Genetic and Functional S of Severe V Arrhythmias

..... ..................................................................................................................................................................... 9 INTRODUCTION .................................................................................................................................................................. 11 REVIEW OF THE LITERATURE ............................................................................................................................................ 13 1. THE ELECTRICAL MOBILITY OF THE HEART MUSCLE ...........................................................................................13 1.1 THE ACTION POTENTIAL ................................................................................................... 13 1.2 VOLTAGE-GATED ION CHANNELS IN THE HEART ....................................................... 14 Voltage-gated sodium channel .............................................................................................. 15 Voltage-gated potassium channels .........................................................................................17 2. CHANNELOPATHIES IN NEURONAL TISSUE, SKELETAL MUSCLE AND CARDIAC MUSCLE ...................................17 2.1 NEURONAL CHANNELOPATHIES ..................................................................................... 18 2.2 SKELETAL MUSCLE CHANNELOPATHIES ........................................................................ 19 2.3 CARDIAC CHANNELOPATHIES ......................................................................................... 19 Potassium channelopathies ................................................................................................... 19 Sodium channelopathies ....................................................................................................... 20 Calcium channelopathies ...................................................................................................... 21 3. LONG QT SYNDROME ........................................................................................................................................... 23 3.1 CLINICAL MANIFESTATIONS ............................................................................................. 23 3.2 DIAGNOSIS AND CLINICAL MANAGEMENT .................................................................. 25 3.3 MOLECULAR GENETICS AND DISEASE MECHANISMS ................................................ 26 Molecular pathogenesis ......................................................................................................... 26 Disease models ....................................................................................................................... 27 Genes and LQTS subtypes .................................................................................................... 28 3.4 ACQUIRED LONG QT SYNDROME ................................................................................... 31 3.5 MODIFIER GENES AND POLYMORPHISMS ..................................................................... 31 3.6 THE GENETIC WORKING ENVIRONMENT .................................................................... 32 The Finnish gene pool .......................................................................................................... 32 The human genome project ................................................................................................. 33 AIMS OF THE STUDY .......................................................................................................................................................... 35 PATIENTS AND METHODS ................................................................................................................................................. 36 1. PATIENTS AND CONTROLS (I-IV) ...........................................................................................................................36 2. MOLECULAR GENETIC STUDIES (I-IV) ...................................................................................................................37 2.1 DNA EXTRACTION (I-IV) .................................................................................................... 37 2.2 POLYMERASE CHAIN REACTION (I-IV) .......................................................................... 37 2.3 DENATURING HIGH PERFORMANCE LIQUID CHROMATOGRAPHIC ANALYSIS (II, III) .................................................................................................................. 37 2.4 SINGLE-STRAND CONFORMATION POLYMORPHISM ANALYSIS (I) ......................... 38 2.5 DNA SEQUENCING (I-IV) ................................................................................................... 38 2.6 SPECIFIC MUTATION DETECTION (I-IV) ........................................................................ 38 2.7 BIOCOMPUTING (I-IV) ....................................................................................................... 38 3. FUNCTIONAL STUDIES (III, IV) ...............................................................................................................................40