Therapeutic Efficacy of Mexiletine for Long QT Syndrome Type 2: Evidence From Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes, Transgenic Rabbits, and Patients-Reference-Cited by-同舟云学术

Therapeutic Efficacy of Mexiletine for Long QT Syndrome Type 2: Evidence From Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes, Transgenic Rabbits, and Patients

Published:2024-08-13 Issue:7 Volume:150 Page:531-543
ISSN:0009-7322
Container-title:Circulation
language:en
Short-container-title:Circulation

Author:

Crotti Lia¹²^ORCID,Neves Raquel³^ORCID,Dagradi Federica¹^ORCID,Musu Giulia¹^ORCID,Giannetti Federica¹^ORCID,Bos J. Martijn³^ORCID,Barbieri Miriam⁴^ORCID,Cerea Paolo¹^ORCID,Giovenzana Fulvio L.F.¹^ORCID,Torchio Margherita¹^ORCID,Mura Manuela⁵^ORCID,Gnecchi Massimiliano⁵⁶^ORCID,Conte Giulio⁷^ORCID,Auricchio Angelo⁷^ORCID,Sala Luca¹⁸^ORCID,Odening Katja E.⁴^ORCID,Ackerman Michael J.³⁹¹⁰^ORCID,Schwartz Peter J.¹^ORCID

Affiliation:

1. Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Istituto Auxologico Italiano, IRCCS, Milan, Italy (L.C., F.D., G.M., F.G., P.C., F.L.F.G., M.T., L.S., P.J.S.).

2. Departments of Medicine and Surgery (L.C.), University of Milano-Bicocca, Milan, Italy.

3. Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (R.N., J.M.B., M.J.A.), Mayo Clinic, Rochester, MN.

4. Translational Cardiology, Department of Cardiology and Department of Physiology, University Hospital Bern, University of Bern, Switzerland (M.B., K.E.O.).

5. Translational Cardiology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (M.M., M.G.).

6. Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Italy (M.G.).

7. Istituto Cardiocentro Ticino, Department of Cardiology, Lugano, Switzerland (G.C., A.A.).

8. Biotechnology and Biosciences (L.S.), University of Milano-Bicocca, Milan, Italy.

9. Department of Cardiovascular Medicine, Divisions of Heart Rhythm Services and Circulatory Failure, Windland Smith Rice Genetic Heart Rhythm Clinic (M.J.A.), Mayo Clinic, Rochester, MN.

10. Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN.

Abstract

BACKGROUND: Despite major advances in the clinical management of long QT syndrome, some patients are not fully protected by beta-blocker therapy. Mexiletine is a well-known sodium channel blocker, with proven efficacy in patients with sodium channel–mediated long QT syndrome type 3. Our aim was to evaluate the efficacy of mexiletine in long QT syndrome type 2 (LQT2) using cardiomyocytes derived from patient-specific human induced pluripotent stem cells, a transgenic LQT2 rabbit model, and patients with LQT2. METHODS: Heart rate–corrected field potential duration, a surrogate for QTc, was measured in human induced pluripotent stem cells from 2 patients with LQT2 (KCNH2-p.A561V, KCNH2-p.R366X) before and after mexiletine using a multiwell multi-electrode array system. Action potential duration at 90% repolarization (APD 90 ) was evaluated in cardiomyocytes isolated from transgenic LQT2 rabbits (KCNH2-p.G628S) at baseline and after mexiletine application. Mexiletine was given to 96 patients with LQT2. Patients were defined as responders in the presence of a QTc shortening ≥40 ms. Antiarrhythmic efficacy of mexiletine was evaluated by a Poisson regression model. RESULTS: After acute treatment with mexiletine, human induced pluripotent stem cells from both patients with LQT2 showed a significant shortening of heart rate–corrected field potential duration compared with dimethyl sulfoxide control. In cardiomyocytes isolated from LQT2 rabbits, acute mexiletine significantly shortened APD 90 by 113 ms, indicating a strong mexiletine-mediated shortening across different LQT2 model systems. Mexiletine was given to 96 patients with LQT2 either chronically (n=60) or after the acute oral drug test (n=36): 65% of the patients taking mexiletine only chronically and 75% of the patients who performed the acute oral test were responders. There was a significant correlation between basal QTc and ∆QTc during the test ( r = −0.8; P <0.001). The oral drug test correctly predicted long-term effect in 93% of the patients. Mexiletine reduced the mean yearly event rate from 0.10 (95% CI, 0.07–0.14) to 0.04 (95% CI, 0.02–0.08), with an incidence rate ratio of 0.40 (95% CI, 0.16–0.84), reflecting a 60% reduction in the event rate ( P =0.01). CONCLUSIONS: Mexiletine significantly shortens cardiac repolarization in LQT2 human induced pluripotent stem cells, in the LQT2 rabbit model, and in the majority of patients with LQT2. Furthermore, mexiletine showed antiarrhythmic efficacy. Mexiletine should therefore be considered a valid therapeutic option to be added to conventional therapies in higher-risk patients with LQT2.

Publisher

Ovid Technologies (Wolters Kluwer Health)

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