Evaluation and management of heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) has grown to become the dominant form of heart failure worldwide, in tandem with ageing of the general population and the increasing prevalences of obesity, diabetes mellitus and hypertension. The clinical syndrome of HFpEF is heterogeneous and must be distinguished from heart failure with reduced ejection fraction as well as other aetiologies that have different treatment strategies. The diagnosis of HFpEF is challenging and ultimately relates to the conceptual definition of heart failure as a clinical syndrome characterized by symptoms that are associated with a reduced capacity of the heart to pump blood adequately at normal filling pressures during diastole. Clinical trials to date have been largely unsuccessful in identifying effective treatments for HFpEF but evidence supports the use of diuretics, mineralocorticoid antagonists and lifestyle interventions. Pathophysiological heterogeneity in the presentation of HFpEF is substantial, and ongoing studies are underway to evaluate the optimal methods to classify patients into phenotypically homogeneous subpopulations to facilitate better individualization of treatment.

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References

  1. Pfeffer, M. A., Shah, A. M. & Borlaug, B. A. Heart failure with preserved ejection fraction in perspective. Circ. Res.124, 1598–1617 (2019). CASPubMedPubMed CentralGoogle Scholar
  2. Shah, A. M. et al. Heart failure stages among older adults in the community: the Atherosclerosis Risk in Communities Study. Circulation135, 224–240 (2017). PubMedGoogle Scholar
  3. Dunlay, S. M., Roger, V. L. & Redfield, M. M. Epidemiology of heart failure with preserved ejection fraction. Nat. Rev. Cardiol.14, 591–602 (2017). PubMedGoogle Scholar
  4. Sidney, S. et al. Association between aging of the US population and heart disease mortality from 2011 to 2017. JAMA Cardiol.4, 1280–1286 (2019). PubMedPubMed CentralGoogle Scholar
  5. Flegal, K. M., Kruszon-Moran, D., Carroll, M. D., Fryar, C. D. & Ogden, C. L. Trends in obesity among adults in the United States, 2005 to 2014. JAMA315, 2284–2291 (2016). CASPubMedGoogle Scholar
  6. Borlaug, B. A. & Redfield, M. M. Diastolic and systolic heart failure are distinct phenotypes within the heart failure spectrum. Circulation123, 2006–2013 (2011). PubMedPubMed CentralGoogle Scholar
  7. Lupon, J. et al. Heart failure with preserved ejection fraction infrequently evolves toward a reduced phenotype in long-term survivors. Circ. Heart Fail.12, e005652 (2019). PubMedGoogle Scholar
  8. Pandey, A. et al. Physical activity, fitness, and obesity in heart failure with preserved ejection fraction. JACC Heart Fail.6, 975–982 (2018). PubMedGoogle Scholar
  9. Borlaug, B. A., Nishimura, R. A., Sorajja, P., Lam, C. S. & Redfield, M. M. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ. Heart Fail.3, 588–595 (2010). PubMedPubMed CentralGoogle Scholar
  10. Obokata, M. et al. Role of diastolic stress testing in the evaluation for heart failure with preserved ejection fraction: a simultaneous invasive-echocardiographic study. Circulation135, 825–838 (2017). PubMedGoogle Scholar
  11. Reddy, Y. N. V., Carter, R. E., Obokata, M., Redfield, M. M. & Borlaug, B. A. A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction. Circulation138, 861–870 (2018). PubMedPubMed CentralGoogle Scholar
  12. Pieske, B. et al. How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur. Heart J.40, 3297–3317 (2019). PubMedGoogle Scholar
  13. Shah, S. J. et al. Phenotype-specific treatment of heart failure with preserved ejection fraction: a multiorgan roadmap. Circulation134, 73–90 (2016). PubMedPubMed CentralGoogle Scholar
  14. Klainer, L. M., Gibson, T. C. & White, K. L. The epidemiology of cardiac failure. J. Chronic Dis.18, 797–814 (1965). CASPubMedGoogle Scholar
  15. McKee, P. A., Castelli, W. P., McNamara, P. M. & Kannel, W. B. The natural history of congestive heart failure: the Framingham study. N. Engl. J. Med.285, 1441–1446 (1971). CASPubMedGoogle Scholar
  16. Ho, J. E. et al. Differential clinical profiles, exercise responses and outcomes associated with existing HFpEF definitions. Circulation140, 353–365 (2019). PubMedPubMed CentralGoogle Scholar
