IL-22 produced by Th22 cells aggravates atherosclerosis development in ApoE-/- mice by enhancing DC-induced Th17 cell proliferation.

Th22 cells are a novel subset of CD4+ T cells that primarily mediate biological effects through IL-22, with both Th22 cells and IL-22 being closely associated with multiple autoimmune and chronic inflammatory diseases. In this study, we investigated whether and how Th22 cells affect atherosclerosis. ApoE-/- mice and age-matched C57BL/6J mice were fed a Western diet for 0, 4, 8 or 12 weeks. The results of dynamic analyses showed that Th22 cells, which secrete the majority of IL-22 among the known CD4+ cells, play a major role in atherosclerosis. ApoE-/- mice fed a Western diet for 12 weeks and administered recombinant mouse IL-22 (rIL-22) developed substantially larger plaques in both the aorta and aortic root and higher levels of CD3+ T cells, CD68+ macrophages, collagen, IL-6, Th17 cells, dendritic cells (DCs) and pSTAT3 but lower smooth muscle cell (SMC) α-actin expression than the control mice. Treatment with a neutralizing anti-IL-22 monoclonal antibody (IL-22 mAb) reversed the above effects. Bone marrow-derived DCs exhibited increased differentiation into mature DCs following rIL-22 and ox-LDL stimulation. IL-17 and pSTAT3 were up-regulated after stimulation with IL-22 and ox-LDL in cells cocultured with CD4+ T cells and mature DC supernatant, but this up-regulation was significantly inhibited by IL-6mAb or the cell-permeable STAT3 inhibitor S31-201. Thus, Th22 cell-derived IL-22 aggravates atherosclerosis development through a mechanism that is associated with IL-6/STAT3 activation, DC-induced Th17 cell proliferation and IL-22-stimulated SMC dedifferentiation into a synthetic phenotype.

Downregulation of CD4+LAP+ and CD4+CD25+ regulatory T cells in acute coronary syndromes.

BACKGROUND: Regulatory T (Treg) cells play a protective role in atherosclerosis prone models and are related to the onset of acute coronary syndromes (ACS, including non-ST-elevation ACS (NSTEACS) and ST-elevation acute myocardial infarction (STEAMI)). CD4+LAP+ Treg cells are a novel subset of Tregs that have been found to ameliorate atherosclerosis in ApoE(-/-) mice, and these cells also exist in humans. The present study was designed to investigate whether CD4+LAP+ Treg cells are involved in the onset of ACS. METHODS: The frequencies of CD4+LAP+ and CD4+CD25+ Treg cells were detected using flow cytometric analysis, and the plasma IL-10 and TGF- ß 1 levels were measured using an ELISA in 29 stable angina (SA) patients, 30 NSTEACS patients, 27 STEAMI patients, and a control group (30 cases). RESULTS: The results revealed a significant decrease in the frequencies of CD4+LAP+ and CD4+CD25+ Treg cells and in the levels of IL-10 and TGF- ß 1 in patients with ACS compared with those in the SA and control groups. CONCLUSIONS: The decrease in the frequencies of CD4+LAP+ and CD4+CD25+ Treg cells may play a role in the onset of ACS.

Circulating Th22 and Th9 levels in patients with acute coronary syndrome.

BACKGROUND: CD4+ T helper (Th) cells play critical roles in the development and progression of atherosclerosis and the onset of acute coronary syndromes (ACS, including acute myocardial infarction (AMI) and unstable angina pectoris (UAP)). In addition to Th1, Th2, and Th17 cells, Th22 and Th9 subsets have been identified in humans. In the present study, we investigated whether Th22 cells and Th9 cells are involved in the onset of ACS. METHODS: The frequencies of Th22 and Th9 cells were detected using a flow cytometric analysis and their related cytokine and transcription factor were measured in the AMI, UAP, stable angina pectoris (SAP), and control groups. RESULTS: The results revealed a significant increase in the peripheral Th22 number, AHR expression, and IL-22 levels in patients with ACS compared with those in the SAP and control groups. Although there was no difference in the peripheral Th9 number among the four groups, the PU.1 expression and IL-9 levels were significantly increased in patients with ACS compared with the SAP and control groups. CONCLUSIONS: Circulating Th22 and Th9 type responses may play a potential role in the onset of ACS symptom.

