder T.G.
        • Voors A.A.
        • Lam C.S.
        • Cowie M.R.
        • et al.
        Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction.
        J Am Coll Cardiol. 2014; 64: 2281-2293
        • Zakeri R.
        • Chamberlain A.M.
        • Roger V.L.
        • Redfield M.M.
        Temporal relationship and prognostic significance of atrial fibrillation in heart failure patients with preserved ejection fraction: a community-based study.
        Circulation. 2013; 128: 1085-1093
        • Paulus W.J.
        • Tschope C.
        A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodelling through coronary microvascular endothelial inflammation.
        J Am Coll Cardiol. 2013; 62: 263-271
        • Shah S.J.
        • Kitzman D.W.
        • Borlaug B.A.
        • van Heerebeek L.
        • Zile M.R.
        • Kass D.A.
        • et al.
        Phenotype-specific treatment of heart failure with preserved ejection fraction: a multiorgan roadmap.
        Circulation. 2016; 134: 73-90
        • Mohammed S.F.
        • Hussain S.
        • Mirzoyev S.A.
        • Edwards W.D.
        • Maleszewski J.J.
        • Redfield M.M.
        Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction.
        Circulation. 2015; 131: 550-559
        • Zile M.R.
        • Baicu C.F.
        • Ikonomidis J.S.
        • Stroud R.E.
        • Nietert P.J.
        • Bradshaw A.D.
        • et al.
        Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin.
        Circulation. 2015; 131: 1247-1259
        • Runte K.E.
        • Bell S.P.
        • Selby D.E.
        • Häußler T.N.
        • Ashikaga T.
        • LeWinter M.M.
        • et al.
        Relaxation and the role of calcium in isolated contracting myocardium from patients with hypertensive heart disease and heart failure with preserved ejection fraction.
        Circ Heart Fail. 2017; 10e004311
        • Borlaug B.A.
        The pathophysiology of heart failure with preserved ejection fraction.
        Nat Rev Cardiol. 2014; 11: 507-515
        • Reddy Y.N.V.
        • Andersen M.J.
        • Obokata M.
        • Koepp K.E.
        • Kane G.C.
        • Melenovsky V.
        • et al.
        Arterial stiffening with exercise in patients with heart failure and preserved ejection fraction.
        J Am Coll Cardiol. 2017; 70: 136-148
        • Triposkiadis F.
        • Butler J.
        • Abboud F.M.
        • Armstrong P.W.
        • Adamopoulos S.
        • Atherton J.J.
        • et al.
        The continuous heart failure spectrum: moving beyond an ejection fraction classification.
        Eur Heart J. 2019; (pii: ehz158 [Epub ahead of print])https://doi.org/10.1093/eurheartj/ehz158
        • Ferrari R.
        • Bohm M.
        • Cleland J.G.
        • Paulus W.J.
        • Pieske B.
        • Rapezzi C.
        • et al.
        Heart failure with preserved ejection fraction: uncertainties and dilemmas.
        Eur J Heart Fail. 2015; 17: 665-671
        • Pellikka P.A.
        • She L.
        • Holly T.A.
        • Lin G.
        • Varadarajan P.
        • Pai R.G.
        • et al.
        Variability in ejection fraction measured by echocardiography, gated single-photon emission computed tomography, and cardiac magnetic resonance in patients with coronary artery disease and left ventricular dysfunction.
        JAMA Netw Open. 2018; 1e181456
        • Kraigher-Krainer E.
        • Shah A.M.
        • Gupta D.K.
        • Santos A.
        • Claggett B.
        • Pieske B.
        • et al.
        Impaired systolic function by strain imaging in heart failure with preserved ejection fraction.
        J Am Coll Cardiol. 2014; 63: 447-456
        • Park J.J.
        • Park J.B.
        • Park J.H.
        • Cho G.Y.
        Global longitudinal strain to predict mortality in patients with acute heart failure.
        J Am Coll Cardiol. 2018; 71: 1947-1957
        • Hlatky M.A.
        • Greenland P.
        • Arnett D.K.
        • Ballantyne C.M.
        • Criqui M.H.
        • Elkind M.S.
        • et al.
        Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association.
        Circulation. 2009; 119: 2408-2416
        • Munagala V.K.
        • Burnett Jr, J.C.
        • Redfield M.M.
