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ABSTRACT
Introduction
Heart failure with preserved ejection fraction (HFpEF) is a disease with a high prevalence. Accounting for more than 50% of all heart failure cases, it carries a significant mortality. There is a lack of therapeutic options that show improvement in morbidity and mortality. Certain novel therapies have shown a decrease in heart failure hospitalizations; however, this beneficial effect was more pronounced for heart failure patients with mildly reduced ejection fraction (EF).
Areas covered
This review summarizes the pathophysiology of the disease to help elucidate the differences between heart failure with reduced ejection fraction (HFrEF), and HFpEF, which could explain why therapies are successful in one (rather than the other). This review focuses on non-standardized nomenclature across major trials, the challenges of finding a therapeutic agent for such a heterogeneous population, and identification of specific phenotypes that have different outcomes and could be a target for future therapies.
Expert opinion
Lack of standardized diagnostic criteria, associated with population heterogeneity, might explain why trials have failed to improve outcomes for patients with HFpEF. Standardizing phenotypes, recapitulating these phenotypes in animal models, and understanding the mechanisms of the disease at the molecular level could be the first steps in identifying promising therapeutic options.
Article highlights
HFpEF definition, according to the range of EF or other structural variables, varies across major clinical trials. Lack of standardization of nomenclature can create a more heterogenous group of patients that often results in different outcomes.
HF with mildly reduced EF (HFmrEF) is probably a form of disease progression from HFpEF to HFrEF. Drugs that are beneficial in HFrEF have shown a greater beneficial effect in patients with HFmrEF compared to patients with HFpEF.
Depending on the presence of other co-morbidities, HFpEF can have different phenotypes with different responses to certain drugs and different outcomes.
Pathologies like amyloidosis, for which there is a specific therapy, can sometimes be underdiagnosed and classified as HFpEF, resulting in lack of response to HFpEF therapies.
Targeting pathophysiologic mechanisms of HFpEF is challenging because of lack of animal models that recapitulate complex HFpEF phenotypes.
Recent trials have shown that certain drugs can decrease the number of HF hospitalizations, but they have not shown to provide a mortality benefit.
This box summarizes key points contained in the article.
Declaration of interest
G. Lanier is on the speaker’s bureau for Bayer and United Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
One referee is a consultant for Bayer, Astra Zeenca, Boehringer Ingelheim/Lilly, Merck, and has stock options in Phasebio SC Pharmaceuticals, SQinnovations, G3 pharmaceuticals, Vifor, KBP Pharmaceuticals, Cereno scientific, Proton Intel, and Brainstorm Medical.
They also have a US patent for site-specific delivery of eplerenone to the myocardium and a US patent pending for histone-modulating agents for the treatment and protection of organ injury. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose