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Current Management and Future Directions of Heart Failure With Preserved Ejection Fraction: a Contemporary Review

  • Heart Failure (W Tang, Section Editor)
  • Published:
Current Treatment Options in Cardiovascular Medicine Aims and scope Submit manuscript

Abstract

Heart failure with preserved ejection fraction (HFpEF), a complex and debilitating syndrome, is commonly seen in elderly populations. Exacerbation of HFpEF is among the most common reasons for hospital admission in the USA. The high rate of morbidity and mortality from this condition underscores the fact that HFpEF is heterogeneous, complex, and poorly characterized. Randomized, controlled trials have been very successful at identifying treatments for HF with reduced ejection fraction (HFrEF), but effective treatment options for HFpEF are lacking. Here, we discuss (1) the pathophysiology of HFpEF, (2) a standardized diagnostic and therapeutic approach, (3) a comparison of the management of recent guidelines, and (4) challenges and future directions for HFpEF management. The authors believe that it is important to identify new subtypes of HFpEF to better classify genotypes and phenotypes of HFpEF and to develop novel targeted therapies. It is our hypothesis that big data analytics will shine new light on unique HFpEF phenotypes that better respond to treatment modalities.

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Abbreviations

AHA:

American Heart Association

ACC:

American College of Cardiology

ESC:

European Society of Cardiology

CABANA:

Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation trial

RAFT-AF:

A Randomized Ablation-based Atrial Fibrillation Rhythm Control Versus Rate Control Trial in Patients with Heart Failure and High Burden Atrial Fibrillation

HYVET:

Hypertension in the Very Elderly Trial

J-DHF:

The Japanese Diastolic Heart Failure Study

COHERE registry:

Carvedilol Heart Failure Registry

SENIORS:

Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure trial

CIBIS-ELD:

Comparison of Bisoprolol and Carvedilol in Elderly HF Patients

OPTIMIZE-HF:

Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure

STRUCTURE:

SpironolacTone in myocaRdial dysfUnCTion with redUced exeRcisE capacity trial

TOPCAT:

Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist

PARAMOUNT:

Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion trial

CHAMPION:

The CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients trial

NEAT-HFpEF:

Nitrate’s Effect on Activity Tolerance in Heart Failure with Preserved Ejection Fraction trial

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Lam CS, Donal E, Kraigher-Krainer E, Vasan RS. Epidemiology and clinical course of heart failure with preserved ejection fraction. Eur J Heart Fail. 2011;13:18–28.

    Article  PubMed  Google Scholar 

  2. 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;355:251–9.

    Article  CAS  PubMed  Google Scholar 

  3. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, et al. ACCF/AHA guideline for the management of heart failure: executive summary. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:1495–539.

    Article  Google Scholar 

  4. Dunlay SM, Roger VL, Weston SA, Jiang R, Redfield MM. Longitudinal changes in ejection fraction in heart failure patients with preserved and reduced ejection fraction. Circ Heart Fail. 2012;5:720–6.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Montero-Perez-Barquero M, Manzano L, Formiga F, Roughton M, Coats A, Rodriguez-Artalejo F, et al. Utility of the SENIORS elderly heart failure risk model applied to the RICA registry of acute heart failure. Int J Cardiol. 2015;182:449–53.

    Article  PubMed  Google Scholar 

  6. Shah SJ, Kitzman DW, Borlaug BA, van Heerebeek L, Zile MR, Kass DA, et al. Phenotype-specific treatment of heart failure with preserved ejection fraction: a multiorgan roadmap. Circulation. 2016;134:73–90.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Senni M, Paulus WJ, Gavazzi A, Fraser AG, Diez J, Solomon SD, et al. New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes. Eur Heart J. 2014;35:2797–815.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Andersen MJ, Hwang SJ, Kane GC, Melenovsky V, Olson TP, Fetterly K, et al. Enhanced pulmonary vasodilator reserve and abnormal right ventricular: pulmonary artery coupling in heart failure with preserved ejection fraction. Circ Heart Fail. 2015;8:542–50.

    Article  PubMed  Google Scholar 

  9. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, 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 Heart J. 2016;37:2129–200.

    Article  PubMed  Google Scholar 

  10. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Colvin MM, Drazner MH, Filippatos GS, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C. 2017 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.

