Association between the cumulative triglyceride-glucose index and the recurrence of atrial fibrillation after radiofrequency catheter ablation.

BACKGROUND: Triglyceride-glucose (TyG) index values are a new surrogate marker for insulin resistance. This study aimed to explore the relationship between cumulative TyG index values and atrial fibrillation (AF) recurrence after radiofrequency catheter ablation (RFCA). METHODS: A total of 576 patients with AF who underwent RFCA at the Second Affiliated Hospital of Xi'an Jiaotong University were included in this study. The participants were grouped based on cumulative TyG index values tertiles within 3 months after ablation. Cox regression and restricted cubic spline analyses were used to determine the relationship between cumulative TyG index values and AF recurrence. The predictive value of all risk factors was assessed by receiver operating curve analysis. RESULTS: There were 375 patients completed the study (age: 63.23 ± 10.73 years, 64.27% male). The risk of AF recurrence increased with increasing cumulative TyG index values tertiles. After adjusting for potential confounders, patients in the medium cumulative TyG index group [hazard ratio (HR) = 4.949, 95% CI: 1.778-13.778, P = 0.002] and the high cumulative TyG index group (HR = 8.716, 95% CI: 3.371-22.536, P < 0.001) had a higher risk of AF recurrence than those in the low cumulative TyG index group. The restricted cubic spline regression model also showed an increased risk of AF recurrence with increasing cumulative TyG index values. When considering cumulative TyG index values, left atrial diameter, and lactate dehydrogenase levels as a comprehensive factor, the model could effectively predict AF recurrence after RFCA [area under the curve (AUC) = 0.847, 95% CI: 0.797-0.897, P < 0.001]. CONCLUSIONS: Cumulative TyG index values were a risk factor for AF recurrence after RFCA. Monitoring longitudinal TyG index values may assist with optimized for risk stratification and outcome prediction for AF recurrence.

Effects of monocyte-endothelium interactions on the expression of type IV collagenases in monocytes.

The adhesion of monocytes to endothelial cells is one of the early stages in the development of atherosclerosis. The expression of type IV collagenases, which include matrix metalloproteinase (MMP)-2 and MMP-9, in monocytes is hypothesized to play an important role in monocyte infiltration and transformation into foam cells. The aim of the present study was to examine the effects of monocyte-endothelium interactions on the expression levels of type IV collagenases and their specific inhibitors in monocytes, and to investigate the roles of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß in this process. Monocytes were single-cultured or co-cultured with endothelial cells. The expression of the type IV collagenases, MMP-2 and MMP-9, and their specific inhibitors, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2, in monocytes was determined by immunohistochemistry followed by image analysis. The expression levels of MMP-2 and MMP-9 were found to be low in the single-culture monocytes, but increased significantly when the monocytes and endothelial cells were co-cultured. However, treatment with monoclonal TNF-α or IL-1ß antibodies partially inhibited the upregulated expression of MMP-2 and MMP-9 in the co-cultured monocytes. Expression of TIMP-1 and TIMP-2 was observed in the single monocyte culture, and a small increase in the expression levels was observed when the monocytes were co-cultured with endothelial cells. Therefore, monocyte-endothlium interactions were shown to increase the expression of type IV collagenases in monocytes, resulting in the loss of balance between MMP-2 and -9 with TIMP-1 and -2. In addition, TNF-α and IL-1ß were demonstrated to play important roles in this process.

Combination of mean platelet volume and the GRACE risk score better predicts future cardiovascular events in patients with acute coronary syndrome.

