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The clinical syndrome comprised of heart failure symptoms but with a left ventricular ejection fraction that is not diminished, e. It remains among the most challenging of clinical syndromes for the practicing clinician and scientist alike, with a multitude of proposed mechanisms involving the heart and other organs and complex interplay with common co-morbidities. Importantly, its morbidity and mortality is on par with heart failure and a reduced ejection fraction, and as the list of failed treatments continues to grow, HFpEF clearly represents a major unmet medical need.

The field is greatly in need of a more unified approach to its definition and view of the syndrome that engages integrative and reserve pathophysiology beyond that related to the heart alone. We need to reflect on prior treatment failures and the message this is providing, and re-direct our approaches likely with a paradigm shift in how the disease is viewed. Success will require interactions between clinicians, translational researchers, and basic physiologists.

Here, we review recent translational and clinical research into HFpEF, give perspectives on its evolving demographics and epidemiology, the role of multi-organ deficiencies, potential mechanisms that involve the heart and other organs, clinical trials, and future directions. Heart failure HF is a clinical syndrome characterized by breathlessness dyspnea at normal or low-level exertion, fatigue, and fluid retention. Given this, it is perhaps not surprising that we have yet to find an evidence-based HFpEF therapy beyond diuretics for fluid overload, and conventional treatments for co-morbidities.

In this article, we provide an overview of HFpEF for both the clinical and basic research scientist that includes a brief examination of its diagnostic criteria and evolving epidemiology, a summary of proposed mechanisms involving the heart and other organs, a discussion of our valiant but unsuccessful prior efforts to develop an effective therapy, and a review of newer potential approaches. HFpEF is currently the accepted form and we stick to that here.

The companion review in this issue by Loffredo et al. Many of these changes are thought to be relevant to HFpEF, though direct evidence remains limited for most of them. In this presentation, we focus on the major human data findings.

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Cameron Sinclair: A call for open-source architecture

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