  11. Borlaug BA, Redfield MM. Diastolic and systolic heart failure are distinct phenotypes within the heart failure spectrum. Circulation. 2011;123:2006–13. discussion 2014

  12. Shah AM, Pfeffer MA. The many faces of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2012;9:555–6.

    Article  PubMed  Google Scholar 

  13. Shah AM, Solomon SD. Phenotypic and pathophysiological heterogeneity in heart failure with preserved ejection fraction. Eur Heart J. 2012;33:1716–7.

    Article  PubMed  Google Scholar 

  14. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J. 2010;

  15. Obokata M, Kane GC, Reddy YNV, Olson TP, Melenovsky V, Borlaug BA. Role of diastolic stress testing in the evaluation for heart failure with preserved ejection fraction: a simultaneous invasive-echocardiographic study. Circulation. 2017;135:825–38.

    Article  PubMed  Google Scholar 

  16. Nedeljkovic I, Banovic M, Stepanovic J, Giga V, Djordjevic-Dikic A, Trifunovic D, et al. The combined exercise stress echocardiography and cardiopulmonary exercise test for identification of masked heart failure with preserved ejection fraction in patients with hypertension. Eur J Prev Cardiol. 2016;23:71–7.

    Article  PubMed  Google Scholar 

  17. Huis in’t Veld AE, de Man FS, van Rossum AC, Handoko ML. How to diagnose heart failure with preserved ejection fraction: the value of invasive stress testing. Neth Hear J. 2016;24:244–51.

    Article  Google Scholar 

  18. Aschauer S, Kammerlander AA, Zotter-Tufaro C, Ristl R, Pfaffenberger S, Bachmann A, et al. The right heart in heart failure with preserved ejection fraction: insights from cardiac magnetic resonance imaging and invasive haemodynamics. Eur J Heart Fail. 2016;18:71–80.

    Article  PubMed  Google Scholar 

  19. 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;130:2310–20.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Paulus WJ, Tschöpe C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, et al. 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;28:2539–50.

    Article  PubMed  Google Scholar 

  21. Unzek S, Popovic ZB, Marwick TH. Effect of recommendations on interobserver consistency of diastolic function evaluation. J Am Coll Cardiol Img. 2011;4:460–7.

    Article  Google Scholar 

  22. Kitzman DW, Shah SJ. The HFpEF obesity phenotype: the elephant in the room. J Am Coll Cardiol. 2016;68:200–3.

    Article  PubMed  Google Scholar 

  23. Nagueh SF, Smiseth OA, Appleton CP, Byrd BF 3rd, Dokainish H, Edvardsen T, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocard: Off Publ Am Soc Echocard. 2016;29:277–314.

    Article  Google Scholar 

  24. Kraigher-Krainer E, Shah AM, Gupta DK, 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;63:447–56.

    Article  PubMed  Google Scholar 

  25. Obokata M, Kane GC, Reddy YN, Olson TP, Melenovsky V, Borlaug BA. Role of diastolic stress testing in the evaluation for heart failure with preserved ejection fraction: a simultaneous invasive-echocardiographic study. Circulation. 2017;135:825–38.

    Article  PubMed  Google Scholar 

  26. Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure—abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med. 2004;350:1953–9.

    Article  CAS  PubMed  Google Scholar 

  27. Valdivia CR, Chu WW, Pu J, Foell JD, Haworth RA, Wolff MR, et al. Increased late sodium current in myocytes from a canine heart failure model and from failing human heart. J Mol Cell Cardiol. 2005;38:475–83.

    Article  CAS  PubMed  Google Scholar 

  28. Burke MA, Katz DH, Beussink L, Selvaraj S, Gupta DK, Fox J, et al. Prognostic importance of pathophysiologic markers in patients with heart failure and preserved ejection fraction. Circ Heart Fail. 2014;7:288–99.

    Article  CAS  PubMed  Google Scholar 

  29. Tan YT, Wenzelburger F, Lee E, Heatlie G, Leyva F, Patel K, et al. The pathophysiology of heart failure with normal ejection fraction: exercise echocardiography reveals complex abnormalities of both systolic and diastolic ventricular function involving torsion, untwist, and longitudinal motion. J Am Coll Cardiol. 2009;54:36–46.

