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Canadian Journal of Cardiology

Heart Failure With Midrange Ejection Fraction—What Is It, If Anything?

Published:December 01, 2020DOI:https://doi.org/10.1016/j.cjca.2020.11.013

      Abstract

      The patient cohort with left ventricular ejection fractions (LVEFs) of 41%-49%, which has been defined as heart failure with midrange ejection fraction (HFmrEF), represent a significant proportion of the heart failure (HF) population. Despite the clear cutoffs established by different society guidelines, confusion remains regarding the exact significance of midrange LVEF within the HF syndrome. Patients with LVEF 41%-49% represent a heterogeneous group of patients sharing pathophysiologic mechanisms, biomarker profiles, comorbidities, and clinical characteristics with patients with preserved and reduced LVEF. In this clinical review, we discuss the underlying pathophysiologic mechanisms that culminate in the clinical syndrome of HF and contribute to the disparities observed between HFpEF, HFrEF, and HFmrEF. We highlight differences and similarities in clinical characteristics and imaging features between HFpEF and HFrEF in an effort to disentangle the heterogeneous group of patients with midrange LVEF, but ultimately we conclude that LVEF should be seen as simply one important element of a continuum throughout the HF syndrome, and that although is useful, it is an oversimplification, because HF syndrome is more of a continuum. The underlying pathophysiology, etiology, and comorbidities of patients presenting with HF is becoming ever more important as the limitations of a classification solely based on LVEF are being better recognised, and as patient-specific personalisation of care is becoming ever more important.

      Résumé

      Les patients présentant une fraction d'éjection ventriculaire gauche (FEVG) de 41 à 49 %, définie comme une insuffisance cardiaque (IC) avec fraction d'éjection (FE) intermédiaire, représentent une proportion significative de la population atteinte d'IC. Malgré les valeurs seuils clairement établies dans les lignes directrices de différentes sociétés, une certaine confusion subsiste concernant ce à quoi correspond exactement une FEVG intermédiaire dans le syndrome de l'IC. Les patients présentant une FEVG de 41 à 49 % constituent un groupe hétérogène dont les mécanismes physiopathologiques, les profils de biomarqueurs, les comorbidités et les caractéristiques cliniques recoupent ceux observés chez les patients qui présentent une FEVG préservée et réduite. Dans ce résumé clinique, nous aborderons les mécanismes physiopathologiques sous-jacents qui mènent au syndrome clinique de l'IC et qui contribuent aux disparités observées entre l'IC avec FE préservée (ICFEP), l'IC avec FE réduite (ICFER), et l'IC avec FE intermédiaire. Nous soulignerons les différences et les similarités quant aux caractéristiques cliniques et aux résultats observés à l'imagerie entre l'ICFEP et l'ICFER, afin d'essayer de démêler le groupe hétérogène de patients présentant une FEVG intermédiaire, pour toutefois en venir à la conclusion que la FEVG devrait être simplement considérée comme un élément important du continuum du syndrome de l'IC. Même si elle est utile, il s'agit d'une simplification excessive, car le syndrome de l'IC est plutôt un continuum. La physiopathologie sous-jacente, l'étiologie et les comorbidités chez les patients atteints d'IC ont une importance encore plus importante maintenant que l'on connaît mieux les limites d'une classification fondée uniquement sur la FEVG, et que la personnalisation des soins en fonction des patients est de plus en plus privilégiée.
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      References

        • CONSENSUS Trial Study Group
        Effects of enalapril on mortality in severe congestive heart failure.
        N Engl J Med. 1987; 316: 1429-1435
        • Yusuf S.
        • Pitt B.
        • Davis C.E.
        • Hood W.B.
        • Cohn J.N.
        Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.
        N Engl J Med. 1991; 325: 293-302
        • Pfeffer M.A.
        • Braunwald E.
        • Moyé L.A.
        • et al.
        Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction.
        N Engl J Med. 1992; 327: 669-677
        • Bhatia R.S.
        • Tu J.V.
        • Lee D.S.
        • et al.
        Outcome of heart failure with preserved ejection fraction in a population-based study.
        N Engl J Med. 2006; 355: 260-269
        • Owan T.E.
        • Hodge D.O.
        • Herges R.M.