        The natriuretic peptides in cardiovascular medicine.
        Curr Probl Cardiol. 2004; 29: 707-769
        • Ponikowski P.
        • Voors A.A.
        • Anker S.D.
        • Bueno H.
        • Cleland J.G.
        • Coats A.J.
        • et al.
        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 J Heart Fail. 2016; 18: 891-975
        • Anjan V.Y.
        • Loftus T.M.
        • Burke M.A.
        • Akhter N.
        • Fonarow G.C.
        • Gheorghiade M.
        • et al.
        Prevalence, clinical phenotype, and outcomes associated with normal B-type natriuretic peptide levels in heart failure with preserved ejection fraction.
        Am J Cardiol. 2012; 110: 870-876
        • Buckley L.F.
        • Canada J.M.
        • Del Buono M.G.
        • Carbone S.
        • Trankle C.R.
        • Billingsley H.
        • et al.
        Low NT-proBNP levels in overweight and obese patients do not rule out a diagnosis of heart failure with preserved ejection fraction.
        ESC Heart Fail. 2018; 5: 372-378
        • de Boer R.A.
        • Nayor M.
        • deFilippi C.R.
        • Enserro D.
        • Bhambhani V.
        • Kizer J.R.
        • et al.
        Association of cardiovascular biomarkers with incident heart failure with preserved and reduced ejection fraction.
        JAMA Cardiol. 2018; 3: 215-224
        • Kang S.H.
        • Park J.J.
        • Choi D.J.
        • Yoon C.H.
        • Oh I.Y.
        • Kang S.M.
        • et al.
        Prognostic value of NT-proBNP in heart failure with preserved versus reduced EF.
        Heart. 2015; 101: 1881-1888
        • van Veldhuisen D.J.
        • Linssen G.C.
        • Jaarsma T.
        • van Gilst W.H.
        • Hoes A.W.
        • Tijssen J.G.
        • et al.
        B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction.
        J Am Coll Cardiol. 2013; 61: 1498-1506
        • Faxén U.L.
        • Lund L.H.
        • Orsini N.
        • Strömberg A.
        • Andersson D.C.
        • Linde C.
        • et al.
        N-terminal pro-B-type natriuretic peptide in chronic heart failure: the impact of sex across the ejection fraction spectrum.
        Int J Cardiol. 2019; 287 (Epub 2019 Apr 11): 66-72https://doi.org/10.1016/j.ijcard.2019.04.023
        • Lourenco P.
        • Ribeiro A.
        • Pintalhao M.
        • Silva S.
        • Bettencourt P.
        Predictors of six-month mortality in BNP-matched acute heart failure patients.
        Am J Cardiol. 2015; 116: 744-748
        • Salah K.
        • Stienen S.
        • Pinto Y.M.
        • Eurlings L.W.
        • Metra M.
        • Bayes-Genis A.
        • et al.
        Prognosis and NT-proBNP in heart failure patients with preserved versus reduced ejection fraction.
        Heart. 2019; (pii: heartjnl-2018-314173 [Epub ahead of print])https://doi.org/10.1136/heartjnl-2018-314173
        • Maeder M.T.
        • Rickenbacher P.
        • Rickli H.
        • Abbuhl H.
        • Gutmann M.
        • Erne P.
        • et al.
        N-terminal pro brain natriuretic peptide-guided management in patients with heart failure and preserved ejection fraction: findings from the Trial of Intensified versus standard medical therapy in elderly patients with congestive heart failure (TIME-CHF).
        Eur J Heart Fail. 2013; 15: 1148-1156
        • Zabarovskaja S.
        • Hage C.
        • Linde C.
        • Daubert J.C.
        • Donal E.
        • Gabrielsen A.
        • et al.
        Adaptive cardiovascular hormones in a spectrum of heart failure phenotypes.
        Int J Cardiol. 2015; 189: 6-11
        • Januzzi Jr, J.L.
        • Filippatos G.
        • Nieminen M.
        • Gheorghiade M.
        Troponin elevation in patients with heart failure: on behalf of the third Universal Definition of Myocardial Infarction Global Task Force: Heart Failure Section.
        Eur Heart J. 2012; 33: 2265-2271
        • Santhanakrishnan R.
        • Chong J.P.
        • Ng T.P.
        • Ling L.H.
