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.