Comprehensive Analysis of the Immune Infiltrates and Aberrant Pathways Activation in Atherosclerotic Plaque.

Atherosclerosis is the pathological basis of many cardiovascular and cerebrovascular diseases. The development of gene chip and high-throughput sequencing technologies revealed that the immune microenvironment of coronary artery disease (CAD) in high-risk populations played an important role in the formation and development of atherosclerotic plaques. Three gene expression datasets related to CAD were assessed using high-throughput profiling. CIBERSORT analysis revealed significant differences in five types of immune cells: activated dendritic cells (DCs), T follicular helper cells (Tfhs), resting CD4+ T cells, regulatory T cells (Tregs), and γδ T cells. Immune transcriptome analysis indicated higher levels of inflammatory markers (cytolytic activity, antigen presentation, chemokines, and cytokines) in the cases than in the controls. The level of activated DCs and the lipid clearance signaling score were negatively correlated. We observed a positive correlation between the fraction of Tfhs and lipid biosynthesis. Resting CD4+ T cells and the activity of pathways related to ossification in bone remodeling and glutathione synthesis showed a negative correlation. Gamma delta T cells negatively correlated with IL-23 signaling activity. GSEA revealed a close association with the inflammatory immune microenvironment. The present study revealed that CAD patients may have an inflammatory immune microenvironment and provides a timely update on anti-inflammatory therapies under current investigation.

Evaluation of the immune response afforded by a subunit vaccine candidate against bluetongue virus in mice and sheep.

Bluetongue virus (BTV), a vector-borne pathogen, is the causative agent of bluetongue disease in ruminants. In view of the recent emergence of BTV in regions previously known to be free from the disease and/or specific serotypes or strains, optimization of the currently available vaccination strategies to control the spread of vector-borne bluetongue is crucial. The main objective of the current study was to develop a subunit vaccine candidate targeting BTV-16, a strain previously isolated in China from sheep with obvious clinical signs. To this end, five polyhistidine-tagged recombinant proteins (BTV-16 VP2, VP3, VP7, NS2 and a truncated version of VP5 (VP5-41amino acids) were expressed using the baculovirus or Escherichia coli expression system for characterization of protective activity. To determine ovine and murine immune responses to the five proteins, sheep and mice were immunized twice at 4- and 2-week intervals, respectively, with one of two different protein combinations in MontanideTM ISA201 VG adjuvant or placebo. Data from the competitive enzyme linked immunosorbent assay revealed significantly higher antibody titers in immunized than control animals. Expressed VP5 and NS2 induced a protein-specific humoral response. Interestingly, a serum neutralization test against the BTV-1 serotype showed promising cross-serotype immune response by the vaccine. Based on the collective data, we suggest that these recombinant purified proteins present promising candidates for the design of effective novel vaccines against BTV.

Impact of red blood cell transfusion on acute coronary syndrome: a meta-analysis.

The impact of red blood cell transfusion on outcomes in patients with acute coronary syndrome is controversial. Pubmed, EMBASE, and Cochrane Library were searched for studies of red blood cell transfusion and acute coronary syndrome that were published in any language, from January 1, 1966, to April 1, 2016. We analyzed 17 observational studies, of 2,525,550 subjects. We conducted a systematic review with meta-analysis of studies assessing the association between blood transfusion and the risk for all-cause mortality and reinfarction. The search yielded 17 observational studies, of 2,525,550 subjects, during a study follow-up period, ranging from 30 days to 5 years. Red blood cell transfusion compared with no blood transfusion is associated with higher short- and long-term all-cause mortality as well as reinfarction rates (adjusted RR 2.23; 95% CI 1.47-3.39; HR 1.93; 95% CI 1.12-3.34; RR 2.61; 95% CI 2.17-3.14, respectively). In hemoglobin-stratified analyses, a graded association between red blood cell transfusion and mortality was observed, transfusion and risk of all-cause mortality was borderline significant at hemoglobin levels below 8.0 g/dL (RR 0.52; 95% CI 0.25-1.06), and was associated with an increased risk of mortality at a hemoglobin above 10 g/dL (RR 3.34; 95% CI 2.25-4.97). Red blood cell transfusion was associated with an increased risk of short- and long-term mortality as well as myocardial reinfarction. However, transfusion appeared to have beneficial or neutral effects on mortality at hemoglobin levels below 8.0 g/dL, and harmful effects above 10 g/dL. A large definitive randomized controlled trial addressing this issue is urgently required.

Statin initiation and renal outcomes following isolated coronary artery bypass grafting: a meta-analysis.

