Combined risk estimates of diabetes and coronary angiography-derived index of microcirculatory resistance in patients with non-ST elevation myocardial infarction.

BACKGROUND: Diabetes mellitus (DM) and coronary microvascular dysfunction (CMD) increase the risk of adverse cardiac events in patients with non-ST-segment elevation myocardial infarction (NSTEMI). This study aimed to evaluate the combined risk estimates of DM and CMD, assessed by the angiography-derived index of microcirculatory resistance (angio-IMR), in patients with NSTEMI. METHODS: A total of 2212 patients with NSTEMI who underwent successful percutaneous coronary intervention (PCI) were retrospectively enrolled from three centers. The primary outcome was a composite of cardiac death or readmission for heart failure at a 2-year follow-up. RESULTS: Post-PCI angio-IMR did not significantly differ between the DM group and the non-DM group (20.13 [17.91-22.70] vs. 20.19 [18.14-22.77], P = 0.530). DM patients exhibited a notably higher risk of cardiac death or readmission for heart failure at 2 years compared to non-DM patients (9.5% vs. 5.4%, P < 0.001). NSTEMI patients with both DM and CMD experienced the highest cumulative incidence of cardiac death or readmission for heart failure at 2 years (24.0%, P < 0.001). The combination of DM and CMD in NSTEMI patients were identified as the most powerful independent predictor for cardiac death or readmission for heart failure at 2 years (adjusted HR: 7.894, [95% CI, 4.251-14.659], p < 0.001). CONCLUSIONS: In patients with NSTEMI, the combination of DM and CMD is an independent predictor of cardiac death or readmission for heart failure. Angio-IMR could be used as an additional evaluation tool for the management of NSTEMI patients with DM. TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov ; Unique identifier: NCT05696379.

Prognostic Value of Coronary Angiography-Derived Index of Microcirculatory Resistance in Non-ST-Segment Elevation Myocardial Infarction Patients.

BACKGROUND: The index of microcirculatory resistance is a reliable measure for evaluating coronary microvasculature, but its prognostic value in patients with non-ST-segment elevation myocardial infarction (NSTEMI) remains unclear. OBJECTIVES: This study aimed to evaluate the prognostic impact of post-percutaneous coronary intervention (PCI) angiography-derived index of microcirculatory resistance (angio-IMR) in patients with NSTEMI. METHODS: The culprit vessel's angio-IMR was measured after PCI in 2,212 NSTEMI patients at 3 sites. The primary endpoint was 2-year major adverse cardiac events (MACEs), defined as a composite of cardiac death, readmission for heart failure, myocardial reinfarction, and target vessel revascularization. RESULTS: The mean post-PCI angio-IMR was 20.63 ± 4.17 in NSTEMI patients. Two hundred six patients were categorized as the high post-PCI angio-IMR group according to maximally selected log-rank statistics. Patients with angio-IMR >25 showed a higher rate of MACEs than those with angio-IMR ≤25 (32.52% vs 9.37%; P < 0.001). Post-PCI angio-IMR >25 was an independent predictor of MACEs (HR: 4.230; 95% CI: 3.151-5.679; P < 0.001) and showed incremental prognostic value compared with conventional risk factors (AUC: 0.774 vs 0.716; P < 0.001; net reclassification index: 0.317; P < 0.001; integrated discrimination improvement: 0.075; P < 0.001). CONCLUSIONS: In patients undergoing PCI for NSTEMI, an increased post-PCI angio-IMR is associated with a higher risk of MACEs. The addition of post-PCI angio-IMR into conventional risk factors significantly improves the ability to reclassify patients and estimate the risk of MACEs. (Angiograph-Derived Index of Microcirculatory Resistance in Patients With Acute Myocardial Infarction; NCT05696379).

LncRNA MIR4697HG Alleviates Endothelial Cell Injury and Atherosclerosis Progression in Mice via the FUS/ANXA5 Axis.

