IKs inhibitor JNJ303 prolongs the QT interval and perpetuates arrhythmia when combined with enhanced inotropy in the CAVB dog

Impaired IKs induced by drugs or due to a KCNQ1 mutation, diagnosed as long QT syndrome type 1 (LQT1) prolongs the QT interval and predisposes the heart to Torsade de Pointes (TdP) arrhythmias. The anesthetized chronic AV block (CAVB) dog is inducible for TdP after remodeling and IKr inhibitor dofet...

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Published in:European journal of pharmacology 2022-10, Vol.932, p.175218-175218, Article 175218
Main Authors: van Bavel, Joanne J.A., Beekman, Henriëtte D.M., van Weperen, Valerie Y.H., van der Linde, Henk J., van der Heyden, Marcel A.G., Vos, Marc A.
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Language:English
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CAVB Dog model
Contractility
IKs
JNJ303
QT interval
Ventricular arrhythmia
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creator van Bavel, Joanne J.A.
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van Weperen, Valerie Y.H.
van der Linde, Henk J.
van der Heyden, Marcel A.G.
Vos, Marc A.
description Impaired IKs induced by drugs or due to a KCNQ1 mutation, diagnosed as long QT syndrome type 1 (LQT1) prolongs the QT interval and predisposes the heart to Torsade de Pointes (TdP) arrhythmias. The anesthetized chronic AV block (CAVB) dog is inducible for TdP after remodeling and IKr inhibitor dofetilide. We tested the proarrhythmic effect of IKs inhibition in the CAVB dog, and the proarrhythmic role of increased contractility herein. Dofetilide-inducible animals were included to test the proarrhythmic effect of 1) IKs inhibition by JNJ303 (0.63 mg/kg/10min i.v.; n = 4), 2) IKs inhibition combined with enhanced inotropy (ouabain, 0.045 mg/kg/1min i.v.; n = 6), and 3) the washout period of the anesthetic regime (n = 10). JNJ303 prolonged the QTc interval (from 477 ± 53 ms to 565 ± 14 ms, P 
doi_str_mv 10.1016/j.ejphar.2022.175218
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The anesthetized chronic AV block (CAVB) dog is inducible for TdP after remodeling and IKr inhibitor dofetilide. We tested the proarrhythmic effect of IKs inhibition in the CAVB dog, and the proarrhythmic role of increased contractility herein. Dofetilide-inducible animals were included to test the proarrhythmic effect of 1) IKs inhibition by JNJ303 (0.63 mg/kg/10min i.v.; n = 4), 2) IKs inhibition combined with enhanced inotropy (ouabain, 0.045 mg/kg/1min i.v.; n = 6), and 3) the washout period of the anesthetic regime (n = 10). JNJ303 prolonged the QTc interval (from 477 ± 53 ms to 565 ± 14 ms, P &lt; 0.02) resembling standardized dofetilide-induced QTc prolongation. Single ectopic beats (n = 4) and ventricular tachycardia (VT) (n = 3) were present, increasing the arrhythmia score (AS) from 1.0 ± 0 to 7.1 ± 6.5. JNJ303 combined with ouabain increased contractile parameters (LVdP/dtmax from 1725 ± 273 to 4147 ± 611 mmHg/s, P &lt; 0.01). Moreover, TdP arrhythmias were induced in 4/6 dogs and AS increased from 1.0 ± 0 to 20.2 ± 19.0 after JNJ303 and ouabain (P &lt; 0.05). Finally, TdP arrhythmias were induced in 4/10 dogs during the anesthesia washout period and the AS increased from 1.1 ± 0.3 to 9.2 ± 11.2. Mimicking LQT1 using IKs inhibitor JNJ303 prolongs the QTc interval and triggers ectopic beats and non-sustained VT in the CAVB dog. 