Empagliflozin alleviates atherosclerotic calcification by inhibiting osteogenic differentiation of vascular smooth muscle cells.

SGLT-2 inhibitors, such as empagliflozin, have been shown to reduce the occurrence of cardiovascular events and delay the progression of atherosclerosis. However, its role in atherosclerotic calcification remains unclear. In this research, ApoE-/- mice were fed with western diet and empagliflozin was added to the drinking water for 24 weeks. Empagliflozin treatment significantly alleviated arterial calcification assessed by alizarin red and von kossa staining in aortic roots and reduced the lipid levels, while had little effect on body weight and blood glucose levels in ApoE-/- mice. In vitro studies, empagliflozin significantly inhibits calcification of primary vascular smooth muscle cells (VSMCs) and aortic rings induced by osteogenic media (OM) or inorganic phosphorus (Pi). RNA sequencing of VSMCs cultured in OM with or without empagliflozin showed that empagliflozin negatively regulated the osteogenic differentiation of VSMCs. And further studies confirmed that empagliflozin significantly inhibited osteogenic differentiation of VSMCs via qRT-PCR. Our study demonstrates that empagliflozin alleviates atherosclerotic calcification by inhibiting osteogenic differentiation of VSMCs, which addressed a critical need for the discovery of a drug-based therapeutic approach in the treatment of atherosclerotic calcification.

How the trabeculae protrude within the left atrial appendage is the key factor affecting thrombosis in patients with atrial fibrillation.

The left atrial appendage (LAA) is a major site of thrombosis in patients with non-valvular atrial fibrillation. The myocardial trabeculae within the LAA have a peculiar tendency to protrude but its relationship to thrombosis remains unknown. This study aimed to investigate the relationship between the condition of trabeculae protrusion and LAA thrombosis. This retrospective study consecutively selected patients diagnosed with non-valvular atrial fibrillation and prepared for radiofrequency ablation from January 2011 to May 2020. Patients were divided into the thrombus group (n = 43), the sludge group (n = 35), and the normal group (n = 407) according to whether the thrombus or sludge was present. The trabeculae protruding angle (TPA), which was measured by the CT scans, was used to quantify the trabeculae protrusion condition. Patients' clinical data, TPA, LAA emptying velocity, and other factors were collected and compared among the three groups. A total of 485 patients were enrolled. The range of TPA was between 0 and 158 degrees, with an average of 89.3 ± 35.6 degrees. The TPA was significantly greater in the thrombus (109.3 ± 14.8 degrees) and sludge groups (110.8 ± 12.8 degrees) than in the normal group (85.3 ± 37.1). The incidence of LAA thrombus and sludge increased with increasing TPA. Multivariate regression analysis showed that the TPA was an independent risk factor for LAA thrombus (OR = 1.046, 95%CI: 1.020-1.073, p < 0.001) and sludge (OR = 1.035, 95%CI: 1.017-1.053, p < 0.001). Further analysis revealed that the TPA was negatively correlated with LAA emptying velocity but its effect on promoting thrombosis was not only mediated by slowing down the flow velocity. The TPA can well reflect the condition of trabeculae protrusion. This study revealed that the TPA was an independent risk factor for LAA thrombus or sludge, providing a potential indicator for future thrombosis risk assessment.

Radiofrequency catheter ablation for improving myocardial work in patients with ventricular pre-excitation.

Background: Previous studies have not consistently found significant improvements in left ventricular ejection fraction or global longitudinal strain (GLS) after radiofrequency catheter ablation (RFCA) in patients with ventricular pre-excitation. The aim of this study was thus to explore the effects of RFCA on left ventricular function in patients with ventricular pre-excitation using a new noninvasive echocardiographic method of myocardial work. Methods: A total of 34 patients with ventricular pre-excitation who underwent RFCA and 18 healthy controls were prospectively included in this study. Before and after participants underwent RFCA, electrocardiographic and echocardiographic data of the patients were collected at resting and pacing heart rates (HRs) of 100 beats per minute (bpm) and 120 bpm (controlled by high right atrial pacing during the procedure). Clinical data of the healthy controls at resting HR were also collected. A self-controlled paired sample t test was used to compare the differences before and after participants underwent RFCA. Results: After participants underwent RFCA, the global wasted work (GWW) of the included patients decreased (resting HR: 165.3±68.8 vs. 92.6±42.5 mmHg%, P<0.001; HR of 100 bpm: 276.3±121.2 vs. 187.9±96.0 mmHg%, P<0.001; HR of 120 bpm: 323.9±126.7 vs. 181.0%±74.3 mmHg%. P<0.001), while the global work efficiency (GWE) increased (resting HR: 91.5%±3.8% vs. 94.9%±1.6%; P<0.001; HR of 100 bpm: 87.0%±5.2% vs. 91.0%±3.3%, P<0.001; HR of 120 bpm: 85.0%±5.1% vs. 90.3%±3.7%, P<0.001). Conclusions: In patients with ventricular pre-excitation, impaired GWW and GWE can be improved with RFCA. In clinical practice, noninvasive myocardial work assessment can be used in patients with ventricular pre-excitation.

