Genetic causes of heart failure with preserved ejection fraction: emerging pharmacological treatments.

Heart failure with preserved ejection fraction (HFpEF) is a major driver of cardiac morbidity and mortality in developed countries, due to ageing populations and the increasing prevalence of comorbidities. While heart failure with reduced ejection fraction is dominated by left ventricular impairment, HFpEF results from a complex interplay of cardiac remodelling, peripheral circulation, and concomitant features including age, hypertension, obesity, and diabetes. In an important subset, however, HFpEF is subtended by specific diseases of the myocardium that are genetically determined, have distinct pathophysiology, and are increasingly amenable to targeted, innovative treatments. While each of these conditions is rare, they collectively represent a relevant subset within HFpEF cohorts, and their prompt recognition has major consequences for clinical practice, as access to dedicated, disease-specific treatments may radically change the quality of life and outcome. Furthermore, response to standard heart failure treatment will generally be modest for these individuals, whose inclusion in registries and trials may dilute the perceived efficacy of treatments targeting mainstream HFpEF. Finally, a better understanding of the molecular underpinnings of monogenic myocardial disease may help identify therapeutic targets and develop innovative treatments for selected HFpEF phenotypes of broader epidemiological relevance. The field of genetic cardiomyopathies is undergoing rapid transformation due to recent, groundbreaking advances in drug development, and deserves greater awareness within the heart failure community. The present review addressed existing and developing therapies for genetic causes of HFpEF, including hypertrophic cardiomyopathy, cardiac amyloidosis, and storage diseases, discussing their potential impact on management and their broader implications for our understanding of HFpEF at large.
Competing Interests: Conflict of interest: I.O. is a consultant for Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Menarini International, Rocket Pharma, and Tenaya and has received research grants from BMS, Cytokinetics, Sanofi Genzyme, Shire Takeda, Amicus, Menarini International, Boston Scientific, Menarini International, and Bayer. J.E.U. serves as the Chair of a DMC for Cytokinetics and is a consultant to Cardurion, Bayer, Reprieve, Sequana, and Alleviant Medical. M.P. has received advisory board honoraria Myers Squibb and speaker fees from Sanofi Genzyme, Shire Takeda, Amicus Therapeutics, Pfizer, and Bristol Myers Squibb. C.R. has served as a speaker and has received consulting fees from Pfizer, Alnylam, and Eidos and has received research grants from Pfizer.
(© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)