Heng Ge

Retinoid X receptor agonists inhibit phorbol-12-myristate-13-acetate (PMA)-induced differentiation of monocytic THP-1 cells into macrophages

Monocyte/macrophage differentiation is an essential process during atherosclerosis development. The retinoid X receptor (RXR) is a member of the nuclear hormone receptor superfamily, which plays an important regulatory role in many metabolic disorders, including atherosclerosis. The purpose of this study was to investigate the effect of RXR agonist on monocyte/macrophage differentiation in vitro. The THP-1 cell line was differentiated into a macrophage-like phenotype by incubation with phorbol-12-myristate-13-acetate (PMA) in the presence or absence of RXR agonist. The viability of adherent differentiated THP-1 cells was determined by MTT assay. Macrophage surface marker CD11b and CD36 was analyzed by flow cytometry. Phagocytosis was measured by fluorescence-labeled latex beads. The production of Cytokine Tunlornecrosisfactor-α (TNF-α), Interlaken-12p70 (IL-12p70), and Matrix metalloproteinase-9 (MMP-9), each of which was analyzed by ELISA. In the presence of the RXR agonists 9-cis retinoic acid or SR11237, PMA-induced THP-1 cells became less adherent, showed decreased macrophage-like morphological changes, decreased cell surface antigen CD11b and CD36 expression, and down regulated the phagocytosis of latex beads and the production of TNF-α and MMP-9. These data suggest that RXR agonists inhibit PMA-induced THP-1 cell differentiation into macrophage-like cells, which may be helpful in understanding the anti-atherosclerotic effect of RXR and its agonists.

Functional relevance of protein glycosylation to the pro-inflammatory effects of extracellular matrix metalloproteinase inducer (EMMPRIN) on monocytes/macrophages.

Background and Objective Extracellular matrix metalloproteinase inducer (EMMPRIN) is an important pro-inflammatory protein involved in the cellular functions of monocytes/macrophages. We have hypothesized that high-level heterogeneousness of protein glycosylation of EMMPRIN may have functional relevance to its biological effects and affect the inflammatory activity of monocytes/macrophages. Methods The glycosylation patterns of EMMPRIN expressed by monocytes/macrophages (THP-1 cells) in response to different extracellular stimuli were observed, and the structures of different glycosylation forms were identified. After the purification of highly- and less-glycosylated proteins respectively, the impacts of different glycosylation forms on the pro-inflammatory effects of EMMPRIN were examined in various aspects, such as cell adhesion to endothelial cells, cell migrations, cytokine expression, and activation of inflammatory signalling pathway. Results 1) It was mainly the highly-glycosylated form of EMMPRIN (HG-EMMPRIN) that increased after being exposed to inflammatory signals (PMA and H2O2). 2) Glycosylation of EMMPRIN in monocytes/macrophages led to N-linked-glycans being added to the protein, with the HG form containing complex-type glycans and the less-glycosylated form (LG) the simple type. 3) Only the HG-EMMPRIN but not the LG-EMMPRIN exhibited pro-inflammatory effects and stimulated inflammatory activities of the monocytes/macrophages (i.e., activation of ERK1/2 and NF-κB pathway, enhanced monocyte-endothelium adhesion, cell migration and matrix metalloproteinase -9 expression). Conclusions Post-transcriptional glycosylation represents an important mechanism that determines the biological effects of EMMPRIN in monocytes/macrophages. Glycosylation of EMMPRIN may serve as a potential target for regulating the inflammatory activities of monocytes/macrophages.

Effect of glucagon-like peptide-1 on major cardiovascular outcomes in patients with type 2 diabetes mellitus: A meta-analysis of randomized controlled trials.

The effect of glucagon-like peptide-1 (GLP-1) treatment in patients with type 2 diabetes mellitus (T2DM) remains controversial. The purpose of this study was to compare the effect of GLP-1 and placebo/conventional antidiabetic agents on cardiovascular risk in T2DM patients. PubMed, EmBase and the Cochrane Library were searched to identify its eligible studies as well as manual searches for the reliability of this study. All eligible trials were performed in T2DM patients who received GLP-1 therapy or placebo/conventional antidiabetic agents. The reported outcomes included major cardiovascular events (MACE), and total mortality. Of 490 identified studies, we included 13 trials reporting data on 11,943 T2DM patients. Overall, the pooled results suggested that GLP-1 therapy has no or little effect on MACE (RR: 0.99; 95% CI: 0.88-1.12; P=0.872) and total mortality (RR: 0.90; 95% CI: 0.70-1.15; P=0.399). Furthermore, sensitivity analysis indicated that GLP-1 was associated with lower incidence of total mortality (RR: 0.28; 95% CI: 0.08-0.93; P=0.037). We concluded that GLP-1 therapy was not associated with MACE and total mortality compared with placebo or antidiabetic agents.