    Article  PubMed  Google Scholar 

  30. Ennezat PV, Lefetz Y, Maréchaux S, Six-Carpentier M, Deklunder G, Montaigne D, et al. Left ventricular abnormal response during dynamic exercise in patients with heart failure and preserved left ventricular ejection fraction at rest. J Card Fail. 2008;14:475–80.

    Article  PubMed  Google Scholar 

  31. Borlaug BA, Olson TP, Lam CS, Flood KS, Lerman A, Johnson BD, et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2010;56:845–54.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Lam CS, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield MM. Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study. J Am Coll Cardiol. 2009;53:1119–26.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Guazzi M, Borlaug BA. Pulmonary hypertension due to left heart disease. Circulation. 2012;126:975–90.

    Article  PubMed  Google Scholar 

  34. Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail. 2010;3:588–95.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Shah SJ. Evolving approaches to the management of heart failure with preserved ejection fraction in patients with coronary artery disease. Curr treat Options Cardio Med. 2010;12:58–75.

    Article  Google Scholar 

  36. 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;62:263–71.

    Article  PubMed  Google Scholar 

  37. Bench T, Burkhoff D, O’Connell JB, Costanzo MR, Abraham WT, St John Sutton M, et al. Heart failure with normal ejection fraction: consideration of mechanisms other than diastolic dysfunction. Curr Heart Failure Rep. 2009;6:57–64.

    Article  Google Scholar 

  38. Borlaug BA, Kass DA. Ventricular-vascular interaction in heart failure. Heart Fail Clin. 2008;4:23–36.

    Article  PubMed  PubMed Central  Google Scholar 

  39. van Heerebeek L, Hamdani N, Falcao-Pires I, Leite-Moreira AF, Begieneman MP, Bronzwaer JG, et al. Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation. 2012;126:830–9.

    Article  PubMed  CAS  Google Scholar 

  40. van Heerebeek L, Franssen CP, Hamdani N, Verheugt FW, Somsen GA, Paulus WJ. Molecular and cellular basis for diastolic dysfunction. Curr Heart Fail Rep. 2012;9:293–302.

    Article  CAS  PubMed  Google Scholar 

  41. Bishu K, Hamdani N, Mohammed SF, Kruger M, Ohtani T, Ogut O, et al. Sildenafil and B-type natriuretic peptide acutely phosphorylate titin and improve diastolic distensibility in vivo. Circulation. 2011;124:2882–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zile MR, Baicu CF, Ikonomidis JS, Stroud RE, Nietert PJ, Bradshaw AD, et al. Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin. Circulation. 2015;131:1247–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gladden JD, Linke WA, Redfield MM. Heart failure with preserved ejection fraction. Pflugers Archiv: Eur J Physiol. 2014;466:1037–53.

    Article  CAS  Google Scholar 

  44. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J. 2011;32:670–9.

    Article  PubMed  Google Scholar 

  45. Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: part I: diagnosis, prognosis, and measurements of diastolic function. Circulation. 2002;105:1387–93.

    Article  PubMed  Google Scholar 

  46. Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: part II: causal mechanisms and treatment. Circulation. 2002;105:1503–8.

    Article  PubMed  Google Scholar 

  47. Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation. 1991;83:1849–65.

    Article  CAS  PubMed  Google Scholar 

  48. Weber KT, Sun Y, Guarda E. Structural remodeling in hypertensive heart disease and the role of hormones. Hypertension (Dallas, Tex: 1979). 1994;23:869–77.

    Article  CAS  Google Scholar 

  49. Weber KT. Cardiac interstitium in health and disease: the fibrillar collagen network. J Am Coll Cardiol. 1989;13:1637–52.

    Article  CAS  PubMed  Google Scholar 

  50. Chung CS, Hutchinson KR, Methawasin M, Saripalli C, Smith JE 3rd, Hidalgo CG, et al. Shortening of the elastic tandem immunoglobulin segment of titin leads to diastolic dysfunction. Circulation. 2013;128:19–28.

    Article  CAS  PubMed  Google Scholar 

  51. Borbély A, van der Velden J, Papp Z, Bronzwaer JGF, Edes I, Stienen GJM, et al. Cardiomyocyte stiffness in diastolic heart failure. Circulation. 2005;111:774–81.

    Article  PubMed  Google Scholar 

  52. Borbely A, Falcao-Pires I, van Heerebeek L, Hamdani N, Edes I, Gavina C, et al. Hypophosphorylation of the stiff N2B titin isoform raises cardiomyocyte resting tension in failing human myocardium. Circ Res. 2009;104:780–6.