Atherosclerosis (AS) manifests with arterial intimal injury, lipid deposition and chronic inflammation, which is a key pathogenic cause of cardio-cerebrovascular disorders. LncRNA MIR4697HG was downregulated in human advanced atherosclerotic plaques. This study probed the precise biological functions and downstream regulatory mechanisms of MIR4697HG during AS progression. MIR4697HG levels in atherosclerotic plaque tissues and normal arterial intima were measured by RT-qPCR. An injury model of human umbilical vein endothelial cells (HUVECs) was induced through treating with oxidative low-density lipoprotein (ox-LDL). MIR4697HG overexpression plasmids (pcDNA-MIR4697HG) was transfected into ox-LDL-treated HUVECs, and then cell viability, apoptosis, reactive oxygen species (ROS) level, oxidative stress marker protein malondialdehyde (MDA) level and superoxide dismutase (SOD) activity, and adhesion molecule intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) levels in HUVECs were determined. Moreover, the binding between MIR4697HG and fused in sarcoma (FUS) was checked with RNA pull-down assay. The interaction between FUS and annexin A5 (ANXA5) was gauged with Co-immunoprecipitation. Then MIR4697HG/FUS/ANXA5 axis mediated HUVEC functions were accessed with rescue experiments. Additionally, an AS model was established via feeding a high-fat diet for ApoE-/- mice, and lentivirus MIR4697HG overexpression vector (Lv-MIR4697HG) was injected into AS mice followed by detection of atherosclerotic plaque area in mice. MIR4697HG was downregulated in atherosclerotic plaque tissues and HUVECs stimulated by ox-LDL. MIR4697HG overexpression attenuated ox-LDL-induced HUVEC viability inhibition, apoptosis, oxidative stress and adhesion molecule release. Moreover, MIR4697HG bound with FUS and facilitated FUS expression in HUVECs. FUS knockdown abrogated the functions of lncRNA MIR4697HG overexpression in ox-LDL induced HUVEC injury. Besides, FUS could bind with ANXA5. FUS overexpression inhibited ox-LDL induced HUVEC injury, while ANXA5 knockdown reversed these effects. Additionally, Lv-MIR4697HG reduced atherosclerotic plaque area in ApoE-/- mice. LncRNA MIR4697HG mitigated ox-LDL-induced apoptosis, oxidative stress and adhesion molecule release in HUVECs and alleviated AS progression in mice through the FUS/ANXA5 axis.

Homeobox A9 is a novel mediator of vascular smooth muscle cell phenotypic switching and proliferation by regulating methyl-CpG binding protein 2.

Aberrant proliferation and phenotypic switching of vascular smooth muscle cells (VSMCs) are considered to be the main pathological processes of atherosclerotic plaque formation. Methyl-CpG binding protein 2 (MECP2) affects cell differentiation via modulating VSMC-specific gene expression and acts as a driver for the development of atherosclerosis (AS). Here, we aimed to elucidate the role of homeobox A9 (HOXA9) on aberrant VSMCs upon injury or AS, and whether HOXA9-mediated VSMC injury was associated with MECP2. Adeno-associated virus serotype 8-mediated knockdown of HOXA9 rescued aortic pathological injury of apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat diet (HFD), characterized by the reduction of lipid accumulation and foam cell formation. Further in vitro evidence suggested that proliferation and migration of primary mouse VSMCs (mVSMCs) stimulated by oxidized low-density lipoprotein (ox-LDL) were inhibited after HOXA9 silencing. In addition, HOXA9 silencing blocked VSMC phenotypic switching from contractile to a pathological synthetic state. HOXA9 overexpression caused opposite alterations in ox-LDL-stimulated mVSMCs. Mechanistically, MECP2 was transcriptionally activated by HOXA9. Forced expression of MECP2 impaired the anti-proliferation, anti-migration, and phenotypic switching abilities of HOXA9 silencing in VSMCs upon ox-LDL stimulation. Collectively, our findings reveal that the role of HOXA9 in pathological vascular remodeling may attribute to transcriptional regulation of MECP2.

New R2-CHA2DS2-VASc score predicts no-reflow phenomenon and long-term prognosis in patients with ST-segment elevation myocardial infarction after primary percutaneous coronary intervention.

