Jere Paavola1,2, Heikki Väänänen3, Kim Larsson4,5, Kirsi Penttinen4,5, Lauri Toivonen2, Kimmo Kontula6, Mika Laine7,2, Katriina Aalto-Setälä4,5,8, Heikki Swan2, Matti Viitasalo2. 1. Minerva Foundation Institute for Medical Research, Helsinki, Finland jere.paavola@helsinki.fi. 2. Division of Cardiology, Heart and Lung Center HUS, Helsinki University Central Hospital, Helsinki, Finland. 3. Department of Biomedical Engineering and Computational Science, Aalto University, Espoo, Finland. 4. School of Medicine, University of Tampere, Tampere, Finland. 5. Biomeditech, University of Tampere, Tampere, Finland. 6. Department of Medicine, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland. 7. Minerva Foundation Institute for Medical Research, Helsinki, Finland. 8. Heart Center, Tampere University Hospital, Tampere, Finland.
Abstract
AIMS: Spontaneous Ca2+ release leads to afterdepolarizations and triggered arrhythmia in catecholaminergic polymorphic ventricular tachycardia (CPVT). Irregular Ca2+ release is hypothesized to manifest as slowed depolarization and irregular repolarization. Our goal was to study depolarization and repolarization abnormalities in CPVT, as they remain largely uninvestigated. METHODS AND RESULTS: We studied intracellular Ca2+ handling and action potentials (APs) in an induced pluripotent stem cell (iPSC) model of CPVT. Induced pluripotent stem cell cardiomyocytes from a RyR2-P2328S patient showed increased non-alternating variability of Ca2+ transients in response to isoproterenol. β-Agonists decreased AP upslope velocity in CPVT cells and in monophasic AP recordings of CPVT patients. We compared 24 h electrocardiograms (ECGs) of 19 CPVT patients carrying RyR2 mutations and 19 healthy controls. Short-term variability (STV) of the QT interval was 6.9 ± 0.5 ms in CPVT patients vs. 5.5 ± 0.4 ms in controls (P < 0.05) and associated with a history of arrhythmic events. Mean T-wave alternans (TWA) was 25 ± 1.4 µV in CPVT patients vs. 31 ± 2.0 µV in controls (P < 0.05). Older CPVT patients showed lower maximal upslope velocity of the ECG R-spike than control patients. CONCLUSION: Catecholaminergic polymorphic ventricular tachycardia patients show higher STV of repolarization but lower TWA on the 24 h ECG than control patients, which is likely to reflect increased non-alternating variability of Ca2+ release by mutant RyR2s as observed in vitro. β-Agonists slow depolarization in RyR2-mutant cells and in CPVT patients. These findings may constitute a marker of arrhythmogenicity. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Spontaneous Ca2+ release leads to afterdepolarizations and triggered arrhythmia in catecholaminergic polymorphic ventricular tachycardia (CPVT). Irregular Ca2+ release is hypothesized to manifest as slowed depolarization and irregular repolarization. Our goal was to study depolarization and repolarization abnormalities in CPVT, as they remain largely uninvestigated. METHODS AND RESULTS: We studied intracellular Ca2+ handling and action potentials (APs) in an induced pluripotent stem cell (iPSC) model of CPVT. Induced pluripotent stem cell cardiomyocytes from a RyR2-P2328Spatient showed increased non-alternating variability of Ca2+ transients in response to isoproterenol. β-Agonists decreased AP upslope velocity in CPVT cells and in monophasic AP recordings of CPVT patients. We compared 24 h electrocardiograms (ECGs) of 19 CPVT patients carrying RyR2 mutations and 19 healthy controls. Short-term variability (STV) of the QT interval was 6.9 ± 0.5 ms in CPVT patients vs. 5.5 ± 0.4 ms in controls (P < 0.05) and associated with a history of arrhythmic events. Mean T-wave alternans (TWA) was 25 ± 1.4 µV in CPVT patients vs. 31 ± 2.0 µV in controls (P < 0.05). Older CPVT patients showed lower maximal upslope velocity of the ECG R-spike than control patients. CONCLUSION: Catecholaminergic polymorphic ventricular tachycardiapatients show higher STV of repolarization but lower TWA on the 24 h ECG than control patients, which is likely to reflect increased non-alternating variability of Ca2+ release by mutant RyR2s as observed in vitro. β-Agonists slow depolarization in RyR2-mutant cells and in CPVT patients. These findings may constitute a marker of arrhythmogenicity. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Alain van Mil; Geerthe Margriet Balk; Klaus Neef; Jan Willem Buikema; Folkert W Asselbergs; Sean M Wu; Pieter A Doevendans; Joost P G Sluijter Journal: Cardiovasc Res Date: 2018-12-01 Impact factor: 10.787
Authors: Alec S T Smith; Jesse Macadangdang; Winnie Leung; Michael A Laflamme; Deok-Ho Kim Journal: Biotechnol Adv Date: 2016-12-20 Impact factor: 14.227
Authors: David Adolfo Sampedro-Puente; Jesus Fernandez-Bes; Bradley Porter; Stefan van Duijvenboden; Peter Taggart; Esther Pueyo Journal: Front Physiol Date: 2019-08-02 Impact factor: 4.566