Notable discoveries in the pathophysiology and treatment of heart failure with preserved ejection fraction (HFpEF) now position this increasingly prevalent phenotype of heart failure from enigmatic to clinically actionable with progressively better outcome expectations. Yet, the condition remains syndromic, requiring keen diagnostic acumen to avoid both mimicry and obfuscation.

HFpEF is frequently a comorbidity for other conditions, eg, aortic stenosis and amyloidosis, or misattributed to chronic obstructive pulmonary disease. Without an elevated awareness, this important condition goes unaddressed and evidence-based therapy otherwise known to be beneficial for the indicated disease is not considered. Overlooking HFpEF is especially problematic in contemporary therapy given the numerous beneficial medical therapies, including nonsteroidal mineralocorticoid receptor antagonists (finerenone), sodium glucose cotransporter inhibitors, and both glucagon-like peptide 1 receptor agonists (GLP1Ra), and the dual agonist therapies targeting GLP-1Ra and gastric inhibitory polypeptide receptors (eg, semaglutide and tirzapatide).