Transgenic LQT2, LQT5, and LQT2‐5 rabbit models with decreased repolarisation reserve for prediction of drug‐induced ventricular arrhythmias
Background and Purpose Reliable prediction of pro‐arrhythmic side effects of novel drug candidates is still a major challenge. Although drug‐induced pro‐arrhythmia occurs primarily in patients with pre‐existing repolarisation disturbances, healthy animals are employed for pro‐arrhythmia testing. To...
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| Published in: | British journal of pharmacology Vol. 177; no. 16; pp. 3744 - 3759 |
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| Main Authors: | , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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Blackwell Publishing Ltd
01-08-2020
John Wiley and Sons Inc |
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| Abstract | Background and Purpose
Reliable prediction of pro‐arrhythmic side effects of novel drug candidates is still a major challenge. Although drug‐induced pro‐arrhythmia occurs primarily in patients with pre‐existing repolarisation disturbances, healthy animals are employed for pro‐arrhythmia testing. To improve current safety screening, transgenic long QT (LQTS) rabbit models with impaired repolarisation reserve were generated by overexpressing loss‐of‐function mutations of human HERG (HERG‐G628S, loss of IKr; LQT2), KCNE1 (KCNE1‐G52R, decreased IKs; LQT5), or both transgenes (LQT2‐5) in the heart.
Experimental Approach
Effects of K+ channel blockers on cardiac repolarisation and arrhythmia susceptibility were assessed in healthy wild‐type (WT) and LQTS rabbits using in vivo ECG and ex vivo monophasic action potential and ECG recordings in Langendorff‐perfused hearts.
Key Results
LQTS models reflect patients with clinically “silent” (LQT5) or “manifest” (LQT2 and LQT2‐5) impairment in cardiac repolarisation reserve: they were more sensitive in detecting IKr‐blocking (LQT5) or IK1/IKs‐blocking (LQT2 and LQT2‐5) properties of drugs compared to healthy WT animals. Impaired QT‐shortening capacity at fast heart rates was observed due to disturbed IKs function in LQT5 and LQT2‐5. Importantly, LQTS models exhibited higher incidence, longer duration, and more malignant types of ex vivo arrhythmias than WT.
Conclusion and Implications
LQTS models represent patients with reduced repolarisation reserve due to different pathomechanisms. As they demonstrate increased sensitivity to different specific ion channel blockers (IKr blockade in LQT5 and IK1 and IKs blockade in LQT2 and LQT2‐5), their combined use could provide more reliable and more thorough prediction of (multichannel‐based) pro‐arrhythmic potential of novel drug candidates. |
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| AbstractList | Reliable prediction of pro-arrhythmic side effects of novel drug candidates is still a major challenge. Although drug-induced pro-arrhythmia occurs primarily in patients with pre-existing repolarisation disturbances, healthy animals are employed for pro-arrhythmia testing. To improve current safety screening, transgenic long QT (LQTS) rabbit models with impaired repolarisation reserve were generated by overexpressing loss-of-function mutations of human HERG (HERG-G628S, loss of I
; LQT2), KCNE1 (KCNE1-G52R, decreased I
; LQT5), or both transgenes (LQT2-5) in the heart.
Effects of K
channel blockers on cardiac repolarisation and arrhythmia susceptibility were assessed in healthy wild-type (WT) and LQTS rabbits using in vivo ECG and ex vivo monophasic action potential and ECG recordings in Langendorff-perfused hearts.
LQTS models reflect patients with clinically "silent" (LQT5) or "manifest" (LQT2 and LQT2-5) impairment in cardiac repolarisation reserve: they were more sensitive in detecting I
-blocking (LQT5) or I
/I
-blocking (LQT2 and LQT2-5) properties of drugs compared to healthy WT animals. Impaired QT-shortening capacity at fast heart rates was observed due to disturbed I
function in LQT5 and LQT2-5. Importantly, LQTS models exhibited higher incidence, longer duration, and more malignant types of ex vivo arrhythmias than WT.
