Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Evaluation and management of heart failure with preserved ejection fraction

Abstract

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.

Key points

  • Heart failure with preserved ejection fraction (HFpEF) has become the most common form of heart failure, associated with substantial morbidity and mortality.

  • HFpEF is defined haemodynamically as a clinical syndrome associated with a lack of capacity of the heart to pump blood adequately without the requirement for elevated cardiac filling pressures.

  • Typical HFpEF must be distinguished from other causes of the clinical syndrome of heart failure, which are treated differently.

  • Diagnosis is challenging and requires the demonstration of objective evidence of congestion or poor cardiac output using assessment of clinical history, physical examination, natriuretic peptide testing, echocardiography data and invasive exercise testing.

  • To date, most clinical trials on the efficacy of treatments for HFpEF have produced neutral results, but strong evidence supports the use of diuretics, mineralocorticoid receptor antagonists and exercise training as effective therapies.

  • Ongoing studies are evaluating the utility of more rigorous pathophysiological characterization of HFpEF into distinct phenotypes to improve the matching of individualized treatments to patients who are most likely to respond favourably.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Diagnostic approach for HFpEF.
Fig. 2: Evidence base for the treatment of HFpEF.
Fig. 3: Phenotyping in patients with HFpEF.

References

  1. 1.

    Pfeffer, M. A., Shah, A. M. & Borlaug, B. A. Heart failure with preserved ejection fraction in perspective. Circ. Res. 124, 1598–1617 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Shah, A. M. et al. Heart failure stages among older adults in the community: the Atherosclerosis Risk in Communities Study. Circulation 135, 224–240 (2017).

    PubMed  PubMed Central  Google Scholar 

  3. 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).

    PubMed  PubMed Central  Google Scholar 

  4. 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).

    PubMed  PubMed Central  Google Scholar 

  5. 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. JAMA 315, 2284–2291 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Borlaug, B. A. & Redfield, M. M. Diastolic and systolic heart failure are distinct phenotypes within the heart failure spectrum. Circulation 123, 2006–2013 (2011).

    PubMed  PubMed Central  Google Scholar 

  7. 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).

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Pandey, A. et al. Physical activity, fitness, and obesity in heart failure with preserved ejection fraction. JACC Heart Fail. 6, 975–982 (2018).

    PubMed  PubMed Central  Google Scholar 

  9. 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).

    PubMed  PubMed Central  Google Scholar 

  10. 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. Circulation 135, 825–838 (2017).

    PubMed  PubMed Central  Google Scholar 

  11. 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. Circulation 138, 861–870 (2018).

    PubMed  PubMed Central  Google Scholar 

  12. 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).

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Shah, S. J. et al. Phenotype-specific treatment of heart failure with preserved ejection fraction: a multiorgan roadmap. Circulation 134, 73–90 (2016).

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Klainer, L. M., Gibson, T. C. & White, K. L. The epidemiology of cardiac failure. J. Chronic Dis. 18, 797–814 (1965).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Ho, J. E. et al. Differential clinical profiles, exercise responses and outcomes associated with existing HFpEF definitions. Circulation 140, 353–365 (2019).

    PubMed  PubMed Central  Google Scholar 

  17. 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).

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Denolin, H., Kuhn, H., Krayenbuehl, H. P., Loogen, F. & Reale, A. The definition of heart failure. Eur. Heart J. 4, 445–448 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 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).

    Google Scholar 

  20. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Butler, J., Anker, S. D. & Packer, M. Redefining heart failure with a reduced ejection fraction. JAMA 322, 1761–1762 (2019).

    Google Scholar 

  23. 23.

    Solomon, S. D. et al. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N. Engl. J. Med. 381, 1609–1620 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 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. Circulation 136, e137–e161 (2017).

    PubMed  PubMed Central  Google Scholar 

  25. 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).

    PubMed  PubMed Central  Google Scholar 

  26. 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).

    PubMed  PubMed Central  Google Scholar 

  27. 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).

    PubMed  PubMed Central  Google Scholar 

  28. 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).

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    Obokata, M. et al. Hemodynamics, dyspnea, and pulmonary reserve in heart failure with preserved ejection fraction. Eur. Heart J. 39, 2810–2821 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 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).

    PubMed  PubMed Central  Google Scholar 

  31. 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).

    PubMed  PubMed Central  Google Scholar 

  32. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 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).

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Luscher, T. F. Lumpers and splitters: the bumpy road to precision medicine. Eur. Heart J. 40, 3292–3296 (2019).

    PubMed  PubMed Central  Google Scholar 

  35. 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).

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Eleid, M. F., Nishimura, R. A., Sorajja, P. & Borlaug, B. A. Systemic hypertension in low-gradient severe aortic stenosis with preserved ejection fraction. Circulation 128, 1349–1353 (2013).

    PubMed  PubMed Central  Google Scholar 

  37. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  38. 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. Imaging 13, 245–257 (2019).

