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5. Gene- and variant-specific efficacy of serum/glucocorticoid-regulated kinase 1 inhibition in long QT syndrome types 1 and 2

Author

Giannetti, Federica, primary, Barbieri, Miriam, additional, Shiti, Assad, additional, Casini, Simona, additional, Sager, Philip T, additional, Das, Saumya, additional, Pradhananga, Sabindra, additional, Srinivasan, Dinesh, additional, Nimani, Saranda, additional, Alerni, Nicolò, additional, Louradour, Julien, additional, Mura, Manuela, additional, Gnecchi, Massimiliano, additional, Brink, Paul, additional, Zehender, Manfred, additional, Koren, Gideon, additional, Zaza, Antonio, additional, Crotti, Lia, additional, Wilde, Arthur A M, additional, Schwartz, Peter J, additional, Remme, Carol Ann, additional, Gepstein, Lior, additional, Sala, Luca, additional, and Odening, Katja E, additional

Published
2023
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6. Gene- and variant-specific efficacy of serum/glucocorticoid-regulated kinase 1 inhibition in long QT syndrome types 1 and 2

Author

Giannetti, Federica, Barbieri, Miriam, Shiti, Assad, Casini, Simona, Sager, Philip T, Das, Saumya, Pradhananga, Sabindra, Srinivasan, Dinesh, Nimani, Saranda, Alerni, Nicolò, Louradour, Julien, Mura, Manuela, Gnecchi, Massimiliano, Brink, Paul, Zehender, Manfred, Koren, Gideon, Zaza, Antonio, Crotti, Lia, Wilde, Arthur A M, Schwartz, Peter J, Remme, Carol Ann, Gepstein, Lior, Sala, Luca, Odening, Katja E, Giannetti, F, Barbieri, M, Shiti, A, Casini, S, Sager, P, Das, S, Pradhananga, S, Srinivasan, D, Nimani, S, Alerni, N, Louradour, J, Mura, M, Gnecchi, M, Brink, P, Zehender, M, Koren, G, Zaza, A, Crotti, L, Wilde, A, Schwartz, P, Remme, C, Gepstein, L, Sala, L, and Odening, K

Subjects
Cellular electrophysiology, Physiology (medical), LQTS, Animal model, 610 Medicine & health, 610 Medizin und Gesundheit, Cardiology and Cardiovascular Medicine, Genotype-specific therapy, hiPSC, Mechanism-based therapy
Abstract

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.

Published
2023

11. Rambam Health Care Campus Research Day Organizing Committee

Author

Blazer, Shraga, Giladi, Hadar Zigdon, Avraham, Karen B., Skorecki, Karl, Beyar, Rafael, Paul, Mical, Koppel, Fidi, Bitterman, Roni, Neuberger, Ami, Ghanem-Zoubi, Nesrin, Stern, Anat, Dickstein, Yaakov, Zbu-Zayyad, Hiba, Mussini, Cristina, Leibovici, Leonard, Yahav, Dafna, Yehudai-Reshef, Shlomit, Sabah, Rawan, Fridman-Dror, Anna, Gabay, Tal, Turgeman, Shira, Zuckerman, Tsila, Cohen-Vaizer, Mauricio, Fridman, Eran, Dakhlallah, Shifaa, Federman, Moria, Khamaysi, Iyad, Ben Hemo, Dalit, Bhattacharya, Udayan, Kinaneh, Safa, Ilan, Neta, Vlodavsky, Israel, Abassi, Zaid, Shinnawi, Rami, Shaheen, Naim, Huber, Irit, Shiti, Assad, Arbel, Gil, Gepstein, Amira, Tijsen, Anke, Borggrefe, Marin, Gepstein, Lior, Solt, Ido, Caspi, Or, Beloosesky, Ron, Weiner, Zeev, Avdor, Eyal, Rechtman, Hilla Korach, Hreish, Maysaa, Fried, Carmit, Gerassy-Vainberg, Shiran, Azzam, Zaher S., Kashi, Yechezkel, Berger, Gidon, Duek, Ori Samuel, Ben Naftali, Yeela, Ullmann, Yehuda, Ullman, Yehuda, Kuperman, Pora, Bosak, Noam, Granovsky, Yelena, Granot, Michal, Bahouth, Hany, Fadel, Shiri, Ben-Lulu, Hen, Marco, Avihu, Buxbaum, Chen, Sprecher, Elliot, Yarnitsky, David, Gelber, Pazit Shachar, Halil, Adnan, Gorelik, Yuri, Hag, Eisa, Hananya, Tomer, Leiba, Ronit, Half, Elizabeth, Fares, Basem, Perets, Ruth, Kurolap, Alina, Naoum, Nadine Damouny, Palacios-Zambrano, Sara, Mory, Adi, Paperna, Tamar, Garesse, Rafael, Mandel, Hanna, Zohar, Yaniv, Fernández-Moreno, Miguel A., Feldman, Hagit Baris, Ofir, Ayala, Pollack, Shirley, Eisenstein, Israel, Tzur, Shay, Magen, Daniella, Beck-Razi, Nira, Gaitini, Diana, Besser, Ziva, Halevi, Dorit, Javitt, Marcia, Horowitz, Netanel, Giryes, Sami, Nasser, Roni, Sharon, Rivka, Azoulay, David, Doppelt, Ofri, Cohen, Gal, Book, Reut, Elimelech, Rina, Tamari, Tal, Zigdon, Hadar, Hochberg, Irit, Alon, Raviv, Yom-Tov, Elad, Lauterbach, Roy, Matanes, Emad, Ben David, Chen, Mor, Omer, Linder, Revital, Cohen-Halbertal, Adi, Zipori, Yaniv, Ginsberg, Yuval, Ilan, Lena, Kabha, Ahmad, Zussman, Eyal, Amiel, Gilad, Mabariki, Therese Shehadeh, Sabo, Edmond, Kremer, Ran, Haverfeld, Ori, Sarig, Galit, Blich, Miry, Oron, Hodaya, Darawsha, Wisam, Suleiman, Mahmoud, Boulos, Monther, Luko, Liel, Parush, Avi, Lowenstein, Lior, Haklai, Ziona, Mendelovic, Joseph, Lavie, Gil, Mustafa-Mikhail, Susana, Amit, Amnon, Weiss, Karin, Steinberg, Maya, Hershkovitz, Tova, Ekhilevitch, Nina, Baris, Hagit N., Dabajah, Hanin, Gruenwald, Ilan, Aharoni, Saar, Tal, Raanan, Appel, Boaz, Ghannam-Shahbari, Dima, Jacob, Eyal, Kakun, Reli Rachel, Wasserman, Tanya, Korsensky, Lina, Sternfeld, Ofir, Kagan, Juliana, Bublik, Debora Rosa, Aviel-Ronen, Sarit, Levanon, Keren, Larisch, Sarit, Oren, Moshe, Hershkovitz, Dov, Zur, Gil, Litvin, Maria, Berkovich, Eyal, Andreus, Maisa, Beck, Nira, Na’ara, Shorook, Amit, Moran, Billan, Salem, Shinnawi, Shadi, Gil, Ziv, Amir, Moran, Yehieli-Cohen, Ravit, Masarwa, Omar, Ginini, Lana, Milman, Neta, and Namora, Khalil

