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Induced Pluripotent Stem Cell-Derived Disease Model for Catecholaminergic Polymorphic Ventricular Tachycardia

Tutkimustuotos

Yksityiskohdat

AlkuperäiskieliEnglanti
KustantajaTampere University of Technology
Sivumäärä114
ISBN (elektroninen)978-952-15-3726-4
ISBN (painettu)978-952-15-3722-6
TilaJulkaistu - 29 huhtikuuta 2016
OKM-julkaisutyyppiG5 Artikkeliväitöskirja

Julkaisusarja

NimiTampere University of Technology. Publication
Vuosikerta1379
ISSN (painettu)1459-2045

Tiivistelmä

Human induced pluripotent stem cells (hiPSCs) offer significant opportunities for cardiac research. With this technology, it is possible to create patient-specific stem cell lines and differentiate them into cardiomyocytes for cardiac research. hiPSC technology has created many expectations for new therapeutic possibilities, and it holds promise for use in drug-testing platforms and in patient-specific drug therapy optimization, as well as later in regenerative medicine.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited, highly lethal arrhythmogenic cardiac disorder. It is primarily caused by cardiac ryanodine receptor gene (RyR2) mutations that result in abnormal calcium release from the sarcoplasmic reticulum to the cytosol, leading to the generation of afterdepolarizations and triggered activity. The estimated clinical prevalence of CPVT is 1:10000. Intracellular calcium ions are crucial to the function of the heart muscle, and disturbances in this process can have fatal consequences, as observed in CPVT. Understanding the mechanisms of arrhythmia and the role of intracellular calcium in CPVT pathophysiology is important for improving disease prevention, diagnosis, and treatment.

The main objective of this work was to develop and characterize models of cardiac cells and to develop and improve techniques for studying electrical field stimulation and calcium cycling of cardiomyocytes. Utilizing electrical field stimulation, the orientation and maturation of neonatal rat cardiomyocytes and the increase in the beating rate of an in vitro disease model for CPVT were studied. For the cell model of CPVT, human iPSC-derived cardiomyocytes were obtained from CPVT patients carrying RyR2 mutations. These iPSCs disease models were used to study the disease mechanisms of CPVT, mutation-specific differences in intracellular calcium cycling and the effect of antiarrhythmic treatment of the cells. Mechanistic insights regarding CPVT arrhythmias and drug responses were also validated in the index patients. Additionally, a new calcium cycling analysis software tool was developed for characterizing abnormal intracellular calcium transients of disease-specific cardiomyocytes.

The results of this work demonstrate that patient-specific iPSC-derived cardiomyocytes corresponded to the clinical phenotype in both the pathophysiology and drug responses of CPVT and encourages the continuation of disease modeling utilizing iPSCs. These studies also presented a new mechanism for arrhythmias in CPVT. These findings encourage the translation of findings in basic research to benefit patients in clinical practice, e.g., in the form of potentially new medications.

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