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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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Representative monophasic action potential (MAP) recording obtained from the epicardial surface of a spontaneously-beating Scn5a+/Δ heart under physiological conditions (a). Following induction of complete atrioventricular (AV) block by crush ablation of the AV node, multiple early afterdepolarizations (*) are seen, along with an associated triggered action potential (arrow) (b). All such features are suppressed following perfusion with physiological buffer solution containing propranolol (1 μm) (c).
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fig01: Representative monophasic action potential (MAP) recording obtained from the epicardial surface of a spontaneously-beating Scn5a+/Δ heart under physiological conditions (a). Following induction of complete atrioventricular (AV) block by crush ablation of the AV node, multiple early afterdepolarizations (*) are seen, along with an associated triggered action potential (arrow) (b). All such features are suppressed following perfusion with physiological buffer solution containing propranolol (1 μm) (c).

Mentions: Crush ablation rendered both Scn5a+/Δ and WT hearts bradycardic (∼100 beats min−1) but nevertheless still spontaneously beating, compared to hearts in which AV block was not induced, (Fig. 1a,b). Bradycardic Scn5a+/Δ hearts spontaneously showed multiple EADs, triggered beats and episodes of non-sustained VT lasting on average 15 beats (range 7–33 beats) (n = 7) (Fig. 1b). In contrast, WT hearts never showed such events (whether EADs or polymorphic VT) following induction of AV block (n = 5).


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)

Representative monophasic action potential (MAP) recording obtained from the epicardial surface of a spontaneously-beating Scn5a+/Δ heart under physiological conditions (a). Following induction of complete atrioventricular (AV) block by crush ablation of the AV node, multiple early afterdepolarizations (*) are seen, along with an associated triggered action potential (arrow) (b). All such features are suppressed following perfusion with physiological buffer solution containing propranolol (1 μm) (c).
© Copyright Policy
Related In: Results  -  Collection

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

fig01: Representative monophasic action potential (MAP) recording obtained from the epicardial surface of a spontaneously-beating Scn5a+/Δ heart under physiological conditions (a). Following induction of complete atrioventricular (AV) block by crush ablation of the AV node, multiple early afterdepolarizations (*) are seen, along with an associated triggered action potential (arrow) (b). All such features are suppressed following perfusion with physiological buffer solution containing propranolol (1 μm) (c).
Mentions: Crush ablation rendered both Scn5a+/Δ and WT hearts bradycardic (∼100 beats min−1) but nevertheless still spontaneously beating, compared to hearts in which AV block was not induced, (Fig. 1a,b). Bradycardic Scn5a+/Δ hearts spontaneously showed multiple EADs, triggered beats and episodes of non-sustained VT lasting on average 15 beats (range 7–33 beats) (n = 7) (Fig. 1b). In contrast, WT hearts never showed such events (whether EADs or polymorphic VT) following induction of AV block (n = 5).

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