Abstract 11641: The Role of Inflammation in a Humanized Mouse Model of Transthyretin Cardiac Amyloidosis

Abstract

Transthyretin cardiac amyloidosis (ATTR) is an under-diagnosed, progressive form of cardiomyopathy, leading to heart failure and death. It is caused by the deposition of amyloid fibrils in the myocardium derived from the plasma protein transthyretin (TTR), but its pathogenesis is poorly understood. Informative in vivo models have proven elusive. Our research identifies inflammation as a potential exacerbating factor in ATTR, suggested by gene expression elevations in inflammatory markers from cardiac biopsies of ATTR-CM patients. To explore this, we created a murine TTR knockout model expressing the human V122I TTR variant. Significant elevations of human TTR were observed in the plasma post-injection (human TTR level (ng/ml) ATTR: 110 ± 10; Control: 28 ± 12; p=0.0008, N=3-5) with preserved cardiac function (FS% ATTR: 20 ± 6; Control: 23± 5; p=0.8162, N=3-5). Notably, the mouse model exhibited amyloid deposits in the heart, confirmed by immunofluorescence and Congo Red staining. Transmission electron microscopy revealed both immature and mature amyloid fibrils in the extracellular matrix (Figure1). RNA-sequencing of the ATTR mouse heart identified distinct transcriptomic patterns and conserved inflammation pathways similar to those seen in a cohort of human ATTR heart samples, such as TNF, T-cell, and B-cell receptor signaling. Up-regulation of inflammatory markers, including CXCL1/2/3 and CCL20, was also observed, and an increased level of CCL5 (MFI ATTR: 801 ± 105; Control: 426± 64; p=0.0061, N=3) was confirmed via luminance-based immunoassay. These chemokines are critical for directing leukocytes to inflammation sites. This study suggests that inflammation may play a role in ATTR pathogenesis. Further in vivo studies are needed to elucidate the mechanisms by which inflammation modulates ATTR amyloidosis.