Current treatments for atrial fibrillation (AFib), a common heart condition characterized by fast and irregular beats that can lead to stroke and heart failure, have multiple side effects and are ineffective for preventing AFib recurrence. Now a new study led by researchers at Massachusetts General Hospital (MGH) reveals that macrophages and macrophage-produced proteins play a major role in the development of AFib.

The findings are published in Science in an article titled, “Recruited macrophages elicit atrial fibrillation,” and suggest targeting these cells may represent a promising strategy to treat and prevent AFib.

Senior author Matthias Nahrendorf, MD, PhD, an investigator in MGH’s Center for Systems Biology and the Richard Moerschner Endowed MGH Research Institute Chair in Men’s Health, and colleagues analyzed single cells from atrial heart tissue collected from patients with and without AFib. The analyses indicated that immune cells called macrophages are the most dynamic cell population in the atria during AFib, and these cells expand more than any other cell type in diseased tissue.

The researchers created a new mouse model of AFib they dubbed “HOMER” and tested if and how macrophages can cause AFib. “We found that recruited macrophages support inflammation and fibrosis, or scarring, of the atria, which hinder electrical conduction between heart cells and lead to AFib. Inhibiting macrophage recruitment reduced AFib,” said Nahrendorf.

“Atrial fibrillation disrupts contraction of the atria, leading to stroke and heart failure,” wrote the researchers. “We deciphered how immune and stromal cells contribute to atrial fibrillation. Single-cell transcriptomes from human atria documented inflammatory monocyte and SPP1+ macrophage expansion in atrial fibrillation. Combining hypertension, obesity, and mitral valve regurgitation (HOMER) in mice elicited enlarged, fibrosed, and fibrillation-prone atria.”

Gene expression analyses revealed that in human and mouse hearts, the SPP1 gene is highly overexpressed in macrophages during AFib. This gene produces the SPP1 protein that promotes tissue scarring and is elevated in the blood of patients with AFib. HOMER mice lacking this protein had reduced numbers of atrial macrophages.

The findings demonstrate future therapeutic strategies for AFib could target macrophages or macrophage-derived signals such as SPP1 that contribute to inflammation and fibrosis.

“We think that this research lays the groundwork for immunomodulatory therapy of AFib, and we are currently working on several strategies to make this happen,” concluded Nahrendorf.

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