Therapeutic effect of statin on aortic stenosis: a review with meta-analysis

Background:  Aortic stenosis (AS) is a common progressive disease. Statins have been hypothesized to delay its progression via pleiotropic mechanisms. However, results of clinical trials focusing on statin therapy in AS patients have been controversial.

Efficacy and safety of drug-eluting stent implantation for the treatment of in-stent restenosis occurring within bare-metal stent and drug-eluting stent.

ObjectiveAlthough drug-eluting stent (DES) implantation is the primary treatment modality for bare-metal stent (BMS) in-stent restenosis (ISR), little is known about the efficacy and safety profile of DES in the treatment of DES-ISR. The goal of this study was to compare the clinical outcomes following DES treatment for BMS-ISR and DES-ISR.MethodsRates of major adverse cardiac events (MACE) were compared in 97 consecutive patients who underwent DES implantation for the treatment of ISR (56 BMS-ISR and 41 DES-ISR) from January 2004 to December 2008.ResultsBaseline clinical and procedural characteristics were comparable, except that the DES used in the BMS-ISR group was longer and had a larger diameter. The length of follow-up was (28.60±1.96) and (20.34±1.54) months for the BMS-ISR and DES-ISR groups, respectively. One patient (1.8%) experienced non-cardiac mortality and one (1.8%) had target-vessel revascularization (TVR) in the BMS-ISR group. In the DES-ISR group, three patients (7.3%) died of sudden death with a documented acute ST-segment elevation myocardial infarction, and three suffered TVR (7.3%). Kaplan-Meier analysis indicated that cumulative survival probability and MACE-free probability were both significantly lower for the DES-ISR group (log rank test P=0.047 and P=0.005, respectively). In Cox regression analysis, DES-ISR remained an independent predictor for future MACE occurrence after adjustment for other factors (compared with BMS-ISR, risk ratio (RR)=8.743, 95% confidence interval (CI) 1.54–49.54, P=0.014). Switching to a different type of DES to treat DES-ISR did not improve the prognosis.ConclusionDES-ISR patients had a poorer prognosis than BMS-ISR patients after DES therapy.

Efficacy and Safety of a Pharmaco-Invasive Strategy With Half-Dose Alteplase Versus Primary Angioplasty in ST-Segment–Elevation Myocardial Infarction: EARLY-MYO Trial (Early Routine Catheterization After Alteplase Fibrinolysis Versus Primary PCI in Acute ST-Segment–Elevation Myocardial Infarction)

Background: Timely primary percutaneous coronary intervention (PPCI) cannot be offered to all patients with ST-segment–elevation myocardial infarction (STEMI). Pharmaco-invasive (PhI) strategy has been proposed as a valuable alternative for eligible patients with STEMI. We conducted a randomized study to compare the efficacy and safety of a PhI strategy with half-dose fibrinolytic regimen versus PPCI in patients with STEMI. Methods: The EARLY-MYO trial (Early Routine Catheterization After Alteplase Fibrinolysis Versus Primary PCI in Acute ST-Segment–Elevation Myocardial Infarction) was an investigator-initiated, prospective, multicenter, randomized, noninferiority trial comparing a PhI strategy with half-dose alteplase versus PPCI in patients with STEMI 18 to 75 years of age presenting ⩽6 hours after symptom onset but with an expected PCI-related delay. The primary end point of the study was complete epicardial and myocardial reperfusion after PCI, defined as thrombolysis in myocardial infarction flow grade 3, thrombolysis in myocardial infarction myocardial perfusion grade 3, and ST-segment resolution ≥70%. We also measured infarct size and left ventricular ejection fraction with cardiac magnetic resonance and recorded 30-day clinical and safety outcomes. Results: A total of 344 patients from 7 centers were randomized to PhI (n=171) or PPCI (n=173). PhI was noninferior (and even superior) to PPCI for the primary end point (34.2% versus 22.8%, P noninferiority<0.05, Psuperiority=0.022), with no significant differences in the frequency of the individual components of the combined end point: thrombolysis in myocardial infarction flow 3 (91.3% versus 89.2%, P=0.580), thrombolysis in myocardial infarction myocardial perfusion grade 3 (65.8% versus 62.9%, P=0.730), and ST-segment resolution ≥70% (50.9% versus 45.5%, P=0.377). Infarct size (23.3%±11.3% versus 25.8%±13.7%, P=0.101) and left ventricular ejection fraction (52.2%±11.0% versus 51.4%±12.0%, P=0.562) were similar in both groups. No significant differences occurred in 30-day rates of total death (0.6% versus 1.2%, P=1.0), reinfarction (0.6% versus 0.6%, P=1.0), heart failure (13.5% versus 16.2%, P=0.545), major bleeding events (0.6% versus 0%, P=0.497), or intracranial hemorrhage (0% versus 0%), but minor bleeding (26.9% versus 11.0%, P<0.001) was observed more often in the PhI group. Conclusions: For patients with STEMI presenting ⩽6 hours after symptom onset and with an expected PCI-related delay, a PhI strategy with half-dose alteplase and timely PCI offers more complete epicardial and myocardial reperfusion when compared with PPCI. Adequately powered trials with this reperfusion strategy to assess clinical and safety outcomes are warranted. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01930682.