Aims: Evaluating the prognostic validity of new R2-CHA2DS2-VASc score for no-reflow phenomena and long-term prognosis in patients following primary percutaneous coronary intervention (PCI) with ST-elevation myocardial infarction (STEMI). Materials and methods: From January 2017 to December 2018, a total of 401 patients with STEMI were continuously enrolled. According to the cut-off value, the patients were separated into two groups: R2-CHA2DS2-VASc < 3 group (n = 275) and R2-CHA2DS2-VASc ≥ 3 group (n = 126). Results: With a sensitivity of 52.6% and a specificity of 73.1%, the optimal cut-off value for predicting no-reflow is R2-CHA2DS2-VASc ≥ 3. R2-CHA2DS2-VASc ≥ 3 as the ideal cut-off value for predicting major adverse cardiovascular events (MACE) with an area under the curve (AUC) of 0.781 [95% Confidence interval (CI): 0.738-0.801, P 0.001], a sensitivity of 50%, and a specificity of 91.1%. The incidence of MACE, death from all causes, and worsening heart failure was greater in the R2-CHA2DS2-VASc ≥ 3 group, although there was no significant difference in the incidence of repeated revascularisation procedures following PCI between the two groups. R2-CHA2DS2-VASc ≥ 3 was also an independent predictor of MACE (hazard ratio = 2.48, 95% confidence interval CI: 1.33-4.62, P = 0.04). Moreover, this score has a greater sensitivity (66.7%) and specificity (88.7%) for predicting the progression of heart failure. Conclusion: R2-CHA2DS2-VASc ≥ 3 was independently associated with no-reflow phenomenon and poor clinical outcomes for patients in STEMI after primary PCI.

Increased risk of adverse cardiovascular events by strict glycemic control after percutaneous coronary intervention (HbA1c < 6.5% at 2 years) in type 2 diabetes mellitus combined with acute coronary syndrome: a 5-years follow-up study.

OBJECTIVE: This study assessed the association between HbA1c level measured 2 years after percutaneous coronary intervention (PCI) and long-term clinical outcomes in type 2 diabetes mellitus combined with acute coronary syndrome (ACS) who underwent PCI. METHODS: This prospective observational study analyzed 2877 ACS patients with type 2 diabetes mellitus whose baseline HbA1c ≥ 7.0% and underwent PCI. All patients were divided into 6 groups according to the HbA1c level at 2 years after PCI. The clinical outcome was major adverse cardiovascular events (MACEs), defined as all-cause death, all myocardial infarction, any revascularization, congestive heart failure, ischemic stroke. The median follow-up duration was 4.1 years. RESULTS: All 2877 patients were divided into 6 groups: 2-year after PCI HbA1c < 6.0% (n = 219), 6.0-6.5% (n = 348), 6.5-7.0% (n = 882), 7.0-7.5% (n = 567), 7.5-8.0% (n = 441), ≥8.0% (n = 420). The 5-year incidence rate of MACEs in HbA1c <6.0% and 6.0-6.5% groups were similar to 7.5-8.0% and ≥8.0% groups, which were significantly higher than in 6.5-7.0% and 7.0-7.5% groups (p = .044). The cumulative incidence rate of MACEs significantly differed among the groups (p = .046). Multivariate Cox regression analysis revealed a U-shaped relationship between 2-year HbA1c level after PCI and risk of MACEs. 2-year HbA1c <6.5% after PCI was an independent risk factor for MACEs in type 2 diabetes mellitus combined with ACS who underwent PCI (p < .001). CONCLUSIONS: The findings indicated an increased risk of MACEs by strict glycemic control after PCI (2-year HbA1c < 6.5% after PCI) in type 2 diabetes mellitus combined with ACS who underwent PCI.

CircMAPK1 promotes the proliferation and migration of vascular smooth muscle cells through miR-22-3p/ methyl-CpG binding protein 2 axis.