Both the Global Registry of Acute Coronary Events (GRACE) risk score and mean platelet volume (MPV) can independently predict adverse cardiovascular disease (CVD) events in patients with acute coronary syndrome (ACS). This study was aimed at investigating whether MPV was related to the GRACE risk score and whether the combination of them could have a better performance in predicting CVD in Patients with ACS. Totally 297 ACS patients were included. MPV was measured on admission. The GRACE risk score was calculated and its predictive value alone and together with MPV was assessed, respectively. During a median period of 52 months (range, 6 to 65), 11 of the 297 subjects (3.7%) were lost to follow-up, and 132 (46.2%) had adverse CVD including 32 deaths. Both MPV and the GRACE score were higher in patients with CVD events than those without events, and the GRACE score increased with the increase of MPV. Multivariate Cox analysis demonstrated that both MPV and the GRACE score were significant and independent predictors for CVD events (HR: 1.13; 95% CI: 1.10 to 1.15; p = 0.006; HR: 1.30; 95% CI: 1.24 to 1.37; p < 0.001; respectively). The area under the ROC curve was 0.70 (95% CI: 0.64 to 0.76, p < 0.001) when the GRACE score was calculated alone, whereas it increased to 0.85 (95% CI: 0.81 to 0.90, p < 0.001) with the addition of MPV, indicating that the combination of MPV with the scoring system improved the predictive value. This study demonstrates for the first time that MPV is positively associated with the GRACE risk score and it may complement the scoring system in predicting CVD events in patients with ACS.

PI3K/AKT signaling pathway plays a role in enhancement of eNOS activity by recombinant human angiotensin converting enzyme 2 in human umbilical vein endothelial cells.

The aim of this study was to investigate the effect of PI3K/AKT signaling pathway in the activity of recombinant human angiotensin converting enzyme 2 (rhACE2) promoted the activity of endothelial nitric oxide synthase (eNOS). The human umbilical vein endothelial cells (HUVEC) were cultured in vitro. Then treated with Ang II (1×10(-6) mol/L) for 24 h. The rhACE2 (100 µmol/L) was added and incubated for 5, 10, 15, 30, 60 min respectively which was based on Ang II intervention. The effect of rhACE2 on phosphorylation eNOS level was also observed in the presence of LY294002 (10 µmol/L) (PI3K/AKT inhibitors). Griess reagent method was applied to measure NO contents in cell culture supernatant, RT-PCR to detect the expression of eNOSmRNA in HUVEC, and Western blot to detect the expression of eNOS and phosphorylated eNOS. In Ang II intervention group, NO contents were significantly lower than control group (P < 0.05). Through rhACE2 treatment, the NO contents in cell culture medium and the expression level of phosphorylated eNOS were significantly higher than in Ang II intervention group (P < 0.05), but eNOSmRNA and non-phosphorylated eNOS protein expression level showed no significant difference (P > 0.05). After HUVEC was intervened by PI3K/AKT pathway inhibitor LY294002, the expression level of phosphorylated eNOS was significantly lower than that in the rhACE2 30 min treatment group (P < 0.05). rhACE2 may reduce the activity of Ang II inhibited endothelial cell eNOS, which can be blocked by PI3K/AKT pathway inhibitor LY294002, suggesting PI3K/AKT signaling pathway plays an important role in rhACE2's promotion of the activity of endothelial cell eNOS.

Protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling pathway plays a major role in reactive oxygen species (ROS)-mediated endoplasmic reticulum stress-induced apoptosis in diabetic cardiomyopathy.

BACKGROUND: Endoplasmic reticulum (ER) stress is considered one of the mechanisms contributing to reactive oxygen species (ROS)-mediated cell apoptosis. In diabetic cardiomyopathy (DCM), cell apoptosis is generally accepted as the etiological factor and closely related to cardiac ROS generation. ER stress is proposed the link between ROS and cell apoptosis; however, the signaling pathways and their roles in participating ER stress-induced apoptosis in DCM are still unclear. METHODS: In this study, we investigated the signaling transductions in ROS-dependent ER stress-induced cardiomocyte apoptosis in animal model of DCM. Moreover, in order to clarify the roles of IRE1 (inositol-requiring enzyme-1), PERK (protein kinase RNA (PKR)-like ER kinase) and ATF6 (activating transcription factor-6) in conducting apoptotic signal in ROS- dependent ER stress-induced cardiomocyte apoptosis, we further investigated apoptosis in high-glucose incubated cardiomyocytes with IRE1, ATF6 and PERK-knocked down respectively. RESULTS: we demonstrated that the ER stress sensors, referred as PERK, IRE1 and ATF6, were activated in ROS-mediated ER stress-induced cell apoptosis in rat model of DCM which was characterized by cardiac pump and electrical dysfunctions. The deletion of PERK in myocytes exhibited stronger protective effect against apoptosis induced by high-glucose incubation than deletion of ATF6 or IRE in the same myocytes. By subcellular fractionation, rather than ATF6 and IRE1, in primary cardiomyocytes, PERK was found a component of MAMs (mitochondria-associated endoplasmic reticulum membranes) which was the functional and physical contact site between ER and mitochondria. CONCLUSIONS: ROS-stimulated activation of PERK signaling pathway takes the major responsibility rather than IRE1 or ATF6 signaling pathways in ROS-medicated ER stress-induced myocyte apoptosis in DCM.

