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these immune cells, we performed PAB on macrophage-depleted mice, CD4 T cells, CD8 T cells or B cells-knockout mice. Only macrophage-depleted mice developed complete atrio-ventricular block leading to sudden death after PAB while the other mice survived. RNA sequences of various tissue macrophages revealed that secretion factor Amphiregulin (Areg) was specifically expressed in cardiac resident macrophages. We also found that cardiac macrophages were the only source of amphiregulin in the heart, which suggested that amphiregulin could play crucial roles in the specific heart function. To examine whether AREG contributes to cardiac electrical impulse conduction, gap junctional intercellular communication between cardiomyocytes of neonatal mouse was assessed by scrape loading dye transfer assay. AREG increased gap junction formation which was abolished by an EGF receptor inhibitor. In addition, gap junction formation between cultured cardiomyocytes was augmented when co-cultured with cardiac macrophages sorted from wild type mice, but not from Areg-knockout mice. To examine the role of Areg in vivo, we performed PAB on Areg-knockout mice and the mice which underwent bone marrow transplantation from Areg-knockout mice. They also developed atrio-ventricular block and sudden death after PAB. The heart section of Areg-knockout mice showed that the connexin43 (Cx43) was expressed abundantly but failed to localize to intercalated discs. Western blotting revealed that phosphorylation of Cx43 which is important for gap junction formation did not occur when AREG was knocked out. To further clarify the effect of AREG on Cx43, we transfected GFP-tagged Cx43 into HeLa cells. Cx43-GFP assembled into gap junction plaques in the adjoining plasma membrane. AREG administration induced larger gap junction plaques than vehicle whose effect was blocked by the EGF receptor inhibitor. Conclusion: Cardiac macrophages are protective against sudden cardiac death through maintaining cardiac electrical impulse conduction in the setting of the right-sided heart failure. AREG secreted from cardiac macrophages facilitates Cx43 localization to intercalated discs through phosphorylation of Cx43. Background: Atrial fibrillation (AF) often heralds electrical and structural abnormalities of the atrial myocardium, collectively referred to as atrial remodeling, which favor AF recurrence and persistence. In this context, growing importance is being given to cardiac fibroblasts (Fib) activated to myofibroblast (myoFib), which secrete collagen and other extracellular matrix components and drive atrial fibrosis. Very recent experimental evidence, obtained with rat cells and different animal models, suggests that thrombin generated in the fibrillating atria may promote tissue remodeling by recruiting myoFib via the G protein-coupled receptor (GPCR), protease-activated receptor (PAR)-1. Purpose: Here we investigated the effects of thrombin on PAR-1 signaling and the activation of human atrial Fib, and whether they could be reversed by dabigatran, a clinical...

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