Cardiac Uptake Reflects Risk in Asymptomatic ATTR Cardiac Amyloid Infiltration

Marianna Fontana, MD, PhD

Credit: Radcliffe Cardiology

Clinical phenotypes impacted the prognosis of patients with asymptomatic transthyretin (ATTR) cardiac amyloid infiltration, including rates of disease progression and the risk of cardiovascular death, according to a new study.¹

Among nearly 500 patients with asymptomatic ATTR cardiac amyloid infiltration, grade 2 or 3 cardiac uptake was linked to greater disease progression rates and a 5-fold higher risk of cardiovascular (CV) death, while grade 1 cardiac uptake revealed a predominance of non-CV death.

“In the absence of randomized clinical trials, these data support the use of disease-modifying treatments in asymptomatic patients with grade 2 or 3 cardiac uptake and highlight the need of large-scale future studies to assess the clinical importance of grade 1 uptake and the role of disease-modifying treatment in these patients,” wrote the investigative team, led by Marianna Fontana, MD, PhD, National Amyloidosis Centre, University College London.

Evidence has recognized transthyretin amyloid cardiomyopathy (ATTR-CM) as a prevalent cause of heart failure (HF), with advancements in noninvasive imaging techniques leading to higher rates of earlier identification. An increasing number of this patient population exhibit signs of asymptomatic ATTR cardiac amyloid infiltration, without signs of HF, but data are lacking on phenotypic classification and disease progression.²

Disease-modifying treatments, including tafamidis (ATTR-ACT), acoramidis (TRIBUTE-CM), and vutrisiran (HELIOS-B), have displayed benefits for people with ATTR-CM and symptoms of heart failure in clinical trials, but patients with asymptomatic cardiac amyloid infiltration were excluded from study, according to Fontana and colleagues.³

Citing the importance of understanding the natural history of asymptomatic cardiac amyloid infiltration for clinical decision-making, and for designing randomized clinical trials, the team sought to define the clinical phenotype and natural history of asymptomatic ATTR cardiac amyloid infiltration. The multi-center cohort study assessed the data of all patients at 12 international centers for amyloidosis from January 2008 to December 2023.¹

Diagnosis of ATTR cardiac amyloid infiltration was established by myocardial uptake on bone scintigraphy, and confirmed as grade 1, 2, or 3 by single-photon emission tomography or computed tomography imaging. Those with an absence of HF history, signs and symptoms, or lack of diuretic therapy at diagnosis were eligible for the analysis.

For the analysis, the primary outcome was all-cause and CV mortality, followed by secondary outcomes of unplanned HF hospitalization, unplanned CV-related hospitalization, and a composite of CV mortality and HF hospitalization. Overall, 660 asymptomatic patients were identified, but 175 (26.5%) patients were enrolled in interventional clinical trials or received disease-modifying therapy and were excluded from the analysis.

A total of 485 patients (mean age, 74.9 years; 85.8% male) with asymptomatic ATTR cardiac amyloid infiltration met study criteria, with 369 (76.1%) reporting grade 2 or 3 and 116 (23.9%) reporting grade 1 cardiac uptake at the baseline. Fontana and colleagues found those with grade 2 or 3 uptake had significantly more cardiac functional and structural abnormalities than grade 1 uptake.

Upon analysis, at the 3-year mark, individuals with grade 2 or 3 uptake had greater HF development than grade 1 uptake (54.3% [95% CI, 47.7–61.3] vs. 23.1% [95% CI, 14.8–35.1]). The population with grade 2 or 3 uptake also experienced increased outpatient diuretic initiation and NT-proBNP progression (35.0% [95% CI, 28–43.2] vs. 12.4% [95% CI, 6.3–23.7]).

HF hospitalizations (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]) also favored grade 2 or 3 uptake. Over a median of 37 months, the team found the all-cause death rate similar between grade 1 and grade 2 or 3 uptake. On the other hand, grade 2 or 3 uptake displayed a significantly higher risk of CV mortality (unadjusted hazard ratio [HR], 5.30; 95% CI, 1.92–14.65).

Referring to the potential for clinical trials, Fontana and colleagues indicated the predominance of non-CV-related deaths in those with grade 1 uptake confirms the hypothesis that mortality risks in this population are less modifiable.

“This hypothesis, coupled with our finding of a significantly lower rate of CV events, may imply that a clinical trial that includes these patients would require large numbers and long-term follow-up,” they added.

References

1. _{Porcari A, Razvi Y, Cappelli F, et al. Clinical Phenotype and Prognosis of Asymptomatic Patients With Transthyretin Cardiac Amyloid Infiltration. JAMA Cardiol. Published online January 22, 2025. doi:10.1001/jamacardio.2024.5221}
2. _{Ioannou A, Patel RK, Razvi Y, et al. Impact of Earlier Diagnosis in Cardiac ATTR Amyloidosis Over the Course of 20 Years. Circulation. 2022;146(22):1657-1670. doi:10.1161/CIRCULATIONAHA.122.060852}
3. _{Fontana M, Berk JL, Gillmore JD, et al. Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy. N Engl J Med. 2025;392(1):33-44. doi:10.1056/NEJMoa2409134}