Longitudinal Variations in Th and Treg Cells Before and After Percutaneous Coronary Intervention, and Their Intercorrelations and Prognostic Value in Acute Syndrome Patients.

T helper (Th) and regulatory T (Treg) cells regulate atherosclerosis, plaque, inflammation to involve in acute coronary syndrome (ACS). The current study aimed to investigate the clinical implications of Th and Treg cells in ACS patients receiving percutaneous coronary intervention (PCI). Blood Th1, Th2, Th17 and Treg cells were detected in 160 ACS patients before PCI, after PCI, at 1 month (M). Short physical performance battery (SPPB) at M1/M3 and major adverse cardiac event (MACE) during follow-ups were evaluated. Th1 and Th17 both showed upward trends during PCI, then greatly declined at M1 (P < 0.001). Th2 exhibited an upward trend during PCI but decreased slightly at M1 (P < 0.001). Treg remained stable during PCI but elevated at M1 (P < 0.001). Moreover, a positive correlation between Th1 and Th17, a negative correlation between Th17 and Treg, were discovered at several timepoints (most P < 0.050). Interestingly, the receiver operating curve (ROC) analyses revealed that Th1 [area under curve (AUC) between 0.633-0.645] and Th17 (AUC between 0.626-0.699) exhibited values estimating SPPB score <= 6 points at M1 or M3 to some extent. Importantly, Th1 (AUC between 0.708-0.710), Th17 (AUC between 0.694-0.783), and Treg (AUC between 0.706-0.729) predicted MACE risk. Multivariate models involving Th and Treg cells along with other characteristics revealed acceptable values estimating SPPB score <= 6 points at M1 or M3 (AUC between 0.690-0.813), and good values predicting MACE risk (AUC between 0.830-0.971). Dynamic variations in Th and Treg cells can predict the prognosis of ACS patients receiving PCI.

JNK Pathway-Associated Phosphatase Deficiency Facilitates Atherosclerotic Progression by Inducing T-Helper 1 and 17 Polarization and Inflammation in an ERK- and NF-κB Pathway-Dependent Manner.

AIM: JNK pathway-associated phosphatase (JKAP) regulates T cell-mediated immunity and inflammation, which are involved in atherosclerosis pathogenesis. This study investigated the effects of JKAP on T-helper (Th) cell polarization, inflammation, and atherosclerotic progression. METHODS: Serum JKAP levels were measured in 30 patients with coronary heart disease (CHD) and 30 controls. CHD blood naïve CD4＋ T cells were acquired, followed by JKAP overexpression and knockdown with or without treatment with PD98059 (ERK inhibitor) or BAY-11-7082 (NF-κB inhibitor) in vitro. CD4＋ T-cell conditional JKAP ablation mice were established in vivo, followed by the construction of an atherosclerosis model. RESULTS: JKAP was reduced and negatively correlated with the Gensini score, CRP, Th1 cells, Th17 cells, and proinflammatory cytokines in patients with CHD. In vitro, JKAP overexpression suppressed Th1 and Th17 cell differentiation and proinflammatory cytokines, whereas JKAP knockdown exerted the opposite effect; however, JKAP modification did not affect Th2 cell differentiation. Interestingly, JKAP negatively regulated the ERK and NF-κB pathways; meanwhile, the PD98059 and BAY-11-7082 treatments repressed Th1 and Th17 cell differentiation, and attenuated the effect of JKAP knockdown on these indices. In vivo, conditional CD4＋ T-cell JKAP ablation increased Th1 and Th17 cell polarization in the spleen, lymph node, blood, and/or aortic root. Furthermore, CD4＋ T-cell conditional JKAP ablation exaggerated atherosclerotic lesions in the aorta, elevated CD4+ cell infiltration and proinflammatory cytokines in the aortic root, and activated the ERK and NF-κB pathways in the aortic root. CONCLUSION: JKAP ablation facilitates atherosclerosis progression by promoting Th1 and 17 polarization and inflammation through regulation of the ERK and NF-κB pathways.

WTAP-MEDIATED M6A MODIFICATION OF KLF6 AGGRAVATES HYPOXIA/REOXYGENATION-INDUCED HUMAN CARDIOMYOCYTE INJURY.

ABSTRACT: Background: Myocardial infarction (MI) is a severe condition that typically results from the ischemia and necrosis of heart muscle. Kruppel-like factor 6 (KLF6) can aggravate myocardial ischemia/reperfusion injury. This work aims to reveal its role and mechanism in hypoxia/reoxygenation (H/R)-induced cardiomyocyte injury. Methods: Human cardiomyocyte (AC16) was exposed to hypoxic treatment to mimic MI-like cell injury. mRNA expression levels of KLF6 and WT1-associated protein (WTAP) were detected by quantitative real-time polymerase chain reaction. Protein expression was detected by western blotting assay. Cell viability was assessed by CCK-8 assay. Cell apoptosis and cell cycle were investigated by flow cytometry. Enzyme-linked immunosorbent assays were conducted to detect IL-1ß, TNF-α and IL-6 levels. Fe 2+ colorimetric assay kit was used to detect Fe 2+ level. MDA Content Assay Kit was used to detect MDA level. Cellular ROS Assay kit was applied to assess ROS level. The association of KLF6 and WTAP was identified by RNA immunoprecipitation assay and dual-luciferase reporter assay. Results: KLF6 and WTAP expression at mRNA and protein levels were significantly upregulated in serum samples of MI patients and H/R-induced AC16 cells when compared with control groups. KLF6 silencing attenuated H/R-induced AC16 cell apoptosis, inflammatory response, oxidative stress, and ferroptosis. Additionally, WTAP stabilized KLF6 mRNA by regulating its m6A modification. Furthermore, WTAP knockdown rescued H/R-induced AC16 cell apoptosis, inflammatory response, oxidative stress, and ferroptosis by decreasing KLF6 expression. Conclusion: WTAP-mediated m6A modification of KLF6 aggravated hypoxia/reoxygenation-induced apoptosis, inflammatory response, oxidative stress, and ferroptosis of human cardiomyocytes, providing a therapeutic strategy for MI.