        • et al.
        Trends in prevalence and outcome of heart failure with preserved ejection fraction.
        N Engl J Med. 2006; 355: 251-259
        • Lee D.S.
        • Gona P.
        • Albano I.
        • et al.
        A systematic assessment of causes of death after heart failure onset in the community.
        Circ Heart Fail. 2011; 4: 36-43
        • Dewan P.
        • Jackson A.
        • Lam C.S.P.
        • et al.
        Interactions between left ventricular ejection fraction, sex and effect of neurohumoral modulators in heart failure.
        Eur J Heart Fail. 2020; 22: 898-901
        • Ponikowski P.
        • Voors A.A.
        • Anker S.D.
        • 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: 2129-2200
        • Yancy C.W.
        • Jessup M.
        • Bozkurt B.
        • et al.
        2013 ACC/AHA guideline for the management of heart failure.
        Circulation. 2013; 128 (e240-27)
        • Atherton J.J.
        • Sindone A.
        • De Pasquale C.G.
        • et al.
        National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: guidelines for the prevention, detection, and management of heart failure in Australia 2018.
        Heart Lung Circ. 2018; 27: 1123-1208
        • Ezekowitz J.A.
        • O’Meara E.
        • McDonald M.A.
        • et al.
        2017 comprehensive update of the Canadian Cardiovascular Society guidelines for the management of heart failure.
        Can J Cardiol. 2017; 33: 1342-1433
        • Savarese G.
        • Vasko P.
        • Jonsson Å.
        • et al.
        The Swedish Heart Failure Registry: a living, ongoing quality assurance and research in heart failure.
        Ups J Med Sci. 2019; 124: 65-69
        • Lakhani I.
        • Leung K.S.K.
        • Tse G.
        • Lee A.P.W.
        Novel mechanisms in heart failure with preserved, midrange, and reduced ejection fraction.
        Front Physiol. 2019; 10: 874
        • Triposkiadis F.
        • Butler J.
        • Abboud F.M.
        • et al.
        The continuous heart failure spectrum: moving beyond an ejection fraction classification.
        Eur Heart J. 2019; 40: 2155-2163
        • Brutsaert D.L.
        Cardiac endothelial-myocardial signaling: its role in cardiac growth, contractile performance, and rhythmicity.
        Physiol Rev. 2003; 83: 59-115
        • Greene S.J.
        • Gheorghiade M.
        • Borlaug B.A.
        • et al.
        The cGMP signaling pathway as a therapeutic target in heart failure with preserved ejection fraction.
        J Am Heart Assoc. 2013; 2e000536
        • de Lemos J.A.
        • Drazner M.H.
        • Omland T.
        • et al.
        Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population.
        JAMA. 2010; 304: 2503-2512
        • Bhambhani V.
        • Kizer J.R.
        • Lima J.A.C.
        • et al.
        Predictors and outcomes of heart failure with mid-range ejection fraction.
        Eur J Heart Fail. 2018; 20: 651-659
        • de Boer R.A.
        • Nayor M.
        • deFilippi C.R.
        • et al.
        Association of cardiovascular biomarkers with incident heart failure with preserved and reduced ejection fraction.
        JAMA Cardiol. 2018; 3: 215-224
        • Gohar A.
        • Chong J.P.C.
        • Liew O.W.
        • 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
        • Park K.C.
        • Gaze D.C.
        • Collinson P.O.
        • Marber M.S.
        Cardiac troponins: from myocardial infarction to chronic disease.
        Cardiovasc Res. 2017; 113: 1708-1718
        • Obokata M.
        • Reddy Y.N.V.
        • Melenovsky V.
        • et al.
        Myocardial injury and cardiac reserve in patients with heart failure and preserved ejection fraction.
        J Am Coll Cardiol. 2018; 72: 29-40
        • Aoki T.
        • Fukumoto Y.
        • Sugimura K.
        • et al.
        Prognostic impact of myocardial interstitial fibrosis in nonischemic heart failure: comparison between preserved and reduced ejection fraction heart failure.
        Circ J. 2011; 75: 2605-2613
        • Roy C.
        • Slimani A.
        • de Meester C.
        • et al.
        Associations and prognostic significance of diffuse myocardial fibrosis by cardiovascular magnetic resonance in heart failure with preserved ejection fraction.
