林徐泽
中国医学科学院阜外心血管病医院 特需病房
BACKGROUND:The role of stress hyperglycemia in acute myocardial infarction (AMI) has long been emphasized. Recently, the stress hyperglycemia ratio (SHR), a novel index reflecting an acute glycemia rise, has shown a good predictive value in AMI. However, its prognostic power in myocardial infarction with nonobstructive coronary arteries (MINOCA) remains unclear.METHODS:In a prospective cohort of 1179 patients with MINOCA, relationships between SHR levels and outcomes were analyzed. SHR was defined as acute-to-chronic glycemic ratio using admission blood glucose (ABG) and glycated hemoglobin. The primary endpoint was defined as major adverse cardiovascular events (MACE), including all-cause death, nonfatal MI, stroke, revascularization, and hospitalization for unstable angina or heart failure. Survival analyses and receiver-operating characteristic (ROC) curve analyses were performed.RESULTS:Over the median follow-up of 3.5 years, the incidence of MACE markedly increased with higher SHR tertile levels (8.1%, 14.0%, 20.5%; p < 0.001). At multivariable Cox analysis, elevated SHR was independently associated with an increased risk of MACE (HR 2.30, 95% CI: 1.21-4.38, p = 0.011). Patients with rising tertiles of SHR also had a significantly higher risk of MACE (tertile 1 as reference; tertile 2: HR 1.77, 95% CI: 1.14-2.73, p = 0.010; tertile 3: HR 2.64, 95% CI: 1.75-3.98, p < 0.001). SHR remained a robust predictor of MACE in patients with and without diabetes; whereas ABG was no longer associated with the MACE risk in diabetic patients. SHR showed an area under the curve of 0.63 for MACE prediction. By incorporating SHR to TIMI risk score, the combined model further improved the discrimination for MACE.CONCLUSIONS:The SHR independently confers the cardiovascular risk after MINOCA, and may serve as a better predictor than glycemia at admission alone, particularly in those with diabetes.KEY MESSAGESStress hyperglycemia ratio (SHR) is independently associated with the prognosis in a distinct population with myocardial infarction with nonobstructive coronary arteries (MINOCA).SHR is a better predictor of prognosis than admission glycemia alone, especially in diabetic patients with MINOCA.SHR may serve as a prognostic marker for risk stratification as well as a potential target for tailored glucose-lowering treatment in MINOCA.
Annals of medicine 2023
BACKGROUND:Hyperglycemia frequently induces apoptosis in endothelial cells and ultimately contributes to microvascular dysfunction in patients with diabetes mellitus (DM). Previous research reported that the expression of integrins as well as their ligands was elevated in the diseased vessels of DM patients. However, the association between integrins and hyperglycemia-induced cell death is still unclear. This research was designed to investigate the role played by integrin subunit β5 (ITGB5) in hyperglycemia-induced endothelial cell apoptosis.METHODS:We used leptin receptor knockout (Lepr-KO) ( db / db ) mice as spontaneous diabetes animal model. Selective deletion of ITGB5 in endothelial cell was achieved by injecting vascular targeted adeno-associated virus via tail vein. Besides, we also applied small interfering RNA in vitro to study the mechanism of ITGB5 in regulating high glucose-induced cell apoptosis.RESULTS:ITGB5 and its ligand, fibronectin, were both upregulated after exposure to high glucose in vivo and in vitro . ITGB5 knockdown alleviated hyperglycemia-induced vascular endothelial cell apoptosis and microvascular rarefaction in vivo.In vitro analysis revealed that knockdown of either ITGB5 or fibronectin ameliorated high glucose-induced apoptosis in human umbilical vascular endothelial cells (HUVECs). In addition, knockdown of ITGB5 inhibited fibronectin-induced HUVEC apoptosis, which indicated that the fibronectin-ITGB5 interaction participated in high glucose-induced endothelial cell apoptosis. By using RNA-sequencing technology and bioinformatic analysis, we identified Forkhead Box Protein O1 (FoxO1) as an important downstream target regulated by ITGB5. Moreover, we demonstrated that the excessive macroautophagy induced by high glucose can contribute to HUVEC apoptosis, which was regulated by the ITGB5-FoxO1 axis.CONCLUSION:The study revealed that high glucose-induced endothelial cell apoptosis was positively regulated by ITGB5, which suggested that ITGB5 could potentially be used to predict and treat DM-related vascular complications.