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The anesthetized chronic AV block (CAVB) dog is inducible for TdP after remodeling and IKr inhibitor dofetilide. We tested the proarrhythmic effect of IKs inhibition in the CAVB dog, and the proarrhythmic role of increased contractility herein. Dofetilide-inducible animals were included to test the proarrhythmic effect of 1) IKs inhibition by JNJ303 (0.63 mg/kg/10min i.v.; n = 4), 2) IKs inhibition combined with enhanced inotropy (ouabain, 0.045 mg/kg/1min i.v.; n = 6), and 3) the washout period of the anesthetic regime (n = 10). JNJ303 prolonged the QTc interval (from 477 ± 53 ms to 565 ± 14 ms, P &lt; 0.02) resembling standardized dofetilide-induced QTc prolongation. Single ectopic beats (n = 4) and ventricular tachycardia (VT) (n = 3) were present, increasing the arrhythmia score (AS) from 1.0 ± 0 to 7.1 ± 6.5. JNJ303 combined with ouabain increased contractile parameters (LVdP/dtmax from 1725 ± 273 to 4147 ± 611 mmHg/s, P &lt; 0.01). Moreover, TdP arrhythmias were induced in 4/6 dogs and AS increased from 1.0 ± 0 to 20.2 ± 19.0 after JNJ303 and ouabain (P &lt; 0.05). Finally, TdP arrhythmias were induced in 4/10 dogs during the anesthesia washout period and the AS increased from 1.1 ± 0.3 to 9.2 ± 11.2. Mimicking LQT1 using IKs inhibitor JNJ303 prolongs the QTc interval and triggers ectopic beats and non-sustained VT in the CAVB dog. Induction of the more severe arrhythmic events (TdP) demands a combination of IKs inhibition with enhanced inotropy or ending the anesthetic regime. •IKs inhibitor JNJ303 prolongs the QT interval with induction of mild arrhythmic events.•JNJ303 combined with enhanced inotropy is proarrhythmic by perpetuation of mild events into severe ventricular arrhythmias.•Washout of anesthesia after JNJ303 and enhanced inotropy is indicated as sympathetic trigger with a proarrhythmic role.</description><subject>CAVB Dog model</subject><subject>Contractility</subject><subject>IKs</subject><subject>JNJ303</subject><subject>QT interval</subject><subject>Ventricular arrhythmia</subject><issn>0014-2999</issn><issn>1879-0712</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNp9kM1uEzEUha0KJELhDVh4ySbBvhOPx5tKJWpLSgVCKmwtj32n42hiT22nVRa8O5NO12zuj3TOkc5HyCfOVpzx-stuhbuxN2kFDGDFpQDenJEFb6RaMsnhDVkwxtdLUEq9I-9z3jHGhAKxIH-33zP1ofetLzHR2x-3FavomOIQw0OmpUf6634SFExPZqAmODpiGrEcTMFMTUr9sfR7b-hzj4HauG99QEeffekpht4EO30-xJLieJyOl8jN5Z-v1MWHD-RtZ4aMH1_3Ofl9fXW_-ba8-3mz3VzeLW3FRZmmddwI11qJKOsGoGuBgxCdVZwL4Tp0qkHooEHb1WsJEhS21bqyshHGVefk85w7FXs8YC5677PFYTAB4yFrkEzWXEmoJ-l6ltoUc07Y6TH5vUlHzZk-0dY7PdPWJ9p6pj3ZLmYbTjWePCadrcdTeZ_QFu2i_3_AP0UCi3w</recordid><startdate>20221015</startdate><enddate>20221015</enddate><creator>van Bavel, Joanne J.A.</creator><creator>Beekman, Henriëtte D.M.</creator><creator>van Weperen, Valerie Y.H.</creator><creator>van der Linde, Henk J.</creator><creator>van der Heyden, Marcel A.G.</creator><creator>Vos, Marc A.</creator><general>Elsevier B.V</general><scope>6I.</scope><scope>AAFTH</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-4225-7942</orcidid></search><sort><creationdate>20221015</creationdate><title>IKs inhibitor JNJ303 prolongs the QT interval and perpetuates arrhythmia when combined with enhanced inotropy in the CAVB dog</title><author>van Bavel, Joanne J.A. ; Beekman, Henriëtte D.M. ; van Weperen, Valerie Y.H. ; van der Linde, Henk J. ; van der Heyden, Marcel A.G. ; Vos, Marc A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c315t-c3cd1a5dbc7ee76822fb21255fc91155dfed98e2f28ecf6472729eb343c785ad3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>CAVB Dog model</topic><topic>Contractility</topic><topic>IKs</topic><topic>JNJ303</topic><topic>QT interval</topic><topic>Ventricular arrhythmia</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>van Bavel, Joanne J.A.