        J Cardiovasc Magn Reson. 2018; 20: 55
        • Doeblin P.
        • Hashemi D.
        • Tanacli R.
        • et al.
        CMR tissue characterization in patients with HFmrEF.
        J Clin Med. 2019; 8: 1877
        • Vergaro G.
        • Aimo A.
        • Prontera C.
        • et al.
        Sympathetic and renin-angiotensin-aldosterone system activation in heart failure with preserved, mid-range and reduced ejection fraction.
        Int J Cardiol. 2019; 296: 91-97
        • Tromp J.
        • Westenbrink B.D.
        • Ouwerkerk W.
        • et al.
        Identifying pathophysiological mechanisms in heart failure with reduced versus preserved ejection fraction.
        J Am Coll Cardiol. 2018; 72: 1081-1090
        • van Linthout S.
        • Tschöpe C.
        Inflammation—cause or consequence of heart failure or both?.
        Curr Heart Fail Rep. 2017; 14: 251-265
        • Lam C.S.P.
        • Voors A.A.
        • de Boer R.A.
        • Solomon S.D.
        • van Veldhuisen D.J.
        Heart failure with preserved ejection fraction: from mechanisms to therapies.
        Eur Heart J. 2018; 39: 2780-2792
        • DuBrock H.M.
        • AbouEzzeddine O.F.
        • Redfield M.M.
        High-sensitivity C-reactive protein in heart failure with preserved ejection fraction.
        PLoS One. 2018; 13e0201836
        • Van Tassell B.W.
        • Trankle C.R.
        • Canada J.M.
        • et al.
        IL-1 blockade in patients with heart failure with preserved ejection fraction.
        Circ. 2018; 11
        • Deftereos S.
        • Giannopoulos G.
        • Panagopoulou V.
        • et al.
        Anti-inflammatory treatment with colchicine in stable chronic heart failure: a prospective, randomized study.
        JACC Heart Fail. 2014; 2: 131-137
        • Chung E.S.
        • Packer M.
        • Lo K.H.
        • Fasanmade A.A.
        • Willerson J.T.
        Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the Anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial.
        Circulation. 2003; 107: 3133-3140
        • Georgiadou P.
        • Adamopoulos S.
        Skeletal muscle abnormalities in chronic heart failure.
        Curr Heart Fail Rep. 2012; 9: 128-132
        • Kitzman D.W.
        • Haykowsky M.J.
        • Tomczak C.R.
        Making the case for skeletal muscle myopathy and its contribution to exercise intolerance in heart failure with preserved ejection fraction.
        Circ Heart Fail. 2017; 10e004281
        • Pugliese N.R.
        • Fabiani I.
        • Santini C.
        • et al.
        Value of combined cardiopulmonary and echocardiography stress test to characterize the haemodynamic and metabolic responses of patients with heart failure and mid-range ejection fraction.
        Eur Heart J Cardiovasc Imaging. 2019; 20: 828-836
        • Paneroni M.
        • Pasini E.
        • Comini L.
        • et al.
        Skeletal muscle myopathy in heart failure: the role of ejection fraction.
        Curr Cardiol Rep. 2018; 20: 116
        • Anker S.D.
        • Chua T.P.
        • Ponikowski P.
        • et al.
        Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia.
        Circulation. 1997; 96: 526-534
        • Chen X.
        • Savarese G.
        • Dahlstrom 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. 2019; 108: 1394-1405
        • Eriksson B.
        • Wandell P.
        • Dahlstrom U.
        • et al.
        Limited value of NT-proBNP as a prognostic marker of all-cause mortality in patients with heart failure with preserved and mid-range ejection fraction in primary care: a report from the Swedish Heart Failure Register.
        Scand J Prim Health Care. 2019; 37: 434-443
        • Fonarow G.C.
        • Stough W.G.
        • Abraham W.T.
        • et al.
        Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure.
        J Am Coll Cardiol. 2007; 50: 768-777
        • Lyu S.
        • Yu L.
        • Tan H.
        • et al.
        Clinical characteristics and prognosis of heart failure with mid-range ejection fraction: insights from a multi-centre registry study in China.
        BMC Cardiovasc Disord. 2019; 19: 209
        • Ibrahim N.E.
