29 results on '"Feliz S"'
Search Results
2. Interplay of electrical and mechanical properties in transgenic rabbit models of long-QT and short-QT syndrome
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Alerni, N, primary, Nimani, S, additional, Hornyik, T, additional, Barbieri, M, additional, Louradour, J, additional, Giammarino, L, additional, Matas, L, additional, Perez-Feliz, S, additional, Zehender, M, additional, Brunner, M, additional, and Odening, K, additional
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- 2024
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3. The Endoscopic Mega Plication Technique. A new approach of use the IOP platform doubling the size of the bites and reducing the number of sutures over 40 % and the cost of the procedure
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Turro, R., additional, Sabater, A. Ortega, additional, Feliz, S., additional, Mata, A., additional, Uchima, H., additional, López-Jurado, R. Temiño, additional, Michelena, J., additional, Rosinach, M., additional, Vila Moix, A., additional, Badia, H. Vergara, additional, Valero, S. Andrés, additional, Ruiz, S., additional, and Espinós, J., additional
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- 2023
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4. SNAP Procedure. Duodenal-Ileal Diversion with Self-Assembling Magnets in Patients with Inadequate Weight Loss or Weight Regain following Sleeve Gastrectomy: Feasibility and Six-Month Results
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Turro, R., additional, Diez-Caballero, A., additional, Sabater, A. Ortega, additional, Mata, A., additional, Feliz, S., additional, Moix, A. Vila, additional, Uchima, H., additional, Hernandez, J. Saez, additional, López-Jurado, R. Temiño, additional, Michelena, J., additional, Rosinach, M., additional, Badia, H. Vergara, additional, Valero, S. Andrés, additional, Ruiz, S., additional, and Espinós, J., additional
- Published
- 2023
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5. The Endoscopic Mega Plication Procedure (EMPP). Prospective Study of the Primary Obesity Surgery Endoluminal (POSE) with Double G-Lix Procedure for treatment of Obesity. Safety and effectiveness at three-month follow-up
- Author
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Turro, R., additional, Sabater, A. Ortega, additional, Feliz, S., additional, Mata, A., additional, Uchima, H., additional, Moix, A. Vila, additional, Badia, H. Vergara, additional, Ruiz, S., additional, Rosinach, M., additional, Michelena, J., additional, López-Jurado, R. Temiño, additional, Valero, S. Andrés, additional, Da Costa, M., additional, and Espinós, J., additional
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- 2023
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6. Metabolic treatment of an electrical disease? Beneficial APD/QT prolongation by L-Carnitine in transgenic SQT1 rabbit models
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Hornyik, T, primary, Bodi, I, additional, Michaelides, K, additional, Mettke, L, additional, Perez-Feliz, S, additional, El-Battrawy, I, additional, Brunner, M, additional, Bode, C, additional, and Odening, K, additional
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- 2021
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7. Differences in extent of mechano-induced QT-changes in SQTS, WT and LQTS rabbit models
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Nimani, S, primary, Hornyik, T, additional, Alerni, N, additional, Lewetag, R, additional, Giammarino, L, additional, Perez-Feliz, S, additional, Matas, L, additional, Moss, K R, additional, Zehender, M, additional, Brunner, M, additional, Seemann, G, additional, and Odening, K E, additional
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- 2021
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8. PMH40 Effects of AXS-05 on Patient Reported Depressive Symptoms in Major Depressive Disorder: Results from the GEMINI Trial
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O'Gorman, C., primary, Feliz, S., additional, Jones, A., additional, Streicher, C., additional, Thomas, Z., additional, and Tabuteau, H., additional
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- 2021
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9. PMH42 Early Improvements in Functioning and Quality of Life with AXS-05 in Major Depressive Disorder: Resultsfrom the GEMINI Trial
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Jones, A., primary, Feliz, S., additional, O'Gorman, C., additional, Streicher, C., additional, Thomas, Z., additional, and Tabuteau, H., additional
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- 2021
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10. Electro-mechanical and mechano-electrical interactions in healthy and drug-induced LQTS rabbit hearts
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Lewetag, R, primary, Hornyik, T, additional, Jacobi, S, additional, Moss, R, additional, Pilia, N, additional, Menza, M, additional, Perez-Feliz, S, additional, Bode, C, additional, Seemann, G, additional, and Odening, KE, additional
- Published
- 2021
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11. P604Docosahexaenoic acid acts as QT-shortening agent with genotype-tspecific beneficial effects in transgenic LQT1, LQT2, LQT5 and LQT2-5 rabbit models
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Castiglione, A, primary, Hornyik, T, additional, Franke, G, additional, Perez-Feliz, S, additional, Bosze, Z, additional, Koren, G, additional, Varro, A, additional, Zehender, M, additional, Brunner, M, additional, Bode, C, additional, Baczko, I, additional, and Odening, K E, additional
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- 2018
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12. 5922Oxytocin has harmful cardiac repolarization prolonging effects - Particularly in context of drug-induced LQTS
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Kreifels, P, primary, Franke, G, additional, Perez-Feliz, S, additional, Bodi, I, additional, Castiglione, A, additional, Ziupa, D, additional, Bode, C, additional, and Odening, K E, additional
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- 2018
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13. Electro-mechanical dysfunction in long QT syndrome: Role for arrhythmogenic risk prediction and modulation by sex and sex hormones
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Lang, C.N., primary, Menza, M., additional, Jochem, S., additional, Franke, G., additional, Perez Feliz, S., additional, Brunner, M., additional, Koren, G., additional, Zehender, M., additional, Bugger, H., additional, Jung, B.A., additional, Foell, D., additional, Bode, C., additional, and Odening, K.E., additional
- Published
- 2016
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14. KCNQ1 suppression-replacement gene therapy in transgenic rabbits with type 1 long QT syndrome.