</creatorcontrib><creatorcontrib>Beekman, Henriëtte D.M.</creatorcontrib><creatorcontrib>van Weperen, Valerie Y.H.</creatorcontrib><creatorcontrib>van der Linde, Henk J.</creatorcontrib><creatorcontrib>van der Heyden, Marcel A.G.</creatorcontrib><creatorcontrib>Vos, Marc A.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>van Bavel, Joanne J.A.</au><au>Beekman, Henriëtte D.M.</au><au>van Weperen, Valerie Y.H.</au><au>van der Linde, Henk J.</au><au>van der Heyden, Marcel A.G.</au><au>Vos, Marc A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>IKs inhibitor JNJ303 prolongs the QT interval and perpetuates arrhythmia when combined with enhanced inotropy in the CAVB dog</atitle><jtitle>European journal of pharmacology</jtitle><date>2022-10-15</date><risdate>2022</risdate><volume>932</volume><spage>175218</spage><epage>175218</epage><pages>175218-175218</pages><artnum>175218</artnum><issn>0014-2999</issn><eissn>1879-0712</eissn><abstract>Impaired IKs induced by drugs or due to a KCNQ1 mutation, diagnosed as long QT syndrome type 1 (LQT1) prolongs the QT interval and predisposes the heart to Torsade de Pointes (TdP) arrhythmias. The anesthetized chronic AV block (CAVB) dog is inducible for TdP after remodeling and IKr inhibitor dofetilide. We tested the proarrhythmic effect of IKs inhibition in the CAVB dog, and the proarrhythmic role of increased contractility herein. Dofetilide-inducible animals were included to test the proarrhythmic effect of 1) IKs inhibition by JNJ303 (0.63 mg/kg/10min i.v.; n = 4), 2) IKs inhibition combined with enhanced inotropy (ouabain, 0.045 mg/kg/1min i.v.; n = 6), and 3) the washout period of the anesthetic regime (n = 10). JNJ303 prolonged the QTc interval (from 477 ± 53 ms to 565 ± 14 ms, P &lt; 0.02) resembling standardized dofetilide-induced QTc prolongation. Single ectopic beats (n = 4) and ventricular tachycardia (VT) (n = 3) were present, increasing the arrhythmia score (AS) from 1.0 ± 0 to 7.1 ± 6.5. JNJ303 combined with ouabain increased contractile parameters (LVdP/dtmax from 1725 ± 273 to 4147 ± 611 mmHg/s, P &lt; 0.01). Moreover, TdP arrhythmias were induced in 4/6 dogs and AS increased from 1.0 ± 0 to 20.2 ± 19.0 after JNJ303 and ouabain (P &lt; 0.05). Finally, TdP arrhythmias were induced in 4/10 dogs during the anesthesia washout period and the AS increased from 1.1 ± 0.3 to 9.2 ± 11.2. Mimicking LQT1 using IKs inhibitor JNJ303 prolongs the QTc interval and triggers ectopic beats and non-sustained VT in the CAVB dog. Induction of the more severe arrhythmic events (TdP) demands a combination of IKs inhibition with enhanced inotropy or ending the anesthetic regime. •IKs inhibitor JNJ303 prolongs the QT interval with induction of mild arrhythmic events.•JNJ303 combined with enhanced inotropy is proarrhythmic by perpetuation of mild events into severe ventricular arrhythmias.•Washout of anesthesia after JNJ303 and enhanced inotropy is indicated as sympathetic trigger with a proarrhythmic role.</abstract><pub>Elsevier B.V</pub><doi>10.1016/j.ejphar.2022.175218</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-4225-7942</orcidid><oa>free_for_read</oa></addata></record>
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subjects CAVB Dog model
Contractility
IKs
JNJ303
QT interval
Ventricular arrhythmia
title IKs inhibitor JNJ303 prolongs the QT interval and perpetuates arrhythmia when combined with enhanced inotropy in the CAVB dog
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