Altered re-excitation thresholds and conduction of extrasystolic action potentials contribute to arrhythmogenicity in murine models of long QT syndrome

R M Duehmke; Sarah M. Pearcey; J D Stefaniak; L Guzadhur; Kamalan Jeevaratnam; C Costopoulos; T H Pedersen; A Grace; C L-H Huang

doi:10.1111/j.1748-1716.2012.02443.x

Altered re-excitation thresholds and conduction of extrasystolic action potentials contribute to arrhythmogenicity in murine models of long QT syndrome

R M Duehmke, Sarah M. Pearcey, J D Stefaniak, L Guzadhur, Kamalan Jeevaratnam, C Costopoulos, T H Pedersen, A Grace, C L-H Huang

Division of Neuroscience

University of Cambridge

Research output: Contribution to journal › Article › peer-review

Abstract

AIM: QT interval prolongation reflecting delayed action potential (AP) repolarization is associated with polymorphic ventricular tachycardia and early after depolarizations potentially initiating extrasystolic APs if of sufficient amplitude. The current experiments explored contributions of altered re-excitation thresholds for, and conduction of, such extrasystolic APs to arrhythmogenesis in Langendorff-perfused, normokalaemic, control wild-type hearts and two experimental groups modelling long QT (LQT). The two LQT groups consisted of genetically modified, Scn5a(+/ΔKPQ) and hypokalaemic wild-type murine hearts.

METHODS: Hearts were paced from their right ventricles and monophasic AP electrode recordings obtained from their left ventricular epicardia, with recording and pacing electrodes separated by 1 cm. An adaptive programmed electrical stimulation protocol applied pacing (S1) stimulus trains followed by premature (S2) extrastimuli whose amplitudes were progressively increased with progressive decrements in S1S2 interval to maintain stimulus capture. Such protocols culminated in either arrhythmic or refractory endpoints.

RESULTS: Arrhythmic outcomes were associated with (1) lower conduction velocities in their initiating extrasystolic APs than refractory outcomes and (2) higher conduction velocities in the LQT groups than in controls. Furthermore, (3) the endpoints were reached at longer S1S2 coupling intervals and with smaller stimulus amplitudes in the LQT groups compared with controls. This was despite (4) similar relationships between conduction velocity and S1S2 coupling interval and between re-excitation thresholds and S1S2 coupling interval in all three experimental groups.

CONCLUSIONS: Arrhythmias induced by extrasystolic APs in the LQT groups thus occur under conditions of higher conduction velocity and greater sensitivity to extrastimuli than in controls.

Original language	English
Pages (from-to)	164-77
Number of pages	14
Journal	Acta physiologica (Oxford, England)
Volume	206
Issue number	3
DOIs	https://doi.org/10.1111/j.1748-1716.2012.02443.x
Publication status	Published - Nov 2012

Keywords

Action Potentials
Animals
Arrhythmias, Cardiac
Electric Stimulation
Endpoint Determination
Female
Heart Conduction System
Hypokalemia
Long QT Syndrome
Male
Mice
Mice, Inbred Strains
Mice, Mutant Strains
Models, Animal
NAV1.5 Voltage-Gated Sodium Channel
Neural Conduction
Time Factors
Ventricular Premature Complexes
Journal Article
Research Support, Non-U.S. Gov't

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10.1111/j.1748-1716.2012.02443.x

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Duehmke, R. M., Pearcey, S. M., Stefaniak, J. D., Guzadhur, L., Jeevaratnam, K., Costopoulos, C., Pedersen, T. H., Grace, A., & Huang, C. L.-H. (2012). Altered re-excitation thresholds and conduction of extrasystolic action potentials contribute to arrhythmogenicity in murine models of long QT syndrome. Acta physiologica (Oxford, England), 206(3), 164-77. https://doi.org/10.1111/j.1748-1716.2012.02443.x

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title = "Altered re-excitation thresholds and conduction of extrasystolic action potentials contribute to arrhythmogenicity in murine models of long QT syndrome",

abstract = "AIM: QT interval prolongation reflecting delayed action potential (AP) repolarization is associated with polymorphic ventricular tachycardia and early after depolarizations potentially initiating extrasystolic APs if of sufficient amplitude. The current experiments explored contributions of altered re-excitation thresholds for, and conduction of, such extrasystolic APs to arrhythmogenesis in Langendorff-perfused, normokalaemic, control wild-type hearts and two experimental groups modelling long QT (LQT). The two LQT groups consisted of genetically modified, Scn5a(+/ΔKPQ) and hypokalaemic wild-type murine hearts.METHODS: Hearts were paced from their right ventricles and monophasic AP electrode recordings obtained from their left ventricular epicardia, with recording and pacing electrodes separated by 1 cm. An adaptive programmed electrical stimulation protocol applied pacing (S1) stimulus trains followed by premature (S2) extrastimuli whose amplitudes were progressively increased with progressive decrements in S1S2 interval to maintain stimulus capture. Such protocols culminated in either arrhythmic or refractory endpoints.RESULTS: Arrhythmic outcomes were associated with (1) lower conduction velocities in their initiating extrasystolic APs than refractory outcomes and (2) higher conduction velocities in the LQT groups than in controls. Furthermore, (3) the endpoints were reached at longer S1S2 coupling intervals and with smaller stimulus amplitudes in the LQT groups compared with controls. This was despite (4) similar relationships between conduction velocity and S1S2 coupling interval and between re-excitation thresholds and S1S2 coupling interval in all three experimental groups.CONCLUSIONS: Arrhythmias induced by extrasystolic APs in the LQT groups thus occur under conditions of higher conduction velocity and greater sensitivity to extrastimuli than in controls.",

keywords = "Action Potentials, Animals, Arrhythmias, Cardiac, Electric Stimulation, Endpoint Determination, Female, Heart Conduction System, Hypokalemia, Long QT Syndrome, Male, Mice, Mice, Inbred Strains, Mice, Mutant Strains, Models, Animal, NAV1.5 Voltage-Gated Sodium Channel, Neural Conduction, Time Factors, Ventricular Premature Complexes, Journal Article, Research Support, Non-U.S. Gov't",

author = "Duehmke, {R M} and Pearcey, {Sarah M.} and Stefaniak, {J D} and L Guzadhur and Kamalan Jeevaratnam and C Costopoulos and Pedersen, {T H} and A Grace and Huang, {C L-H}",

note = "{\textcopyright} 2012 The Authors Acta Physiologica {\textcopyright} 2012 Scandinavian Physiological Society.",

year = "2012",

month = nov,

doi = "10.1111/j.1748-1716.2012.02443.x",

language = "English",

volume = "206",

pages = "164--77",

journal = "Acta physiologica (Oxford, England)",

issn = "1748-1708",

publisher = "John Wiley & Sons Ltd",

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Duehmke, RM, Pearcey, SM, Stefaniak, JD, Guzadhur, L, Jeevaratnam, K, Costopoulos, C, Pedersen, TH, Grace, A & Huang, CL-H 2012, 'Altered re-excitation thresholds and conduction of extrasystolic action potentials contribute to arrhythmogenicity in murine models of long QT syndrome', Acta physiologica (Oxford, England), vol. 206, no. 3, pp. 164-77. https://doi.org/10.1111/j.1748-1716.2012.02443.x

TY - JOUR

T1 - Altered re-excitation thresholds and conduction of extrasystolic action potentials contribute to arrhythmogenicity in murine models of long QT syndrome

AU - Duehmke, R M

AU - Pearcey, Sarah M.

AU - Stefaniak, J D

AU - Guzadhur, L

AU - Jeevaratnam, Kamalan

AU - Costopoulos, C

AU - Pedersen, T H

AU - Grace, A

AU - Huang, C L-H

PY - 2012/11

Y1 - 2012/11

N2 - AIM: QT interval prolongation reflecting delayed action potential (AP) repolarization is associated with polymorphic ventricular tachycardia and early after depolarizations potentially initiating extrasystolic APs if of sufficient amplitude. The current experiments explored contributions of altered re-excitation thresholds for, and conduction of, such extrasystolic APs to arrhythmogenesis in Langendorff-perfused, normokalaemic, control wild-type hearts and two experimental groups modelling long QT (LQT). The two LQT groups consisted of genetically modified, Scn5a(+/ΔKPQ) and hypokalaemic wild-type murine hearts.METHODS: Hearts were paced from their right ventricles and monophasic AP electrode recordings obtained from their left ventricular epicardia, with recording and pacing electrodes separated by 1 cm. An adaptive programmed electrical stimulation protocol applied pacing (S1) stimulus trains followed by premature (S2) extrastimuli whose amplitudes were progressively increased with progressive decrements in S1S2 interval to maintain stimulus capture. Such protocols culminated in either arrhythmic or refractory endpoints.RESULTS: Arrhythmic outcomes were associated with (1) lower conduction velocities in their initiating extrasystolic APs than refractory outcomes and (2) higher conduction velocities in the LQT groups than in controls. Furthermore, (3) the endpoints were reached at longer S1S2 coupling intervals and with smaller stimulus amplitudes in the LQT groups compared with controls. This was despite (4) similar relationships between conduction velocity and S1S2 coupling interval and between re-excitation thresholds and S1S2 coupling interval in all three experimental groups.CONCLUSIONS: Arrhythmias induced by extrasystolic APs in the LQT groups thus occur under conditions of higher conduction velocity and greater sensitivity to extrastimuli than in controls.

AB - AIM: QT interval prolongation reflecting delayed action potential (AP) repolarization is associated with polymorphic ventricular tachycardia and early after depolarizations potentially initiating extrasystolic APs if of sufficient amplitude. The current experiments explored contributions of altered re-excitation thresholds for, and conduction of, such extrasystolic APs to arrhythmogenesis in Langendorff-perfused, normokalaemic, control wild-type hearts and two experimental groups modelling long QT (LQT). The two LQT groups consisted of genetically modified, Scn5a(+/ΔKPQ) and hypokalaemic wild-type murine hearts.METHODS: Hearts were paced from their right ventricles and monophasic AP electrode recordings obtained from their left ventricular epicardia, with recording and pacing electrodes separated by 1 cm. An adaptive programmed electrical stimulation protocol applied pacing (S1) stimulus trains followed by premature (S2) extrastimuli whose amplitudes were progressively increased with progressive decrements in S1S2 interval to maintain stimulus capture. Such protocols culminated in either arrhythmic or refractory endpoints.RESULTS: Arrhythmic outcomes were associated with (1) lower conduction velocities in their initiating extrasystolic APs than refractory outcomes and (2) higher conduction velocities in the LQT groups than in controls. Furthermore, (3) the endpoints were reached at longer S1S2 coupling intervals and with smaller stimulus amplitudes in the LQT groups compared with controls. This was despite (4) similar relationships between conduction velocity and S1S2 coupling interval and between re-excitation thresholds and S1S2 coupling interval in all three experimental groups.CONCLUSIONS: Arrhythmias induced by extrasystolic APs in the LQT groups thus occur under conditions of higher conduction velocity and greater sensitivity to extrastimuli than in controls.

KW - Action Potentials

KW - Animals

KW - Arrhythmias, Cardiac

KW - Electric Stimulation

KW - Endpoint Determination

KW - Female

KW - Heart Conduction System

KW - Hypokalemia

KW - Long QT Syndrome

KW - Male

KW - Mice

KW - Mice, Inbred Strains

KW - Mice, Mutant Strains

KW - Models, Animal

KW - NAV1.5 Voltage-Gated Sodium Channel

KW - Neural Conduction

KW - Time Factors

KW - Ventricular Premature Complexes

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1111/j.1748-1716.2012.02443.x

DO - 10.1111/j.1748-1716.2012.02443.x

M3 - Article

C2 - 22510251

SN - 1748-1708

VL - 206

SP - 164

EP - 177

JO - Acta physiologica (Oxford, England)

JF - Acta physiologica (Oxford, England)

IS - 3

ER -

Altered re-excitation thresholds and conduction of extrasystolic action potentials contribute to arrhythmogenicity in murine models of long QT syndrome

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Keywords

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