  17. Abudiab, M. M. et al. Cardiac output response to exercise in relation to metabolic demand in heart failure with preserved ejection fraction. Eur. J. Heart Fail.15, 776–785 (2013). PubMedPubMed CentralGoogle Scholar
  18. Denolin, H., Kuhn, H., Krayenbuehl, H. P., Loogen, F. & Reale, A. The definition of heart failure. Eur. Heart J.4, 445–448 (1983). CASPubMedGoogle Scholar
  19. Ponikowski, P. et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur. Heart J.37, 2129–2200 (2016). PubMedGoogle Scholar
  20. Lund, L. H. et al. Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum. Eur. J. Heart Fail.20, 1230–1239 (2018). CASPubMedGoogle Scholar
  21. Solomon, S. D. et al. Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure and preserved ejection fraction. Eur. Heart J.37, 455–462 (2016). CASPubMedGoogle Scholar
  22. Butler, J., Anker, S. D. & Packer, M. Redefining heart failure with a reduced ejection fraction. JAMA322, 1761–1762 (2019). PubMedGoogle Scholar
  23. Solomon, S. D. et al. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N. Engl. J. Med.381, 1609–1620 (2019). CASPubMedGoogle Scholar
  24. Yancy, C. W. et al. 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. Circulation136, e137–e161 (2017). PubMedGoogle Scholar
  25. Obokata, M. et al. Myocardial injury and cardiac reserve in patients with heart failure and preserved ejection fraction. J. Am. Coll. Cardiol.72, 29–40 (2018). PubMedPubMed CentralGoogle Scholar
  26. Borlaug, B. A. et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J. Am. Coll. Cardiol.56, 845–854 (2010). PubMedPubMed CentralGoogle Scholar
  27. Borlaug, B. A., Kane, G. C., Melenovsky, V. & Olson, T. P. Abnormal right ventricular-pulmonary artery coupling with exercise in heart failure with preserved ejection fraction. Eur. Heart J.37, 3293–3302 (2016). PubMedPubMed CentralGoogle Scholar
  28. Reddy, Y. N. V. et al. The haemodynamic basis of lung congestion during exercise in heart failure with preserved ejection fraction. Eur Heart J.40, 3721–3730 (2019). PubMedPubMed CentralGoogle Scholar
  29. Obokata, M. et al. Hemodynamics, dyspnea, and pulmonary reserve in heart failure with preserved ejection fraction. Eur. Heart J.39, 2810–2821 (2018). CASPubMedPubMed CentralGoogle Scholar
  30. Reddy, Y. N. V., Olson, T. P., Obokata, M., Melenovsky, V. & Borlaug, B. A. Hemodynamic correlates and diagnostic role of cardiopulmonary exercise testing in heart failure with preserved ejection fraction. JACC Heart Fail.6, 665–675 (2018). PubMedPubMed CentralGoogle Scholar
  31. Eisman, A. S. et al. Pulmonary capillary wedge pressure patterns during exercise predict exercise capacity and incident heart failure. Circ. Heart Fail.11, e004750 (2018). PubMedPubMed CentralGoogle Scholar
  32. Dorfs, S. et al. Pulmonary capillary wedge pressure during exercise and long-term mortality in patients with suspected heart failure with preserved ejection fraction. Eur. Heart J.35, 3103–3112 (2014). CASPubMedGoogle Scholar
  33. Paulus, W. J. & 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.62, 263–271 (2013). PubMedGoogle Scholar
  34. Luscher, T. F. Lumpers and splitters: the bumpy road to precision medicine. Eur. Heart J.40, 3292–3296 (2019). PubMedGoogle Scholar
  35. Hwang, S. J., Melenovsky, V. & Borlaug, B. A. Implications of coronary artery disease in heart failure with preserved ejection fraction. J. Am. Coll. Cardiol.63, 2817–2827 (2014). PubMedGoogle Scholar
  36. Eleid, M. F., Nishimura, R. A., Sorajja, P. & Borlaug, B. A. Systemic hypertension in low-gradient severe aortic stenosis with preserved ejection fraction. Circulation128, 1349–1353 (2013). PubMedGoogle Scholar
  37. Tamargo, M. et al. Functional mitral regurgitation and left atrial myopathy in heart failure with preserved ejection fraction. Eur. J. Heart Fail.https://doi.org/10.1002/ejhf.1699 (2020). ArticlePubMedGoogle Scholar
  38. Obokata, M., Reddy, Y. N. V. & Borlaug, B. A. Diastolic dysfunction and heart failure with preserved ejection fraction: understanding mechanisms by using noninvasive methods. JACC Cardiovasc. Imaging13, 245–257 (2019). PubMedPubMed CentralGoogle Scholar
  39. Davie, A. P., Francis, C. M., Caruana, L., Sutherland, G. R. & McMurray, J. J. Assessing diagnosis in heart failure: which features are any use? QJM90, 335–339 (1997). CASPubMedGoogle Scholar