Frame counting improves the assessment of post-reperfusion microvascular patency by TIMI myocardial perfusion grade: Evidence from cardiac magnetic resonance imaging

BACKGROUND Quantitative modification of TIMI myocardial perfusion grade (TMPG) by the method of frame counting may improve its sensitivity and the false negative rate for post-reperfusion microvascular dysfunction (MVD) in ST segment-elevated myocardial infarction (STEMI) patients. METHODS The durations of contrast-washout from infarction area of 139 patients were measured by counting the cine-frame numbers between the appearance and disappearance of myocardial blush. The achieved new index, TMP Frame Counting (TMP-FC) was referenced by cardiac magnetic resonance, by which MVD was defined as microvascular obstruction on gadolinium late-enhancement imaging. RESULTS Median TMP-FC differed significantly between patients with and without MVD (126 frames, IQR 105-160 vs. 86 frames, IQR 75-100, p<0.001). By receiver-operating characteristic analysis, the cutoff of TMP-FC at ≥ 95.5 frames represented an independent predictor of MVD (OR=11.61, p<0.001). TMP-FC had similar specificity (75%) and positive predictive value (88%), but significantly improved sensitivity (85.3%) and negative predictive value (70.2%) for MVD compared with TMPG (88.6%, 86.5%, 33.7% and 38.2%, respectively) and other traditional angiographic assessments, leading to a better overall accuracy (area under the curve: 0.801 compared with 0.612 from TMPG, p<0.001) for the evaluation of microvascular patency. TMP-FC was positively correlated with MVD extent (r=0.5, p<0.001). Abnormal TMP-FC was associated with larger infarction size (28.67 ± 13.72% vs. 16.51 ± 10.68% of left ventricular mass, p<0.001) and lower LVEF (49.37 ± 11.06% vs. 56.84 ± 9.72%, p<0.001). CONCLUSION Frame counting can improve the accuracy of TMPG for MVD. Moreover, TMP-FC is correlated with the degree of MVD and cardiac detriments, which is useful for risk stratification.

Impact of Early ST-Segment Changes on Cardiac Magnetic Resonance-Verified Intramyocardial Haemorrhage and Microvascular Obstruction in ST-Elevation Myocardial Infarction Patients.

