Cardiovascular Consequences of Duchenne and Becker Muscular Dystrophinopathies

摘要/项目摘要 Duchenne和Becker肌营养不良症(DMD/BMD)的dystrophin基因发生突变， 加在一起，占所有肌营养不良症病例的80%以上。从历史上看，呼吸衰竭是主要的 发病和死亡的原因，但最近的治疗进展改变了预后，扩大了 心肌病和由此导致的心力衰竭现在是主要的死亡原因。目前，没有 关于心脏病轨迹的预测因素，何时开始心脏药物治疗，或 评估治疗对DMD和DMD患者心脏影响的最合适的结果指标 骨密度。长期目标是减少扩张型心肌病/心脏的发生率并延缓进展 患有DMD和BMD的儿童失败。本研究的目的是确定DMD和BMD的影响 对外周血管功能和左心室(LV)脉动负荷的影响，并确定这些变量 可以预测心脏功能。中心假设是DMD和BMD患者都会表现出有害的 他们的外周血管健康和左心室搏动负荷的变化将与他们的心功能有关。 这一假说是基于新的初步数据显示外周血管功能减弱和 DMD和DMD的中心压和波反射增加，提示脉动负荷增加 BMD患者。核心假设将通过追求三个具体目标来检验：1)确定 DMD和BMD对周围血管功能的影响；2)测定DMD和BMD对脉动负荷的影响 LV；以及3)确定外周血管功能和LV上的脉动负荷是否有助于预测心脏 DMD和BMD患者的功能。在第一个目标下，外周血管功能将用 DMD和BMD患者队列的横断面(基线)和纵向(12-24个月)设计 和典型的--发展中的孩子。对于第二个目标，将通过评估来评估LV的脉动负载 反射幅度、前向波幅、主动脉特性阻抗和动脉僵硬 设计和受试者作为研究目标1.最后，第三个目标将使用周围血管功能的测量 和脉动负荷来评估超声心动图测量的心功能预测因子。这项研究 本申请中提出的是创新的，因为它代表了确定外围设备的初始尝试 DMD和BMD患者的血管功能和左室搏动负荷是符合逻辑的下一步 动物研究。此外，这项研究使用了新的、最先进的非侵入性方法，具有 有可能整合到常规临床实践中，以更好地诊断和预测心肌病 在整个DMD和BMD疾病的发展过程中。这项拟议的研究意义重大，因为它 将为未来的介入研究提供信息，包括最终将改变护理轨迹的临床试验 与DMD和BMD相关的心肌病作斗争的年轻患者。

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.