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Therapy for heart failure with preserved ejection fraction: current status, unique challenges, and future directions

Heart Failure Reviews volume 23, pages 609–629 (2018)Cite this article

Abstract

Heart failure (HF) with preserved ejection fraction (HFpEF) is the most common form of HF. Among elderly women, HFpEF comprises more than 80% of incident HF cases. Adverse outcomes—exercise intolerance, poor quality of life, frequent hospitalizations, and reduced survival—approach those of classic HF with reduced EF (HFrEF). However, despite its importance, our understanding of the pathophysiology of HFpEF is incomplete, and despite intensive efforts, optimal therapy remains uncertain, as most trials to date have been negative. This is in stark contrast to management of HFrEF, where dozens of positive trials have established a broad array of effective, guidelines-based therapies that definitively improve a range of clinically meaningful outcomes. In addition to providing an overview of current management status, we examine evolving data that may help explain this paradox, overcome past challenges, provide a roadmap for future success, and that underpin a wave of new trials that will test novel approaches based on these insights.

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References

  1. Kitzman DW, Gardin JM, Gottdiener JS et al (2001) Importance of heart failure with preserved systolic function in patients > or = 65 years of age. CHS Research Group. Cardiovascular Health Study. Am J Cardiol 87:413–419

    PubMed  Article  CAS  Google Scholar 

  2. Aurigemma GP, Gottdiener JS, Shemanski L, Gardin JM, Kitzman DW (2001) Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: The Cardiovacular Health Study. J Am Coll Cardiol 37:1042–1048

    PubMed  Article  CAS  Google Scholar 

  3. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM (2006) Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 355:251–259

    PubMed  Article  CAS  Google Scholar 

  4. Dunlay SM, Redfield MM, Weston SA et al (2009) Hospitalizations after heart failure diagnosis: a community perspective. J Am Coll Cardiol 54:1695–1702

    PubMed  PubMed Central  Article  Google Scholar 

  5. Yancy CW, Jessup M, Bozkurt B et al (2017) 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. J Am Coll Cardiol 70:776–803

    PubMed  Article  Google Scholar 

  6. Wright JT Jr, Williamson JD, Whelton PK et al (2015) A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 373:2103–2116

    PubMed  Article  CAS  Google Scholar 

  7. Upadhya B, Rocco M, Lewis CE et al (2017) Effect of intensive blood pressure treatment on heart failure events in the systolic blood pressure reduction intervention trial. Circ Heart Fail 10:e003613

    PubMed  PubMed Central  Article  Google Scholar 

  8. Williamson JD, Supiano MA, Applegate WB et al (2016) Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged >/=75 years: a randomized clinical trial. JAMA 315:2673–2682

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  9. Lindenfeld J, Albert NM, Boehmer JP et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail 2010;16:e1-194.

  10. Ather S, Chan W, Bozkurt B et al (2012) 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 59:998–1005

    PubMed  PubMed Central  Article  Google Scholar 

  11. Shah SJ, Gheorghiade M (2008) Heart failure with preserved ejection fraction: treat now by treating comorbidities. JAMA 300:431–433

    PubMed  Article  CAS  Google Scholar 

  12. Murad K, Kitzman D (2011) Frailty and multiple comorbidities in the elderly patient with heart failure: implications for management. Heart Fail Rev 17:581–588

    Article  Google Scholar 

  13. Borlaug BA, Olson TP, Lam CSP et al (2010) Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol 56:845–854

    PubMed  PubMed Central  Article  Google Scholar 

  14. Hwang SJ, Melenovsky V, Borlaug BA (2014) Implications of coronary artery disease in heart failure with preserved ejection fraction. J Am Coll Cardiol 63:2817–2827

    PubMed  Article  Google Scholar 

  15. Rusinaru D, Houpe D, Szymanski C, Levy F, Marechaux S, Tribouilloy C (2014) Coronary artery disease and 10-year outcome after hospital admission for heart failure with preserved and with reduced ejection fraction. Eur J Heart Fail 16:967–976

    PubMed  Article  Google Scholar 

  16. Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfield MM (2015) Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation 131:550–559

    PubMed  Article  Google Scholar 

  17. Yancy CW, Jessup M, Bozkurt B et al (2013) ACCF/AHA guideline for the management of heart-failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 62:e147–e239

    PubMed  Article  Google Scholar 

  18. Gandhi SK, Powers JC, Nomeir AM et al (2001) The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 344:17–22

    PubMed  Article  CAS  Google Scholar 

  19. Kramer K, Kirkman P, Kitzman DW, Little WC (2000) Flash pulmonary edema: association with hypertension, reocurrence despite coronary revascularization. Am Heart J 140:451–455

    PubMed  Article  CAS  Google Scholar 

  20. Zakeri R, Borlaug BA, McNulty SE et al (2014) Impact of atrial fibrillation on exercise capacity in heart failure with preserved ejection fraction: a RELAX trial ancillary study. Circ Heart Fail 7:123–130

    PubMed  Article  CAS  Google Scholar 

  21. Lam CS, Rienstra M, Tay WT et al (2016) Atrial fibrillation in heart failure with preserved ejection fraction: association with exercise capacity, left ventricular filling pressures, natriuretic peptides, and left atrial volume. JACC Heart Fail 5:92–98

    PubMed  Article  Google Scholar 

  22. Machino-Ohtsuka T, Seo Y, Ishizu T et al (2013) Efficacy, safety, and outcomes of catheter ablation of atrial fibrillation in patients with heart failure with preserved ejection fraction. J Am Coll Cardiol 62:1857–1865

    PubMed  Article  Google Scholar 

  23. Cohen RA, Tong X (2010) Vascular oxidative stress: the common link in hypertensive and diabetic vascular disease. J Cardiovasc Pharmacol 55:308–316

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  24. Yusuf S, Pfeffer MA, Swedberg K et al (2003) Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 362:777–781

    PubMed  Article  CAS  Google Scholar 

  25. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J (2006) The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 27:2338–2345