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Bains S, Giammarino L, Nimani S, Alerni N, Tester DJ, Kim CSJ, Christoforou N, Louradour J, Horváth A, Beslac O, Barbieri M, Matas L, Hof TS, Lopez R, Perez-Feliz S, Parodi C, Garcia Casalta LG, Jurgensen J, Barry MA, Bego M, Keyes L, Owens J, Pinkstaff J, Koren G, Zehender M, Brunner M, Casoni D, Praz F, Haeberlin A, Brooks G, Ackerman MJ, and Odening KE
- Abstract
Background and Aims: Type 1 long QT syndrome (LQT1) is caused by pathogenic variants in the KCNQ1-encoded Kv7.1 potassium channels, which pathologically prolong ventricular action potential duration (APD). Herein, the pathologic phenotype in transgenic LQT1 rabbits is rescued using a novel KCNQ1 suppression-replacement (SupRep) gene therapy., Methods: KCNQ1-SupRep gene therapy was developed by combining into a single construct a KCNQ1 shRNA (suppression) and an shRNA-immune KCNQ1 cDNA (replacement), packaged into adeno-associated virus serotype 9, and delivered in vivo via an intra-aortic root injection (1E10 vg/kg). To ascertain the efficacy of SupRep, 12-lead electrocardiograms were assessed in adult LQT1 and wild-type (WT) rabbits and patch-clamp experiments were performed on isolated ventricular cardiomyocytes., Results: KCNQ1-SupRep treatment of LQT1 rabbits resulted in significant shortening of the pathologically prolonged QT index (QTi) towards WT levels. Ventricular cardiomyocytes isolated from treated LQT1 rabbits demonstrated pronounced shortening of APD compared to LQT1 controls, leading to levels similar to WT (LQT1-UT vs. LQT1-SupRep, P < .0001, LQT1-SupRep vs. WT, P = ns). Under β-adrenergic stimulation with isoproterenol, SupRep-treated rabbits demonstrated a WT-like physiological QTi and APD90 behaviour., Conclusions: This study provides the first animal-model, proof-of-concept gene therapy for correction of LQT1. In LQT1 rabbits, treatment with KCNQ1-SupRep gene therapy normalized the clinical QTi and cellular APD90 to near WT levels both at baseline and after isoproterenol. If similar QT/APD correction can be achieved with intravenous administration of KCNQ1-SupRep gene therapy in LQT1 rabbits, these encouraging data should compel continued development of this gene therapy for patients with LQT1., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
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- 2024
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15. Beneficial normalization of cardiac repolarization by carnitine in transgenic SQT1 rabbit models.
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Bodi I, Mettke L, Michaelides K, Hornyik T, Meier S, Nimani S, Perez-Feliz S, El-Battrawy I, Bugger H, Zehender M, Brunner M, Heijman J, and Odening KE
- Abstract
Aims: Short-QT-syndrome type 1 (SQT1) is a genetic channelopathy caused by gain-of-function variants in HERG underlying the rapid delayed-rectifier K+ current (IKr), leading to QT-shortening, ventricular arrhythmias, and sudden cardiac death. Data on efficient pharmaco-therapy for SQT1 are scarce. In patients with primary carnitine-deficiency, acquired-SQTS has been observed and rescued by carnitine-supplementation. Here, we assessed whether carnitine exerts direct beneficial (prolonging) effects on cardiac repolarization in genetic SQTS., Methods and Results: Adult wild-type (WT) and transgenic SQT1 rabbits (HERG-N588K, gain of IKr) were used. In vivo ECGs, ex vivo monophasic action potentials (APs) in Langendorff-perfused hearts, and cellular ventricular APs and ion currents were assessed at baseline and during L-Carnitine/C16-Carnitine-perfusion. 2D computer simulations were performed to assess reentry-based VT-inducibility.L-Carnitine/C16-Carnitine prolonged QT intervals in WT and SQT1, leading to QT-normalization in SQT1. Similarly, monophasic and cellular AP duration (APD) was prolonged by L-Carnitine/C16-Carnitine in WT and SQT1. As underlying mechanisms, we identified acute effects on the main repolarizing ion currents: IKr-steady, which is pathologically increased in SQT1, was reduced by L-Carnitine/C16-Carnitine and deactivation kinetics were accelerated. Moreover, L-Carnitine/C16-Carnitine decreased IKs-steady and IK1. In silico modelling identified IKr-changes as main factor for L-Carnitine/C16-Carnitine-induced APD-prolongation. 2D-simulations revealed increased sustained reentry-based arrhythmia formation in SQT1 compared to WT, which was decreased to the WT-level when adding carnitine-induced ion current changes., Conclusion: L-Carnitine/C16-Carnitine prolong/normalize QT and whole heart/cellular APD in SQT1 rabbits. These beneficial effects are mediated by acute effects on IKr. L-Carnitine may serve as potential future QT-normalizing, anti-arrhythmic therapy in SQT1., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2024
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16. Mechano-electrical interactions and heterogeneities in wild-type and drug-induced long QT syndrome rabbits.