    Article  CAS  PubMed  Google Scholar 

  53. Faris RF, Flather M, Purcell H, Poole-Wilson PA, Coats AJ. Diuretics for heart failure. Cochrane Database Syst Rev. 2012:Cd003838.

  54. Faris R, Flather M, Purcell H, Henein M, Poole-Wilson P, Coats A. Current evidence supporting the role of diuretics in heart failure: a meta analysis of randomised controlled trials. Int J Cardiol. 2002;82:149–58.

    Article  CAS  PubMed  Google Scholar 

  55. Adamson PB, Abraham WT, Bourge RC, Costanzo MR, Hasan A, Yadav C, et al. Wireless pulmonary artery pressure monitoring guides management to reduce decompensation in heart failure with preserved ejection fraction. Circulation. Heart Failure. 2014;7:935–44.

    Article  PubMed  Google Scholar 

  56. Yip GW, Wang M, Wang T, Chan S, Fung JW, Yeung L, et al. The Hong Kong diastolic heart failure study: a randomised controlled trial of diuretics, irbesartan and ramipril on quality of life, exercise capacity, left ventricular global and regional function in heart failure with a normal ejection fraction. Heart. 2008;94:573–80.

    Article  CAS  PubMed  Google Scholar 

  57. Davis BR, Kostis JB, Simpson LM, Black HR, Cushman WC, Einhorn PT, et al. Heart failure with preserved and reduced left ventricular ejection fraction in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Circulation. 2008;118:2259–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358:1887–98.

    Article  CAS  PubMed  Google Scholar 

  59. Lund LH, Benson L, Dahlstrom U, Edner M, Friberg L. Association between use of beta-blockers and outcomes in patients with heart failure and preserved ejection fraction. JAMA. 2014;312:2008–18.

    Article  PubMed  CAS  Google Scholar 

  60. Bergstrom A, Andersson B, Edner M, Nylander E, Persson H, Dahlstrom U. Effect of carvedilol on diastolic function in patients with diastolic heart failure and preserved systolic function. Results of the Swedish Doppler-echocardiographic study (SWEDIC). Eur J Heart Fail. 2004;6:453–61.

    Article  CAS  PubMed  Google Scholar 

  61. Yamamoto K, Origasa H, Hori M. Effects of carvedilol on heart failure with preserved ejection fraction: the Japanese Diastolic Heart Failure Study (J-DHF). Eur J Heart Fail. 2013;15:110–8.

    Article  CAS  PubMed  Google Scholar 

  62. Massie BM, Nelson JJ, Lukas MA, Greenberg B, Fowler MB, Gilbert EM, et al. Comparison of outcomes and usefulness of carvedilol across a spectrum of left ventricular ejection fractions in patients with heart failure in clinical practice. Am J Cardiol. 2007;99:1263–8.

    Article  CAS  PubMed  Google Scholar 

  63. Flather MD, Shibata MC, Coats AJS, Van Veldhuisen DJ, Parkhomenko A, Borbola J, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005;26:215–25.

    Article  CAS  PubMed  Google Scholar 

  64. van Veldhuisen DJ, Cohen-Solal A, Bohm M, Anker SD, Babalis D, Roughton M, et al. Beta-blockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction: data from SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure). J Am Coll Cardiol. 2009;53:2150–8.

    Article  PubMed  CAS  Google Scholar 

  65. Conraads VM, Metra M, Kamp O, De Keulenaer GW, Pieske B, Zamorano J, et al. Effects of the long-term administration of nebivolol on the clinical symptoms, exercise capacity, and left ventricular function of patients with diastolic dysfunction: results of the ELANDD study. Eur J Heart Fail. 2012;14:219–25.

    Article  CAS  PubMed  Google Scholar 

  66. Edelmann F, Musial-Bright L, Gelbrich G, Trippel T, Radenovic S, Wachter R, et al. Tolerability and feasibility of beta-blocker titration in HFpEF versus HFrEF: insights from the CIBIS-ELD trial. JACC Heart Fail. 2016;4:140–9.