    PubMed  Article  CAS  Google Scholar 

  26. Massie BM, Carson PE, McMurray JJ et al (2008) Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 359:2456–2467

    PubMed  Article  CAS  Google Scholar 

  27. Pitt B, Pfeffer M, Assmann S et al (2014) Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 370:1383–1392

    PubMed  Article  CAS  Google Scholar 

  28. Dunlay SM, Weston SA, Redfield MM, Killian JM, Roger VL (2008) Anemia and heart failure: a community study. Am J Med 121:726–732

    PubMed  PubMed Central  Article  Google Scholar 

  29. Paulus W, Tschope C (2013) 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 62:263–271

    PubMed  Article  Google Scholar 

  30. Fu M, Zhou J, Thunstrom E et al (2016) Optimizing the Management of Heart Failure with Preserved Ejection Fraction in the Elderly by Targeting Comorbidities (OPTIMIZE-HFPEF). J Card Fail 22:539–544

    PubMed  Article  Google Scholar 

  31. Kitzman DW. Diastolic dysfunction in the elderly; genesis and diagnostic and therapeutic implications. In: Kovacs SJ, ed. Cardiology Clinics of North America—Diastolic Function. Vol 18(3) ed. Philadelphia: W. B. Saunders; 2000;597-617.

  32. Stewart S, Marley JE, Horowitz JD (1999) Effects of a multidisciplinary, home-based intervention on unplanned readmissions and survival among patients with chronic congestive heart failure: a randomised controlled study. Lancet 354:1077–1083

    PubMed  Article  CAS  Google Scholar 

  33. Rich MW, Beckham V, Wittenberg C, Leven CL, Freedland KE, Carney R (1995) A multidisciplinary intervention to prevent the readmission of elderly patients with congestive heart failure. N Engl J Med 333:1190–1195

    PubMed  Article  CAS  Google Scholar 

  34. Stewart S, Vanderheyden M, Pearson S, Horowitz JD (1999) Prolonged beneficial effects of a home-based intervention on unplanned readmissions and mortality among patients with congestive heart failure. Arch Intern Med 159:257–261

    PubMed  Article  CAS  Google Scholar 

  35. Tsuyuki RT, McKelvie RS, Arnold JM et al (2001) Acute precipitants of congestive heart failure exacerbations. Arch Intern Med 161:2337–2342

    PubMed  Article  CAS  Google Scholar 

  36. Kitzman D, Brubaker P, Morgan T, Stewart K, Little W (2010) Exercise training in older patients with heart failure and preserved ejection fraction. Circ Heart Fail 3:659–667

    PubMed  PubMed Central  Article  Google Scholar 

  37. Kitzman DW, Brubaker PH, Herrington DM et al (2013) Effect of endurance exercise training on endothelial function and arterial stiffness in older patients with heart failure and preserved ejection fraction: A randomized, controlled, single-blind trial. J Am Coll Cardiol 62:584–592

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. Haykowsky MJ, Brubaker PH, Stewart KP, Morgan TM, Eggebeen J, Kitzman DW (2012) Effect of endurance training on the determinants of peak exercise oxygen consumption in elderly patients with stable compensated heart failure and preserved ejection fraction. J Am Coll Cardiol 60:120–128

    PubMed  PubMed Central  Article  Google Scholar 

  39. Kitzman DW, Brubaker P, Morgan T et al (2016) Effect of caloric restriction or aerobic exercise training on peak oxygen consumption and quality of life in obese older patients with heart failure with preserved ejection fraction: a randomised clinical trial. JAMA 315:36–46

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  40. Edelmann F, Gelbrich G, Dungen H et al (2011) Exercise training improves exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction: results of the Ex-DHF (Exercise training in Diastolic Heart Failure) pilot study. J Am Coll Cardiol 58:1780–1791

    PubMed  Article  Google Scholar 

  41. Smart NA, Haluska B, Jeffriess L, Leung D (2012) Exercise training in heart failure with preserved systolic function: a randomized controlled trial of the effects on cardiac function and functional capacity. Congest Heart Fail 18:295–301

    PubMed  Article  Google Scholar 

  42. Fu TC, Yang NI, Wang CH et al (2016) Aerobic interval training elicits different hemodynamic adaptations between heart failure patients with preserved and reduced ejection fraction. Am J Phys Med Rehabil 95:15–27

    PubMed  Article  Google Scholar 

  43. Angadi SS, Mookadam F, Lee CD, Tucker WJ, Haykowsky MJ, Gaesser GA (2014) High-intensity interval training vs. moderate-intensity continuous exercise training in heart failure with preserved ejection fraction: a pilot study. J Appl Physiol 95:15–27

    Google Scholar 

  44. Gary RA, Sueta CA, Dougherty M et al (2004) Home-based exercise improves functional performance and quality of life in women with diastolic heart failure. Heart Lung 33:210–218

    PubMed  Article  Google Scholar 

  45. Bensimhon DR, Leifer E, Ellis SJ et al (2008) Reproducibility of peak oxygen uptake and other cardiopulmonary exercise testing parameters in patients with heart failure. Am J Cardiol 102:712–717

    PubMed  PubMed Central  Article  Google Scholar 

  46. Marburger CT, Brubaker PH, Pollock WE, Morgan TM, Kitzman DW (1998) Reproducibility of cardiopulmonary exercise testing in elderly heart failure patients. Am J Cardiol 82:905–909

    PubMed  Article  CAS  Google Scholar 

  47. Haykowsky MJ, Brubaker PH, John JM, Stewart KP, Morgan TM, Kitzman DW (2011) Determinants of exercise intolerance in elderly heart failure patients with preserved ejection fraction. J Am Coll Cardiol 58:265–274

    PubMed  PubMed Central  Article  Google Scholar 

  48. Haykowsky MJ, Brubaker PH, Stewart KP, Morgan TM, Eggebeen J, Kitzman DW (2012) Effect of endurance training on the determinants of peak exercise oxygen consumption in elderly patients with stable compensated heart failure and preserved ejection fraction. J Am Coll Cardiol 60:120–128