Predicting Risk Factors of Acute Kidney Injury in the First 7 Days after Admission: Analysis of a Group of Critically Ill Patients.

Background: Acute kidney injury (AKI) is a common complication in critically ill patients. Some predictive models have been reported, but the conclusions are controversial. The aim of this study was the formation of nomograms to predict risk factors for AKI in critically ill patients within the first 7 days after admission to the intensive care unit (ICU). Methods: Data were extracted from the Medical Information Mart for Intensive Care- (MIMIC-) III database. The random forest method was used to fill in the missing values, and least absolute shrinkage and selection operator (Lasso) regression analysis was performed to screen for possible risk factors. Results: A total of 561 patients were enrolled. Complication with AKI is significantly associated with a longer length of stay (LOS). For all patients, the predictors contained in the prediction nomogram included hypertension, coronary artery disease (CAD), cardiopulmonary bypass (CPB), coronary artery bypass grafting (CABG), Simplified Acute Physiology Score II (SAPS II), central venous pressure (CVP) measured for the first time after admission, and maximum and minimum mean artery pressure (MAP). The model showed good discrimination (C - index = 0.818, 95% CI: 0.779-0.857). In the subgroup of patients with well-controlled blood glucose levels, the significant predictors included hypertension, CABG, CPB, SAPS II, and maximum and minimum MAP. Good discrimination was also present before (C - index = 0.785, 95% CI: 0.736-0.834) and after adjustment (adjusted C - index = 0.770). Conclusion: Hypertension, CAD, CPB, CABG, SAPS II, CVP measured for the first time after admission, and maximum and minimum MAP were independent risk factors for AKI in critically ill patients.

Comparison of renal impairment post-myocardial infarction with reduced and preserved left ventricular function in rats with normal renal function.

This study aimed to compare the renal impairments in post-myocardial infarction (MI) rats with normal renal biochemical parameters at baseline with versus without cardiac dysfunction and explore the potential mechanisms involved in these differences. Sprague-Dawley rats with permanent ligation of coronary artery were used as MI models. Renal function, histological and molecular changes were compared between the reduced ejection fraction (EF) (EF < 40%) group and the preserved EF (EF ≥ 40%) group 3 or 9 weeks post-MI. The results revealed that blood cystatin C increased significantly at 9 but not 3 weeks, but it was not associated with cardiac dysfunction. Renal fibrosis and inflammatory cell infiltrations increased significantly in the reduced EF group than in the preserved EF group at 3 and 9 weeks. Glomerular podocyte injury, identified by increased immunostaining for desmin and decreased immunostaining for Wilms' tumor-1, was more significant in the reduced EF group than in the preserved EF group at 9, but not 3 weeks. The number of p16ink4a-positive and 8-hydroxy-2'-deoxyguanosine-positive podocytes was greater in the reduced EF group than in the preserved EF group at both time points. These changes were associated with increased expression of angiotensin II type 1/2 receptors at both time points. In conclusion, our study demonstrated that cardiac dysfunction accounted for substantially severity in renal parenchymal impairment in a partially time-dependent manner, and local activation of angiotensin II receptors, increased cell senescence and oxidative stress, and enhanced inflammatory reaction may be potential modulators participated in the deterioration of renal parenchymal injury.

Mesenchymal stem cell-derived exosomes ameliorate cardiomyocyte apoptosis in hypoxic conditions through microRNA144 by targeting the PTEN/AKT pathway.

