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Pharmacological separation of early afterdepolarizations from arrhythmogenic substrate in DeltaKPQ Scn5a murine hearts modelling human long QT 3 syndrome.

Thomas G, Killeen MJ, Grace AA, Huang CL - Acta Physiol (Oxf) (2007)

Bottom Line: Left ventricular endocardial and epicardial monophasic action potentials and arrhythmogenic tendency were compared in isolated wild type (WT) and Scn5a+/Delta hearts perfused with 0.1 and 1 microm propranolol and paced from the right ventricular epicardium.Thus 0.1 microm propranolol reduced epicardial but not endocardial APD(90) from 54.7 +/- 1.6 to 44.0 +/- 2.0 ms, restoring DeltaAPD(90) from -3.8 +/- 1.6 to 3.5 +/- 2.5 ms (all n = 5), close to WT values.However, 1 microm propranolol increased epicardial APD(90) to 72.5 +/- 1.2 ms and decreased endocardial APD(90) from 50.9 +/- 1.0 to 24.5 +/- 0.3 ms, increasing DeltaAPD(90) to -48.0 +/- 1.2 ms.

View Article: PubMed Central - PubMed

Affiliation: Section of Cardiovascular Biology, Department of Biochemistry, University of Cambridge, Cambridge, UK.

ABSTRACT

Aim: To perform an empirical, pharmacological, separation of early afterdepolarizations (EADs) and transmural gradients of repolarization in arrhythmogenesis in a genetically modified mouse heart modelling human long QT syndrome (LQT) 3.

Methods: Left ventricular endocardial and epicardial monophasic action potentials and arrhythmogenic tendency were compared in isolated wild type (WT) and Scn5a+/Delta hearts perfused with 0.1 and 1 microm propranolol and paced from the right ventricular epicardium.

Results: All spontaneously beating bradycardic Scn5a+/Delta hearts displayed EADs, triggered beats and ventricular tachycardia (VT; n = 7), events never seen in WT hearts (n = 5). Perfusion with 0.1 and 1 microm propranolol suppressed all EADs, triggered beats and episodes of VT. In contrast, triggering of VT persisted following programmed electrical stimulation in 6 of 12 (50%), one of eight (12.5%), but six of eight (75%) Scn5a+/Delta hearts perfused with 0, 0.1 and 1 microm propranolol respectively in parallel with corresponding alterations in repolarization gradients, reflected in action potential duration (DeltaAPD(90)) values. Thus 0.1 microm propranolol reduced epicardial but not endocardial APD(90) from 54.7 +/- 1.6 to 44.0 +/- 2.0 ms, restoring DeltaAPD(90) from -3.8 +/- 1.6 to 3.5 +/- 2.5 ms (all n = 5), close to WT values. However, 1 microm propranolol increased epicardial APD(90) to 72.5 +/- 1.2 ms and decreased endocardial APD(90) from 50.9 +/- 1.0 to 24.5 +/- 0.3 ms, increasing DeltaAPD(90) to -48.0 +/- 1.2 ms.

Conclusion: These findings empirically implicate EADs in potentially initiating spontaneous arrhythmogenic phenomena and transmural repolarization gradients in the re-entrant substrate that would sustain such activity when provoked by extrasystolic activity in murine hearts modelling human LQT3 syndrome.

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Numbers of Scn5a+/Δ hearts with inducible polymorphic ventricular tachycardia (pVT) during programmed electrical stimulation following perfusion with physiological buffer followed by increasing concentrations of propranolol (0, 0.1 and 1 μm).
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fig03: Numbers of Scn5a+/Δ hearts with inducible polymorphic ventricular tachycardia (pVT) during programmed electrical stimulation following perfusion with physiological buffer followed by increasing concentrations of propranolol (0, 0.1 and 1 μm).

Mentions: We then investigated the effects of propranolol upon provoked arrhythmogenesis using PES that incorporated extrasystolic stimuli in Scn5a+/Δ and WT murine hearts. The application of PES to Scn5a+/Δ (n = 12) and WT (n = 10) hearts following perfusion with physiological buffer solution induced VT in 6 of 12 Scn5a+/Δ hearts (Fig. 2a) but not in any WT control hearts (n = 10) (Fig. 2b). PES was then repeated in Scn5a+/Δ (n = 8) and WT (n = 8) hearts at 30 min intervals, following perfusion with physiological buffer solution containing increasing concentrations of propranolol of 0.1 and 1 μm respectively. Subsequent PES procedures induced VT in one of eight Scn5a+/Δ hearts perfused with 0.1 μm propranolol as summarized in Figure 3. However, VT was induced in six of eight Scn5a+/Δ hearts following perfusion with 1 μm propranolol, confirming our previous observations (Head et al. 2005). In contrast, PES failed to induce VT in all WT preparations at all concentrations of propranolol.