    Article  PubMed  Google Scholar 

  67. El-Refai M, Peterson EL, Wells K, Swadia T, Sabbah HN, Spertus JA, et al. Comparison of beta-blocker effectiveness in heart failure patients with preserved ejection fraction versus those with reduced ejection fraction. J Card Fail. 2013;19:73–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Zhou J, Shi H, Zhang J, Lu Y, Fu M, Ge J. Rationale and design of the beta-blocker in heart failure with normal left ventricular ejection fraction (beta-PRESERVE) study. Eur J Heart Fail. 2010;12:181–5.

    Article  CAS  PubMed  Google Scholar 

  69. Hernandez AF, Hammill BG, O’Connor CM, Schulman KA, Curtis LH, Fonarow GC. 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;53:184–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Liu F, Chen Y, Feng X, Teng Z, Yuan Y, Bin J. Effects of beta-blockers on heart failure with preserved ejection fraction: a meta-analysis. PLoS One. 2014;9:e90555.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Bavishi C, Chatterjee S, Ather S, Patel D, Messerli FH. Beta-blockers in heart failure with preserved ejection fraction: a meta-analysis. Heart Fail Rev. 2015;20:193–201.

    Article  CAS  PubMed  Google Scholar 

  72. •• Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014, 370:1383–92. Landmark clinical trials for HFpEF

  73. Pfeffer MA, Claggett B, Assmann SF, Boineau R, Anand IS, Clausell N, et al. Regional variation in patients and outcomes in the treatment of preserved cardiac function heart failure with an aldosterone antagonist (TOPCAT) trial. Circulation. 2015;131:34–42.

    Article  CAS  PubMed  Google Scholar 

  74. Shah AM, Claggett B, Sweitzer NK, Shah SJ, Anand IS, O’Meara E, et al. Cardiac structure and function and prognosis in heart failure with preserved ejection fraction: findings from the echocardiographic study of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. Circulation Heart Failure. 2014;7:740–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. •• Zile MR, Gottdiener JS, Hetzel SJ, McMurray JJ, Komajda M, McKelvie R, et al. Prevalence and significance of alterations in cardiac structure and function in patients with heart failure and a preserved ejection fraction. Circulation. 2011;124:2491–501. Landmark clinical trials for HFpEF

    Article  PubMed  Google Scholar 

  76. Chen Y, Wang H, Lu Y, Huang X, Liao Y, Bin J. Effects of mineralocorticoid receptor antagonists in patients with preserved ejection fraction: a meta-analysis of randomized clinical trials. BMC Med. 2015;13:10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Solomon SD, Claggett B, Lewis EF, Desai A, Anand I, Sweitzer NK, et al. Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction. Eur Heart J. 2016;37:455–62.

    Article  CAS  PubMed  Google Scholar 

  78. Anand IS, Claggett B, Liu J, Shah AM, Rector TS, Shah SJ, et al. Interaction between spironolactone and natriuretic peptides in patients with heart failure and preserved ejection fraction: from the TOPCAT trial. JACC Heart Failure. 2017;5:241–52.

    Article  PubMed  Google Scholar 

  79. Pfeffer MA, Claggett B, Assmann SF, Boineau R, Anand IS, Clausell N, et al. Regional variation in patients and outcomes in the treatment of preserved cardiac function heart failure with an aldosterone antagonist (TOPCAT) trial. Circulation. 2014;

  80. de Denus S, O’Meara E, Desai AS, Claggett B, Lewis EF, Leclair G, et al. Spironolactone metabolites in TOPCAT—new insights into regional variation. N Engl J Med. 2017;376:1690–2.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Kosmala W, Rojek A, Przewlocka-Kosmala M, Wright L, Mysiak A, Marwick TH. Effect of aldosterone antagonism on exercise tolerance in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2016;68:1823–34.

    Article  CAS  PubMed  Google Scholar 

  82. Zannad F, McMurray JJV, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364:11–21.

    Article  CAS  PubMed  Google Scholar 

  83. Edelmann F, Wachter R, Schmidt AG, Kraigher-Krainer E, Colantonio C, Kamke W, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA. 2013;309:781–91.

    Article  CAS  PubMed  Google Scholar 

  84. Pandey A, Garg S, Matulevicius SA, Shah AM, Garg J, Drazner MH, et al. Effect of mineralocorticoid receptor antagonists on cardiac structure and function in patients with diastolic dysfunction and heart failure with preserved ejection fraction: a meta-analysis and systematic review. J Am Heart Assoc. 2015;4:e002137.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Setaro JF, Zaret BL, Schulman DS, Black HR, Soufer R. Usefulness of verapamil for congestive heart failure associated with abnormal left ventricular diastolic filling and normal left ventricular systolic performance. Am J Cardiol. 1990;66:981–6.