    PubMed  PubMed Central  Article  Google Scholar 

  49. Tucker WJ, Lijauco CC, Hearon CM Jr et al (2018) Mechanisms of the improvement in peak VO2 with exercise training in heart failure with reduced or preserved ejection fraction. Heart Lung Circ 27:9–21

    PubMed  Article  Google Scholar 

  50. Poole DC, Richardson RS, Haykowsky MJ, Hirai DM, Musch TI (2018) Exercise limitations in heart failure with reduced and preserved ejection fraction. J Appl Physiol (1985) 124:jap007472017

    Article  Google Scholar 

  51. Sullivan M, Higginbotham MB, Cobb FR (1988) Exercise training in patients with severe left ventricular dysfunction. Hemodynamic and metabolic effects. Circulation 78:506–515

    PubMed  Article  CAS  Google Scholar 

  52. Haykowsky M, Liang Y, Pechter D, Jones L, Alister F, Cark A (2007) A meta-analysis of the effect of exercise training on left ventricular remodeling in heart failure patients: the benefit depends on the type of training performed. J Am Coll Cardiol 49:2329–2336

    PubMed  Article  Google Scholar 

  53. Houstis NE, Eisman AS, Pappagianopoulos PP et al (2018) Exercise intolerance in heart failure with preserved ejection fraction: diagnosing and ranking its causes using personalized O2 pathway analysis. Circulation 137:148–161

    PubMed  Article  Google Scholar 

  54. Hambrecht R, Gielen S, Linke A et al (2000) Effects of exercise training on left ventricular function and peripheral resistance in patients with chronic heart failure. JAMA 283:3095–3101

    PubMed  Article  CAS  Google Scholar 

  55. Edelmann F, Gelbrich G, Dungen H et al (2011) Exercise training improves exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction: results of the Ex-DHF (Exercise training in Diastolic Heart Failure) pilot study. J Am Coll Cardiol 58:1780–1791

    PubMed  Article  Google Scholar 

  56. Fujimoto N, Prasad A, Hastings JL et al (2012) Cardiovascular effects of 1 year of progressive endurance exercise training in patients with heart failure with preserved ejection fraction. Am Heart J 164:869–877

    PubMed  Article  Google Scholar 

  57. Erbs S, Hollriegel R, Linke A et al (2010) Exercise training in patients with advanced chronic heart failure (NYHA IIIb) promotes restoration of peripheral vasomotor function, induction of endogenous regeneration, and improvement of left ventricular function. Circ Heart Fail 3:486–494

    PubMed  Article  Google Scholar 

  58. Esposito F, Reese V, Shabetai R, Wagner PD, Richardson RS (2011) Isolated quadriceps training increases maximal exercise capacity in chronic heart failure: the role of skeletal muscle convective and diffusive oxygen transport. J Am Coll Cardiol 58:1353–1362

    PubMed  PubMed Central  Article  Google Scholar 

  59. Haykowsky M, Kouba EJ, Brubaker PH, Nicklas BJ, Eggebeen J, Kitzman DW (2014) Skeletal muscle composition and its relation to exercise intolerance in older patients with heart failure and preserved ejection fraction. Am J Cardiol 113:1211–1216

    PubMed  PubMed Central  Article  Google Scholar 

  60. Kitzman DW, Nicklas B, Kraus WE et al (2014) Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction. Am J Physiol Heart Circ Physiol 306:H1364–H1370

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  61. Molina AJ, Bharadwaj MS, Van Horn C et al (2016) Skeletal muscle mitochondrial content, oxidative capacity, and Mfn2 expression are reduced in older patients with heart failure and preserved ejection fraction and are related to exercise intolerance. JACC Heart Fail 4:636–645

    PubMed  PubMed Central  Article  Google Scholar 

  62. Suchy C, Massen L, Rognmo O et al (2014) Optimising exercise training in prevention and treatment of diastolic heart failure (OptimEx-CLIN): rationale and design of a prospective, randomised, controlled trial. Eur J Prev Cardiol 21:18–25

    PubMed  Article  Google Scholar 

  63. Koifman E, Grossman E, Elis A et al (2014) Multidisciplinary rehabilitation program in recently hospitalized patients with heart failure and preserved ejection fraction: rationale and design of a randomized controlled trial. Am Heart J 168:830–837

    PubMed  Article  Google Scholar 

  64. Centers for Medicare and Medicaid Services (2014) Decision memo for cardiac rehabilitation (CR) programs—chronic heart failure (CAG-00437N). February 18:2014

    Google Scholar 

  65. O'Connor CM, Whellan DJ, Lee KL et al (2009) Efficacy and safety of exercise training in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA 301:1439–1450

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  66. Kitzman DW, Shah SJ (2016) The HFpEF obesity phenotype: the elephant in the room. J Am Coll Cardiol 68:200–203

    PubMed  Article  Google Scholar 

  67. Civitarese AE, Carling S, Heilbronn LK et al (2007) Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med 4:e76

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  68. Hummel S, Seymour E, Brook R et al (2012) Low-sodium dietary approaches to stop hypertension diet reduces blood pressure, arterial stiffness, and oxidative stress in hypertensive heart failure with preserved ejection fraction. Hypertension 60:1200–1206

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  69. Hummel S, Seymour E, Brook R et al (2013) Low-sodium DASH diet improves diastolic function and ventricular-arterial coupling in hypertensive heart failure with preserved ejection fraction. Circ Heart Fail 6:1165–1171

  70. Mathew AV, Seymour EM, Byun J, Pennathur S, Hummel SL (2015) Altered metabolic profile with sodium-restricted dietary approaches to stop hypertension diet in hypertensive heart failure with preserved ejection fraction. J Card Fail 21:963–967

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  71. Chen J, Shearer GC, Chen Q et al (2011) Omega-3 fatty acids prevent pressure overload-induced cardiac fibrosis through activation of cyclic GMP/protein kinase G signaling in cardiac fibroblasts. Circulation 123:584–593

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  72. Abraham WT, Adamson PB, Bourge RC et al (2011) Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 377:658–666

    PubMed  Article  Google Scholar 

  73. Adamson PB, Abraham WT, Bourge RC et al (2014) Wireless pulmonary artery pressure monitoring guides management to reduce decompensation in heart failure with preserved ejection fraction. Circ Heart Fail 7:935–944

