Antiarrhythmic Effects of Carvedilol and Flecainide in Cardiomyocytes Derived from Catecholaminergic Polymorphic Ventricular Tachycardia Patients
Mutations in the cardiac ryanodine receptor (RYR2) are the leading cause for catecholaminergic polymorphic ventricular tachycardia (CPVT). In this study, we evaluated antiarrhythmic efficacy of carvedilol and flecainide in CPVT patient-specific induced pluripotent stem cell-derived cardiomyocytes (i...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2018-01-01
|
| Series: | Stem Cells International |
| Online Access: | http://dx.doi.org/10.1155/2018/9109503 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832548166981910528 |
|---|---|
| author | R. P. Pölönen K. Penttinen H. Swan K. Aalto-Setälä |
| author_facet | R. P. Pölönen K. Penttinen H. Swan K. Aalto-Setälä |
| author_sort | R. P. Pölönen |
| collection | DOAJ |
| description | Mutations in the cardiac ryanodine receptor (RYR2) are the leading cause for catecholaminergic polymorphic ventricular tachycardia (CPVT). In this study, we evaluated antiarrhythmic efficacy of carvedilol and flecainide in CPVT patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carrying different mutations in RYR2. iPSC-CMs were generated from skin biopsies of CPVT patients carrying exon 3 deletion and L4115 or V4653F mutation in RYR2 and of a healthy individual. Ca2+ kinetics and drug effects were studied with Fluo-4 AM indicator. Carvedilol abolished Ca2+ abnormalities in 31% of L4115F, 36% of V4653F, and 46% of exon 3 deletion carrying CPVT cardiomyocytes and flecainide 33%, 30%, and 52%, respectively. Both drugs lowered the intracellular Ca2+ level and beating rate of the cardiomyocytes significantly. Moreover, flecainide caused abnormal Ca2+ transients in 61% of controls compared to 26% of those with carvedilol. Carvedilol and flecainide were equally effective in CPVT iPSC-CMs. However, flecainide induced arrhythmias in 61% of control cells. CPVT cardiomyocytes carrying the exon 3 deletion had the most severe Ca2+ abnormalities, but they had the best response to drug therapies. According to this study, the arrhythmia-abolishing effect of neither of the drugs is optimal. iPSC-CMs provide a unique platform for testing drugs for CPVT. |
| format | Article |
| id | doaj-art-fd75127f08904d7c93cf07e751291b14 |
| institution | Kabale University |
| issn | 1687-966X 1687-9678 |
| language | English |
| publishDate | 2018-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Stem Cells International |
| spelling | doaj-art-fd75127f08904d7c93cf07e751291b142025-02-03T06:42:12ZengWileyStem Cells International1687-966X1687-96782018-01-01201810.1155/2018/91095039109503Antiarrhythmic Effects of Carvedilol and Flecainide in Cardiomyocytes Derived from Catecholaminergic Polymorphic Ventricular Tachycardia PatientsR. P. Pölönen0K. Penttinen1H. Swan2K. Aalto-Setälä3Faculty of Medicine and Life Sciences and BioMediTech Institute, University of Tampere, Tampere, FinlandFaculty of Medicine and Life Sciences and BioMediTech Institute, University of Tampere, Tampere, FinlandHelsinki University Central Hospital, Helsinki, FinlandFaculty of Medicine and Life Sciences and BioMediTech Institute, University of Tampere, Tampere, FinlandMutations in the cardiac ryanodine receptor (RYR2) are the leading cause for catecholaminergic polymorphic ventricular tachycardia (CPVT). In this study, we evaluated antiarrhythmic efficacy of carvedilol and flecainide in CPVT patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carrying different mutations in RYR2. iPSC-CMs were generated from skin biopsies of CPVT patients carrying exon 3 deletion and L4115 or V4653F mutation in RYR2 and of a healthy individual. Ca2+ kinetics and drug effects were studied with Fluo-4 AM indicator. Carvedilol abolished Ca2+ abnormalities in 31% of L4115F, 36% of V4653F, and 46% of exon 3 deletion carrying CPVT cardiomyocytes and flecainide 33%, 30%, and 52%, respectively. Both drugs lowered the intracellular Ca2+ level and beating rate of the cardiomyocytes significantly. Moreover, flecainide caused abnormal Ca2+ transients in 61% of controls compared to 26% of those with carvedilol. Carvedilol and flecainide were equally effective in CPVT iPSC-CMs. However, flecainide induced arrhythmias in 61% of control cells. CPVT cardiomyocytes carrying the exon 3 deletion had the most severe Ca2+ abnormalities, but they had the best response to drug therapies. According to this study, the arrhythmia-abolishing effect of neither of the drugs is optimal. iPSC-CMs provide a unique platform for testing drugs for CPVT.http://dx.doi.org/10.1155/2018/9109503 |
| spellingShingle | R. P. Pölönen K. Penttinen H. Swan K. Aalto-Setälä Antiarrhythmic Effects of Carvedilol and Flecainide in Cardiomyocytes Derived from Catecholaminergic Polymorphic Ventricular Tachycardia Patients Stem Cells International |
| title | Antiarrhythmic Effects of Carvedilol and Flecainide in Cardiomyocytes Derived from Catecholaminergic Polymorphic Ventricular Tachycardia Patients |
| title_full | Antiarrhythmic Effects of Carvedilol and Flecainide in Cardiomyocytes Derived from Catecholaminergic Polymorphic Ventricular Tachycardia Patients |
| title_fullStr | Antiarrhythmic Effects of Carvedilol and Flecainide in Cardiomyocytes Derived from Catecholaminergic Polymorphic Ventricular Tachycardia Patients |
| title_full_unstemmed | Antiarrhythmic Effects of Carvedilol and Flecainide in Cardiomyocytes Derived from Catecholaminergic Polymorphic Ventricular Tachycardia Patients |
| title_short | Antiarrhythmic Effects of Carvedilol and Flecainide in Cardiomyocytes Derived from Catecholaminergic Polymorphic Ventricular Tachycardia Patients |
| title_sort | antiarrhythmic effects of carvedilol and flecainide in cardiomyocytes derived from catecholaminergic polymorphic ventricular tachycardia patients |
| url | http://dx.doi.org/10.1155/2018/9109503 |
| work_keys_str_mv | AT rppolonen antiarrhythmiceffectsofcarvedilolandflecainideincardiomyocytesderivedfromcatecholaminergicpolymorphicventriculartachycardiapatients AT kpenttinen antiarrhythmiceffectsofcarvedilolandflecainideincardiomyocytesderivedfromcatecholaminergicpolymorphicventriculartachycardiapatients AT hswan antiarrhythmiceffectsofcarvedilolandflecainideincardiomyocytesderivedfromcatecholaminergicpolymorphicventriculartachycardiapatients AT kaaltosetala antiarrhythmiceffectsofcarvedilolandflecainideincardiomyocytesderivedfromcatecholaminergicpolymorphicventriculartachycardiapatients |