Intracoronary Glycoprotein IIb/IIIa Inhibitors Improve Short-Term Mortality and Reinfarction in East Asian Patients with ST-Segment Elevation Myocardial Infarction after Thrombus Aspiration: A Meta-Analysis.

OBJECTIVE: Intracoronary (IC) glycoprotein IIb/IIIa inhibitors (GPIs) after thrombus aspiration (TA) for patients with ST-segment elevation myocardial infarction (STEMI), as compared with percutaneous coronary interventions (PCI) alone, is still on debate. To address this issue, we performed a meta-analysis of results from prospective or randomized controlled trials on the topic. METHODS: We searched electronic and printed sources (up to June 20, 2016) according to the selection criteria. Data were abstraction and meta-analysis was performed using RevMan 5.3 software. RESULTS: The cohorts involved 14 articles describing 1,918 participants were included. The incidence of the short-term major adverse cardiac events (MACE) was significantly reduced with intracoronary GPIs after TA (odds ratio [OR]: 0.29; 95% confidence interval [CI]: 0.13 to 0.65, p=0.003). Benefits were noted for short-term mortality (OR: 0.31; 95% CI: 0.17 to 0.57, p=0.0002) and reinfarction (OR: 0.28; 95% CI: 0.10 to 0.78, p=0.01) in subjects who received intracoronary GPIs after TA. Moreover, the Thrombolysis in Myocardial Infarction (TIMI) trial grade 3 postprocedure (OR: 2.29; 95% CI: 1.72 to 3.04, P<0.00001) and complete ST-segment resolution (STR) rate (OR: 2.68; 95% CI: 1.85 to 3.87, P<0.00001) were both improved with intracoronary GPIs after TA. As a result, left ventricular ejection fraction (LVEF) at short-term follow-up showed a significant difference (OR: 7.33; 95% CI: 5.60 to 9.06, p<0.0001) in favor of the TA and intracoronary GPIs administration. CONCLUSIONS: Our study demonstrates that intracoronary GPIs may have a synergistic effect with thrombus aspiration on short-term mortality, reinfarction, and cardiac functional recovery.

Efficacy and safety of proprotein convertase subtilisin/kexin type 9 monoclonal antibody in adults with familial hypercholesterolemia.

Proprotein convertase-subtilisin/kexin type 9 (PCSK9) monoclonal antibody is a new therapy to reduce low-density lipoprotein cholesterol (LDL-C) level in patients with familial hypercholesterolemia (FH). This pooled analysis aimed to estimate the efficacy and safety of PCSK9 antibody therapy in FH. Reports of randomized controlled trials (RCTs) comparing PCSK9 antibody to placebo were retrieved by a search of MEDLINE via PubMed, EMBASE, the Cochrane Library databases, ClinicalTrials.gov and Clinical Trial Results (up to November 30, 2015) with no language restriction. Data were abstracted by a standardized protocol. We found eight RCTs (1,879 patients with FH) for the pooled analysis. As compared with placebo, PCSK9 antibody therapy remarkably reduced LDL-C level (mean reduction: -48.54 %, 95 % CI: -53.19 to -43.88), total cholesterol (mean reduction: -31.08%, 95 % CI: -35.20 to -26.95), lipoprotein (a) (mean reduction: -20.44%, 95 % CI: -25.21 to -15.66), and apolipoprotein B (mean reduction: -36.32%, 95 % CI: -40.75 to -31.90) and elevated the level of high-density lipoprotein cholesterol (mean change: 6.29 %, 95 % CI: 5.12 to 7.46) and apolipoprotein A1(mean change: 4.86%, 95 % CI: 3.77 to 5.95). Therapy with and without PCSK9 antibodies did not differ in rate of adverse events (pooled rate: 50.86 % vs. 48.63%; RR: 1.03; 95 % CI: 0.92 to 1.15; P = 0.64; heterogeneity P = 0.13; I2= 40%) or serious adverse events (pooled rate: 7.14% vs. 6.74%; RR: 1.05; 95 % CI: 0.70 to 1.58; P = 0.80; heterogeneity P = 0.69; I2= 0%). PCSK9 antibody may be an effective and safe treatment for FH.

Angiotensin-(1-7) treatment mitigates right ventricular fibrosis as a distinctive feature of diabetic cardiomyopathy.

