G q -Mediated Arrhythmogenic Signaling Promotes Atrial Fibrillation

Background: Atrial fibrillation (AF) is promoted by various stimuli like angiotensin II, endothelin-1, epinephrine/norepinephrine, vagal activation, or mechanical stress, all of which activate receptors coupled to G-proteins of the Gα q /Gα 11 -family (G q ). Besides pro-fibrotic and pro-inflammatory effects, G q -mediated signaling induces inositol trisphosphate receptor (IP 3 R)-mediated intracellular Ca 2+ mobilization related to delayed after-depolarisations and AF. However, direct evidence of arrhythmogenic G q -mediated signaling is absent. Methods and results: To define the role of G q in AF, transgenic mice with tamoxifen-inducible, cardiomyocyte-specific Gα q /Gα 11 -deficiency (G q -KO) were created and exposed to intracardiac electrophysiological studies. Baseline electrophysiological properties, including heart rate, sinus node recovery time, and atrial as well as AV nodal effective refractory periods, were comparable in G q -KO and control mice. However, inducibility and mean duration of AF episodes were significantly reduced in G q -KO mice—both before and after vagal stimulation. To explore underlying mechanisms, left atrial cardiomyocytes were isolated from G q -KO and control mice and electrically stimulated to study Ca 2+ -mobilization during excitation–contraction coupling using confocal microscopy. Spontaneous arrhythmogenic Ca 2+ waves and sarcoplasmic reticulum content-corrected Ca 2+ sparks were less frequent in G q -KO mice. Interestingly, nuclear but not cytosolic Ca 2+ transient amplitudes were significantly decreased in G q -KO mice. Conclusion: G q -signaling promotes arrhythmogenic atrial Ca 2+ -release and AF in mice. Targeting this pathway, ideally using G q -selective, biased receptor ligands, may be a promising approach for the treatment and prevention of AF. Importantly, the atrial-specific expression of the G q -effector IP 3 R confers atrial selectivity mitigating the risk of life-threatening ventricular pro-arrhythmic effects.