IL-35: a potential target for the treatment of atherosclerosis.

The imbalance of anti- inflammatory/pro-inflammatory cytokines plays an important role in the process of atherosclerosis. IL-35 is an anti-inflammatory cytokine comprising the p35 subunit of IL-12 and the subunit Epstein-Barr virus (EBV) -induced gene 3(EBI3). Accumulating evidence showed that IL-35 up-regulates the expression of anti-inflammatory cytokines, induces the generation of CD4 + regulatory T cells, inhibits CD4 + effector T cells response and other target cells activity, and reduces the progression of inflammatory and autoimmune diseases. In addition, it has been found that Ebi3 and p35 strongly coexpressed in human advanced lesions. Therefore, we hypothesize that IL-35 may become a novel target for the treatment of atherosclerosis. Further studies are required to investigate the precise effect and the signaling pathway of IL-35 in atherosclerosis process.

Efficacy and safety of aranidipine enteric-coated tablets compared with amlodipine in Chinese patients with mild to moderate essential hypertension: a multicenter, randomized, double-blind, parallel-controlled clinical trial.

This is a multicenter, randomized, double-blind, parallel-controlled study, conducted in Chinese patients with mild to moderate essential hypertension. After a 2-week washout period, 236 eligible patients were randomly to receive aranidipine 5-10 mg/d (n = 118) or amlodipine 5-10 mg/d (n = 118) for 10 weeks. The blood pressure and heart rate were evaluated in outpatient clinics, and ambulatory blood pressure monitoring was performed in 24 patients in each group. The blood pressure was significantly decreased in both groups. Compared with amlodipine, the patients who received aranidipine had less response in blood pressure (P < 0.01). The trough/peak ratios of diastolic blood pressure in aranidipine and amlodipine groups were 0.57 ± 0.20 and 0.68 ± 0.19, respectively (P = 0.119). Adverse events occurred at 11.86% and 7.63% in the aranidipine and amlodipine groups, respectively (P = 0.348). Headache was observed at an incidence of >3.0% in both groups, and the serum glucose and lipid profile had no significant change in the amlodipine group. In conclusion, once-daily administration of aranidipine (5-10 mg) effectively controlled blood pressure, and the short-term treatment might result in it being less effective than amlodipine. It had a stable action over 24-hour period, and the mechanism of that is not yet clear. Aranidipine had a good safety similar to that of amlodipine.

[Evaluation of circulating microRNA-92a for endothelial damage induced by percutaneous coronary intervention].

OBJECTIVE: To explore the role of microRNA-92a (miR-92a) in evaluating endothelium damage induced by percutaneous coronary intervention (PCI). METHODS: A case control study was prospectively conducted. Fifty-eight patients with ST-segment elevation acute myocardial infarction (STEAMI) received PCI were enrolled. MiR-92a expression in circulation was determined on the next day after PCI (reverse transcription-polymerase chain reaction). The correlation between miR-92a expression in circulation and PCI influence factors, such as inflation pressure, duration of balloon inflation and length of culprit atheromatous plaque were explored. RESULTS: MiR-92a was lower in inflation pressure 11-19 atm (1 atm=101.325 kPa) group [n=43, mean -0.36, 95% confidence interval (95%CI) -0.60 to -0.12] than inflation pressure ≤10 atm group (n=11, mean 1.16, 95%CI 0.80 to 1.52, P<0.01) and ≥ 20 atm group (n=4, mean 0.26, 95%CI 0.26 to 0.26, P=0.1); and also lower in duration of balloon inflation 6-7 seconds group (n=24, mean -0.42, 95%CI -0.83 to -0.01) than in duration of balloon inflation ≤ 5 seconds group (n=9, mean 0.63, 95%CI 0.49 to 0.78, P=0.03) and ≥ 8 seconds group (n=25, mean 0.45, 95%CI 0.10 to 0.80, P<0.001); lower in implanted stent length ≤30 mm (n=31, mean -0.48, 95%CI -0.80 to -0.16) than those >30 mm (n=27, mean 0.16, 95%CI 0.01 to 0.32, P<0.01). A significantly negative correlation was found between inflation pressure and duration of balloon inflation. (r=-0.48, P<0.001). CONCLUSIONS: There is a relationship between circulating miR-92a, inflation pressure and duration of balloon inflation. Circulating miR-92a could be used to evaluate the endothelium injury induced by PCI, and be used as a new target of prevention and treatment of endothelial dysfunction following revascularization.

