Paced Electrogram Fractionation Analysis of Arrhythmogenic Tendency in ΔKPQ <i>Scn5a</i> Mice

Head, Catherine; Balasubramaniam, Richard; Thomas, Glyn; Goddard, Catharine A.; Lei, Ming; Colledge, William H; Grace, Andrew A.; Huang, Christopher L.‐H.

doi:10.1111/j.1540-8167.2005.00200.x

Cited by 61 publications

(63 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…QT intervals were then quantified in murine Scn5a +/Δ KPQ hearts containing the ΔKPQ (1,505–1,507) gain-of-function Scn5a deletion, modeling human long QT syndrome and expected to demonstrate chronic QT-interval prolongation (7, 18). Ventricular APs were obtained from 40 cells in three Scn5a +/Δ KPQ hearts.…”

Section: Resultsmentioning

confidence: 99%

Measurement and interpretation of electrocardiographic QT intervals in murine hearts

Zhang

King

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Alterations in ECG QT intervals correlate with the risk of potentially fatal arrhythmias, for which transgenic murine hearts are becoming increasingly useful experimental models. However, QT intervals are poorly defined in murine ECGs. As a consequence, several different techniques have been used to measure murine QT intervals. The present work develops a consistent measure of the murine QT interval that correlates with changes in the duration of ventricular myocyte action potentials (APs). Volume-conducted ECGs were compared with simultaneously recorded APs, obtained using floating intracellular microelectrodes in Langendorff-perfused mouse hearts. QT intervals were measured from the onset of the QRS complex. The interval, Q-APR90, measured to the time at 90% AP recovery, was compared with two measures of the QT interval. QT1 was measured to the recovery of the ECG trace to the isoelectric baseline for entirely positive T-waves or to the trough of any negative T-wave undershoot. QT2—used extensively in previous studies—was measured to the return of any ECG trough to the isoelectric baseline. QT1, but not QT2, closely correlated with changes in Q-APR90. These findings were confirmed over a range of pacing rates, in low K+ concentration solutions, and in Scn5a+/ΔKPQ hearts used to model human long QT syndrome. Application of this method in whole anesthetized mice similarly demonstrated a prolonged corrected QT (QTc) in Scn5a+/ΔKPQ hearts. We therefore describe a robust method for the determination of QT and QTc intervals that correlate with the duration of ventricular myocyte APs in murine hearts.

show abstract

Section: Resultsmentioning

confidence: 99%

Measurement and interpretation of electrocardiographic QT intervals in murine hearts

Zhang

King

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…All the experiments described complied with the UK Animals (Scientific Procedures) Act 1986. The procedures for the preparation of Langendorff-perfused mouse hearts have been described previously (36). Mice were sacrificed by cervical dislocation in accordance with Sections 1(c) and 2 of Schedule 1 of the UK Animals (Scientific Procedures) Act 1986.…”

Section: Methodsmentioning

confidence: 99%

Anti-arrhythmic effects of hypercalcemia in hyperkalemic, Langendorff-perfused mouse hearts

et al. 2016

View full text Add to dashboard Cite

The present study examined the ventricular arrhythmic and electrophysiological properties during hyperkalemia (6.3 mM [K+] vs. 4 mM in normokalemia) and anti-arrhythmic effects of hypercalcemia (2.2 mM [Ca2+]) in Langendorff-perfused mouse hearts. Monophasic action potential recordings were obtained from the left ventricle during right ventricular pacing. Hyperkalemia increased the proportion of hearts showing provoked ventricular tachycardia (VT) from 0 to 6 of 7 hearts during programmed electrical stimulation (Fisher's exact test, P<0.05). It shortened the epicardial action potential durations (APDx) at 90, 70, 50 and 30% repolarization and ventricular effective refractory periods (VERPs) (analysis of variance, P<0.05) without altering activation latencies. Endocardial APDx and VERPs were unaltered. Consequently, ∆APDx (endocardial APDx-epicardial APDx) was increased, VERP/latency ratio was decreased and critical intervals for reexcitation (APD90-VERP) were unchanged. Hypercalcemia treatment exerted anti-arrhythmic effects during hyperkalemia, reducing the proportion of hearts showing VT to 1 of 7 hearts. It increased epicardial VERPs without further altering the remaining parameters, returning VERP/latency ratio to normokalemic values and also decreased the critical intervals. In conclusion, hyperkalemia exerted pro-arrhythmic effects by shortening APDs and VERPs. Hypercalcemia exerted anti-arrhythmic effects by reversing VERP changes, which scaled the VERP/latency ratio and critical intervals.

show abstract

“…LQTS3 patients commonly exhibit bradycardia, and they show a greater risk of arrhythmia at lower heart rates, such as during rest and sleep [64]. The most common mechanism of LQTS3 pathophysiology is the disruption of the fast inactivation kinetics of the channel, enhancing I Na-L [30]. However, the list of mutations in Table 1 suggests that each hypothetical alteration in activation and inactivation properties proposed above is associated with a particular case of LQTS3.…”

Section: Introductionmentioning

confidence: 99%

Sodium channel biophysics, late sodium current and genetic arrhythmic syndromes

Chadda

Jeevaratnam

Lei

et al. 2017

Pflugers Arch - Eur J Physiol

Self Cite

View full text Add to dashboard Cite

Arrhythmias arise from breakdown of orderly action potential (AP) activation, propagation and recovery driven by interactive opening and closing of successive voltage-gated ion channels, in which one or more Na+ current components play critical parts. Early peak, Na+ currents (I Na) reflecting channel activation drive the AP upstroke central to cellular activation and its propagation. Sustained late Na+ currents (I Na-L) include contributions from a component with a delayed inactivation timecourse influencing AP duration (APD) and refractoriness, potentially causing pro-arrhythmic phenotypes. The magnitude of I Na-L can be analysed through overlaps or otherwise in the overall voltage dependences of the steady-state properties and kinetics of activation and inactivation of the Na+ conductance. This was useful in analysing repetitive firing associated with paramyotonia congenita in skeletal muscle. Similarly, genetic cardiac Na+ channel abnormalities increasing I Na-L are implicated in triggering phenomena of automaticity, early and delayed afterdepolarisations and arrhythmic substrate. This review illustrates a wide range of situations that may accentuate I Na-L. These include (1) overlaps between steady-state activation and inactivation increasing window current, (2) kinetic deficiencies in Na+ channel inactivation leading to bursting phenomena associated with repetitive channel openings and (3) non-equilibrium gating processes causing channel re-opening due to more rapid recoveries from inactivation. All these biophysical possibilities were identified in a selection of abnormal human SCN5A genotypes. The latter presented as a broad range of clinical arrhythmic phenotypes, for which effective therapeutic intervention would require specific identification and targeting of the diverse electrophysiological abnormalities underlying their increased I Na-L.

show abstract

Paced Electrogram Fractionation Analysis of Arrhythmogenic Tendency in ΔKPQ Scn5a Mice

Cited by 61 publications

References 46 publications

Measurement and interpretation of electrocardiographic QT intervals in murine hearts

Measurement and interpretation of electrocardiographic QT intervals in murine hearts

Anti-arrhythmic effects of hypercalcemia in hyperkalemic, Langendorff-perfused mouse hearts

Sodium channel biophysics, late sodium current and genetic arrhythmic syndromes

Contact Info

Product

Resources

About