    PubMed  Article  Google Scholar 

  74. Heywood JT, Jermyn R, Shavelle D et al (2017) Impact of practice-based management of pulmonary artery pressures in 2000 patients implanted with the CardioMEMS Sensor. Circulation 135:1509–1517

    PubMed  Article  Google Scholar 

  75. Zile MR, Bennett TD, El Hajj S et al (2017) Intracardiac pressures measured using an implantable hemodynamic monitor: relationship to mortality in patients with chronic heart failure. Circ Heart Fail 10:e003594

    PubMed  Article  Google Scholar 

  76. Kaye D, Shah SJ, Borlaug BA et al (2014) Effects of an interatrial shunt on rest and exercise hemodynamics: results of a computer simulation in heart failure. J Card Fail 20:212–221

    PubMed  Article  Google Scholar 

  77. Hasenfuss G, Hayward C, Burkhoff D et al (2016) 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 387:1298–1304

    PubMed  Article  Google Scholar 

  78. Burkhoff D, Maurer MS, Joseph SM et al (2015) Left atrial decompression pump for severe heart failure with preserved ejection fraction: theoretical and clinical considerations. JACC Heart Fail 3:275–282

    PubMed  Article  Google Scholar 

  79. Yu CM, Zhang Q, Yip GW et al (2007) Diastolic and systolic asynchrony in patients with diastolic heart failure: a common but ignored condition. J Am Coll Cardiol 49:97–105

    PubMed  Article  Google Scholar 

  80. Santos AB, Kraigher-Krainer E, Bello N et al (2014) Left ventricular dyssynchrony in patients with heart failure and preserved ejection fraction. Eur Heart J 35:42–47

    PubMed  Article  CAS  Google Scholar 

  81. Penicka M, Kocka V, Herman D, Trakalova H, Herold M (2010) Cardiac resynchronization therapy for the causal treatment of heart failure with preserved ejection fraction: insight from a pressure–volume loop analysis. Eur J Heart Fail 12:634–636

    PubMed  Article  Google Scholar 

  82. Brubaker PH, Joo KC, Stewart KP, Fray B, Moore B, Kitzman DW (2006) Chronotropic incompetence and its contribution to exercise intolerance in older heart failure patients. J Cardiopulm Rehabil 26:86–89

    PubMed  Article  Google Scholar 

  83. Borlaug BA, Melenovsky V, Russell SD et al (2006) Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation 114:2138–2147

    PubMed  Article  Google Scholar 

  84. Kass DA, Kitzman DW, Alvarez GE (2010) The Restoration of Chronotropic CompEtence in Heart Failure PatientS with Normal Ejection FracTion (RESET) study: rationale and design. J Card Fail 16:17–24

    PubMed  Article  Google Scholar 

  85. Borggrefe M, Burkhoff D (2012) Clinical effects of cardiac contractility modulation (CCM) as a treatment for chronic heart failure. Eur J Heart Fail 14:703–712

    PubMed  Article  CAS  Google Scholar 

  86. Tschope C, Van Linthout S, Spillmann F et al (2016) Cardiac contractility modulation signals improve exercise intolerance and maladaptive regulation of cardiac key proteins for systolic and diastolic function in HFpEF. Int J Cardiol 203:1061–1066

    PubMed  Article  Google Scholar 

  87. Abraham WT, Zile MR, Weaver FA et al (2015) Baroreflex activation therapy for the treatment of heart failure with a reduced ejection fraction. JACC Heart Fail 3:487–496

    PubMed  Article  Google Scholar 

  88. Georgakopoulos D, Little WC, Abraham WT, Weaver FA, Zile MR (2011) Chronic baroreflex activation: a potential therapeutic approach to heart failure with preserved ejection fraction. J Card Fail 17:167–178

    PubMed  Article  Google Scholar 

  89. Brandt MC, Mahfoud F, Reda S et al (2012) Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension. J Am Coll Cardiol 59:901–909

    PubMed  Article  Google Scholar 

  90. Patel HC, Rosen SD, Hayward C et al (2016) Renal denervation in heart failure with preserved ejection fraction (RDT-PEF): a randomized controlled trial. Eur J Heart Fail 18:703–712

    PubMed  Article  CAS  Google Scholar 

  91. Bitter T, Faber L, Hering D, Langer C, Horstkotte D, Oldenburg O (2009) Sleep-disordered breathing in heart failure with normal left ventricular ejection fraction. Eur J Heart Fail 11:602–608

    PubMed  Article  Google Scholar 

  92. Dursunoglu D, Dursunoglu N, Evrengul H et al (2005) Impact of obstructive sleep apnoea on left ventricular mass and global function. Eur Respir J 26:283–288

    PubMed  Article  CAS  Google Scholar 

  93. Usui Y, Takata Y, Inoue Y et al (2013) Severe obstructive sleep apnea impairs left ventricular diastolic function in non-obese men. Sleep Med 14:155–159

    PubMed  Article  Google Scholar 

  94. Lattimore JL, Wilcox I, Skilton M, Langenfeld M, Celermajer DS (2006) Treatment of obstructive sleep apnoea leads to improved microvascular endothelial function in the systemic circulation. Thorax 61:491–495

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  95. Golbin JM, Somers VK, Caples SM (2008) Obstructive sleep apnea, cardiovascular disease, and pulmonary hypertension. Proc Am Thorac Soc 5:200–206

    PubMed  PubMed Central  Article  Google Scholar 

  96. Romero-Corral A, Somers VK, Pellikka PA et al (2007) Decreased right and left ventricular myocardial performance in obstructive sleep apnea. Chest 132:1863–1870

    PubMed  Article  Google Scholar 

  97. Oldenburg O, Schmidt A, Lamp B et al (2008) Adaptive servoventilation improves cardiac function in patients with chronic heart failure and Cheyne–Stokes respiration. Eur J Heart Fail 10:581–586