  40. Mentz, R. J., Broderick, S., Shaw, L. K., Fiuzat, M. & O’Connor, C. M. Heart failure with preserved ejection fraction: comparison of patients with and without angina pectoris (from the Duke Databank for Cardiovascular Disease). J. Am. Coll. Cardiol.63, 251–258 (2014). PubMedGoogle Scholar
  41. Shah, S. J. et al. Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction: PROMIS-HFpEF. Eur. Heart J.39, 3439–3450 (2018). CASPubMedPubMed CentralGoogle Scholar
  42. Yang, J. H. et al. Endothelium dependent and independent coronary microvascular dysfunction in patients with heart failure with preserved ejection fraction. Eur. J. Heart Fail.https://doi.org/10.1002/ejhf.1671 (2020). ArticlePubMedGoogle Scholar
  43. Mohammed, S. F. et al. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation131, 550–559 (2015). PubMedGoogle Scholar
  44. Gorter, T. M. et al. Right heart dysfunction and failure in heart failure with preserved ejection fraction: mechanisms and management. Position statement on behalf of the Heart Failure Association of the European Society of Cardiology. Eur. J. Heart Fail.20, 16–37 (2018). PubMedGoogle Scholar
  45. Reddy, Y. N. V., Obokata, M., Gersh, B. J. & Borlaug, B. A. High prevalence of occult heart failure with preserved ejection fraction among patients with atrial fibrillation and dyspnea. Circulation137, 534–535 (2018). PubMedPubMed CentralGoogle Scholar
  46. Obokata, M., Reddy, Y. N., Pislaru, S. V., Melenovsky, V. & Borlaug, B. A. Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction. Circulation136, 6–19 (2017). CASPubMedPubMed CentralGoogle Scholar
  47. Drazner, M. H. et al. The relationship of right- and left-sided filling pressures in patients with heart failure and a preserved ejection fraction. Circ. Heart Fail.3, 202–206 (2010). PubMedPubMed CentralGoogle Scholar
  48. From, A. M. et al. Bedside assessment of cardiac hemodynamics: the impact of noninvasive testing and examiner experience. Am. J. Med.124, 1051–1057 (2011). PubMedGoogle Scholar
  49. Stevenson, L. W. & Perloff, J. K. The limited reliability of physical signs for estimating hemodynamics in chronic heart failure. JAMA261, 884–888 (1989). CASPubMedGoogle Scholar
  50. Lam, C. S. et al. Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study. J. Am. Coll. Cardiol.53, 1119–1126 (2009). PubMedPubMed CentralGoogle Scholar
  51. Iwanaga, Y. et al. B-type natriuretic peptide strongly reflects diastolic wall stress in patients with chronic heart failure: comparison between systolic and diastolic heart failure. J. Am. Coll. Cardiol.47, 742–748 (2006). CASPubMedGoogle Scholar
  52. Mueller, C. et al. Heart failure association of the European Society of Cardiology practical guidance on the use of natriuretic peptide concentrations. Eur. J. Heart Fail.21, 715–731 (2019). CASPubMedGoogle Scholar
  53. Cleland, J. G., Taylor, J. & Tendera, M. Prognosis in heart failure with a normal ejection fraction. N. Engl. J. Med.357, 829–830 (2007). CASPubMedGoogle Scholar
  54. van Veldhuisen, D. J. et al. B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction. J. Am. Coll. Cardiol.61, 1498–1506 (2013). PubMedGoogle Scholar
  55. Anjan, V. Y. et al. Prevalence, clinical phenotype, and outcomes associated with normal B-type natriuretic peptide levels in heart failure with preserved ejection fraction. Am. J. Cardiol.110, 870–876 (2012). CASPubMedPubMed CentralGoogle Scholar
  56. Wang, T. J. et al. Impact of obesity on plasma natriuretic peptide levels. Circulation109, 594–600 (2004). CASPubMedGoogle Scholar
  57. Andersen, M. J. & Borlaug, B. A. Invasive hemodynamic characterization of heart failure with preserved ejection fraction. Heart Fail. Clin.10, 435–444 (2014). PubMedGoogle Scholar
  58. Borlaug, B. A. et al. Diastolic relaxation and compliance reserve during dynamic exercise in heart failure with preserved ejection fraction. Heart97, 964–969 (2011). PubMedGoogle Scholar
  59. Andersen, M. J., Olson, T. P., Melenovsky, V., Kane, G. C. & Borlaug, B. A. Differential hemodynamic effects of exercise and volume expansion in people with and without heart failure. Circ. Heart Fail.8, 41–48 (2015). PubMedGoogle Scholar
  60. Maron, B. A., Cockrill, B. A., Waxman, A. B. & Systrom, D. M. The invasive cardiopulmonary exercise test. Circulation127, 1157–1164 (2013). PubMedGoogle Scholar
  61. Maeder, M. T., Thompson, B. R., Brunner-La Rocca, H. P. & Kaye, D. M. Hemodynamic basis of exercise limitation in patients with heart failure and normal ejection fraction. J. Am. Coll. Cardiol.56, 855–863 (2010). PubMedGoogle Scholar
