Lian Wang

Decreased mobilization of endothelial progenitor cells contributes to impaired neovascularization in diabetes

1  Circulating bone marrow (BM)‐derived endothelial progenitor cells (EPCs) play an important role in neovascularization. In the present study, we investigated the mechanisms underlying the reduction in circulating EPCs in a mouse model of diabetes induced by streptozotocin. 2  Compared with non‐diabetic controls, diabetic mice had reduced circulating EPCs (0.59 ± 0.11 vs 0.94 ± 0.21%, respectively; P < 0.01) and increased plasma endothelial microparticles (18 642 ± 6809 vs 5692 ± 1862/mL, respectively; P < 0.01). In a mouse bone marrow (BM) transplantation model, increased adhesion of transplanted BM cells to aortas of diabetic mice was observed compared with control (900 ± 194 vs 431 ± 109 cells/mm2, respectively; P < 0.01). 3  Following hindlimb ischaemia, diabetic mice exhibited suppressed EPC mobilization, a reduction in the expected increase in capillary density and suppressed restoration of transcutaneous oxygen pressure in the ischaemic tissue. Diabetic mice also showed impaired ischaemia‐induced upregulation of vascular endothelial growth factor (VEGF), hypoxia‐inducible factor (HIF)‐1α and interleukin‐1β, an exaggerated increase in matrix metalloproteinase (MMP)‐2 and ‐9 and a suppressed increase in tissue inhibitor of matrix metalloproteinase (TIMP)‐1. On multivariate analysis, VEGF expression was the only independent factor related to circulating EPC count. 4  In conclusion, the data indicate that the decrease in basal circulating EPCs in diabetes may be attributable, in part, to consumptive loss of EPCs due to increased endothelial damage. Impairment of ischaemia‐induced EPC mobilization in the diabetic mouse model is associated with altered HIF‐1α/VEGF and MMP/TIMP regulation and represents a novel mechanism underlying defective postischaemic neovascularization in diabetes.

Selective Serotonin Reuptake Inhibitors (SSRIs) and the Risk of Congenital Heart Defects: A Meta-Analysis of Prospective Cohort Studies

Background Recent studies have reported conflicting results on the association between selective serotonin reuptake inhibitors (SSRIs) and the risk of heart defects. We aimed to assess the association between SSRIs in pregnant women during the first trimester and the risk of congenital heart defects. Methods and Results PubMed and EMBASE up to July 2014 were searched for population-based cohort studies that reported SSRIs in pregnant women during the first trimester and live infants’ heart defects at follow-up. A meta-analysis of published data was undertaken primarily by means of fixed-effects models. Four cohort studies including 1 996 519 participants were included with a mean follow-up period ranging from discharge to 72 months. SSRIs were not associated with increased risks of heart defects 1.06 (95% confidence interval: 0.94 to 1.18). Conclusions SSRIs during the first trimester in pregnant women were not associated with increased risks for newborn heart defects.

Long-term efficacy and safety of carotid artery stenting versus endarterectomy: A meta-analysis of randomized controlled trials.

Background Many recent trials have investigated the long-term efficacy and safety of endarterectomy versus stenting in treating patients with carotid artery stenosis. We aimed to determine the long-term comparative efficacy and safety of both procedures by pooling this evidence in a meta-analysis. Methods We searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials for studies published until May 6, 2016. Randomized controlled trials, which reported outcomes of interest with a median follow-up of at least 4-year, were included. Results Eight trials involving 7005 patients and 41824 patient-years of follow-up were included. In terms of the periprocedural outcomes, stenting was associated with a lower risk of myocardial infarction (OR: 0.51; 95% CI: 0.33 to 0.80; P = 0.003) but a higher risk of death or stroke (the composite endpoint, OR: 1.76; 95% CI: 1.38 to 2.25; P < 0.0001), a result that was primarily driven by minor stroke (OR: 2.19; 95% CI: 1.59 to 3.01; P < 0.0001), less so by periprocedural death (OR: 1.68; 95% CI: 0.82 to 3.44; P = 0.16) and major stroke (OR: 1.41; 95% CI: 0.95 to 2.09; P = 0.09). In terms of the long-term outcomes, stenting was associated with a higher risk of stroke (OR 1.45; 95% CI: 1.22 to 1.73; P < 0.0001) and the composite outcome of death or stroke (OR 1.25; 95% CI: 1.05 to 1.48; P = 0.01). No difference was found in long-term all-cause mortality between stenting and endarterectomy (OR: 1.09; 95% CI: 0.95 to 1.26; P = 0.21) and restenosis (OR: 1.48 (95% CI: 0.93 to 2.35; P = 0.10). No evidence of significant heterogeneity was found in any of the analyses. Conclusions Carotid endarterectomy was found to be superior to stenting for short- and long-term outcomes, although endarterectomy was associated with a higher risk of periprocedural myocardial infarction. Carotid endarterectomy should be offered as the first choice for carotid stenosis at present, however, more evidence is needed because rapid progress in concurrent devices and medical treatments is being made.