        • Song Y.
        • Cannon C.P.
        • et al.
        Heart failure with mid-range ejection fraction: characterization of patients from the PINNACLE Registry.
        ESC Heart Fail. 2019; 6: 784-792
        • Martone R.
        • Marchionni N.
        • Cappelli F.
        Heart failure with mid-range ejection fraction: current evidence and uncertainties.
        Monaldi Arch Chest Dis. 2019; 89: 63-66
        • Mesquita E.T.
        • Barbetta L.
        • Correia E.T.O.
        Heart failure with mid-range ejection fraction—state of the art.
        Arq Bras Cardiol. 2019; 112: 784-790
        • Streng K.W.
        • Nauta J.F.
        • Hillege H.L.
        • et al.
        Noncardiac comorbidities in heart failure with reduced, mid-range and preserved ejection fraction.
        Int J Cardiol. 2018; 271: 132-139
        • Koh A.S.
        • Tay W.T.
        • Teng T.H.K.
        • et al.
        A comprehensive population-based characterization of heart failure with mid-range ejection fraction.
        Eur J Heart Fail. 2017; 19: 1624-1634
        • Petutschnigg J.
        • Edelmann F.
        Heart failure with mid-range ejection fraction and with preserved ejection fraction.
        Herz. 2018; 43: 392-405
        • Wang N.
        • Hales S.
        • Barin E.
        • Tofler G.
        Characteristics and outcome for heart failure patients with mid-range ejection fraction.
        J Cardiovasc Med (Hagerstown). 2018; 19: 297-303
        • Borrelli C.
        • Gentile F.
        • Sciarrone P.
        • et al.
        Central and obstructive apneas in heart failure with reduced, mid-range and preserved ejection fraction.
        Front Cardiovasc Med. 2019; 6: 125
        • Zhu N.
        • Jiang W.
        • Wang Y.
        • Wu Y.
        • Chen H.
        • Zhao X.
        Plasma levels of free fatty acid differ in patients with left ventricular preserved, mid-range, and reduced ejection fraction.
        BMC Cardiovasc Disord. 2018; 18: 104
        • Zafrir B.
        • Lund L.H.
        • Laroche C.
        • et al.
        Prognostic implications of atrial fibrillation in heart failure with reduced, mid-range, and preserved ejection fraction: a report from 14 964 patients in the European Society of Cardiology Heart Failure Long-Term Registry.
        Eur Heart J. 2018; 39: 4277-4284
        • Johansson I.
        • Dahlstrom U.
        • Edner M.
        • et al.
        Type 2 diabetes and heart failure: characteristics and prognosis in preserved, mid-range and reduced ventricular function.
        Diab Vasc Dis Res. 2018; 15: 494-503
        • Stolfo D.
        • Uijl A.
        • Vedin O.
        • et al.
        Sex-based differences in heart failure across the ejection fraction spectrum: phenotyping, and prognostic and therapeutic implications.
        JACC Heart Fail. 2019; 7: 505-515
        • Bouabdallaoui N.
        • Rouleau J.
        Evolving toward a more realistic approach to the importance of left ventricular ejection fraction and sex in heart failure and its therapy.
        Eur J Heart Fail. 2020; 22: 800-803
        • savarese g.
        • vedin o.
        • d’amario d.
        • et al.
        prevalence and prognostic implications of longitudinal ejection fraction change in heart failure.
        JACC Heart Fail. 2019; 7: 306-317
        • McGowan J.H.
        • Cleland J.G.
        Reliability of reporting left ventricular systolic function by echocardiography: a systematic review of 3 methods.
        Am Heart J. 2003; 146: 388-397
        • Marwick T.H.
        Ejection fraction pros and cons: JACC state-of-the-art review.
        J Am Coll Cardiol. 2018; 72: 2360-2379
        • Bayés-Genís A.
        • Núñez J.
        • Lupón J.
        Heart failure with mid-range ejection fraction: a transition phenotype?.
        Eur J Heart Fail. 2017; 19: 1635-1637
        • Lupón J.
        • Gavidia-Bovadilla G.
        • Ferrer E.
        • et al.
        Dynamic trajectories of left ventricular ejection fraction in heart failure.