BACKGROUND: A growing body of evidence suggests that stem cell-derived exosomal microRNAs (miRNAs) could be a promising cardioprotective therapy in the context of hypoxic conditions. The present study aims to explore how miRNA-144 (miR-144), a miRNA contained in bone marrow mesenchymal stem cell (MSC)-derived exosomes, exerts a cardioprotective effect on cardiomyocyte apoptosis in the context of hypoxic conditions and identify the underlying mechanisms. METHODS: MSCs were cultured using the whole bone marrow adherent method. MSC-derived exosomes were isolated using the total exosome isolation reagent and confirmed by nanoparticle trafficking analysis as well as western blotting using TSG101 and CD63 as markers. The hypoxic growth conditions for the H9C2 cells were established using the AnaeroPack method. Treatment conditions tested included H9C2 cells pre-incubated with exosomes, transfected with miR-144 mimics or inhibitor, or treated with the PTEN inhibitor SF1670, all under hypoxic growth conditions. Cell apoptosis was determined by flow cytometry using 7-ADD and Annexin V together. The expression levels of the miRNAs were detected by real-time PCR, and the expression levels of AKT/p-AKT, Bcl-2, caspase-3, HIF-1α, PTEN, and Rac-1 were measured by both real-time PCR and western blotting. RESULTS: Exosomes were readily internalized by H9C2 cells after co-incubation for 12 h. Exosome-mediated protection of H9C2 cells from apoptosis was accompanied by increasing levels of p-AKT. MiR-144 was found to be highly enriched in MSC-derived exosomes. Transfection of cells with a miR-144 inhibitor weakened exosome-mediated protection from apoptosis. Furthermore, treatment of cells grown in hypoxic conditions with miR-144 mimics resulted in decreased PTEN expression, increased p-AKT expression, and prevented H9C2 cell apoptosis, whereas treatment with a miR-144 inhibitor resulted in increased PTEN expression, decreased p-AKT expression, and enhanced H9C2 cell apoptosis in hypoxic conditions. We also validated that PTEN was a target of miR-144 by using luciferase reporter assay. Additionally, cells treated with SF1670, a PTEN-specific inhibitor, resulted in increased p-AKT expression and decreased H9C2 cell apoptosis. CONCLUSIONS: These findings demonstrate that MSC-derived exosomes inhibit cell apoptotic injury in hypoxic conditions by delivering miR-144 to cells, where it targets the PTEN/AKT pathway. MSC-derived exosomes could be a promising therapeutic vehicle to facilitate delivery of miRNA therapies to ameliorate ischemic conditions.

Angiotensin II receptor blocker reverses heart failure by attenuating local oxidative stress and preserving resident stem cells in rats with myocardial infarction.

The present study aimed to test whether angiotensin receptor blockers (ARBs) are cardioprotective after myocardial infarction (MI) by preventing augmented local renin-angiotensin-system (RAS)-induced oxidative stress injury and senescence, preserving resident stem cells, and restoring the insulin-like growth factor (IGF-1)/IGF-1 receptor (IGF-R) pathway. Sprague-Dawley rats with ligated or unligated coronary arteries were treated with losartan (20 mg/kg/d) or vehicle for 3 or 9 weeks. Heart function and molecular and histological changes were assessed. It was found MI induced left ventricular dysfunction and remodeling, increased levels of the oxidative stress marker 8-hydroxy-2'-deoxyguanosine and cell senescence marker p16ink4a, and downregulated the IGF-1/IGF-1R/Akt pathway after both 3 and 9 weeks post-MI. MI induced an increase in stem cells identified by immunostaining for c-kit and Wilms' tumor-1 predominantly after 3 weeks. Losartan significantly inhibited local cardiac RAS activation and improved left ventricular function and remodeling at both timepoints. Losartan also preserved c-kit- and Wilms' tumor-1-positive cells (particularly at 3 weeks), attenuated 8-hydroxy-2'-deoxyguanosine- and p16ink4a-positive cardiomyocytes, and restored the IGF-1/IGF-1R/Akt pathway at both 3 and 9 weeks. In conclusion, ARBs aided cardiac repair post-MI through short-term preservation of stem cells and persistent anti-oxidative stress and anti-senescence effects, partially by attenuating activation of cardiac RAS and restoring the local IGF-1/IGF-1R/Akt pathway.

Effects of anti-hypertensive treatment on major cardiovascular events in populations within prehypertensive levels: a systematic review and meta-analysis.

