{
  "abstract": "Objectives To characterise the myocardial transcriptomic landscape of patients with systemic sclerosis (SSc) with primary heart involvement (pHI) and identify molecular pathways underlying its pathogenesis.Design A single-centre study exploring the molecular pathogenesis of SSc-pHI through transcriptomic analysis of endomyocardial biopsy specimens.Setting Basic research.Participant This study enrolled seven patients with SSc-pHI and eight patients with dilated cardiomyopathy (DCM) who had undergone endomyocardial biopsy for clinical practice purposes.Interventions No intervention.Main outcome measures Not applicable.Methods 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).Results 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.Conclusions SSc myocardium exhibits metabolic reprogramming characterised by mitochondrial dysfunction and enhanced autophagy, accompanied by macrophage activation.",
  "authors": [
    {
      "affiliations": [
        "Department of Allergy and Rheumatology, Nippon Medical Schoo, Tokyo, Japan"
      ],
      "name": "Yohei Isomura"
    },
    {
      "affiliations": [
        "Department of Pharmacy, Faculty of Pharmaceutical Sciences, Tokyo University of Science—Katsushika Campus, Tokyo, Japan"
      ],
      "name": "Yoshio Nakano"
    },
    {
      "affiliations": [
        "Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan"
      ],
      "name": "Yoshiaki Kubota"
    },
    {
      "affiliations": [
        "Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan"
      ],
      "name": "Tsunenori Saito"
    },
    {
      "affiliations": [
        "Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan"
      ],
      "name": "Satsuki Noma"
    },
    {
      "affiliations": [
        "Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo, Japan"
      ],
      "name": "Kai Miyazaki"
    },
    {
      "affiliations": [
        "Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo, Japan"
      ],
      "name": "Yukako Shintani-Domoto"
    },
    {
      "affiliations": [
        "Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan"
      ],
      "name": "Kuniya Asai"
    },
    {
      "affiliations": [
        "Department of Pharmacy, Faculty of Pharmaceutical Sciences, Tokyo University of Science—Katsushika Campus, Tokyo, Japan"
      ],
      "name": "Satoru Miyazaki"
    },
    {
      "affiliations": [
        "Department of Molecular and Cellular Dynamics, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo, Japan"
      ],
      "name": "Hayashi Yamamoto"
    },
    {
      "affiliations": [
        "Department of Allergy and Rheumatology, Nippon Medical Schoo, Tokyo, Japan",
        "Scleroderma Myositis Center of Excellence, Nippon Medical School Hospital, Tokyo, Japan"
      ],
      "name": "Masataka Kuwana"
    }
  ],
  "title": "Transcriptomic profiling of myocardial biopsies reveals metabolic suppression and autophagy activation in systemic sclerosis-associated primary heart involvement",
  "uid": "0f97da03-e253-569a-8677-75d0595723eb"
}