A Cell study by Maarten Hulsmans et al. reports the presence of abundant resident macrophages (Mφ) in the heart atrioventricular (AV) node, and provide first evidence that Mφ 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. It is known that cardiac healing after injury requires Mφ but the role of these major innate immunity cells 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 Mφ 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 Mφ 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.
A 2018 Med Sci (Paris) review by Jean-Sébastien Silvestre and Grégoire Vandecasteele (article in French) highlights the role of the specific subset of Mφ residing within the distal atrioventricular node in mice and humans. These Mφ directly couple with cardiomyocytes via connexin-43-containing gap junctions and increase atrioventricular conduction by accelerating cardiomyocyte repolarization. Conditional deletion of connexin-43 in Mφ or congenital lack of macrophages delay nodal conduction and foster progressive atrioventricular block.
Figure: Les macrophages (Mφ) résidents dans le système de conduction électrique cardiaque orchestrent le rythme cardiaque. Les Mφ cardiaques facilitent la conduction électrique du noeud auriculo-ventriculaire distal. Les cellules cardiomyocytaires conductrices sont réparties au milieu de macrophages exprimant la protéine jonctionnelle connexine 43. Les Mφ rendent le potentiel de membrane de repos des cardiomyocytes plus positif et accélèrent leur repolarisation. La photo-stimulation des macrophages exprimant le canal rhodopsine de type 2 améliore la conduction auriculo-ventriculaire. À l’inverse, la délétion conditionnelle de la connexine 43 dans les Mφ , ou l’ablation des Mφ, retardent la conduction auriculo-ventriculaire et peuvent induire l’apparition d’un bloc auriculo-ventriculaire. From: [Heart rate: when macrophages hit the note] by Jean-Sébastien Silvestre and Grégoire Vandecasteele, Med Sci (Paris), 2018 Oct;34(10):820-823. doi: 10.1051/medsci/2018207. Free (Open) Access, Public domain.
A 2019 study by Yu-Dong Fei et al. published in Theranostics reports that the pro-inflammatory mononuclear cells percentage is elevated in patients with post-myocardial infarction (MI) arrhythmias, and Mφ form a gap junction with cardiomyocytes in MI border zones of MI patient and mice.
Of note, the action potential durations (APDs), and particularly the APD90 of cardiomyocytes connected with M1 Mφ were significantly prolonged, which were effectively attenuated by gap junction inhibition, KCa3.1 inhibition, and KCa3.1 silencing. The authors of this study concluded that the macrophage polarization leads to APD heterogeneity and post-MI arrhythmias via gap junction and KCa3.1 activation.
Cover Image Credit (Left panel): Macrophages: The mononuclear phagocytic system consists of monocytes circulating in the blood and macrophages in the tissues. The monocyte is considered a leukocyte in transit through the blood, which becomes a macrophage when fixed in a tissue. Monocytes and macrophages as well as granulocytes are able to ingest particulate matter (microorganisms, cells, inert particles) and are said to have phagocytic functions. The phagocytic activity is greater in macrophages, particularly after activation by soluble mediators released during immune responses, than in monocytes. From: Macrophages-Introductions and Functions, by Sagar Aryal, August 5, 2021, microbenotes.com