Subjects
Guest Lecturers, Oral Presentations, Selected Abstracts from Rambam Research Day, Supplement
Published
2019

12. Human Induced Pluripotent Stem Cell-Derived Cardiac Cell Sheets Expressing Genetically Encoded Voltage Indicator for Pharmacological and Arrhythmia Studies

Author

Shaheen, Naim, primary, Shiti, Assad, additional, Huber, Irit, additional, Shinnawi, Rami, additional, Arbel, Gil, additional, Gepstein, Amira, additional, Setter, Noga, additional, Goldfracht, Idit, additional, Gruber, Amit, additional, Chorna, Snizhanna V., additional, and Gepstein, Lior, additional

Published
2018
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13. Abstract 12495: Atrial Cardiomyocytes Derived From Human Induced Pluripotent Stem Cells for Studying Short QT Syndrome Related Atrial Fibrillation.

Author

Shiti, Assad, Arbil, Gil, Shaheen, Naim, Huber, Irit, and Gepstein, Lior

Subjects
*INDUCED pluripotent stem cells, *TACHYARRHYTHMIAS, *ATRIAL fibrillation, *POPULATION, *SYNDROMES
Abstract

Background: Atrial fibrillation (AF) is the most common clinical arrhythmia and is associated with significant morbidity and mortality. Recent studies suggested that AF has strong genetic basis, including distinct monogenic cases of familial AF. Yet, the functional consequences of these variants on human atrial cells have not been fully elucidated due to the lack of appropriate human tissue models. One of the genetic causes is the short QT syndrome (SQTS), characterized by a short QT interval on the ECG and increased propensity for atrial and ventricular tachyarrhythmias. Objectives: 1) To establish chamber-specific differentiation protocols to yield purified populations of human induced pluripotent stem cell (hiPSC)-derived atrial and ventricular cardiomyocytes (CMs). 2) To characterize the electrical properties of the SQTS-hiPSC-atrial CMs and to provide mechanistic insights into the atrial arrhythmogenecity in this syndrome. Results: Patient-specific hiPSC lines from a healthy individual and a SQTS patient, carrying a missense mutation (N588K) in the hERG gene, along with a CRISPR/Cas9 corrected isogenic-control line were coaxed to differentiate to the cardiac lineage. Retinoic acid (RA) was either supplemented or not on days 3-5 to derive pure atrial or ventricular populations, respectively. Immunofluorescence of hiPSC-atrial CMs showed the absence of ventricular isoform MLC2v and upregulation of the atrial-specific TF COUP-TF1. FACS analysis further confirmed low percentages (<10%) of MLC2v+ populations. Patch-clamp recordings of the hiPSC-atrial CMs revealed shorter AP duration (APD90: 233.2±1.5 vs 363.7±2.7 ms, p<0.01) and a more triangular APs with steeper repolarization (APD90/APD50: 3.07±0.41 vs 1.28±0.12, p<0.05) in comparison to APs from hiPSC-ventricular CMs. Voltage-clamp recordings confirmed the presence of the atrial ACh-sensitive potassium current (at -120mV: -3.8±1.65 vs 0.17±0.27 pA/pF, p<0.0001). Eventually, SQTS-hiPSC-atrial CMs exhibited even shorter AP duration compared to both healthy-control and SQTS-corrected-hiPSC-atrial CMs. (APD90: 135.7±1.8 vs 233.2±1.5 and 204.3±1.6 ms, p<0.0001 and p<0.05, respectively). Conclusions: 1) RA promotes the differentiation of hiPSCs to atrial CMs with distinct molecular and electrical characteristics. 2) hERG N588K mutation results in shortening of the AP duration in hiPSC-atrial CMs. 3) hiPSC-atrial CMs, coupled with gene editing technologies, offer a novel platform for studying the functional consequences of AF-related genetic variants. [ABSTRACT FROM AUTHOR]

Published
2018

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