  62. Fujimoto, N. et al. Hemodynamic responses to rapid saline loading: the impact of age, sex, and heart failure. Circulation127, 55–62 (2013). CASPubMedGoogle Scholar
  63. Guazzi, M. et al. 2016 Focused update: clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations. Circulation133, e694–e711 (2016). PubMedGoogle Scholar
  64. Lancellotti, P. et al. The clinical use of stress echocardiography in non-ischaemic heart disease: recommendations from the European association of cardiovascular imaging and the american society of echocardiography. Eur. Heart J. Cardiovasc. Imaging17, 1191–1229 (2016). PubMedGoogle Scholar
  65. Holland, D. J., Prasad, S. B. & Marwick, T. H. Contribution of exercise echocardiography to the diagnosis of heart failure with preserved ejection fraction (HFpEF). Heart96, 1024–1028 (2010). PubMedGoogle Scholar
  66. Burgess, M. I., Jenkins, C., Sharman, J. E. & Marwick, T. H. Diastolic stress echocardiography: hemodynamic validation and clinical significance of estimation of ventricular filling pressure with exercise. J. Am. Coll. Cardiol.47, 1891–1900 (2006). PubMedGoogle Scholar
  67. Talreja, D. R., Nishimura, R. A. & Oh, J. K. Estimation of left ventricular filling pressure with exercise by Doppler echocardiography in patients with normal systolic function: a simultaneous echocardiographic-cardiac catheterization study. J. Am. Soc. Echocardiogr.20, 477–479 (2007). PubMedGoogle Scholar
  68. Obokata, M. & Borlaug, B. A. The strengths and limitations of E/e’ in heart failure with preserved ejection fraction. Eur. J. Heart Fail.20, 1312–1314 (2018). PubMedGoogle Scholar
  69. Nauta, J. F. et al. Correlation with invasive left ventricular filling pressures and prognostic relevance of the echocardiographic diastolic parameters used in the 2016 ESC heart failure guidelines and in the 2016 ASE/EACVI recommendations: a systematic review in patients with heart failure with preserved ejection fraction. Eur. J. Heart Fail.20, 1303–1311 (2018). PubMedGoogle Scholar
  70. Santos, M. et al. E/e’ ratio in patients with unexplained dyspnea: lack of accuracy in estimating left ventricular filling pressure. Circ. Heart Fail.8, 749–756 (2015). PubMedPubMed CentralGoogle Scholar
  71. Sharifov, O. F. & Gupta, H. What is the evidence that the tissue doppler index E/e’ reflects left ventricular filling pressure changes after exercise or pharmacological intervention for evaluating diastolic function? A systematic review. J. Am. Heart Assoc.6, e004766 (2017). PubMedPubMed CentralGoogle Scholar
  72. Paulus, W. J. H2FPEF score. Circulation138, 871–873 (2018). PubMedGoogle Scholar
  73. Segar, M. W., Patel, K. V., Berry, J. D., Grodin, J. L. & Pandey, A. Generalizability and implications of the H2FPEF score in a cohort of patients with heart failure with preserved ejection fraction. Circulation139, 1851–1853 (2019). PubMedGoogle Scholar
  74. Myhre, P. L. et al. Application of the H2 FPEF score to a global clinical trial of patients with heart failure with preserved ejection fraction: the TOPCAT trial. Eur. J. Heart Fail.21, 1288–1291 (2019). PubMedGoogle Scholar
  75. Sepehrvand, N. et al. External validation of the H2F-PEF model in diagnosing patients with heart failure and preserved ejection fraction. Circulation139, 2377–2379 (2019). PubMedGoogle Scholar
  76. Cleland, J. G. et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur. Heart J.27, 2338–2345 (2006). CASPubMedGoogle Scholar
  77. Yusuf, S. et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-preserved trial. Lancet362, 777–781 (2003). CASPubMedGoogle Scholar
  78. Massie, B. M. et al. Irbesartan in patients with heart failure and preserved ejection fraction. N. Engl. J. Med.359, 2456–2467 (2008). CASPubMedGoogle Scholar
  79. Solomon, S. D. et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet380, 1387–1395 (2012). CASPubMedGoogle Scholar
  80. 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.15, 110–118 (2013). CASPubMedGoogle Scholar
  81. Conraads, V. M. 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.14, 219–225 (2012). CASPubMedGoogle Scholar
  82. Pitt, B. et al. Spironolactone for heart failure with preserved ejection fraction. N. Engl. J. Med.370, 1383–1392 (2014). CASPubMedGoogle Scholar
