Differential immunological signature at the culprit site distinguishes acute coronary syndrome with intact from acute coronary syndrome with ruptured fibrous cap: results from the prospective translational OPTICO-ACS study

Abstract

Aims Acute coronary syndromes with intact fibrous cap (IFC-ACS), i.e. caused by coronary plaque erosion, account for approximately one-third of ACS. However, the underlying pathophysiological mechanisms as compared with ACS caused by plaque rupture (RFC-ACS) remain largely undefined. The prospective translational OPTICO-ACS study programme investigates for the first time the microenvironment of ACS-causing culprit lesions (CL) with intact fibrous cap by molecular high-resolution intracoronary imaging and simultaneous local immunological phenotyping. Methods and results The CL of 170 consecutive ACS patients were investigated by optical coherence tomography (OCT) and simultaneous immunophenotyping by flow cytometric analysis as well as by effector molecule concentration measurements across the culprit lesion gradient (ratio local/systemic levels). Within the study cohort, IFC caused 24.6% of ACS while RFC-ACS caused 75.4% as determined and validated by two independent OCT core laboratories. The IFC-CL were characterized by lower lipid content, less calcification, a thicker overlying fibrous cap, and largely localized near a coronary bifurcation as compared with RFC-CL. The microenvironment of IFC-ACS lesions demonstrated selective enrichment in both CD4+ and CD8+ T-lymphocytes (+8.1% and +11.2%, respectively, both P < 0.05) as compared with RFC-ACS lesions. T-cell-associated extracellular circulating microvesicles (MV) were more pronounced in IFC-ACS lesions and a significantly higher amount of CD8+ T-lymphocytes was detectable in thrombi aspirated from IFC-culprit sites. Furthermore, IFC-ACS lesions showed increased levels of the T-cell effector molecules granzyme A (+22.4%), perforin (+58.8%), and granulysin (+75.4%) as compared with RFC plaques (P < 0.005). Endothelial cells subjected to culture in disturbed laminar flow conditions, i.e. to simulate coronary flow near a bifurcation, demonstrated an enhanced adhesion of CD8+T cells. Finally, both CD8+T cells and their cytotoxic effector molecules caused endothelial cell death, a key potential pathophysiological mechanism in IFC-ACS. Conclusions The OPTICO-ACS study emphasizes a novel mechanism in the pathogenesis of IFC-ACS, favouring participation of the adaptive immune system, particularly CD4+ and CD8+ T-cells and their effector molecules. The different immune signatures identified in this study advance the understanding of coronary plaque progression and may provide a basis for future development of personalized therapeutic approaches to ACS with IFC. Trial registration The study was registered at clinicalTrials.gov (NCT03129503).

Predictors of Coronary Plaque Erosion in Current and Non-Current Smokers With ST-Segment Elevation Myocardial Infarction ― An Optical Coherence Tomography Study ―

“…Compared with plaque rupture, the correlation between plaque erosion and current smoking status complements clinicians' understanding of plaque erosion. compared with ruptured fibrous cap culprit lesions, 37 which is similar to our results. A nearby bifurcation will increase the endothelial sheer stress of the main vessel and further accelerate coronary endothelial injury, leading to thrombosis and plaque erosion.…”

The Spectrum of ACS: Towards a More Personalized Approach

“…Histopathological and experimental data suggest that endothelial denudation as well as extracellular matrix (ECM) degradation are key features of plaque erosion [28]. Recently, an important role for the local cytotoxic response mediated by CD8 T lymphocytes in plaque erosion occurring in the presence of a local alteration of shear stress has been suggested as a major mechanism [29].…”

Potential Influential Factors of In‐Hospital Myocardial Reinfarction in ST‐Segment Elevation Myocardial Infarction (STEMI) Patients: Finding from the Improving Care for Cardiovascular Disease in China‐ (CCC‐) Acute Coronary Syndrome (ACS) Project

“…The CCC-ACS project, whose aim is to improve and evaluate the quality of care for ACS inpatients, is a nationwide quality improvement registry We used a standard Cox survival regression and a competing risk regression that considered in-hospital death as a competing risk event to address potential risk factors (e.g., 3 Oxidative Medicine and Cellular Longevity age, sex, heart rate, smoking, MI history, HF history, COPD history, stroke, hypertension, diabetes, PCI treatment, administration of DAPT, and statins) of in-hospital reinfarction (the framework can be seen in Figure 1).…”

“…Cardiovascular disease (CVD) remains a public health concern, causing death in 40% of the Chinese population [1]. Acute coronary syndrome (ACS), especially ST-segment elevation myocardial infarction (STEMI), is the most devastating clinical manifestation of CVD [2][3][4][5]. The prognosis of STEMI varies among individuals [6][7][8][9].…”