The influences of both heart muscle metabolism and mitochondrial function on the pathogenesis of heart failure and heart muscle viability are becoming increasingly prioritized in efforts to identify therapeutic targets, and a powerful means for evaluating all of these parameters in the intact, functioning or in vivo heart is the use of NM spectroscopy and imaging. With the fact that cardiovascular disease remains the largest cause of death in the nation and being increasingly understood to be the primary cause of death in women in the USA, it is paramount that Center for Cardiovascular Research NMR Facility maintain reliable and state-of-the- art capabilities for the 14.098 T wide bore (89 mm) magnet (Bruker Biospin) interfaced to a 600 MHz NMR/MRI system console. This 600 MHz system supports specific aims for online evaluations of metabolic flux in intact beating hearts using stable isotope kinetics pioneered in this laboratory, unique high resolution tagged cardiac MR imaging to transmurrally detect early indices of impaired cardiac function across the 1 mm thick left ventricular wall of in vivo mouse hearts, MRI of diastolic dysfunction, in vitro biochemical characterization of novel transgenic models of heart disease and novel applications for multi-organ MRE. The 14 active NIH grants dependent on this equipment total $3,680,814 in annual direct costs. Major users are PI's on 8 R01 grants, an NIH MERIT Award (R37), a Pioneer Award (DP1) and a Program Project Grant (P01). Pending NIH grants extend the commitment of the system to ongoing, preliminary work. These projects, representing extensive NIH support, risk shutdown, because the existing Bruker DRX 600 MHz console for these NIH commitments is obsolete with electronics no longer produced, and is not supported for service as an existing product line. A particular concern is the lack of signal generator units (SGU) in the 13-year old DRX console that requires third party frequency synthesizers that are also no longer produced for interfacing to the DRX console. The stark reality is that one electronics failure holds potentil to shutdown work on NIH sponsored program projects, a MERIT award, and numerous R01 type grants. Longitudinal studies have already been compromised due to untimely system downtime and delays in the availability of third party frequency synthesizers. To avert eventual shutdown of current and future NIH sponsored work and enhance the quality of data and scope of current research, we propose funding for a new AVANCEIII 600 MHz console (Bruker Biospin). The console, as proposed, will enhance critical needs: 1) system capability; 2) system reliability; 3) system compatibility. As opposed to a scattered research focus, this proposal supports a broad yet cohesive, range research heavily dependent on NMR and MRI that converge on the central, long-term objective of identifying fundamental mechanisms of disease and developing therapeutic approaches to counter target mechanisms. The consortium of researchers includes on-campus, regional, and national investigators and collaborations, with potential for funding to support new NIH funded PI's and forge new powerful collaborations.
