Inflammation crucially drives atherosclerosis from disease initiation to the emergence of clinical complications. Targeting pivotal inflammatory pathways without compromising the host defense could compliment therapy with lipid-lowering agents, anti-hypertensive treatment, and lifestyle interventions to address the substantial residual cardiovascular risk that remains beyond classical risk factor control. Detailed understanding of the intricate immune mechanisms that propel plaque instability and disruption is indispensable for the development of novel therapeutic concepts. In this review, we provide an overview on the role of key immune cells in plaque inception and progression, and discuss recently identified maladaptive immune phenomena that contribute to plaque destabilization, including epigenetically programmed trained immunity in myeloid cells, pathogenic conversion of autoreactive regulatory T-cells and expansion of altered leukocytes due to clonal hematopoiesis. From a more global perspective, the article discusses how systemic crises such as acute mental stress or infection abruptly raise plaque vulnerability and summarizes recent advances in understanding the increased cardiovascular risk associated with COVID-19 disease. Stepping outside the box, we highlight the role of gut dysbiosis in atherosclerosis progression and plaque vulnerability. The emerging differential role of the immune system in plaque rupture and plaque erosion as well as the limitations of animal models in studying plaque disruption are reviewed.
Background Acute coronary syndromes (ACS) remain the most devastating clinical manifestation of cardiovascular disease, the most common cause of global mortality. ACS frequently arises from rupture of the coronary fibrous cap, in which a highly thrombogenic necrotic core is exposed to circulating blood, thereby triggering thrombus formation and impairing myocardial perfusion. While inflammation has been implicated as a key mechanism contributing to atherosclerotic plaque vulnerability and rupture, the underlying mechanisms leading to coronary plaque erosion, another form of ACS, are not well understood. In recent findings, flow cytometric (FACS) analysis of blood from the site of patients with culprit lesion plaque erosion showed significant enrichment of both CD4+ and CD8+ T-lymphocytes (+8.1% and +11.2%, respectively, both P<0.05) as well as effector molecules such as granzyme A (+22.4%), perforin (+58.8%), and granulysin (+75.4%) as compared with patients with plaque rupture culprit lesion. The proximity of eroded lesions to coronary bifurcations seen by optical coherence tomography provides further elucidations linking shear stress alterations to the occurrence of erosional ACS. Purpose We aim to further explore the underlying immune cell mechanisms of coronary plaque erosion via a novel single cell multi-omic approach, never before established from samples aspirated from the arterial sheath. Methods Patients presenting with Myocardial Infarction underwent emergent coronary angiography & percutaneous coronary intervention. Infarction was characterized as either coronary plaque rupture or erosion by optical coherence tomography, in which then blood samples were obtained by being aspirated directly along the arterial sheath. Peripheral blood mononuclear cells were isolated via density gradient within four hours of sample aspiration and cryopreserved. Samples from 24 patients were promptly thawed, washed and incubated with 137 oligonucleotide barcoded antibodies to detect surface protein expression as well as a cellular hashtag antibody. Bioinformatic integration of single cell epitope and transcriptome information was performed derived from custom pipelines. Results Our analysis found 32 unique leukocyte clusters that allowed us to rigorously compare each patients sequenced single cell data -totaling approximately 140,000 singe cells. Additionally, the discovery of T cell oligoclonality amongst certain disease patients alludes to antigen-specific activation. We also observed increased CCL4 expression in CD8+ T-lymphocytes within erosional ACS. Conclusion Our high-parametric immune cell analysis shows distinct differences in the adaptive immune system, particularly CD8+ T-lymphocytes and their effector molecules, in the pathogenesis of erosional versus ruptured ACS. Furthermore, our observations found on the oligoclonal expansion of T cell clones aids us to further elucidate underlying mechanisms of culprit lesion formation in ACS. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): DGK - German Cardiac SocietyDGF - TRR 259 Aortic Disease German Research Foundation
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