Abstract Body (Do not enter title and authors here): Background: 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.

Aim: The aim of the study was to characterize the natural history and long-term outcomes of patients with ATTR cardiac amyloid infiltration and no HF symptoms.

Methods: Data of consecutive patients at 12 international centres for amyloidosis (2008-2023) were analysed. Asymptomatic ATTR cardiac amyloid infiltration was defined as absence of HF and diuretic therapy, monoclonal gammopathy with evidence of cardiac uptake on bone scintigraphy (Perugini grade 1 to 3).

Results: The study comprised 660 patients with ATTR cardiac amyloid infiltration and no HF symptoms (74.1±9.7 years, 87% male, 21.5% hereditary ATTR amyloidosis), 81.5% (n=538) with Perugini grade 2 and 3, and 18.5% (n=122) with Perugini grade 1. The number of new diagnoses progressively increased over time, from 27 in 2008-2011 to 350 in 2020-2023. Perugini 2 and 3 patients exhibited significant cardiac functional and structural abnormalities, in keeping with ATTR cardiomyopathy, whilst Perugini grade 1 patients generally had normal cardiac structure and function. At 3 years, the rate of cardiovascular (CV) events in the overall population was elevated and consistently higher in Perugini grade 2 and 3 compared to grade 1 (development of symptomatic HF [50% vs 23%], diuretic initiation and NT-proBNP progression [32.5% vs 12.6%], HF hospitalization [6.6% vs 0%] and unplanned CV hospitalization [16.7% vs 4%]) (Figure 1). Over 38 months (IQR 22-61), the death rate was high, and similar in Perugini grade 1 vs 2 and 3 (5.0 vs 4.5 deaths per 100 patient-years), however Perugini grade 2 and 3 patients had a 3-fold higher risk of CV mortality (hazard ratio [HR] 3.0 [95%CI 1.19-7.56], p=0.020) compared to Perugini grade 1 (Figure 2).

Conclusions: Asymptomatic ATTR cardiac amyloid infiltration is increasingly common and encompasses a wide spectrum of disease severity. The Perugini grade enables potential characterization of patients into clinical profiles with varying disease progression and risks of CV and non-CV mortality. In the absence of randomized trials, these data may inform clinicians regarding the use of disease-modifying treatment in patients with asymptomatic ATTR cardiac amyloid infiltration.