AbstractThe aim of this study was to explore the significance of different ST-segment changes before and after percutaneous coronary intervention (PCI), in relation to cardiac magnetic resonance (CMR)-verified microvascular obstruction (MVO) along with intramyocardial hemorrhage (IMH) in ST-elevation myocardial infarction (STEMI) patients.This study enrolled 108 STEMI patients who received primary PCI and had no contraindication of CMR investigation. Sum ST-segment elevation (STE), maximal STE on admission and sum ST-segment resolution (STR), and single-lead STR and residual STE at 60 minutes after primary PCI were assessed. MVO and IMH were determined by contrast-enhanced CMR.Patients were classified into 3 groups: 30 patients with MVO(−)/IMH(−), 25 with MVO(+)/IMH(−), and 53 with MVO(+)/IMH(+). Sum STE (P = 0.001), maximal STE (P < 0.001), and residual STE (P = 0.025) were highest and single-lead STR was lowest (P = 0.044) in the MVO(+)/IMH(+) group. Receiver operator characteristics curve analysis revealed that maximal STE was the most powerful factor for distinguishing between MVO(+) and MVO(−) patients (optimal threshold = 0.5 mV, area under the curve, AUC = 0.718, P < 0.001), or IMH(+) and IMH(−) patients (optimal threshold = 0.5 mV, AUC = 0.697, P < 0.001). In multivariate analysis, maximal STE was identified as the most powerful independent predictor of MVO (odds ratio [OR] = 4.30, P < 0.001) and IMH (OR = 2.44, P = 0.001), whereas sum STE was the strongest correlate of both the number of MVO segments (r = 0.42, P < 0.001) and IMH segments (r = 0.43, P < 0.001).The presence of MVO and IMH in infarcted tissue was relevant to ST-segment changes in STEMI patients. Maximal STE was a powerful independent predictor of the presence of MVO and IMH, whereas sum STE was a strong correlate of the number of MVO and IMH segments.

Association between Tissue Characteristics of Coronary Plaque and Distal Embolization after Coronary Intervention in Acute Coronary Syndrome Patients: Insights from a Meta-Analysis of Virtual Histology- Intravascular Ultrasound Studies

Background and Objectives The predictive value of plaque characteristics assessed by virtual histology-intravascular ultrasound (VH-IVUS) including fibrous tissue (FT), fibrofatty (FF), necrotic core (NC) and dense calcium (DC) in identifying distal embolization after percutaneous coronary intervention (PCI) is still controversial. We performed a systematic review and meta-analysis to summarize the association of pre-PCI plaque composition and post-PCI distal embolization in acute coronary syndrome patients. Methods Studies were identified in PubMed, OVID, EMBASE, the Cochrane Library, the Current Controlled Trials Register, reviews, and reference lists of relevant articles. A meta-analysis using both fixed and random effects models with assessment of study heterogeneity and publication bias was performed. Results Of the 388 articles screened, 10 studies with a total of 872 subjects (199 with distal embolization and 673 with normal flow) met the eligibility of our study. Compared with normal flow groups, significant higher absolute volume of NC [weighted mean differences (WMD): 5.79 mm3, 95% CI: 3.02 to 8.55 mm3; p<0.001] and DC (WMD: 2.55 mm3, 95% CI: 0.22 to 4.88 mm3; p = 0.03) were found in acute coronary syndrome patients with distal embolization. Further subgroup analysis demonstrated that the predictive value of tissue characteristics in determining distal embolization was correlated to clinical scenario of the patients, definition of distal embolization, and whether the percutaneous aspiration thrombectomy was applied. Conclusion Our study that pooled current evidence showed that plaque components were closely related to the distal embolization after PCI, especially the absolute volume of NC and DC, supporting further studies with larger sample size and high-methodological quality.

Early resolution of ST-segment elevation after reperfusion therapy for acute myocardial infarction: Its relation to echocardiography-determined left ventricular global and regional function and deformation

AIMS To evaluate the relationships between ST-segment resolution (STR) and echocardiography-determined left ventricular (LV) global and regional function and deformation in the sub-acute phase of STEMI. METHODS AND RESULTS STR, defined as either complete (≥70%) or incomplete (<70%), was evaluated 60minutes after primary percutaneous coronary intervention (PCI) of 84 STEMI patients. Conventional two-dimensional (2D) echocardiography and 2D speckle-tracking echocardiography (STE) were performed at 3-7days after reperfusion. LV deformation [including the infarction-related regional longitudinal (RLS), circumferential (RCS), and radial (RRS) strains, and global longitudinal (GLS), circumferential (GCS), and radial (GRS) strains] was measured by 2D STE. LV segmental function was assessed by wall motion score index (WMSI). Patients in incomplete vs. complete STR groups had higher WMSI (p<0.001); decreased peak amplitude of RLS (p<0.001), RCS (p=0.008), RRS (p=0.002); and decreased peak amplitude of GLS (p<0.001), GCS (p<0.001), GRS (p=0.003). RLS (r=0.27, p=0.015) and GLS (r=0.33, p=0.003) were best correlates of STR at the regional and global level, respectively. CONCLUSIONS STR correlated with global and regional LV function and deformation in patients with sub-acute phase of STEMI after PCI. RLS and GLS were the strongest correlates of STR at the regional and global levels, respectively.