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

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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Long QT syndrome type 2: mechanism-based therapies

Future Cardiology ◽

10.2217/fca-2020-0234 ◽

2021 ◽

Author(s):

Kofi Oliver Taylor Cox ◽

Brian Xiangzhi Wang

Keyword(s):

Long Qt Syndrome ◽

Cardiac Electrophysiology ◽

Current Treatment ◽

Delayed Rectifier ◽

Adrenergic Blockade ◽

Syndrome Type ◽

Long Qt ◽

Life Threatening ◽

Qt Syndrome

Long QT syndrome type 2 is a life-threatening disorder of cardiac electrophysiology. It can lead to sudden cardiac death as a result of QT prolongation and can remain undetected until it presents clinically in the form of life-threatening cardiac arrythmias. Current treatment relies on symptom management largely through the use of β-adrenergic blockade and presently no mechanism-based therapies exist to treat the dysfunction in the hERG channels responsible for the rapid delayed rectifier K+ current which is the pathological source of long QT syndrome type 2. We review the pathophysiology, diagnosis and current management of this life-threatening condition and also analyze some promising potential mechanism-based therapies.

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Retraction: Sex differences in the expression of sodium/calcium exchanger influence the arrhythmia phenotype in the long QT syndrome type 2

British Journal of Pharmacology ◽

10.1038/bjp.2008.183 ◽

2008 ◽

Cited By ~ 1

Author(s):

G Salama ◽

B London ◽

L J Kerchner ◽

N R Salama ◽

T Liu

Keyword(s):

Sex Differences ◽

Long Qt Syndrome ◽

Syndrome Type ◽

Sodium Calcium Exchanger ◽

Long Qt ◽

Sodium Calcium ◽

Qt Syndrome

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A novel KCNH2 frameshift mutation (c.46delG) associated with high risk of sudden death in a family with congenital long QT syndrome type 2

International Journal of Arrhythmia ◽

10.1186/s42444-020-00029-1 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Hyun Sok Yoo ◽

Nancy Medina ◽

María Alejandra von Wulffen ◽

Natalia Ciampi ◽

Analia Paolucci ◽

...

Keyword(s):

Sudden Cardiac Death ◽

Long Qt Syndrome ◽

Cardiac Death ◽

Frameshift Mutation ◽

Alpha Subunit ◽

Syndrome Type ◽

Long Qt ◽

Qt Syndrome ◽

Congenital Long Qt Syndrome

Abstract Background The congenital long QT syndrome type 2 is caused by mutations in KCNH2 gene that encodes the alpha subunit of potassium channel Kv11.1. The carriers of the pathogenic variant of KCNH2 gene manifest a phenotype characterized by prolongation of QT interval and increased risk of sudden cardiac death due to life-threatening ventricular tachyarrhythmias. Results A family composed of 17 members with a family history of sudden death and recurrent syncopes was studied. The DNA of proband with clinical manifestations of long QT syndrome was analyzed using a massive DNA sequencer that included the following genes: KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, ANK2, KCNJ2, CACNA1, CAV3, SCN1B, SCN4B, AKAP9, SNTA1, CALM1, KCNJ5, RYR2 and TRDN. DNA sequencing of proband identified a novel pathogenic variant of KCNH2 gene produced by a heterozygous frameshift mutation c.46delG, pAsp16Thrfs*44 resulting in the synthesis of a truncated alpha subunit of the Kv11.1 ion channel. Eight family members manifested the phenotype of long QT syndrome. The study of family segregation using Sanger sequencing revealed the identical variant in several members of the family with a positive phenotype. Conclusions The clinical and genetic findings of this family demonstrate that the novel frameshift mutation causing haploinsufficiency can result in a congenital long QT syndrome with a severe phenotypic manifestation and an elevated risk of sudden cardiac death.

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