Junctional Ectopic Tachycardia Caused by Junctophilin-2 Expression Silencing Is Selectively Sensitive to Ryanodine Receptor Blockade

Qixin Yang; Hanna J. Tadros; Bo Sun; Minu Tshyeto Bidzimou; Jordan E. Ezekian; Feng Li; Andreas Ludwig; Xander H.T. Wehrens; Andrew P. Landstrom

doi:10.1016/j.jacbts.2023.07.008

Junctional Ectopic Tachycardia Caused by Junctophilin-2 Expression Silencing Is Selectively Sensitive to Ryanodine Receptor Blockade

Qixin Yang, Hanna J. Tadros, Bo Sun, Minu Tshyeto Bidzimou, Jordan E. Ezekian, Feng Li, Andreas Ludwig, Xander H.T. Wehrens, Andrew P. Landstrom

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

1 Scopus citations

Abstract

Junctional ectopic tachycardia (JET) is a potentially fatal cardiac arrhythmia. Hcn4:shJph2 mice serve as a model of nodal arrhythmias driven by ryanodine type 2 receptor (RyR2)–mediated Ca²⁺ leak. EL20 is a small molecule that blocks RyR2 Ca²⁺ leak. In a novel in vivo model of JET, Hcn4:shJph2 mice demonstrated rapid conversion of JET to sinus rhythm with infusion of EL20. Primary atrioventricular nodal cells demonstrated increased Ca²⁺ transient oscillation frequency and increased RyR2-mediated stored Ca²⁺ leak which was normalized by EL20. EL20 was found to be rapidly degraded in mouse and human plasma, making it a potential novel therapy for JET.

Original language	English (US)
Pages (from-to)	1577-1588
Number of pages	12
Journal	JACC: Basic to Translational Science
Volume	8
Issue number	12
DOIs	https://doi.org/10.1016/j.jacbts.2023.07.008
State	Published - Dec 2023
Externally published	Yes

Keywords

JET
Jph2
calcium
junctional ectopic tachycardia
ryanodine receptor

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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10.1016/j.jacbts.2023.07.008

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title = "Junctional Ectopic Tachycardia Caused by Junctophilin-2 Expression Silencing Is Selectively Sensitive to Ryanodine Receptor Blockade",

abstract = "Junctional ectopic tachycardia (JET) is a potentially fatal cardiac arrhythmia. Hcn4:shJph2 mice serve as a model of nodal arrhythmias driven by ryanodine type 2 receptor (RyR2)–mediated Ca2+ leak. EL20 is a small molecule that blocks RyR2 Ca2+ leak. In a novel in vivo model of JET, Hcn4:shJph2 mice demonstrated rapid conversion of JET to sinus rhythm with infusion of EL20. Primary atrioventricular nodal cells demonstrated increased Ca2+ transient oscillation frequency and increased RyR2-mediated stored Ca2+ leak which was normalized by EL20. EL20 was found to be rapidly degraded in mouse and human plasma, making it a potential novel therapy for JET.",

keywords = "JET, Jph2, calcium, junctional ectopic tachycardia, ryanodine receptor",

author = "Qixin Yang and Tadros, {Hanna J.} and Bo Sun and Bidzimou, {Minu Tshyeto} and Ezekian, {Jordan E.} and Feng Li and Andreas Ludwig and Wehrens, {Xander H.T.} and Landstrom, {Andrew P.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = dec,

doi = "10.1016/j.jacbts.2023.07.008",

language = "English (US)",

volume = "8",

pages = "1577--1588",

journal = "JACC: Basic to Translational Science",

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AU - Yang, Qixin

AU - Tadros, Hanna J.

AU - Sun, Bo

AU - Bidzimou, Minu Tshyeto

AU - Ezekian, Jordan E.

AU - Li, Feng

AU - Ludwig, Andreas

AU - Wehrens, Xander H.T.

AU - Landstrom, Andrew P.

PY - 2023/12

Y1 - 2023/12

N2 - Junctional ectopic tachycardia (JET) is a potentially fatal cardiac arrhythmia. Hcn4:shJph2 mice serve as a model of nodal arrhythmias driven by ryanodine type 2 receptor (RyR2)–mediated Ca2+ leak. EL20 is a small molecule that blocks RyR2 Ca2+ leak. In a novel in vivo model of JET, Hcn4:shJph2 mice demonstrated rapid conversion of JET to sinus rhythm with infusion of EL20. Primary atrioventricular nodal cells demonstrated increased Ca2+ transient oscillation frequency and increased RyR2-mediated stored Ca2+ leak which was normalized by EL20. EL20 was found to be rapidly degraded in mouse and human plasma, making it a potential novel therapy for JET.

AB - Junctional ectopic tachycardia (JET) is a potentially fatal cardiac arrhythmia. Hcn4:shJph2 mice serve as a model of nodal arrhythmias driven by ryanodine type 2 receptor (RyR2)–mediated Ca2+ leak. EL20 is a small molecule that blocks RyR2 Ca2+ leak. In a novel in vivo model of JET, Hcn4:shJph2 mice demonstrated rapid conversion of JET to sinus rhythm with infusion of EL20. Primary atrioventricular nodal cells demonstrated increased Ca2+ transient oscillation frequency and increased RyR2-mediated stored Ca2+ leak which was normalized by EL20. EL20 was found to be rapidly degraded in mouse and human plasma, making it a potential novel therapy for JET.

KW - JET

KW - Jph2

KW - calcium

KW - junctional ectopic tachycardia

KW - ryanodine receptor

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Junctional Ectopic Tachycardia Caused by Junctophilin-2 Expression Silencing Is Selectively Sensitive to Ryanodine Receptor Blockade

Abstract

Keywords

ASJC Scopus subject areas

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