    Article  CAS  PubMed  Google Scholar 

  86. Hung MJ, Cherng WJ, Kuo LT, Wang CH. Effect of verapamil in elderly patients with left ventricular diastolic dysfunction as a cause of congestive heart failure. Int J Clin Pract. 2002;56:57–62.

    CAS  PubMed  Google Scholar 

  87. Klingbeil AU, Schneider M, Martus P, Messerli FH, Schmieder RE. A meta-analysis of the effects of treatment on left ventricular mass in essential hypertension. Am J Med. 2003;115:41–6.

    Article  PubMed  Google Scholar 

  88. Aronow WS, Kronzon I. Effect of enalapril on congestive heart failure treated with diuretics in elderly patients with prior myocardial infarction and normal left ventricular ejection fraction. Am J Cardiol. 1993;71:602–4.

    Article  CAS  PubMed  Google Scholar 

  89. Cleland JGF, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J. 2006;27:2338–45.

    Article  CAS  PubMed  Google Scholar 

  90. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved trial. Lancet (London, England). 2003;362:777–81.

    Article  CAS  Google Scholar 

  91. Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359:2456–67.

    Article  CAS  PubMed  Google Scholar 

  92. McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–1004.

    Article  PubMed  CAS  Google Scholar 

  93. •• Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, et al. The angiotensin receptor neprilysin inhibitor lcz696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet. 2012;380:1387–95 Landmark clinical trials for HFpEF.

    Article  CAS  PubMed  Google Scholar 

  94. Komajda M, Isnard R, Cohen-Solal A, Metra M, Pieske B, Ponikowski P, et al. Effect of ivabradine in patients with heart failure with preserved ejection fraction: the EDIFY randomized placebo-controlled trial. Eur J Heart Fail. 2017.

  95. Kosmala W, Holland DJ, Rojek A, Wright L, Przewlocka-Kosmala M, Marwick TH. Effect of if-channel inhibition on hemodynamic status and exercise tolerance in heart failure with preserved ejection fraction: a randomized trial. J Am Coll Cardiol. 2013;62:1330–8.

    Article  CAS  PubMed  Google Scholar 

  96. Kjekshus J, Apetrei E, Barrios V, Böhm M, Cleland JGF, Cornel JH, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007;357:2248–61.

    Article  CAS  PubMed  Google Scholar 

  97. Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet (London, England). 2008;372:1231–9.

    Article  CAS  Google Scholar 

  98. Fukuta H, Sane DC, Brucks S, Little WC. Statin therapy may be associated with lower mortality in patients with diastolic heart failure: a preliminary report. Circulation. 2005;112:357–63.

    Article  CAS  PubMed  Google Scholar 

  99. Ouzounian M, Tu JV, Austin PC, Chong A, Liu PP, Lee DS. Statin therapy and clinical outcomes in heart failure: a propensity-matched analysis. J Card Fail. 2009;15:241–8.

    Article  CAS  PubMed  Google Scholar 

  100. Gomez-Garre D, Gonzalez-Rubio ML, Munoz-Pacheco P, Caro-Vadillo A, Aragoncillo P, Fernandez-Cruz A. Rosuvastatin added to standard heart failure therapy improves cardiac remodelling in heart failure rats with preserved ejection fraction. Eur J Heart Fail. 2010;12:903–12.

    Article  CAS  PubMed  Google Scholar 

  101. Chattopadhyay S, Alamgir MF, Nikitin NP, Rigby AS, Clark AL, Cleland JG. Lack of diastolic reserve in patients with heart failure and normal ejection fraction. Circ Heart Fail. 2010;3:35–43.

    Article  PubMed  Google Scholar 

  102. Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfield MM. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation. 2015;131:550–9.

    Article  PubMed  Google Scholar 

  103. Hattori T, Shimokawa H, Higashi M, Hiroki J, Mukai Y, Tsutsui H, et al. Long-term inhibition of rho-kinase suppresses left ventricular remodeling after myocardial infarction in mice. Circulation. 2004;109:2234–9.

