European Heart Journal最新文献

Background and aims: Atherosclerotic plaques are the leading cause of cardiovascular events. Single-cell approaches have identified diverse human plaque cell phenotypes but their spatial distribution and interactions remain unclear. Here, intercellular communication patterns in human plaque microenvironments were mapped to reveal novel targets to prevent atherosclerotic events.

Methods: Spatial transcriptomics (Visium, 10x) from 13 carotid plaques, and single-cell transcriptomics (cells = 51 981) were used to analyse cell phenotypes, cell trajectories, and intercellular communications. Cells contributing to plaque stability were explored using deconvolution of plaque bulk RNA-seq data (n = 78), histology, and survival analyses. Key cells and pathways were validated in apolipoprotein E (Apoe)-/- mice and in vitro. Genome-wide association study enrichment analyses were conducted using summary statistics of atherosclerotic diseases. LINCS L1000 data were used to explore drug repurposing.

Results: A fibroblast-like vascular smooth muscle cell (VSMC) phenotype associated with extracellular matrix formation pathways (validated in Apoe-/- mice) emerged as a key regulator of intra-plaque ligand-receptor signalling, in particular in the cap region. A higher proportion of fibroblast-like VSMCs was found in asymptomatics, associated with stable plaque features and predicted a lower risk of future events. Genes specific to this VSMC phenotype were enriched in coronary artery disease and myocardial infarction. Finally, compounds, which could induce key marker genes were identified and validated in vitro.

Conclusions: This study provides the first comprehensive spatial transcriptomics map of cell communication in human plaque microenvironments. A pivotal role of a fibroblast-like VSMC, orchestrating intraplaque cell signalling and contributing to plaque stability, was identified. Targeting these cells might present promising novel avenues for therapies.

Background and aims: Fulminant myocarditis (FM) is a life-threatening inflammatory cardiomyopathy with high mortality. Soluble ST2 (sST2), traditionally regarded as a decoy receptor for interleukin-33 (IL-33), is markedly elevated in FM, yet its mechanistic and translational roles remain unclear.

Methods: A Coxsackievirus B3-induced FM mouse model was used to define the cellular source and function of sST2 through histological, molecular, and integrated single-cell and single-nucleus transcriptomic analyses. Cardiomyocyte responses were assessed in neonatal murine cardiomyocytes and human engineered heart tissues. The therapeutic efficacy and safety of sST2-neutralizing antibodies were evaluated in vivo, with clinical relevance examined in a cohort of FM patients.

Results: sST2 originated predominantly from infiltrating CCR2+ macrophages in FM hearts and aggravated cardiac damage by amplifying inflammation, mitochondrial dysfunction, and contractile failure. Mechanistically, sST2 acted independently of IL-33. It entered cardiomyocytes via IGF2R and bound the transcription factor YY1, preventing its nuclear translocation and repressing mitochondrial electron transport chain gene expression, thereby reducing ATP synthesis. Neutralizing antibodies targeting sST2 effectively restored mitochondrial function, improved hemodynamics, and reduced mortality without evident short-term systemic toxicity. Integrated single-cell and single-nucleus transcriptomic analyses revealed broad therapeutic effects across cardiomyocytes, fibroblasts, endothelial cells, and macrophages. Combined glucocorticoid and anti-sST2 therapy provided additive benefit. Clinically, elevated plasma sST2 independently predicted 30-day mortality or extracorporeal membrane oxygenation requirement in FM patients, outperforming N-terminal pro-B-type natriuretic peptide and cardiac troponin I for prognostic discrimination.

Conclusions: sST2 drives FM by disrupting cardiomyocyte mitochondrial homeostasis independently of IL-33 and represents both a clinically prognostic biomarker and a therapeutic target.