New Concepts on the Pathophysiology of Acute Coronary Syndrome.

Acute coronary syndrome (ACS) is the most severe form of ischemic heart disease. Although it is caused by atherosclerotic plaque thrombosis or nonatherosclerotic causes, its pathophysiological mechanism of ACS is not fully understood, and its concept is constantly updated and developed. At present, the main pathophysiological mechanisms include plaque rupture, plaque erosion, calcified nodules (CN) and non-atherosclerotic causes such as coronary vasospasm and myocardial bridging (MB). These mechanisms may overlap and coexist in some ACS patients. Therefore, the pathophysiological mechanism of ACS is complex, and is of great significance for the diagnosis and treatment of ACS. This review will discuss the pathophysiological mechanisms of ACS to provide new thoughts on the pathogenesis, diagnosis and treatment of ACS.

Impact of Radial Wall Strain on Serial Changes in Vascular Physiology in Patients with Intermediate Coronary Stenosis.

Background: Coronary biomechanical stress contributes to the plaque rupture and subsequent events. This study aimed to investigate the impact of plaque biomechanical stability on the physiological progression of intermediate lesions, as assessed by the radial wall strain (RWS) derived from coronary angiography. Methods: Patients with at least one medically treated intermediate lesion at baseline who underwent follow-up coronary angiography over 6 months were included. The maximal RWS ( RWS max ) of the interrogated lesion was calculated from the baseline angiogram. The primary endpoint was to determine the association between baseline RWS max and the functional progression of coronary lesions, defined as an increase in the lesion-specific △ quantitative flow ratio (L- △ QFR, calculated as the absolute change in QFR across the lesion) on serial angiograms. Results: Among 175 lesions in 156 patients, 63 lesions showed an increase in L- △ QFR during a median follow-up period of 12.4 months. Baseline RWS max values were significantly higher in lesions with increased L- △ QFR than in those with stabilized or decreased L- △ QFR (11.8 [10.7, 13.7] vs.10.8 [9.7, 11.7]; p = 0.001). Baseline RWS max presented an area under the curve of 0.658 (95% confidence interval [CI]: 0.572-0.743, p < 0.001) for the prediction of increased L- △ QFR. After full adjustment for clinical and angiographic factors, a high RWS max ( > 12) was found to be an independent predictor of functional lesion progression (odds ratio: 2.871, 95% CI: 1.343-6.138, p = 0.007). Conclusions: A high RWS max calculated from baseline angiograms was independently associated with the subsequent physiological progression in patients with intermediate coronary lesions.

MiR-206 may regulate mitochondrial ROS contribute to the progression of Myocardial infarction via TREM1.

Myocardial infarction (MI) is a leading cause of mortality. To better understand its molecular and cellular mechanisms, we used bioinformatic tools and molecular experiments to explore the pathogenesis and prognostic markers. Differential gene expression analysis was conducted using GSE60993 and GSE66360 datasets. Hub genes were identified through pathway enrichment analysis and PPI network construction, and four hub genes (AQP9, MMP9, FPR1, and TREM1) were evaluated for their predictive performance using AUC and qRT-PCR. miR-206 was identified as a potential regulator of TREM1. Finally, miR-206 was found to induce EC senescence and ER stress through upregulating mitochondrial ROS levels via TREM1. These findings may contribute to understanding the pathogenesis of MI and identifying potential prognostic markers.

KLF4 inhibited the senescence-associated secretory phenotype in ox-LDL-treated endothelial cells via PDGFRA/NAMPT/mitochondrial ROS.

BACKGROUND: Inflammation is one of the significant consequences of ox-LDL-induced endothelial cell (EC) dysfunction. The senescence-associated secretory phenotype (SASP) is a critical source of inflammation factors. However, the molecular mechanism by which the SASP is regulated in ECs under ox-LDL conditions remains unknown. RESULTS: The level of SASP was increased in ox-LDL-treated ECs, which could be augmented by KLF4 knockdown whereas restored by KLF4 knock-in. Furthermore, we found that KLF4 directly promoted PDGFRA transcription and confirmed the central role of the NAPMT/mitochondrial ROS pathway in KLF4/PDGFRA-mediated inhibition of SASP. Animal experiments showed a higher SASP HFD-fed mice, compared with normal feed (ND)-fed mice, and the endothelium of EC-specific KLF4-/- mice exhibited a higher proportion of SA-ß-gal-positive cells and lower PDGFRA/NAMPT expression. CONCLUSIONS: Our results revealed that KLF4 inhibits the SASP of endothelial cells under ox-LDL conditions through the PDGFRA/NAMPT/mitochondrial ROS. METHODS: Ox-LDL-treated ECs and HFD-fed mice were used as endothelial senescence models in vitro and in vivo. SA-ß-gal stain, detection of SAHF and the expression of inflammatory factors determined SASP and senescence of ECs. The direct interaction of KLF4 and PDGFRA promotor was analyzed by EMSA and fluorescent dual luciferase reporting analysis.