[The influence of statin therapy on circulating microRNA-92a expression in patients with coronary heart disease].

OBJECTIVE: To investigate the modulatory function of statin therapy on circulating microRNA-92a (miR-92a) in patients with coronary heart disease (CHD), and to evaluate the possibility of miR-92a as a new target of treatment for endothelial dysfunction. METHODS: A case control study was conducted. Prevalence of abnormal blood fat content, statin treatment rate, and attainment rate of low density lipoprotein-cholesterol (LDL-C) lowered to expected level in 236 patients with CHD were analyzed. Relationship between statin therapy in patients with type 2 diabetes mellitus (DM), and level of LDL-C and circulating miR-92a expression was analyzed by multivariate general linear factorial analysis. The incidence of acute coronary syndrome (ACS) was compared in patients with CHD receiving statin therapy in all groups. RESULTS: Prevalence of abnormal LDL-C was 95.7% (112/117) in CHD patients of non-statin therapy group, and 47.5% (112/236) of patients with CHD who should receive statin therapy but did not. Attainment rate of lowering of LDL-C to expected level in statin therapy group was 27.7% (33/119). LDL-C level (mmol/L) was significantly lower in statin therapy group than that in non-statin therapy group (2.457 ± 0.802 vs. 3.218 ± 1.130, Z = -9.760, P = 0.001), and incidence of ACS was significantly lower in statin therapy group than that in non-statin therapy group [33.6% vs. 71.8%, χ(2) = 34.491, P = 0.001]. There was no significant difference in incidence of ACS between patients with or without attaining the expected low value of LDL-C in statin therapy group [33.3% vs. 33.7%,χ(2) = 0.002, P = 0.968]. Circulating miR-92a expression was significantly higher in patients with stable angina pectoris (SAP) complicated with DM than those without DM (0.492 vs. -0.121, Z = -3.038, P = 0.002). It was found that statin therapy could down regulate miR-92a expression in patients with SAP complicated with DM as compared with that with non-statin therapy (0.419 vs. 0.687, Z = 1.289, P = 0.072). There was no significant difference in circulating miR-92a expression between statin therapy and non-statin therapy in patients with SAP without co-existing DM (-0.032 vs. -0.198, Z = -0.614, P = 0.539). Multivariate general linear factorial analysis showed that statin therapy was the major influential factor on LDL-C level in patients with CHD (F = 22.863, P = 0.001), and complicating DM was the major influential factor on circulating miR-92a expression in patients with SAP (F = 9.641, P = 0.003). CONCLUSION: Regulation of circulating miR-92a expression may be considered as a new clinical target for statin treating endothelial dysfunction in patients with CHD.

[Circulating microRNA-92a in patients with ST-segment elevation myocardial infarction].

OBJECTIVE: To examine the expression of circulating microRNA-92a (miR-92a) in patients with ST-segment elevation myocardial infarction (STEMI), and the impact of percutaneous coronary intervention (PCI) on such expression. METHODS: The level of circulating miR-92a was measured in three groups of patients: 58 STEMI patients received PCI, 24 STEMI patients received no PCI, and 116 patients with stable angina pectoris (SAP) without PCI. RESULTS: On the day next to admission, STEMI patients received no PCI were found to have higher level of circulating miR-92a as compared to SAP patients without PCI (0.2869 ± 0.8167 vs. -0.0555 ± 0.9855, F = 2.438, P = 0.121). Twenty-four hours after the PCI, the level of circulating miR-92a in STEMI patients received the procedure was lower than those without it (-0.0324 ± 0.9563 vs. 0.2869 ± 0.8167, F = 2.054, P = 0.156). The SAP patients (without PCI) had higher survival rate as compared to the STEMI patients without PCI (100.0% vs. 75.0% P = 0.001), and the survival rate in STEMI patients received PCI was higher than those without it (89.7% vs. 75.0%, P = 0.088). CONCLUSIONS: In STEMI patients, the expression of circulating miR-92a is up-regulated. PCI therapy may suppress such up-regulation. Survival rate is higher in patients showing down-regulation of miR-92a. Our data suggest that miR-92a might have potential for diagnosis and therapeutic application in the prevention and treatment of STEMI.

