Gene- and variant-specific efficacy of serum/glucocorticoid-regulated kinase 1 inhibition in long QT syndrome types 1 and 2
© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology..
AIMS: Current long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2.
METHODS AND RESULTS: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum/glucocorticoid-regulated kinase 1 inhibition effects (300 nM-10 µM) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3 µM) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2-p.A561V/p.A614V/p.G628S/IVS9-28A/G), SGK1-Inh dose-dependently shortened FPD/APD at 0.3-10 µM (by 20-32%/25-30%/44-45%). Importantly, in LQT2 rabbit CMs, 3 µM SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1-p.R594Q hiPSC-CMs at 1/3/10 µM (by 19/26/35%) and in KCNQ1-p.A341V hiPSC-CMs at 10 µM (by 29%). No SGK1-Inh-induced FPD/APD shortening effect was observed in LQT1 KCNQ1-p.A341V hiPSC-CMs or KCNQ1-p.Y315S rabbit CMs at 0.3-3 µM.
CONCLUSION: A robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:25 |
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| Enthalten in: |
Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology - 25(2023), 5 vom: 19. Mai |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Giannetti, Federica [VerfasserIn] |
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| Links: |
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| Themen: |
Animal models |
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| Anmerkungen: |
Date Completed 01.06.2023 Date Revised 23.08.2023 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/europace/euad094 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Giannetti, Federica |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Gene- and variant-specific efficacy of serum/glucocorticoid-regulated kinase 1 inhibition in long QT syndrome types 1 and 2 |
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| 500 | |a Date Completed 01.06.2023 | ||
| 500 | |a Date Revised 23.08.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. | ||
| 520 | |a AIMS: Current long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2 | ||
| 520 | |a METHODS AND RESULTS: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum/glucocorticoid-regulated kinase 1 inhibition effects (300 nM-10 µM) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3 µM) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2-p.A561V/p.A614V/p.G628S/IVS9-28A/G), SGK1-Inh dose-dependently shortened FPD/APD at 0.3-10 µM (by 20-32%/25-30%/44-45%). Importantly, in LQT2 rabbit CMs, 3 µM SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1-p.R594Q hiPSC-CMs at 1/3/10 µM (by 19/26/35%) and in KCNQ1-p.A341V hiPSC-CMs at 10 µM (by 29%). No SGK1-Inh-induced FPD/APD shortening effect was observed in LQT1 KCNQ1-p.A341V hiPSC-CMs or KCNQ1-p.Y315S rabbit CMs at 0.3-3 µM | ||
| 520 | |a CONCLUSION: A robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Animal models | |
| 650 | 4 | |a Cellular electrophysiology | |
| 650 | 4 | |a Genotype-specific therapy | |
| 650 | 4 | |a LQTS | |
| 650 | 4 | |a Mechanism-based therapy | |
| 650 | 4 | |a hiPSC | |
| 650 | 7 | |a Glucocorticoids |2 NLM | |
| 650 | 7 | |a KCNQ1 Potassium Channel |2 NLM | |
| 700 | 1 | |a Barbieri, Miriam |e verfasserin |4 aut | |
| 700 | 1 | |a Shiti, Assad |e verfasserin |4 aut | |
| 700 | 1 | |a Casini, Simona |e verfasserin |4 aut | |
| 700 | 1 | |a Sager, Philip T |e verfasserin |4 aut | |
| 700 | 1 | |a Das, Saumya |e verfasserin |4 aut | |
| 700 | 1 | |a Pradhananga, Sabindra |e verfasserin |4 aut | |
| 700 | 1 | |a Srinivasan, Dinesh |e verfasserin |4 aut | |
| 700 | 1 | |a Nimani, Saranda |e verfasserin |4 aut | |
| 700 | 1 | |a Alerni, Nicolò |e verfasserin |4 aut | |
| 700 | 1 | |a Louradour, Julien |e verfasserin |4 aut | |
| 700 | 1 | |a Mura, Manuela |e verfasserin |4 aut | |
| 700 | 1 | |a Gnecchi, Massimiliano |e verfasserin |4 aut | |
| 700 | 1 | |a Brink, Paul |e verfasserin |4 aut | |
| 700 | 1 | |a Zehender, Manfred |e verfasserin |4 aut | |
| 700 | 1 | |a Koren, Gideon |e verfasserin |4 aut | |
| 700 | 1 | |a Zaza, Antonio |e verfasserin |4 aut | |
| 700 | 1 | |a Crotti, Lia |e verfasserin |4 aut | |
| 700 | 1 | |a Wilde, Arthur A M |e verfasserin |4 aut | |
| 700 | 1 | |a Schwartz, Peter J |e verfasserin |4 aut | |
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| 700 | 1 | |a Odening, Katja E |e verfasserin |4 aut | |
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