Differences in sino-atrial and atrio-ventricular function with age and sex attributable to the Scn5a+/- mutation in a murine cardiac model.

AIM: To investigate the interacting effects of age and sex on electrocardiographic (ECG) features of Scn5a(+/-) mice modelling Brugada syndrome. METHODS: Recordings were performed on anaesthetized wild-type (WT) and Scn5a(+/-) mice and differences attributable to these risk factors statistically stratified. RESULTS: Scn5a(+/-) exerted sex-dependent effects upon sino-atrial function that only became apparent with age. RR intervals were greater in old male than in old female Scn5a(+/-). Atrio-ventricular (AV) conduction was slower in young female mice, whether WT and Scn5a(+/-), than the corresponding young male WT and Scn5a(+/-). However, PR intervals lengthened with age in male but not in female Scn5a(+/-) giving the greatest PR intervals in old male Scn5a(+/-) compared with either old male WT or young male Scn5a(+/-) mice. In contrast, PR intervals were similar in old female Scn5a(+/-) and in old female WT. QTc was prolonged in Scn5a(+/-) compared with WT, and female Scn5a(+/-) compared with female WT. Age-dependent alterations in durations of ventricular repolarization relative to WT affected male but not female Scn5a(+/-). Thus, T-wave durations were greater in old male Scn5a(+/-) compared with old male WT, but indistinguishable between old female Scn5a(+/-) and old female WT. Finally, analysis for combined interactions of genotype, age and sex demonstrated no effects on P wave and QRS durations and QTc intervals. CONCLUSION: We demonstrate for the first time that age, sex and genotype exert both independent and interacting ECG effects. The latter suggest alterations in cardiac pacemaker function, atrio-ventricular conduction and ventricular repolarization greatest in ageing male Scn5a(+/-)

Differences in sino-atrial and atrio-ventricular function with age and sex attributable to the Scn5a+/- mutation in a murine cardiac model.

AIM: To investigate the interacting effects of age and sex on electrocardiographic (ECG) features of Scn5a(+/-) mice modelling Brugada syndrome. METHODS: Recordings were performed on anaesthetized wild-type (WT) and Scn5a(+/-) mice and differences attributable to these risk factors statistically stratified. RESULTS: Scn5a(+/-) exerted sex-dependent effects upon sino-atrial function that only became apparent with age. RR intervals were greater in old male than in old female Scn5a(+/-). Atrio-ventricular (AV) conduction was slower in young female mice, whether WT and Scn5a(+/-), than the corresponding young male WT and Scn5a(+/-). However, PR intervals lengthened with age in male but not in female Scn5a(+/-) giving the greatest PR intervals in old male Scn5a(+/-) compared with either old male WT or young male Scn5a(+/-) mice. In contrast, PR intervals were similar in old female Scn5a(+/-) and in old female WT. QTc was prolonged in Scn5a(+/-) compared with WT, and female Scn5a(+/-) compared with female WT. Age-dependent alterations in durations of ventricular repolarization relative to WT affected male but not female Scn5a(+/-). Thus, T-wave durations were greater in old male Scn5a(+/-) compared with old male WT, but indistinguishable between old female Scn5a(+/-) and old female WT. Finally, analysis for combined interactions of genotype, age and sex demonstrated no effects on P wave and QRS durations and QTc intervals. CONCLUSION: We demonstrate for the first time that age, sex and genotype exert both independent and interacting ECG effects. The latter suggest alterations in cardiac pacemaker function, atrio-ventricular conduction and ventricular repolarization greatest in ageing male Scn5a(+/-)

The age-dependence of atrial arrhythmogenicity in Scn5a+/- murine hearts reflects alterations in action potential propagation and recovery.

1. In the present study, we investigated the effect of age on atrial electrophysiological properties in Scn5a(+/-) hearts used to model corresponding increases in atrial arrhythmic tendency in human Brugada syndrome. 2. Atrial action potential initiation, propagation and recovery were compared in young (3 month old) and aged (12 month old), wild-type (WT) and Scn5a(+/-) hearts. Multielectrode array recordings assessed the spatial propagation of intrinsic electrical activity in superfused atrial preparations, whereas bipolar electrogram recordings measured basic cycle lengths (BCL) in Langendorff preparations. The duration of electrogram activity (EGD) during regular and extrasystolic stimulation with programmed electrical stimulation provided EGD ratios and atrial effective refractory periods (AERP). Monophasic recordings measured action potential durations (APD). 3. Systematic statistical explorations for independent and interacting effects of age and the Scn5a(+/-) condition demonstrated that both young and aged Scn5a(+/-) mice exhibited slowed propagation of atrial excitation relative to corresponding WT mice, with the greatest effects in aged Scn5a(+/-) mice, which additionally exhibited increased intrinsic BCL. 4. Young Scn5a(+/-) mice exhibited greater EGD and EGD ratios, as well as APD/AERP ratios, suggesting increased arrhythmic tendency compared with WT mice. 5. Aged Scn5a(+/-) mice exhibited normal EGD, EGD ratios and APD compared to aged WT and young Scn5a(+/-), and increased AERP and smaller APD/AERP ratios compared with young Scn5a(+/-). 6. These electrophysiological findings indicate increased atrial arrhythmogenicity with maximal effects on both conduction and repolarization characteristics in young compared with aged Scn5a(+/-) mice

