Abstract Rationale Sarcoidosis is a heterogeneous granulomatous disease with variable organ involvement and clinical trajectories. Cardiac sarcoidosis (CS) drives arrhythmia, heart failure, and sudden death, yet its molecular distinction from pulmonary sarcoidosis (PS) remains unclear. Because cellular metabolism programs immune activation and fibrogenesis, we hypothesized that organ tropism in sarcoidosis would manifest as distinct systemic (serum) immunometabolic phenotypes. Accordingly, we interrogated the serum metabolome in cardiac sarcoidosis to define signatures of CS to compare to PS. Methods Ultra-performance liquid-chromatography tandem mass spectrometry (UPLC-MS/MS) metabolomics was performed on serum from University of Maryland cohort. Subjects were classified as pulmonary sarcoidosis progressors (n = 20), pulmonary resolvers (n = 8), cardiac sarcoidosis (n = 7), and healthy controls (n = 7). Progressor was defined as FVC or DLCO decline ≥10%, new/advancing HRCT fibrosis, or initiation of systemic therapy and resolvers are stable with improved lung function without therapy. Processing included peak detection/alignment, HMDB compounds annotation, normalization, and QA/QC. Group differences were assessed by multivariate modeling (PLS-DA with internal cross-validation) and covariate-adjusted univariate testing (Benjamini-Hochberg FDR0.05; |fold-change|1.5). Pathway enrichment was performed on mapped metabolites. Results Cardiac only sarcoidosis patients showed distinct metabolic profiles than those with lung disease only. CS showed enrichment of long-chain acylcarnitines and β-oxidation intermediates, consistent with increased fatty-acid oxidation demand and myocardial mitochondrial stress; signals also suggested altered cardiac-relevant amino-acid flux and ketone handling. PS, particularly progressors, exhibited broader systemic immune-oxidative signatures: elevations in GSSG, cystine, tyrosine, and short- to medium-chain fatty acids, with pathway shifts in redox balance, amino-acid metabolism (e.g., arginine/ornithine, proline), and lipid remodeling. Collectively, the data support organ-specific immunometabolic phenotypes, with fatty-acid oxidation and mitochondrial programs predominating in CS versus redox, amino-acid and lipid-inflammatory remodeling in progressive PS. Conclusions Metabolites are small, bioactive, and analytically sensitive, attributes leveraged for early detection in other conditions such as newborn screening for inborn errors, renal dysfunction, and cardiometabolic risk stratification. Despite of modest sample sizes that require external validation, our pilot suggests that sarcoidosis is not metabolically uniform. This divergence between CS and PS is consistent with the idea that organ tropism shapes systemic immunometabolic states and may influence clinical trajectories. These findings support pursuing CS-specific metabolic biomarker development for earlier detection, organ-informed risk stratification, and hypothesis-driven therapeutic strategies in CS. This abstract is funded by: K24127501
Ma et al. (Fri,) studied this question.