Sodium-Calcium Exchanger (NCX1) is Essential for Atrioventricular Node Automaticity and Conduction, as Revealed through Atrial-Specific Knockout of NCX1

Abstract

The atrioventricular node (AVN), unlike the sinoatrial node (SAN), can act as an oscillator and conductor of the proximal cardiac conduction system. Using a sarcolipin cre-induced atrial-specific sodium-calcium exchanger 1 (NCX1) KO mouse, we previously demonstrated that NCX1 (and the calcium clock) is an essential component of SAN automaticity (Groenke et al., 2013; Torrente et al., 2015). Here, we used the same mouse to test the hypothesis that NCX1 and the calcium clock are necessary components of AVN automaticity and conduction. qPCR analysis confirmed a 79% reduction of NCX mRNA in AVN tissue, and ECGs demonstrated a slow junctional escape rhythm driving the heart rate. Voltage mapping and confocal imaging of isolated NCX1 KO AVN tissue showed slowed or absent AVN automaticity compared to WT, as action potential and calcium transient rates decreased by 94% (p <0.05) and 78% (p <0.01), respectively. To characterize the conduction properties of the AVN in NCX1 KO mice, we used in vivo catheter pacing of the atrium and simultaneous recording of surface ECG. Resting heart rates in control mice were 542 +/- 16.65 BPM (cycle length of 111 +/- 3.32 ms) and could be paced up to 954 +/- 18.86 BPM (63 +/- 1.23 ms) before developing atrioventricular block (43% increase). In line with their slow junctional rhythm at rest, NCX KO mice had a reduced resting heart rate of 356.8 +/- 12.24 BPM (169 +/- 5.83 ms) and could only tolerate a 17% increase in pacing rate (436 +/-27.48 BPM or 140 +/- 10.44 ms) before exhibiting AV Block. Thus, lack of NCX1 in atrial tissue results in abnormal AVN automaticity and conduction. These data indicate an essential role for NCX1 in AVN function.