Macrophage heterogeneity in atrial remodeling

Atrial remodeling, including dilation and fibrosis, can lead to hemodynamic deterioration and atrial fibrillation. As a consequence, cardiac output declines and atrial clots embolize to the brain, intestines and other organs. While valve surgery and anticoagulation therapy reduce heart failure and stroke, there are nevertheless numerous patients who would benefit from a therapy inhibiting atrial remodeling and its consequences. To address this urgent unmet clinical need, we here propose to investigate the role of macrophages, the fourth most numerous cardiac cell, in atrial remodeling. In preliminary work for this application, i) we developed and validated a new mouse model of atrial remodeling that combines key clinical risk factors, ii) we obtained single- cell RNA-sequencing (scRNA-seq) data from the left atria of mice with atrial remodeling, iii) we determined the ontogeny of atrial macrophages in the steady state and after atrial remodeling, and iv) we established a pipeline for scRNA-seq of human left atrial tissues from patients with atrial disease undergoing heart surgery at MGH. We now propose to test if macrophages form the atria's Achilles' heel promoting atrial remodeling, fibrosis and atrial fibrillation. We will explore the role of macrophage subsets in atrial remodeling using genetic and pharmaceutical cell depletion strategies. We hypothesize that during atrial remodeling, disease-promoting macrophages are derived from blood monocytes while locally sourced macrophages are protective. In these studies, we will profile structural remodeling of the left atrium by echocardiography, hemodynamic and electrophysiological studies, histological analysis and FACS followed by real-time qPCR. Our preliminary scRNA-seq data provide us with a wealth of potential targets to study the causal role of fibrosis-related macrophage genes in atrial remodeling by loss- and gain-of-function studies. We will test the hypothesis that gene deletion in bone marrow-derived cells, i.e. recruited macrophage subsets, attenuates atrial fibrosis by cross-talk to fibroblasts and reduced collagen deposition, leading to less atrial remodeling and reduced inducibility of atrial fibrillation. In a translational aim, we will study macrophage heterogeneity in human atrial tissues by scRNA-seq. We will focus on the comparison between human and mouse scRNA-seq data sets using state-of-the-art computational methods to steer the preclinical discovery work towards pathways that are important in human disease. Our collaborative application unites an interdisciplinary team with expertise in immunology, cardiovascular science and computational biology. While the novel research plan is ambitious, we believe that our preliminary data demonstrate feasibility and provide us with a unique opportunity to study a question with high clinical relevance.