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Atrial arrhythmogenesis in wild-type and Scn5a+/delta murine hearts modelling LQT3 syndrome.

Dautova Y, Zhang Y, Sabir I, Grace AA, Huang CL - Pflugers Arch. (2009)

Bottom Line: Long QT(3) (LQT3) syndrome is associated with abnormal repolarisation kinetics, prolonged action potential durations (APD) and QT intervals and may lead to life-threatening ventricular arrhythmias.Quinidine similarly exerted anti-arrhythmic effects, prolonged AERP over corresponding APD(90) in both WT and KPQ groups.They attribute these findings to differences in the CI between WT and mutant hearts, in the presence or absence of these drugs.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Biology Group, Physiological Laboratory, University of Cambridge, Cambridge, UK.

ABSTRACT
Long QT(3) (LQT3) syndrome is associated with abnormal repolarisation kinetics, prolonged action potential durations (APD) and QT intervals and may lead to life-threatening ventricular arrhythmias. However, there have been few physiological studies of its effects on atrial electrophysiology. Programmed electrical stimulation and burst pacing induced atrial arrhythmic episodes in 16 out of 16 (16/16) wild-type (WT) and 7/16 genetically modified Scn5a+/Delta (KPQ) Langendorff-perfused murine hearts modelling LQT3 (P < 0.001 for both), and in 14/16 WT and 1/16 KPQ hearts (P < 0.001 for both; Fisher's exact test), respectively. The arrhythmogenic WT hearts had significantly larger positive critical intervals (CI), given by the difference between atrial effective refractory periods (AERPs) and action potential durations at 90% recovery (APD(90)), compared to KPQ hearts (8.1 and 3.2 ms, respectively, P < 0.001). Flecainide prevented atrial arrhythmias in all arrhythmogenic WT (P < 0.001) and KPQ hearts (P < 0.05). It prolonged the AERP to a larger extent than it did the APD(90) in both WT and KPQ groups, giving negative CIs. Quinidine similarly exerted anti-arrhythmic effects, prolonged AERP over corresponding APD(90) in both WT and KPQ groups. These findings, thus, demonstrate, for the first time, inhibitory effects of the KPQ mutation on atrial arrhythmogenesis and its modification by flecainide and quinidine. They attribute these findings to differences in the CI between WT and mutant hearts, in the presence or absence of these drugs. Thus, prolongation of APD(90) over AERP gave positive CI values and increased atrial arrhythmogenicity whereas lengthening of AERP over APD(90) reduced such CI values and produced the opposite effect.

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Effect of flecainide on mean atrial effective refractory periods (AERP) in WT and KPQ hearts. AERPs observed during 8 Hz (A) and 10 Hz (B) PES before (dashed bars) and after addition of 1 μM flecainide (open bars) and 3 μM flecainide (black bars) to WT and KPQ hearts. The results of one-way ANOVA for correlated samples are shown (***P < 0.0001) and compare AERP between control and 1 μM flecainide and control and 3 μM flecainide for KPQ and WT groups, respectively. X marking represents loss of capture with 3 μM flecainide for KPQ preparations. The results comparing control AERP between WT and KPQ groups are also shown (P < 0.0001 (#))
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Fig5: Effect of flecainide on mean atrial effective refractory periods (AERP) in WT and KPQ hearts. AERPs observed during 8 Hz (A) and 10 Hz (B) PES before (dashed bars) and after addition of 1 μM flecainide (open bars) and 3 μM flecainide (black bars) to WT and KPQ hearts. The results of one-way ANOVA for correlated samples are shown (***P < 0.0001) and compare AERP between control and 1 μM flecainide and control and 3 μM flecainide for KPQ and WT groups, respectively. X marking represents loss of capture with 3 μM flecainide for KPQ preparations. The results comparing control AERP between WT and KPQ groups are also shown (P < 0.0001 (#))

Mentions: In contrast to previous studies of ventricular arrhythmogenesis [39, 40], the present experiments demonstrated that KPQ hearts showed a reduced propensity to atrial arrhythmogenesis compared to WT, and this tendency was reduced further by both flecainide and quinidine in both genetic variants. Yet KPQ hearts also showed increased atrial APD90 values compared to WT hearts. Furthermore, flecainide and quinidine exerted anti-arrhythmic effects in both KPQ and WT. Yet flecainide also increased APD90 in WT, and both flecainide and quinidine increased APD90 in KPQ hearts. However comparisons of refractory periods in KPQ and WT hearts provided possible correlates with their contrasting arrhythmogenic properties. Thus, Fig. 5 shows significantly longer mean AERPs in KPQ hearts compared to WT hearts when these were subject to PES conducted at either 8 or 10 Hz stimulation frequencies (P < 0.0001 for both). AERP observed at 8 Hz in WT hearts was 14.0 ± 1.0 ms (n = 30, eight hearts) and in KPQ hearts was equal to 21.3 ± 0.7 ms (n = 41, 16 hearts). At 10 Hz, these values were 13.7 ± 0.8 ms (n = 33, 15 hearts) and 21.2 ± 0.8 (n = 43, 15 hearts) in WT and KPQ experimental groups, respectively.Fig. 5


Atrial arrhythmogenesis in wild-type and Scn5a+/delta murine hearts modelling LQT3 syndrome.

