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Multicenter Study
. 2025 May 1;10(5):437-445.
doi: 10.1001/jamacardio.2024.5221.

Clinical Phenotype and Prognosis of Asymptomatic Patients With Transthyretin Cardiac Amyloid Infiltration

Aldostefano Porcari  1   2   3 , Yousuf Razvi  1 , Francesco Cappelli  4   5 , Christian Nitsche  6 , Matteo Serenelli  7 , Simone Longhi  3   8 , Giulio Sinigiani  9 , Alberto Cipriani  9 , Alberto Aimo  10   11 , Daniela Tomasoni  12 , Mattia Zampieri  4   5 , Anna Cantone  7 , Valentina Allegro  2   3 , Giuseppe Vergaro  10   11 , Ahmad Masri  13 , Marcus Urey  14 , Adam Ioannou  1 , Aviva Petrie  1 , Navid Noory  15 , Finn Gustafsson  15 , Michael Poledniczek  6 , Michele Emdin  10   11 , Marco Metra  12 , Gianfranco Sinagra  2   3 , Ana Martinez-Naharro  1 , Ashutosh D Wechalekar  1 , Helen Lachman  1 , Carol Whelan  1 , Philip N Hawkins  1 , Scott D Solomon  16 , Julian D Gillmore  1 , Marianna Fontana  1
Affiliations
Multicenter Study

Clinical Phenotype and Prognosis of Asymptomatic Patients With Transthyretin Cardiac Amyloid Infiltration

Aldostefano Porcari et al. JAMA Cardiol. .

Abstract

Importance: Patients with transthyretin (ATTR) cardiac amyloid infiltration are increasingly diagnosed at earlier disease stages with no heart failure (HF) symptoms and a wide range of cardiac amyloid infiltration.

Objective: To characterize the clinical phenotype and natural history of asymptomatic patients with ATTR cardiac amyloid infiltration.

Design, setting, and participants: This cohort study analyzed data of all patients at 12 international centers for amyloidosis from January 1, 2008, through December 31, 2023. Inclusion criteria were asymptomatic ATTR cardiac amyloid infiltration, defined as an absence of HF history, HF signs and symptoms, diuretic therapy, and plasma cell dyscrasia with evidence of myocardial uptake on bone scintigraphy. If plasma cell dyscrasia was present, histologic confirmation of ATTR amyloid was required.

Exposure: Asymptomatic ATTR cardiac amyloid infiltration.

Main outcomes and measures: The primary outcomes were all-cause and cardiovascular (CV) mortality. The secondary outcomes were unplanned HF hospitalization, unplanned CV-related hospitalization, and a composite outcome of CV mortality and HF hospitalization.

Results: The study comprised 485 patients with asymptomatic ATTR cardiac amyloid infiltration (mean [SD] age, 74.9 [9.9] years, 85.8% male, 112 [23.1%] with hereditary ATTR amyloidosis), with 369 (76.1%) having grade 2 or 3 and 116 (23.9%) having grade 1 cardiac uptake at baseline. Patients with grade 2 or 3 uptake exhibited significantly more cardiac functional and structural abnormalities vs patients with grade 1 uptake. At 3 years, compared with grade 1 uptake, patients with grade 2 or 3 uptake had greater development of HF (54.3% [95% CI, 47.7%-61.3%] vs 23.1% [95% CI, 14.8%-35.1%]), greater outpatient diuretic initiation and N-terminal pro-B-type natriuretic peptide progression (35.0% [95% CI, 28.0%-43.2%] vs 12.4% [95% CI, 6.3%-23.7%]), and greater HF hospitalization (8.7% [95% CI, 5.9%-12.9%] vs 0%) and unplanned CV hospitalization (20.0% [95% CI, 15.7%-25.3%] vs 4.3% [95% CI, 1.6%-11.3%]). Over a median follow-up of 37 months (IQR, 20-64 months), the all-cause death rate was similar between patients with grade 1 vs 2 and 3 uptake; however, those with grade 2 or 3 compared with grade 1 uptake had a significantly higher risk of CV mortality (unadjusted hazard ratio, 5.30; 95% CI, 1.92-14.65).

