Hidden overlap between heart failure with preserved ejection fraction and transthyretin amyloid cardiomyopathy: Why it matters and how to avoid missing it.

Transthyretin cardiac amyloidosis (ATTR-CM) is increasingly recognized as a treatable cause of heart failure, while heart failure with preserved ejection fraction (HFpEF) has become one of the most common and heterogeneous heart failure syndromes worldwide. Growing evidence shows that a substantial proportion of patients diagnosed with HFpEF actually harbor unrecognized ATTR-CM. Missing this diagnosis may limit the effectiveness of HFpEF therapies and delay initiation of disease-modifying treatment. Screening studies consistently demonstrate that ATTR-CM represents an important subset of HFpEF, particularly in individuals with increased left ventricular wall thickness, elevated natriuretic peptides, or unexplained conduction abnormalities. Although HFpEF and ATTR-CM share significant clinical overlap, several reproducible red-flags such as discordance between electrocardiographic voltages and wall thickness, pseudo infarct patterns, carpal tunnel syndrome, progressive troponin elevation, and apical sparing on strain imaging provide important early diagnostic clues. These features, together with emerging scoring tools, help identify patients at increased risk. In addition, bone scintigraphy has transformed the diagnostic pathway by enabling noninvasive confirmation of ATTR-CM in the absence of monoclonal protein. As disease-modifying agents such as tafamidis, acoramidis, and vutrisiran become widely available, early recognition is increasingly essential. This review synthesizes epidemiologic data on the prevalence of ATTR-CM among HFpEF cohorts, highlights key diagnostic pitfalls, and outlines practical strategies to facilitate timely detection. The aim is to support clinicians managing HFpEF by proposing a pragmatic, red-flag based screening framework that reduces missed diagnoses and enables appropriate initiation of disease-modifying therapy.