    PubMed  Article  Google Scholar 

  98. Eulenburg C, Wegscheider K, Woehrle H et al (2016) Mechanisms underlying increased mortality risk in patients with heart failure and reduced ejection fraction randomly assigned to adaptive servoventilation in the SERVE-HF study: results of a secondary multistate modelling analysis. Lancet Respir Med 4:873–881

    PubMed  Article  Google Scholar 

  99. O'Connor CM, Whellan DJ, Fuizat M et al (2017) Cardiovascular outcomes with minute ventilation-targeted adaptive servo-ventilation therapy in heart failure. J Am Coll Cardiol 69:1577–1587

    PubMed  Article  Google Scholar 

  100. Yoshihisa A, Suzuki S, Yamaki T et al (2013) Impact of adaptive servo-ventilation on cardiovascular function and prognosis in heart failure patients with preserved left ventricular ejection fraction and sleep-disordered breathing. Eur J Heart Fail 15:543–550

    PubMed  Article  CAS  Google Scholar 

  101. Wright JW, Mizutani S, Harding JW (2008) Pathways involved in the transition from hypertension to hypertrophy to heart failure. Treatment strategies. Heart Fail Rev 13:367–375

    PubMed  Article  CAS  Google Scholar 

  102. Nguyen Dinh Cat A, Montezano AC, Burger D, Touyz RM (2013) Angiotensin II, NADPH oxidase, and redox signaling in the vasculature. Antioxid Redox Signal 19:1110–1120

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  103. Edelmann F, investigators A-DHF (2013) 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 309:781–791

    PubMed  Article  CAS  Google Scholar 

  104. Deswal A, Richardson P, Bozkurt B, Mann D (2011) Results of the Randomized Aldosterone Antagonism in Heart Failure With Preserved Ejection Fraction Trial (RAAM-PEF). J Card Fail 17:634–642

    PubMed  Article  Google Scholar 

  105. Upadhya B, Hundley WG, Brubaker PH, Morgan TM, Stewart KP, Kitzman DW (2017) Effect of spironolactone on exercise tolerance and arterial function in older adults with heart failure with preserved ejection fraction. J Am Geriatr Soc 65:2374–2382

    PubMed  Article  Google Scholar 

  106. Kosmala W, Rojek A, Przewlocka-Kosmala M, Wright L, Mysiak A, Marwick TH (2016) Effect of aldosterone antagonism on exercise tolerance in heart failure with preserved ejection fraction. J Am Coll Cardiol 68:1823–1834

    PubMed  Article  CAS  Google Scholar 

  107. Patel K, Fonarow GC, Kitzman DW et al (2013) Aldosterone antagonists and outcomes in real-world older patients with heart failure and preserved ejection fraction. JACC Heart Fail 1:40–47

    PubMed  PubMed Central  Article  Google Scholar 

  108. Pfeffer MA, Claggett B, Assmann SF et al (2015) Regional variation in patients and outcomes in the treatment of preserved cardiac function heart failure with an Aldosterone Antagonist (TOPCAT) Trial. Circulation 131:34–42

    PubMed  Article  CAS  Google Scholar 

  109. Zile MR, Gottdiener JS, Hetzel SJ et al (2011) Prevalence and significance of alterations in cardiac structure and function in patients with heart failure and a preserved ejection fraction. Circulation 124:2491–2501

    PubMed  Article  Google Scholar 

  110. Katz DH, Beussink L, Sauer AJ, Freed BH, Burke MA, Shah SJ (2013) Prevalence, clinical characteristics, and outcomes associated with eccentric versus concentric left ventricular hypertrophy in heart failure with preserved ejection fraction. Am J Cardiol 112:1158–1164

    PubMed  PubMed Central  Article  Google Scholar 

  111. Solomon S, Zile M, Pieske B et al (2012) The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. The Lancet 380:1387–1395

    Article  CAS  Google Scholar 

  112. Lam CS, Roger VL, Rodeheffer RJ et al (2007) Cardiac structure and ventricular–vascular function in persons with heart failure and preserved ejection fraction from Olmsted County, Minnesota. Circulation 115:1982–1990

    PubMed  PubMed Central  Article  Google Scholar 

  113. Maurer MS, Burkhoff D, Fried LP, Gottdiener J, King DL, Kitzman DW (2007) Ventricular structure and function in hypertensive participants with heart failure and a normal ejection fraction: The Cardiovascular Health Study. J Am Coll Cardiol 49:972–981

    PubMed  Article  Google Scholar 

  114. Solomon SD, Verma A, Desai A et al (2010) Effect of intensive versus standard blood pressure lowering on diastolic function in patients with uncontrolled hypertension and diastolic dysfunction. Hypertension 55:241–248

    PubMed  Article  CAS  Google Scholar 

  115. Kitzman D, Upadhya B (2014) Heart failure with preserved ejection fraction: a heterogenous disorder with multifactorial pathophysiology. J Am Coll Cardiol 63:457–459

    PubMed  Article  Google Scholar 

  116. Su MY, Lin LY, Tseng YH et al (2014) CMR-verified diffuse myocardial fibrosis is associated with diastolic dysfunction in HFpEF. JACC Cardiovasc Imaging 7:991–997

    PubMed  Article  Google Scholar 

  117. Yamamoto K, Origasa H, Hori M, J-DHF Investigators (2013) Effects of carvedilol on heart failure with preserved ejection fraction: the Japanese Diastolic Heart Failure Study (J-DHF). Eur J Heart Fail 15:110–118

    PubMed  Article  CAS  Google Scholar 

  118. Conraads V, Metra M, Kamp O et al (2012) 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 14:219–225

    PubMed  Article  CAS  Google Scholar 

  119. Hernandez AF, Hammill BG, O'Connor CM, Schulman KA, Curtis LH, Fonarow GC (2009) 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 53:184–192

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  120. Setaro JF, Zaret BL, Schulman DS, Black HR (1990) Usefulness of verapamil for congestive heart failure associated with abnormal left ventricular diastolic filling and normal left ventricular systolic performance. Am J Cardiol 66:981–986

    PubMed  Article  CAS  Google Scholar 

  121. Ponikowski P, Voors AA, Anker SD 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 J Heart Fail 2016;18:891-975.