  83. Edelmann, F. 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. JAMA309, 781–791 (2013). CASPubMedGoogle Scholar
  84. Redfield, M. M. et al. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA309, 1268–1277 (2013). CASPubMedGoogle Scholar
  85. Redfield, M. M. et al. Isosorbide mononitrate in heart failure with preserved ejection fraction. N. Engl. J. Med.373, 2314–2324 (2015). CASPubMedPubMed CentralGoogle Scholar
  86. Borlaug, B. A. et al. Effect of inorganic nitrite vs placebo on exercise capacity among patients with heart failure with preserved ejection fraction: the INDIE-HFpEF randomized clinical trial. JAMA320, 1764–1773 (2018). CASPubMedPubMed CentralGoogle Scholar
  87. Pieske, B. et al. Vericiguat in patients with worsening chronic heart failure and preserved ejection fraction: results of the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED EF (SOCRATES-PRESERVED) study. Eur. Heart J.38, 1119–1127 (2017). CASPubMedPubMed CentralGoogle Scholar
  88. Filippatos, G. et al. Patient-reported outcomes in the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED ejection fraction (SOCRATES-PRESERVED) study. Eur. J. Heart Fail.19, 782–791 (2017). CASPubMedGoogle Scholar
  89. Ahmed, A. et al. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial. Circulation114, 397–403 (2006). CASPubMedPubMed CentralGoogle Scholar
  90. Komajda, M. et al. Effect of ivabradine in patients with heart failure with preserved ejection fraction: the EDIFY randomized placebo-controlled trial. Eur. J. Heart Fail.19, 1495–1503 (2017). CASPubMedGoogle Scholar
  91. Shah, S. J. et al. Effect of neladenoson bialanate on exercise capacity among patients with heart failure with preserved ejection fraction: a randomized clinical trial. JAMA321, 2101–2112 (2019). CASPubMedPubMed CentralGoogle Scholar
  92. Abraham, W. T. et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet377, 658–666 (2011). PubMedGoogle Scholar
  93. Adamson, P. B. et al. Wireless pulmonary artery pressure monitoring guides management to reduce decompensation in heart failure with preserved ejection fraction. Circ. Heart Fail.7, 935–944 (2014). PubMedGoogle Scholar
  94. Pandey, A. et al. Exercise training in patients with heart failure and preserved ejection fraction: meta-analysis of randomized control trials. Circ. Heart Fail.8, 33–40 (2015). PubMedGoogle Scholar
  95. Kitzman, D. W. et al. 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 randomized clinical trial. JAMA315, 36–46 (2016). CASPubMedPubMed CentralGoogle Scholar
  96. Anand, I. S. et al. Interaction between spironolactone and natriuretic peptides in patients with heart failure and preserved ejection fraction: from the TOPCAT trial. JACC Heart Fail.5, 241–252 (2017). PubMedGoogle Scholar
  97. Pfeffer, M. A. et al. Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. Circulation131, 34–42 (2015). CASPubMedGoogle Scholar
  98. de Denus, S. et al. Spironolactone metabolites in TOPCAT - new insights into regional variation. N. Engl. J. Med.376, 1690–1692 (2017). PubMedPubMed CentralGoogle Scholar
  99. Selvaraj, S. et al. Utility of the cardiovascular physical examination and impact of spironolactone in heart failure with preserved ejection fraction. Circ. Heart Fail.12, e006125 (2019). CASPubMedPubMed CentralGoogle Scholar
  100. Vaduganathan, M. et al. Prior heart failure hospitalization, clinical outcomes, and response to sacubitril/valsartan compared with valsartan in HFpEF. J. Am. Coll. Cardiol.75, 245–254 (2020). CASPubMedGoogle Scholar
  101. Mentz, R. J. et al. Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J. Am. Coll. Cardiol.64, 2281–2293 (2014). PubMedPubMed CentralGoogle Scholar
  102. Schwartzenberg, S. et al. Effects of vasodilation in heart failure with preserved or reduced ejection fraction implications of distinct pathophysiologies on response to therapy. J. Am. Coll. Cardiol.59, 442–451 (2012). PubMedGoogle Scholar
  103. Tsimploulis, A. et al. Systolic blood pressure and outcomes in patients with heart failure with preserved ejection fraction. JAMA Cardiol.3, 288–297 (2018). PubMedPubMed CentralGoogle Scholar
  104. Alehagen, U., Benson, L., Edner, M., Dahlstrom, U. & Lund, L. H. Association between use of statins and mortality in patients with heart failure and ejection fraction of ≥50. Circ. Heart Fail.8, 862–870 (2015). CASPubMedGoogle Scholar
