Dissertation: Utilizing patients’ stem cell –derived cardiomyocytes to study an inherited cardiac arrhythmia (CPVT)
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inherited cardiac arrhythmia associated with an increased risk of sudden cardiac death. The prevalence of CPVT is approximately 1:10,000, and the mortality rate without treatment is around 35 % by the age of 30. Most CPVT cases are caused by mutations in the gene coding for the cardiac ryanodine receptor RYR2. Patients with CPVT experience arrhythmias during exercise or emotional stress. Therefore, patients with CPVT cannot exercise and must avoid situations of excitement. There is no optimal treatment for CPVT yet.
Human induced pluripotent stem cells (hiPSCs) can be generated in a laboratory environment e.g. from skin fibroblasts or blood sample. Human iPSCs can be further differentiated into beating cardiomyocytes (CMs). These hiPSC-derived CMs carry the same genome as the individual from which they were generated.
The technique provides an endless source of cardiomyocytes for patient-specific disease modelling and treatment optimization for personalized medicine. In addition, preclinical animal models, which fail to recapitulate human physiology, could be replaced by hiPSC-derived CMs in drug development.
This dissertation focused on hiPSC CMs derived from CPVT patients carrying different mutations in RYR2 for the purpose of testing the antiarrhythmic potential of beta-blocker carvedilol and sodium channel blocker flecainide. Electrophysiological characteristics and the incidence of arrhythmias caused by exposure to adrenaline were assessed in CPVT and control CMs. Normal cardiomyocytes derived from a healthy individual were used as a control.
The results showed that adrenaline increased the arrhythmias in CPVT but not in control CMs. Carvedilol and flecainide decreased the amount of arrhythmias but did not completely abolish them. Both drugs were the most efficient abolishing arrhythmias in CPVT CMs derived from a patient carrying exon 3 deletion in RYR2. In addition, it was found out that the CPVT CMs carrying the exon 3 deletion had distinctive electrophysiological characteristics compared to other CMs.
The results of this dissertation highlight the usefulness of hiPSC CMs as a model for disease modelling and drug screening. In the future, studies based on these models could be used to establish personalized treatment.
Pölönen was born in Kuopio. He is conducting his research in the cardiac research group led by Professor Katriina Aalto-Setälä at the Tampere University.
The doctoral dissertation of MSc Risto-Pekka Pölönen in the field of medicine Modelling arrhythmias and drug responses in CPVT patient-specific hiPSC-derived cardiomyocytes will be publicly examined in the Faculty of Medicine and Health Technology at Tampere University on Friday 31st May 2019 at 12 o'clock in the auditorium F114 of the Arvo building, Arvo Ylpön katu 34. The opponent is Professor Lior Gepstein from the Israel Institute of Technology. The Custos will be Professor Katriina Aalto-Setälä from Tampere University.
The dissertation is available at http://urn.fi/URN:ISBN:978-952-03-1077-6
Photograph: Jonne Renvall