Proteostasis is disrupted in human endothelial cells by serum from ATTR patients and is rescued by tafamidis treatment

BACKGROUND: The vascular effects of wild-type (ATTRwt-CM) and hereditary (ATTRv-CM) transthyretin cardiac amyloidosis, and the impact of tafamidis treatment, remain unclear. METHODS: Serum from ATTRwt-CM and ATTRv-CM patients (pre- and 6-months post-Tafamidis treatment) elderly and young controls, was applied on human umbilical vein endothelial cells (HUVECs). Viability, motility, and stress responses and serum cytokine and proteomic profiles were assessed. Recombinant TTR, with and without tafamidis co-treatment, were also evaluated. Pulse wave velocity (PWV) was longitudinally assessed in ATTRwt-CM patients pre- and post-tafamidis treatment and in elderly controls. RESULTS: ATTRwt-CM or ATTRv serum reduced HUVECs viability and motility, inducing proteotoxic and oxidative stress, while serum cytokine and proteome profiling revealed inflammatory-related signatures; All these effects were attenuated in HUVECs treated with post-Tafamidis serum. Recombinant TTR also induced proteotoxic stress, which was attenuated by tafamidis co-treatment (safety range ≤ 16 μM). Consistently, PWV was reduced in ATTRwt-CM patients after Tafamidis, as compared to controls, correlating with increased serum transthyretin and reduced PBMCs' proteasome activity. CONCLUSIONS: and improved arterial stiffness in ATTRwt-CM patients, implying protective vascular effects of tafamidis in ATTR-CM beyond direct myocardial transthyretin stabilization.