Clinical Phenotype and Prognosis of Asymptomatic Patients With Transthyretin Cardiac Amyloid Infiltration
Authors: Porcari Aldostefano , Razvi Yousuf , Cappelli Francesco , Nitsche Christian , Serenelli Matteo , Longhi Simone , Sinigiani Giulio , Cipriani Alberto , Aimo Alberto , Tomasoni Daniela , Zampieri Mattia , Cantone Anna , Allegro Valentina , Vergaro Giuseppe , Masri Ahmad , Urey Marcus , Ioannou Adam , Petrie Aviva , Noory Navid , Gustafsson Finn , Poledniczek Michael , Emdin Michele , Metra Marco , Sinagra Gianfranco , Martinez-Naharro Ana , Wechalekar Ashutosh D. , Lachman Helen , Whelan Carol , Hawkins Philip N. , Solomon Scott D. , Gillmore Julian D. , Fontana Marianna 
Published: January 2025

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.