Complete atrial-specific knockout of NCX1 eliminated sinoatrial node pacemaker activity, resulting in an absence of P-waves and a slower junctional escape rhythm of 292 bpm compared to 491 bpm in wild-type mice.
Does atrial-specific knockout of NCX1 eliminate sinoatrial node pacemaker activity in mice?
Complete atrial-specific knockout of NCX1 eliminates sinoatrial node pacemaker activity, providing strong evidence that the sodium-calcium exchanger is required for normal pacemaker function.
Absolute Event Rate: 292% vs 491%
p-value: p=<0.001
The origin of sinoatrial node (SAN) pacemaker activity in the heart is controversial. The leading candidates are diastolic depolarization by "funny" current (If) through HCN4 channels (the "Membrane Clock" hypothesis), depolarization by cardiac Na-Ca exchange (NCX1) in response to intracellular Ca cycling (the "Calcium Clock" hypothesis), and a combination of the two ("Coupled Clock"). To address this controversy, we used Cre/loxP technology to generate atrial-specific NCX1 KO mice. NCX1 protein was undetectable in KO atrial tissue, including the SAN. Surface ECG and intracardiac electrograms showed no atrial depolarization and a slow junctional escape rhythm in KO that responded appropriately to β-adrenergic and muscarinic stimulation. Although KO atria were quiescent they could be stimulated by external pacing suggesting that electrical coupling between cells remained intact. Despite normal electrophysiological properties of If in isolated patch clamped KO SAN cells, pacemaker activity was absent. Recurring Ca sparks were present in all KO SAN cells, suggesting that Ca cycling persists but is uncoupled from the sarcolemma. We conclude that NCX1 is required for normal pacemaker activity in murine SAN.
Groenke et al. (Thu,) conducted a other in Sinoatrial node pacemaker activity. Atrial-specific knockout of NCX1 vs. Wild-type littermates was evaluated on Heart rate (ventricular rate) and presence of sinoatrial node pacemaker activity (p=<0.001). Complete atrial-specific knockout of NCX1 eliminated sinoatrial node pacemaker activity, resulting in an absence of P-waves and a slower junctional escape rhythm of 292 bpm compared to 491 bpm in wild-type mice.