Back
Acta Physiologica 2012; Volume 204, Supplement 689
91st Annual Meeting of The German Physiological Society
3/22/2012-3/25/2012
Dresden, Germany
IN A PATIENT-SPECIFIC STEM CELL MODEL OF CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA DANTROLENE RESCUES ARRHYTHMOGENIC RYR2 DEFECT
Abstract number: O70
Jung1 C., Moretti1,2 A., Mederos y Schnitzler3 M., Iop1 L., Storch3 U., Bellin1 M., Dorn1 T., Ruppenthal4 S., Pfeiffer3 S., Goedel1,2 A., Dirschinger1,2 R.J., Seyfarth5 M., Lam1 J.T., Sinnecker1 D., Gudermann3 T., Laugwitz1,2 K.-L., Lipp4 *P.
1Klinikum rechts der Isar TU Muenchen, I. Medizinische Klinik - Kardiologie, Muenchen, Germany
2Deutsches Herzzentrum - TU Muenchen, Erwachsenenkardiologie, Muenchen, Germany
3Ludwig-Maximilians Universitaet, Walther-Straub-Institut fr Pharmakologie and Toxikologie, Muenchen, Germany
4Saarland University, Medical Faculty, Institute for Molecular Cell Biology, Homburg/Saar, Germany
5Universitaet Witten-Herdecke, III. Medizinische Klinik Kardiologie, Wuppertal, Germany
Question:
Coordinated release of calcium (Ca2+) from the sarcoplasmic reticulum (SR) through cardiac ryanodine receptor (RYR2) channels is essential for cardiomyocyte function. In catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited disease characterized by stress-induced ventricular arrhythmias in young patients with structurally normal hearts, autosomal dominant mutations in RYR2 or recessive mutations in calsequestrin lead to aberrant diastolic Ca2+ release from the SR causing arrhythmogenic delayed afterdepolarizations (DADs).
Methods:
Induced pluripotent stem cells (iPSCs) were generated from a CPVT patient carrying a novel RyR2 (S406L) mutation. We used expression analysis, electrophysiology, global calcium imaging and ultra-fast confocal imaging to characterise those iPSCs by comparing cells derived from a CPVT patient with those derived from a patient with sinus rhythm not carrying that mutation.
Results:
In patient iPSC-derived cardiomyocytes, catecholaminergic stress led to elevated diastolic Ca2+ concentrations, a reduced SR Ca2+ content, and an increased susceptibility to DADs and arrhythmia as compared to control myocytes. This was due to increased frequency and duration of elementary Ca2+ release events (Ca2+ sparks). Dantrolene, a drug effective on malignant hyperthermia, restored normal Ca2+ spark properties and rescued the arrhythmogenic phenotype. This suggests defective inter-domain interactions within the RyR2 channel as the pathomechanism of the S406L mutation.
Conclusion:
Our work provides a new in vitro model to study the pathogenesis of human cardiac arrhythmias and develop novel therapies for CPVT.
To cite this abstract, please use the following information:
Acta Physiologica 2012; Volume 204, Supplement 689 :O70