Corrigendum: Single-cell RNA sequencing of peripheral blood mononuclear cells from acute myocardial infarction.

[This corrects the article DOI: 10.3389/fimmu.2022.908815.].

The relationship between glycemic risk and longitudinal changes in total physiological atherosclerotic burden in patients with coronary artery disease.

Background: The effects of glycemic status on coronary physiology have not been well evaluated. This study aimed to investigate changes in coronary physiology by using angiographic quantitative flow ratio (QFR), and their relationships with diabetes mellitus (DM) and glycemic control status. Methods: This retrospective cohort study included 530 patients who underwent serial coronary angiography (CAG) measurements between January 2016 and December 2021 at Tongji Hospital of Tongji University. Based on baseline and follow-up angiograms, 3-vessel QFR (3V-QFR) measurements were performed. Functional progression of coronary artery disease (CAD) was defined as a change in 3V-QFR (Δ3V-QFR = 3V-QFRfollow-up - 3V-QFRbaseline) ≤-0.05. Univariable and multivariable logistic regression analyses were applied to identify the independent predictors of coronary functional progression. Subgroup analysis according to diabetic status was performed. Results: During a median interval of 12.1 (10.6, 14.3) months between the two QFR measurements, functional progression was observed in 169 (31.9%) patients. Follow-up glycosylated hemoglobin (HbA1c) was predictive of coronary functional progression with an area under the curve (AUC) of 0.599 [95% confidence interval (CI): 0.546-0.651; P<0.001] in the entire population. Additionally, the Δ3V-QFR values were significantly lower in diabetic patients with HbA1c ≥7.0% compared to those with well-controlled HbA1c or non-diabetic patients [-0.03 (-0.09, 0) vs. -0.02 (-0.05, 0.01) vs. -0.02 (-0.05, 0.02); P=0.002]. In a fully adjusted multivariable logistics analysis, higher follow-up HbA1c levels were independently associated with progression in 3V-QFR [odds ratio (OR), 1.263; 95% CI: 1.078-1.479; P=0.004]. Furthermore, this association was particularly strong in diabetic patients (OR, 1.353; 95% CI: 1.082-1.693; P=0.008) compared to patients without DM. Conclusions: Among patients with established CAD, on-treatment HbA1c levels were independently associated with progression in physiological atherosclerotic burden, especially in patients with DM.

Screening of Potential Circulating Diagnostic Biomarkers and Molecular Mechanisms of Systemic Lupus Erythematosus-Related Myocardial Infarction by Integrative Analysis.

Background: The risk of acute myocardial infarction (AMI) is elevated in patients with systemic lupus erythematosus (SLE), and it is of great clinical value to identify potential molecular mechanisms and diagnostic markers of AMI associated with SLE by analyzing public database data and transcriptome sequencing data. Methods: AMI and SLE-related sequencing datasets GSE62646, GSE60993, GSE50772 and GSE81622 were downloaded from the Gene Expression Omnibus (GEO) database and divided into prediction and validation cohorts. To identify the key genes associated with AMI related to SLE, WGCNA and DEGs analysis were performed for the prediction and validation cohorts, respectively. The related signaling pathways were identified by GO/KEGG enrichment analysis. Peripheral blood mononuclear cells (PBMCs) from patients with AMI were collected for transcriptome sequencing to validate the expression of key genes in patients with AMI. Least absolute shrinkage and selection operator (LASSO) regression analysis was applied to screen diagnostic biomarkers. The diagnostic efficacy of biomarkers was validated by ROC analysis, and the CIBERSORTx platform was used to analyze the composition of immune cells in AMI and SLE. Results: A total of 108 genes closely related to AMI and SLE were identified in the prediction cohort, and GO/KEGG analysis showed significantly enriched signaling pathways. The results of differential analysis in validation cohort were consistent with them. By transcriptional sequencing of PBMCs from peripheral blood of AMI patients, combined with the results of prediction and validation cohort analysis, seven genes were finally screened out. LASSO analysis finally identifies DYSF, LRG1 and CSF3R as diagnostic biomarkers of SLE-related-AMI. CIBERSORTx analysis revealed that the biomarkers were highly correlated with neutrophils. Conclusion: Neutrophil degranulation and NETs formation play important roles in SLE-related AMI, and DYSF, LRG1 and CSF3R were identified as important diagnostic markers for the development and progression of SLE-related AMI.

