University of Tampere, Finland
Title: Genetic ventricular arrhythmia: Clinical presentation and disease modeling using iPSC-derived cardiomyocytes
Biography: Katriina Aalto-Setala
Background: Genetic cardiac arrhythmias are often severe, but due to their rare nature, no specific treatment exists. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe arrhythmia caused by mutations in the RyR2 gene. This gene is important in regulating Ca2+ release from sarcoplasmic reticulum. The purpose of this study was to create induced pluripotent stem cells (iPSCs) from individuals having CPVT and to study the functional properties of the cardiomyocytes.
Methodology: iPSC lines were derived from six individuals carrying different RyR2 gene mutations. Arrhythmias of cardiomyocytes were analyzed using Ca2+ imaging.
Findings: Patients’ heart rates were increased by stress exercise test and this induced in all of them polymorphic ventricular extra beats. When their cardiomyocytes were treated with adrenaline, similar irregular beating was observed. If the patients were treated with dantrolene, in some individuals all arrhythmias were abolished, but in some, it did not have any effect. As their cardiomyocytes were treated with the same drug, adrenaline-induced arrhythmias were abolished, but only from those cardiomyocytes derived from individuals who also clinically responded to the treatment. However, arrhythmias were not abolished from cardiomyocytes derived from the patients having no response to the medication.
Conclusion & Significance: With this drug, we could demonstrate that all individuals did not respond to this medication the same way even though their clinical phenotype was the same and they had mutations in the same gene. Importantly, iPSC-derived cardiomyocytes demonstrated the very same phenomenon: If the patient responded, also his cardiomyocytes responded, but if the drug did not remove arrhythmias from the patient, they were not abolished from his cardiomyocytes either. This study demonstrate that iPSC-derived cells reproduce the effect observed in the patients and they could be used to tailor medication especially in patients having severe, potentially lethal arrhythmias.
- Aalto-Setälä K, Conklin BR, and Lo, B. Obtaining consent for future research with induced pluripotent cells: Opportunities and challenges. PLoS Biology 7:e42, 2009.
- Lahti AL, Kujala VJ, Pekkanen-Mattila M, Kerkelä E, Chapman H, Koivisto A-P, Hyttinen J, Kontula K, Swan H, Yamanaka S, Conklin B, Silvennoinen O, Aalto-Setälä K. Cardiomyocytes derived by iPS cell technology from a long QT syndrome type 2 patient display the disease phenotype. Disease Models and Mechanisms 2012 Mar;5(2):220-30. doi: 10.1242/dmm.008409. Epub 2011 Nov 3.
- Kujala, K., Paavola, J., Lahti, A., Larsson, K., Pekkanen-Mattila, M., Viitasalo, M., Lahtinen, A.M., Toivonen, L., Kontula, K., Swan, H., Laine, M., Silvennoinen, O., and Aalto-Setälä, K. Cell Model of Catecholaminergic Polymorphic Ventricular Tachycardia Reveals Early and Delayed Afterdepolarizations PLoS ONE 2012;7(9):e44660. Epub Sep 4, 2012.
- Kiviaho AL., Ahola, A., Larsson, K., Kujala K., Pekkanen-Mattila, M., Venäläinen, H., Paavola, K., Hyttinen J. and Aalto-Setälä, K. Distinct electrophysiological and mechanical beating phenotypes of Long QT syndrome type 1 -specific cardiomyocytes carrying different mutations. International Journal of Cardiology, 8:19-31, 2015
- Penttinen, K , Swan H, Vanninen, S, Paavola J, Lahtinen A.M., Kontula, K and Aalto-Setälä K. Demonstration of the Antiarrhythmic Effect of Dantrolene in a Subset of CPVT Patients That is Predicted in iPSC Model PLoS One, Aug 26;10(8):e0135806. doi: 10.1371/journal.pone.0135806. eCollection 2015.
- Penttinen K, Siirtola H, Ávalos-Salguero J, Vainio T, Juhola M, Aalto-Setälä K. A Novel Analysis Software to Detect and Classify Ca2+ Transient Abnormalities in Stem Cell Derived Cardiomyocytes. Plos One, PLoS One. 2015 Aug 26;10(8):e0135806. doi: 10.1371/journal.pone.0135806. eCollection 2015
- Ojala M, Prajapati C, Pölönen R-P, Rajala K, Pekkanen-Mattila M, Larsson K, Aalto-Setälä K Mutation-specific phenotypes in hiPSC-derived cardiomyocytes carrying either myosin-binding protein C or α-tropomyosin for hypertrophic cardiomyopathy. Stem Cells International 2016, ID 1684792.