Pharmacological separation of early afterdepolarizations from arrhythmogenic substrate in DeltaKPQ Scn5a murine hearts modelling human long QT 3 syndrome.

Thomas G, Killeen MJ, Grace AA, Huang CL - Acta Physiol (Oxf) (2007)

Numbers of Scn5a+/Δ hearts with inducible polymorphic ventricular tachycardia (pVT) during programmed electrical stimulation following perfusion with physiological buffer followed by increasing concentrations of propranolol (0, 0.1 and 1 μm).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2268972&req=5

fig03: Numbers of Scn5a+/Δ hearts with inducible polymorphic ventricular tachycardia (pVT) during programmed electrical stimulation following perfusion with physiological buffer followed by increasing concentrations of propranolol (0, 0.1 and 1 μm).
Mentions: We then investigated the effects of propranolol upon provoked arrhythmogenesis using PES that incorporated extrasystolic stimuli in Scn5a+/Δ and WT murine hearts. The application of PES to Scn5a+/Δ (n = 12) and WT (n = 10) hearts following perfusion with physiological buffer solution induced VT in 6 of 12 Scn5a+/Δ hearts (Fig. 2a) but not in any WT control hearts (n = 10) (Fig. 2b). PES was then repeated in Scn5a+/Δ (n = 8) and WT (n = 8) hearts at 30 min intervals, following perfusion with physiological buffer solution containing increasing concentrations of propranolol of 0.1 and 1 μm respectively. Subsequent PES procedures induced VT in one of eight Scn5a+/Δ hearts perfused with 0.1 μm propranolol as summarized in Figure 3. However, VT was induced in six of eight Scn5a+/Δ hearts following perfusion with 1 μm propranolol, confirming our previous observations (Head et al. 2005). In contrast, PES failed to induce VT in all WT preparations at all concentrations of propranolol.

Bottom Line: Left ventricular endocardial and epicardial monophasic action potentials and arrhythmogenic tendency were compared in isolated wild type (WT) and Scn5a+/Delta hearts perfused with 0.1 and 1 microm propranolol and paced from the right ventricular epicardium.Thus 0.1 microm propranolol reduced epicardial but not endocardial APD(90) from 54.7 +/- 1.6 to 44.0 +/- 2.0 ms, restoring DeltaAPD(90) from -3.8 +/- 1.6 to 3.5 +/- 2.5 ms (all n = 5), close to WT values.However, 1 microm propranolol increased epicardial APD(90) to 72.5 +/- 1.2 ms and decreased endocardial APD(90) from 50.9 +/- 1.0 to 24.5 +/- 0.3 ms, increasing DeltaAPD(90) to -48.0 +/- 1.2 ms.

View Article: PubMed Central - PubMed

Affiliation: Section of Cardiovascular Biology, Department of Biochemistry, University of Cambridge, Cambridge, UK.

ABSTRACT

Aim: To perform an empirical, pharmacological, separation of early afterdepolarizations (EADs) and transmural gradients of repolarization in arrhythmogenesis in a genetically modified mouse heart modelling human long QT syndrome (LQT) 3.

Methods: Left ventricular endocardial and epicardial monophasic action potentials and arrhythmogenic tendency were compared in isolated wild type (WT) and Scn5a+/Delta hearts perfused with 0.1 and 1 microm propranolol and paced from the right ventricular epicardium.

Results: All spontaneously beating bradycardic Scn5a+/Delta hearts displayed EADs, triggered beats and ventricular tachycardia (VT; n = 7), events never seen in WT hearts (n = 5). Perfusion with 0.1 and 1 microm propranolol suppressed all EADs, triggered beats and episodes of VT. In contrast, triggering of VT persisted following programmed electrical stimulation in 6 of 12 (50%), one of eight (12.5%), but six of eight (75%) Scn5a+/Delta hearts perfused with 0, 0.1 and 1 microm propranolol respectively in parallel with corresponding alterations in repolarization gradients, reflected in action potential duration (DeltaAPD(90)) values. Thus 0.1 microm propranolol reduced epicardial but not endocardial APD(90) from 54.7 +/- 1.6 to 44.0 +/- 2.0 ms, restoring DeltaAPD(90) from -3.8 +/- 1.6 to 3.5 +/- 2.5 ms (all n = 5), close to WT values. However, 1 microm propranolol increased epicardial APD(90) to 72.5 +/- 1.2 ms and decreased endocardial APD(90) from 50.9 +/- 1.0 to 24.5 +/- 0.3 ms, increasing DeltaAPD(90) to -48.0 +/- 1.2 ms.

Conclusion: These findings empirically implicate EADs in potentially initiating spontaneous arrhythmogenic phenomena and transmural repolarization gradients in the re-entrant substrate that would sustain such activity when provoked by extrasystolic activity in murine hearts modelling human LQT3 syndrome.

Show MeSH
Related in: MedlinePlus