The effects of ageing and adrenergic challenge on electrocardiographic phenotypes in a murine model of long QT syndrome type 3

Abstract

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 β-adrenergic agents. We investigated for independent and interacting effects of age and Scn5a+/ΔKPQ genotype in anaesthetised mice modelling LQTS3 on ECG phenotypes before and following β-agonist challenge, and upon fibrotic change. Prolonged ventricular recovery was independently associated with Scn5a+/ΔKPQ and age. Ventricular activation was prolonged in old Scn5a+/ΔKPQ mice (p = 0.03). We associated Scn5a+/ΔKPQ with increased atrial and ventricular fibrosis (both: p < 0.001). Ventricles also showed increased fibrosis with age (p < 0.001). Age and Scn5a+/ΔKPQ 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+/ΔKPQ mice, dobutamine delayed the changes in ventricular repolarisation following corresponding increases in ventricular rate. The present findings implicate interactions between age and Scn5a+/ΔKPQ 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 β-adrenergic challenge, have therapeutic implications for ageing LQTS patients.

Targeting the β‐adrenergic receptor in the clinical management of congenital long QT syndrome

“…77 Similarly, in a Scn5a + / KPQ murine model of LQTS3, dobutamine sympathetic stimulation reduced the incidence of repolarization alternans. 94 Thus, decreased TDR following adrenergic stimulation in LQTS3 suppresses the development of an arrhythmic substrate. Therefore, clinical and experimental data appear to suggest that sympathetic stimulation results in a decrease in both arrhythmic trigger and substrate, and hence decreases the risk of cardiac arrhythmias.…”

“…However, some studies contradicting this conclusion have reported that sympathetic activity may be without effect, or may even be proarrhythmic. [94][95][96][97] These discrepancies arise because of differences in the protocol of sympathetic stimulation and dose of pharmacological agonists. These reports showed a protective effect of sympathetic activity in response to a progressive increase in adrenergic stimulation.…”

“…These results were further complimented by in vivo LQTS3 murine reports: following an increase in ventricular rate produced by dobutamine sympathetic stimulation, a delay in ventricular repolarization adaptation was reported. 94 This may represent an increased arrhythmic risk by sympathetic stimulation following transient HR increase.…”

“…[99][100][101][102][103] For example, I Na plays the same physiological role in both mouse and humans, being responsible for the rapid depolarization phase of the AP 102 and thus enabling the study of Na + channel abnormalities, such as LQTS3. [94][95][96]102 However, important differences exist, particularly regarding the less prominent Ca 2+ current and different expression and role of potassium channels in repolarization. 99,103 Considered together, this means mouse ventricular AP lacks the typical plateau phase present in human ventricular AP, as well as having a shorter APD.…”

“…Nonetheless, transgenic Scn5a + / KPQ mice that model LQTS3 have been shown to reflect the LQTS3 human phenotype, including prolonged APD, arrhythmic tendency, and ECG features. [94][95][96]105 In summary, the effects of sympathetic stimulation are largely dependent on the clinical context and the experimental protocols used, which may influence the recommendation of use of β-blocker therapy in LQTS3 patients.…”