        • Sim D.
        • Leong K.T.
        • et al.
        Growth differentiation factor 15, ST2, high-sensitivity troponin T, and N-terminal pro brain natriuretic peptide in heart failure with preserved vs. reduced ejection fraction.
        Eur J Heart Fail. 2012; 14: 1338-1347
        • Pandey A.
        • Golwala H.
        • Sheng S.
        • DeVore A.D.
        • Hernandez A.F.
        • Bhatt D.L.
        • 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: 136-145
        • Gohar A.
        • Chong J.P.C.
        • Liew O.W.
        • den Ruijter H.
        • de Kleijn D.P.V.
        • Sim D.
        • et al.
        The prognostic value of highly sensitive cardiac troponin assays for adverse events in men and women with stable heart failure and a preserved vs. reduced ejection fraction.
        Eur J Heart Fail. 2017; 19: 1638-1647
        • Su M.Y.
        • Lin L.Y.
        • Tseng Y.H.
        • Chang C.C.
        • Wu C.K.
        • Lin J.L.
        • et al.
        CMR-verified diffuse myocardial fibrosis is associated with diastolic dysfunction in HFpEF.
        JACC Cardiovasc Imaging. 2014; 7: 991-997
        • Weber K.T.
        • Sun Y.
        • Bhattacharya S.K.
        • Ahokas R.A.
        • Gerling I.C.
        Myofibroblast-mediated mechanisms of pathological remodelling of the heart.
        Nat Rev Cardiol. 2013; 10: 15-26
        • Jellis C.
        • Martin J.
        • Narula J.
        • Marwick T.H.
        Assessment of nonischemic myocardial fibrosis.
        J Am Coll Cardiol. 2010; 56: 89-97
        • Januzzi Jr, J.L.
        ST2 as a cardiovascular risk biomarker: from the bench to the bedside.
        J Cardiovasc Transl Res. 2013; 6: 493-500
        • Zile M.R.
        • Jhund P.S.
        • Baicu C.F.
        • Claggett B.L.
        • Pieske B.
        • Voors A.A.
        • et al.
        Plasma biomarkers reflecting profibrotic processes in heart failure with a preserved ejection fraction: data from the prospective comparison of ARNI with ARB on management of heart failure with preserved ejection fraction study.
        Circ Heart Fail. 2016; 9e002551
        • Mueller T.
        • Leitner I.
        • Egger M.
        • Haltmayer M.
        • Dieplinger B.
        Association of the biomarkers soluble ST2, galectin-3 and growth-differentiation factor-15 with heart failure and other non-cardiac diseases.
        Clin Chim Acta. 2015; 445: 155-160
        • Manzano-Fernandez S.
        • Mueller T.
        • Pascual-Figal D.
        • Truong Q.A.
        • Januzzi J.L.
        Usefulness of soluble concentrations of interleukin family member ST2 as predictor of mortality in patients with acutely decompensated heart failure relative to left ventricular ejection fraction.
        Am J Cardiol. 2011; 107: 259-267
        • Solomon S.D.
        • Rizkala A.R.
        • Gong J.
        • Wang W.
        • Anand I.S.
        • Ge J.
        • et al.
        Angiotensin receptor neprilysin inhibition in heart failure with preserved ejection fraction: rationale and design of the PARAGON-HF trial.
        JACC Heart Fail. 2017; 5: 471-482
        • de Boer R.A.
        • Voors A.A.
        • Muntendam P.
        • van Gilst W.H.
        • van Veldhuisen D.J.
        Galectin-3: a novel mediator of heart failure development and progression.
        Eur J Heart Fail. 2009; 11: 811-817
        • Carrasco-Sanchez F.J.
        • Aramburu-Bodas O.
        • Salamanca-Bautista P.
        • Morales-Rull J.L.
        • Galisteo-Almeda L.
        • Paez-Rubio M.I.
        • et al.
        Predictive value of serum galectin-3 levels in patients with acute heart failure with preserved ejection fraction.
        Int J Cardiol. 2013; 169: 177-182
        • Edelmann F.
        • Holzendorf V.
        • Wachter R.
        • Nolte K.
        • Schmidt A.G.
        • Kraigher-Krainer E.
        • et al.
        Galectin-3 in patients with heart failure with preserved ejection fraction: results from the Aldo-DHF trial.
