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

Jeevaratnam, Kamalan; Zhang, Y.; Guzadhur, Laila; Duehmke, Rudolf; Lei, Ming; Grace, Andrew A.; Huang, Christopher L.‐H.

doi:10.1111/j.1748-1716.2010.02110.x

Cited by 24 publications

(42 citation statements)

References 34 publications

(32 reference statements)

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“…Such a notion would parallel recent descriptions of atrial remodeling phenomena in the presence of Scn5a modification [6] and merits further investigation. Nevertheless, the present findings do demonstrate differing action potential latencies corroborating earlier ECG findings [7] under circumstances in which action potential characteristics remained similar.…”

Section: Discussionsupporting

confidence: 92%

“…Nevertheless, they complemented our earlier studies in exploring for interacting effects of genotype, age, and sex and permitted a novel statistical analysis of activation times and their dispersions both over the regions of interest studied and through successive intrinsic beats. Stratification of these results into experimental groups paralleled and therefore permitted direct comparisons with the earlier, similarly stratified, ECG results [7], thus adding to these a full clarification of alterations in electrogram latencies at the tissue level. They went further to achieve direct correlations of such altered conduction with quantitative assessments of the level of fibrosis.…”

Section: Discussionmentioning

confidence: 88%

“…Finally, recent ECG measurements particularly of PR and RR intervals then went on to fully clarify both the independent and the interacting effects of genotype, age, and sex upon conduction characteristics in fully stratified experimental groups. These showed in particular that old male Scn5a +/− showed marked increases in such conduction durations [7]. …”

Section: Discussionmentioning

confidence: 99%

“…Scn5a +/− mice showed ~20% increases in the durations of their QRS complexes [17]. More recent detailed electrocardiographic (ECG) studies demonstrated independent and interacting effects of age and sex on both sino-atrial and atrioventricular function, consistent with marked conduction alterations particularly in old male Scn5a +/− that paralleled clinical arrhythmogenic findings [7]. …”

Section: Introductionmentioning

confidence: 98%

See 3 more Smart Citations

Delayed conduction and its implications in murine Scn5a+/− hearts: independent and interacting effects of genotype, age, and sex

Jeevaratnam

Tee

Zhang

et al. 2010

Pflugers Arch - Eur J Physiol

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We explored for relationships between SCN5A haploinsufficiency, implicated in clinical arrhythmogenicity, and right ventricular (RV) conduction disorders in Langendorff-perfused, male and female, and young (3 months) and old (>12 month old) Scn5a+/− and wild type (WT) hearts. The investigated conditions of genotype, age, and sex affected latencies but not repolarization time courses of RV monophasic action potentials. This prompted examination of the patterns of RV epicardial activation, its dispersion, and their interrelationships as possible arrhythmic mechanisms using a 64-channel, multi-electrode array. Mean ventricular activation times (T*MEAN), spatial dispersions (D*S) between recording channels/cardiac cycle, and maximum activation times (T*MAX) representing the slowest possible conduction in any given heart were all higher in old male Scn5a+/− compared with young male and old female Scn5a+/− and old male WT. Temporal dispersions (D*T) of recording channels were similarly higher in old male Scn5a+/− compared with old male WT. All groupings of D*T, D*S, and T*MAX nevertheless linearly correlated with T*MEAN, with indistinguishable slopes. The variates explored thus influence D*T, D*S, and T*MAX through actions on T*MEAN. These findings in turn correlated with increased levels of fibrosis in young male, young female, and old male Scn5a+/− compared with the corresponding WTs. We thus demonstrate for the first time independent and interacting effects of genotype, age, and sex on epicardial conduction and its dispersions at least partially attributable to fibrotic change, resulting in the greatest effects in old male Scn5a+/− in an absence of alterations in repolarization time courses. This directly implicates altered depolarization in the clinical arrhythmogenicity associated with Scn5a+/−.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

Delayed conduction and its implications in murine Scn5a+/− hearts: independent and interacting effects of genotype, age, and sex

Jeevaratnam

Tee

Zhang

et al. 2010

Pflugers Arch - Eur J Physiol

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“…Thus, their P‐waves, and PR, QRS and QT intervals, continue to reflect atrial and ventricular, depolarisation and repolarisation whose alterations could reflect potentially pro‐arrhythmic electrophysiological changes. Alterations in murine ECG waveforms have thus proven useful in studying murine models for the Brugada syndrome,19, 20 long QT syndrome type 321 and catecholaminergic polymorphic ventricular tachycardia 22…”

Section: Introductionmentioning

confidence: 99%

Age‐dependent electrocardiographic changes in Pgc‐1β deficient murine hearts

Ahmad

Valli

Salvage

et al. 2017

Clin Exp Pharma Physio

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SummaryIncreasing evidence implicates chronic energetic dysfunction in human cardiac arrhythmias. Mitochondrial impairment through Pgc‐1β knockout is known to produce a murine arrhythmic phenotype. However, the cumulative effect of this with advancing age and its electrocardiographic basis have not been previously studied. Young (12‐16 weeks) and aged (>52 weeks), wild type (WT) (n = 5 and 8) and Pgc‐1β−/− (n = 9 and 6), mice were anaesthetised and used for electrocardiographic (ECG) recordings. Time intervals separating successive ECG deflections were analysed for differences between groups before and after β1‐adrenergic (intraperitoneal dobutamine 3 mg/kg) challenge. Heart rates before dobutamine challenge were indistinguishable between groups. The Pgc‐1β−/− genotype however displayed compromised nodal function in response to adrenergic challenge. This manifested as an impaired heart rate response suggesting a functional defect at the level of the sino‐atrial node, and a negative dromotropic response suggesting an atrioventricular conduction defect. Incidences of the latter were most pronounced in the aged Pgc‐1β−/− mice. Moreover, Pgc‐1β−/− mice displayed electrocardiographic features consistent with the existence of a pro‐arrhythmic substrate. Firstly, ventricular activation was prolonged in these mice consistent with slowed action potential conduction and is reported here for the first time. Additionally, Pgc‐1β−/− mice had shorter repolarisation intervals. These were likely attributable to altered K+ conductance properties, ultimately resulting in a shortened QTc interval, which is also known to be associated with increased arrhythmic risk. ECG analysis thus yielded electrophysiological findings bearing on potential arrhythmogenicity in intact Pgc‐1β−/− systems in widespread cardiac regions.

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

Guzadhur

Pearcey

Duehmke

et al. 2010

Pflugers Arch - Eur J Physiol

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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+/ΔKPQ 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+/ΔKPQ than young WT. These levels increased with age in WT but not Scn5a+/ΔKPQ. Both young and aged Scn5a+/ΔKPQ mice showed lower heart rates and longer PR intervals than their WT counterparts. Young Scn5a+/ΔKPQ mice showed longer QT and QTc intervals than young WT. Aged Scn5a+/ΔKPQ 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+/ΔKPQ. Aged murine Scn5a+/ΔKPQ hearts thus exhibit an increased atrial arrhythmogenicity. The differing Nav1.5 expression and electrocardiographic indicators of slowed cardiac conduction between Scn5a+/ΔKPQ and WT, which show further variations associated with aging, may contribute toward atrial arrhythmia in aged Scn5a+/ΔKPQ hearts.

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

Abstract: 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(+/-).

Cited by 24 publications

References 34 publications

Delayed conduction and its implications in murine Scn5a+/− hearts: independent and interacting effects of genotype, age, and sex

Delayed conduction and its implications in murine Scn5a+/− hearts: independent and interacting effects of genotype, age, and sex

Age‐dependent electrocardiographic changes in Pgc‐1β deficient murine hearts

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

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