In diabetic patients, left ventricular (LV) remodeling is highly prevalent; however, little is known about the impact of diabetes on right ventricular (RV) structure and function. We recently found that overexpression of angiotensin (ANG)-converting enzyme 2 (ACE2), which metabolizes ANG-II to ANG-(1-7) and ANG-I to ANG-(1-9), may improve LV remodeling in diabetic cardiomyopathy (DCM). Here, we aimed to assess whether LV remodeling and dysfunction are paralleled by RV alterations and the effects of ANG-(1-7) on RV remodeling in DCM. After 12 wk of diabetes induced by a single intraperitoneal injection of streptozotocin, rats were treated with saline, ANG-(1-7), perindopril, ANG-(1-7) plus perindopril, ANG-(1-7) plus Mas receptor antagonist A779, or ANG-(1-7) plus ANG-II type 2 receptor antagonist PD123319 for 4 wk. RV remodeling in diabetic rats was indicated by fibrosis of the RV free wall in the absence of hypertrophy and apoptosis. Treatment with ANG-(1-7) prevented diabetes-induced RV fibrosis and dysfunction. ANG-(1-7) (800 ng·kg(-1)·min(-1)) was superior to perindopril in improving RV fibrosis. The major mechanisms involved a complex interaction of ANG-II type 2 and Mas receptors for subsequent downregulation of ACE expression and activity and ANG-II type 1 receptor expression, as well as upregulation of ACE2 expression and activity and the expression of ANG-II type 2 receptor and sarco(endo)plasmic reticulum Ca(2+)-ATPase. Thus RV fibrosis and dysfunction plays a central role in DCM, and ANG-(1-7) mitigates diabetes-induced RV alterations.

Traditional Chinese medication for cardiovascular disease.

Traditional Chinese medication (TCM) is increasingly used to treat cardiovascular disease (CVD) in China and some other Asian countries. However, therapeutic efficacy and adverse effects of TCM are difficult to evaluate because few large-scale, randomized controlled trials (RCTs) enrolling patients with CVD have been performed. In this Review, we critically examine the current evidence on the cardiovascular effects of TCM. We reviewed 68 RCTs that included a total of 16,171 patients. The methodological quality of the trials was generally low. Only three reports described adverse cardiovascular events specifically, although in most studies TCM was associated with significant improvements in surrogate end points for hypertension, coronary heart disease, cardiac arrhythmias, and heart failure. The risk of adverse effects was not increased compared with no intervention, placebo, or Western medications. However, whether TCM is effective in reducing the all-cause or cardiovascular mortality in patients with CVD remains unknown and must be tested in large-scale RCTs with adverse cardiovascular events as primary end points.

Evaluation of (131)I-anti-angiotensin II type 1 receptor monoclonal antibody as a reporter for hepatocellular carcinoma.

BACKGROUND: Finding a specific agent is useful for early detection of tumor. Angiotensin II type 1 receptor (AT1R) was reported to be elevated in a variety of tumors and participate in tumor progression. The aim of our study was to evaluate whether (131)I-anti-AT1R monoclonal antibody (mAb) is an efficient imaging reporter for the detection of hepatocellular carcinoma. METHODOLOGY/PRINCIPAL FINDINGS: AT1R mAb or isotype IgG was radioiodinated with (131)I and the radiochemical purity and stability of the two imaging agents and the affinity of (131)I-anti-AT1R mAb against AT1R were measured. 3.7 MBq (131)I-anti-AT1R mAb or isotype (131)I-IgG was intravenously injected to mice with hepatocellular carcinoma through tail vein, and then the whole-body autoradiography and biodistribution of the two imaging agents and the pharmacokinetics of (131)I-anti-AT1R mAb were studied. (131)I-anti-AT1R mAb and (131)I-IgG were successfully radioiodinated and both maintained more stable in serum than in saline. The (131)I-anti-AT1R mAb group showed much clearer whole-body images for observing hepatocellular carcinoma than the (131)I-IgG group. The biodistributions of the two imaging agents suggested that hepatocellular carcinoma tissue uptook more (131)I-anti-AT1R mAb than other tissues (%ID/g = 1.82±0.40 and T/NT ratio = 7.67±0.64 at 48 h), whereas hepatocellular carcinoma tissue did not selectively uptake (131)I-IgG (%ID/g = 0.42±0.06 and T/NT ratio = 1.33±0.08 at 48 h). The pharmacokinetics of (131)I-anti-AT1R mAb was in accordance with the two-compartment model, with a rapid distribution phase and a slow decline phase. These results were further verified by real-time RT-PCR, immunohistochemistry staining and Western blot. CONCLUSIONS/SIGNIFICANCE: (131)I-anti-AT1R mAb may be a potential target for early detection of tumor.

