AIMS: In cardiac amyloidosis (CA), transthyretin-related (ATTR) CA is reported to have more microcalcifications in the interventricular septum (IVS) than other subtypes. This study investigates whether IVS microcalcifications can differentiate CA subtypes. METHODS AND RESULTS: A total of 442 patients with CA were enrolled at 18 collaborating institutions of the Japan Cardiac Amyloidosis Survey of typical Echocardiographic findings (J-CASE) Study: 139 light chain/amyloid A (AL/AA) type, 255 wild type ATTR (ATTRwt), 48 variant ATTR (ATTRv), and 19 patients with hypertensive heart disease (HHD). Echocardiographic pixel brightness quantification of the IVS was performed using public domain software. The IVS brightness index (IVSBI) was defined as the ratio of the average pixel brightness in the IVS to the opposite left ventricular (LV) wall. The IVSBI from the apical 4-chamber view was higher in both the ATTRwt group (median 1.40, IQR 1.22 to 1.67) and the ATTRv group (1.59, 1.32 to 2.00) compared to the HHD group (1.20, 1.02 to 1.37) and the AL/AA group (1.25, 1.11 to 1.46), respectively (P <
0.05). In the Cox proportional hazards analysis, a 0.5 increase in IVSBI from the apical 4-chamber view was associated with a hazard ratio of 2.54 (95 % CI: 1.42-4.56, P = 0.002) for all-cause mortality in ATTRwt-CA (n = 157), adjusted for age, gender, LVEF, and National Amyloidosis Centre staging. CONCLUSION: An IVSBI obtained from the apical 4-chamber view may be useful in distinguishing ATTR-CA from other forms of CA, potentially identifying subtle septal calcifications. Elevated IVSBI in ATTRwt-CA may have prognostic value.