Dautova Y, Zhang Y, Sabir I, Grace AA, Huang CL - Pflugers Arch. (2009)

Effect of flecainide on mean atrial effective refractory periods (AERP) in WT and KPQ hearts. AERPs observed during 8 Hz (A) and 10 Hz (B) PES before (dashed bars) and after addition of 1 μM flecainide (open bars) and 3 μM flecainide (black bars) to WT and KPQ hearts. The results of one-way ANOVA for correlated samples are shown (***P < 0.0001) and compare AERP between control and 1 μM flecainide and control and 3 μM flecainide for KPQ and WT groups, respectively. X marking represents loss of capture with 3 μM flecainide for KPQ preparations. The results comparing control AERP between WT and KPQ groups are also shown (P < 0.0001 (#))
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Related In: Results  -  Collection

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Fig5: Effect of flecainide on mean atrial effective refractory periods (AERP) in WT and KPQ hearts. AERPs observed during 8 Hz (A) and 10 Hz (B) PES before (dashed bars) and after addition of 1 μM flecainide (open bars) and 3 μM flecainide (black bars) to WT and KPQ hearts. The results of one-way ANOVA for correlated samples are shown (***P < 0.0001) and compare AERP between control and 1 μM flecainide and control and 3 μM flecainide for KPQ and WT groups, respectively. X marking represents loss of capture with 3 μM flecainide for KPQ preparations. The results comparing control AERP between WT and KPQ groups are also shown (P < 0.0001 (#))
Mentions: In contrast to previous studies of ventricular arrhythmogenesis [39, 40], the present experiments demonstrated that KPQ hearts showed a reduced propensity to atrial arrhythmogenesis compared to WT, and this tendency was reduced further by both flecainide and quinidine in both genetic variants. Yet KPQ hearts also showed increased atrial APD90 values compared to WT hearts. Furthermore, flecainide and quinidine exerted anti-arrhythmic effects in both KPQ and WT. Yet flecainide also increased APD90 in WT, and both flecainide and quinidine increased APD90 in KPQ hearts. However comparisons of refractory periods in KPQ and WT hearts provided possible correlates with their contrasting arrhythmogenic properties. Thus, Fig. 5 shows significantly longer mean AERPs in KPQ hearts compared to WT hearts when these were subject to PES conducted at either 8 or 10 Hz stimulation frequencies (P < 0.0001 for both). AERP observed at 8 Hz in WT hearts was 14.0 ± 1.0 ms (n = 30, eight hearts) and in KPQ hearts was equal to 21.3 ± 0.7 ms (n = 41, 16 hearts). At 10 Hz, these values were 13.7 ± 0.8 ms (n = 33, 15 hearts) and 21.2 ± 0.8 (n = 43, 15 hearts) in WT and KPQ experimental groups, respectively.Fig. 5

Bottom Line: Long QT(3) (LQT3) syndrome is associated with abnormal repolarisation kinetics, prolonged action potential durations (APD) and QT intervals and may lead to life-threatening ventricular arrhythmias.Quinidine similarly exerted anti-arrhythmic effects, prolonged AERP over corresponding APD(90) in both WT and KPQ groups.They attribute these findings to differences in the CI between WT and mutant hearts, in the presence or absence of these drugs.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Biology Group, Physiological Laboratory, University of Cambridge, Cambridge, UK.

ABSTRACT
Long QT(3) (LQT3) syndrome is associated with abnormal repolarisation kinetics, prolonged action potential durations (APD) and QT intervals and may lead to life-threatening ventricular arrhythmias. However, there have been few physiological studies of its effects on atrial electrophysiology. Programmed electrical stimulation and burst pacing induced atrial arrhythmic episodes in 16 out of 16 (16/16) wild-type (WT) and 7/16 genetically modified Scn5a+/Delta (KPQ) Langendorff-perfused murine hearts modelling LQT3 (P < 0.001 for both), and in 14/16 WT and 1/16 KPQ hearts (P < 0.001 for both; Fisher's exact test), respectively. The arrhythmogenic WT hearts had significantly larger positive critical intervals (CI), given by the difference between atrial effective refractory periods (AERPs) and action potential durations at 90% recovery (APD(90)), compared to KPQ hearts (8.1 and 3.2 ms, respectively, P < 0.001). Flecainide prevented atrial arrhythmias in all arrhythmogenic WT (P < 0.001) and KPQ hearts (P < 0.05). It prolonged the AERP to a larger extent than it did the APD(90) in both WT and KPQ groups, giving negative CIs. Quinidine similarly exerted anti-arrhythmic effects, prolonged AERP over corresponding APD(90) in both WT and KPQ groups. These findings, thus, demonstrate, for the first time, inhibitory effects of the KPQ mutation on atrial arrhythmogenesis and its modification by flecainide and quinidine. They attribute these findings to differences in the CI between WT and mutant hearts, in the presence or absence of these drugs. Thus, prolongation of APD(90) over AERP gave positive CI values and increased atrial arrhythmogenicity whereas lengthening of AERP over APD(90) reduced such CI values and produced the opposite effect.

Show MeSH
Related in: MedlinePlus