Abstract Fri050: The Role of Macrophages in the Progression of Amyloid Transthyretin Cardiomyopathy

Introduction: Amyloid Transthyretin Cardiomyopathy (ATTR-CM) is caused by the myocardial uptake of transthyretin (TTR), resulting in protein aggregation, cytotoxicity, and ultimately dysfunction. Methods to enhance degradation of deposited TTR is a critical unmet need. Macrophages are known to digest TTR, which has garnered attention as a potential therapeutic target. However, the subtypes of macrophages (infiltrative vs. resident) that best digest TTR and the underlying signaling pathways are unknown. Hypothesis: We hypothesize that myocardial resident macrophages (homoeostatic, largely anti-inflammatory) are cardioprotective in ATTR-CM. However, as the disease progresses more infiltrative, proinflammatory macrophages are recruited to the myocardium leading to increased cardiac dysfunction. Methods: We investigated the role of macrophages in myocardial samples from ATTR-CM patients vs non-failing (NF) controls via histology and proteomics; in addition to TTR consumption and cytokine release in an in vitro model of ATTR-CM. Results: We found the myocardium of ATTR-CM patients has greater macrophage infiltration compared to NF via histology (NF, n=7; ATTR-CM, n=4, p=0.0286). Furthermore, proteomics analyses revealed ATTR-CM hearts have greater inflammatory signaling. In vitro, we found alternatively activated (anti-inflammatory, homeostatic) macrophages digest TTR aggregates better than classically activated (inflammatory) macrophages (n=6, p=0.0022). Interestingly, all macrophage subtypes became more inflammatory following exposure to TTR aggregates in vitro, indicated by greater IL-1b and IL-6 release (n=6, p=0.0003 and p<0.0001 respectively). Conclusions: These data suggest macrophages play a key role in the pathogenesis of ATTR-CM. Specifically, cardiac resident macrophages digest TTR aggregates better than inflammatory subtypes and reducing pro-inflammatory signaling may be cardioprotective for ATTR-CM patients.