INTRODUCTION: The effects of preoperative statin therapy (PST) on renal outcomes in patients with isolated coronary artery bypass grafting (CABG) are in controversial. This study aimed to assess the effects of preoperative statin use on postoperative renal outcomes in patients undergoing isolated CABG. EVIDENCE ACQUISITION: PubMed, EMBASE, and Cochrane Library were searched for studies published up to February 2017. Pooled odds ratio (OR) and its corresponding 95% confidence interval (95% CI) were calculated. Outcomes evaluated were occurrence of postoperative acute kidney injury (AKI)/failure, requirement of any postoperative renal replacement therapy (RRT) and change in serum creatinine (Scr) levels. We used random-effects model and calculated pooled effect estimate of outcome between statin and non-statin use groups. EVIDENCE SYNTHESIS: Eighteen studies consisting of 32,747 patients following CABG were included. PST was associated with a significant protective effect for perioperative renal dysfunction (OR 0.89; 95% CI: 0.82-0.97; P=0.01) and postoperative requirement for RRT (OR 0.54; 95% CI: 0.41-0.72; P=0.001) in patients undergoing CABG surgery. However, there were no effects of preoperative statin therapy on the risk of postoperative AKI and serum creatinine concentration. In the subgroup of patients after on-pump CABG surgery, PST significantly reduced the perioperative renal dysfunction and requirement for RRT (OR 0.69; 95% CI: 0.53-0.89; P=0.005, OR 0.51; 95% CI: 0.30-0.87; P=0.014, respectively). CONCLUSIONS: In patients undergoing isolated CABG, PST might be associated with lower risk of postoperative renal dysfunction and the requirement for RRT. However, PST may not reduce the risk of AKI. Future large well-designed randomized controlled trials are needed on this topic.

Impact of gender on short-term and long-term all-cause mortality in patients with non-ST-segment elevation acute coronary syndromes: a meta-analysis.

A meta-analysis to determine the impact of gender on mortality in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS): PubMed, EMBASE, and Cochrane Library, was systematically searched. Two investigators independently reviewed retrieved articles and assessed eligibility. Unadjusted mortality rates or adjusted effect estimates regarding gender-specific short-term and long-term all-cause mortality were identified. A total of 30 studies involving 358,827 patients with NSTE-ACS (129, 632 women and 229,195 men) were identified. In the unadjusted analysis, women had significantly higher risk of short-term all-cause mortality (RR 1.37; 95% CI 1.26-1.49; P < 0.00001) and long-term all-cause mortality (RR 1.18; 95% CI 1.07-1.31; P = 0.001) compared with men. However, when a meta-analysis was performed using adjusted effect estimates, the association between women and higher risk of short-term mortality (RR 0.99; 95% CI 0.91-1.07; P = 0.74) and long-term all-cause mortality (RR 0.84; 95% CI 0.68-1.03; P = 0.09) was markedly attenuated. Adjusted short-term and long-term all-cause mortality appeared similar in women and men. In conclusion, women with NSTE-ACS have higher short-term and long-term mortality compared with men. However, gender differences do not differ following adjustment for baseline cardiovascular risk factors and clinical differences.

Off-pump versus on-pump coronary artery bypass grafting in patients with diabetes: a meta-analysis.

AIMS: The effects of off-pump CABG (OFF-CABG) versus on-pump CABG (ON-CABG) in diabetic patients remain controversial. The aim of our study was to compare mortality and postoperative morbidity between OFF-CABG and ON-CABG for diabetic patients. METHODS: Electronic databases including PubMed, EMBASE and Cochrane Library for studies investigating clinical outcomes of OFF-CABG versus ON-CABG in diabetic patients were searched, collecting data from inception until June 2016. We pooled the odds ratios from individual studies and performed heterogeneity, quality assessment and publication bias analysis. RESULTS: A total of 543,220 diabetic patients in 10 studies were included. The overall mortality (OR, 0.87; 95% CI, 0.58-1.31; p = 0.50) was comparable between the OFF-CABG and ON-CABG. OFF-CABG was associated with significantly fewer cerebrovascular accidents (OR, 0.45; 95% CI, 0.31-0.65; p < 0.0001), bleeding complications (OR, 0.59; 95% CI, 0.43-0.80; p < 0.001) and pulmonary complications. However, no differences in myocardial infarction (OR, 0.76; 95% CI, 0.52-1.12; p = 0.16), renal failure (OR, 0.74; 95% CI, 0.50-1.11; p = 0.14) and other postoperative morbidity outcomes were found. CONCLUSIONS: OFF-CABG significantly reduces the incidence of postoperative cerebrovascular accidents and bleeding complications compared with ON-CABG in diabetic patients. No differences were found regarding mortality, myocardial infarction and renal failure between these two techniques. Our study suggests that OFF-CABG may be an optimal strategy for diabetic patients although adequately powered randomized trials are needed to further verify the finding.