LQTS models represent patients with reduced repolarisation reserve due to different pathomechanisms. As they demonstrate increased sensitivity to different specific ion channel blockers (I
blockade in LQT5 and I
and I
blockade in LQT2 and LQT2-5), their combined use could provide more reliable and more thorough prediction of (multichannel-based) pro-arrhythmic potential of novel drug candidates. BACKGROUND AND PURPOSEReliable prediction of pro-arrhythmic side effects of novel drug candidates is still a major challenge. Although drug-induced pro-arrhythmia occurs primarily in patients with pre-existing repolarisation disturbances, healthy animals are employed for pro-arrhythmia testing. To improve current safety screening, transgenic long QT (LQTS) rabbit models with impaired repolarisation reserve were generated by overexpressing loss-of-function mutations of human HERG (HERG-G628S, loss of IKr ; LQT2), KCNE1 (KCNE1-G52R, decreased IKs ; LQT5), or both transgenes (LQT2-5) in the heart. EXPERIMENTAL APPROACHEffects of K+ channel blockers on cardiac repolarisation and arrhythmia susceptibility were assessed in healthy wild-type (WT) and LQTS rabbits using in vivo ECG and ex vivo monophasic action potential and ECG recordings in Langendorff-perfused hearts. KEY RESULTSLQTS models reflect patients with clinically "silent" (LQT5) or "manifest" (LQT2 and LQT2-5) impairment in cardiac repolarisation reserve: they were more sensitive in detecting IKr -blocking (LQT5) or IK1 /IKs -blocking (LQT2 and LQT2-5) properties of drugs compared to healthy WT animals. Impaired QT-shortening capacity at fast heart rates was observed due to disturbed IKs function in LQT5 and LQT2-5. Importantly, LQTS models exhibited higher incidence, longer duration, and more malignant types of ex vivo arrhythmias than WT. CONCLUSION AND IMPLICATIONSLQTS models represent patients with reduced repolarisation reserve due to different pathomechanisms. As they demonstrate increased sensitivity to different specific ion channel blockers (IKr blockade in LQT5 and IK1 and IKs blockade in LQT2 and LQT2-5), their combined use could provide more reliable and more thorough prediction of (multichannel-based) pro-arrhythmic potential of novel drug candidates. Background and Purpose Reliable prediction of pro‐arrhythmic side effects of novel drug candidates is still a major challenge. Although drug‐induced pro‐arrhythmia occurs primarily in patients with pre‐existing repolarisation disturbances, healthy animals are employed for pro‐arrhythmia testing. To improve current safety screening, transgenic long QT (LQTS) rabbit models with impaired repolarisation reserve were generated by overexpressing loss‐of‐function mutations of human HERG (HERG‐G628S, loss of IKr; LQT2), KCNE1 (KCNE1‐G52R, decreased IKs; LQT5), or both transgenes (LQT2‐5) in the heart. Experimental Approach Effects of K+ channel blockers on cardiac repolarisation and arrhythmia susceptibility were assessed in healthy wild‐type (WT) and LQTS rabbits using in vivo ECG and ex vivo monophasic action potential and ECG recordings in Langendorff‐perfused hearts. Key Results LQTS models reflect patients with clinically “silent” (LQT5) or “manifest” (LQT2 and LQT2‐5) impairment in cardiac repolarisation reserve: they were more sensitive in detecting IKr‐blocking (LQT5) or IK1/IKs‐blocking (LQT2 and LQT2‐5) properties of drugs compared to healthy WT animals. Impaired QT‐shortening capacity at fast heart rates was observed due to disturbed IKs function in LQT5 and LQT2‐5. Importantly, LQTS models exhibited higher incidence, longer duration, and more malignant types of ex vivo arrhythmias than WT. Conclusion and Implications LQTS models represent patients with reduced repolarisation reserve due to different pathomechanisms. As they demonstrate increased sensitivity to different specific ion channel blockers (IKr blockade in LQT5 and IK1 and IKs blockade in LQT2 and LQT2‐5), their combined use could provide more reliable and more thorough prediction of (multichannel‐based) pro‐arrhythmic potential of novel drug candidates. |
| Author | Franke, Gerlind Baczkó, István Castiglione, Alessandro Major, Péter Bősze, Zsuzsanna Hornyik, Tibor Koren, Gideon Varró, András Zehender, Manfred Hiripi, László Brunner, Michael Bode, Christoph Perez‐Feliz, Stefanie Odening, Katja E. |
| AuthorAffiliation | 7 Translational Cardiology, Department of Cardiology, Inselspital, Bern University Hospital, and Institute of Physiology University of Bern Bern Switzerland 1 Department of Cardiology and Angiology I Heart Center University of Freiburg, Medical Faculty Freiburg Germany 2 Institute of Experimental Cardiovascular Medicine Heart Center University of Freiburg, Medical Faculty Freiburg Germany 3 Department of Pharmacology and Pharmacotherapy University of Szeged Szeged Hungary 4 Cardiovascular Research Center Brown University Providence Rhode Island USA 5 NARIC‐Agricultural Biotechnology Institute Animal Biotechnology Department Gödöllő Hungary 6 Department of Cardiology and Medical Intensive Care St. Josefskrankenhaus Freiburg Germany |