    PubMed  PubMed Central  Google Scholar 

  39. 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? QJM 90, 335–339 (1997).

    CAS  Google Scholar 

  40. 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).

    PubMed  PubMed Central  Google Scholar 

  41. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Mohammed, S. F. et al. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation 131, 550–559 (2015).

    PubMed  PubMed Central  Google Scholar 

  44. 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).

    PubMed  PubMed Central  Google Scholar 

  45. 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. Circulation 137, 534–535 (2018).

    PubMed  PubMed Central  Google Scholar 

  46. 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. Circulation 136, 6–19 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 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).

    PubMed  PubMed Central  Google Scholar 

  48. 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).

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Stevenson, L. W. & Perloff, J. K. The limited reliability of physical signs for estimating hemodynamics in chronic heart failure. JAMA 261, 884–888 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 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).

    PubMed  PubMed Central  Google Scholar 

  51. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 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).

    PubMed  PubMed Central  Google Scholar 

  55. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Wang, T. J. et al. Impact of obesity on plasma natriuretic peptide levels. Circulation 109, 594–600 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Andersen, M. J. & Borlaug, B. A. Invasive hemodynamic characterization of heart failure with preserved ejection fraction. Heart Fail. Clin. 10, 435–444 (2014).

    PubMed  PubMed Central  Google Scholar 

  58. 58.

    Borlaug, B. A. et al. Diastolic relaxation and compliance reserve during dynamic exercise in heart failure with preserved ejection fraction. Heart 97, 964–969 (2011).

    PubMed  PubMed Central  Google Scholar 

  59. 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).

    PubMed  PubMed Central  Google Scholar 

  60. 60.

    Maron, B. A., Cockrill, B. A., Waxman, A. B. & Systrom, D. M. The invasive cardiopulmonary exercise test. Circulation 127, 1157–1164 (2013).

    PubMed  PubMed Central  Google Scholar 

  61. 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).

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Fujimoto, N. et al. Hemodynamic responses to rapid saline loading: the impact of age, sex, and heart failure. Circulation 127, 55–62 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Guazzi, M. et al. 2016 Focused update: clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations. Circulation 133, e694–e711 (2016).

    PubMed  PubMed Central  Google Scholar 

  64. 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. Imaging 17, 1191–1229 (2016).

    PubMed  PubMed Central  Google Scholar 

  65. 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). Heart 96, 1024–1028 (2010).

    PubMed  PubMed Central  Google Scholar 

  66. 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).

    PubMed  PubMed Central  Google Scholar 

  67. 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).

    PubMed  PubMed Central  Google Scholar 

  68. 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).

    PubMed  PubMed Central  Google Scholar 

  69. 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).

    PubMed  PubMed Central  Google Scholar 

  70. 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).

    PubMed  PubMed Central  Google Scholar 

  71. 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).

    PubMed  PubMed Central  Google Scholar 

  72. 72.

    Paulus, W. J. H2FPEF score. Circulation 138, 871–873 (2018).

    PubMed  PubMed Central  Google Scholar 

  73. 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. Circulation 139, 1851–1853 (2019).

    PubMed  PubMed Central  Google Scholar 

  74. 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).

    PubMed  PubMed Central  Google Scholar 

  75. 75.

    Sepehrvand, N. et al. External validation of the H2F-PEF model in diagnosing patients with heart failure and preserved ejection fraction. Circulation 139, 2377–2379 (2019).

    PubMed  PubMed Central  Google Scholar 

  76. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Massie, B. M. et al. Irbesartan in patients with heart failure and preserved ejection fraction. N. Engl. J. Med. 359, 2456–2467 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 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. Lancet 380, 1387–1395 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 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. JAMA 309, 781–791 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 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. JAMA 309, 1268–1277 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 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. JAMA 320, 1764–1773 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Ahmed, A. et al. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial. Circulation 114, 397–403 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 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. JAMA 321, 2101–2112 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Abraham, W. T. et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 377, 658–666 (2011).

    PubMed  PubMed Central  Google Scholar 

  93. 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).

    PubMed  PubMed Central  Google Scholar 

  94. 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).

    PubMed  PubMed Central  Google Scholar 

  95. 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. JAMA 315, 36–46 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 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).

    PubMed  PubMed Central  Google Scholar 

  97. 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. Circulation 131, 34–42 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    de Denus, S. et al. Spironolactone metabolites in TOPCAT - new insights into regional variation. N. Engl. J. Med. 376, 1690–1692 (2017).

    PubMed  PubMed Central  Google Scholar 

  99. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 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).

    PubMed  PubMed Central  Google Scholar 

  102. 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).

    PubMed  PubMed Central  Google Scholar 

  103. 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).

    PubMed  PubMed Central  Google Scholar 

  104. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 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).

    PubMed  PubMed Central  Google Scholar 

  106. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 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. Circulation 128, 1085–1093 (2013).

