PROJECT SUMMARY Heart failure represents a major cause of illness and mortality in the United States. Preemptive and preventative care are the most effective methods for mitigating the severity of this disease. Thus, the early detection of heart failure is critical to patient prognosis and overall cardiovascular health. The conventional methods for diagnosis are limited to detection of significant cardiac damage and pathological remodeling. We propose using 2- [18F]fluoropropionic acid ([18F]FPA) to image the metabolic alterations in fatty acid metabolism which precede cardiac injury. [18F]FPA-PET is favorably suited for imaging these events and translation to the clinic as: 1) [18F]FPA-PET has been used for imaging tumors in humans and accumulates in the heart, thereby confirming its safety and favorable dosimetry, 2) short chain fatty acids, such as [18F]FPA, are preferentially taken up by the injured heart in response to the impairment in long chain fatty acid oxidation, 3) propionic acid metabolism is restricted to a single mitochondrial pathway which targets [18F]FPA to this organelle and limits its potential for degradation. We predict the metabolic alterations that occur during heart failure effectively increase the uptake and sequestration of [18F]FPA to the myocardium. The metabolic trapping of [18F]FPA is driven by acetyl-CoA synthetase short chain family 1 (ACSS1), which converts these short chain fatty acids to metabolically active and membrane impermeable CoA intermediates. ACSS1 expression and activity are upregulated in patients experiencing heart failure, and many animal models of heart failure. Thus, we hypothesize that [18F]FPA effectively accumulates in the injured heart and can be applied to image the early manifestations of cardiac disease which precede irreversible cardiac injury and remodeling. The goals of this fellowship project are to 1) determine if [18F]FPA can be used to image heart failure, and 2) investigate the role of ACSS1 in accounting for the cardiac accumulation of [18F]FPA. The successful application of most imaging probes depends on a comprehensive understanding of the biochemical pathways that these probes report on. In building our understanding, we can develop precise applications for these tracers to image heart failure, as well as other disease states. The long-term goals of this project will serve as a foundation for the applicant's independent research career. These will be facilitated by the technical, conceptual, and practical knowledge that he will gain over the course of the fellowship training.

PROJECT NARRATIVE Early diagnosis and therapeutic intervention for the treatment of heart failure are key determinants of patient overall health. The current methods for diagnosis are restricted to detecting markers of cardiac injury and irreversible remodeling. We propose the use of 2-[18F]fluoropropionic acid-based PET to image the metabolic changes in cardiac metabolism which occur before the onset of debilitating disease.