Divergent Immune Pathways in Coronary Artery Disease and Aortic Stenosis: The Role of Chronic Inflammation and Senescence

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Abstract
Coronary artery disease (CAD) remains a major cause of cardiovascular morbidity and mortality, with growing evidence linking immune dysregulation to its pathogenesis. Aortic stenosis often coexists with CAD (ASCAD), representing an advanced disease form. This study investigates immune pathways in isolated CAD (iCAD) and ASCAD. For this purpose, peripheral blood from 72 individuals (healthy donors, iCAD, and ASCAD patients) was analysed via flow cytometry to assess immune populations. Circulating cytokine levels were measured, and machine learning models identified predictive immune biomarkers. Our data showed that both iCAD and ASCAD patients exhibited immune dysregulation, with reduced dendritic cells, basophils, NK cells, B cells, and T cells, alongside lower frequencies of DCs, lymphocytes, CD8+CD28+ T cells, and CD57+ T cells. Elevated IL-15 and fractalkine, but reduced IL-8 and MCP-1, suggest impaired monocyte and neutrophil mobilisation due to immune cell sequestration in vascular lesions. Distinct immune features emerged between iCAD and ASCAD. iCAD patients showed heightened immune activation, with increased inflammatory CD14+CD16+ monocytes, higher Treg frequencies, and greater CD4+ T cell differentiation into TEM and TEMRA phenotypes. In contrast, ASCAD patients exhibited pronounced immunosenescence, with higher neutrophil counts, lymphopenia, and increased NK and T cell cytotoxicity. Our predictive model distinguished iCAD from ASCAD with high accuracy, identifying CD4+ T cell memory subsets and CD57 expression as key discriminators. This study reveals iCAD as being driven by immune activation and ASCAD by immunosenescence and cytotoxicity. These insights advance CAD immunopathology understanding and support immune-based classification, particularly for ASCAD, where treatment remains limited to surgical intervention.
Funding Information
  • Instituto de Salud Carlos III (PI1900075, FI20/00194, PE-COVID-0053–2020, PI-0324–2018)
  • European Union (PI1900075, FI20/00194, PE-COVID-0053–2020, PI-0324–2018)
  • Junta de Andalucía (PI1900075, FI20/00194, PE-COVID-0053–2020, PI-0324–2018)
  • Fundación para la Investigación Biomédica de Córdoba (PI1900075, FI20/00194, PE-COVID-0053–2020, PI-0324–2018)

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