PROJECT SUMMARY Sarcoidosis is a systemic condition characterized by non-caseating granulomas affecting ~200,000 Americans. Granuloma infiltration in the myocardium leads to inflammation, fibrogenesis, ventricular arrhythmias, and increased morbidity and mortality. Imaging determinants of cardiac sarcoidosis (CS) include late gadolinium enhancement (LGE) on cardiac MR (CMR) indicating fibrosis, uptake of 18F-FDG on PET indicating inflamma- tion, and perfusion deficits on 82Rb myocardial PET perfusion imaging (MPI) indicating microvascular constric- tion secondary to either fibrosis or inflammation. Each have been identified as predictors of future clinical events. While early immune-suppressant therapy (IST) can mitigate cardiac dysfunction and improve longer- term outcomes, treatment guidelines for CS are not well developed. Given the deleterious effects of prolonged IST (with corticosteroids), and the availability of combination approaches using steroids and steroid-sparing medications, optimization of the therapeutic strategy is an important clinical need. An elevated FDG signal (SUVmax) and its subsequent reduction are widely regarded as a trigger for IST and evidence of response to therapy, respectively, however agreed-upon quantitative thresholds for such determinations are lacking. Our overarching goals are, 1) to determine the imaging response to therapy of multiple imaging parameters (Aims 1&2) and to establish thresholds that are associated with changes in cardiac function (LVEF and NYHA Class) after IST; 2) to correlate imaging parameters with changes in cardiac function and change in LGE (fibrosis) after IST and with the occurrence of adverse clinical events (Aim 3). We propose a prospective study, with serial imaging beyond completion of IST to assess sustained changes after IST, comprehensive imaging (LGE- CMR, FDG PET, Rb MPI, advanced CMR mapping, and quantitative perfusion measurements), and a standardized IST regimen to improve generalizability of our findings. We will enroll 174 patients with confirmed CS (biopsy-proven extra-CS with cardiac involvement according to WASOG and HRS criteria or biopsy-proven CS with clinical evidence of extra-CS), a perfusion deficit on MPI, and who are treatment naïve at baseline. 112 patients with elevated FDG will undergo IST and serial imaging at Time Point (TP) 1 prior to IST, TP2, after IST (12-16 weeks), and TP3, after steroid tapering (28-36 weeks). Clinical adverse events (cardiac arrest, VT, heart failure, new heart block) will be monitored for the duration of the study. The central innovation in the study is the development of a multi-parametric approach and the hypothesis that composite multi- parametric measures will be superior predictors of overall risk and subsequently response to therapy. In Aim 1, we focus on SUVmax and other standard imaging parameters, addressing an immediate need. In Aim 2, we evaluate advanced CMR mapping parameters (T2, T1, extracellular volume (ECV)), quant...