| First Author | Wu J | Year | 2012 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 302 |
| Issue | 7 | Pages | H1510-23 |
| PubMed ID | 22287583 | Mgi Jnum | J:186583 |
| Mgi Id | MGI:5432660 | Doi | 10.1152/ajpheart.00357.2011 |
| Citation | Wu J, et al. (2012) Altered sinoatrial node function and intra-atrial conduction in murine gain-of-function Scn5a+/DeltaKPQ hearts suggest an overlap syndrome. Am J Physiol Heart Circ Physiol 302(7):H1510-23 |
| abstractText | Mutations in SCN5A, the gene encoding the pore-forming subunit of cardiac Na(+) channels, cause a spectrum of arrhythmic syndromes. Of these, sinoatrial node (SAN) dysfunction occurs in patients with both loss- and gain-of-function SCN5A mutations. We explored for corresponding alterations in SAN function and intracardiac conduction and clarified possible mechanisms underlying these in an established mouse long QT syndrome type 3 model carrying a mutation equivalent to human SCN5A-DeltaKPQ. Electrophysiological characterizations of SAN function in living animals and in vitro sinoatrial preparations were compared with cellular SAN and two-dimensional tissue models exploring the consequences of Scn5a+/DeltaKPQ mutations. Scn5a+/DeltaKPQ mice showed prolonged electrocardiographic QT and corrected QT intervals confirming long QT phenotypes. They showed frequent episodes of sinus bradycardia, sinus pause/arrest, and significantly longer sinus node recovery times, suggesting compromised pacemaker activity compared with wild-type mice. Electrocardiographic waveforms suggested depressed intra-atrial, atrioventricular node, and intraventricular conduction in Scn5a+/DeltaKPQ mice. Isolated Scn5a+/DeltaKPQ sinoatrial preparations similarly showed lower mean intrinsic heart rates and overall slower conduction through the SAN to the surrounding atrium than did wild-type preparations. Computer simulations of both single SAN cells as well as two-dimensional SAN-atrial models could reproduce the experimental observations of impaired pacemaker and sinoatrial conduction in terms of changes produced by both augmented tail and reduced total Na(+) currents, respectively. In conclusion, the gain-of-function long QT syndrome type 3 murine Scn5a+/DeltaKPQ cardiac system, in overlap with corresponding features reported in loss-of-function Na(+) channel mutations, shows compromised SAN pacemaker and conduction function explicable in modeling studies through a combination of augmented tail and reduced peak Na(+) currents. |