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Lewetag RD, Nimani S, Alerni N, Hornyik T, Jacobi SF, Moss R, Menza M, Pilia N, Walz TP, HajiRassouliha A, Perez-Feliz S, Zehender M, Seemann G, Zgierski-Johnston CM, Lopez R, and Odening KE
- Abstract
Electromechanical reciprocity - comprising electro-mechanical (EMC) and mechano-electric coupling (MEC) - provides cardiac adaptation to changing physiological demands. Understanding electromechanical reciprocity and its impact on function and heterogeneity in pathological conditions - such as (drug-induced) acquired long QT syndrome (aLQTS) - might lead to novel insights in arrhythmogenesis. Our aim is to investigate how electrical changes impact on mechanical function (EMC) and vice versa (MEC) under physiological conditions and in aLQTS. To measure regional differences in EMC and MEC in vivo, we used tissue phase mapping cardiac MRI and a 24-lead ECG vest in healthy (control) and I
Kr -blocker E-4031-induced aLQTS rabbit hearts. MEC was studied in vivo by acutely increasing cardiac preload, and ex vivo by using voltage optical mapping (OM) in beating hearts at different preloads. In aLQTS, electrical repolarization (heart rate corrected RT-interval, RTn370) was prolonged compared to control (P < 0.0001) with increased spatial and temporal RT heterogeneity (P < 0.01). Changing electrical function (in aLQTS) resulted in significantly reduced diastolic mechanical function and prolonged contraction duration (EMC), causing increased apico-basal mechanical heterogeneity. Increased preload acutely prolonged RTn370 in both control and aLQTS hearts (MEC). This effect was more pronounced in aLQTS (P < 0.0001). Additionally, regional RT-dispersion increased in aLQTS. Motion-correction allowed us to determine APD-prolongation in beating aLQTS hearts, but limited motion correction accuracy upon preload-changes prevented a clear analysis of MEC ex vivo. Mechano-induced RT-prolongation and increased heterogeneity were more pronounced in aLQTS than in healthy hearts. Acute MEC effects may play an additional role in LQT-related arrhythmogenesis, warranting further mechanistic investigations. KEY POINTS: Electromechanical reciprocity comprising excitation-contraction coupling (EMC) and mechano-electric feedback loops (MEC) is essential for physiological cardiac function. Alterations in electrical and/or mechanical heterogeneity are known to have potentially pro-arrhythmic effects. In this study, we aimed to investigate how electrical changes impact on the mechanical function (EMC) and vice versa (MEC) both under physiological conditions (control) and in acquired long QT syndrome (aLQTS). We show that changing the electrical function (in aLQTS) results in significantly altered mechanical heterogeneity via EMC and, vice versa, that increasing the preload acutely prolongs repolarization duration and increases electrical heterogeneity, particularly in aLQTS as compared to control. Our results substantiate the hypothesis that LQTS is an ‛electro-mechanical', rather than a 'purely electrical', disease and suggest that acute MEC effects may play an additional role in LQT-related arrhythmogenesis., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)- Published
- 2023
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17. A computational model of rabbit geometry and ECG: Optimizing ventricular activation sequence and APD distribution.
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Moss R, Wülfers EM, Lewetag R, Hornyik T, Perez-Feliz S, Strohbach T, Menza M, Krafft A, Odening KE, and Seemann G
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- Action Potentials physiology, Animals, Electrocardiography, Pericardium physiology, Rabbits, Endocardium physiology, Heart Ventricles diagnostic imaging, Heart Ventricles metabolism
- Abstract
Computational modeling of electrophysiological properties of the rabbit heart is a commonly used way to enhance and/or complement findings from classic lab work on single cell or tissue levels. Yet, thus far, there was no possibility to extend the scope to include the resulting body surface potentials as a way of validation or to investigate the effect of certain pathologies. Based on CT imaging, we developed the first openly available computational geometrical model not only of the whole heart but also the complete torso of the rabbit. Additionally, we fabricated a 32-lead ECG-vest to record body surface potential signals of the aforementioned rabbit. Based on the developed geometrical model and the measured signals, we then optimized the activation sequence of the ventricles, recreating the functionality of the Purkinje network, and we investigated different apico-basal and transmural gradients in action potential duration. Optimization of the activation sequence resulted in an average root mean square error between measured and simulated signal of 0.074 mV/ms for all leads. The best-fit T-Wave, compared to measured data (0.038 mV/ms), resulted from incorporating an action potential duration gradient from base to apex with a respective shortening of 20 ms and a transmural gradient with a shortening of 15 ms from endocardium to epicardium. By making our model and measured data openly available, we hope to give other researchers the opportunity to verify their research, as well as to create the possibility to investigate the impact of electrophysiological alterations on body surface signals for translational research., Competing Interests: The authors have declared that no competing interests exist.
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- 2022
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18. Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder: A Phase 3 Randomized Clinical Trial (GEMINI).