[Management and outcome of 47 patients with acute myocardial infarction complicating cardiogenic shock].

OBJECTIVE: To evaluate the clinical outcomes of patients with acute myocardial infarction (AMI) complicating cardiogenic shock underwent various treatments. METHODS: From January, 2002 to May, 2007, 47 AMI patients with cardiogenic shock were treated in our department by optimal medication (dopamine, epinephrine, norepinephrine, etc.), intra-aortic balloon pump (IABP), mechanical ventilation when indicated, percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). Outcome and factors related to mortality for these patients were analyzed in this retrospective study. RESULTS: Besides optimal medication and IABP in all patients, 31 patients underwent PCI (66.0%), 6 patients received emergency CABG (12.8%). The overall in-hospital mortality rate was 36.2% (17/47), 6 patients (14.9%) died before coronary revascularization and 11 patients (21.3%) died after revascularization. Nine patients died of pump failure and 8 patients died of renal and (or) respiratory failure. Regression analysis showed that acute renal failure (r = 0.734, P = 0.000), acute respiratory failure (r = 0.606, P = 0.000) and diabetes (r = 0.372, P = 0.012) were positively related to in-hospital mortality. CONCLUSION: Despite improvements in treatment options for AMI patients complicating cardiogenic shock, in-hospital mortality remained high, especially for patients complicating further with acute renal failure and acute respiratory failure.

Clinical comparative analysis of histidine-tryptophan-ketoglutarate solution and St. Thomas crystalloid cardioplegia: A 12-year study from a single institution.

Cardioplegic reperfusion during a long-term ischemic period interrupts cardiac surgery and increases cellular edema due to repeated administration. The present clinical study compared the protective effects of histidine-ketoglutarate-tryptophan (HTK) solution and St. Thomas crystalloid cardioplegia. Clinical experiences of the myocardial protection induced by one single perfusion with HTK were reviewed in high-risk patients with severe pulmonary arterial hypertension associated with complex congenital heart disease. This retrospective study included 88 high-risk patients (aortic cross-clamp time, >120 min) between March 2001 and July 2012. The cohort was divided into two groups according to the technique used. Either myocardial protection was performed with one single perfusion with HTK solution (HTK group) or with conventional St. Thomas crystalloid cardioplegia (St group). The duration of cardiopulmonary bypass did not differ between the two groups. The mortality, morbidity, intensive care unit (ICU) stay, postoperative hospitalization, and transfusions of HTK group are significantly lower than those of the St group (P<0.05). Univariate and multivariate analysis demonstrated that HTK is a statistically significant independent predictor of decreased early mortality and morbidity (P<0.05). In conclusion, the present findings suggested that HTK solution decreases mortality, morbidity, ICU stay, postoperative hospitalization, and transfusions in high-risk patients with severe pulmonary arterial hypertension associated with complex congenital heart disease.

[Evaluation of regional wall movement abnormalities in coronary artery disease by quantitative tissue velocity imaging].

OBJECTIVE: To evaluate the clinical value of quantitative tissue velocity imaging (QTVI) in detection of regional wall movement abnormalities in patients with coronary artery disease (CAD). METHODS: The segmental left ventricular wall motion velocity was measured in 45 normal subjects and 48 patients with CAD, and the parameters of QTVI were analyzed between the two groups. RESULTS: Velocity decrement and wave form alterations were shown in abnormal segmental movements in the CAD group. There were obvious differences in the velocity between normal and abnormal segment. CONCLUSION: QTVI is valuable in quantitative and sensitive evaluation of regional wall movement abnormalities for non-invasive diagnosis of CAD.