Divergent T Cell Programs in Plaque Rupture and Erosion Revealed by Single-Cell Multiomics in the OPTICO-ACS Study

Clin Res Cardiol (2026). DOI 10.1007/s00392-026-02870-1
C. Wolfram (Berlin)¹, H. Horstmann (Freiburg)², Y. Abdelwahed (Berlin)¹, D. Meteva (Berlin)¹, M. Heiser (Berlin)¹, P. Stapmanns (Berlin)³, C. Seppelt (Frankfurt am Main)⁴, L. Zanders (Frankfurt am Main)⁴, G. Nelles (Frankfurt am Main)⁴, M. Franitza (Köln)⁵, K. Becker (Köln)⁵, C. Losert (Neuherberg)⁶, M. Heinig (Neuherberg)⁶, K. Stark (München)⁷, M. Joner (München)⁸, A. Lang (Düsseldorf)⁹, N. Gerdes (Düsseldorf)⁹, S. Baldus (Köln)¹⁰, C. Gianarelli (New York)¹¹, D. Wolf (Freiburg)², U. Landmesser (Berlin)¹, N. Kränkel (Berlin)¹, D. Leistner (Frankfurt am Main)⁴, H. Winkels (Köln)¹², T. Gerhardt (Berlin)^1
1Deutsches Herzzentrum der Charite (DHZC) Klinik für Kardiologie, Angiologie und Intensivmedizin Berlin, Deutschland; ²Universitäts-Herzzentrum Freiburg - Bad Krozingen Klinik für Kardiologie und Angiologie Freiburg, Deutschland; ³Charite - Universitätsmedizin Berlin Abteilung Sportmedizin Berlin, Deutschland; ⁴Universitätsklinikum Frankfurt Med. Klinik III - Kardiologie, Angiologie Frankfurt am Main, Deutschland; ⁵Zentrum für Molekulare Medizin Köln Köln, Deutschland; ⁶Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) Neuherberg, Deutschland; ⁷LMU Klinikum der Universität München Medizinische Klinik und Poliklinik I München, Deutschland; ⁸TUM Klinikum Deutsches Herzzentrum Klinik für Herz- und Kreislauferkrankungen München, Deutschland; ⁹Universitätsklinikum Düsseldorf Klinik für Kardiologie, Pneumologie und Angiologie Düsseldorf, Deutschland; ¹⁰Herzzentrum der Universität zu Köln Klinik für Kardiologie, Angiologie, Pneumologie und Internistische Intensivmedizin Köln, Deutschland; ¹¹New York University Cardiovascular Research Center New York, USA; ¹²Herzzentrum der Universität zu Köln Klinik III für Innere Medizin Köln, Deutschland

Background and aims: Acute coronary syndromes (ACS) remain a leading cause of death in the western world. Plaque erosion underlies 30–40% of ACS and, unlike plaque rupture, is defined by thrombus formation on an intact fibrous cap following endothelial loss. A growing body of histopathological, laboratory, imaging, and clinical evidence points towards fundamental differences in vascular inflammation and immune responses between erosion- and rupture-driven ACS. Erosion appears to involve more localized and selective immune processes within the vascular wall. Yet, the nature of the adaptive immune involvement in these divergent settings and how it shapes the local inflammatory response remains unclear.

Methods: We prospectively enrolled 133 consecutive ACS patients with plaque erosion or rupture classified by optical coherence tomography ACS-causing culprit lesion. Blood was sampled from the coronary culprit lesion and peripheral circulation. T cells were profiled by flow cytometry and multiplex plasma proteomics. In a subgroup of erosions and ruptures (n=16) carefully matched for age, sex and cardiovascular risk factors, coronary samples underwent CITE-seq (single-cell transcriptome with surface protein profiling) and paired TCR sequencing for comprehensive characterization of T cell responses in the culprit lesion environment.

Results: Flow cytometry showed a pronounced enrichment of activated memory helper and cytotoxic T cells with anti-inflammatory features at erosion sites, whereas rupture lesions were dominated by naïve and proinflammatory subsets, including TH1 and TH1/TH17 cells. CITE-seq revealed erosion-specific activation of pathways linked to lymphocyte activation, proliferation, adhesion, and tissue repair in T cells. In contrast, rupture-associated T cells exhibited enhanced interferon signaling, cytokine production, and innate inflammatory pathways. TCR sequencing further demonstrated pronounced clonal expansion in erosion, suggesting antigen-driven activation, whereas rupture displayed broader clonal diversity.

Conclusion: Our findings delineate fundamentally different T cell profiles in erosion and rupture. While erosion exhibits memory-skewed, clonally expanded regulatory and cytotoxic T cell subsets, rupture is characterized by proinflammatory phenotypes, diverse TCR repertoire and heightened inflammatory signaling. This work provides the first single-cell study of intracoronary culprit-lesion blood during ACS and the first application of single-cell multiomics comparing its two principal pathomechanisms. The findings support morphology-tailored immunotherapy with established anti-inflammatory treatments for rupture and selective T cell–directed strategies for erosion.