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Early Detection of Physiologic and Functional Changes of Common Structural Protein Mutations Underlying Human Diseases by Mri

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Early Detection of Physiologic and Functional Changes of Common Structural Protein Mutations Underlying Human Diseases by Mri EARLY DETECTION OF PHYSIOLOGIC AND FUNCTIONAL CHANGES OF COMMON STRUCTURAL PROTEIN MUTATIONS UNDERLYING HUMAN DISEASES BY MRI by CANDIDA LAURA GOODNOUGH Submitted in partial fulfillment of requirements for the degree of Doctor of Philosophy Thesis Advisor: Xin Yu, ScD Department of Physiology & Biophysics School of Medicine Case Western Reserve University May 2015 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of CANDIDA LAURA GOODNOUGH candidate for the degree of Doctor of Philosophy Committee Chair William Schilling, PhD Committee Member George Dubyak, PhD Committee Member Chris Flask, PhD Committee Member Charles Hoppel, MD Thesis Advisor Xin Yu, ScD Date of Defense March 4, 2015 *We also certify that written approval has been obtained for any proprietary material contained therein. Dedicated to Henry and Harrison – the two loves of my life i TABLE OF CONTENTS LIST OF TABLES................................................................................................... V LIST OF FIGURES ................................................................................................ VI LIST OF COMMONLY USED ABBREVIATIONS…………………………………….…VIII ABSTRACT .......................................................................................................... 1 CHAPTER 1. INTRODUCTION AND SIGNIFICANCE ................................................... 3 SIGNIFICANCE ....................................................................................................... 3 HYPERTROPHIC CARDIOMYOPATHY ........................................................................ 6 INTRODUCTION ............................................................................................... 6 CLINICAL PICTURE ........................................................................................... 7 PATHOLOGY .................................................................................................... 7 GENETICS ......................................................................................................... 8 PRESENTATION .............................................................................................. 10 DIAGNOSIS ………………………………………………………………………… .11 TREATMENT ……………………………………………………………………….. 13 RESEARCH ADVANCES …………………………………………………………….. 15 DUCHENNE MUSCULAR DYSTROPHY .................................................................... 18 INTRODUCTION ............................................................................................. 18 CLINICAL PICTURE .......................................................................................... 20 PATHOLOGY .................................................................................................. 21 GENETICS ...................................................................................................... 22 PRESENTATION .............................................................................................. 23 DIAGNOSIS .................................................................................................... 25 TREATMENT .................................................................................................. 27 RESEARCH ADVANCES .................................................................................... 27 MAGNETIC RESONANCE IMAGING ……………………………………………..……. 31 DISPLACEMENT ENCODING WITH STIMULATED ECHOES ................................... 31 ARTERIAL SPIN LABELING ............................................................................... 33 DIFFUSION-WEIGHTED IMAGING .................................................................... 33 REFERENCES ………………………………………..………………………………… 35 CHAPTER 2.CARDIAC MYOSIN BINDING PROTEIN C INSUFFICIENCY LEADS TO EARLY ONSET OF MECHANICAL DYSFUNCTION ................................................... 43 ABSTRACT: .......................................................................................................... 43 INTRODUCTION .................................................................................................... 44 MATERIALS AND METHODS .................................................................................. 46 ANIMAL MODELS ............................................................................................... 46 SKINNED FIBER EXPERIMENTS ............................................................................ 46 IN VIVO MRI MEASUREMENTS OF CARDIAC FUNCTION ......................................... 46 STATISTICAL ANALYSIS ...................................................................................... 46 i ii RESULTS .............................................................................................................. 47 MYOFILAMENT PROTEIN EXPRESSION AND PHOSPHORYLATION IN WT AND CMYBPC MUTANT MYOCARDIUM ..................................................................................... 47 MECHANICAL PROPERTIES OF SKINNED MYOCARDIUM ISOLATED FROM WT AND CMYBPC MUTANT HEARTS ................................................................................. 50 IN VIVO ASSESSMENT OF CARDIAC MORPHOLOGY AND MECHANICAL FUNCTION .. 51 LV MORPHOLOGY AND CONTRACTILE FUNCTION ................................................ 51 MYOCARDIAL STRAIN ........................................................................................ 53 VENTRICULAR TWIST AND TORSION. .................................................................. 54 DISCUSSION ......................................................................................................... 57 MYOFILAMENT FUNCTION IN CMYBPC MUTANT MYOCARDIUM ............................ 58 EFFECTS OF DECREASED CMYPBPC EXPRESSION ON IN VIVO MECHANICAL FUNCTION ........................................................................................................................ 60 POTENTIAL FUNCTIONAL CONSEQUENCES OF CMYBPC HAPLOINSUFFICIENCY ...... 62 CLINICAL IMPLICATIONS .................................................................................... 63 LIMITATIONS ..................................................................................................... 64 CLINICAL PERSPECTIVE. ..................................................................................... 65 REFERENCES: ....................................................................................................... 67 CHAPTER 3.COMPARISON OF VELOCITY VECTOR IMAGING ECHOCARDIOGRAPHY WITH MAGNETIC RESONANCE IMAGING IN MOUSE MODELS OF CARDIOMYOPATHY ........................................................................................................................... 71 ABSTRACT ........................................................................................................... 71 INTRODUCTION .................................................................................................... 72 MATERIALS AND METHODS .................................................................................. 74 EXPERIMENTAL ANIMALS .................................................................................. 74 MAGNETIC RESONANCE IMAGING ...................................................................... 74 ECHOCARDIOGRAPHY ....................................................................................... 75 STATISTICAL ANALYSIS ...................................................................................... 78 RESULTS .............................................................................................................. 79 ECHOCARDIOGRAPHIC AND MRI VOLUMETRIC VARIABLES ................................... 79 GLOBAL STRAIN ................................................................................................ 79 REGIONAL STRAIN ............................................................................................. 81 INTERPRETATIVE VARIABILITY ........................................................................... 83 DISCUSSION ......................................................................................................... 83 LIMITATIONS ..................................................................................................... 86 CLINICAL PERSPECTIVE. ..................................................................................... 88 REFERENCES ........................................................................................................ 90 CHAPTER 4. ARTERIAL SPIN LABELING-FAST IMAGING WITH STEADY-STATE FREE PRECESSION (ASL-FISP): A RAPID AND QUANTITATIVE PERFUSION TECHNIQUE FOR HIGH-FIELD MRI ..................................................................................... 92 ABSTRACT ........................................................................................................... 92 INTRODUCTION .................................................................................................... 93 ii iii MATERIALS AND METHODS .................................................................................. 95 IN VIVO COMPARISON OF IMAGE ARTIFACTS AT 7T .............................................. 96 ASL-FISP PULSE SEQUENCE DESIGN ..................................................................... 96 INITIAL IN VIVO ASL-FISP PERFUSION ASSESSMENTS IN MOUSE BRAIN .................. 97 ADDITIONAL IN VIVO ASL-FISP EXPERIMENTS: MOUSE BRAIN ISCHEMIA STROKE MODEL AND HEALTHY MOUSE KIDNEYS ............................................................ 101 RESULTS ............................................................................................................
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