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First Evidence that Macrophages Modulate Heart Electrical Conduction System

Cardiac Macrophages Heart Electrical Conduction

In a recent Cell study, Maarten Hulsmans et al. report the presence of abundant resident macrophages in the heart atrioventricular (AV) node, and provide first evidence that macrophages modulate the electrical conduction and activity of cardiomyocytes. This phenomenon may be related to the pathogenic electrical conduction in heart conditions such as atrial fibrillation and ventricular arrhythmias.

The heart rhythm is controlled by electrical impulses generated in the sinoatrial node that propagates towards the atrium, AV node, His and Purkinje systems and ventricles. The AV node is composed by cardiomyocytes and plays an essential role in conducting electrical impulses between atria and ventricles. Of note, AV abnormalities (AV blocks) are serious life threatening conditions, and pacemaker implantation is essential to restore node conductibility.

Macrophages (Mφ) are found in all body tissues and are classically known for their involvement in immune homeostasis and inflammation control. In the heart, Mφ are distributed along with myocytes, fibroblasts and endothelial cells, but their role in cardiac activity is unknown.

In the Cell  study, the multicentre, multinational team from the US, Ireland, Germany France and the UK, firstly identified the precise morphology and location of cardiac macrophages in Cx3Cr1GFP/+ mice, which express the GFP protein in Mφ. Cardiac Cx3Cr1GFP/+ Mφ are located mostly in the AV node and neural bundle and have an elongated morphology with far-reaching cytoplasmatic projections.

The authors also showed that these Mφ express ion channels and exchangers, and genes associated to electrical conduction. In addition, these cells interact with cardiomyocytes through gap juntion proteins (connexin 43) that mediate intercellular communication and influence cardiomyocytes’ resting potential. In fact, Mφ increase cardiomyocyte resting membrane potentials, suggesting their role in cardiomyocyte repolarization.

When optogenetics are employed to photostimulate AV Mφ, cyclical Mφ depolarization modulated cardiomyocytes activity and improved AV nodal conduction. On the other side, congenital lack of Mφ, acute Mφ depletion or connexin 43 KO mice presented similar clinical features of cardiac electrical conduction pathologies, as prolongation in PR (AV block) and AH (delayed conduction from AV node to the His bundle) intervals, demonstrating impaired AV conduction.

The authors discuss that conditions such as myocardial infarction, heart failure and diabetes or inflammatory diseases of the heart such as Chagas, Lyme, sarcoid, and myocarditis are related to changes in macrophages’ phenotype and numbers, which in turn may contribute to arrhythmias and conduction abnormalities.

According to the authors this new pathophysiologic role of AV Mφ may also suggest novel therapeutic strategies focusing on AV Mφ activity.

Source: Cell, 2017. 169(3): 510-522 18. doi: 10.1016/j.cell.2017.03.050
Read more: Cell

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