BACKGROUND AND AIMS: Atherosclerosis is a chronic inflammatory disease. The proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to intimal hyperplasia. CircRNAs are class of endogenous RNA and implicated in the various biological processes. However, the role of circRNAs in atherosclerosis remains largely unknown. METHODS AND RESULTS: Mice models of atherosclerosis were established using APOE-/- mice fed with high-fat diet. High-throughput sequencing was performed to profile the expression of circRNAs in atherosclerosis. A total of 1289 circRNAs were identified. Six circRNAs were up-regulated and 12 circRNAs were down-regulated in the atherosclerotic plaque tissues. Then we focused on circMAPK1, which showed a high level in atherosclerosis. Silencing circMAPK1 suppressed the proliferation and migration of VSMCs. Further study showed that circMAPK1 bound with miR-22-3p. CircMAPK1 silencing increased the level of miR-22-3p and suppressed the level of MECP2, a known target of miR-22-3p. Interestingly, suppression of miR-22-3p rescued the effect of circMAPK1 silencing on the proliferation and migration of VSMCs. CONCLUSION: CircMPAK1 promoted the proliferation and migration of VSMCs through miR-22-3p/MECP2 axis. Our study revealed the role of circMAPK1 in atherosclerosis and shed lights on the treatment of atherosclerosis.

The value of fragmented QRS in predicting the prognosis of chronic total occlusion patients with myocardial infarction history undergoing percutaneous coronary intervention: A 24-months follow-up study.

BACKGROUND: Fragmented QRS (fQRS) is a marker of local myocardial scar. This study aimed to analyze the relationship between fQRS and coronary collateral circulation (CCC) and evaluate the predictive value of fQRS for long-term clinical outcomes among patients with chronic total occlusion (CTO) and prior myocardial infarction (MI) who underwent percutaneous coronary intervention (PCI). METHODS: A total of 862 patients with a definite history of MI who had one CTO coronary artery and underwent PCI between 2013 and 2018 were continuously analyzed. Patients were divided into group A (no Q wave and fQRS, n = 206), group B (fQRS, n = 265), group C (Q wave, n = 391). All patients were followed up for 2 years. RESULTS: The incidence rate of major adverse cardiovascular events (MACE) in group B was significantly lower than in group C (group B vs. C: 7.2% vs. 11.3%, P = 0.043). The percentage of good CCC was 94.2%, 88.3%, and 82.9% in group A, B, and C (p < .001), respectively. The improvement of cardiac function in group B and A were more significant than in group C. Multivariate Cox regression analysis showed fQRS was an independent protective factor of MACE after PCI within 2 years in CTO patients with prior MI (RR = 0.668, 95% CI [0.422-0.917], p = .001). CONCLUSION: fQRS is an independent protective factor of prognosis in patients with prior MI and one CTO vessel who underwent PCI, presenting with a higher rate of good CCC, less occurrence of MACE, and better heart function than in Q wave patients.

Secular trends of hypertension prevalence based on 2017 ACC/AHA and 2018 Chinese hypertension guidelines: Results from CHNS data (1991-2015).

This study aimed to assess the impact of the 2017 American College of Cardiology and American Heart Association (ACC/AHA) guideline and the 2018 Chinese hypertension guidelines on the different secular trends for hypertension prevalence. A total of 82 665 eligible individuals aged ≥20 years were selected from nine cross-sectional study periods (1991-2015) from the China Health and Nutrition Survey (CHNS). Over the 24-year period, the long-term trend for the prevalence of the 2017 ACC/AHA-defined age-adjusted hypertension showed an increase from 32.2% (95% confidence interval (CI): 31.0%-33.3%) in 1991 to 60.0% (95% CI: 58.6%-61.3%) in 2015 (Ptrend  < 0.001). According to the 2018 Chinese guideline for hypertension, the weighted hypertension prevalence increased from 10.0% (95% CI: 9.4%-10.5%) in 1991 to 28.7% (95% CI: 27.9%-29.6%) in 2015 (Ptrend  < 0.001). However, slopes of increasing prevalence of hypertension were significantly greater according to the 2017 ACC/AHA guideline than that based on Joint National Committee (JNC 7) report (ß = 1.00% vs ß = 0.67% per year, respectively, P = 0.041). Based on the 2017 ACC/AHA definition, the prevalence of stage 1 hypertension and elevated blood pressure significantly increase from 22.3% and 6.9% in 1991 to 31.2% and 10.1% in 2015 (all P < 0.05), respectively. The secular trend for the prevalence of hypertension according to the 2017 ACC/AHA guideline showed a greater rate of increase compared with the prevalence based on the 2018 Chinese hypertension guidelines. Public health initiatives should focus on the current status of hypertension in China because of the possible high prevalence of hypertension and concomitant vascular risks.