Lipoprotein-associated phospholipase A2 in coronary heart disease: Review and meta-analysis.

BACKGROUND: Risk associations between lipoprotein-associated phospholipase A2 (Lp-PLA2) and adverse outcomes in patients with coronary heart disease (CHD) remain unclear. The aim of the meta-analysis was to investigate the association between Lp-PLA2 and prognosis of CHD. METHODS: PubMed and Embase were examined for prospective studies published before June 2016. Multivariate-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for the risk of adverse outcomes according to Lp-PLA2 activity or mass were extracted, pooled, and weighted using generic inverse-variance and random-effect modeling. RESULTS: Fifteen studies with 30,857 participants were included. Overall, higher Lp-PLA2 activity or mass was not significantly related to increased risk of long-term all-cause mortality. However, higher Lp-PLA2 activity or mass was independently associated with an increased risk of long-term cardiovascular events, with pooled HR for cardiovascular events of 1.55 (95% CI, 1.08-2.23; P=0.018) and 1.62 (95% CI, 1.09-2.41; P=0.017), respectively. The prognostic value of Lp-PLA2 in predicting cardiovascular events was observed in patients with stable CHD who were not receiving therapies for inhibiting Lp-PLA2. CONCLUSIONS: Greater Lp-PLA2 activity or mass was independently associated with cardiovascular events in patients with CHD, particularly in patients with stable CHD who were not receiving therapies for inhibiting Lp-PLA2.

Improvement of the microcirculation in the acute ischemic rat limb during intravenous infusion of drag-reducing polymers.

Drag-reducing polymers (DRPs) are blood-soluble macromolecules that can increase blood flow and reduce vascular resistance. The purpose of the present study is to examine the effects of DRPs on microcirculation in rat hind limb during acute femoral artery occlusion. Two groups of 20 male Wistar rats were subjected to either hemodynamic measurement or contrast enhanced ultrasound (CEU) imaging during peripheral ischemia. Both groups were further subdivided into a DRP-treated group or a saline-treated group. Polyethylene oxide (PEO) was chosen as the test DRP, and rats were injected with either 10 ppm PEO solution or saline through the caudal vein at a constant rate of 5 ml/h for 20 min. Abdominal aortic flow, iliac artery pressure, iliac vein pressure, heart rate, carotid artery pressure and central venous pressure (CVP) were monitored, and vascular resistance was calculated by (iliac artery pressure-iliac vein pressure)/abdominal aortic blood flow. Flow perfusion and capillary volume of skeletal muscle were measured by CEU. During PEO infusion, abdominal aortic blood flow increased (p<0.001) and vascular resistance decreased (p<0.001) compared to rats that received saline during peripheral ischemia. There was no significant change in ischemic skeletal capillary volume (A) with DRP treatment (p>0.05), but red blood cell velocity (ß) and capillary blood flow (A×ß) increased significantly (p<0.05) during PEO infusion. In addition, A, ß and A×ß all increased (p<0.05) in the contralateral hind limb muscle. In contrast, PEO had no significant influence on heart rate, mean carotid artery blood pressure or CVP. Intravenous infusion of drag reducing polymers may offer a novel hydrodynamic approach for improving microcirculation during acute peripheral ischemia.

[Effect of polyethylene oxide on red blood cell velocity in rat cremaster microcirculation].

OBJECTIVE: To investigate the drag-reducing effect of polyethylene oxide (PEO) on the velocity of red blood cells in rat cremaster microcirculation. METHODS: Blood samples were collected from 6 Wistar male rats (100-110 g) via the post-orbital venous plexus. The red blood cells were separated by centrifugation and labeled by fluorescinisothiocyate (FITC). After successful establishment of cremaster model, the labeled red blood cells were injected into the jugular vein, and the microcirculation was observed and recorded under fluorescence microscope. The hemodynamic parameters and microcirculation video was recorded every 4 min since 4 min before PEO or normal saline injection. Both PEO (10 ppm) and normal saline was injected into the same rat in random sequence at a constant rate of 3.5 ml/h for 20 min followed by observation for another 20 min. The velocity of the labeled-red blood cells was determined by IPP 6.0 software. RESULTS: Compared with normal saline, PEO significantly increased the velocity of the red blood cells in the rat cremaster microcirculation (498.7-/+182.89 microm/s vs 773.54-/+308.27 microm/s, P=0.012). No significant changes in the heart rate and arterial blood pressure were observed during the experiment (P=0.836, P=0.420). CONCLUSION: PEO at an extremely low concentration can significantly increase the velocity of the red blood cells in rat cremaster microcirculation and produces no significant impact on heart rate and arterial blood pressure.