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Iosifescu DV, Jones A, O'Gorman C, Streicher C, Feliz S, Fava M, and Tabuteau H
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- Bupropion therapeutic use, Dextromethorphan adverse effects, Double-Blind Method, Humans, Quality of Life, Depressive Disorder, Major diagnosis, Depressive Disorder, Major drug therapy
- Abstract
Objective: Altered glutamatergic neurotransmission has been implicated in the pathogenesis of depression. This trial evaluated the efficacy and safety of AXS-05 (dextromethorphan-bupropion), an oral N -methyl-
D -aspartate (NMDA) receptor antagonist and σ1 receptor agonist, in the treatment of major depressive disorder (MDD)., Methods: This double-blind, phase 3 trial, was conducted between June 2019 and December 2019. Patients with a DSM-5 diagnosis of MDD were randomized in a 1:1 ratio to receive dextromethorphan-bupropion (45 mg-105 mg tablet) or placebo, orally (once daily for days 1-3, twice daily thereafter) for 6 weeks. The primary endpoint was the change from baseline to week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Other efficacy endpoints and variables included MADRS changes from baseline at week 1 and 2, clinical remission (MADRS score ≤ 10), clinical response (≥ 50% reduction in MADRS score from baseline), clinician- and patient-rated global assessments, Quick Inventory of Depressive Symptomatology-Self-Rated, Sheehan Disability Scale, and quality of life measures., Results: A total of 327 patients were randomized: 163 patients to dextromethorphan-bupropion and 164 patients to placebo. Mean baseline MADRS total scores were 33.6 and 33.2 in the dextromethorphan-bupropion and placebo groups, respectively. The least-squares mean change from baseline to week 6 in MADRS total score was -15.9 points in the dextromethorphan-bupropion group and -12.0 points in the placebo group (least-squares mean difference, -3.87; 95% confidence interval [CI], -1.39 to -6.36; P = .002). Dextromethorphan-bupropion was superior to placebo for MADRS improvement at all time points including week 1 ( P = .007) and week 2 ( P < .001). Remission was achieved by 39.5% of patients with dextromethorphan-bupropion versus 17.3% with placebo (treatment difference, 22.2; 95% CI, 11.7 to 32.7; P < .001), and clinical response by 54.0% versus 34.0%, respectively (treatment difference, 20.0%; 95% CI, 8.4%, 31.6%; P < .001), at week 6. Results for most secondary endpoints were significantly better with dextromethorphan-bupropion than with placebo at almost all time points (eg, CGI-S least-squares mean difference at week 6, -0.48; 95% CI, -0.48 to -0.79; P = .002). The most common adverse events in the dextromethorphan-bupropion group were dizziness, nausea, headache, somnolence, and dry mouth. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, or increased sexual dysfunction., Conclusions: In this phase 3 trial in patients with MDD, treatment with dextromethorphan-bupropion (AXS-05) resulted in significant improvements in depressive symptoms compared to placebo starting 1 week after treatment initiation and was generally well tolerated., Trial Registration: ClinicalTrials.gov Identifier: NCT04019704., (© Copyright 2022 Physicians Postgraduate Press, Inc.)- Published
- 2022
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19. Oxytocin exerts harmful cardiac repolarization prolonging effects in drug-induced LQTS.
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Kreifels P, Bodi I, Hornyik T, Franke G, Perez-Feliz S, Lewetag R, Moss R, Castiglione A, Ziupa D, Zehender M, Brunner M, Bode C, and Odening KE
- Abstract
Background: Oxytocin is used therapeutically in psychiatric patients. Many of these also receive anti-depressant or anti-psychotic drugs causing acquired long-QT-syndrome (LQTS) by blocking HERG/I
Kr . We previously identified an oxytocin-induced QT-prolongation in LQT2 rabbits, indicating potential harmful effects of combined therapy. We thus aimed to analyze the effects of dual therapy with oxytocin and fluoxetine/risperidone on cardiac repolarization., Methods: Effects of risperidone, fluoxetine and oxytocin on QT/QTc, short-term variability (STV) of QT, and APD were assessed in rabbits using in vivo ECG and ex vivo monophasic AP recordings in Langendorff-perfused hearts. Underlying mechanisms were assessed using patch clamp in isolated cardiomyocytes., Results: Oxytocin, fluoxetine and risperidone prolonged QTc and APD in whole hearts. The combination of fluoxetine + oxytocin resulted in further QTc- and APD-prolongation, risperidone + oxytocin tended to increase QTc and APD compared to monotherapy. Temporal QT instability, STVQTc was increased by oxytocin, fluoxetine / fluoxetine + oxytocin and risperidone / risperidone + oxytocin. Similar APD-prolonging effects were confirmed in isolated cardiomyocytes due to differential effects of the compounds on repolarizing ion currents: Oxytocin reduced IKs , fluoxetine and risperidone reduced IKr , resulting in additive effects on IKtotal -tail. In addition, oxytocin reduced IK1 , further reducing the repolarization reserve., Conclusion: Oxytocin, risperidone and fluoxetine prolong QTc / APD. Combined treatment further prolongs QTc/APD due to differential effects on IKs and IK1 (block by oxytocin) and IKr (block by risperidone and fluoxetine), leading to pronounced impairment of repolarization reserve. Oxytocin should be used with caution in patients in the context of acquired LQTS., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)- Published
- 2022
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20. Docosahexaenoic acid normalizes QT interval in long QT type 2 transgenic rabbit models in a genotype-specific fashion.
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Castiglione A, Hornyik T, Wülfers EM, Giammarino L, Edler I, Jowais JJ, Rieder M, Perez-Feliz S, Koren G, Bősze Z, Varró A, Zehender M, Brunner M, Bode C, Liin SI, Larsson HP, Baczkó I, and Odening KE
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- Animals, Animals, Genetically Modified, Arrhythmias, Cardiac drug therapy, Arrhythmias, Cardiac genetics, Arrhythmias, Cardiac prevention & control, Electrocardiography, Genotype, Humans, Rabbits, Docosahexaenoic Acids pharmacology, Long QT Syndrome drug therapy, Long QT Syndrome genetics
- Abstract
Aim: Long QT syndrome (LQTS) is a cardiac channelopathy predisposing to ventricular arrhythmias and sudden cardiac death. Since current therapies often fail to prevent arrhythmic events in certain LQTS subtypes, new therapeutic strategies are needed. Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid, which enhances the repolarizing IKs current., Methods and Results: We investigated the effects of DHA in wild type (WT) and transgenic long QT Type 1 (LQT1; loss of IKs), LQT2 (loss of IKr), LQT5 (reduction of IKs), and LQT2-5 (loss of IKr and reduction of IKs) rabbits. In vivo ECGs were recorded at baseline and after 10 µM/kg DHA to assess changes in heart-rate corrected QT (QTc) and short-term variability of QT (STVQT). Ex vivo monophasic action potentials were recorded in Langendorff-perfused rabbit hearts, and action potential duration (APD75) and triangulation were assessed. Docosahexaenoic acid significantly shortened QTc in vivo only in WT and LQT2 rabbits, in which both α- and β-subunits of IKs-conducting channels are functionally intact. In LQT2, this led to a normalization of QTc and of its short-term variability. Docosahexaenoic acid had no effect on QTc in LQT1, LQT5, and LQT2-5. Similarly, ex vivo, DHA shortened APD75 in WT and normalized it in LQT2, and additionally decreased AP triangulation in LQT2., Conclusions: Docosahexaenoic acid exerts a genotype-specific beneficial shortening/normalizing effect on QTc and APD75 and reduces pro-arrhythmia markers STVQT and AP triangulation through activation of IKs in LQT2 rabbits but has no effects if either α- or β-subunits to IKs are functionally impaired. Docosahexaenoic acid could represent a new genotype-specific therapy in LQT2., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2022
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21. Transgenic LQT2, LQT5, and LQT2-5 rabbit models with decreased repolarisation reserve for prediction of drug-induced ventricular arrhythmias.