  105. Obokata, M., Reddy, Y. N. V., Melenovsky, V., Pislaru, S. & Borlaug, B. A. Deterioration in right ventricular structure and function over time in patients with heart failure and preserved ejection fraction. Eur. Heart J.40, 689–697 (2019). PubMedGoogle Scholar
  106. Zakeri, R. et al. 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 (2014). CASPubMedGoogle Scholar
  107. Zakeri, R., Chamberlain, A. M., Roger, V. L. & Redfield, M. M. Temporal relationship and prognostic significance of atrial fibrillation in heart failure patients with preserved ejection fraction: a community-based study. Circulation128, 1085–1093 (2013). PubMedPubMed CentralGoogle Scholar
  108. Packer, D. L. et al. Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: the CABANA randomized clinical trial. JAMA321, 1261–1274 (2019). CASPubMedPubMed CentralGoogle Scholar
  109. Packer, M. Effect of catheter ablation on pre-existing abnormalities of left atrial systolic, diastolic, and neurohormonal functions in patients with chronic heart failure and atrial fibrillation. Eur. Heart J.40, 1873–1879 (2019). PubMedPubMed CentralGoogle Scholar
  110. Melenovsky, V. et al. Left atrial remodeling and function in advanced heart failure with preserved or reduced ejection fraction. Circ. Heart Fail.8, 295–303 (2015). PubMedGoogle Scholar
  111. Freed, B. H. et al. Prognostic utility and clinical significance of cardiac mechanics in heart failure with preserved ejection fraction: importance of left atrial strain. Circ. Cardiovasc. Imaging9, e003754 (2016). PubMedGoogle Scholar
  112. Reddy, Y. N. V. et al. Left atrial strain and compliance in the diagnostic evaluation of heart failure with preserved ejection fraction. Eur. J. Heart Fail.21, 891–900 (2019). PubMedGoogle Scholar
  113. Telles, F. et al. Impaired left atrial strain predicts abnormal exercise haemodynamics in heart failure with preserved ejection fraction. Eur. J. Heart Fail.21, 495–505 (2019). CASPubMedGoogle Scholar
  114. Kitzman, D. W., Brubaker, P. H., Morgan, T. M., Stewart, K. P. & Little, W. C. Exercise training in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial. Circ. Heart Fail.3, 659–667 (2010). PubMedPubMed CentralGoogle Scholar
  115. Edelmann, F. et al. 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 (2011). PubMedGoogle Scholar
  116. Haykowsky, M. J. et al. 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 (2012). PubMedPubMed CentralGoogle Scholar
  117. Hummel, S. L. et al. 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 (2013). CASPubMedPubMed CentralGoogle Scholar
  118. Reddy, Y. N. V. et al. Characterization of the obese phenotype of heart failure with preserved ejection fraction: a RELAX trial ancillary study. Mayo Clin. Proc.94, 1199–1209 (2019). PubMedGoogle Scholar
  119. Reddy, Y. N. V. et al. Adverse renal response to decongestion in the obese phenotype of heart failure with preserved ejection fraction. J. Card. Fail.26, 101–107 (2020). PubMedGoogle Scholar
  120. Miller, W. L. & Borlaug, B. A. Impact of obesity on volume status in patients with ambulatory chronic heart failure. J. Card. Fail.26, 112–117 (2020). PubMedGoogle Scholar
  121. Reddy, Y. N. V. et al. Quality of life in heart failure with preserved ejection fraction: importance of obesity, functional capacity, and physical inactivity. Eur. J. Heart Fail. https://doi.org/10.1002/ejhf.1788 (2020). ArticlePubMedGoogle Scholar
  122. Reddy, Y. N. V. et al. Hemodynamic effects of weight loss in obesity: a systematic review and meta-analysis. JACC Heart Fail.7, 678–687 (2019). PubMedGoogle Scholar
  123. Zelniker, T. A. et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet393, 31–39 (2019). CASPubMedGoogle Scholar
  124. McMurray, J. J. V. et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N. Engl. J. Med.381, 1995–2008 (2019). CASPubMedGoogle Scholar
  125. Lam, C. S. P., Chandramouli, C., Ahooja, V. & Verma, S. SGLT-2 inhibitors in heart failure: current management, unmet needs, and therapeutic prospects. J. Am. Heart Assoc.8, e013389 (2019). PubMedPubMed CentralGoogle Scholar
  126. Vaduganathan, M. et al. Sudden death in heart failure with preserved ejection fraction: a competing risks analysis from the TOPCAT trial. JACC Heart Fail.6, 653–661 (2018). PubMedGoogle Scholar
  127. Borlaug, B. A. et al. Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation114, 2138–2147 (2006). PubMedGoogle Scholar
