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Title: Functional characterisation and validation of an in vitro model of Catecholaminergic Polymorphic Ventricular Tachycardia type 1
Author: Bigares, João
ISNI:       0000 0004 5919 7725
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2015
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In the UK alone 28 000 sudden cardiac deaths a year are found to be unrelated to structural heart problems, likely having ion channel malfunction and arrhythmia as an underlying cause. With the discovery of human induced pluripotent stem cells (hiPSC), a new field has emerged, allowing the creation of personalised cellular models of disease that can be studied in vitro. In this study we aim to functionally characterize and validate an in vitro model of Catecholaminergic Polymorphic Ventricular Tachycardia type 1 (CPVT1), an adrenergically elicited arrhythmic condition caused by a mutation in the cardiac ryanodine receptor (S2246L). The cardiac ryanodine receptor (RyR2) is an intracellular ion channel that releases Ca2+ stores essential to cardiac contraction during EC-coupling. Inherited defects in the RyR2 can result in an intracellular calcium leak during diastole that may lead to arrhythmia. The most frequent arrhythmic events at a cellular level in CPVT cardiomyocytes (CM) are delayed afterdepolarizations (DADs) although early afterdepolarizations (EADs) and triggered activity (TA) may also occur. With the need of obtaining a human cell based disease model to establish in vitro valid assays for CPVT study and drug screening, a standardized quantitative approach is ideal. Nonetheless, because the quantitative definition of these arrhythmic endpoints is subjective by nature, most studies using hiPSC CPVT derived CM have assessed these cells only from a qualitative point of view. Using whole cell patch clamp in the ruptured membrane modality and Ca2+ fluorescence imaging, this study aimed to provide a quantitative characterization of arrhythmic endpoints in a CPVT hiPSC model. Pharmacological rescue was carried out using flecainide, propafenone, dantrolene (10μM for all drugs) and propranolol (1μM) in the presence of isoprenaline. Our results show that the average response of hiPSC CPVT CM to recapitulate disease is heterogeneous and therefore not a consistent in vitro model of disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: R Medicine (General)