UCLA

Cardiovascular disease is the leading cause of death in patients with Duchenne muscular dystrophy (DMD) – a fatal X-linked genetic disorder characterized by progressive muscle weakness and pediatric onset cardiomyopathy. The genetic mutations associated with DMD are variable since the very large dystrophin gene is comprised of 79 exons encoded within 2.4 million nucleotides, resulting in a wide range of phenotypes observed in affected patients. Symptom recognition is difficult in non-ambulatory patients, therefore clinical evidence of cardiac dysfunction is frequently limited to imaging findings when severe or end-stage cardiomyopathic change has occurred. Conventional late gadolinium enhancement (LGE) imaging is the clinical current gold standard for detecting myocardial tissue remodeling (i.e., replacement fibrosis), but it is often a late finding (mean onset observed at 15.2 � 5.1 years) in the DMD disease process. Reduced left ventricular ejection fraction (LVEF), a marker of cardiac dysfunction, is also a late outcome in DMD. Sensitive imaging methods are needed to identify early cardiac involvement in this high-risk population. Importantly, a biomarker capable of detecting early myocardial remodeling prior to LGE, a decline in EF, and without the need for an exogenous contrast agent could significantly improve the care of boys with DMD. A brief introduction to DMD and its natural progression to the heart is provided in Chapter 1. In Chapter 2, an introduction to Nuclear Magnetic Resonance (NMR) and MRI fundamentals is offered. This leads to the description of cardiovascular MRI and common techniques that provide a quantitative assessment of cardiac function and microstructure in Chapter 3. In Chapter 4, we present a descriptive overview of current and emerging biomarkers of microstructure in DMD. In Chapter 5 and Chapter 6, the use T1 mapping MRI, an alternative to conventional LGE imaging, is extended for the quantification of myocardial fibrosis in the left and right heart of boys with DMD. In Chapter 5 specifically, we use 3T MRI in the left heart for the following: (1) characterize global and regional myocardial pre-contrast T1 differences between healthy controls and LGE + and LGE− boys with DMD; and (2) to report global and regional myocardial post- contrast T1 values and myocardial ECV estimates in boys with DMD; and (3) to identify left ventricular (LV) T1-mapping biomarkers capable of distinguishing between healthy controls and boys with DMD and detecting LGE status in DMD. In Chapter 6, using the same technique, we evaluate several analysis methods and identify the most reliable one to measure RV pre- and post-contrast T1 (RV-T1) and to characterize myocardial remodeling in the RV of boys with DMD. In Chapter 7 we explore the onset of intramyocardial and excessive pericardial fat in boys with DMD. Specifically, we present the use of a chemical-shift-based multi-echo MRI (CS-MRI) technique, another alternative to LGE imaging, for the detection of myocardial remodeling in boys with DMD. We report and compare the LV intramyocardial and pericardial fat content in boys with DMD and healthy controls and we aim to determine if fatty infiltration precedes the appearance of LGE in boys with DMD. In Chapter 8, we evaluate T1 mapping biomarkers for repeatability and prognosis. We first define the intra-exam repeatability of T1 mapping biomarkers and calculate the smallest detectable change. Regional myocardial T1 differences between the septal and lateral mid- ventricular LV wall suggest myocardial heterogeneity in the DMD heart which that may be indicative of progressive myocardial remodeling. Thus, we characterize regional pre- and post- contrast T1 and ECV differences at the basal, mid-ventricular, and apical wall in boys with DMD and healthy controls. In Chapter 9, we provide concluding thoughts on quantitative MRI biomarkers of myocardial remodeling in DMD. Additionally, we share a future perspective for the work presented in this dissertation, and its implications on the clinical care for boys with DMD. The work described in this dissertation provides a framework for evaluating CMR biomarkers of tissue-composition in boys with DMD. This work will enable us to detect early myocardial remodeling and to quantify an individual patient’s degree of disease severity and/or progression, which in turn, establishes a step towards providing patient-specific diagnostic and prognostic information and informing treatment for cardiomyopathy.