Angiotensin-(1-7) dose-dependently inhibits atherosclerotic lesion formation and enhances plaque stability by targeting vascular cells.

OBJECTIVE: To test the hypothesis that chronic infusion of angiotensin-(1-7) [Ang-(1-7)] may dose-dependently inhibit atherosclerotic lesion formation by targeting vascular smooth muscle cells and a large dose of Ang-(1-7) may stabilize mature plaque by targeting macrophages. APPROACH AND RESULTS: In vivo, the effects of Ang-(1-7) on atherogenesis and plaque stability were observed in ApoE(-/-) mice fed a high-fat diet and chronic angiotensin II infusion. In vitro, the effects of Ang-(1-7) on vascular smooth muscle cells' proliferation and migration, and macrophage inflammatory cytokines were examined. Ang-(1-7) dose-dependently attenuated early atherosclerotic lesions and inhibited vascular smooth muscle cells' proliferation and migration via suppressing extracellular regulated protein kinase/P38 mitogen-activated protein kinase and janus kinase/signal transducers and activators of transcription activities and enhancing smooth muscle 22α and angiotensin II type 2 receptor expression. Ang-(1-7) treatment resulted in high contents of collagen and vascular smooth muscle cells, and low contents of macrophages and lipids in carotid mature plaques. Ang-(1-7) lowered the expression levels of proinflammatory cytokines and activities of matrix metalloproteinases in mature plaques. CONCLUSIONS: Ang-(1-7) treatment inhibits early atherosclerotic lesions and increases plaque stability in ApoE(-/-) mice, thus providing a novel and promising approach to the treatment of atherosclerosis.

Association of plasma angiotensin-(1-7) level and left ventricular function in patients with type 2 diabetes mellitus.

BACKGROUND: We recently found that overexpression of angiotensin (Ang)-converting enzyme 2, which metabolizes Ang-II to Ang-(1-7) and Ang-I to Ang-(1-9), may prevent diabetes-induced left ventricular remodeling and dysfunction in rats. Our objective was to evaluate the association of plasma Ang-(1-7) level and left ventricular function in patients with type 2 diabetes mellitus. METHODOLOGY/PRINCIPAL FINDINGS: We measured the left ventricular ejection fraction (EF), ratio of early to late left ventricular filling velocity (E/A) and ratio of early diastolic mitral inflow to annular velocity (E/Ea) by ultrasonography in 110 patients with type 2 diabetes mellitus for more than 5 years. Anthropometric and fasting blood values were obtained from medical records. The plasma Ang-(1-7) level in patients with a poor EF (<50%) was significantly lower than that in patients with EF ≥50%; the level in patients with E/A <1 was significantly lower than that in patients with E/A ≥1; and the level in patients with E/Ea >15 was significantly lower than that in patients with E/Ea ≤15. Ang-(1-7) level was negatively correlated with E/Ea and Log-N-terminal pro-B-type natriuretic peptide and positively with EF and E/A. Stepwise multiple regression analysis revealed that Ang-(1-7), hemoglobin A1c and Ang-II levels as well as duration of diabetes predicted EF; Ang-(1-7) level, fasting blood glucose, low-density lipoprotein cholesterol level and duration of diabetes predicted E/A; and Ang-(1-7) and hemoglobin A1c levels predicted E/Ea. CONCLUSIONS/SIGNIFICANCE: Plasma Ang-(1-7) level is independently associated with left ventricular function in patients with type 2 diabetes mellitus and may be a biomarker for assessing cardiac function in such patients.

Efficacy and safety of intensive insulin therapy for critically ill neurologic patients: a meta-analysis.