High glucose promotes intracellular lipid accumulation in vascular smooth muscle cells by impairing cholesterol influx and efflux balance.

AIMS: High glucose promotes macrophage-derived foam cell formation involved in increased influx or reduced efflux of lipids. The aim of this study is to investigate the influence of hyperglycaemia on foam cell transformation of vascular smooth muscle cells (VSMCs) and possible mechanisms contributing to these effects. METHODS AND RESULTS: The results showed that high glucose increased the expression of CD36, a regulator of lipid influx, and suppressed the expression and activity of the adenosine triphosphate-binding cassette (ABC) transporter ABCG1, a regulator of cholesterol efflux to high-density lipoprotein, in a dose- and time-dependent manner. However, cholesterol efflux to lipid-free apoAI was not impaired. VSMCs exposed to high glucose readily developed into lipid-loaded cells, as demonstrated by Oil Red O staining and cholesterol content analysis. In addition, high glucose-induced down-regulation of ABCG1 was reversed by nuclear factor-kappaB (NF-kappaB) inhibitors BAY 11-7085 and tosyl-phenylalanine chloromethyl ketone and by the antioxidant N-acetyl-L-cysteine (NAC). This reversal was accompanied by reduced cellular lipid content. Also, NAC and NF-kappaB inhibitors can effectively block the high glucose-induced activity of NF-kappaB binding to DNA and/or peroxide production. CONCLUSION: These results suggested that hyperglycaemia-induced foam cell formation in VSMCs was related to the imbalanced lipid flux by increasing CD36-mediated modified low-density lipoprotein uptake and reducing ABCG1-regulated cellular cholesterol efflux. Moreover, this effect was associated with increased oxidative stress and activated NF-kappaB pathway signalling.

[High glucose suppresses ABCG1 expression by increasing oxidative stress and inducing nuclear factor-kappaB activation in vascular smooth muscle cells].

OBJECTIVE: To investigate the role of high glucose in the expression of ATP-binding cassette (ABC) transporters A1 (ABCA1) and G1 (ABCG1) in human vascular smooth muscle cells (VSMCs) and its possible mechanisms. METHODS: VSMCs were incubated in the presence of glucose at the concentrations ranging from 5 to 30 mmol/L for 1 to 7 days, and real-time PCR and Western blotting were used to measure the mRNA and protein expressions of ABCA1 and ABCG1. The effects of cells pretreatment with antioxidant NAC (10 mmol/L) and nuclear factor-kappaB (NF-kappaB) inhibitors BAY 11-7085 (10 micromol/L) and TPCK (10 micromol/L) were also tested on ABCA1 and ABCG1 expressions. RESULTS: High glucose suppressed, in a time- and dose-dependent manner, ABCG1 expression in incubated human VSMCs, and this effect was abolished by pretreatment with the antioxidant and nuclear factor-kappaB (NF-kappaB) inhibitors, but ABCA1 expression was not significantly decreased in the presence of high glucose. CONCLUSION: High glucose suppresses ABCG1 expression in human VSMCs possibly due to increased oxidative stress and NF-kappaB activation induced by high glucose.