    Article  CAS  PubMed  Google Scholar 

  104. Martin J, Denver R, Bailey M, Krum H. In vitro inhibitory effects of atorvastatin on cardiac fibroblasts: implications for ventricular remodelling. Clin Exp Pharmacol Physiol. 2005;32:697–701.

    Article  CAS  PubMed  Google Scholar 

  105. Ahmed A, Rich MW, Fleg JL, Zile MR, Young JB, Kitzman DW, et al. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial. Circulation. 2006;114:397–403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Meyer P, White M, Mujib M, Nozza A, Love TE, Aban I, et al. Digoxin and reduction of heart failure hospitalization in chronic systolic and diastolic heart failure. Am J Cardiol. 2008;102:1681–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Zhang M, Koitabashi N, Nagayama T, Rambaran R, Feng N, Takimoto E, et al. Expression, activity, and pro-hypertrophic effects of pde5a in cardiac myocytes. Cell Signal. 2008;20:2231–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study. Circulation. 2011;124:164–74.

    Article  CAS  PubMed  Google Scholar 

  109. 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;309:1268–77.

    Article  CAS  PubMed  Google Scholar 

  110. Redfield MM, Anstrom KJ, Levine JA, Koepp GA, Borlaug BA, Chen HH, et al. Isosorbide mononitrate in heart failure with preserved ejection fraction. N Engl J Med. 2015;373:2314–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Borlaug BA, Melenovsky V, Koepp KE. Inhaled sodium nitrite improves rest and exercise hemodynamics in heart failure with preserved ejection fraction. Circ Res. 2016;119:880–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. • Reddy YNV, Lewis GD, Shah SJ, LeWinter M, Semigran M, Davila-Roman VG, et al. INDIE-HFpEF (inorganic nitrite delivery to improve exercise capacity in heart failure with preserved ejection fraction): rationale and design. Circulation. Heart Failure. 2017. 10. Promising approach for future HFpEF therapies.

  113. Sondergaard L, Reddy V, Kaye D, Malek F, Walton A, Mates M, et al. Transcatheter treatment of heart failure with preserved or mildly reduced ejection fraction using a novel interatrial implant to lower left atrial pressure. Eur J Heart Fail. 2014;16:796–801.

    Article  PubMed  Google Scholar 

  114. Malek F, Neuzil P, Gustafsson F, Kaye DM, Walton A, Mates M, et al. Clinical outcome of transcatheter treatment of heart failure with preserved or mildly reduced ejection fraction using a novel implant. Int J Cardiol. 2015;187:227–8.

    Article  PubMed  Google Scholar 

  115. Hasenfuß G, Hayward C, Burkhoff D, Silvestry FE, McKenzie S, Gustafsson F, et al. A transcatheter intracardiac shunt device for heart failure with preserved ejection fraction (REDUCE LAP-HF): a multicentre, open-label, single-arm, phase 1 trial. Lancet. 2016;387:1298–304.

    Article  PubMed  Google Scholar 

  116. Feldman T, Mauri L, Kahwash R, Litwin S, Ricciardi MJ, van der Harst P, et al. A transcatheter interatrial shunt device for the treatment of heart failure with preserved ejection fraction (REDUCE LAP-HF I): a phase 2, randomized, sham-controlled trial. Circulation. 2017.

  117. Kitzman DW, Little WC, Brubaker PH, Anderson RT, Hundley WG, Marburger CT, et al. Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA. 2002;288:2144–50.

    Article  PubMed  Google Scholar 

  118. Gary RA, Sueta CA, Dougherty M, Rosenberg B, Cheek D, Preisser J, et al. Home-based exercise improves functional performance and quality of life in women with diastolic heart failure. Heart Lung: J Crit Care. 2004;33:210–8.

    Article  Google Scholar 

  119. Smart N, Haluska B, Jeffriess L, Marwick TH. Exercise training in systolic and diastolic dysfunction: effects on cardiac function, functional capacity, and quality of life. Am Heart J. 2007;153:530–6.

    Article  PubMed  Google Scholar 

  120. Kitzman DW, Brubaker PH, Morgan TM, Stewart KP, Little WC. Exercise training in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial. Circ Heart Failure. 2010;3:659–67.

    Article  PubMed  Google Scholar 

  121. Taylor RS, Davies EJ, Dalal HM, Davis R, Doherty P, Cooper C, et al. Effects of exercise training for heart failure with preserved ejection fraction: a systematic review and meta-analysis of comparative studies. Int J Cardiol. 2012;162:6–13.