Prognostic Implications of Changes in Total Physiological Atherosclerotic Burden in Patients With Coronary Artery Disease-A Serial QFR Study.

The association between coronary physiological progression and clinical outcomes has not been investigated. A total of 421 patients who underwent serial coronary angiography at least 6 months apart were included. Total physiological atherosclerotic burden was characterized by sum of quantitative flow ratio in 3 epicardial vessels (3V-QFR). The relationships of the 3V-QFR and its longitudinal change (△3V-QFR) with major adverse cardiovascular events (MACE) were explored. 3V-QFR values derived from follow-up angiograms were slightly lower compared with baseline (2.85 [2.77, 2.90] vs 2.86 [2.80, 2.90], P < .001). The median △3V-QFR value was -0.01 (-0.05, 0.02). The multivariable models demonstrated that follow-up 3V-QFR and △3V-QFR were independently associated with MACE (both P < .05). Patients with both low follow-up 3V-QFR (≤2.78) and low △3V-QFR (≤-0.05) presented 3 times higher risk of MACE than those without (hazard ratio: 2.953, 95% confidence interval 1.428-6.104, P = .003). Furthermore, adding patient-level 3V-QFR and △3V-QFR to clinical model significantly improved the predictability for MACE. In conclusion, total physiological atherosclerotic burden and its progression can provide incremental prognostic value over clinical characteristics, supporting the use of coronary physiology in the evaluation of disease progression and for the identification of vulnerable patients.

Angiographic quantitative flow ratio in acute coronary syndrome: beyond a tool to define ischemia-causing stenosis-a literature review.

Background and Objective: Numerous studies have demonstrated the safety and effectiveness of physiology-guided coronary revascularization in chronic coronary syndrome, resulting in a high level of guideline recommendation for these patients. However, the application of coronary physiology in acute coronary syndrome (ACS), especially in the acute phase of myocardial infarction, remains challenging. Over the last decade, the number of novel physiological indices derived from the computation of angiography have been developed as alternatives to pressure wire-based fractional flow reserve. Among these angiography-based indices, the quantitative flow ratio (QFR) is undoubtedly the one with the largest amount of data cumulated so far. In this article, we aim to review the related studies that describe efforts to investigate the diagnostic role of QFR and discuss perspectives for its current and future applications in the setting of the ACS. Methods: A literature search was performed on the electronic databases, including PubMed, Google Scholar and Web of Science covering publications in English up to May 2022. Key Content and Findings: An emerging body of evidence has validated the diagnostic accuracy of angiography-derived QFR for the assessment of functional severity of coronary stenosis in both acute and chronic coronary syndromes. In parallel, multiple technologies, i.e., QFR-based pullback pressure gradient index, angiography-derived index of microcirculatory resistance and intravascular imaging-based morphofunctional evaluation methods, have been proposed, allowing operators to easily obtained physiological data of micro and macro-circulation, together with atherosclerotic lesion characteristics in catheterization laboratories. More recently, promising results supporting the clinical value of QFR in guiding revascularization and predicting outcomes for ACS patients have been published. Conclusions: Angiography-based QFR bears the potential of a wider adoption of coronary physiology assessment in the ACS setting due to its quicker and less-invasive nature. However, the current evidence mainly derived from retrospective studies or post-hoc analyses of prospective trials. Future studies are needed to further explore the benefits of QFR-guided revascularization on outcomes in ACS.

Exploration of the Crucial Genes and Molecular Mechanisms Mediating Atherosclerosis and Abnormal Endothelial Shear Stress.