The Prognostic Significance of Right Bundle Branch Block: A Meta-analysis of Prospective Cohort Studies

The prognostic significance of right bundle branch block (RBBB) is inconsistent across studies. We aimed to assess the association between RBBB (in general population and patients with heart disease) and risk of all‐cause mortality, cardiac death, acute myocardial infarction (MI), and heart failure (HF).

Intracoronary Transplantation of Mesenchymal Stem Cells with Overexpressed Integrin-Linked Kinase Improves Cardiac Function in Porcine Myocardial Infarction.

The effect of mesenchymal stem cell (MSCs)-based therapy on treating acute myocardial infarction (MI) is limited due to poor engraftment and limited regenerative potential. Here we engineered MSCs with integrin-linked kinase (ILK), a pleiotropic protein critically regulating cell survival, proliferation, differentiation, and angiogenesis. We firstly combined ferumoxytol with poly-L-lysine (PLL), and found this combination promisingly enabled MRI visualization of MSCs in vitro and in vivo with good safety. We provided visually direct evidence that intracoronary ILK-MSCs had substantially enhanced homing capacity to infarct myocardium in porcine following cardiac catheterization induced MI. Intracoronary transplantation of allogeneic ILK-MSCs, but not vector-MSCs, significantly enhanced global left ventricular ejection fraction (LVEF) by 7.8% compared with baseline, by 10.3% compared with vehicles, and inhibited myocardial remodeling compared with vehicles at 15-day follow-up. Compared with vector-MSCs, ILK-MSCs significantly improved regional LV contractile function, reduced scar size, fibrosis, cell apoptosis, and increased regional myocardial perfusion and cell proliferation. This preclinical study indicates that ILK-engineered MSCs might promote the clinical translation of MSC-based therapy in post-MI patients, and provides evidence that ferumoxytol labeling of cells combined with PLL is feasible in in vivo cell tracking.

High Mobility Group Box-1: A Missing Link between Diabetes and Its Complications

High mobility group box-1 (HMGB-1), a damage-associated molecular pattern, can be actively or passively released from various cells under different conditions and plays a pivotal role in the pathogenesis of inflammation and angiogenesis-dependent diseases. More and more evidence suggests that inflammation, in addition to its role in progression of diabetes, also promotes initiation and development of diabetic complications. In this review, we focus on the role of HMGB-1 in diabetes-related complications and the therapeutic strategies targeting HMGB-1 in diabetic complications.

Percutaneous intervention versus coronary artery bypass graft surgery in left main coronary artery stenosis: a systematic review and meta-analysis

BackgroundThe optimal revascularization technique in patients with left main coronary artery disease (CAD) remains controversial. We aimed to compare the long-term performance of percutaneous coronary intervention (PCI) versus coronary artery bypass graft (CABG) surgery in treatment of left main CAD.MethodsPubMed, EMBASE, and the Cochrane Library were searched until November 16, 2016.ResultsSix randomized controlled trials and 22 matched observational studies including 22,487 patients and 90,167 patient-years of follow-up were included. PCI was associated with an overall higher risk for the major adverse cardiac and cerebrovascular events (hazard ratio (HR), 1.42; 95% confidence interval (CI), 1.14–1.77), mainly driven by higher rates of myocardial infarction (HR, 1.69; 95% CI, 1.22–2.34) and revascularization (HR, 2.80; 95% CI, 1.86–4.22). The overall risks for all-cause death (HR, 1.05; 95% CI, 0.93–1.20), cardiac death (HR, 1.05; 95% CI, 0.69–1.59), stroke (HR, 0.64; 95% CI, 0.33–1.24), and the composite safety endpoint of death, myocardial infarction, or stroke (HR, 1.06; 95% CI, 0.97–1.16) were similar between PCI and CABG. Stratified analysis based on stent types showed that the increased risk for myocardial infarction associated with PCI was only evident in patients with bare-metal stents or early-generation drug-eluting stents (DES), but not newer-generation DES. Stratified analyses based on study designs showed largely similar findings with the overall analyses, except for a significantly higher incidence of myocardial infarction in adjusted studies (HR, 2.01; 95% CI, 1.64–2.45) but a trend toward higher incidence in randomized trials (HR, 1.39; 95% CI, 0.85–2.27) associated with PCI.ConclusionsCompared with CABG, PCI with newer-generation DES might be a safe alternative revascularization strategy for treatment of left main CAD, but is associated with more repeat revascularization.

Syndecan-4 shedding impairs macrovascular angiogenesis in diabetes mellitus.