    Article  PubMed  Google Scholar 

  122. Kitzman DW, Nicklas B, Kraus WE, Lyles MF, Eggebeen J, Morgan TM, et al. Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction. Am J Physiol Heart Circ Physiol. 2014;306:H1364–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Pandey A, Parashar A, Kumbhani DJ, Agarwal S, Garg J, Kitzman D, et al. Exercise training in patients with heart failure and preserved ejection fraction: meta-analysis of randomized control trials. Circulation. Heart Failure. 2015;8:33–40.

    Article  PubMed  Google Scholar 

  124. Chan E, Giallauria F, Vigorito C, Smart NA. Exercise training in heart failure patients with preserved ejection fraction: a systematic review and meta-analysis. Monaldi Archives for Chest Disease; Vol 86, No 1–2 (2016): Cardiac Series. 2016.

  125. Krittanawong C, Zhang H, Wang Z, Aydar M, Kitai T. Artificial intelligence in precision cardiovascular medicine. J Am Coll Cardiol. 2017;69:2657–64.

    Article  PubMed  Google Scholar 

  126. Krittanawong C. Future physicians in the era of precision cardiovascular medicine. Circulation. 2017;136:1572–4.

    Article  PubMed  Google Scholar 

  127. • Shah SJ, Katz DH, Selvaraj S, Burke MA, Yancy CW, Gheorghiade M, et al. Phenomapping for novel classification of heart failure with preserved ejection fraction. Circulation. 2015;131:269–79. Promising approach for future HFpEF therapies

    Article  PubMed  Google Scholar 

  128. Obokata M, Reddy YNV, Pislaru SV, Melenovsky V, Borlaug BA. Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction. Circulation. 2017;136:6–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Gorter TM, Hoendermis ES, van Veldhuisen DJ, Voors AA, Lam CS, Geelhoed B, et al. Right ventricular dysfunction in heart failure with preserved ejection fraction: a systematic review and meta-analysis. Eur J Heart Fail. 2016;18:1472–87.

    Article  PubMed  Google Scholar 

  130. Bytyci I, Bajraktari G. Left atrial changes in early stages of heart failure with preserved ejection fraction. Echocardiography (Mount Kisco, NY). 2016;33:1479–87.

    Article  Google Scholar 

  131. Patel RB, Vaduganathan M, Shah SJ, Butler J. Atrial fibrillation in heart failure with preserved ejection fraction: insights into mechanisms and therapeutics. Pharmacol Ther. 2016.

  132. Bahramali E, Rajabi M, Jamshidi J, Mousavi SM, Zarghami M, Manafi A, et al. Association of ace gene d polymorphism with left ventricular hypertrophy in patients with diastolic heart failure: a case–control study. BMJ Open. 2016;6.

  133. Dong S, Ma W, Hao B, Hu F, Yan L, Yan X, et al. MicroRNA-21 promotes cardiac fibrosis and development of heart failure with preserved left ventricular ejection fraction by up-regulating Bcl-2. Int J Clin Exp Pathol. 2014;7:565–74.

    PubMed  PubMed Central  Google Scholar 

  134. Reuter SE, Evans AM. Carnitine and acylcarnitines: pharmacokinetic, pharmacological and clinical aspects. Clin Pharmacokinet. 2012;51:553–72.

    Article  CAS  PubMed  Google Scholar 

  135. Krittanawong C, Xanthopoulos A, Kitai T, Branis N, Zhang H, Kukin M. Dpp-4 inhibitors and heart failure: a potential role for pharmacogenomics. Heart Fail Rev. 2017.

  136. Krittanawong C, Namath A, Lanfear DE, Tang WHW. Practical pharmacogenomic approaches to heart failure therapeutics. Curr Treat Options Cardiovasc Med. 2016;18:60.

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors thank Professor W.H. Wilson Tang, MD, FACC, FAHA, FHFSA (Division of Cardiovascular Medicine, Cleveland Clinic’s Heart and Vascular Institute, OH, USA), for valuable comments and suggestions to improve the quality of the paper.

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Krittanawong, C., Kukin, M.L. Current Management and Future Directions of Heart Failure With Preserved Ejection Fraction: a Contemporary Review. Curr Treat Options Cardio Med 20, 28 (2018). https://doi.org/10.1007/s11936-018-0623-1

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