Crush is superior to Culotte in two-stent strategy for treatment of left main coronary artery bifurcations: A systematic review and meta-analysis.

PURPOSE: Crush and Culotte techniques have been used increasingly to treat patients with complex unprotected left main coronary artery bifurcation lesions. This article compares published data on these two techniques. METHODS: Databases, including PubMed, Embase, Cochrane Library, Wanfang Data and China National Knowledge Infrastructure, were searched for articles published before Aug 21, 2019 to identify all relevant studies on left main coronary artery bifurcation lesions treated by Crush versus Culotte techniques. The pooled data were analyzed using either fixed- or random-effects model depending on heterogeneity (assessed via the I2 index). The endpoints were major adverse cardiac events, target lesion revascularization, cardiac death, stent thrombosis, myocardial infarction and target vessel revascularization. RESULTS: Eight articles with a total of 1,283 patients were included, and 710 patients were treated with Crush, and 573 ones with Culotte. Crush group was trend to decreased major adverse cardiac event compared with Culotte group [Relative ratio (RR) 0.63,95% confidence interval(CI) 0.39-1.04, I2 =72.7%], mainly driven by decreased cardiac death [RR 0.49, 95% CI(0.25-0.99), I2 =0%], decreased myocardial infarction [RR 0.40, 95% CI(0.21-0.76), I2 =21.6%],and lower stent thrombosis [RR 0.39, 95% CI(0.16-0.98), I2 =39.4%]. There was no significant difference in target lesion revascularization and target vessel revascularization between Crush and Culotte [RR 0.77, 95% CI 0.46-1.28, I2=61.1%; RR 0.78, 95% CI (0.30-2.02), I2 =73.1%, respectively]. CONCLUSION: Crush was superior to Culotte for treatment of left main coronary artery bifurcation lesions with a trend of lower incidence of long-term major adverse cardiac events, mainly derived from decreased myocardial infarction, stent thrombosis and cardiac death.

Non-ST-elevated myocardial infarction with "N" wave on electrocardiogram and culprit vessel in left circumflex has a risk equivalent to ST-elevated myocardial infarction.

BACKGROUND: It was found that delayed activation wave often appeared in terminal QRS wave in non-ST-elevated myocardial infarction (NSTEMI) with culprit vessel in left circumflex artery (LCX), yet little is known about the similarities among non-"N"-wave non-ST-elevated myocardial infarction (N-NSTEMI) and ST-elevated myocardial infarction (STEMI). HYPOTHESIS: In AMI patients with the culprit vessel in LCX, "N" wave NSTEMI has a risk equivalent to STEMI. METHODS: All 874 patients admitted to Shenjing Hospital of China Medical University between January 1, 2013 and December 30, 2017 were included and whose coronary angiography (CAG) indicated the culprit vessel in LCX. Patients were divided into three groups: ST-elevated myocardial infarction group (STEMI group, n = 322), "N" wave non-ST-elevated myocardial infarction group (N-NSTEMI group, n = 232) and non-"N"-wave NSTEMI group (non N-NSTEMI group, n = 320). The basic data and the incidence of MACE during hospitalization and 12 months were analyzed. RESULTS: In STEMI and N-NSTEMI groups, AST, CK, CK-MB, TnI, and stenosis severity were significantly higher than non N-NSTEMI (P < .05). The lesions in the N-NSTEMI and STEMI groups were more often located proximal LCX before giving rise to OM1 of LCX (P < .05), however, the non N-NSTEMI group was often located distal LCX after giving rise to OM1 and the OM1 (P < .05). The incidence rates of all MACEs, all-cause death, ST, TVR, and rUAP were similar in N-NSTEMI and STEMI groups, which were greater than non N-NSTEMI (P < .05). Both N-NSTEMI and STEMI are independent risk factors for MACE (P < .05). CONCLUSION: The basic data and the incidence of major adverse cardiac event were similar in N-NSTEMI and STEMI patients, N-NSTEMI has a risk equivalent to acute STEMI.

Prevalence and Predictors of Contrast-Induced Nephropathy (CIN) in Patients with ST-Segment Elevation Myocardial Infarction (STEMI) Undergoing Percutaneous Coronary Intervention (PCI): A Meta-Analysis.