- Author
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Hornyik T, Castiglione A, Franke G, Perez-Feliz S, Major P, Hiripi L, Koren G, Bősze Z, Varró A, Zehender M, Brunner M, Bode C, Baczkó I, and Odening KE
- Subjects
- Action Potentials, Animals, Animals, Genetically Modified, Arrhythmias, Cardiac chemically induced, Arrhythmias, Cardiac genetics, Heart Ventricles, Humans, Rabbits, Long QT Syndrome chemically induced, Long QT Syndrome genetics, Pharmaceutical Preparations
- 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 I
Kr ; 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., (© 2020 The British Pharmacological Society.)- Published
- 2020
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22. Comment: postpartum hormones oxytocin and prolactin cause pro-arrhythmic prolongation of cardiac repolarization in long QT syndrome type 2-Authors' reply.
- Author
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Bodi I, Wuelfers EM, Castiglione A, Perez-Feliz S, Zehender M, Brunner M, Bode C, Seemann G, and Odening KE
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- Female, Humans, Oxytocin, Postpartum Period, Prolactin, Long QT Syndrome
- Published
- 2019
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23. Postpartum hormones oxytocin and prolactin cause pro-arrhythmic prolongation of cardiac repolarization in long QT syndrome type 2.
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Bodi I, Sorge J, Castiglione A, Glatz SM, Wuelfers EM, Franke G, Perez-Feliz S, Koren G, Zehender M, Bugger H, Seemann G, Brunner M, Bode C, and Odening KE
- Subjects
- Action Potentials, Animals, Disease Models, Animal, Female, Myocytes, Cardiac drug effects, Postpartum Period, Rabbits, Heart Conduction System drug effects, Long QT Syndrome chemically induced, Oxytocin metabolism, Prolactin metabolism
- Abstract
Aims: Women with long QT syndrome 2 (LQT2) have a particularly high postpartal risk for lethal arrhythmias. We aimed at investigating whether oxytocin and prolactin contribute to this risk by affecting repolarization., Methods and Results: In female transgenic LQT2 rabbits (HERG-G628S, loss of IKr), hormone effects on QT/action potential duration (APD) were assessed (0.2-200 ng/L). Hormone effects (200 ng/L) on ion currents and cellular APD were determined in transfected cells and LQT2 cardiomyocytes. Hormone effects on ion channels were assessed with qPCR and western blot. Experimental data were incorporated into in silico models to determine the pro-arrhythmic potential. Oxytocin prolonged QTc and steepened QT/RR-slope in vivo and prolonged ex vivo APD75 in LQT2 hearts. Prolactin prolonged APD75 at high concentrations. As underlying mechanisms, we identified an oxytocin- and prolactin-induced acute reduction of IKs-tail and IKs-steady (-25.5%, oxytocin; -13.3%, prolactin, P < 0.05) in CHO-cells and LQT2-cardiomyocytes. IKr currents were not altered. This oxytocin-/prolactin-induced IKs reduction caused APD90 prolongation (+11.9%/+13%, P < 0.05) in the context of reduced/absent IKr in LQT2 cardiomyocytes. Hormones had no effect on IK1 and ICa,L in cardiomyocytes. Protein and mRNA levels of CACNA1C/Cav1.2 and RyR2 were enhanced by oxytocin and prolactin. Incorporating these hormone effects into computational models resulted in reduced repolarization reserve and increased propensity to pro-arrhythmic permanent depolarization, lack of capture and early afterdepolarizations formation., Conclusions: Postpartum hormones oxytocin and prolactin prolong QT/APD in LQT2 by reducing IKs and by increasing Cav1.2 and RyR2 expression/transcription, thereby contributing to the increased postpartal arrhythmic risk in LQT2., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2019
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24. Transgenic short-QT syndrome 1 rabbits mimic the human disease phenotype with QT/action potential duration shortening in the atria and ventricles and increased ventricular tachycardia/ventricular fibrillation inducibility.
