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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 quinidine on mean 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 quinidine (open bars) and 3 μM quinidine (black bars) to WT and KPQ hearts. The results of one-way ANOVA for correlated samples are shown (***P < 0.0001, **P < 0.001) and compare AERP between control and 1 μM quinidine and control and 3 μM quinidine for KPQ and WT groups, respectively. The results comparing control AERP between WT and KPQ groups are also shown (#P < 0.0001)
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Fig6: Effect of quinidine on mean 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 quinidine (open bars) and 3 μM quinidine (black bars) to WT and KPQ hearts. The results of one-way ANOVA for correlated samples are shown (***P < 0.0001, **P < 0.001) and compare AERP between control and 1 μM quinidine and control and 3 μM quinidine for KPQ and WT groups, respectively. The results comparing control AERP between WT and KPQ groups are also shown (#P < 0.0001)

Mentions: Figure 6 illustrates effects of 1 and 3 μM quinidine on AERP in WT and KPQ hearts obtained during PES conducted at 8 Hz (A) and 10 Hz (B) stimulation frequencies. In WT hearts, a significant increase in AERP from 13.7 ± 0.8 ms (n = 33, 15 hearts) to 19.4 ± 1.2 (n = 13, five hearts) on addition of 1 μM quinidine was only observed at 10 Hz (P < 0.001). AERP further increased to 53.7 ± 2.7 (n = 17, six hearts) in addition of 3 μM quinidine at this frequency (P < 0.0001). The same concentration of quinidine also significantly increased AERP from 14.0 ± 1.0 ms (n = 30, eight hearts) to 35.6 ± 3.5 (n = 19, six hearts) at an 8 Hz stimulation frequency in this experimental group (P < 0.0001). In addition, AERPs obtained at 1 and 3 μM concentrations of the drug were significantly different whether at 8 Hz (P = 0.03) and 10 Hz (P < 0.0001) stimulation frequencies. In KPQ hearts a highly significant increase in AERP from 21.3 ± 0.7 ms (n = 41, 16 hearts) to 37.2 ± 4.0 (n = 14, four hearts) and from 21.2 ± 0.8 ms (n = 43, 15 hearts) to 51.3 ± 8.6 (n = 12, four hearts) was observed at 8 and 10 Hz, respectively, in addition of quinidine 1 μM (P < 0.0001 for both frequencies). Quinidine (3 μM) also significantly increased AERP to 35.4 ± 1.8 (n = 15, five hearts) and 47.7 ± 3.7 (n = 15, five hearts) at 8 and 10 Hz, respectively when compared to control (P < 0.0001) in mutant hearts, doing so to similar extents as obtained with 1 μM quinidine for either frequency (P > 0.05).Fig. 6


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 quinidine on mean 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 quinidine (open bars) and 3 μM quinidine (black bars) to WT and KPQ hearts. The results of one-way ANOVA for correlated samples are shown (***P < 0.0001, **P < 0.001) and compare AERP between control and 1 μM quinidine and control and 3 μM quinidine for KPQ and WT groups, respectively. The results comparing control AERP between WT and KPQ groups are also shown (#P < 0.0001)
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Fig6: Effect of quinidine on mean 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 quinidine (open bars) and 3 μM quinidine (black bars) to WT and KPQ hearts. The results of one-way ANOVA for correlated samples are shown (***P < 0.0001, **P < 0.001) and compare AERP between control and 1 μM quinidine and control and 3 μM quinidine for KPQ and WT groups, respectively. The results comparing control AERP between WT and KPQ groups are also shown (#P < 0.0001)
Mentions: Figure 6 illustrates effects of 1 and 3 μM quinidine on AERP in WT and KPQ hearts obtained during PES conducted at 8 Hz (A) and 10 Hz (B) stimulation frequencies. In WT hearts, a significant increase in AERP from 13.7 ± 0.8 ms (n = 33, 15 hearts) to 19.4 ± 1.2 (n = 13, five hearts) on addition of 1 μM quinidine was only observed at 10 Hz (P < 0.001). AERP further increased to 53.7 ± 2.7 (n = 17, six hearts) in addition of 3 μM quinidine at this frequency (P < 0.0001). The same concentration of quinidine also significantly increased AERP from 14.0 ± 1.0 ms (n = 30, eight hearts) to 35.6 ± 3.5 (n = 19, six hearts) at an 8 Hz stimulation frequency in this experimental group (P < 0.0001). In addition, AERPs obtained at 1 and 3 μM concentrations of the drug were significantly different whether at 8 Hz (P = 0.03) and 10 Hz (P < 0.0001) stimulation frequencies. In KPQ hearts a highly significant increase in AERP from 21.3 ± 0.7 ms (n = 41, 16 hearts) to 37.2 ± 4.0 (n = 14, four hearts) and from 21.2 ± 0.8 ms (n = 43, 15 hearts) to 51.3 ± 8.6 (n = 12, four hearts) was observed at 8 and 10 Hz, respectively, in addition of quinidine 1 μM (P < 0.0001 for both frequencies). Quinidine (3 μM) also significantly increased AERP to 35.4 ± 1.8 (n = 15, five hearts) and 47.7 ± 3.7 (n = 15, five hearts) at 8 and 10 Hz, respectively when compared to control (P < 0.0001) in mutant hearts, doing so to similar extents as obtained with 1 μM quinidine for either frequency (P > 0.05).Fig. 6

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