BACKGROUND: Contrast-induced nephropathy (CIN) becomes more and more frequent after percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). There have been no reported meta-analyses to determine the role of these risk factors in predicting CIN in patients with STEMI undergoing PCI. So we made this meta-analysis to summarize the incidence of CIN in patients with STEMI undergoing PCI and to study associations between CIN and several risk factors that are mentioned in most prevention guidelines. HYPOTHESIS: The overall incidence of CIN in patients with STEMI undergoing PCI is not low. Many risk factors could influence the occurrence of CIN, such as hypertension, diabetes mellitus (DM), and lower estimated glomerular filtration rate. METHODS: Databases, including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Chinese BioMedical (CBM), were searched for articles published before May 21, 2019, to identify all relevant studies on CIN. The pooled data were analyzed using either fixed-effects or random-effects models depending on heterogeneity (assessed via the I 2 index). RESULTS: Twelve articles encompassing a total of 6342 patients were included. The overall pooled CIN incidence was 13.3% (95% CI: 10.4-17.1). The forest plots showed positive associations between CIN and the presence of hypertension, diabetes mellitus, history of prior myocardial infarction, age, damaged left anterior descending artery, Killip class ≥2, decreased left ventricular ejection fraction, lower estimated glomerular filtration rate, and left ventricular ejection fraction <40%; the odds ratios for these factors were 1.85 (95% CI: 1.57-2.18; p < 0.00001), 1.83 (95% CI: 1.47-2.29; p < 0.00001), 2.14 (95% CI: 1.46-3.14; p < 0.0001), 7.79 (95% CI: 5.24-10.34; p < 0.00001), 1.92 (95% CI: 1.15-3.22; p=0.01), 3.12 (95% CI: 2.21-4.40; p < 0.00001), -6.15 (95% CI: -9.52 to -2.79; p=0.0003), -15.06 (95% CI: -24.75 to -5.36; p=0.002), and 5.53 (95% CI: 1.10-27.95; p=0.04), respectively. CONCLUSION: The overall incidence of CIN in patients with STEMI undergoing PCI was not low and was closely associated with hypertension, diabetes mellitus, history of prior myocardial infarction, age, damaged left anterior descending artery, Killip class ≥2, decreased left ventricular ejection fraction, lower estimated glomerular filtration rate, and left ventricular ejection fraction <40%.

MicroRNA-126-3p Attenuates Intracerebral Hemorrhage-Induced Blood-Brain Barrier Disruption by Regulating VCAM-1 Expression.

BACKGROUND: miR-126 is closely related to the occurrence of various complications after intracerebral hemorrhage (ICH), but the molecular mechanism is not fully elucidated. This study aimed to explore the mechanism of miR-126-3p in alleviating brain injury after ICH. METHODS: Serum miR-126-3p levels were compared between patients with IHC and healthy controls. A rat model of ICH was generated by intracerebral injection of Type VII collagenase. The rats were intracerebral injected with miR-126-3p mimics or negative control miRNA. Rat brain microvascular endothelial cells (BMECs) were used as a cell model of blood-brain barrier (BBB), and validated by immunofluorescence staining of Factor VIII. The BBB permeability of BMECs after miR-126-3p antagomir transfection was determined by FITC-dextran 20 through a confluent BMECs layer (measured over 120 min). The binding site of miR-126-3p in the 3'UTR of VCAM-1 was predicated by TargetScan, and verified by dual luciferase reporter assay. The expression levels of miR-126-3p and vascular cell adhesion molecule-1 (VCAM-1) in rat brain tissues and BMECs were measured by real-time PCR or western blotting. RESULTS: Serum miR-126-3p level was markedly down-regulated in patients with ICH. The rats with ICH had decreased miR-126-3p levels in serum and hemorrhagic area, while those changes were reversed by the treatment with miR-126-3p mimic. VCAM-1 is a direct target of miR-126-3p, and VCAM-1 expression in hemorrhagic area was down-regulated by the administration of miR-126-3p mimic in rats. Inhibition of miR-126-3p by anti-miR126 treatment in BMECs resulted in barrier leakage. CONCLUSION: miR-126-3p attenuates intracerebral hemorrhage-induced blood-brain barrier disruption, which is associated with down-regulated expression of VCAM-1 in hemorrhagic area.