Background: Abnormal endothelial shear stress (ESS) is a significant risk factor for atherosclerosis (AS); however, the genes and pathways between ESS and AS are poorly understood. Here, we screened hub genes and potential regulatory targets linked to the progression of AS induced by abnormal ESS. Methods: The microarray data of ESS and AS were downloaded from the Gene Expression Omnibus (GEO) database. The coexpression modules related to shear stress and AS were identified with weighted gene coexpression network analysis (WGCNA). Coexpression genes in modules obtained from GSE28829 and GSE160611 were considered as SET1. The results were validated in validation set by differential gene analysis. The limma package in R was used to identify differentially expressed genes (DEGs). The common DEGs of GSE100927 and GSE103672 were regarded as SET2. Next, Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was conducted. Protein-protein interaction (PPI) enrichment analysis was assembled, and hub genes were identified using MCODE and ClueGO in Cytoscape. ROC curve analyses were conducted to assess the ability of common hub genes to distinguish samples of atherosclerotic plaque from normal arterial. The expression of common hub gene was verified in ox-LDL-induced foam cells and GSE41571. Results: We identified three gene modules (the blue, tan, and cyan modules) related to AS and three shear stress-related modules (the brown, red, and pink modules). A total of 129 genes in SET1 and 476 genes in SET2 were identified. CCRL2, LGALS9, and PLCB2 were identified as common hub genes and validated in the GSE100927, GSE28829, and GSE41571. ROC analysis indicates the expression of CCRL2, LGALS9, and PLCB2 could effectively distinguish the atherosclerotic plaque and normal arterial. The expression level of CCRL2, LGALS9, and PLCB2 increases with the accumulation of lipid increased. Conclusion: We identified CCRL2, LGALS9, and PLCB2 as key genes associated with abnormal ESS and AS and may provide potential prevention and treatment target of AS induced by abnormal ESS.

Mechanism of homocysteine-mediated endothelial injury and its consequences for atherosclerosis.

Homocysteine (Hcy) is an intermediate amino acid formed during the conversion from methionine to cysteine. When the fasting plasma Hcy level is higher than 15 µmol/L, it is considered as hyperhomocysteinemia (HHcy). The vascular endothelium is an important barrier to vascular homeostasis, and its impairment is the initiation of atherosclerosis (AS). HHcy is an important risk factor for AS, which can promote the development of AS and the occurrence of cardiovascular events, and Hcy damage to the endothelium is considered to play a very important role. However, the mechanism by which Hcy damages the endothelium is still not fully understood. This review summarizes the mechanism of Hcy-induced endothelial injury and the treatment methods to alleviate the Hcy induced endothelial dysfunction, in order to provide new thoughts for the diagnosis and treatment of Hcy-induced endothelial injury and subsequent AS-related diseases.

Single-Cell RNA Sequencing of Peripheral Blood Mononuclear Cells From Acute Myocardial Infarction.

Background: Acute myocardial infarction (AMI) can occur in patients with atherosclerotic disease, with or without plaque rupture. Previous studies have indicated a set of immune responses to plaque rupture. However, the specific circulating immune cell subsets that mediate inflammatory plaque rupture remain elusive. Methods: Ten AMI patients were enrolled in our study (five with and five without plaque rupture; plaque characteristics were identified by optical coherence tomography). By single-cell RNA sequencing, we analyzed the transcriptomic profile of peripheral blood mononuclear cells. Results: We identified 27 cell clusters among 82,550 cells, including monocytes, T cells, NK cells, B cells, megakaryocytes, and CD34+ cells. Classical and non-classical monocytes constitute the major inflammatory cell types, and pro-inflammatory genes such as CCL5, TLR7, and CX3CR1 were significantly upregulated in patients with plaque rupture, while the neutrophil activation and degranulation genes FPR2, MMP9, and CLEC4D were significantly expressed in the intermediate monocytes derived from patients without plaque rupture. We also found that CD4+ effector T cells may contribute to plaque rupture by producing a range of cytokines and inflammatory-related chemokines, while CD8+ effector T cells express more effector molecules in patients without plaque rupture, such as GZMB, GNLY, and PRF1, which may contribute to the progress of plaque erosion. Additionally, NK and B cells played a significant role in activating inflammatory cells and promoting chemokine production in the plaque rupture. Cell-cell communication elaborated characteristics in signaling pathways dominated by inflammatory activation of classical monocytes in patients with plaque rupture. Conclusions: Our studies demonstrate that the circulating immune cells of patients with plaque rupture exhibit highly pro-inflammatory characteristics, while plaque erosion is mainly associated with intermediate monocyte amplification, neutrophil activation, and degranulation. These findings may provide novel targets for the precise treatment of patients with AMI.