  128. US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT02145351 (2020).
  129. Hasenfuss, G. 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. Lancet387, 1298–1304 (2016). PubMedGoogle Scholar
  130. Kaye, D. M. et al. One-year outcomes after transcatheter insertion of an interatrial shunt device for the management of heart failure with preserved ejection fraction. Circ. Heart Fail.9, e003662 (2016). PubMedPubMed CentralGoogle Scholar
  131. Feldman, T. et al. Transcatheter interatrial shunt device for the treatment of heart failure with preserved ejection fraction (REDUCE LAP-HF I [Reduce elevated left atrial pressure in patients with heart failure]): a phase 2, randomized, sham-controlled trial. Circulation137, 364–375 (2018). PubMedGoogle Scholar
  132. Shah, S. J. et al. One-year safety and clinical outcomes of a transcatheter interatrial shunt device for the treatment of heart failure with preserved ejection fraction in the reduce elevated left atrial pressure in patients with heart failure (REDUCE LAP-HF I) trial: a randomized clinical trial. JAMA Cardiol.3, 968–977 (2018). PubMedPubMed CentralGoogle Scholar
  133. Obokata, M. et al. Effects of interatrial shunt on pulmonary vascular function in heart failure with preserved ejection fraction. J. Am. Coll. Cardiol.74, 2539–2550 (2019). PubMedGoogle Scholar
  134. Borlaug, B. A. & Reddy, Y. N. V. The role of the pericardium in heart failure: implications for pathophysiology and treatment. JACC Heart Fail.7, 574–585 (2019). PubMedPubMed CentralGoogle Scholar
  135. US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT03499236 (2020).
  136. US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT03088033 (2020).
  137. Borlaug, B. A. et al. Percutaneous pericardial resection: a novel potential treatment for heart failure with preserved ejection fraction. Circ. Heart Fail.10, e003612 (2017). CASPubMedPubMed CentralGoogle Scholar
  138. Borlaug, B. A. et al. Pericardiotomy enhances left ventricular diastolic reserve with volume loading in humans. Circulation138, 2295–2297 (2018). PubMedPubMed CentralGoogle Scholar
  139. US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT03923673 (2020).
  140. Tromp, J. et al. Identifying pathophysiological mechanisms in heart failure with reduced versus preserved ejection fraction. J. Am. Coll. Cardiol.72, 1081–1090 (2018). CASPubMedGoogle Scholar
  141. Obokata, M. et al. The neurohormonal basis of pulmonary hypertension in heart failure with preserved ejection fraction. Eur. Heart J.40, 3707–3717 (2019). PubMedPubMed CentralGoogle Scholar
  142. Tromp, J. et al. Novel endotypes in heart failure: effects on guideline-directed medical therapy. Eur. Heart J.39, 4269–4276 (2018). CASPubMedGoogle Scholar
  143. Tromp, J. et al. Biomarker profiles in heart failure patients with preserved and reduced ejection fraction. J. Am. Heart Assoc.6, e003989 (2017). PubMedPubMed CentralGoogle Scholar
  144. Sanders-van Wijk, S. et al. Circulating biomarkers of distinct pathophysiological pathways in heart failure with preserved vs. reduced left ventricular ejection fraction. Eur. J. Heart Fail.17, 1006–1014 (2015). CASPubMedGoogle Scholar
  145. Tromp, J. et al. Biomarker correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction. Circulation140, 1359–1361 (2019). CASPubMedPubMed CentralGoogle Scholar
  146. Hoeper, M. M. et al. Pulmonary hypertension in heart failure with preserved ejection fraction: a plea for proper phenotyping and further research. Eur. Heart J.38, 2869–2873 (2017). PubMedGoogle Scholar
  147. Borlaug, B. A. & Obokata, M. Is it time to recognize a new phenotype? Heart failure with preserved ejection fraction with pulmonary vascular disease. Eur. Heart J.38, 2874–2878 (2017). PubMedPubMed CentralGoogle Scholar
  148. Gorter, T. M., Obokata, M., Reddy, Y. N. V., Melenovsky, V. & Borlaug, B. A. Exercise unmasks distinct pathophysiologic features in heart failure with preserved ejection fraction and pulmonary vascular disease. Eur. Heart J.39, 2825–2835 (2018). PubMedPubMed CentralGoogle Scholar
  149. Borlaug, B. A., Lam, C. S., Roger, V. L., Rodeheffer, R. J. & Redfield, M. M. Contractility and ventricular systolic stiffening in hypertensive heart disease insights into the pathogenesis of heart failure with preserved ejection fraction. J. Am. Coll. Cardiol.54, 410–418 (2009). PubMedPubMed CentralGoogle Scholar