        Eur J Heart Fail. 2015; 17: 214-223
        • AbouEzzeddine O.F.
        • Haines P.
        • Stevens S.
        • Nativi-Nicolau J.
        • Felker G.M.
        • Borlaug B.A.
        • 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 Fail. 2015; 3: 245-252
        • Zile M.R.
        • Baicu C.F.
        • Ikonomidis J.
        • Stroud R.E.
        • Nietert P.J.
        • Bradshaw A.D.
        • et al.
        Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin.
        Circulation. 2015; 131: 1247-1259
        • Spinale F.G.
        • Janicki J.S.
        • Zile M.R.
        Membrane-associated matrix proteolysis and heart failure.
        Circ Res. 2013; 112: 195-208
        • Gonzalez A.
        • Lopez B.
        • Querejeta R.
        • Zubillaga E.
        • Echeverria T.
        • Diez J.
        Filling pressures and collagen metabolism in hypertensive patients with heart failure and normal ejection fraction.
        Hypertension. 2010; 55: 1418-1424
        • Duprez D.A.
        • Gross M.D.
        • Kizer J.R.
        • Ix J.H.
        • Hundley W.G.
        • Jacobs Jr, D.R.
        Predictive value of collagen biomarkers for heart failure with and without preserved ejection fraction: MESA (Multi-Ethnic Study of Atherosclerosis).
        J Am Heart Assoc. 2018; 7e007885
        • Zile M.R.
        • Desantis S.M.
        • Baicu C.F.
        • Stroud R.E.
        • Thompson S.B.
        • McClure C.D.
        • et al.
        Plasma biomarkers that reflect determinants of matrix composition identify the presence of left ventricular hypertrophy and diastolic heart failure.
        Circ Heart Fail. 2011; 4: 246-256
        • Lopez B.
        • Gonzalez A.
        • Ravassa S.
        • Beaumont J.
        • Moreno M.U.
        • San Jose G.
        • et al.
        Circulating biomarkers of myocardial fibrosis: the need for a reappraisal.
        J Am Coll Cardiol. 2015; 65: 2449-2456
        • Kalogeropoulos A.
        • Georgiopoulou V.
        • Psaty B.M.
        • Rodondi N.
        • Smith A.L.
        • Harrison D.G.
        • et al.
        Inflammatory markers and incident heart failure risk in older adults: the Health ABC (Health, Aging, and Body Composition) study.
        J Am Coll Cardiol. 2010; 55: 2129-2137
        • Chirinos J.A.
        • Akers S.R.
        • Trieu L.
        • Ischiropoulos H.
        • Doulias P.T.
        • Tariq A.
        • et al.
        Heart failure, left ventricular remodeling, and circulating nitric oxide metabolites.
        J Am Heart Assoc. 2016; 5e004133
        • Schiattarella G.G.
        • Altamirano F.
        • Tong D.
        • French K.M.
        • Villalobos E.
        • Kim S.Y.
        • et al.
        Nitrosative stress drives heart failure with preserved ejection fraction.
        Nature. 2019; 568: 351-356
        • Redfield M.M.
        • Anstrom K.J.
        • Levine J.A.
        • Koepp G.A.
        • Borlaug B.A.
        • Chen H.H.
        • et al.
        Isosorbide mononitrate in heart failure with preserved ejection fraction.
        N Engl J Med. 2015; 373: 2314-2324
        • Borlaug B.A.
        • Anstrom K.J.
        • Lewis G.D.
        • Shah S.J.
        • Levine J.A.
        • Koepp G.A.
        • 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: 1764-1773
        • Stahrenberg R.
        • Edelmann F.
        • Mende M.
        • Kockskamper A.
        • Dungen H.D.
        • Luers C.
        • et al.
        The novel biomarker growth differentiation factor 15 in heart failure with normal ejection fraction.
        Eur J Heart Fail. 2010; 12: 1309-1316
        • Chan M.M.
        • Santhanakrishnan R.
        • Chong J.P.
        • Chen Z.
        • Tai B.C.
        • Liew O.W.
        • et al.
        Growth differentiation factor 15 in heart failure with preserved vs. reduced ejection fraction.
        Eur J Heart Fail. 2016; 18: 81-88
        • Carrizzo A.
        • Lenzi P.
        • Procaccini C.
