title: Slowed depolarization and irregular repolarization in catecholaminergic polymorphic ventricular tachycardia: a study from cellular Ca2+ transients and action potentials to clinical monophasic action potentials and electrocardiography.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Minerva Foundation Institute for Medical Research, Helsinki, Finland jere.paavola@helsinki.fi.|Division of Cardiology, Heart and Lung Center HUS, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Jere
authors.initials: J
authors.lastname: Paavola
authors.affiliation: Department of Biomedical Engineering and Computational Science, Aalto University, Espoo, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Väänänen
authors.affiliation: School of Medicine, University of Tampere, Tampere, Finland.|Biomeditech, University of Tampere, Tampere, Finland.
authors.forename: Kim
authors.initials: K
authors.lastname: Larsson
authors.affiliation: School of Medicine, University of Tampere, Tampere, Finland.|Biomeditech, University of Tampere, Tampere, Finland.
authors.forename: Kirsi
authors.initials: K
authors.lastname: Penttinen
authors.affiliation: Division of Cardiology, Heart and Lung Center HUS, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Lauri
authors.initials: L
authors.lastname: Toivonen
authors.affiliation: Department of Medicine, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Kimmo
authors.initials: K
authors.lastname: Kontula
authors.affiliation: Minerva Foundation Institute for Medical Research, Helsinki, Finland.|Division of Cardiology, Heart and Lung Center HUS, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Laine
authors.affiliation: School of Medicine, University of Tampere, Tampere, Finland.|Biomeditech, University of Tampere, Tampere, Finland.|Heart Center, Tampere University Hospital, Tampere, Finland.
authors.forename: Katriina
authors.initials: K
authors.lastname: Aalto-Setälä
authors.affiliation: Division of Cardiology, Heart and Lung Center HUS, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Swan
authors.affiliation: Division of Cardiology, Heart and Lung Center HUS, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Viitasalo
mesh_terms: D000200:Action Potentials; D000318:Adrenergic beta-Agonists / Q000627:therapeutic use; D000328:Adult; D020013:Calcium Signaling; D016022:Case-Control Studies; D015716:Electrocardiography, Ambulatory; D005260:Female; D005387:Finland; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D007545:Isoproterenol / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000503:physiopathology*; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D000318:Adrenergic beta-Agonists; C000621072:RyR2 protein, human; D019837:Ryanodine Receptor Calcium Release Channel; D007545:Isoproterenol
keywords: Alternans; Calcium; Catecholaminergic polymorphic ventricular tachycardia; Ryanodine receptor; Variability