        J Am Coll Cardiol. 2018; 72: 591-601
        • Rastogi A.
        • Novak E.
        • Platts A.E.
        • Mann D.L.
        Epidemiology, pathophysiology and clinical outcomes for heart failure patients with a mid-range ejection fraction.
        Eur J Heart Fail. 2017; 19: 1597-1605
        • Tsuji K.
        • Sakata Y.
        • Nochioka K.
        • et al.
        Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 study.
        Eur J Heart Fail. 2017; 19: 1258-1269
        • Pellikka P.A.
        • She L.
        • Holly T.A.
        • 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
        • Konstam M.A.
        • Abboud F.M.
        Ejection fraction.
        Circulation. 2017; 135: 717-719
        • Kerkhof P.L.M.
        Characterizing heart failure in the ventricular volume domain.
        Clin Med Insights Cardiol. 2015; 25 (9): 11-31
        • Cikes M.
        • Solomon S.D.
        Beyond ejection fraction: an integrative approach for assessment of cardiac structure and function in heart failure.
        Eur Heart J. 2016; 37: 1642-1650
        • Doughty R.N.
        • Gardin J.M.
        • Hobbs F.D.R.
        • et al.
        A meta-analysis of echocardiographic measurements of the left heart for the development of normative reference ranges in a large international cohort: the EchoNORMAL study.
        Eur Heart J Cardiovasc Imaging. 2013; 15: 341-348
        • Al Saikhan L.
        • Hughes A.D.
        • Chung W.S.
        • Alsharqi M.
        • Nihoyannopoulos P.
        Left atrial function in heart failure with mid-range ejection fraction differs from that of heart failure with preserved ejection fraction: a 2D speckle-tracking echocardiographic study.
        Eur Heart J Cardiovasc Imaging. 2019; 20: 279-290
        • Huang W.M.
        • Sung S.H.
        • Yu W.C.
        • et al.
        Perturbations of pulsatile hemodynamics and clinical outcomes in patients with acute heart failure and reduced, mid-range or preserved ejection fraction.
        PLoS One. 2019; 14e0220183
        • Srivastava P.K.
        • Hsu J.J.
        • Ziaeian B.
        • Fonarow G.C.
        Heart failure with mid-range ejection fraction.
        Curr Heart Fail Rep. 2020; 17: 1-8
        • Puntmann V.O.
        • Peker E.
        • Chandrashekhar Y.
        • Nagel E.
        T1 Mapping in characterizing myocardial disease.
        Circ Res. 2016; 119: 277-299
        • Branca L.
        • Sbolli M.
        • Metra M.
        • Fudim M.
        Heart failure with mid-range ejection fraction: pro and cons of the new classification of heart failure by European Society of Cardiology guidelines.
        ESC Heart Fail. 2020; 7: 381-399
        • Lee S.E.
        • Cho H.J.
        • Lee H.Y.
        • et al.
        A multicentre cohort study of acute heart failure syndromes in Korea: rationale, design, and interim observations of the Korean Acute Heart Failure (KorAHF) registry.
        Eur J Heart Fail. 2014; 16: 700-708
        • Cho J.H.
        • Choe W.S.
        • Cho H.J.
        • et al.
        Comparison of characteristics and 3-year outcomes in patients with acute heart failure with preserved, mid-range, and reduced ejection fraction.
        Circ J. 2019; 83: 347-356
        • Guo P.
        • Dai J.F.
        • Feng C.
        • Chen S.T.
        • Feng J.P.
        Special prognostic phenomenon for patients with mid-range ejection fraction heart failure: a systematic review and meta-analysis.
        Chin Med J. 2020; 133: 452-461
        • Margolis G.
        • Khoury S.
        • Ben-Shoshan J.
        • et al.
        Prognostic implications of mid-range left ventricular ejection fraction on patients presenting with ST-segment elevation myocardial infarction.
        Am J Cardiol. 2017; 120: 186-190
        • Chioncel O.
        • Lainscak M.
        • Seferovic P.M.
        • et al.
        Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry.
        Eur J Heart Fail. 2017; 19: 1574-1585
        • Tu J.V.
        • Donovan L.R.
        • Lee D.S.
        • et al.
        Effectiveness of public report cards for improving the quality of cardiac care: the EFFECT study: a randomized trial.