    PubMed  PubMed Central  Google Scholar 

  108. 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. JAMA 321, 1261–1274 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 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).

    PubMed  PubMed Central  Google Scholar 

  110. 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).

    PubMed  PubMed Central  Google Scholar 

  111. 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. Imaging 9, e003754 (2016).

    PubMed  PubMed Central  Google Scholar 

  112. 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).

    PubMed  PubMed Central  Google Scholar 

  113. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 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).

    PubMed  PubMed Central  Google Scholar 

  115. 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).

    PubMed  PubMed Central  Google Scholar 

  116. 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).

    PubMed  PubMed Central  Google Scholar 

  117. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 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).

    PubMed  PubMed Central  Google Scholar 

  119. 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).

    PubMed  PubMed Central  Google Scholar 

  120. 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).

    PubMed  PubMed Central  Google Scholar 

  121. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  122. 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).

    PubMed  PubMed Central  Google Scholar 

  123. 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. Lancet 393, 31–39 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 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).

    PubMed  PubMed Central  Google Scholar 

  126. 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).

    PubMed  PubMed Central  Google Scholar 

  127. 127.

    Borlaug, B. A. et al. Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation 114, 2138–2147 (2006).

    PubMed  PubMed Central  Google Scholar 

  128. 128.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02145351 (2020).

  129. 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. Lancet 387, 1298–1304 (2016).

    PubMed  PubMed Central  Google Scholar 

  130. 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).

    PubMed  PubMed Central  Google Scholar 

  131. 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. Circulation 137, 364–375 (2018).

    PubMed  PubMed Central  Google Scholar 

  132. 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).

    PubMed  PubMed Central  Google Scholar 

  133. 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).

    PubMed  PubMed Central  Google Scholar 

  134. 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).

    PubMed  PubMed Central  Google Scholar 

  135. 135.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03499236 (2020).

  136. 136.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03088033 (2020).

  137. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Borlaug, B. A. et al. Pericardiotomy enhances left ventricular diastolic reserve with volume loading in humans. Circulation 138, 2295–2297 (2018).

    PubMed  PubMed Central  Google Scholar 

  139. 139.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03923673 (2020).

  140. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 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).

    PubMed  PubMed Central  Google Scholar 

  142. 142.

    Tromp, J. et al. Novel endotypes in heart failure: effects on guideline-directed medical therapy. Eur. Heart J. 39, 4269–4276 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Tromp, J. et al. Biomarker profiles in heart failure patients with preserved and reduced ejection fraction. J. Am. Heart Assoc. 6, e003989 (2017).

    PubMed  PubMed Central  Google Scholar 

  144. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Tromp, J. et al. Biomarker correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction. Circulation 140, 1359–1361 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 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).

    PubMed  PubMed Central  Google Scholar 

  147. 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).

    PubMed  PubMed Central  Google Scholar 

  148. 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).

    PubMed  PubMed Central  Google Scholar 

  149. 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).

    PubMed  PubMed Central  Google Scholar 

  150. 150.

    Shah, A. M. et al. Prognostic importance of impaired systolic function in heart failure with preserved ejection fraction and the impact of spironolactone. Circulation 132, 402–414 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 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. 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).

    PubMed  PubMed Central  Google Scholar 

  154. 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. Circulation 137, 148–161 (2018).

    PubMed  PubMed Central  Google Scholar 

  155. 155.

    Fayyaz, A. U. et al. Global pulmonary vascular remodeling in pulmonary hypertension associated with heart failure and preserved or reduced ejection fraction. Circulation 137, 1796–1810 (2018).

    PubMed  PubMed Central  Google Scholar 

  156. 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).

    PubMed  PubMed Central  Google Scholar 

  157. 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).

    PubMed  PubMed Central  Google Scholar 

  158. 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).

    PubMed  PubMed Central  Google Scholar 

  159. 159.

    Shah, S. J. et al. Phenomapping for novel classification of heart failure with preserved ejection fraction. Circulation 131, 269–279 (2015).

    PubMed  PubMed Central  Google Scholar 

  160. 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).

    PubMed  PubMed Central  Google Scholar 

  161. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 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? Circulation 140, 366–369 (2019).

    PubMed  PubMed Central  Google Scholar 

  163. 163.

    Andersson, C. et al. Risk factor-based subphenotyping of heart failure in the community. PLoS One 14, e0222886 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Maurer, M. S. et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N. Engl. J. Med. 379, 1007–1016 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 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).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

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

Author information

Affiliations

Authors

Corresponding author

Correspondence to Barry A. Borlaug.

Ethics declarations

Competing interests

The author declares no competing interests.

Additional information

Peer review information

Nature Reviews Cardiology thanks A. Desai, M. Metra and W. Paulus for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Borlaug, B.A. Evaluation and management of heart failure with preserved ejection fraction. Nat Rev Cardiol 17, 559–573 (2020). https://doi.org/10.1038/s41569-020-0363-2

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing