Electrophysiological studies of transgenic long QT type 1 and type 2 rabbits reveal genotype-specific differences in ventricular refractoriness and His conduction

Katja E. Odening, Malcolm Kirk, Michael Brunner, Ohad Ziv, Peem Lorvidhaya, Gong Xin Liu, Lorraine Schofield, Leonard Chaves, Xuwen Peng, Manfred Zehender, Bum Rak Choi, Gideon Koren

Research output: Contribution to journalArticle

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Abstract

We have generated transgenic rabbits lacking cardiac slow delayed-rectifier K+ current [IKs; long QT syndrome type 1 (LQT1)] or rapidly activating delayed-rectifier K+ current [IKr; long QT syndrome type 2 (LQT2)]. Rabbits with either genotype have prolonged action potential duration and QT intervals; however, only LQT2 rabbits develop atrioventricular (AV) blocks and polymorphic ventricular tachycardia. We therefore sought to characterize the genotype-specific differences in AV conduction and ventricular refractoriness in LQT1 and LQT2 rabbits. We carried out in vivo electrophysiological studies in LQT1, LQT2, and littermate control (LMC) rabbits at baseline, during isoproterenol infusion, and after a bolus of dofetilide and ex vivo optical mapping studies of the AV node/His-region at baseline and during dofetilide perfusion. Under isoflurane anesthesia, LQT2 rabbits developed infra-His blocks, decremental His conduction, and prolongation of the Wenckebach cycle length. In LQT1 rabbits, dofetilide altered the His morphology and slowed His conduction, resulting in intra-His block, and additionally prolonged the ventricular refractoriness, leading to pseudo-AV block. The ventricular effective refractory period (VERP) in right ventricular apex and base was significantly longer in LQT2 than LQT1 (P < 0.05) or LMC (P < 0.01), with a greater VERP dispersion in LQT2 than LQT1 rabbits. Isoproterenol reduced the VERP dispersion in LQT2 rabbits by shortening the VERP in the base more than in the apex but had no effect on VERP in LQT1. EPS and optical mapping experiments demonstrated genotype-specific differences in AV conduction and ventricular refractoriness. The occurrence of infra-His blocks in LQT2 rabbits under isoflurane and intra-His block in LQT1 rabbits after dofetilide suggest differential regional sensitivities of the rabbit His-Purkinje system to drugs blocking IKr and IKs.

Original languageEnglish (US)
Pages (from-to)H643-H655
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume299
Issue number3
DOIs
StatePublished - Sep 1 2010

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Romano-Ward Syndrome
Long QT Syndrome
Genotype
Rabbits
Atrioventricular Block
Isoflurane
Isoproterenol
Atrioventricular Node
Ventricular Tachycardia
Action Potentials
Anesthesia
Perfusion

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Odening, Katja E. ; Kirk, Malcolm ; Brunner, Michael ; Ziv, Ohad ; Lorvidhaya, Peem ; Liu, Gong Xin ; Schofield, Lorraine ; Chaves, Leonard ; Peng, Xuwen ; Zehender, Manfred ; Choi, Bum Rak ; Koren, Gideon. / Electrophysiological studies of transgenic long QT type 1 and type 2 rabbits reveal genotype-specific differences in ventricular refractoriness and His conduction. In: American Journal of Physiology - Heart and Circulatory Physiology. 2010 ; Vol. 299, No. 3. pp. H643-H655.
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Electrophysiological studies of transgenic long QT type 1 and type 2 rabbits reveal genotype-specific differences in ventricular refractoriness and His conduction. / Odening, Katja E.; Kirk, Malcolm; Brunner, Michael; Ziv, Ohad; Lorvidhaya, Peem; Liu, Gong Xin; Schofield, Lorraine; Chaves, Leonard; Peng, Xuwen; Zehender, Manfred; Choi, Bum Rak; Koren, Gideon.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 299, No. 3, 01.09.2010, p. H643-H655.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Electrophysiological studies of transgenic long QT type 1 and type 2 rabbits reveal genotype-specific differences in ventricular refractoriness and His conduction

AU - Odening, Katja E.

AU - Kirk, Malcolm

AU - Brunner, Michael

AU - Ziv, Ohad

AU - Lorvidhaya, Peem

AU - Liu, Gong Xin

AU - Schofield, Lorraine

AU - Chaves, Leonard

AU - Peng, Xuwen

AU - Zehender, Manfred

AU - Choi, Bum Rak

AU - Koren, Gideon

PY - 2010/9/1

Y1 - 2010/9/1

N2 - We have generated transgenic rabbits lacking cardiac slow delayed-rectifier K+ current [IKs; long QT syndrome type 1 (LQT1)] or rapidly activating delayed-rectifier K+ current [IKr; long QT syndrome type 2 (LQT2)]. Rabbits with either genotype have prolonged action potential duration and QT intervals; however, only LQT2 rabbits develop atrioventricular (AV) blocks and polymorphic ventricular tachycardia. We therefore sought to characterize the genotype-specific differences in AV conduction and ventricular refractoriness in LQT1 and LQT2 rabbits. We carried out in vivo electrophysiological studies in LQT1, LQT2, and littermate control (LMC) rabbits at baseline, during isoproterenol infusion, and after a bolus of dofetilide and ex vivo optical mapping studies of the AV node/His-region at baseline and during dofetilide perfusion. Under isoflurane anesthesia, LQT2 rabbits developed infra-His blocks, decremental His conduction, and prolongation of the Wenckebach cycle length. In LQT1 rabbits, dofetilide altered the His morphology and slowed His conduction, resulting in intra-His block, and additionally prolonged the ventricular refractoriness, leading to pseudo-AV block. The ventricular effective refractory period (VERP) in right ventricular apex and base was significantly longer in LQT2 than LQT1 (P < 0.05) or LMC (P < 0.01), with a greater VERP dispersion in LQT2 than LQT1 rabbits. Isoproterenol reduced the VERP dispersion in LQT2 rabbits by shortening the VERP in the base more than in the apex but had no effect on VERP in LQT1. EPS and optical mapping experiments demonstrated genotype-specific differences in AV conduction and ventricular refractoriness. The occurrence of infra-His blocks in LQT2 rabbits under isoflurane and intra-His block in LQT1 rabbits after dofetilide suggest differential regional sensitivities of the rabbit His-Purkinje system to drugs blocking IKr and IKs.

AB - We have generated transgenic rabbits lacking cardiac slow delayed-rectifier K+ current [IKs; long QT syndrome type 1 (LQT1)] or rapidly activating delayed-rectifier K+ current [IKr; long QT syndrome type 2 (LQT2)]. Rabbits with either genotype have prolonged action potential duration and QT intervals; however, only LQT2 rabbits develop atrioventricular (AV) blocks and polymorphic ventricular tachycardia. We therefore sought to characterize the genotype-specific differences in AV conduction and ventricular refractoriness in LQT1 and LQT2 rabbits. We carried out in vivo electrophysiological studies in LQT1, LQT2, and littermate control (LMC) rabbits at baseline, during isoproterenol infusion, and after a bolus of dofetilide and ex vivo optical mapping studies of the AV node/His-region at baseline and during dofetilide perfusion. Under isoflurane anesthesia, LQT2 rabbits developed infra-His blocks, decremental His conduction, and prolongation of the Wenckebach cycle length. In LQT1 rabbits, dofetilide altered the His morphology and slowed His conduction, resulting in intra-His block, and additionally prolonged the ventricular refractoriness, leading to pseudo-AV block. The ventricular effective refractory period (VERP) in right ventricular apex and base was significantly longer in LQT2 than LQT1 (P < 0.05) or LMC (P < 0.01), with a greater VERP dispersion in LQT2 than LQT1 rabbits. Isoproterenol reduced the VERP dispersion in LQT2 rabbits by shortening the VERP in the base more than in the apex but had no effect on VERP in LQT1. EPS and optical mapping experiments demonstrated genotype-specific differences in AV conduction and ventricular refractoriness. The occurrence of infra-His blocks in LQT2 rabbits under isoflurane and intra-His block in LQT1 rabbits after dofetilide suggest differential regional sensitivities of the rabbit His-Purkinje system to drugs blocking IKr and IKs.

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