        JAMA. 2009; 302: 2330-2337
        • Van Spall H.G.C.
        • Lee S.F.
        • Xie F.
        • et al.
        Effect of patient-centered transitional care services on clinical outcomes in patients hospitalized for heart failure: the PACT-HF randomized clinical trial.
        JAMA. 2019; 321: 753-761
        • Nadar S.K.
        • Tariq O.
        What is heart failure with mid-range ejection fraction? A new subgroup of patients with heart failure.
        Card Fail Rev. 2018; 4: 6-8
        • Nauta J.F.
        • Hummel Y.M.
        • van Melle J.P.
        • et al.
        What have we learned about heart failure with mid-range ejection fraction one year after its introduction?.
        Eur J Heart Fail. 2017; 19: 1569-1573
        • Yusuf S.
        • Pfeffer M.A.
        • Swedberg K.
        • et al.
        Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved trial.
        Lancet. 2003; 362: 777-781
        • Armstrong P.W.
        • Pieske B.
        • Anstrom K.J.
        • et al.
        Vericiguat in patients with heart failure and reduced ejection fraction.
        N Engl J Med. 2020; 382: 1883-1893
        • Pieske B.
        • Maggioni A.P.
        • Lam C.S.P.
        • et al.
        Vericiguat in patients with worsening chronic heart failure and preserved ejection fraction: results of the Soluble Guanylate Cyclase Stimulator in Heart Failure Patients with Preserved EF (SOCRATES-Preserved) study.
        Eur Heart J. 2017; 38: 1119-1127
        • Armstrong P.W.
        • Lam C.S.P.
        • Anstrom K.J.
        • et al.
        Effect of vericiguat vs placebo on quality of life in patients with heart failure and preserved ejection fraction: the VITALITY-HFpEF randomized clinical trial.
        JAMA. 2020; 324: 1512-1521
        • Schiattarella G.G.
        • Altamirano F.
        • Tong D.
        • 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.
        • et al.
        Isosorbide mononitrate in heart failure with preserved ejection fraction.
        N Engl J Med. 2015; 373: 2314-2324
        • Redfield M.M.
        • Chen H.H.
        • Borlaug B.A.
        • 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: 1268-1277
        • Cleland J.G.F.
        • Bunting K.V.
        • Flather M.D.
        • et al.
        Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials.
        Eur Heart J. 2018; 39: 26-35
        • Hernandez A.F.
        • Hammill B.G.
        • O’Connor C.M.
        • et al.
        Clinical effectiveness of beta-blockers in heart failure: findings from the OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) registry.
        J Am Coll Cardiol. 2009; 53: 184-192
        • Park J.J.
        • Choi H.M.
        • Hwang I.C.
        • et al.
        Myocardial strain for identification of beta-blocker responders in heart failure with preserved ejection fraction.
        J Am Soc Echocardiogr. 2019; 32 (e1468): 1462-1469
        • Lauritsen J.
        • Gustafsson F.
        • Abdulla J.
        Characteristics and long-term prognosis of patients with heart failure and mid-range ejection fraction compared with reduced and preserved ejection fraction: a systematic review and meta-analysis.
        ESC Heart Fail. 2018; 5: 685-694
        • Wilcox J.E.
        • Mann D.L.
        Beta-blockers for the treatment of heart failure with a mid-range ejection fraction: deja-vu all over again?.
        Eur Heart J. 2018; 39: 36-38
        • Kozhuharov N.
        • Goudev A.
        • Flores D.
        • et al.
        Effect of a strategy of comprehensive vasodilation vs usual care on mortality and heart failure rehospitalization among patients with acute heart failure: the GALACTIC randomized clinical trial.
        JAMA. 2019; 322: 2292-2302
        • Gatzoulis K.A.
        • Tsiachris D.
        • Arsenos P.
        • et al.
        Arrhythmic risk stratification in post-myocardial infarction patients with preserved ejection fraction: the PRESERVE EF study.
        Eur Heart J. 2019; 40: 2940-2949
        • Horak P.
        • Klink B.
        • Heining C.
        • et al.
        Precision oncology based on omics data: the NCT Heidelberg experience.
        Int J Cancer. 2017; 141: 877-886