  122. Reil JC, Hohl M, Reil GH et al (2013) Heart rate reduction by If-inhibition improves vascular stiffness and left ventricular systolic and diastolic function in a mouse model of heart failure with preserved ejection fraction. Eur Heart J 34:2839–2849

    PubMed  Article  Google Scholar 

  123. Kosmala W, Holland DJ, Rojek A, Wright L, Przewlocka-Kosmala M, Marwick TH (2013) 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 62:1330–1338

    PubMed  Article  CAS  Google Scholar 

  124. Pal N, Sivaswamy N, Mahmod M et al (2015) Effect of selective heart rate slowing in heart failure with preserved ejection fraction. Circulation 132:1719–1725

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  125. Higginbotham MB, Morris KG, Williams RS, McHale PA, Coleman RD, Cobb FR (1986) Regulation of stroke volume during submaximal and maximal upright exercise in normal man. Circ Res 58:281–291

    PubMed  Article  CAS  Google Scholar 

  126. Phan T, Shivu G, Weaver R, Ahmed I, Frenneaux M (2010) Impaired heart rate recovery and chronotropic incompetence in patients with heart failure with preserved ejection fraction. Circ Heart Fail 3:29–34

    PubMed  Article  Google Scholar 

  127. Jacobshagen C, Belardinelli L, Hasenfuss G, Maier L (2011) Ranolazine for the treatment of heart failure with preserved ejection fraction: background, aims, and design of the RALI-DHF study. Clin Cardiol 34:426–432

    PubMed  Article  Google Scholar 

  128. Maier LS, Layug B, Karwatowska-Prokopczuk E et al (2013) RAnoLazIne for the treatment of diastolic heart failure in patients with preserved ejection fraction: the RALI-DHF proof-of-concept study. JACC Heart Fail 1:115–122

    PubMed  Article  Google Scholar 

  129. Ahmed A, Pitt B, Rahimtoola SH et al (2008) Effects of digoxin at low serum concentrations on mortality and hospitalization in heart failure: a propensity-matched study of the DIG trial. Int J Cardiol 123:138–146

    PubMed  Article  Google Scholar 

  130. Hattori T, Shimokawa H, Higashi M et al (2004) Long-term inhibition of Rho-kinase suppresses left ventricular remodeling after myocardial infarction in mice. Circulation 109:2234–2239

    PubMed  Article  CAS  Google Scholar 

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

    PubMed  Article  CAS  Google Scholar 

  132. Ferrier KE, Muhlmann MH, Baguet JP et al (2002) Intensive cholesterol reduction lowers blood pressure and large artery stiffness in isolated systolic hypertension. J Am Coll Cardiol 39:1020–1025

    PubMed  Article  CAS  Google Scholar 

  133. Landmesser U, Bahlmann F, Mueller M et al (2005) Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation 111:2356–2363

    PubMed  Article  CAS  Google Scholar 

  134. Davignon J (2004) Beneficial cardiovascular pleiotropic effects of statins. Circulation 109:III39–III43

    PubMed  Google Scholar 

  135. Fukuta H, Little W (2008) Observational studies of statins in heart failure with preserved systolic function. Heart Fail Clin 4:209–216

    PubMed  Article  Google Scholar 

  136. Shah R, Wang Y, Foody JM (2008) Effect of statins, angiotensin-converting enzyme inhibitors, and beta blockers on survival in patients >=65 years of age with heart failure and preserved left ventricular systolic function. Am J Cardiol 101:217–222

    PubMed  Article  CAS  Google Scholar 

  137. Alehagen U, Benson L, Edner M, Dahlstrom U, Lund LH (2015) Association between use of statins and mortality in patients with heart failure and ejection fraction greater than or equal to 50. Circ Heart Fail 8:862–870

    PubMed  Article  CAS  Google Scholar 

  138. Tsujimoto T, Kajio H. Favorable effects of statins in the treatment of heart failure with preserved ejection fraction in patients without ischemic heart disease. Int J Cardiol 2018;Epub ahead of print.

  139. Fukuta H, Goto T, Wakami K, Ohte N (2016) The effect of statins on mortality in heart failure with preserved ejection fraction: a meta-analysis of propensity score analyses. Int J Cardiol 214:301–306

    PubMed  Article  Google Scholar 

  140. Kitzman DW, Little WC, Brubaker PH et al (2002) Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA 288:2144–2150

    PubMed  Article  Google Scholar 

  141. Maisel A (2002) B-type natriuretic peptide levels: diagnostic and prognostic in congestive heart failure: what’s next? Circulation 105:2328–2331

    PubMed  Article  Google Scholar 

  142. Anjan VY, Loftus TM, Burke MA et al (2012) Prevalence, clinical phenotype, and outcomes associated with normal B-type natriuretic peptide levels in heart failure with preserved ejection fraction. Am J Cardiol 110:870–876

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  143. Shah SJ, Kitzman DW, Borlaug BA et al (2016) Phenotype-specific treatment of heart failure with preserved ejection fraction: a multiorgan roadmap. Circulation 134:73–90

    PubMed  PubMed Central  Article  Google Scholar 

  144. Kanwar M, Agarwal R, Barnes M et al (2013) Role of phosphodiesterase-5 inhibitors in heart failure: emerging data and concepts. Curr Heart Fail Rep 10:26–35

    PubMed  Article  CAS  Google Scholar 

  145. Redfield M, Chen H, Borlaug B et al (2013) Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 309:1268–1277

    PubMed  Article  CAS  Google Scholar 

  146. Redfield M, Anstrom K, Levine J et al (2015) Isosorbide mononitrate in heart failure with preserved ejection fraction. N Engl J Med 373:2314–2324

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  147. Lundberg JO, Weitzberg E, Gladwin MT (2008) The nitrate–nitrite–nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov 7:156–167

    PubMed  Article  CAS  Google Scholar 

  148. Cosby K, Partovi KS, Crawford JH et al (2003) Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nature Med 9:1498–1505

