Abstract 15668: Abnormal Sinoatrial Node Pacemaker Activity Persists in Atrial-Specific Na+-Ca2+ Exchanger Knockout Mice
Atrial-specific Na+-Ca2+ exchanger (NCX1) KO mice live into adulthood with mild cardiac hypertrophy but have no P waves on the surface electrocardiogram (ECG) and instead depend upon a junctional rhythm. This raises the possibility that the sinoatrial (SA) node relies exclusively upon the “calcium clock” for pacemaker activity. To further test this hypothesis, we used high speed laser scanning confocal microscopy to examine Ca2+ handling in a tissue preparation of either the isolated SA or Atrioventricular (AV) nodes perfused with modified Tyrodes solution at 20oC. Slow and irregular spontaneous Ca2+ transients indicative of depolarization were present in the NCX1 KO SA node (47 ± 14 bpm in KO versus 86 ± 6 bpm in WT). When challenged by isoproterenol (ISO, 100 nM) the NCX1 KO SA node often responded with burst activity indicating an ability to respond to β-adrenergic stimulation despite the absence of NCX1. Surprisingly, we found no evidence of spontaneous transients in AV node tissue isolated from the NCX1 KO (0 bpm) compared to WT (35 ± 10 bpm). However, spontaneous activity could be restored in ∼50% of NCX1 KO AV nodes exposed to ISO. To more thoroughly analyze the depolarization, we performed optical voltage mapping with di-4-anepps in a larger tissue preparation that included both SA and AV nodes as well as right and left atria. Unlike the organized and rapid spread of depolarization from the SA node to both atria in WT, there were several unusual features in the mapping of the NCX1 KO SA node: the leading pacemaker region was poorly defined; more than one leading region competed to start the depolarization; the depolarization spread more slowly throughout the SA node and the SA node appeared unable to depolarize the atria. The inability of the NCX1 KO SA node to depolarize the atria could explain the lack of P waves on ECG in the intact animal (sino-atrial exit block), but does not reveal the source of the escape rhythm in these mice since the AV node is silent. An attractive possibility is that the AV node of the KO in vivo functions in response to tonic β-adrenergic stimulation, especially at 37oC. It is notable that a slow pacemaker mechanism persists in the SA node despite the lack of NCX1. Perhaps If and/or L-type Ca2+ channels maintain some pacemaker activity in the absence of NCX1.
- © 2012 by American Heart Association, Inc.