Saturday, November 23, 2024
11/23/2024
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.
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