Artemisinin inhibits tumour necrosis factor-α-induced vascular smooth muscle cell proliferation in vitro and attenuates balloon injury-induced neointima formation in rats.

The aim of this study was to evaluate the effect of artemisinin (ART) on rat vascular smooth muscle cell (VSMC) proliferation induced by tumour necrosis factor (TNF)-α, cell cycle arrest, and apoptosis, and its effect on neointima formation after balloon injury of rat carotid artery. Primary rat VSMC were identified by immunofluorescence assay. The proliferation of VSMC induced by TNF-α was significantly inhibited by ART treatment in a dose-dependent manner. Treatment with 100-µM ART significantly reduced the expression of proliferating cell nuclear antigen. In contrast, the same treatment arrested the cell cycle in G0/G1 phase. Western blot analysis showed that the cell cycle-related proteins cyclin D1, cyclin E, cyclin-dependent kinase 2, and cyclin-dependent kinase 4 were downregulated by ART in TNF-α-stimulated VSMC. For apoptosis induced by ART, cleaved caspase-3/-9 was detected, and the pro-apoptotic protein Bcl-2-associated X protein was upregulated while the anti-apoptotic protein Bcl-2 was downregulated. The results suggest that ART can effectively inhibit the proliferation of VSMC induced by TNF-α through the apoptotic induction pathway and cell cycle arrest. Also, balloon injury indicated that ART significantly inhibited neointima formation in the rat carotid arteries.

Artemisinin inhibits the proliferation, migration, and inflammatory reaction induced by tumor necrosis factor-α in vascular smooth muscle cells through nuclear factor kappa B pathway.

BACKGROUND: Atherosclerosis is an inflammatory disease with the most common pathologic process leading to cardiovascular diseases. The aim of this study was to evaluate the effect of artemisinin (ART) on the proliferation, migration, and inflammation induced by tumor necrosis factor-α (TNF-α) of rat vascular smooth muscle cells (VSMCs). MATERIALS AND METHODS: Primary rat VSMCs were pretreated with ART and then co-incubated with TNF-α. Cell proliferation was evaluated by MTT assay. Cell migration was assessed by transwell assay. Reactive oxygen species (ROS) production was measured by flow cytometry after staining with dichloro-dihydro-fluorescein diacetate. Inflammation factors of nitric oxide and prostaglandin E2 (PGE2) were measured by responding assay kits. Expression levels of nuclear factor kappa B (NF-κB) subunit NF-κB p65 and the regulator inhibitor of nuclear factor kappa-B kinase-alpha (IκBα) were tested by Western blot, meanwhile, the activation of NF-κB was observed by immunofluorescence assay. RESULTS: The proliferation, migration, and inflammation of VSMCs induced by TNF-α were significantly inhibited by ART treatment in a dose-dependent manner. Treatment with 100 µM ART for 2 h significantly reduced the expression of proliferating cell nuclear antigen and migration-related proteins matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). On the other hand, the same treatment decreased the inflammation factors production of nitric oxide and PGE2. Fluorescence-activated cell sorting analysis revealed that ART suppressed the ROS production induced by TNF-α. Western blot analysis showed that both inflammation mediators inducible nitric oxide synthase and cyclooxygenase and the NF-κB pathway subunit NF-κB p65 were downregulated by ART. CONCLUSIONS: The results suggest that ART can effectively inhibit the proliferation, migration, and inflammation of VSMCs induced by TNF-α through ROS-mediated NF-κB signal pathway.

The delayed activation wave in non-ST-elevation myocardial infarction.

