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Cardiovascular Consequences of Duchenne and Becker Muscular Dystrophinopathies

杜氏肌营养不良症和贝克尔肌营养不良症的心血管后果

基本信息

批准号：
10478824
负责人：
Melissa A.H. Witman
金额：
$ 63.99万
依托单位：
UNIVERSITY OF DELAWARE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10478824
关键词：
Animal Model Animals Attenuated Becker Muscular Dystrophy Biological Markers Birth Blood Vessels Cardiac Cardiomyopathies Cardiovascular system Caring Cause of Death Cell Death Characteristics Child Clinical Trials Consensus Cross-Sectional Studies Data Development Diagnosis Dilated Cardiomyopathy Disease Progression Duchenne muscular dystrophy Dystrophin Echocardiography Endothelium Exhibits Fibrosis Functional disorder Future General Population Genes Goals Health Heart Heart Diseases Heart failure Impairment Incidence Intervention Studies Left ventricular structure Leg Life Measures Methodology Mission Modeling Morbidity - disease rate Movement Muscle Muscular Dystrophies Mutation Myocardium NOS3 gene Neuromuscular Diseases Nitric Oxide Nitric Oxide Synthase Type I Outcome Outcome Measure Participant Patients Peripheral Pharmaceutical Preparations Physiologic pulse Prognosis Public Health Research Respiratory Failure Respiratory Muscles Risk Risk Factors Skeletal Muscle Suggestion Testing Time United States United States National Institutes of Health Vascular Diseases Ventricular Remodeling arterial stiffness attenuation base clinical practice cohort density design disability dystrophinopathy electric impedance experience heart function innovation longitudinal design male mortality novel pressure reactive hyperemia therapeutic target

项目摘要

ABSTRACT/PROJECT SUMMARY Duchenne and Becker muscular dystrophinopathies (DMD/BMD) have a mutation in the dystrophin gene that, together, represent over 80% of all cases of muscular dystrophy. Historically, respiratory failure was the major cause of morbidity and mortality but recent treatment advances have changed the prognosis, with dilated cardiomyopathy and the resulting heart failure now being the leading cause of death. Currently, there is no consensus on predictors of cardiac disease trajectory, when to start treatment with cardiac medications, or the most appropriate outcome measures to evaluate the impact of therapies on the heart in patients with DMD and BMD. The long-term goal is to reduce the incidence and delay the progression of dilated cardiomyopathy/heart failure in children with DMD and BMD. The objective of this study is to determine the effects of DMD and BMD on peripheral vascular function and pulsatile load on the left ventricle (LV), and to determine if these variables can predict cardiac function. The central hypothesis is that both DMD and BMD patients will exhibit detrimental changes in their peripheral vascular health and pulsatile load on the LV which will relate to their cardiac function. This hypothesis is based on novel preliminary data showing an attenuation in peripheral vascular function and augmented central pressures and wave reflections, suggestive of increased pulsatile load, in both DMD and BMD patients. The central hypothesis will be tested by pursuing three specific aims: 1) Determine the effects of DMD and BMD on peripheral vascular function; 2) Determine the effects of DMD and BMD on pulsatile load on the LV; and 3) Determine if peripheral vascular function and pulsatile load on the LV can help predict cardiac function in patients with DMD and BMD. Under the first aim peripheral vascular function will be assessed using both a cross-sectional (baseline) and longitudinal design (12 & 24 months) in cohorts of DMD and BMD patients and typically-developing children. For the second aim, pulsatile load on the LV will be evaluated by assessing reflection magnitude, forward wave amplitude, aortic characteristic impedance, and arterial stiffness in the same design and participants as study aim 1. Finally, the third aim will use measures of peripheral vascular function and pulsatile load to evaluate predictors of cardiac function measured by echocardiography. The research proposed in this application is innovative because it represents the initial attempts at determining peripheral vascular function and pulsatile load on the LV in DMD and BMD patients which is the logical next step to previous animal studies. Additionally, the study uses novel, state-of-the-art non-invasive methodology that has the potential to be integrated into regular clinical practice to better diagnose and possibly predict cardiomyopathy development throughout DMD and BMD disease progression. The proposed research is significant because it will inform future interventional studies, including clinical trials that will ultimately alter the trajectory of care for the young patients struggling with DMD and BMD-related cardiomyopathy.