Sacubitril Does Not Exert Proarrhythmic Effects in Combination with Different Antiarrhythmic Drugs
<b>Background:</b> Previous studies suggest a direct effect of sacubitril on cardiac electrophysiology and indicate potential arrhythmic interactions between sacubitril and antiarrhythmic drugs. Therefore, the aim of this study was to explore the electrophysiologic effects of combining s...
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MDPI AG
2025-02-01
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| Online Access: | https://www.mdpi.com/1424-8247/18/2/230 |
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| author | Christian Ellermann Carlo Mengel Julian Wolfes Felix K. Wegner Benjamin Rath Julia Köbe Lars Eckardt Gerrit Frommeyer |
| author_facet | Christian Ellermann Carlo Mengel Julian Wolfes Felix K. Wegner Benjamin Rath Julia Köbe Lars Eckardt Gerrit Frommeyer |
| author_sort | Christian Ellermann |
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| description | <b>Background:</b> Previous studies suggest a direct effect of sacubitril on cardiac electrophysiology and indicate potential arrhythmic interactions between sacubitril and antiarrhythmic drugs. Therefore, the aim of this study was to explore the electrophysiologic effects of combining sacubitril with the antiarrhythmic drugs d,l-sotalol and mexiletine in isolated hearts. <b>Methods and results:</b> A total of 25 rabbit hearts were perfused using a Langendorff setup. Following baseline data collection, hearts were treated with mexiletine (25 µM, 13 hearts) or d,l-sotalol (100 µM, 12 hearts). Monophasic action potential demonstrated an abbreviation of action potential duration (APD<sub>90</sub>) after administration of mexiletine. Spatial dispersion of repolarization remained unchanged after mexiletine treatment, whereas effective refractory periods (ERP) were significantly prolonged. D,l-sotalol prolonged cardiac repolarization and amplified spatial dispersion. Further infusion of sacubitril (5 µM) led to a significant reduction in APD<sub>90</sub> and ERP in the mexiletine group. In the d,l-sotalol group, additional administration of sacubitril shortened cardiac repolarization duration without affecting spatial dispersion. No proarrhythmic effect was observed after mexiletine treatment as assessed by a predefined pacing protocol. Additional sacubitril treatment did not increase ventricular vulnerability. When potassium concentration was reduced, 30 episodes of torsade de pointes tachycardia occurred after d,l-sotalol treatment. Additional sacubitril treatment significantly suppressed torsade de pointes tachycardia (eight episodes) in the d,l-sotalol-group. <b>Conclusions:</b> In class IB- and class III-pretreated hearts, sacubitril shortened refractory periods and cardiac repolarization duration. The combination of sacubitril with the antiarrhythmic drugs d,l-sotalol and mexiletine demonstrates a safe electrophysiologic profile and sacubitril reduces the occurrence of class III-related proarrhythmia, i.e., torsade de pointes tachycardia. |
| format | Article |
| id | doaj-art-cc0e0e5016dc4bde820bb6c09105ff27 |
| institution | DOAJ |
| issn | 1424-8247 |
| language | English |
| publishDate | 2025-02-01 |
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| spelling | doaj-art-cc0e0e5016dc4bde820bb6c09105ff272025-08-20T02:45:01ZengMDPI AGPharmaceuticals1424-82472025-02-0118223010.3390/ph18020230Sacubitril Does Not Exert Proarrhythmic Effects in Combination with Different Antiarrhythmic DrugsChristian Ellermann0Carlo Mengel1Julian Wolfes2Felix K. Wegner3Benjamin Rath4Julia Köbe5Lars Eckardt6Gerrit Frommeyer7Department of Cardiology II (Electrophysiology), University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, GermanyDepartment of Cardiology II (Electrophysiology), University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, GermanyDepartment of Cardiology II (Electrophysiology), University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, GermanyDepartment of Cardiology II (Electrophysiology), University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, GermanyDepartment of Cardiology II (Electrophysiology), University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, GermanyDepartment of Cardiology II (Electrophysiology), University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, GermanyDepartment of Cardiology II (Electrophysiology), University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, GermanyDepartment of Cardiology II (Electrophysiology), University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany<b>Background:</b> Previous studies suggest a direct effect of sacubitril on cardiac electrophysiology and indicate potential arrhythmic interactions between sacubitril and antiarrhythmic drugs. Therefore, the aim of this study was to explore the electrophysiologic effects of combining sacubitril with the antiarrhythmic drugs d,l-sotalol and mexiletine in isolated hearts. <b>Methods and results:</b> A total of 25 rabbit hearts were perfused using a Langendorff setup. Following baseline data collection, hearts were treated with mexiletine (25 µM, 13 hearts) or d,l-sotalol (100 µM, 12 hearts). Monophasic action potential demonstrated an abbreviation of action potential duration (APD<sub>90</sub>) after administration of mexiletine. Spatial dispersion of repolarization remained unchanged after mexiletine treatment, whereas effective refractory periods (ERP) were significantly prolonged. D,l-sotalol prolonged cardiac repolarization and amplified spatial dispersion. Further infusion of sacubitril (5 µM) led to a significant reduction in APD<sub>90</sub> and ERP in the mexiletine group. In the d,l-sotalol group, additional administration of sacubitril shortened cardiac repolarization duration without affecting spatial dispersion. No proarrhythmic effect was observed after mexiletine treatment as assessed by a predefined pacing protocol. Additional sacubitril treatment did not increase ventricular vulnerability. When potassium concentration was reduced, 30 episodes of torsade de pointes tachycardia occurred after d,l-sotalol treatment. Additional sacubitril treatment significantly suppressed torsade de pointes tachycardia (eight episodes) in the d,l-sotalol-group. <b>Conclusions:</b> In class IB- and class III-pretreated hearts, sacubitril shortened refractory periods and cardiac repolarization duration. The combination of sacubitril with the antiarrhythmic drugs d,l-sotalol and mexiletine demonstrates a safe electrophysiologic profile and sacubitril reduces the occurrence of class III-related proarrhythmia, i.e., torsade de pointes tachycardia.https://www.mdpi.com/1424-8247/18/2/230drug-induced proarrhythmiaLangendorffarrhythmiatorsade de pointessafety electrophysiologyventricular tachycardia |
| spellingShingle | Christian Ellermann Carlo Mengel Julian Wolfes Felix K. Wegner Benjamin Rath Julia Köbe Lars Eckardt Gerrit Frommeyer Sacubitril Does Not Exert Proarrhythmic Effects in Combination with Different Antiarrhythmic Drugs Pharmaceuticals drug-induced proarrhythmia Langendorff arrhythmia torsade de pointes safety electrophysiology ventricular tachycardia |
| title | Sacubitril Does Not Exert Proarrhythmic Effects in Combination with Different Antiarrhythmic Drugs |
| title_full | Sacubitril Does Not Exert Proarrhythmic Effects in Combination with Different Antiarrhythmic Drugs |
| title_fullStr | Sacubitril Does Not Exert Proarrhythmic Effects in Combination with Different Antiarrhythmic Drugs |
| title_full_unstemmed | Sacubitril Does Not Exert Proarrhythmic Effects in Combination with Different Antiarrhythmic Drugs |
| title_short | Sacubitril Does Not Exert Proarrhythmic Effects in Combination with Different Antiarrhythmic Drugs |
| title_sort | sacubitril does not exert proarrhythmic effects in combination with different antiarrhythmic drugs |
| topic | drug-induced proarrhythmia Langendorff arrhythmia torsade de pointes safety electrophysiology ventricular tachycardia |
| url | https://www.mdpi.com/1424-8247/18/2/230 |
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