Conclusions and relevance: This study shows that asymptomatic ATTR cardiac amyloid infiltration encompasses a wide spectrum of disease severity, with patients with grade 2 or 3 cardiac uptake experiencing an increased rate of CV events and CV mortality and patients with grade 1 uptake experiencing a lower CV event rate and predominantly non-CV mortality. These findings support the use of disease-modifying treatments in asymptomatic patients with grade 2 or 3 uptake and highlight the need of large-scale studies to assess their role in grade 1 uptake.

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Conflict of interest statement

Conflict of Interest Disclosures: Prof Cappelli reported receiving personal fees from Pfizer, AstraZeneca, BridgeBio Pharma, Novo Nordisk, Alnylam Pharmaceuticals, Bayer, and Amicus outside the submitted work. Dr Nitsche reported receiving grants from Pfizer outside the submitted work. Dr Cipriani reported receiving grants from Pfizer and personal fees from Alnylam Pharmaceuticals, AstraZeneca, and Bayer outside the submitted work. Dr Tomasoni reported receiving personal fees from Pfizer, Alnylam Pharmaceuticals, Roche Diagnostics, AstraZeneca, and Boehringer Ingelheim outside the submitted work. Dr Masri reported receiving grants from Pfizer, Ionis, Attralus, and Cytokinetics and personal fees from Cytokinetics, Bristol Myers Squibb, BridgeBio Pharma, Pfizer, Ionis, Lexicon, Attralus, Alnylam Pharmaceuticals, Haya, Alexion, Akros, Lexeo, Prothena, BioMarin, AstraZeneca, and Tenaya outside the submitted work. Dr Urey reported receiving personal fees from AstraZeneca, Alnylam Pharmaceuticals, BridgeBio Pharma, and Pfizer and clinical trial support from Alexion, Ionis, and Intellia Therapeutics outside the submitted work. Prof Gustafsson reported receiving personal fees from Abbott, Alnylam Pharmaceuticals, Ionis, AstraZeneca, Bayer, Pfizer, and Roche outside the submitted work. Prof Metra reported receiving consulting honoraria from Abbott, Bayer, Boehringer Ingelheim, Cytokinetics, AstraZeneca, Edwards LifeSciences, Novo Nordisk, and Roche Diagnostics and speaking fees from Boehringer Ingelheim outside the submitted work. Dr Solomon reported receiving grants to his institution from Alexion, Alnylam Pharmaceuticals, Applied Therapeutics, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Boston Scientific, Cytokinetics, Edgewise, Eidos/BridgeBio Pharma, Gossamer, GlaxoSmithKline, Ionis, Eli Lilly, National Institutes of Health (National Heart, Lung, and Blood Institute), Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Tenaya, Theracos, and US2.AI and consulting fees from Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, GlaxoSmithKline, Intellia Therapeutics, Eli Lilly, Novartis, Roche, Theracos, Quantum Genomics, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo outside the submitted work. Prof Gillmore reported receiving consulting fees from Alnylam Pharmaceuticals, Attralus, BridgeBio Pharma, AstraZeneca, Pfizer, Ionis, Lycia, and Intellia Therapeutics and an investigator-led study grant from Alnylam Pharmaceuticals outside the submitted work. Prof Fontana reported receiving consultant fees from and/or service on advisory boards for Alnylam Pharmaceuticals, Alexion/Caelum Biosciences, AstraZeneca, Eidos/BridgeBio Pharma, Prothena, Attralus, Intellia Therapeutics, Ionis, Cardior, Lexeo Therapeutics, Janssen Pharmaceuticals, Prothena, Pfizer, Novo Nordisk, Bayer, and Mycardium; research grants from Alnylam Pharmaceuticals, BridgeBio Pharma, AstraZeneca, and Pfizer; intermediate fellowship salary from the British Heart Foundation; share options in Lexeo Therapeutics; and shares in Mycardium outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Mortality for the Total Study Population and According to Perugini Grade of Cardiac Uptake at Diagnosis
CV indicates cardiovascular.
Figure 2.
Figure 2.. Unplanned Hospitalization for the Total Study Population and According to Grade of Cardiac Uptake at Diagnosis
CV indicates cardiovascular; HF, heart failure.
See this image and copyright information in PMC

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