Transcriptomic profiling of myocardial biopsies reveals metabolic suppression and autophagy activation in systemic...

To characterise the myocardial transcriptomic landscape of patients with systemic sclerosis (SSc) with primary heart involvement (pHI) and identify molecular pathways underlying its pathogenesis.

A single-centre study exploring the molecular pathogenesis of SSc-pHI through transcriptomic analysis of endomyocardial biopsy specimens.

Basic research.

This study enrolled seven patients with SSc-pHI and eight patients with dilated cardiomyopathy (DCM) who had undergone endomyocardial biopsy for clinical practice purposes.

No intervention.

Not applicable.

Endomyocardial biopsy specimens from patients with SSc-pHI and those with DCM underwent whole RNA sequencing. To enable indirect comparison with non-failing (NF) myocardium, public RNA sequencing data of NF and DCM samples were integrated using DCM as a shared reference. Differential gene expression, pathway enrichment (Ingenuity Pathway Analysis and Gene Set Enrichment Analysis) and immune and stromal cell deconvolution were performed. Histopathological evaluation included LC3 immunostaining and transmission electron microscopy (TEM).

A total of 700 genes were differentially expressed between SSc and DCM myocardium. Mitochondrial energy metabolism pathways, including oxidative phosphorylation, fatty acid β-oxidation and the tricarboxylic acid cycle, were markedly suppressed in SSc. Indirect comparison with NF myocardium confirmed reciprocal regulation of mitochondrial metabolism and suggested enhanced autophagy. Cell deconvolution revealed enrichment of M1-like macrophages in SSc myocardium. LC3 immunostaining and TEM revealed increased autophagic vacuoles, lipid droplet accumulation and ischaemia-like ultrastructural alterations.

SSc myocardium exhibits metabolic reprogramming characterised by mitochondrial dysfunction and enhanced autophagy, accompanied by macrophage activation.