Abstract Fri066: Role of Inflammation and JAK/STAT3 Signaling in AML Mediated Atrial Fibrillation

The number of cancer survivors is increasing with advanced treatment and care, many of whom develop cardiac comorbidities, including atrial fibrillation (AF). While multiple groups have explored the cardiotoxic effects of therapies, cancer itself may be a risk factor for AF. These studies show a correlation between cancer therapies and AF (onco-AF); however, the underlying pathways remain unknown, mainly due to the lack of animal models enabling cause-and-effect studies. Therefore, our long-term goal is to uncover the mechanisms underlying onco-AF by establishing novel mouse models for the study of cardio-oncology. We hypothesize that enhanced inflammation and JAK/STAT3 signaling in the atria of AML-mice promote atrial fibrosis and AF. We established a model of onco-AF by grafting acute myeloid leukemia (AML) into wild-type C57/BL6J mice and assessed their susceptibility to AF via programmed electrical stimulation. RNA-seq was performed from the atria of AML-mice and bioinformatic analyses were used to reveal the altered genetic landscape due to AML. We found, for the first time, that AML-mice have a 55.6% susceptibility to AF (p = 0.046), compared to 9.1% in control mice. GSEA analysis of the RNA-seq data revealed TNFα mediated inflammatory pathway to be the most activated pathway in the atria of AML-mice. RT-qPCR analysis confirmed increased expression of TNFα in AML-mice (2.2 fold, p=0.008). Since macrophages are one of the largest sources of TNFα, we assessed if there was increased expression of macrophage marker F4/80 in the atria of AML-mice. Indeed, F4/80 mRNA was increased in AML-mice (2.0 fold, p<0.001). Furthermore, we found an increase in the mRNA levels of macrophage recruiting chemokine CCL2 in AML-mice (2.1 fold, p=0.004). Similarly, elevated expression of STAT3 was observed in AML-mice. Furthermore, RT-qPCR revealed increased expression of fibrotic marker Col1 (2.8 fold, p=0.001), and myofibroblast marker alpha smooth muscle actin Acta2a in AML-mice (2.5 fold, p=0.004), indicating increased fibrosis in the atria of the AML-mice. Our results show that AML itself is a risk factor for AF. This increased susceptibility to onco-AF is likely driven by macrophage mediated inflammation via increased TNFα secretion that activates STAT3 signaling and promotes fibrosis in the atria of AML.