Uncertainties still remain in terms of the efficacy of anti-hypertensive treatment on the risk of major cardiovascular (CV) events within prehypertensive levels. This review aims to assess the efficacy and safety of anti-hypertensives on the CV risks in populations within prehypertensive levels. Randomized controlled trials (RCTs) concerning active treatment vs placebo in populations within prehypertensive levels were identified through electronic database and manual search. Outcomes included the first co-primary outcomes, stroke, heart failure (HF), myocardial infarction (MI), all-cause mortality, and cardiovascular mortality. The first co-primary outcomes were defined as composite cardiovascular disease (CVD) events in the included studies. A total of 29 RCTs involving 127,641 participants were identified. Pooled analysis showed active treatment was associated with a significant 7% reduction in risk of the first co-primary outcomes, 14% in stroke, and 10% in HF as compared to placebo (0.86, 0.77-0.96; 0.93, 0.89-0.98; and 0.90, 0.83-0.97). However, there were no significant reductions in risk of MI, all-cause mortality, and cardiovascular mortality. A significant reduction in risk of the first co-primary outcomes was observed in subpopulations with systolic blood pressure (SBP) 130-139 mmHg (0.94, 0.89-0.99) or prior CVDs (0.88, 0.82-0.94). Meta-regression analyses showed no significant relative risk reductions proportional to the magnitude of the mean baseline BP, mean on-treatment BP, the mean absolute change in BP, the proportion of patients with hypertension, and mean age. In summary, anti-hypertensive treatment has beneficial cardiovascular effects in populations within prehypertensive levels, especially in subpopulations with SBP 130-139 mmHg or prior CVDs.

Nicotinic Acetylcholine Receptor Alpha7 Subunit Mediates Vagus Nerve Stimulation-Induced Neuroprotection in Acute Permanent Cerebral Ischemia by a7nAchR/JAK2 Pathway.

BACKGROUND The role of nicotinic acetylcholine receptor alpha7 subunit (a7nAchR) in the treatment of acute cerebral ischemia by VNS has not been thoroughly clarified to date. Therefore, this study aimed to investigate the specific role of a7nAchR and explore whether this process is involved in the mechanisms of VNS-induced neuroprotection in rats undergoing permanent middle cerebral artery occlusion (PMCAO) surgery. MATERIAL AND METHODS Rats received a7nAChR antagonist (A) or antagonist placebo injection for control (AC), followed by PMCAO and VNS treatment, whereas the a7nAChR agonist (P) was utilized singly without VNS treatment but only with PMCAO pretreatment. The rats were randomly divided into 6 groups: sham PMCAO, PMCAO, PMCAO+VNS, PMCAO+VNS+A, PMCAO+VNS+AC, and PMCAO+P. Neurological function and cerebral infarct volume were measured to evaluate the level of brain injury at 24 h after PMCAO or PMCAO-sham. Moreover, the related proteins levels of a7nAChR, p-JAK2, and p-STAT3 in the ischemic penumbra were assessed by Western blot analysis. RESULTS Rats pretreated with VNS had significantly improved neurological function and reduced cerebral infarct volume after PMCAO injury (p<0.05). In addition, VNS enhanced the levels of a7nAchR, p-JAK2, and p-STAT3 in the ischemic penumbra (p<0.05). However, inhibition of a7nAchR not only attenuated the beneficial neuroprotective effects induced by VNS, but also decreased levels of p-JAK2 and p-STAT3. Strikingly, pharmacological activation of a7nAchR can partially substitute for VNS-induced beneficial neurological protection. CONCLUSIONS These results suggest that a7nAchR is a pivotal mediator of VNS-induced neuroprotective effects on PMCAO injury, which may be related to suppressed inflammation via activation of the a7nAchR/JAK2 anti-inflammatory pathway.

Downregulation of Cavin-1 Expression via Increasing Caveolin-1 Degradation Prompts the Proliferation and Migration of Vascular Smooth Muscle Cells in Balloon Injury-Induced Neointimal Hyperplasia.

