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Peer-reviewedCC BY 4.0JACC: Advances

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

  • Manuela Iseppi1
  • Michele Moretti1
  • Teresa Maria Capovilla2
  • Elisa Zaro3,4
  • Giulia Barbati5
  • Eleonora Bonvicini1
  • Fabiola Morat1
  • Massimiliano Marini1
  • Roberto Bonmassari1
  • Gianfranco Sinagra3,4
  • Marco Merlo3,4
  • Aldostefano Porcari3,4
5 affiliations
  1. 1Division of Cardiology, Ospedale Santa Chiara, Azienda Sanitaria Universitaria Integrata del Trentino, Trento, Italy
  2. 2Division of Cardiology, Ospedale Santa Maria Del Carmine, Azienda Sanitaria Universitaria Integrata del Trentino, Rovereto, Italy
  3. 3Center for Diagnosis and Treatment of Cardiomyopathies, Cardiovascular Department, Azienda Sanitaria Universitaria Giuliano-Isontina, University of Trieste, Trieste, Italy
  4. 4European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart, Trieste, Italy
  5. 5Biostatistics Unit, Department of Medical Sciences, University of Trieste, Trieste, Italy
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{iseppi2026clinical,
  title = {{Clinical Impact of Diagnostic Delay by Red Flags Assessment in Transthyretin Amyloid Cardiomyopathy}},
  author = {Manuela Iseppi and Michele Moretti and Teresa Maria Capovilla and Elisa Zaro and Giulia Barbati and Eleonora Bonvicini and Fabiola Morat and Massimiliano Marini and Roberto Bonmassari and Gianfranco Sinagra and Marco Merlo and Aldostefano Porcari},
  journal = {JACC: Advances},
  year = {2026},
  month = sep,
  doi = {10.1016/j.jacadv.2026.103200},
  url = {https://doi.org/10.1016/j.jacadv.2026.103200},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Clinical Impact of Diagnostic Delay by Red Flags Assessment in Transthyretin Amyloid Cardiomyopathy
AU  - Manuela Iseppi
AU  - Michele Moretti
AU  - Teresa Maria Capovilla
AU  - Elisa Zaro
AU  - Giulia Barbati
AU  - Eleonora Bonvicini
AU  - Fabiola Morat
AU  - Massimiliano Marini
AU  - Roberto Bonmassari
AU  - Gianfranco Sinagra
AU  - Marco Merlo
AU  - Aldostefano Porcari
PY  - 2026
DA  - 2026/09/09
JO  - JACC: Advances
DO  - 10.1016/j.jacadv.2026.103200
UR  - https://doi.org/10.1016/j.jacadv.2026.103200
AB  - 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.
SN  - 2772-963X
ER  -