Christopher T. Nguyen - US grants

DESCRIPTION (provided by applicant): The long-term objective is to develop an innovative and clinically robust cardiac diffusion MRI sequence that is sensitive to changes to myocardial tissue microstructure. The ability to characterize myocardial tissue microstructure will allow for unique insight to the pathophysiological progression of cardiovascular diseases (CVD) such as acute coronary syndrome, myocarditis, and cardiomyopathy, which are among the leading causes of morbidity and mortality of the US. Conventional cardiac MRI (CMR) techniques have shown to be clinically valuable in revealing morphological changes in the myocardium while providing excellent soft tissue contrast. However, validated CMR techniques used for myocardial tissue characterization require the use contrast agents. For patients with compromised renal systems such as those with Chronic Kidney Disease (CKD), these patients cannot benefit from these contrast-based techniques. Furthermore, 25% of CKD patients have a severe form of CVD that results in left ventricular hypertrophy (LVH) and can directly benefit from characterization of myocardial tissue fibrosis. Therefore, there is a need for a novel MR technique capable of non- contrast quantification of myocardial fibrosis, which we believe can be achieved with cardiac diffusion MRI. In this proposed project, a clinically translatable cardiac diffusion MR technique capable of myocardial fibrosis characterization of the human myocardium will be applied in hypertrophic cardiomyopathy patients (HCM) who are known to have high degree of fibrosis validated with contrast-enhanced CMR. Specific Aim 1 addresses the technical challenges of the clinical translation of a newly established cardiac diffusion MR technique developed by our lab, which requires better spatial coverage, spatial resolution, and shorter scan times. Specific Aim 2 will apply the proposed technique developed in Specific Aim 1 to HCM patients to characterize the extent of myocardial fibrosis and compare it with validated contrast-enhanced CMR methods. Hypothesis: Clinical translation of cardiac diffusion MRI requires major technical innovation, and a key application to demonstrate the technique's clinical utility for CKD+LVH patients would be to characterize myocardial fibrosis in HCM patients without the use of contrast agents.

Project Summary / Abstract 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.

Project Summary / Abstract 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.

Project Summary / Abstract Heart failure (HF) is accounts for 1 in 9 deaths in the United States and currently affects ~6 million with 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 HF is exercise (aerobic) therapy that has demonstrated various cardioprotective properties to halt and potentially reverse adverse structural remodeling. However, dosing of exercise therapy remains a challenge due to each individual's inherent differences and consequentially, serial non-invasive monitoring of the therapy would be necessary to evaluate the change on structural remodeling. 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 exercise therapy in HF patients cannot be fully realized representing an unmet need in ultimately improving therapy. The proposed project aims to improve the therapy monitoring of exercise training to cardioprotect against HF by revealing its effect on microstructural remodeling with cardiac diffusion tensor MRI (DT-MRI). DT-MRI 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 cardiac DT-MRI methods to be applied robustly in a clinical setting. In this project, an innovative 5-min ?push button? DT-MRI method will be developed that overcomes such limitations. We also leverage institutional strengths to further quantify the accuracy of in vivo DT-MRI in revealing myocardial microstructure using novel tissue cleared 3D histology. The central hypothesis is that addressing these major technical challenges will allow for clinical translation of cardiac DT-MRI to serve as a tool to monitor the therapeutic effects of HF on microstructural remodeling. This is achieved by extending previously developed technologies used for myocardial fibrosis detection with diffusion-weighted MRI. The proposed project is designed to systematically develop an innovative and robust clinical DT-MRI methodology and rigorously validate in a pre-clinical setting the effects of exercise therapy on the microstructural remodeling of HF thereby laying the groundwork for potential optimization of dosing exercise therapy.

Abstract: Stenosis and/or regurgitation of the aortic and mitral valves imposes an excess load on the left ventricle (LV). The LV can compensate for this load for some time by undergoing hypertrophy and/or dilation, but ultimately fails. It is well recognized that replacement or repair of the valve before the development of overt heart failure improves outcome. More recently, experimental data have suggested that early intervention, before the development of subclinical LV fibrosis, can also improve outcome. This realization, coupled with the growing ability to replace/repair the aortic and mitral valves with catheter-based techniques, has made the need to detect early fibrosis and other subclinical changes in LV microstructure even more pressing. Here we propose a two- pronged approach involving diffusion tensor MRI (DTI) of the LV and RNA-sequencing of the extracellular vesicles in blood. Our group has played a major role in the development of DTI in the heart and has shown that it can provide unique readouts of cardiomyocyte orientation, anisotropy and disorder. Here we will use a novel ultra-high resolution DTI technique, recently developed in our group, that involves the use of a tailored 64- element radiofrequency coil, a spatially-selective 2D excitation pulse, diffusion-encoding gradients compensated for the first and second moments of motion, and a reconstruction scheme using low-rank tensor modeling and a multitasking framework. This approach has improved the spatial resolution of in vivo DTI data by almost an order of magnitude and has allowed us to detect hitherto unknown microstructural patterns in the LV. This novel deep- phenotyping technique will be integrated with a novel approach for genotyping the LV, which involves the sequencing of mRNAs contained in the extracellular vesicles secreted into the blood. We hypothesize that pressure and volume overload will produce significant changes in both the transcriptome and microstructure of the LV well before the onset of overt dysfunction. We further hypothesize that these changes are plastic and may be reversible with timely removal of the excess load. In aim 1, we will study subjects across the broad phenotypic spectrum of aortic stenosis. In aim 2, we will study subjects with aortic and mitral regurgitation. In aim 3 of the proposal we will characterize the impact of valve replacement/repair on the microstructure and transcriptome of the LV. Execution of the study will provide important insights into the pathophysiology of valvular heart disease and provide new tools to assess risk and guide the timing of valve replacement/repair. As the armamentarium of catheter-based techniques continues to grow, this proposal addresses a large knowledge gap and an unmet clinical need and, therefore, is of major medical and public health significance.