Current gaps in HFpEF trials: Time to reconsider patients' selection and to target phenotypes.

Heart Failure with preserved Ejection Fraction (HFpEF) is an increasingly prevalent clinical condition associated with cardiovascular aging, characterized by different pathophysiological mechanisms and poor outcomes. In this manuscript, we analysed the main differences in terms of updated diagnostic criteria and patients' selection in the most recent HFpEF trials. Recent algorithm purposed for HFpEF diagnosis, does not reflect common criteria adopted in clinical trials. Patients included in the larger studies experienced different characteristics in terms of clinical presentation and echocardiographic features. Current concerns complicate results interpretation and could hypothesize different stages of disease progression, rather than different cardiac phenotypes. Both the lack of diagnostic standardization and the population heterogeneity, might explain why trials investigating the effects of different therapeutic interventions failed to show improved outcomes for patients with HFpEF. Accordingly, we propose to exceed current view mainly based on the morphological adaptations evaluating patients' characterisation, their cardiovascular risk, associated diseases, and structural features consistent with disease progression. Detailed clinical, imaging and biological characterisation of this population, along with the identification of mechanisms linked with disease progression and prognosis, would allow for tailored treatments and provide important mechanistic insights into the complex HFpEF pathophysiology.