Heart failure with preserved ejection fraction (HFPEF) is responsible for half the disease burden of heart failure worldwide, yet there is still much we do not know about this syndrome. Its pathophysiology is classically attributed to diastolic dysfunction (thus “diastolic heart failure”), but accumulating evidence suggests that heterogeneous mechanisms contribute to HFPEF, including systolic abnormalities. Importantly, there remains no proven therapy for HFPEF. To date, clinical trials of neurohormonal blockade have failed to improve outcomes in HFPEF, despite their proven benefits in heart failure with reduced ejection fraction (HFREF). Therefore, it is still an urgent need to better understand the pathophysiology of HFPEF and identify new therapeutic targets. Such potential targets include the myocyte protein titin, intracellular calcium regulation, as well as modulation of the extracellular matrix. We also need to understand why the previous large trials have failed in HFPEF. Are we studying the right patients? How do we best diagnose this syndrome? Are we assessing the appropriate outcomes? Causes of mortality and morbidity differ between HFPEF and HFREF, and the high burden of comorbidities in HFPEF may contribute to noncardiovascular outcomes. Newer therapeutic approaches should be developed with these considerations in mind.

In conclusion, HFPEF is still an enigma. New pathophysiological concepts, improved diagnostic strategies, and a better understanding of patient factors are needed to generate new therapeutic options in the future.