Transcriptomic profiling of granuloma in patients with cardiac sarcoidosis.

Abstract

Cardiac sarcoidosis (CS) is an inflammatory condition characterized by the accumulation and clustering of immune cells, primarily macrophages, leading to granuloma formation. Despite its clinical significance, CS remains relatively understudied, particularly concerning the molecular mechanisms driving fibrosis and disease progression. To explore potential therapeutic targets, we aimed to characterize the transcriptomic landscape of CS granulomas. Methods: We performed RNA sequencing, immunostaining, and Western blot analysis on granulomatous tissue from explanted CS hearts. We used myocardial tissue from patients with aortic stenosis, preserved ejection fraction, and normal myocardium as a reference group. Gene ontology analysis was conducted, and upstream pathway analysis was performed to determine key modulators driving gene expression within the granulomas. Results: RNA sequencing revealed differential gene expression patterns in granulomatous tissue, highlighting a distinct set of up- and down-regulated genes. Specifically, we observed significant expression of human leukocyte antigens, chitinase-3-like protein 1 (CHI3L1), chitotriosidase-1 (CHIT1), and several immunoglobulin genes within macrophages. Gene ontology analysis identified the activation of immune response pathways, signaling cascades, and cytokine secretion mechanisms. Upstream pathway analysis identified CSF1R as a primary regulator of gene expression, with IL7R also playing a role. The predominance of M2-associated transcripts suggests that granulomas exhibit an anti-inflammatory and tissue remodeling phenotype, whereas the presence of M1-associated transcripts indicates an early inflammatory response that may transition to an M2 phenotype over time. Conclusions: Our findings provide new insights into the immune landscape of CS granulomas and highlight the role of macrophage polarization in granuloma expansion and fibrosis development. The identification of CSF1R as a key upstream regulator, together with the prominence of CHI3L1 and CHIT1, highlights potential targets for therapeutic intervention. These findings support the notion that an M1 to M2 transition may drive fibrotic remodeling, ultimately contributing to heart failure.