Immune targets for the treatment of atrial fibrillation

  • Matthias NAHRENDORF, Massachusetts General Hospital (USA)
  • Stefan KAAB, Ludwig-Maximilians University Munich (Germany)
  • Patrick ELLINOR, Broad Institute of MIT and Harvard (USA)
  • Kamila NAXEROVA, Broad Institute of MIT and Harvard (USA)
  • Sebastian CLAUSS, Ludwig-Maximilians University Munich (Germany)
  • Florent GINHOUX, Gustave Roussy, INSERM (FRANCE)
  • Ulrich SCHOTTEN, Maastricht University (Netherlands)

Though atrial fibrillation (AFib) is the most common arrhythmia and frequently leads to stroke, heart failure and increased mortality, current anti-arrhythmic drug treatment has limited efficacy. We propose to address this significant therapeutic gap by targeting macrophages, which are white blood cells with key roles in multiple common diseases. Our preliminary data show macrophages are the most dynamic atrial cells and promote atrial stiffening (fibrosis) and enlargement in both AFib patients and animal models. During AFib, atrial macrophage frequencies double compared to controls. By studying the numerical and functional changes that atrial macrophages undergo due to common AFib risk factors in patients and in animals, we expect to uncover new, druggable immune pathways to combat the atrial tissue remodeling that underlies AFib. We will examine how atrial macrophage subsets, origins, phenotypes and crosstalk with other cells affect atrial structure and function, especially electrical conduction, cardiomyocyte excitation and metabolism, interstitial fibrosis and cardiac innervation. Our newly assembled consortium merges, for the first time, world experts in the traditionally separated fields of electrophysiology and macrophage biology. Our team will collect synergistic data in cell systems, macrophage-specific knockout mice, AFib pigs treated with macrophage-targeted drug candidates and AFib patients with diverse risk factors. Our ultimate goal is to develop new therapeutic targets for AFib patients.