BACKGROUND: Whether intensive insulin therapy (IIT) may improve clinical outcomes for patients admitted to intensive care units, especially critically ill neurologic patients, is still debated. In the present study, we performed a meta-analysis of literature comparing the efficacy and safety of IIT and conventional insulin therapy (CIT) for critically ill neurologic patients in terms of mortality, infection rate, neurologic outcome, and hypoglycemia. METHODS: We searched for published reports of studies of randomized control trials (up to March 10, 2011) of patients admitted to neurologic intensive care units and investigated an IIT (target of blood glucose control <120 mg/dL) with a control of CIT. Data were abstracted by a standardized protocol. RESULTS: We retrieved reports of five studies involving 924 patients. The risk of mortality, infection rate, and neurologic outcome did not differ with IIT or CIT. However, the incidence of hypoglycemic episodes was significantly higher with IIT than CIT (78.8% vs. 48.9%), with a relative risk of 2.62 (95% confidence interval [CI]: 1.07-6.43; p < 0.04). CONCLUSIONS: As compared with CIT, IIT may not benefit critically ill neurologic patients in terms of mortality, infection rate, or neurologic outcome and in fact may be associated with increased hypoglycemic complications. Therefore, IIT cannot be recommended over conventional control for critical neurologic disease, but further study is warranted.

Meta-analysis of aldehyde dehydrogenase 2 gene polymorphism and Alzheimer's disease in East Asians.

BACKGROUND: The association of genetic polymorphism of mitochondrial aldehyde dehydrogenase 2 (ALDH2) and Alzheimer's disease (AD) has been controversial and has been investigated only in several small-sample studies. In the present study, we performed a meta-analysis to evaluate the cross-sectional association of ALDH2 variants and AD risk in East Asian populations. METHODS: Trials were retrieved through MEDLINE, EMBASE, J-STAGE and the China National Knowledge Internet databases (from January 1, 1994 to November 1, 2010) without any restriction on language. Data were abstracted by a standardized protocol. RESULTS: We found four studies of 821AD patients and 1380 healthy controls that qualified for the analysis. The variant ALDH2 genotype GA/AA was not associated with increased AD risk (odds ratio (OR) = 1.35; 95% confidence interval (CI) = 0.75-2.42; p = 0.32), even after stratification for the status of apolipoprotein E epsilon 4 allele. However, in the subgroup analyses, the association was significant for men (OR = 1.72; 95% CI = 1.10-2.67; p = 0.02). CONCLUSIONS: This study adds to the evidence that ALDH2 GA/AA genotype increases the risk of AD among East Asian men, although the effect size is moderate.

Effects of ulinastatin, a urinary trypsin inhibitor, on synaptic plasticity and spatial memory in a rat model of cerebral ischemia/reperfusion injury.

Established therapies for cerebral ischemia-reperfusion injury are currently limited. The urinary trypsin inhibitor ulinastatin (UTI) is considered cytoprotective against ischemia-reperfusion injury in internal organs through its anti-inflammatory activity. We aimed to investigate the neuroprotective effects of UTI on learning and memory of rats after cerebral ischemia-reperfusion injury. Rats were treated with UTI at 10,000 U/kg body weight, then underwent ischemia and reperfusion by the middle cerebral arterial occlusion (MCAO) method. At various times after the onset of reperfusion, we evaluated neurologic impairment scores. Brain sections underwent immunohistochemical staining for synaptophysin and calcium-binding protein S100ß. Other rats underwent the Morris water maze test to determine the effects of UTI on learning and memory. Spatial reference learning and memory were improved with UTI treatment by down-regulating S100ß-positive cells and preventing the loss of neural cells. Thus, UTI has a neuroprotective role on synaptic plasticity and spatial memory with cerebral ischemia-reperfusion injury in rats.

Efficacy and safety of drug-eluting stents in patients with acute ST-segment-elevation myocardial infarction: a meta-analysis of randomized controlled trials.