Chinese medical journal 2023
Background Perivascular adipose tissue (PVAT) releases exosomes (EXOs) to regulate vascular homeostasis. PVAT-derived EXOs reduce macrophage foam cell formation, but the underlying molecular mechanism has yet to be fully elucidated. We hypothesize that PVAT release miRNA through EXOs and regulate the expression of cholesterol transporter of macrophages, thereby reducing foam cell formation. Methods and results Through RT-qPCR, we identified that miR-382-5p, which was expressed at lower levels in PVAT-EXOs from coronary atherosclerotic heart disease patients than healthy individuals, was expressed at higher levels in wild-type C57BL/6 J mouse aortic PVAT-EXOs than in subcutaneous adipose tissue-derived EXOs. We explored macrophage lipid accumulation through oil red O staining, assessed cholesterol uptake and efflux, and verified cholesterol transporter expression. We found that transfection with a miR-382-5p inhibitor offset PVAT-EXO-related reductions in macrophage foam cell formation and increases in cholesterol efflux mediated by ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1). In addition, bone morphogenetic protein 4 (BMP4) pretreatment and si-peroxisome proliferator-activated receptor γ (PPARγ) transfection showed that BMP4-PPARγ participated in PVAT-EXO-mediated upregulation of the cholesterol efflux transporters ABCA1 and ABCG1. Conclusions PVAT-EXOs reduce macrophage foam cell formation through miR-382-5p- and BMP4-PPARγ-mediated upregulation of the cholesterol efflux transporters ABCA1 and ABCG1. This finding suggests a promising strategy for the prevention and treatment of atherosclerosis.
Vascular pharmacology 2022
BACKGROUND:Little is known about risk stratification in patients with myocardial infarction with nonobstructive coronary arteries (MINOCA). We investigated whether the age, creatinine, and ejection fraction (ACEF) score (age [years]/ejection fraction [%] + 1 [if creatinine >176 μmol/L]) might predict long-term outcomes after MINOCA.HYPOTHESIS:The ACEF score enables accurate risk prediction in patients with MINOCA.METHODS:A total of 1179 patients with MINOCA were enrolled and divided based on their ACEF score tertile levels. The primary endpoint was a composite of major adverse cardiovascular events (MACE), including all-cause death, nonfatal MI, nonfatal stroke, revascularization, and hospitalization for unstable angina or heart failure. Kaplan-Meier and Cox regression analyses were performed. Discrimination was defined as the area under the curve (AUC) using receiver operating characteristic analysis.RESULTS:During the median follow-up of 41.7 months, patients with MINOCA with higher ACEF score tertiles had a significantly higher incidence of MACE (6.3%, 12.5%, and 23.8%, respectively; p < .001). The adjusted risk of MACE increased with the rising ACEF score tertiles (1st tertile as reference; 2nd tertile: HR 2.70, 95% CI: 1.38-5.29, p = .004; and 3rd tertile: HR 5.35, 95% CI: 2.72-10.51, p < .001). Moreover, an elevated ACEF score was closely associated with an increased risk of MACE overall (HR 4.23, 95% CI: 3.37-5.30, p < .001) and in subgroups (all p < .05). The ACEF score also yielded a good predictive value (AUC 0.79) for MACE.CONCLUSION:Elevated ACEF scores were strongly associated with a poor prognosis after MINOCA. This simple and valid risk score may facilitate risk stratification and decision making in the population with MINOCA.
Clinical cardiology 2021
BACKGROUND:Low triiodothyronine syndrome (LT3S), frequently seen in patients with acute myocardial infarction (AMI), has been regarded as a predictor of poor outcomes after AMI. However, little is known about the prognostic value of LT3S in euthyroid patients with myocardial infarction with nonobstructive coronary arteries (MINOCA).METHODS:A total of 1162 MINOCA patients were enrolled and divided into LT3S and no-LT3S groups. LT3S was defined as decreased free T3 (fT3 < 2.36 pg/mL) with normal values of thyroid-stimulating hormone. The primary endpoint was a composite of major adverse cardiovascular events (MACE), including all-cause death, nonfatal MI, stroke, revascularization, and hospitalization for unstable angina or heart failure. Kaplan-Meier, Cox regression, propensity score matching (PSM), and receiver-operating characteristic analyses were performed.RESULTS:Patients with LT3S (prevalence of 17.5%) had a significantly higher incidence of MACE (19.6% vs. 12.9%; p = .013) than patients without during the median follow-up of 41.7 months. LT3S was closely associated with an increased risk of MACE even after multivariable adjustment (HR 1.50, 95% CI: 1.03-2.18, p = .037). After PSM, 197 pairs of patients with or without LT3S were identified, and LT3S remained a robust risk factor of worse outcomes (HR 1.53, 95% CI: 1.02-2.65, p = .042). Moreover, LT3S had an area under the curve (AUC) of 0.60 for predicting MACE. When adding LT3S to the thrombolysis in myocardial infarction (TIMI) risk score, the combined model yielded a significant improvement in discrimination for MACE.CONCLUSIONS:LT3S was independently associated with poor outcomes after MINOCA. Routine assessment of LT3S may provide valuable prognostic information in this specific population.