Impact of post-dilatation on post-procedural physiology, microcirculatory resistance, and target vessel failure in STEMI patients undergoing PPCI: A single-center experience.

BACKGROUND: Suboptimal stent deployment is frequently observed in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PPCI). This study sought to investigate whether these patients could benefit from post-dilatation with respect to post-procedural physiology, microcirculatory resistance, and long-term clinical outcomes. METHODS: This was a retrospective study of consecutive STEMI patients who underwent successful stent implantation during PPCI from February 2016 to November 2021. Post-procedural physiology and microcirculatory resistance were assessed by Murray law-based quantitative flow ratio (µQFR) and angiographic microcirculatory resistance (AMR), respectively. The primary outcome was target vessel failure (TVF), a composite of cardiac death, target vessel-oriented myocardial infarction, and clinically driven target vessel revascularization. RESULTS: A total of 671 patients (671 culprit vessels) were included. Post-dilatation was selectively performed in 430 (64.1%) culprit vessels, resulting in a 0.02 (interquartile range: 0.00-0.05, p < 0.001) increase in post-procedural µQFR but no significant impact on AMR. During a median follow-up of 2.8 years (interquartile range: 1.4-3.0 years), TVF occurred in 47 (7.0%) patients. Post-dilatation demonstrated a trend toward a reduction in TVF (5.3% vs. 10.0%; adjusted hazard ratio: 0.60, 95% confidence interval: 0.33-1.09, p = 0.094), mainly driven by a lower incidence of clinically driven target vessel revascularization (1.6% vs. 4.1%; adjusted hazard ratio: 0.32, 95% confidence interval: 0.11-0.90, p = 0.030). CONCLUSIONS: In STEMI patients undergoing PPCI, selective post-dilatation was associated with improved post-procedural physiological results and a trend toward less TVF events without aggravating microcirculatory resistance.

Effects of C-reactive protein on K(+) channel interaction protein 2 in cardiomyocytes.

Several studies have found that C-reactive protein (CRP) was associated with QTc interval prolongation and ventricular arrhythmia. However, little is known about the mechanisms involved. K(+) channel interaction protein 2 (KChIP2) is a necessary subunit for the formation of transient outward potassium current (Ito.f) which plays a critical role in early repolarization and QTc interval of heart. In this study, we aimed to evaluate the effects of CRP on KChIP2 and Ito.f in cardiomyocytes and to explore the potential mechanism. The neonatal mice ventricular cardiomyocytes were cultured and treated with CRP at different concentrations. The expression of KChIP2 was detected by real time quantitative PCR and Western blot. In addition, Ito.f current density was evaluated by whole cell patch clamp techniques. Our results showed that CRP significantly decreased the mRNA and protein expression of KChIP2 in time and doses dependent manners (P < 0.05), and also reduced the current density of Ito.f (P < 0.05). In addition, CRP increased the expression of NF-κB and decreased IκBα expression without significant influence on the expression of ERK1/2 and JNK. Meanwhile, the NF-κB inhibitor PDTC significantly attenuated the effects of CRP on KChIP2 and Ito.f current density. In conclusion, CRP could significantly down-regulate KChIP2 expression and reduce current density of Ito.f partly through NF-κB pathway, suggesting that CRP may directly or indirectly influence QTc interval and arrhythmia via influencing KChIP2 expression and Ito.f current density of cardiomyocytes.

Epicardial adipose tissue: the accomplice implicated in the genesis and maintenance of atrial fibrillation.

OBJECTIVE: The purpose of this review was to delineate our current knowledge of the close relationship between the abundance of epicardial adipose tissue (EAT) and the risk of all major cardiovascular disease, especially atrial fibrillation (AF). DATA SOURCES: The data analyzed in this review were mainly from articles reported in PubMed published from 1972 to 2014. STUDY SELECTION: Original articles and critical reviews relevant to EAT and AF were selected. RESULTS: EAT, a particular form of metabolically active visceral fat deposited around the heart, is being regarded as an important independent predictor of cardio-metabolic diseases. EAT is composed of smaller adipocytes than other visceral fat depots and functioned like brown adipose tissue (BAT) to protect adjacent tissues. Improving the understanding of EAT in AF genesis and maintenance may contribute to prevent AF and reduce the complications associated with AF. CONCLUSION: The findings suggest that EAT associates with AF severity and the recurrence of AF after catheter ablation even after adjustment for AF risk factors, but the precise mechanisms are not fully elucidated.