Key result
Cardiac macrophages amplify the effects of flecainide on electrophysiological properties of cardiomyocytes by facilitating the recruitment of Nav1.5 to the cell membrane via Cx43.
Why the study?
Cardiac macrophages facilitate AV-node electrical conduction in mice, but the potential role of cardiomyocyte-macrophage coupling on antiarrhythmic therapy effects had not been investigated.
Does macrophage-cardiomyocyte coupling enhance the electrophysiological effects of flecainide in preclinical models?
Does macrophage-cardiomyocyte coupling enhance the electrophysiological effects of flecainide in preclinical models?
p-value: p=<0.05
Cardiac macrophages amplify the electrophysiological effects of flecainide on cardiomyocytes in vivo and in vitro by facilitating Nav1.5 recruitment to the cell membrane via Cx43.
Macrophage-AV node coupling may modulate flecainide response; leaves open any human therapeutic relevance pending in vivo validation.
Cardiac macrophages facilitate electrical conduction through the atrioventricular-node (AV) in mice. A possible role for cardiomyocyte-macrophage coupling on the effect of antiarrhythmic therapy has not been investigated yet. Holter monitoring was conducted in LysM Cre xCsf1r LsL−DTR mice (MM DTR ) under baseline conditions and after an elctrophysiological stress test by flecainide. In vivo effects were recapitulated in vitro by patch-clamp experiments. The underlying mechanism was characterized by expression and localization analysis of connexin43 (Cx43) and voltage-gated-sodium-channel-5 (Na v 1.5). ECG monitoring in MM DTR mice did not show any significant conduction abnormalities but a significantly attenuated flecainide-induced extension of RR- and PP-intervals. Patch-clamp analysis revealed that the application of flecainide to neonatal rat ventricular cardiomyocytes (CMs) changed their resting-membrane-potential (RMP) to more negative potentials and decreased action-potential-duration (APD50). Coupling of macrophages to CMs significantly enhances the effects of flecainide, with a further reduction of the RMP and APD50, mediated by an upregulation of Cx43 and Na v 1.5 surface expression. Macrophage depletion in mice does not correlate with cardiac electric conduction delay. Cardiac macrophages amplify the effects of flecainide on electrophysiological properties of cardiomyocytes in vivo and in vitro . Mechanistically, formation of macrophage-cardiomyocyte cell–cell-contacts via Cx43 facilitates the recruitment of Na v 1.5 to the cell membrane increasing flecainide effects.
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Bogert et al. (2024) studied Cardiac electrical conduction (n=8). Macrophage depletion and flecainide vs. Control mice (LysMCre) / Cardiomyocytes alone was evaluated on Flecainide-induced changes in heart rate, RR-interval, and PP-interval (p=<0.05). Cardiac macrophages amplify the effects of flecainide on electrophysiological properties of cardiomyocytes by facilitating the recruitment of Nav1.5 to the cell membrane via Cx43.
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