Clinical Impact of Diagnostic Delay by Red Flags Assessment in Transthyretin Amyloid Cardiomyopathy

Background: Diagnostic delay remains a major barrier to timely treatment in transthyretin amyloid cardiomyopathy (ATTR-CM). Although current approaches describe disease status at diagnosis, they do not capture the temporal evolution of disease manifestations preceding clinical recognition. The prognostic relevance of prediagnostic red flags and their timing remains poorly defined. Objectives: The objectives of the study were to characterize prediagnostic trajectories of ATTR-CM, quantify the median time from amyloidosis red-flag onset to diagnosis, and evaluate its association with survival. Methods: We retrospectively included consecutive patients with ATTR-CM from 2 referral centers in Italy. Red flags before diagnosis were assessed across cardiac, neurological, orthopedic, and renal domains. For each patient, the median time from red-flag onset to diagnosis was calculated. The primary outcome was all-cause mortality. The secondary outcome was cardiovascular (CV) mortality. Results: A total of 208 patients were included (median age 80 years; 83.7% male; 96.6% wild-type transthyretin amyloidosis). Red flags frequently emerged several years before diagnosis, with orthopedic and neurologic manifestations representing the earliest signals. In this contemporary cohort, diagnostic pathways were heterogeneous but converged mainly through cardiology referral (74.5%). A longer median time from red-flag onset to diagnosis was independently associated with a higher risk of all-cause mortality (adjusted HR: 1.07; 95% CI: 1.01-1.14; P = 0.049) and CV mortality (adjusted HR: 1.10; 95% CI: 1.02-1.18; P = 0.025). Conclusions: The median time from red-flag onset to ATTR-CM diagnosis is an independent predictor of all-cause and CV mortality. Enhancing early identification of noncardiac red flags across specialties may shorten the diagnostic pathway, facilitate earlier initiation of disease-modifying therapy, and ultimately improve clinical outcomes.