Natural History of Cardiac Transthyretin Amyloidosis - Mechanistic Insights by Multimodality Imaging

Experimental Design The study design is an open label prospective longitudinal study with serial imaging at baseline and after 12-month follow-up. The entire study population will include 50 participants with cardiac ATTR amyloidosis, as recently defined by multi-societal criteria.

Conventional markers of disease progression

These markers are collected during routine clinical follow-up of patients in our Outpatient Clinic. The markers are divided into three domains and include the following outcomes:

• Clinical and functional: any heart failure hospitalization, NYHA class, Kansas City Cardiomyopathy Questionnaire, 6-minute walk test;
• Laboratory biomarkers: NT-proBNP, troponin, creatinine;
• Imaging and ECG: LV wall thickness, diastolic dysfunction, LVEF, stroke volume, global longitudinal strain, conduction disturbance.

Data Analysis Plan Power calculation for sample size is challenging as no previous study has evaluated the response of our endpoints in myocardial FAPI uptake or serum BMP4 concentration to tafamidis. We therefore focused sample size calculation of echocardiographic myocardial stiffness. Based on our own preliminary data, we estimate median baseline values for myocardial stiffness of 2.6 m/s [IQR, 1.7-3.8] in cardiac amyloidosis. Disease progression is expected in about 30% of participants. While myocardial stiffness is expected to remain unchanged in cardiac amyloidosis without disease progression a 20% relative increase (i.e. 0.5 ± 0.5 m/s) is considered in cardiac amyloidosis with disease progression. A sample size of 40 participants (i.e. 30 participants without and 10 participants with disease progression) has a statistical power of 80% to predict a difference in response of myocardial stiffness to tafamidis.