Annals of medicine 2021
BACKGROUND Kawasaki disease (KD) is a systemic vasculitis that predominantly occurs in children, but the pathogenesis of KD remains unclear. Here, we explored key genes and underlying mechanisms potentially involved in KD using bioinformatic analyses. MATERIAL AND METHODS The shared differentially expressed genes (DEGs) in KD compared to control samples were identified using the microarray data from the Gene Expression Omnibus Series (GSE) 18606, GSE68004, and GSE73461. Analyses of the functional annotation, protein-protein interaction (PPI) network, microRNA-target DEGs regulatory network, and immune cell infiltration were performed. The expression of hub genes before and after intravenous immunoglobulin (IVIG) treatment in KD was further verified using GSE16797. RESULTS A total of 195 shared DEGs (164 upregulated and 31 downregulated genes) were identified between KD and healthy controls. These shared DEGs were mainly enriched in immune and inflammatory responses. Ten upregulated hub genes (ITGAX, SPI1, LILRB2, MMP9, S100A12, C3AR1, RETN, MAPK14, TLR5, MYD88) and the most significant module were identified in the PPI network. There were 309 regulatory relationships detected within 70 predicted microRNAs and 193 target DEGs. The immune cell infiltration analysis showed that monocytes, neutrophils, activated mast cells, and activated natural killer cells had relatively high proportions and were significantly more infiltrated in KD samples. Six hub genes of ITGAX, LILRB2, C3AR1, MAPK14, TLR5, and MYD88 were markedly downregulated after IVIG treatment for KD. CONCLUSIONS Our study identified the candidate genes and associated molecules that may be related to the KD process, and provided new insights into potential mechanisms and therapeutic targets for KD.
Medical science monitor : international medical journal of experimental and clinical research 2021
BACKGROUND AND AIMS:Triglyceride-glucose (TyG) index has been reported as a novel surrogate marker of insulin resistance and a risk factor in patients with coronary artery disease. We aimed to investigate the prognostic value of TyG index in a distinct entity with myocardial infarction with nonobstructive coronary arteries (MINOCA).METHODS AND RESULTS:A total of 1179 MINOCA patients were recruited and divided according to tertile levels of TyG index. The primary endpoint was a composite of major adverse cardiovascular events (MACE), including all-cause death, reinfarction, stroke, revascularization and hospitalization for unstable angina or heart failure. Kaplan-Meier, Cox regression and receiver-operating characteristic analyses were performed. Patients with higher tertiles of TyG index had a significantly higher incidence of MACE (9.6%, 14.9%, 18.0%; p = 0.003) over the median follow-up of 41.7 months. After multivariate adjustment, elevated TyG index was significantly associated with an increased risk of MACE (HR 1.33, 95% CI: 1.04-1.69, p = 0.020). The adjusted risk of MACE also increased with rising tertiles of TyG index (tertile 1 as reference; tertile 2: HR 1.64, 95% CI: 1.06-2.53, p = 0.025; tertile 3: HR 1.85, 95% CI: 1.17-2.93, p = 0.008). The TyG index remained a robust risk factor in overall and subgroups of MINOCA patients (all p < 0.05). Moreover, the TyG index yielded a moderate predictive value of MACE (area under the curve 0.66, 95% CI:0.61-0.71, p < 0.001).CONCLUSION:Elevated TyG index was independently associated with a poor prognosis after MINOCA. Routine assessment of TyG index may improve risk stratification and facilitate decision making in MINOCA patients.