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Odening KE, Bodi I, Franke G, Rieke R, Ryan de Medeiros A, Perez-Feliz S, Fürniss H, Mettke L, Michaelides K, Lang CN, Steinfurt J, Pantulu ND, Ziupa D, Menza M, Zehender M, Bugger H, Peyronnet R, Behrends JC, Doleschall Z, Zur Hausen A, Bode C, Jolivet G, and Brunner M
- Subjects
- Animals, Animals, Genetically Modified, Anti-Arrhythmia Agents pharmacology, Disease Models, Animal, Electrocardiography, Female, Heart Conduction System physiopathology, Humans, Male, Phenotype, Quinidine pharmacology, Rabbits, Action Potentials drug effects, Action Potentials genetics, Action Potentials physiology, Arrhythmias, Cardiac genetics, Arrhythmias, Cardiac physiopathology, Heart Atria physiopathology, Heart Conduction System abnormalities, Heart Defects, Congenital genetics, Heart Defects, Congenital physiopathology, Heart Ventricles physiopathology
- Abstract
Aims: Short-QT syndrome 1 (SQT1) is an inherited channelopathy with accelerated repolarization due to gain-of-function in HERG/IKr. Patients develop atrial fibrillation, ventricular tachycardia (VT), and sudden cardiac death with pronounced inter-individual variability in phenotype. We generated and characterized transgenic SQT1 rabbits and investigated electrical remodelling., Methods and Results: Transgenic rabbits were generated by oocyte-microinjection of β-myosin-heavy-chain-promoter-KCNH2/HERG-N588K constructs. Short-QT syndrome 1 and wild type (WT) littermates were subjected to in vivo ECG, electrophysiological studies, magnetic resonance imaging, and ex vivo action potential (AP) measurements. Electrical remodelling was assessed using patch clamp, real-time PCR, and western blot. We generated three SQT1 founders. QT interval was shorter and QT/RR slope was shallower in SQT1 than in WT (QT, 147.8 ± 2 ms vs. 166.4 ± 3, P < 0.0001). Atrial and ventricular refractoriness and AP duration were shortened in SQT1 (vAPD90, 118.6 ± 5 ms vs. 154.4 ± 2, P < 0.0001). Ventricular tachycardia/fibrillation (VT/VF) inducibility was increased in SQT1. Systolic function was unaltered but diastolic relaxation was enhanced in SQT1. IKr-steady was increased with impaired inactivation in SQT1, while IKr-tail was reduced. Quinidine prolonged/normalized QT and action potential duration (APD) in SQT1 rabbits by reducing IKr. Diverse electrical remodelling was observed: in SQT1, IK1 was decreased-partially reversing the phenotype-while a small increase in IKs may partly contribute to an accentuation of the phenotype., Conclusion: Short-QT syndrome 1 rabbits mimic the human disease phenotype on all levels with shortened QT/APD and increased VT/VF-inducibility and show similar beneficial responses to quinidine, indicating their value for elucidation of arrhythmogenic mechanisms and identification of novel anti-arrhythmic strategies., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)
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- 2019
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25. Electro-mechanical (dys-)function in long QT syndrome type 1.
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Ziupa D, Menza M, Koppermann S, Moss R, Beck J, Franke G, Perez Feliz S, Brunner M, Mayer S, Bugger H, Koren G, Zehender M, Jung BA, Seemann G, Foell D, Bode C, and Odening KE
- Subjects
- Action Potentials drug effects, Animals, Animals, Genetically Modified, Anti-Arrhythmia Agents pharmacology, Biomechanical Phenomena, Disease Models, Animal, Magnetic Resonance Imaging, Cine, Male, Myocardial Contraction drug effects, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Piperidines pharmacology, Pyridines pharmacology, Rabbits, Romano-Ward Syndrome diagnosis, Romano-Ward Syndrome drug therapy, Action Potentials physiology, Electrocardiography methods, Myocardial Contraction physiology, Romano-Ward Syndrome physiopathology
- Abstract
Background: Prolonged repolarization is the hallmark of long QT syndrome (LQTS), which is associated with subclinical mechanical dysfunction. We aimed at elucidating mechanical cardiac function in LQTS type 1 (loss of I
Ks ) and its modification upon further prolongation of the action potential (AP) by IKr -blockade (E-4031)., Methods: Transgenic LQT1 and wild type (WT) rabbits (n = 12/10) were subjected to tissue phase mapping MRI, ECG, and epicardial AP recording. Protein and mRNA levels of ion channels and Ca2+ handling proteins (n = 4/4) were determined. In silico single cell AP and tension modeling was performed., Results: At baseline, QT intervals were longer in LQT1 compared to WT rabbits, but baseline systolic and diastolic myocardial peak velocities were similar in LQT1 and WT. E-4031 prolonged QT more pronouncedly in LQT1. Additionally, E-4031 increased systolic and decreased diastolic peak velocities more markedly in LQT1 - unmasking systolic and diastolic LQT1-specific mechanical alterations. E-4031-induced alterations of diastolic peak velocities correlated with the extent of QT prolongation., Conclusion: While baseline mechanical function is normal in LQT1 despite a distinct QT prolongation, further prolongation of repolarization by IKr -blocker E-4031 unmasks mechanical differences between LQT1 and WT with enhanced systolic and impaired diastolic function only in LQT1. These data indicate an importance of the extent of QT prolongation and the contribution of different impaired ion currents for conveying mechanical dysfunction., (Copyright © 2018 Elsevier B.V. All rights reserved.)- Published
- 2019
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26. A novel LMNA nonsense mutation causes two distinct phenotypes of cardiomyopathy with high risk of sudden cardiac death in a large five-generation family.