BACKGROUND: Little is known about the relationship between the electrocardiographic characteristics and the infarct related artery (IRA) in non-ST-elevation myocardial infarction (NSTEMI). We found a curious phenomenon in electrocardiograms of patients with acute occlusion of left circumflex artery in NSTEM: A notch or deflection was often present in the terminal QRS complex in leads II,III and aVF or I,aVL . The objective of this study was to determine whether the previously unreported ECG phenomenon that we have found in NSTEMI could identify the culprit artery in non-ST-elevation myocardial infarction. METHODS AND RESULTS: Our study included 218 NSTEMI patients who presented to our institution and underwent coronary angiography within 24 hours of admission. For convenience, 'N' wave was defined as a notch or deflection in the terminal QRS complex of the surface ECG. The duration of QRS with N wave before PCI was more prolonged than the duration of QRS without N wave (121 ± 12 ms vs 106 ± 11 ms, P<0.01). In the LCX group, 66(77%) patients had N wave in leads II, III and aVF, whereas only 5(6%) patients in the LAD group and 9(18%) patients in the RCA group had such ECG feature (P<0.001). A greater proportion of patients in the LCX group also had N waves in leads I and aVL (P<0.001). N wave in leads II, III and aVF was associated with 77% sensitivity and 89% specificity, respectively. N wave in leads I and aVL was associated with 64% sensitivity and 96% specificity, respectively. CONCLUSION: The abnormal waveform in terminal QRS complex in NSTEMI ,which is described above, is the delayed activation wave of left ventricular basal region which the left circumflex artery supplies. It is associated with a higher specificity and higher sensitivity for culprit LCX in non-ST-elevation myocardial infarction. The delayed activation wave is a new pattern of ischemia in ECG.

[Protective effects of hypoxia-inducible factor-1 alpha on myocardial ischemia/reperfusion injury in rat and the role of protein kinase C in signal pathway].

OBJECTIVE: To study the expression of hypoxia-inducible factor-1 alpha (HIF-1 alpha) in a rat model of myocardial ischemia/reperfusion injury (IRI) and the role of protein kinase C (PKC) in signal pathway. METHODS: A rat model of myocardial IRI was reproduced by 30 minutes of left anterior descending coronary artery (LCA) occlusion followed by 180 minutes of reperfusion. Thirty-two healthy male Wistar rats were randomly divided into four groups. The first group was ischemic preconditioning (IPC) group; the second group was simple IRI group; the third group was IPC plus PKC inhibitor group (IPC+I group); the fourth group was the sham-operation group without ligation of LCA. Eight rats were used in each group. The heart was harvested 180 minutes post-reperfusion, the mRNA and protein expression of HIF-1 alpha and heme oxygenase-1 (HO-1) were assessed. Meanwhile, the protein expression of caspase-3 was assayed. Blood samples were obtained from heart to determine the levels of interleukin-8 (IL-8) and myeloperoxidase (MPO). RESULTS: The mRNA and protein expression of HIF-1 alpha and HO-1 increased significantly in the IRI group compared with the sham-operation group, while the protein expression of caspase-3 increased significantly in the IRI group (HIF-1 alpha mRNA: 0.849+/-0.032 vs. 0.356+/-0.022, HIF-1 alpha protein: 0.762+/-0.042 vs. 0.324+/-0.016, HO-1 mRNA: 0.862+/-0.045 vs. 0.332+/-0.012, HO-1 protein: 0.792+/-0.044 vs. 0.335+/-0.031, caspase-3 protein: 0.371+/-0.015 vs. 0.061+/-0.012, respectively, all P<0.01). The levels of IL-8 and MPO increased significantly in the IRI group [IL-8: (812+/-26) ng/L vs. (72+/-13) ng/L, MPO: (78.7+/-2.9) kU/L vs. (13.3+/-1.5) kU/L, both P<0.01]. The protein and mRNA expression of HIF-1 alpha and HO-1 increased significantly in the IPC group compared with IRI group (HIF-1 alpha mRNA: 1.412+/-0.039, HIF-1 alpha protein: 1.362+/-0.045, HO-1 mRNA: 1.523+/-0.038, HO-1 protein: 1.420+/-0.041, respectively), meanwhile the protein expression of caspase-3 (0.129+/-0.019) decreased significantly in the IPC group (all P<0.01). The levels of IL-8 [(432+/-59) ng/L] and MPO [(43.2+/-5.9) kU/L] decreased significantly in the IPC group compared with IRI group (both P<0.01). All above parameters showed no significant change between IPC+I group and IRI group. CONCLUSION: HIF-1 alpha plays a protective role in myocardial IRI, PKC is an important signal pathway of HIF-1 alpha gene expression in IRI.