Proteomics Profiling Reveals Molecular Subtypes of Transthyretin Cardiac Amyloidosis.

Published in Circulation. Heart failure. Abstract: Transthyretin cardiac amyloidosis (ATTR-CA) may involve heterogeneity in biological mechanisms (ie, molecular subtypes). Molecular subtypes potentially lead to differences in prognosis and treatment response to tafamidis-the first disease-modifying therapy for ATTR-CA. We aimed to derive molecular subtypes of ATTR-CA through comprehensive plasma proteomics profiling and to examine their associations with prognosis and estimated treatment effect of tafamidis. We applied unsupervised machine learning to comprehensive plasma proteomics profiling of 7289 proteins to identify molecular subtypes in our prospective cohort of patients with ATTR-CA enrolled at Columbia University. We compared all-cause mortality risk and estimated the treatment effect of tafamidis among the identified molecular subtypes, adjusting for age, sex, TTR genotype, and concomitant medication use. We also performed pathway analysis comparing the worst prognosis subtype with the other subtypes combined. Among 142 patients eligible for analysis, 96 patients received tafamidis treatment. We identified 3 molecular subtypes (subtype A: n=49, subtype B: n=38, and subtype C: n=55) with different survival risks during a median follow-up of 5.2 years (log-rank P =0.035), without significant differences in traditional clinical stages. Mortality risk was highest in subtype A, followed by B and then C (eg, adjusted hazard ratio of subtype A versus C [95% CI], 1.95 [1.03-3.66]; P =0.04). The largest treatment effect of ta...