P323RGS 4 KO mice are predisposed to atrial fibrillation (AF) and show disrupted sympathovagal balance, making RGS 4 a potential therapeutic target for AF

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Abstract

Purpose

The electrophysiological basis of AF is not understood. Acetylcholine from the vagus nerve binds to muscarinic receptors causing dissociation of α- βγ subunits of the inhibitory G-protein, activating G-protein gated inward rectifying potassium (GIRK) channels. The result is bradycardia, shortening of the APD and propensity for AF. Gi2 is the predominant cardiac G-protein and RGS 4 terminates Gi2.

Methods

In vivo studies were performed in RGS 4 KO and wild type (WT) mice. Electrophysiological studies (EPS) were undertaken in 8-week old anaesthetised mice with a 1.1F catheter inserted into the right atrium via the right internal jugular vein. ECG and EP parameters were recorded. AF induction was attempted with burst pacing for 25 seconds and repeated after injection of 0.5mg/kg carbachol. Telemetry probes were inserted intra-abdominally into 12-week old mice. After a two week recovery period, ECGs were recorded in conscious mice for 48 hours and studied for AF and atrial ectopics (AE). An ECG post carbachol injection was analysed. Heart rate variability (HRV) was measured from 12 to 2pm, when murine vagal tone is highest.

Results

ECG and EP parameters were comparable. RGS 4 KO mice developed AF (76.9 vs 38.5%, P=0.04). Mean duration of AF for WT was 70.2 ± 29.8 (1.9 to 770) versus 222.6 ± 164.9 (1 to 2867.4, P=0.69) seconds for RGS 4 KO mice. Although this did not reach significance, there was a trend to a longer duration of AF in RGS 4 KO mice. Carbachol did not increase AF in KO or WT (P= 0.28), although a trend was apparent. Conscious RGS 4 KO mice were tachycardic (634.3 ± 52.6 vs 562.6 ± 36.3 bpm, P=0.03), and had an enhanced bradycardic response to carbachol (288.2 ± 37.9 vs 524.3 ± 24.2 bpm, P=0.02). ECG and HRV parameters of WT and RGS 4 KO mice without and with carbachol were comparable (P > 0.05). Carbachol- treated RGS 4 KO mice had disrupted HRV (P=0.008) compared to RGS 4 KO mice alone. This was not seen with WT treated with carbachol (P > 0.05). Carbachol-treated RGS 4 KO mice had several pauses, 2 to 7 AE, but no AF. WT mice treated with carbachol had a maximum of one AE. Without carbachol, no AE or AF was seen in RGS 4 KO or WT mice.

Conclusions

This is the first report of AF and HRV in the RGS 4 KO mouse in vivo. These are tachycardic, have an increased bradycardic response to carbachol and disrupted HRV. This signifies altered sympathovagal balance.

Conclusions

Mechanistic studies are underway to understand the electrophysiological basis of AF in the RGS 4 KO mouse. RGS 4 is a potential therapeutic target in the treatment of AF.

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