Modelling Brugada Syndrome using induced pluripotent stem cells

______________________________________________ IV ACKNOWLEDGEMENTS ______________________________________ VI TABLE OF CONTENTS _______________________________________ VII LIST OF FIGURES _________________________________________ XIII LIST OF TABLES __________________________________________ XV LIST OF ABBREVIATIONS ____________________________________ XVI CHAPTER 1 GENERAL INTRODUCTION 1.1 Brugada Syndrome _________________________________________________ 2 1.1.1 SCN5A ___________________________________________________________ 4 1.1.2 Murine model of Brugada Syndrome ___________________________________ 7 1.1.2.1 Scn5a heterozygous knock-out mice ______________________________ 7 1.1.2.2 Scn5a-1798insD knock-in mice __________________________________ 10 1.1.2.3 Scn1b knock-out mice _________________________________________ 11 1.1.2.4 Strengths and limitations of the murine model ____________________ 11 1.1.3 Porcine model ____________________________________________________ 12 1.1.4 Canine Model of Brugada Syndrome __________________________________ 12 1.1.4.1 J-wave/Osborne wave ________________________________________ 12 1.1.4.2 ST segment elevation _________________________________________ 13 1.1.4.3 T-Wave alternans and VF/VT ___________________________________ 14 1.1.4.4 Sex differences ______________________________________________ 15 1.1.4.5 Prediction of high risk patients and treatment ____________________ 15 1.1.4.6 Strengths and limitations of the canine model ____________________ 16 1.1.5 Expression systems modelling Brugada Syndrome ______________________ 17 1.1.5.1 Altered Nav1.5 properties _____________________________________ 17 1.1.5.2 Complete loss of INa __________________________________________ 19 1.1.5.3 Induced Brugada Syndrome ____________________________________ 20 1.1.5.4 Other genes associated with Brugada Syndrome ___________________ 21 1.1.5.5 Strengths and limitations of expression systems ___________________ 24