| First Author | Chadda KR | Year | 2017 |
| Journal | Sci Rep | Volume | 7 |
| Issue | 1 | Pages | 11070 |
| PubMed ID | 28894151 | Mgi Jnum | J:255390 |
| Mgi Id | MGI:6109128 | Doi | 10.1038/s41598-017-11210-3 |
| Citation | Chadda KR, et al. (2017) The effects of ageing and adrenergic challenge on electrocardiographic phenotypes in a murine model of long QT syndrome type 3. Sci Rep 7(1):11070 |
| abstractText | Long QT Syndrome 3 (LQTS3) arises from gain-of-function Nav1.5 mutations, prolonging action potential repolarisation and electrocardiographic (ECG) QT interval, associated with increased age-dependent risk for major arrhythmic events, and paradoxical responses to beta-adrenergic agents. We investigated for independent and interacting effects of age and Scn5a+/DeltaKPQ genotype in anaesthetised mice modelling LQTS3 on ECG phenotypes before and following beta-agonist challenge, and upon fibrotic change. Prolonged ventricular recovery was independently associated with Scn5a+/DeltaKPQ and age. Ventricular activation was prolonged in old Scn5a+/DeltaKPQ mice (p = 0.03). We associated Scn5a+/DeltaKPQ with increased atrial and ventricular fibrosis (both: p < 0.001). Ventricles also showed increased fibrosis with age (p < 0.001). Age and Scn5a+/DeltaKPQ interacted in increasing incidences of repolarisation alternans (p = 0.02). Dobutamine increased ventricular rate (p < 0.001) and reduced both atrioventricular conduction (PR segment-p = 0.02; PR interval-p = 0.02) and incidences of repolarisation alternans (p < 0.001) in all mice. However, in Scn5a+/DeltaKPQ mice, dobutamine delayed the changes in ventricular repolarisation following corresponding increases in ventricular rate. The present findings implicate interactions between age and Scn5a+/DeltaKPQ in prolonging ventricular activation, correlating them with fibrotic change for the first time, adding activation abnormalities to established recovery abnormalities in LQTS3. These findings, together with dynamic electrophysiological responses to beta-adrenergic challenge, have therapeutic implications for ageing LQTS patients. |
