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Updated: Aug 30, 2025
Author Spotlight: Developing a Translational Model for Atrial Fibrillation Research Across Species
Published on: November 21, 2023
Effect of macrophage migration inhibitory factor on pulmonary vein arrhythmogenesis through late sodium current
Chye-Gen Chin1,2, Yao-Chang Chen3, Yung-Kuo Lin2,4
1Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei 11031, Taiwan.
Aims:
Macrophage migration inhibitory factor (MIF), a pleiotropic inflammatory cytokine, is highly expressed in patients with atrial fibrillation (AF). Inflammation increases the risk of AF and is primarily triggered by pulmonary vein (PV) arrhythmogenesis. This study investigated whether MIF can modulate the electrical activity of the PV and examined the underlying mechanisms of MIF.
Methods And Results:
A conventional microelectrode, a whole-cell patch clamp, western blotting, and immunofluorescent confocal microscopy were used to investigate electrical activity, calcium (Ca2+) regulation, protein expression, ionic currents, and cytosolic reactive oxygen species (ROS) in rabbit PV tissue and isolated single cardiomyocytes with and without MIF incubation (100 ng/mL, treated for 6 h). The MIF (100 ng/mL)-treated PV tissue (n = 8) demonstrated a faster beating rate (1.8 ± 0.2 vs. 2.6 ± 0.1 Hz, P < 0.05), higher incidence of triggered activity (12.5 vs. 100%, P < 0.05), and premature atrial beat (0 vs. 100%, P < 0.05) than the control PV tissue (n = 8). Compared with the control PV cardiomyocytes, MIF-treated single PV cardiomyocytes had larger Ca2+ transients (0.6 ± 0.1 vs. 1.0 ± 0.1, ΔF/F0, P < 0.05), sarcoplasmic reticulum Ca2+ content (0.9 ± 0.20 vs. 1.7 ± 0.3 mM of cytosol, P < 0.05), and cytosolic ROS (146.8 ± 5.3 vs. 163.7 ± 3.8, ΔF/F0, P < 0.05). Moreover, MIF-treated PV cardiomyocytes exhibited larger late sodium currents (INa-Late), L-type Ca2+ currents, and Na+/Ca2+ exchanger currents than the control PV cardiomyocytes. KN93 [a selective calcium/calmodulin-dependent protein kinase II (CaMKII) blocker, 1 μM], ranolazine (an INa-Late inhibitor, 10 μM), and N-(mercaptopropionyl) glycine (ROS inhibitor, 10 mM) reduced the beating rates and the incidence of triggered activity and premature captures in the MIF-treated PV tissue.
Conclusion:
Macrophage migration inhibitory factor increased PV arrhythmogenesis through Na+ and Ca2+ dysregulation through the ROS activation of CaMKII signalling, which may contribute to the genesis of AF during inflammation. Anti-CaMKII treatment may reverse PV arrhythmogenesis. Our results clearly reveal a key link between MIF and AF and offer a viable therapeutic target for AF treatment.
Insights
Macrophage migration inhibitory factor (MIF) promotes atrial fibrillation (AF) by increasing pulmonary vein (PV) electrical instability. Inhibiting CaMKII signaling may reverse this arrhythmogenesis, offering a therapeutic target for AF.
Area of Science:
- Cardiology
- Electrophysiology
- Inflammation Biology
Background:
- Atrial fibrillation (AF) is linked to inflammation, with pulmonary vein (PV) arrhythmogenesis as a key trigger.
- Macrophage migration inhibitory factor (MIF), an inflammatory cytokine, is highly expressed in AF patients.
Purpose of the Study:
- To investigate if MIF modulates PV electrical activity.
- To elucidate the underlying mechanisms of MIF's effects on PV.
Main Methods:
- Utilized microelectrode recordings, whole-cell patch clamp, western blotting, and confocal microscopy in rabbit PV tissue and cardiomyocytes.
- Assessed electrical activity, calcium handling, protein expression, ionic currents, and reactive oxygen species (ROS) with and without MIF exposure.
- Investigated the effects of CaMKII, INa-Late, and ROS inhibitors.
Main Results:
- MIF exposure significantly increased PV beating rate, triggered activity, and premature atrial beats.
- MIF enhanced calcium transients, sarcoplasmic reticulum calcium content, and cytosolic ROS levels in PV cardiomyocytes.
- MIF increased late sodium (INa-Late), L-type calcium, and Na+/Ca2+ exchanger currents.
- CaMKII, INa-Late, and ROS inhibitors attenuated MIF-induced PV electrical abnormalities.
Conclusions:
- MIF promotes PV arrhythmogenesis via ROS-mediated activation of CaMKII signaling, leading to Na+ and Ca2+ dysregulation.
- This mechanism contributes to AF development in inflammatory conditions.
- Targeting CaMKII may represent a therapeutic strategy to reverse MIF-induced PV arrhythmogenesis and treat AF.