Atrial arrhythmogenicity in aged Scn5a+/DeltaKPQ mice modeling long QT type 3 syndrome and its relationship to Na+ channel expression and cardiac conduction.

Recent studies have reported that human mutations in Nav1.5 predispose to early age onset atrial arrhythmia. The present experiments accordingly assess atrial arrhythmogenicity in aging Scn5a+/KPQ mice modeling long QT3 syndrome in relationship to cardiac Na(+) channel, Nav1.5, expression. Atrial electrophysiological properties in isolated Langendorff-perfused hearts from 3- and 12-month-old wild type (WT), and Scn5a+/KPQ mice were assessed using programmed electrical stimulation and their Nav1.5 expression assessed by Western blot. Cardiac conduction properties were assessed electrocardiographically in intact anesthetized animals. Monophasic action potential recordings demonstrated increased atrial arrhythmogenicity specifically in aged Scn5a+/DeltaKPQ hearts. These showed greater action potential duration/refractory period ratios but lower atrial Nav1.5 expression levels than aged WT mice. Atrial Nav1.5 levels were higher in young Scn5a+/DeltaKPQ than young WT. These levels increased with age in WT but not Scn5a+/DeltaKPQ. Both young and aged Scn5a+/DeltaKPQ mice showed lower heart rates and longer PR intervals than their WT counterparts. Young Scn5a+/DeltaKPQ mice showed longer QT and QTc intervals than young WT. Aged Scn5a+/DeltaKPQ showed longer QRS durations than aged WT. PR intervals were prolonged and QT intervals were shortened in young relative to aged WT. In contrast, ECG parameters were similar between young and aged Scn5a+/DeltaKPQ. Aged murine Scn5a+/DeltaKPQ hearts thus exhibit an increased atrial arrhythmogenicity. The differing Nav1.5 expression and electrocardiographic indicators of slowed cardiac conduction between Scn5a+/DeltaKPQ and WT, which show further variations associated with aging, may contribute toward atrial arrhythmia in aged Scn5a+/DeltaKPQ hearts

Altered re-excitation thresholds and conduction of extrasystolic action potentials contribute to arrhythmogenicity in murine models of long QT syndrome.

AIM: QT interval prolongation reflecting delayed action potential (AP) repolarization is associated with polymorphic ventricular tachycardia and early after depolarizations potentially initiating extrasystolic APs if of sufficient amplitude. The current experiments explored contributions of altered re-excitation thresholds for, and conduction of, such extrasystolic APs to arrhythmogenesis in Langendorff-perfused, normokalaemic, control wild-type hearts and two experimental groups modelling long QT (LQT). The two LQT groups consisted of genetically modified, Scn5a(+/ΔKPQ) and hypokalaemic wild-type murine hearts. METHODS: Hearts were paced from their right ventricles and monophasic AP electrode recordings obtained from their left ventricular epicardia, with recording and pacing electrodes separated by 1 cm. An adaptive programmed electrical stimulation protocol applied pacing (S1) stimulus trains followed by premature (S2) extrastimuli whose amplitudes were progressively increased with progressive decrements in S1S2 interval to maintain stimulus capture. Such protocols culminated in either arrhythmic or refractory endpoints. RESULTS: Arrhythmic outcomes were associated with (1) lower conduction velocities in their initiating extrasystolic APs than refractory outcomes and (2) higher conduction velocities in the LQT groups than in controls. Furthermore, (3) the endpoints were reached at longer S1S2 coupling intervals and with smaller stimulus amplitudes in the LQT groups compared with controls. This was despite (4) similar relationships between conduction velocity and S1S2 coupling interval and between re-excitation thresholds and S1S2 coupling interval in all three experimental groups. CONCLUSIONS: Arrhythmias induced by extrasystolic APs in the LQT groups thus occur under conditions of higher conduction velocity and greater sensitivity to extrastimuli than in controls