We compared the efficacy and safety of drug-eluting stents with that of bare-metal stents in patients who experienced acute ST-segment-elevation myocardial infarction (STEMI) and underwent primary percutaneous coronary intervention. To do this, we performed a meta-analysis of 13 randomized controlled trials in which drug-eluting stents were compared with bare-metal stents in STEMI patients. The trials involved 6,769 patients (4,246 received drug-eluting stents and 2,523 received bare-metal stents) and follow-up periods of 6 to 48 months. In comparison with bare-metal stents, drug-eluting stents significantly reduced the incidence of major adverse cardiac events, with a risk ratio (RR) of 0.59 (95% confidence interval [CI], 0.47-0.73; P < 0.00001). Drug-eluting stents were not associated with a significant reduction in overall death (RR = 0.94; 95% CI, 0.74-1.20; P = 0.64), but were associated with significant reductions in recurrent myocardial infarction (RR = 0.76; 95% CI, 0.58-0.98; P = 0.03), target-vessel revascularization (RR = 0.47; 95% CI, 0.39-0.56; P <0.00001), and in-stent restenosis (RR = 0.32; 95% CI, 0.25-0.39; P < 0.00001). Moreover, no significant difference was found in the comparative risk of stent thrombosis (RR = 0.85; 95% CI, 0.63-1.14; P = 0.27).On the basis of risk ratio, we conclude that using drug-eluting stents in STEMI patients who undergo primary percutaneous coronary intervention is safe with regard to stent thrombosis within 48 months, and that drug-eluting stents improve clinical outcomes by reducing the risks of major adverse cardiac events, recurrent myocardial infarction, reintervention, and in-stent restenosis, compared with bare-metal stents. However, in order to investigate possible very late stent thrombosis, follow-up of these trials beyond 48 months is warranted.

Angiotensin II type 1 receptor gene A1166C polymorphism and essential hypertension in Chinese: a meta-analysis.

INTRODUCTION: We performed a meta-analysis with the aim of assessing the association of the angiotensin II type 1 (AT(1)) receptor gene A1166C polymorphism with essential hypertension in Chinese case-control studies. METHODS: Studies were searched from the Chinese Biomedicine Database, the China National Knowledge Infrastructure platform, Pubmed and Medline, using the search terms 'hypertension', 'angiotensin II type 1 receptor', 'AT(1)R', 'polymorphism', 'China' and 'Chinese', without limiting to any specific language. The strength of the association between the A1166C polymorphism and hypertension was evaluated by the odds ratio (OR) with the corresponding 95% confidence interval (CI). The analyses were performed with Cochrane RevMan software version 4.2. RESULTS: Overall, the variant genotype AC/CC was associated with a statistically increased essential hypertension risk with the pooled OR 1.48 (95% CI: 1.20-1.83). In the subgroup analyses, the association was also significant among studies using Northern populations, Southern populations, Han Chinese and hospital-based controls. The age did not influence the relationship between the AT( 1) receptor A1166C polymorphism and hypertension in the subgroup analyses. CONCLUSIONS: The present meta-analysis suggests that the AT(1) receptor 1166 AC/CC genotype is associated with susceptibility to hypertension in the Chinese population.

Meta-analysis of the role of high-dose statins administered prior to percutaneous coronary intervention in reducing major adverse cardiac events in patients with coronary artery disease.

1. There is considerable evidence regarding the efficacy of statins for the primary and secondary prevention of coronary artery disease (CAD). However, due to lack of sufficient evidence, there is still doubt whether high-dose statin therapy prior to percutaneous coronary intervention (PCI) is beneficial. In the present study, we performed a meta-analysis to evaluate the effect of preoperative high-dose statin therapy on the incidence of major adverse cardiac events (MACE) after successful PCI. 2. Trials were retrieved through Medline (1980-2009) and the reference files limited to English-language articles. Data were abstracted using a standardized protocol and a meta-analysis was performed. 3. Five studies of a total 1789 patients with CAD qualified for analysis. Administration of high-dose statins in CAD patients before PCI was associated with a significant reduction in MACE 30 days after the procedure. The incidence of MACE in the high-dose statin group (6.98%) was significantly lower than that in the placebo group (14.77%), with an odds ratio (OR) of 0.43 (95% confidence interval (CI) 0.31-0.59; P < 0.00001). The incidence of post-PCI increases in creatine kinase MB in the high-dose statin and placebo groups was 9.20%vs 18.83%, respectively (OR 0.43; 95% CI 0.33-0.58; P < 0.00001), whereas the incidence of increases in troponin I was 30.13%vs 44.53%, respectively (OR 0.53; 95% CI 0.43-0.67; P < 0.00001), respectively. 4. In conclusion, high-dose statin therapy before PCI provides a significant benefit over placebo in preventing post-PCI MACE. Findings from the present analysis strongly support a strategy of routine loading of high-dose statins before interventional therapy.