PURPOSE Syndecan-4 (synd4) is a ubiquitous heparan sulfate proteoglycan cell surface receptor that modulates cell proliferation, migration, mechanotransduction, and endocytosis. The extracellular domain of synd4 sheds heavily in acute inflammation, but the shedding of synd4 in chronic inflammation, such as diabetes mellitus (DM), is still undefined. We investigated the alterations of synd4 endothelial expression in DM and the influence of impaired synd4 signaling on angiogenesis in human umbilical vein endothelial cells (HUVECs), diabetic rats, synd4 null mice, and db/db mice. MATERIAL AND METHODS HUVECs were incubated with advanced glycation end products (AGEs). Western blot analysis was used to determine synd4 protein expression and ELISA was used to detect soluble synd4 fragments. The concentration of synd4 in the aortic endothelia of diabetic rats was detected by immunohistochemical staining. Aortic ring assays were performed to study the process of angiogenesis in the diabetic rats and in synd4 null and db/db mice. Recombinant adenoviruses containing the synd4 gene or null were constructed to enhance synd4 aortic expression in db/db mice. RESULTS Western blot analysis showed decreased expression of the synd4 extracellular domain in HUVECs, and ELISA detected increased soluble fragments of synd4 in the media. Synd4 endothelial expression in the aortas of diabetic rats was decreased. Aortic ring assay indicated impaired angiogenesis in synd4 null and db/db mice, which was partially reversed by synd4 overexpression in db/db mice. CONCLUSION Synd4 shedding from vascular endothelial cells played an important role in the diabetes-related impairment of angiogenesis.

A meta-analysis for efficacy and safety evaluation of transcatheter left atrial appendage occlusion in patients with nonvalvular atrial fibrillation.

Objectives: This meta-analysis was conducted to evaluate the efficacy and safety of transcatheter left atrial appendage (LAA) occlusion in patients with nonvalvular atrial fibrillation. Methods: The randomized controlled trials (RCT) or observational studies with any transcatheter LAA occlusion devices were searched in PubMed, Embase, and Cochrane library from inception to November 2015. The incidence rates from individual studies were combined to evaluate the procedural efficacy and safety, including all-cause death, cardiac/neurological death, stroke, transient ischemic attack (TIA), thrombosis, hemorrhagic complications, and pericardial effusion/tamponade. Results: Thirty-eight studies involving 3585 patients and 6 different occlusion devices were eligible for our inclusion criteria. The procedural failure rate for LAA closure was 0.02 (95% CI: 0.02–0.03). The all-cause mortality was 0.03 (95% CI: 0.02–0.03) and cardiac/neurological mortality was 0 (95% CI: 0.00–0.01). The stroke/TIA rate was estimated only 0.01 (95% CI: 0.01–0.01). The incidence of thrombus on devices was 0.01 (95% CI: 0.01–0.02). The major hemorrhagic complication rate was estimated 0.01 (95% CI: 0.00–0.01). Pericardial effusion/tamponade was estimated 0.02 (95% CI: 0.02–0.03). No heterogeneity was observed for above pooled estimates (I 2 = 0). In devices subgroups analysis, the all-cause mortality and cardiac/neurological mortality of PLAATO group were the highest (P = 0.01 and P < 0.01 respectively), whereas the incidence of thrombus on devices in the ACP group was the highest (P < 0.01). In follow-up period subgroups analysis, there were significant differences in all-cause death, stroke/TIA, major hemorrhage, and pericardial effusion/tamponade events between the shorter and longer follow-up period subgroups (P < 0.05). However, the differences among the subgroups were numerically small. Conclusions: the pooled data demonstrated that transcatheter LAA occlusion was effective and safe in the patients with nonvalvular atrial fibrillation who were not suitable for lifelong antithrombotic therapy.

Association of Arg389Gly β1-adrenergic receptor polymorphism with effective dose of β blocker in congestive heart failure among Chinese Han population

Background To investigate the relationship between β1-adrenergic receptor (ADRB1) gene polymorphisms and the response to medication in patients with congestive heart failure (CHF). Methods and Results Two hundred and sixty patients with CHF were enrolled. Ser49Gly and Arg389Gly polymorphisms were identified. During one-year follow-up, differences of echocardiographic parameters and major adverse cardiac events (MACE) were analyzed. For Ser49Gly polymorphisms, there were no differences between AA genotype and AG/GG genotype of baseline clinical features and echocardiographic parameters as well as one-year incidence of MACE. For Arg389Gly polymorphisms, there were no significant differences in baseline clinical characteristics, LVDd and LVEF among the three genotypes. However, the increase amplitude of LVEF after one year among patients carrying GG genotype was significantly higher than those carrying CC genotype (11.7% vs 1.3%, P<0.05). The incidence of MACE among different genotypes of CC, CG and GG were 22.2%, 10.0% and 8.3%,with statistical difference (P=0.021). Conclusions The study suggested there was no relationship between Ser49Gly polymorphisms of the ADRB1 gene and the therapeutic effect and prognosis in CHF patients under the same dosage of drugs. However, the improvement of cardiac function and prognosis in patients carrying the Gly389 allele were significantly better than those of Arg389Arg homozygous.