    PubMed  Article  CAS  Google Scholar 

  149. Eggebeen J, Kim-Shapiro DB, Haykowsky MJ et al (2015) One week of daily dosing with beetroot juice improves submaximal endurance and blood pressure in older patients with heart failure and preserved ejection fraction. JACC Heart Fail 4:428–437

    Article  Google Scholar 

  150. Borlaug BA, Melenovsky V, Koepp KE (2016) Inhaled sodium nitrite improves rest and exercise hemodynamics in heart failure with preserved ejection fraction. Circ Res 119:880–886

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  151. Borlaug BA, Koepp KE, Melenovsky V (2015) Sodium nitrite improves exercise hemodynamics and ventricular performance in heart failure with preserved ejection fraction. J Am Coll Cardiol 66:1672–1682

    PubMed  Article  CAS  Google Scholar 

  152. Reddy YNV, Lewis GD, Shah SJ et al (2017) INDIE-HFpEF (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure With Preserved Ejection Fraction). Circ Heart Fail 10:e003862

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  153. Bonderman D, Pretsch I, Steringer-Mascherbauer R et al (2014) Acute hemodynamic effects of riociguat in patients with pulmonary hypertension associated with diastolic heart failure (dilate-1): a randomized, double-blind, placebo-controlled, single-dose study. CHEST Journal 146:1274–1285

    Article  Google Scholar 

  154. Pieske B, Maggioni AP, Lam CSP et al (2017) 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 38:1119–1127

    PubMed  PubMed Central  Article  Google Scholar 

  155. Fitchett D, Zinman B, Wanner C et al (2016) Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME(R) trial. Eur Heart J 37:1526–1534

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  156. Tanaka A, Inoue T, Kitakaze M et al (2016) Rationale and design of a randomized trial to test the safety and non-inferiority of canagliflozin in patients with diabetes with chronic heart failure: the CANDLE trial. Cardiovasc Diabetol 15:57

    PubMed  PubMed Central  Article  Google Scholar 

  157. Scalzo RL, Moreau KL, Ozemek C et al (2017) Exenatide improves diastolic function and attenuates arterial stiffness but does not alter exercise capacity in individuals with type 2 diabetes. J Diabetes Complications 31:449–455

    PubMed  Article  Google Scholar 

  158. Wang P, Zhuo X, Chu W, Tang X (2017) Exenatide-loaded microsphere/thermosensitive hydrogel long-acting delivery system with high drug bioactivity. Int J Pharm 528:62–75

    PubMed  Article  CAS  Google Scholar 

  159. Sabbah HN, Gupta RC, Kohli S, Wang M, Hachem S, Zhang K (2016) Chronic therapy with elamipretide (MTP-131), a novel mitochondria-targeting peptide, improves left ventricular and mitochondrial function in dogs with advanced heart failure. Circ Heart Fail 9:e002206

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  160. Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J (2001) International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53:527–552

    PubMed  CAS  Google Scholar 

  161. Yuan K, Cao C, Han JH, Kim SZ, Kim SH (2005) Adenosine-stimulated atrial natriuretic peptide release through A1 receptor subtype. Hypertension 46:1381–1387

    PubMed  Article  CAS  Google Scholar 

  162. Schutte F, Burgdorf C, Richardt G, Kurz T (2006) Adenosine A1 receptor-mediated inhibition of myocardial norepinephrine release involves neither phospholipase C nor protein kinase C but does involve adenylyl cyclase. Can J Physiol Pharmacol 84:573–577

    PubMed  Article  Google Scholar 

  163. Greene SJ, Sabbah HN, Butler J et al (2016) Partial adenosine A1 receptor agonism: a potential new therapeutic strategy for heart failure. Heart Fail Rev 21:95–102

    PubMed  Article  CAS  Google Scholar 

  164. Age-associated changes in Ca(2+)-ATPase and oxidative damage in sarcoplasmic reticulum of rat heart.: 2012.

  165. Lancel S, Qin F, Lennon S et al (2010) Oxidative posttranslational modifications mediate decreased SERCA activity and myocyte dysfunction in Galphaq-overexpressing mice. Circ Res 107:228–232

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  166. Qin F, Siwik D, Lancel S et al (2013) Hydrogen peroxide-mediated SERCA cysteine 674 oxidation contributes to impaired cardiac myocyte relaxation in senescent mouse heart. J Am Heart Assoc 2:e000184

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  167. Jessup M, Greenberg B, Mancini D et al (2011) Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure. Circulation 124:304–313

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  168. Zsebo K, Yaroshinsky A, Rudy JJ et al (2014) Long-term effects of AAV1/SERCA2a gene transfer in patients with severe heart failure: analysis of recurrent cardiovascular events and mortality. Circ Res 114:101–108

    PubMed  Article  CAS  Google Scholar 

  169. Boon RA, Iekushi K, Lechner S et al (2013) MicroRNA-34a regulates cardiac ageing and function. Nature 495:107–110

    PubMed  Article  CAS  Google Scholar 

  170. Nair N, Gupta S, Collier IX, Gongora E, Vijayaraghavan K (2014) Can microRNAs emerge as biomarkers in distinguishing HFpEF versus HFrEF? Int J Cardiol 175:395–399

    PubMed  Article  Google Scholar 

  171. Chiao YA, Ramirez TA, Zamilpa R et al (2012) Matrix metalloproteinase-9 deletion attenuates myocardial fibrosis and diastolic dysfunction in ageing mice. Cardiovasc Res 96:444–455

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  172. Zhao L, Buxbaum JN, Reixach N (2013) Age-related oxidative modifications of transthyretin modulate its amyloidogenicity. Biochemistry (Mosc) 52:1913–1926

    Article  CAS  Google Scholar 

  173. Packer M (2011) Can bain natriuretic peptide be used to guide the management of patients with heart failure and a preserved ejection fraction? Circ Heart Fail 4:538–540

    PubMed  Article  Google Scholar 

  174. Shah AM, Solomon SD (2012) Phenotypic and pathophysiological heterogeneity in heart failure with preserved ejection fraction. Eur Heart J 33:1716–1717