Nutrition, metabolism, and cardiovascular diseases : NMCD 2021
Background: Accumulating evidence demonstrates that perivascular adipose tissue (PVAT) plays an important role in maintaining vascular homeostasis. The formation of macrophage foam cells is a central feature of atherosclerosis. This study aimed to evaluate the effect of PVAT-derived exosomes (EXOs) on the lipid accumulation of macrophages and verify the anti-atherogenic characteristics of PVAT. Methods and Results: We extracted EXOs from the PVAT and subcutaneous adipose tissue (SCAT) of wild-type C57BL/6J mice. After coincubation, the EXOs were taken up by RAW264.7 cells. Oil Red O staining revealed that macrophage foam cell formation and intracellular lipid accumulation were ameliorated by PVAT-EXOs. Flow cytometry showed that PVAT-EXOs significantly reduced macrophage uptake of fluorescence-labelled oxidised low-density lipoprotein (ox-LDL). In addition, high-density lipoprotein-induced cholesterol efflux was promoted by PVAT-EXOs. Western blot analysis showed the downregulation of macrophage scavenger receptor A and the upregulation of ATP-binding cassette transporter A1 and ATP-binding cassette transporter G1, which could be mediated by the overexpression of peroxisome proliferator-activated receptor γ and was independent of liver X receptor α. Conclusion: Our findings suggest that PVAT-EXOs reduce macrophage foam cell formation by regulating the expression of cholesterol transport proteins, which provides a novel mechanism by which PVAT protects the vasculature from atherosclerosis.
Frontiers in cardiovascular medicine 2021
The association between elevated lipoprotein(a) [Lp(a)] and poor outcomes in coronary artery disease (CAD) has been addressed for decades. However, little is known about the prognostic value of Lp(a) in patients with myocardial infarction with nonobstructive coronary arteries (MINOCA). A total of 1179 patients with MINOCA were enrolled and divided into low, medium, and high Lp(a) groups based on the cut-off value of 10 and 30mg/dL. The primary endpoint was major adverse cardiovascular events (MACE), a composite of all-cause death, nonfatal MI, nonfatal stroke, revascularization, and hospitalization for unstable angina or heart failure. Kaplan-Meier and Cox regression analyses were performed. Accuracy was defined as area under the curve (AUC) using a receiver-operating characteristic analysis. Patients with higher Lp(a) levels had a significantly higher incidence of MACE (9.5%, 14.6%, 18.5%; p = 0.002) during the median follow-up of 41.7 months. The risk of MACE also increased with the rising Lp(a) levels even after multivariate adjustment [low Lp(a) group as reference, medium group: hazard ratio (HR) 1.55, 95% confidence interval (CI): 1.02-2.40, p = 0.047; high group: HR 2.07, 95% CI: 1.32-3.25, p = 0.001]. Further, clinically elevated Lp(a) defined as Lp(a) ≥30 mg/dL was closely associated with an increased risk of MACE in overall and in subgroups (all p <0.05). When adding Lp(a) (AUC 0.61) into the Thrombolysis in Myocardial Infarction (TIMI) score (AUC 0.68), the combined model (AUC 0.73) yielded a significant improvement in discrimination for MACE (ΔAUC 0.05, p = 0.032). In conclusion, elevated Lp(a) was strongly associated with a poor prognosis in patients with MINOCA. Adding Lp(a) to traditional risk score further improved risk prediction. Our data, for the first time, confirmed the Lp(a) as a residual risk factor for MINOCA.
The American journal of cardiology 2021
BACKGROUND:Abnormal glucose metabolism including diabetes (DM) and prediabetes (pre-DM) have been reported as predictors of poorer outcomes after acute myocardial infarction (AMI). However, the prognostic value of pre-DM in patients with myocardial infarction with nonobstructive coronary arteries (MINOCA) remains unclear.METHODS:A total of 1179 MINOCA patients were prospectively recruited and divided into normoglycemia (NG), pre-DM, and DM groups according to glycated hemoglobin (HbA1c) levels or past history. The primary endpoint was a composite of major adverse cardiovascular events (MACE), including all-cause death, nonfatal MI, nonfatal stroke, revascularization and hospitalization for unstable angina or heart failure. Kaplan-Meier and Cox regression analyses were performed.RESULTS:Patients with pre-DM and DM had a significantly higher incidence of MACE compared with NG group (10.8%, 16.1%, 19.4%; p = 0.003) over the median follow-up of 41.7 months. After multivariate adjustment, both pre-DM and DM were significantly associated with an increased risk of MACE (NG as reference; pre-DM: 1.45, 95% CI 1.03-2.09, p = 0.042; DM: HR 1.79, 95% CI 1.20-2.66, p = 0.005). At subgroup analysis, pre-DM remained a robust risk factor of MACE compared to NG. In addition, pre-DM had a similar impact as DM on long-term prognosis in patients with MINOCA.CONCLUSIONS:Pre-DM defined as raised HbA1c was associated with a poor prognosis in patients with MINOCA. Routine assessment of HbA1c enables an early recognition of pre-DM and thus may facilitate risk stratification in this specific population.
Diabetology & metabolic syndrome 2021