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Glöcklhofer CR, Steinfurt J, Franke G, Hoppmann A, Glantschnig T, Perez-Feliz S, Alter S, Fischer J, Brunner M, Rainer PP, Köttgen A, Bode C, and Odening KE
- Subjects
- Adult, Arrhythmias, Cardiac mortality, Arrhythmias, Cardiac physiopathology, Arrhythmias, Cardiac therapy, Cardiomyopathy, Dilated mortality, Cardiomyopathy, Dilated physiopathology, Cardiomyopathy, Dilated therapy, Death, Sudden, Cardiac prevention & control, Defibrillators, Implantable, Disease Progression, Electric Countershock instrumentation, Female, Genetic Predisposition to Disease, Heart Transplantation, Heredity, Humans, Male, Middle Aged, Pedigree, Phenotype, Prognosis, Risk Factors, Severity of Illness Index, Arrhythmias, Cardiac genetics, Cardiomyopathy, Dilated genetics, Codon, Nonsense, Death, Sudden, Cardiac etiology, Lamin Type A genetics
- Abstract
Aims: Characterization of the cardiac phenotype associated with the novel LMNA nonsense mutation c.544C>T, p.Q182*, which we have identified in a large five-generation family., Methods and Results: A family tree was constructed. Clinical data [arrhythmia, syncope, sudden cardiac death (SCD), New York Heart Association (NYHA) class] were collected from living and deceased family members. DNA of 23 living family members was analysed for mutations in LMNA. Additionally, dilated cardiomyopathy multi-gene-panel testing and whole exome sequencing were performed in some family members to identify potential phenotype-modifiers. In this five-generation family (n = 65), 17 SCDs occurred at 49.3 ± 10.0 years. Furthermore, we identified eight additional mutation-carriers, seven symptomatic (44 ± 13 years), and one asymptomatic (44 years). First signs of disease [sinus bradycardia with atrioventricular (AV)-block I°] occurred at 36.5 ± 8.1 years. Paroxysmal atrial fibrillation (AF) (onset at 41.8 ± 5.7 years) rapidly progressed to permanent AF (46.2 ± 9.8 years). Subsequently, AV-conduction worsened, syncope, pacemaker-dependence, and non-sustained ventricular tachycardia (43.3 ± 8.2 years) followed. Ventricular arrhythmia caused SCD in patients without implantable cardioverter-defibrillator (ICD). Patients protected by ICD developed rapidly progressive heart failure (45.2 ± 10.6 years). A different phenotype was seen in a sub-family in three patients with early onset of rapidly decompensating heart failure and only minor prior arrhythmia-related symptoms. One patient received high-urgency heart transplantation (HTX) at 32 years, while two died prior to HTX. One of them developed lethal peripartum-associated heart failure. Possible disease-modifiers were identified in this 'heart failure sub-family'., Conclusion: The novel LMNA nonsense mutation c.544C>T causes a severe arrhythmogenic phenotype manifesting with high incidence of SCD in most patients; and in one sub-family, a distinct phenotype with fast progressing heart failure, indicating the need for early consideration of ICD-implantation and listing for heart-transplantation.
- Published
- 2018
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27. Pronounced effects of HERG-blockers E-4031 and erythromycin on APD, spatial APD dispersion and triangulation in transgenic long-QT type 1 rabbits.
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Ziupa D, Beck J, Franke G, Perez Feliz S, Hartmann M, Koren G, Zehender M, Bode C, Brunner M, and Odening KE
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- Action Potentials physiology, Animals, Animals, Genetically Modified, Erythromycin therapeutic use, Female, Heart physiopathology, Long QT Syndrome physiopathology, Piperidines therapeutic use, Pyridines therapeutic use, Rabbits, Action Potentials drug effects, Erythromycin pharmacology, Heart drug effects, Long QT Syndrome drug therapy, Piperidines pharmacology, Pyridines pharmacology
- Abstract
Background: Prolongation of action potential duration (APD), increased spatial APD dispersion, and triangulation are major factors promoting drug-induced ventricular arrhythmia. Preclinical identification of HERG/IKr-blocking drugs and their pro-arrhythmic potential, however, remains a challenge. We hypothesize that transgenic long-QT type 1 (LQT1) rabbits lacking repolarizing IKs current may help to sensitively detect HERG/IKr-blocking properties of drugs., Methods: Hearts of adult female transgenic LQT1 and wild type littermate control (LMC) rabbits were Langendorff-perfused with increasing concentrations of HERG/IKr-blockers E-4031 (0.001-0.1 µM, n=9/7) or erythromycin (1-300 µM, n=9/7) and APD, APD dispersion, and triangulation were analyzed., Results: At baseline, APD was longer in LQT1 than in LMC rabbits in LV apex and RV mid. Erythromycin and E-4031 prolonged APD in LQT1 and LMC rabbits in all positions. However, erythromycin-induced percentaged APD prolongation related to baseline (%APD) was more pronounced in LQT1 at LV base-lateral and RV mid positions (100 µM, LQT1, +40.6 ± 9.7% vs. LMC, +24.1 ± 10.0%, p<0.05) and E-4031-induced %APD prolongation was more pronounced in LQT1 at LV base-lateral (0.01 µM, LQT1, +29.6 ± 10.6% vs. LMC, +19.1 ± 3.8%, p<0.05) and LV base-septal positions. Moreover, erythromycin significantly increased spatial APD dispersion only in LQT1 and increased triangulation only in LQT1 in LV base-septal and RV mid positions. Similarly, E-4031 increased triangulation only in LQT1 in LV apex and base-septal positions., Conclusions: E-4031 and erythromycin prolonged APD and increased triangulation more pronouncedly in LQT1 than in LMC rabbits. Moreover, erythromycin increased APD dispersion only in LQT1, indicating that transgenic LQT1 rabbits could serve as sensitive model to detect HERG/IKr-blocking properties of drugs.
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- 2014
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28. Spatial correlation of action potential duration and diastolic dysfunction in transgenic and drug-induced LQT2 rabbits.
