Heart Failure with Preserved Ejection Fraction in the Elderly: Basic Mechanisms and Clinical Considerations

Heart failure (HF) with preserved ejection fraction (HFpEF) refers to a clinical condition in which the signs of HF, such as pulmonary congestion, peripheral edema and increased natriuretic-peptide levels, are present despite normal ejection-fractions and the absence of other causes (e.g. pericardial disease). The ejection-fraction cutoff for the definition of HFpEF has varied in the past, but recent society guidelines have settled on a consensus of 50%. HFpEF is particularly common in the elderly. The aim of this narrative review is to summarize the available literature regarding HFpEF in the elderly in terms of evidence for the age-dependence, specific clinical features and underlying mechanisms. In the clinical arena, we review the epidemiology, discuss distinct clinical phenotypes typically seen in the elderly, the importance of frailty, the role of biomarkers and the role of medical therapies (including sodium-glucose cotransport protein 2 (SGLT2)-inhibitors, renin-angiotensin-aldosterone system (RAAS) blockers, angiotensin-receptor/neprilysin inhibitors, diuretics and beta-adrenergic receptor blockers). We then go on to discuss the basic mechanisms implicated in HFpEF, including cellular senescence, fibrosis, inflammation, mitochondrial dysfunction, enhanced production of reactive-oxygen species, abnormal cellular calcium handling, changes in microRNA signaling, insulin resistance, and sex-hormone changes. Finally, we review knowledge gaps and promising areas of future investigation. Improved understanding of the specific clinical manifestations of HFpEF in the elderly and of the fundamental mechanisms contributing to the age-related risk of HFpEF promises to lead to novel diagnostic and treatment approaches that will improve outcomes for this common cardiac disorder in a vulnerable population.