        • Damato A.
        • Biagioni F.
        • Ambrosio M.
        • et al.
        Pentraxin 3 induces vascular endothelial dysfunction through a P-selectin/matrix metalloproteinase-1 pathway.
        Circulation. 2015; 131: 1495-1505
        • Matsubara J.
        • Sugiyama S.
        • Nozaki T.
        • Sugamura K.
        • Konishi M.
        • Ohba K.
        • et al.
        Pentraxin 3 is a new inflammatory marker correlated with left ventricular diastolic dysfunction and heart failure with normal ejection fraction.
        J Am Coll Cardiol. 2011; 57: 861-869
        • Matsubara J.
        • Sugiyama S.
        • Nozaki T.
        • Akiyama E.
        • Matsuzawa Y.
        • Kuorkawa H.
        • et al.
        Incremental prognostic significance of the elevated levels of pentraxin 3 in patients with heart failure with normal left ventricular ejection fraction.
        J Am Heart Assoc. 2014; 3e000928
        • Kleber M.E.
        • Koller L.
        • Goliasch G.
        • Sulzgruber P.
        • Scharnagl H.
        • Silbernagel G.
        • et al.
        Von Willebrand factor improves risk prediction in addition to N-terminal pro-B-type natriuretic peptide in patients referred to coronary angiography and signs and symptoms of heart failure and preserved ejection fraction.
        Circ Heart Fail. 2015; 8: 25-32
        • Kang J.
        • Park J.J.
        • Cho Y.J.
        • Oh I.Y.
        • Park H.A.
        • Lee S.E.
        • et al.
        Predictors and prognostic value of worsening renal function during admission in HFpEF versus HFrEF: data from the KorAHF (Korean Acute Heart Failure) registry.
        J Am Heart Assoc. 2018; 7: 6
        • Stehouwer C.D.
        • Smulders Y.M.
        Microalbuminuria and risk for cardiovascular disease: Analysis of potential mechanisms.
        J Am Soc Nephrol. 2006; 17: 2106-2111
        • Katz D.H.
        • Burns J.A.
        • Aguilar F.G.
        • Beussink L.
        • Shah S.J.
        Albuminuria is independently associated with cardiac remodeling, abnormal right and left ventricular function, and worse outcomes in heart failure with preserved ejection fraction.
        JACC Heart Fail. 2014; 2: 586-596
        • Yancy C.W.
        • Jessup M.
        • Bozkurt B.
        • Butler J.
        • Casey Jr, D.E.
        • Colvin M.M.
        • et al.
        ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
        Circulation. 2017; 136: e137-e161
        • Ledwidge M.
        • Gallagher J.
        • Conlon C.
        • Tallon E.
        • O’Connell E.
        • Dawkins I.
        • et al.
        Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial.
        JAMA. 2013; 310: 66-74
        • Sinning C.
        • Kempf T.
        • Schwarzl M.
        • Lanfermann S.
        • Ojeda F.
        Biomarkers for characterization of heart failure - Distinction of heart failure with preserved and reduced ejection fraction.
        Int J Cardiol. 2017; 227: 272-277
        • Wong L.L.
        • Armugam A.
        • Sepramaniam S.
        • Karolina D.S.
        • Lim K.Y.
        • Lim J.Y.
        • et al.
        Circulating microRNAs in heart failure with reduced and preserved left ventricular ejection fraction.
        Eur J Heart Fail. 2015; 17: 393-404
        • Zordoky B.N.
        • Sung M.M.
        • Ezekowitz J.
        • Mandal R.
        • Han B.
        • Bjorndahl T.C.
        • et al.
        Metabolomic fingerprint of heart failure with preserved ejection fraction.
        PLoS One. 2015; 10e0124844
        • Shah S.J.
        • Katz D.H.
        • Selvaraj S.
        • Burke M.A.
        • Yancy C.W.
        • Gheorghiade M.
        • et al.
        Phenomapping for novel classification of heart failure with preserved ejection fraction.
        Circulation. 2015; 131: 269-279
        • Ahmad T.
        • Fiuzat M.
        • Pencina M.J.
        • Geller N.L.
        • Zannad F.
        • Cleland J.G.
        • et al.
        Charting a roadmap for heart failure biomarker studies.
        JACC Heart Fail. 2014; 2: 477-478