| AuthorAffiliation_xml | – name: 1 Department of Cardiology and Angiology I Heart Center University of Freiburg, Medical Faculty Freiburg Germany – name: 6 Department of Cardiology and Medical Intensive Care St. Josefskrankenhaus Freiburg Germany – name: 7 Translational Cardiology, Department of Cardiology, Inselspital, Bern University Hospital, and Institute of Physiology University of Bern Bern Switzerland – name: 2 Institute of Experimental Cardiovascular Medicine Heart Center University of Freiburg, Medical Faculty Freiburg Germany – name: 5 NARIC‐Agricultural Biotechnology Institute Animal Biotechnology Department Gödöllő Hungary – name: 3 Department of Pharmacology and Pharmacotherapy University of Szeged Szeged Hungary – name: 4 Cardiovascular Research Center Brown University Providence Rhode Island USA |
| Author_xml | – sequence: 1 givenname: Tibor surname: Hornyik fullname: Hornyik, Tibor organization: University of Szeged – sequence: 2 givenname: Alessandro surname: Castiglione fullname: Castiglione, Alessandro organization: Heart Center University of Freiburg, Medical Faculty – sequence: 3 givenname: Gerlind orcidid: 0000-0002-3202-6876 surname: Franke fullname: Franke, Gerlind organization: Heart Center University of Freiburg, Medical Faculty – sequence: 4 givenname: Stefanie surname: Perez‐Feliz fullname: Perez‐Feliz, Stefanie organization: Heart Center University of Freiburg, Medical Faculty – sequence: 5 givenname: Péter orcidid: 0000-0001-5408-8069 surname: Major fullname: Major, Péter organization: Animal Biotechnology Department – sequence: 6 givenname: László orcidid: 0000-0002-1023-0112 surname: Hiripi fullname: Hiripi, László organization: Animal Biotechnology Department – sequence: 7 givenname: Gideon surname: Koren fullname: Koren, Gideon organization: Brown University – sequence: 8 givenname: Zsuzsanna orcidid: 0000-0002-2493-759X surname: Bősze fullname: Bősze, Zsuzsanna organization: Animal Biotechnology Department – sequence: 9 givenname: András orcidid: 0000-0003-0745-3603 surname: Varró fullname: Varró, András organization: University of Szeged – sequence: 10 givenname: Manfred surname: Zehender fullname: Zehender, Manfred organization: Heart Center University of Freiburg, Medical Faculty – sequence: 11 givenname: Michael orcidid: 0000-0002-0287-9560 surname: Brunner fullname: Brunner, Michael organization: St. Josefskrankenhaus – sequence: 12 givenname: Christoph surname: Bode fullname: Bode, Christoph organization: Heart Center University of Freiburg, Medical Faculty – sequence: 13 givenname: István orcidid: 0000-0002-9588-0797 surname: Baczkó fullname: Baczkó, István organization: University of Szeged – sequence: 14 givenname: Katja E. orcidid: 0000-0001-6999-841X surname: Odening fullname: Odening, Katja E. email: katja.odening@uniklinik-freiburg.de, katja.odening@pyl.unibe.ch organization: University of Bern |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/32436214$$D View this record in MEDLINE/PubMed |
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| Notes | István Baczkó and Katja E. Odening shared last authorship. Tibor Hornyik and Alessandro Castiglione shared first authorship. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The copyright line for this article was changed on 3 September 2020 after original online publication. |
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Reliable prediction of pro‐arrhythmic side effects of novel drug candidates is still a major challenge. Although drug‐induced... Reliable prediction of pro-arrhythmic side effects of novel drug candidates is still a major challenge. Although drug-induced pro-arrhythmia occurs primarily... Background and PurposeReliable prediction of pro‐arrhythmic side effects of novel drug candidates is still a major challenge. Although drug‐induced... BACKGROUND AND PURPOSEReliable prediction of pro-arrhythmic side effects of novel drug candidates is still a major challenge. Although drug-induced... |
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| SubjectTerms | Action potential Animal models Arrhythmia Cardiac arrhythmia Drug development EKG Heart Potassium channels Predictions Research Paper Research Papers Transgenes Ventricle |
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| Title | Transgenic LQT2, LQT5, and LQT2‐5 rabbit models with decreased repolarisation reserve for prediction of drug‐induced ventricular arrhythmias |
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