Dilated cardiomyopathy (DCM) is the most common form of heart failure, a condition that accounts for 1 in 9 deaths in the United States and currently affects ~6 million. DCM specifically has a prevalence of 250,00- 400,000 and incidence of 70,000-120,000. Current therapy does not address the underlying loss of functional heart muscle and adverse structural remodeling. One novel potential treatment of DCM is the intracoronary injection of cardiosphere-derived cells (CDCs), which has been demonstrated to reduce fibrotic infiltrate and exhibit various other cardioprotective properties. However, the underlying mechanisms of how reducing the fibrotic load exactly leads to improved structural remodeling remains unclear. Furthermore, current non- invasive technologies characterize structural remodeling with surrogate measures and thus, there is no consensus on a single clinical gold-standard. Without a tool to monitor and characterize the degree of structural remodeling, the evaluation of the therapeutic potential of CDC in DCM patients cannot be fully realized representing an unmet need in ultimately improving therapy. The proposed project aims to improve the therapy monitoring of CDC application to DCM patients by revealing its effect on microstructural remodeling with diffusion tensor cardiac MRI (DT-CMR). DT-CMR is a unique, non-invasive technology capable of characterizing myocardial fiber orientation and directly reflecting microstructural remodeling. However, despite major advances, there are fundamental challenges that limit the capability of current DT-CMR methods to be applied robustly in a clinical setting. In this project, an innovative DT-CMR method will be developed that overcomes such limitations. The central hypothesis is that addressing these major technical challenges will allow for clinical translation of DT-CMR to serve as a tool to monitor the therapeutic effects of CDCs on microstructural remodeling. This is achieved by extending previously developed technologies used for myocardial fibrosis detection with diffusion-weighted CMR. The proposed project is designed to systematically develop an innovative and robust clinical DT-CMR methodology and rigorously validate in a pre-clinical setting the effects of CDC therapy on the microstructural remodeling of DCM thereby laying the groundwork for potential optimization or improvement of CDC therapy.
This project ultimately aims at optimizing the non-invasive monitoring of novel regenerative medicine therapy in heart failure patients to potentially improve outcome. The research strategy is designed to systematically develop an innovative diffusion cardiac MRI method that overcomes major shortcomings of the conventional methods including clinical translation. Successful completion of this project will result in a clinically robust diffusion cardiac MRI method that can effectively monitor the efficacy of novel regenerative therapies potentially improve treatment of heart failure.
| Nguyen, Christopher T; Dawkins, James; Bi, Xiaoming et al. (2018) Diffusion Tensor Cardiac Magnetic Resonance Reveals Exosomes From Cardiosphere-Derived Cells Preserve Myocardial Fiber Architecture After Myocardial Infarction. JACC Basic Transl Sci 3:97-109 |
| Ma, Sen; Nguyen, Christopher T; Christodoulou, Anthony G et al. (2018) Accelerated Cardiac Diffusion Tensor Imaging Using Joint Low-Rank and Sparsity Constraints. IEEE Trans Biomed Eng 65:2219-2230 |
| Zhou, Zhengwei; Nguyen, Christopher; Chen, Yuhua et al. (2017) Optimized CEST cardiovascular magnetic resonance for assessment of metabolic activity in the heart. J Cardiovasc Magn Reson 19:95 |