[Effects of polyethylene oxide at different concentrations on abdominal aortic blood flow and vascular resistance in rats].

OBJECTIVE: To observe the effect of polyethylene oxide (PEO) solution at different concentrations on abdominal aortic blood flow and vascular resistance in rats and evaluate the safety and drag-reducing effect of PEO solution. METHODS: Thirty-two rats were anesthetized and randomly divided into 4 groups. An ultrasonic flow probe was deployed on the abdominal aorta (5 mm above the common iliac artery) to measure the blood flow. The carotid artery pressure, iliac artery pressure, iliac vein pressure, central venous pressure (CVP) and ECG were also monitored. Saline or different concentrations of PEO [(1x10(-6)(low), 1x10(-5)(middle) and 5x10(-5)(high) g/ml)] were injected in the 4 groups of rats through the caudal vein at a constant rate of 5 ml/h for 20 min, and the changes of the vascular resistance was observed. RESULTS After injections of 1x10(-6) and 1x10(-5) g/ml PEO, the abdominal aortic flow increased significantly (P<0.05) while the vascular resistance was reduced (P(low)=0.052, P(middle)<0.001) as compared to those in the saline control group. Following the injection with 5x10(-5) g/ml PEO, the abdominal aortic flow increased to a threshold in the initial 4 min, after which it rapidly decreased to approach the baseline levels despite continuous infusion. Blood pressure remained stable after the injections except for 5x10(-5) g/mlPEO injection, which resulted in a reduction of the blood pressure by about 10 mmHg (P=0.014). The heart rate and CVP both underwent no significant changes following the injections. CONCLUSION: The drag-reducing effect of PEO is closely related to its concentration, and compared with 1x10(-6) g/ml, 1x10(-5) g/ml PEO more effectively increases the blood flow and decreases the resistance. The effectiveness and safety of EPO are attenuated at a concentration higher than 5x10(-5) g/ml.

[Impact of ultrasound-mediated microbubbles on myocardial vascular permeability in rats].

OBJECTIVE: To investigate the impact of high-dose microbubbles induced by high mechanical index myocardial contrast echocardiography (MCE) on vascular permeability and its recovery time in rats. METHODS: Thirty male Wistar rats were randomized into 4 MCE groups (groups A-D) and a control group. In the MCE groups, Evans blue was injected at 10 s before MCE (A), immediately after the end of MCE (B), and at 5 min (C) and 20 min after the end of MCE (D). In the control group, the microbubbles and Evans blue were injected at the end of a 5-min ultrasound exposure. All the rats were sacrificed 5 min after Evans blue injection, and the content of Evans blue in the myocardium and the percentage of Evans blue leakage area were determined. RESULTS: The percentage of Evans blue leakage area in groups A, B and C were significantly higher than that in the control group (P<0.05), while the percentage was similar between group D and the control group (P>0.05). Evans blue contents in groups A and B were significantly higher than that in the control group (P<0.05), but groups C and D showed comparable contents with the control group E (P>0.05). No significant changes of the heart rates and premature beat number were observed during and after MCE in these groups (P>0.05). CONCLUSION: High mechanical index MCE and a high contrast dose may induce increased microvascular leakage in rats, and the vascular permeability can recover in 20 min after MCE.

[Evaluation of left ventricular diastolic function in canine acute myocardial ischemia using velocity vector imaging and quantitative tissue velocity imaging].

OBJECTIVE: To assess the value of velocity vector imaging (VVI) and quantitative tissue velocity imaging (QTVI) in assessing left ventricular diastolic function of the dogs with acute myocardial ischemia. METHODS: Six healthy mongrel dogs were subjected to ligation of the left circumflex artery or left anterior descending artery to induce coronary artery stenosis of varying degrees. The mean peak diastolic velocity (Em) of the ventricular walls around the mitral annulus was recorded with VVI or QTVI in the coronary blood flow. The left ventricular end diastolic pressure (LVEDP) was measured with pigtail catheter in the left ventricle. RESULTS: As the coronary blood flow decreased, LVEDP was gradually increased, and Em measured by VVI or QTVI were also gradually decreased. A good linear correlation was shown between Em measured by VVI or QTVI and LVEDP (r=-0.834, P<0.001, and r=-0.68, P<0.001, respectively). A significant difference was observed in the correlation coefficient between VVI and QTVI (Z=2.625, P=0.0087). CONCLUSION: VVI and QTVI both provide good noninvasive means for measuring left ventricular diastolic function. VVI, a new echocardiographic modality without angular dependence, is better than QTVI in evaluating left ventricular diastolic function.