  150. Shah, A. M. et al. Prognostic importance of impaired systolic function in heart failure with preserved ejection fraction and the impact of spironolactone. Circulation132, 402–414 (2015). CASPubMedPubMed CentralGoogle Scholar
  151. Melenovsky, V., Hwang, S. J., Lin, G., Redfield, M. M. & Borlaug, B. A. Right heart dysfunction in heart failure with preserved ejection fraction. Eur. Heart J.35, 3452–3462 (2014). CASPubMedPubMed CentralGoogle Scholar
  152. Sabbah, M. S. et al. Obese-inflammatory phenotypes in heart failure with preserved ejection fraction. J. Am. Coll. Cardiol.73 (Suppl. 1), 661 (2019). Google Scholar
  153. Van Tassell, B. W. et al. IL-1 blockade in patients with heart failure with preserved ejection fraction. Circ. Heart Fail.11, e005036 (2018). PubMedPubMed CentralGoogle Scholar
  154. Houstis, N. E. et al. Exercise intolerance in heart failure with preserved ejection fraction: diagnosing and ranking its causes using personalized O2 pathway analysis. Circulation137, 148–161 (2018). PubMedGoogle Scholar
  155. Fayyaz, A. U. et al. Global pulmonary vascular remodeling in pulmonary hypertension associated with heart failure and preserved or reduced ejection fraction. Circulation137, 1796–1810 (2018). PubMedGoogle Scholar
  156. Molina, A. J. et al. 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 (2016). PubMedPubMed CentralGoogle Scholar
  157. Rommel, K. P. et al. Extracellular volume fraction for characterization of patients with heart failure and preserved ejection fraction. J. Am. Coll. Cardiol.67, 1815–1825 (2016). PubMedGoogle Scholar
  158. Yap, J. et al. Association of diabetes mellitus on cardiac remodeling, quality of life, and clinical outcomes in heart failure with reduced and preserved ejection fraction. J. Am. Heart Assoc.8, e013114 (2019). PubMedPubMed CentralGoogle Scholar
  159. Shah, S. J. et al. Phenomapping for novel classification of heart failure with preserved ejection fraction. Circulation131, 269–279 (2015). PubMedGoogle Scholar
  160. Kao, D. P. et al. Characterization of subgroups of heart failure patients with preserved ejection fraction with possible implications for prognosis and treatment response. Eur. J. Heart Fail.17, 925–935 (2015). PubMedGoogle Scholar
  161. Segar, M. W. et al. Phenomapping of patients with heart failure with preserved ejection fraction using machine learning-based unsupervised cluster analysis. Eur. J. Heart Fail.22, 148–158 (2020). CASPubMedGoogle Scholar
  162. Senni, M., Caravita, S. & Paulus, W. J. Do existing definitions identify subgroup phenotypes or reflect the natural history of heart failure with preserved ejection fraction? Circulation140, 366–369 (2019). PubMedGoogle Scholar
  163. Andersson, C. et al. Risk factor-based subphenotyping of heart failure in the community. PLoS One14, e0222886 (2019). CASPubMedPubMed CentralGoogle Scholar
  164. Borlaug, B. A., Melenovsky, V. & Koepp, K. E. Inhaled sodium nitrite improves rest and exercise hemodynamics in heart failure with preserved ejection fraction. Circ. Res.119, 880–886 (2016). CASPubMedPubMed CentralGoogle Scholar
  165. Borlaug, B. A., Koepp, K. E. & Melenovsky, V. Sodium nitrite improves exercise hemodynamics and ventricular performance in heart failure with preserved ejection fraction. J. Am. Coll. Cardiol.66, 1672–1682 (2015). CASPubMedGoogle Scholar
  166. Reddy, Y. N. V. et al. The β-adrenergic agonist albuterol improves pulmonary vascular reserve in heart failure with preserved ejection fraction. Circ. Res.124, 306–314 (2019). CASPubMedPubMed CentralGoogle Scholar
  167. Maurer, M. S. et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N. Engl. J. Med.379, 1007–1016 (2018). CASPubMedGoogle Scholar
  168. Gonzalez-Lopez, E. et al. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur. Heart J.36, 2585–2594 (2015). CASPubMedGoogle Scholar
  169. Mohammed, S. F. et al. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail.2, 113–122 (2014). PubMedPubMed CentralGoogle Scholar

Acknowledgements

The author is supported by grants RO1 HL128526 and UO1 HL125205.