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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 and quinidine on atrial APDs in WT and KPQ hearts. MAPs recorded during regular pacing at 8 Hz in WT (A) and KPQ (B) hearts before (a, A and B) and after addition of 1 μM (B, b) and 3 μM (A, b) flecainide and 3 μM quinidine (c, A and B). The bar chart (C) summarises effect of 1 μM flecainide (open bars; KPQ) and 3 μM flecainide (WT) and 3 μM quinidine (black bars) on mean APD90 of both experimental groups. Stars represent significantly different results (*P < 0.0001) between control (dashed bars) and drug-treated mean APD90 within each experimental group, while # indicates significantly different control mean APD90 between WT and KPQ hearts (#P < 0.0001)
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Fig4: Effect of flecainide and quinidine on atrial APDs in WT and KPQ hearts. MAPs recorded during regular pacing at 8 Hz in WT (A) and KPQ (B) hearts before (a, A and B) and after addition of 1 μM (B, b) and 3 μM (A, b) flecainide and 3 μM quinidine (c, A and B). The bar chart (C) summarises effect of 1 μM flecainide (open bars; KPQ) and 3 μM flecainide (WT) and 3 μM quinidine (black bars) on mean APD90 of both experimental groups. Stars represent significantly different results (*P < 0.0001) between control (dashed bars) and drug-treated mean APD90 within each experimental group, while # indicates significantly different control mean APD90 between WT and KPQ hearts (#P < 0.0001)

Mentions: Figure 4 illustrates the effects of flecainide and quinidine on atrial action potential durations at the 90% repolarisation level (APD90) in WT and KPQ hearts. In these experiments, hearts were regularly paced at 8 Hz; at the faster pacing frequency of 10 Hz, it was often not possible clearly to demonstrate full recovery of the action potential to baseline, which was necessary for a full characterisation of APD90 values. It displays action potential waveforms in WT (A) and KPQ hearts (B), before (a) and following addition of flecainide (b) and quinidine (c). Flecainide 3 μM (Ab and open bars in C) significantly prolonged APD90 in WT hearts (P < 0.0001) from 22.1 ± 0.4 (n = 13, seven hearts) to 27.3 ± 0.8 (n = 13, six hearts) but failed to ensure consistent capture in KPQ hearts. A lower concentration of 1 μM flecainide did not change APD90 in KPQ hearts, with values for mean APD90 being 24.5 ± 0.3 (n = 17, ten hearts) before and 23.9 ± 0.7 (n = 11, seven hearts) after addition of the drug (Bb and open bars in C). Monophasic action potential waveforms (MAPs) recorded during regular pacing at 8 Hz in WT and KPQ hearts both significantly (P < 0.0001 for both groups) increased in duration on addition of 3 μM quinidine (c, A and B, respectively, black bars in C) from 22.1 ± 0.4 (n = 13, seven hearts) to 31.0 ± 0.6 (n = 8, four hearts) and 24.5 ± 0.3 (n = 17, ten hearts) to 32.3 ± 0.6 (n = 7, four hearts), respectively. Figure 4C also shows that control mean APD90 was significantly (P < 0.0001 (#)) longer in KPQ (24.5 ± 0.3 (n = 17, ten hearts)) when compared to WT (22.1 ± 0.4 (n = 13, seven hearts)) hearts.Fig. 4


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 and quinidine on atrial APDs in WT and KPQ hearts. MAPs recorded during regular pacing at 8 Hz in WT (A) and KPQ (B) hearts before (a, A and B) and after addition of 1 μM (B, b) and 3 μM (A, b) flecainide and 3 μM quinidine (c, A and B). The bar chart (C) summarises effect of 1 μM flecainide (open bars; KPQ) and 3 μM flecainide (WT) and 3 μM quinidine (black bars) on mean APD90 of both experimental groups. Stars represent significantly different results (*P < 0.0001) between control (dashed bars) and drug-treated mean APD90 within each experimental group, while # indicates significantly different control mean APD90 between WT and KPQ hearts (#P < 0.0001)
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Related In: Results  -  Collection

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Fig4: Effect of flecainide and quinidine on atrial APDs in WT and KPQ hearts. MAPs recorded during regular pacing at 8 Hz in WT (A) and KPQ (B) hearts before (a, A and B) and after addition of 1 μM (B, b) and 3 μM (A, b) flecainide and 3 μM quinidine (c, A and B). The bar chart (C) summarises effect of 1 μM flecainide (open bars; KPQ) and 3 μM flecainide (WT) and 3 μM quinidine (black bars) on mean APD90 of both experimental groups. Stars represent significantly different results (*P < 0.0001) between control (dashed bars) and drug-treated mean APD90 within each experimental group, while # indicates significantly different control mean APD90 between WT and KPQ hearts (#P < 0.0001)
Mentions: Figure 4 illustrates the effects of flecainide and quinidine on atrial action potential durations at the 90% repolarisation level (APD90) in WT and KPQ hearts. In these experiments, hearts were regularly paced at 8 Hz; at the faster pacing frequency of 10 Hz, it was often not possible clearly to demonstrate full recovery of the action potential to baseline, which was necessary for a full characterisation of APD90 values. It displays action potential waveforms in WT (A) and KPQ hearts (B), before (a) and following addition of flecainide (b) and quinidine (c). Flecainide 3 μM (Ab and open bars in C) significantly prolonged APD90 in WT hearts (P < 0.0001) from 22.1 ± 0.4 (n = 13, seven hearts) to 27.3 ± 0.8 (n = 13, six hearts) but failed to ensure consistent capture in KPQ hearts. A lower concentration of 1 μM flecainide did not change APD90 in KPQ hearts, with values for mean APD90 being 24.5 ± 0.3 (n = 17, ten hearts) before and 23.9 ± 0.7 (n = 11, seven hearts) after addition of the drug (Bb and open bars in C). Monophasic action potential waveforms (MAPs) recorded during regular pacing at 8 Hz in WT and KPQ hearts both significantly (P < 0.0001 for both groups) increased in duration on addition of 3 μM quinidine (c, A and B, respectively, black bars in C) from 22.1 ± 0.4 (n = 13, seven hearts) to 31.0 ± 0.6 (n = 8, four hearts) and 24.5 ± 0.3 (n = 17, ten hearts) to 32.3 ± 0.6 (n = 7, four hearts), respectively. Figure 4C also shows that control mean APD90 was significantly (P < 0.0001 (#)) longer in KPQ (24.5 ± 0.3 (n = 17, ten hearts)) when compared to WT (22.1 ± 0.4 (n = 13, seven hearts)) hearts.Fig. 4

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