Cell Model of Catecholaminergic Polymorphic Ventricular Tachycardia Reveals Early and Delayed Afterdepolarizations

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dc.contributor.author Kujala, Kirsi
dc.contributor.author Paavola, Jere
dc.contributor.author Lahti, Anna
dc.contributor.author Larsson, Kim
dc.contributor.author Pekkanen-Mattila, Mari
dc.contributor.author Viitasalo, Matti
dc.contributor.author Lahtinen, Annukka M
dc.contributor.author Toivonen, Lauri
dc.contributor.author Kontula, Kimmo
dc.contributor.author Swan, Heikki
dc.contributor.author Laine, Mika
dc.contributor.author Silvennoinen, Olli
dc.contributor.author Aalto-Setälä, Katriina
dc.date.accessioned 2012-10-19T08:33:52Z
dc.date.available 2012-10-19T08:33:52Z
dc.date.issued 2012
dc.identifier.issn 1932-6203 -
dc.identifier.uri http://tampub.uta.fi/handle/10024/66364
dc.description Public Library of Science open access -
dc.description.abstract Background Induced pluripotent stem cells (iPSC) provide means to study the pathophysiology of genetic disorders. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a malignant inherited ion channel disorder predominantly caused by mutations in the cardiac ryanodine receptor (RyR2). In this study the cellular characteristics of CPVT are investigated and whether the electrophysiological features of this mutation can be mimicked using iPSC -derived cardiomyocytes (CM). Methodology/Principal Findings Spontaneously beating CMs were differentiated from iPSCs derived from a CPVT patient carrying a P2328S mutation in RyR2 and from two healthy controls. Calcium (Ca2+) cycling and electrophysiological properties were studied by Ca2+ imaging and patch-clamp techniques. Monophasic action potential (MAP) recordings and 24h-ECGs of CPVT-P2328S patients were analyzed for the presence of afterdepolarizations. We found defects in Ca2+ cycling and electrophysiology in CPVT CMs, reflecting the cardiac phenotype observed in the patients. Catecholaminergic stress led to abnormal Ca2+ signaling and induced arrhythmias in CPVT CMs. CPVT CMs also displayed reduced sarcoplasmic reticulum (SR) Ca2+ content, indicating leakage of Ca2+ from the SR. Patch-clamp recordings of CPVT CMs revealed both delayed afterdepolarizations (DADs) during spontaneous beating and in response to adrenaline and also early afterdepolarizations (EADs) during spontaneous beating, recapitulating the changes seen in MAP and 24h-ECG recordings of patients carrying the same mutation. Conclusions/Significance This cell model shows aberrant Ca2+ cycling characteristic of CPVT and in addition to DADs it displays EADs. This cell model for CPVT provides a platform to study basic pathology, to screen drugs, and to optimize drug therapy. -
dc.language.iso en -
dc.title Cell Model of Catecholaminergic Polymorphic Ventricular Tachycardia Reveals Early and Delayed Afterdepolarizations -
dc.type fi=Artikkeli aikakauslehdessä | en=Journal Article| -
dc.identifier.urn URN:NBN:fi:uta-201210191062 -
dc.identifier.doi 10.1371/journal.pone.0044660 -
dc.type.version fi=Kustantajan versio | en=Publisher's version| -
dc.subject.okm fi=Lääketieteen bioteknologia | en=Medical biotechnology| -
dc.administrativeunit fi=Biolääketieteellisen teknologian yksikkö | en=Institute of Biomedical Technology| -
dc.administrativeunit fi=Lääketieteen yksikkö | en=School of Medicine| -
dc.journal.title Plos ONE -
dc.journal.volume 7 -
dc.journal.number 9 -
dc.journal.volumepagerange 1-10 -
dc.journal.url http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0044660 -
dc.ismoreauthorsthanlisted 0 -

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