Duchenne muscular dystrophy (DMD) is a devastating disease with no cure. DMD results in loss of ambulation, respiratory failure, cardiomyopathy (CM), and premature death. CM is now the leading cause of death in DMD. Novel, targeted therapeutics are necessary to treat DMD CM, but evaluation of DMD therapeutics can be challenging. A better understanding of CM disease progression is critical to improve clinical trial efficiency. The primary obstacles to improving DMD CM mortality include: 1) the small number of patients followed at each center and the variability in evaluation and therapeutic approach; 2) the variability in progression of DMD CM and the lack of surrogate CM biomarkers for early detection and prediction of mortality. To address the first obstacle, this study will form a consortium of like-minded investigators with similar CMR equipment and protocols to rigorously study DMD CM. This methodology will increase the power for detection of meaningful biomarkers and create scaffolding for future CM drug trials. To address the second obstacle, this study focuses on myocardial fibrosis as an early biomarker of disease and ultimately mortality. This proposal concentrates on the combination of serum and imaging biomarkers to more accurately characterize disease progression. The central hypothesis of this proposal is that imaging and blood biomarkers detect subclinical myocardial fibrosis and can be used as modifiable surrogate CM markers in DMD. We further hypothesize that the creation of a consortium of like-minded investigators will address sample size issues in DMD CM research and can be used as scaffolding for future CM drug trials.
Aim 1 will define the relationship between imaging measures of myocardial fibrosis and the subsequent change in cardiac function in DMD.
Aim 2 will create a pipeline for cardiac specific blood biomarker discovery in DMD.
Aim 3 will create a consortium of like-minded DMD clinical investigators with standardized cardiac imaging protocols. The proposed studies will include three of the larger cardiac muscular dystrophy centers in the country and will create the largest cohort of DMD patients with extensive cardiovascular phenotyping. The consortium will be constructed to allow additional sites to join in order to foster the larger collaborative efforts necessary to achieve meaningful results in this rare disease. The innovation of this grant is the integration of imaging and blood biomarkers to identify surrogate outcome measures of cardiovascular disease. The ability to readily test novel and targeted therapies is crucial for lengthening and improving the quality of life of children and men with DMD.
Heart dysfunction is now the leading cause of death in patients with Duchenne muscular dystrophy (DMD). The central objectives of this proposal are to use blood and imaging biomarkers to detect heart muscle fibrosis or scar. These aims have the potential to decrease the size and cost of therapeutic clinical trials for DMD heart disease, speeding up the adoption of new therapies and improving quality of life in children and men with DMD.