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Odening KE, Jung BA, Lang CN, Cabrera Lozoya R, Ziupa D, Menza M, Relan J, Franke G, Perez Feliz S, Koren G, Zehender M, Bode C, Brunner M, Sermesant M, and Föll D
- Subjects
- Animals, Animals, Genetically Modified, Anti-Arrhythmia Agents, Arrhythmias, Cardiac diagnosis, Diastole physiology, Female, Long QT Syndrome diagnosis, Magnetic Resonance Imaging, Piperidines, Pyridines, Rabbits, Action Potentials physiology, Arrhythmias, Cardiac etiology, Arrhythmias, Cardiac physiopathology, Long QT Syndrome etiology, Long QT Syndrome physiopathology
- Abstract
Background: Enhanced dispersion of action potential duration (APD) is a major contributor to long QT syndrome (LQTS)-related arrhythmias., Objective: To investigate spatial correlations of regional heterogeneities in cardiac repolarization and mechanical function in LQTS., Methods: Female transgenic LQTS type 2 (LQT2; n = 11) and wild-type littermate control (LMC) rabbits (n = 9 without E4031 and n = 10 with E4031) were subjected to phase contrast magnetic resonance imaging to assess regional myocardial velocities. In the same rabbits' hearts, monophasic APDs were assessed in corresponding segments., Results: In LQT2 and E4031-treated rabbits, APD was longer in all left ventricular segments (P < .01) and APD dispersion was greater than that in LMC rabbits (P < .01). In diastole, peak radial velocities (Vr) were reduced in LQT2 and E4031-treated compared to LMC rabbits in LV base and mid (LQT2: -3.36 ± 0.4 cm/s, P < .01; E4031-treated: -3.24 ± 0.6 cm/s, P < .0001; LMC: -4.42 ± 0.5 cm/s), indicating an impaired diastolic function. Regionally heterogeneous diastolic Vr correlated with APD (LQT2: correlation coefficient [CC] 0.38, P = .01; E4031-treated: CC 0.42, P < .05). Time-to-diastolic peak Vr were prolonged in LQT2 rabbits (LQT2: 196.8 ± 2.9 ms, P < .001; E4031-treated: 199.5 ± 2.2 ms, P < .0001, LMC 183.1 ± 1.5), indicating a prolonged contraction duration. Moreover, in transgenic LQT2 rabbits, diastolic time-to-diastolic peak Vr correlated with APD (CC 0.47, P = .001). In systole, peak Vr were reduced in LQT2 and E4031-treated rabbits (P < .01) but longitudinal velocities or ejection fraction did not differ. Finally, random forest machine learning algorithms enabled a differentiation between LQT2, E4031-treated, and LMC rabbits solely based on "mechanical" magnetic resonance imaging data., Conclusions: The prolongation of APD led to impaired diastolic and systolic function in transgenic and drug-induced LQT2 rabbits. APD correlated with regional diastolic dysfunction, indicating that LQTS is not purely an electrical but an electromechanical disorder., (© 2013 Heart Rhythm Society. All rights reserved.)
- Published
- 2013
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29. Differential effects of the β-adrenoceptor blockers carvedilol and metoprolol on SQT1- and SQT2-mutant channels.
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Bodi I, Franke G, Pantulu ND, Wu K, Perez-Feliz S, Bode C, Zehender M, zur Hausen A, Brunner M, and Odening KE
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- Action Potentials, Animals, Arrhythmias, Cardiac genetics, CHO Cells, Carvedilol, Cricetulus, Dose-Response Relationship, Drug, ERG1 Potassium Channel, Ether-A-Go-Go Potassium Channels genetics, Ether-A-Go-Go Potassium Channels metabolism, HEK293 Cells, Heart Conduction System metabolism, Heart Defects, Congenital genetics, Humans, KCNQ1 Potassium Channel genetics, KCNQ1 Potassium Channel metabolism, Kinetics, Potassium metabolism, Transfection, Adrenergic beta-Antagonists pharmacology, Arrhythmias, Cardiac metabolism, Carbazoles pharmacology, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, Heart Conduction System abnormalities, Heart Defects, Congenital metabolism, KCNQ1 Potassium Channel antagonists & inhibitors, Metoprolol pharmacology, Mutation, Potassium Channel Blockers pharmacology, Propanolamines pharmacology
- Abstract
Background: N588K-KCNH2 and V307L-KCNQ1 mutations lead to a gain-of-function of IKr and IKs thus causing short-QT syndromes (SQT1, SQT2). Combined pharmacotherapies using K(+) -channel-blockers and β-blockers are effective in SQTS. Since β-blockers can block IKr and IKs , we aimed at determining carvedilol's and metoprolol's electrophysiological effects on N588K-KCNH2 and V307L-KCNQ1 channels., Methods: Wild-type (WT)-KCNH2, WT-KCNQ1 and mutant N588K-KCNH2 and V307L-KCNQ1 channels were expressed in CHO-K1 or HEK-293T cells and IKs and IKr were recorded at baseline and during β-blocker exposure., Results: Carvedilol (10 μM) reduced IKs tail in WT- and V307L-KCNQ1 by 36.5 ± 5% and 18.6 ± 9% (P < 0.05). IC50 values were 16.3 μM (WT) and 46.1 μM (V307L), indicating a 2.8-fold decrease in carvedilol's IKs -blocking potency in V307L-KCNQ1. Carvedilol's (1 μM) inhibition of the IKr tail was attenuated in N588K-KCNH2 (4.5 ± 3% vs 50.3 ± 4%, WT, P < 0.001) with IC50 values of 2.8 μM (WT) and 25.4 μM (N588K). Carvedilol's IKr end-pulse inhibition, however, was increased in N588K-KCNH2 (10 μM, 60.7 ± 6% vs 36.5 ± 5%, WT, P < 0.01). Metoprolol (100 μM) reduced IKr end-pulse by 0.23 ± 3% (WT) and 74.1 ± 7% (N588K, P < 0.05), IKr tail by 32.9 ± 10% (WT) and 68.8 ± 7% (N588K, P < 0.05), and reduced IKs end-pulse by 18.3 ± 5% (WT) and 57.1 ± 11% (V307L, P < 0.05) and IKs tail by 3.3 ± 1% (WT) and 45.1 ± 13 % (V307L, P < 0.05), indicating an increased sensitivity to metoprolol in SQT mutated channels., Conclusions: N588K-KCNH2 and V307L-KCNQ1 mutations decrease carvedilol's inhibition of the IKs or IKr tail but increase carvedilol's IKr end-pulse inhibition and metoprolol's inhibition of tail and end-pulse currents. These different effects on SQT1 and SQT2 mutated channels should be considered when using β-blocker therapy in SQTS patients., (© 2013 Wiley Periodicals, Inc.)
- Published
- 2013
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