Abstract P118: The Promotion Of Cardiac Dysfunction By Resiquimod-accelerated Systemic Lupus

Abstract

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by autoantibody formation and immune complex deposition in target organs. Individuals with SLE are more than twice as likely to experience a cardiovascular event than the rest of the population, contributing to the increased morbidity and mortality of individuals with this disease. While this increased risk of cardiovascular events in lupus is well known, SLE-specific phenotypes and mechanisms remain unknown. Therefore, we hypothesized that inducing the acceleration of SLE would lead to higher incidence of cardiovascular pathology in a lupus-prone murine model. To test this hypothesis, we treated female B6.Nba2 mice aged 10-14 weeks with Resiquimod (R848; 100μg/30μL), a TLR7/8 agonist shown to induce SLE, twice weekly for four weeks. The mice were followed with echocardiography every 4 weeks, up to 16 weeks. By 16 weeks, organs were harvested, weighed, and fixed or frozen for analysis. Echocardiographic imaging found left ventricular wall thickening 4 weeks after the start of R848 treatment. This was followed by a progressive increase in left ventricular internal dimensions, and a simultaneous decrease in ejection fraction (39.95 ± 0.05 vs 57.68 ± 1.12, p=0.0007) over the course of 16 weeks, culminating in significant cardiac dysfunction compared to vehicle controls. Moreover, tissue harvest revealed significant cardiomegaly (p<0.0001), as well as a four-fold increase in spleen weight of R848-treated mice compared to their vehicle treated counterparts. Furthermore, we investigated the mechanosensitive cation channel Piezo1 by protein and gene expression in cardiac tissues, and found that R848 acceleration of SLE significantly increased protein expression in the heart (1.37 ± 0.13 vs 1.00 ± 0.05, p=0.0208). Our data demonstrates that R848-accelerated SLE in female, lupus-prone B6.Nba2 mice does increase the occurrence of cardiac pathology compared to vehicle controls, and revealed potential for a Piezo-1 mechanism for cardiac dysfunction in Systemic Lupus. These findings present potentially new insight into the development of SLE-associated cardiovascular dysfunction.