    PubMed  Article  Google Scholar 

  175. Shah SJ, Katz DH, Selvaraj S et al (2015) Phenomapping for novel classification of heart failure with preserved ejection fraction. Circulation 131:269–279

    PubMed  Article  Google Scholar 

  176. Lewis GA, Schelbert EB, Williams SG et al (2017) Biological phenotypes of heart failure with preserved ejection fraction. J Am Coll Cardiol 70:2186–2200

    PubMed  Article  Google Scholar 

  177. Davis BR, Kostis J, Simpson LM et al (2008) Heart failure with preserved and reduced left ventricular ejection fraction in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Circulation 118:2259–2267

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  178. Pandey A, Parashar A, Kumbhani DJ et al (2015) Exercise training in patients with heart failure and preserved ejection fraction: meta-analysis of randomized control trials. Circ Heart Fail 8:33–40

    PubMed  Article  Google Scholar 

  179. Miranda W, Batsis J, Sarr M et al (2013) Impact of bariatric surgery on quality of life, functional capacity, and symptoms in patients with heart failure. OBES SURG 23:1011–1015

    PubMed  Article  Google Scholar 

  180. Justice J, Miller JD, Newman JC et al (2016) Frameworks for proof-of-concept clinical trials of interventions that target fundamental aging processes. J Gerontol A Biol Sci Med Sci 71:1415–1423

  181. De Keulenaer GW, Segers VFM, Zannad F, Brutsaert DL (2017) The future of pleiotropic therapy in heart failure. Lessons from the benefits of exercise training on endothelial function. Eur J Heart Fail 19:603–614

    PubMed  Article  Google Scholar 

  182. Conceicao G, Heinonen I, Lourenco AP, Duncker DJ, Falcao-Pires I (2016) Animal models of heart failure with preserved ejection fraction. Neth Heart J 24:275–286

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  183. Alves AJ, Ribeiro F, Goldhammer E et al (2012) Exercise training improves diastolic function in heart failure patients. Med Sci Sports Exerc 44:776–785

    PubMed  Article  Google Scholar 

  184. Zamani P, Rawat D, Shiva-Kumar P et al (2015) Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction. Circulation. 131:371–380

  185. Guazzi M, Vicenzi M, Arena R, Guazzi MD (2011) Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study. Circulation 124:164–174

    PubMed  Article  CAS  Google Scholar 

  186. Guazzi M, Bandera F, Forfia P (2013) Sildenafil and exercise capacity in heart failure. JAMA 310:432

    PubMed  Article  CAS  Google Scholar 

  187. Kitzman DW, Hundley WG, Brubaker P, Stewart K, Little WC (2010) A randomized, controlled, double-blinded trial of enalapril in older patients with heart failure and preserved ejection fraction; effects on exercise tolerance, and arterial distensibility. Circ Heart Fail 3:477–485

    PubMed  PubMed Central  Article  Google Scholar 

  188. van Veldhuisen DJ, Cohen-Solal A, Bohm M et al (2009) 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 53:2150–2158

    PubMed  Article  CAS  Google Scholar 

  189. Hoendermis ES, Liu LC, Hummel YM et al (2015) Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled trial. Eur Heart J 36:2565–2573

    PubMed  Article  CAS  Google Scholar 

  190. Zamani P, Akers S, Soto-Calderon H et al (2017) Isosorbide dinitrate, with or without hydralazine, does not reduce wave reflections, left ventricular hypertrophy, or myocardial fibrosis in patients with heart failure with preserved ejection fraction. J Am Heart Assoc 6:e004262

    PubMed  PubMed Central  Article  Google Scholar 

  191. Little WC, Zile MR, Kitzman DW, Hundley WG, O'Brien TX, deGroof RC (2005) The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure. J Card Fail 11:191–195

    PubMed  Article  CAS  Google Scholar 

  192. Zile MR, Bourge RC, Redfield MM, Zhou D, Baicu CF, Little WC (2014) Randomized, double-blind, placebo-controlled study of sitaxsentan to improve impaired exercise tolerance in patients with heart failure and a preserved ejection fraction. JACC Heart Fail 2:123–130

    PubMed  Article  Google Scholar 

  193. Filippatos G, Teerlink JR, Farmakis D et al (2014) Serelaxin in acute heart failure patients with preserved left ventricular ejection fraction: results from the RELAX-AHF trial. Eur Heart J 35:1041–1050

    PubMed  Article  CAS  Google Scholar 

  194. Wessler JD, Maurer MS, Hummel SL (2015) Evaluating the safety and efficacy of sodium-restricted/Dietary Approaches to Stop Hypertension diet after acute decompensated heart failure hospitalization: design and rationale for the Geriatric OUt of hospital Randomized MEal Trial in Heart Failure (GOURMET-HF). Am Heart J 169:342–348

    PubMed  PubMed Central  Article  CAS  Google Scholar 

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Affiliations

  1. Cardiovascular Medicine Section, Department of Internal Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157-1045, USA

    Bharathi Upadhya & Dalane W. Kitzman

  2. College of Nursing and Health Innovation, University of Texas Arlington, Arlington, TX, USA

    Mark J. Haykowsky

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  1. Bharathi Upadhya
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Correspondence to Dalane W. Kitzman.

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D.W.K. declares the following relationships: consultant for Abbvie, Bayer, Merck, Medtronic, GSK, Relypsa, Regeneron, Merck, Corvia Medical, DCRI, and Actavis, research grant funding from Novartis, St. Luke’s Medical Center, and stock ownership in Gilead Sciences.

B.U. has received research funding from Novartis and Corvia.

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Supported in part by: NIH Grants R01AG045551 and R01AG18915; The Claude D. Pepper Older Americans Independence Center of Wake Forest School of Medicine Winston-Salem, NC, and National Institute of Nursing Research Grant R15NR016826.

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Upadhya, B., Haykowsky, M.J. & Kitzman, D.W. Therapy for heart failure with preserved ejection fraction: current status, unique challenges, and future directions. Heart Fail Rev 23, 609–629 (2018). https://doi.org/10.1007/s10741-018-9714-z

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Keywords

  • Heart failure
  • Preserved ejection fraction
  • Therapy