BACKGROUND: Percutaneous coronary intervention has been widely used in the treatment of ischemic heart disease, but vascular restenosis is a main limitation of percutaneous coronary intervention. Our previous work reported that caveolin-1 had a key functional role in intimal hyperplasia, whereas whether Cavin-1 (another important caveolae-related protein) was involved is still unknown. Therefore, we will investigate the effect of Cavin-1 on neointimal formation. METHODS AND RESULTS: Balloon injury markedly reduced Cavin-1 protein and enhanced ubiquitin protein expression accompanied with neointimal hyperplasia in injured carotid arteries, whereas Cavin-1 mRNA had no change. In cultured vascular smooth muscle cells (VSMCs), Cavin-1 was downregulated after inhibition of protein synthesis by cycloheximide, which was distinctly prevented by pretreatment with proteasome inhibitor MG132 but not by lysosomal inhibitor chloroquine, suggesting that proteasomal degradation resulted in Cavin-1 downregulation. Knockdown of Cavin-1 by local injection of Cavin-1 short hairpin RNA (shRNA) into balloon-injured carotid arteries in vivo promoted neointimal formation. In addition, inhibition or overexpression of Cavin-1 in cultured VSMCs in vitro prompted or suppressed VSMC proliferation and migration via increasing or decreasing extracellular signal-regulated kinase phosphorylation and matrix-degrading metalloproteinases-9 activity, respectively. However, under basic conditions, the effect of Cavin-1 on VSMC migration was stronger than on proliferation. Moreover, our results indicated that Cavin-1 regulated caveolin-1 expression via lysosomal degradation pathway. CONCLUSIONS: Our study revealed the role and the mechanisms of Cavin-1 downregulation in neointimal formation by promoting VSMC proliferation, migration, and synchronously enhancing caveolin-1 lysosomal degradation. Cavin-1 may be a potential therapeutic target for the treatment of postinjury vascular remodeling.

Stretch-activated channel Piezo1 is up-regulated in failure heart and cardiomyocyte stimulated by AngII.

Mechanotransduction is the conversion of extracellular mechanical stimuli into intracellular biochemical signals, and plays an important role in heart responses to its own mechanical environment. Piezo1 as a distinct stretch-activated channel (SAC) in mammal involves in not only vascular remodeling during embryonic development but also arterial remodeling upon to hypertension at adult stage. In the present study, the expression of Piezo1 was up-regulated in failure heart induced by myocardial infarction (MI) by real-time PCR, Western blot and immunohistochemistry analysis. Expression of Piezo1 mRNA and protein was enhanced by AngiotensinII (AngII) in neonatal rat ventricular myocytes via AT1 receptor depended methods. Furthermore, the Piezo1 expression was attenuated by Erk1/2 chemical inhibitor (U0126) only, but not by p38 MAPK inhibitor (SB203580), or JNK inhibitor (SP600125). Finally, systolic function improvement followed by chronic treatment with angiotensin receptor blocker (ARB) losartan prevented Piezo1 up-regulation in failure heart in vivo. In conclusion, our studies linked mechanotransduction which involved renin-angiotensin system that mediated up-regulation of Piezo1 to a clinically relevant heart failure.

Association of TNFSF4 (rs3850641) gene polymorphisms and coronary heart disease: an evidence-based meta-analysis.

OBJECTIVE: To clarify the effects of TNFSF4 (rs3850641) polymorphisms on coronary heart disease (CHD) risk. METHOD: Published literature from Pubmed, Embase, ISI Wed of Knowledge, Cochrane Library, and Chinese databases were retrieved. All studies evaluating the association between TNFSF4 (rs3850641) polymorphisms and CHD risk were included. Summary odds ratios (ORs) and 95% confidence intervals (CI) were calculated employing random-effects models irrespective of between-study heterogeneity. RESULTS: A total of 9 eligible studies was included in this meta-analysis. Overall analysis showed that the rs3850641 G allele was not associated with CHD, compared with the A allele, with OR of 1.10 (95% CI, 0.96-1.27; p = 0.174). Genotypic analysis showed that there was no significant association between the GG, GA, GG + GA, and CHD, compared with participants with AA, with ORs of 1.23 (95% CI, 0.75-2.03; p = 0.409), 1.04 (95% CI, 0.84-1.29; p = 0.705), and 1.07 (95% CI, 0.85-1.34; p = 0.589), respectively. On the other hand, in the subgroup analysis by ethnicity, source of controls, genotyping methods, or matching criteria, there was still no statistically significant association between TNFSF4 (rs3850641) polymorphisms and CHD risk. CONCLUSIONS: This meta-analysis reveals that TNFSF4 (rs3850641) polymorphisms is not associated with CHD risk.

Myopia and/or longer axial length are protective against diabetic retinopathy: a meta-analysis.

PURPOSE: To evaluate the current evidence of the relationship between myopia, together with its structural and refractive component, and diabetic retinopathy (DR) risk. METHODS: A systematic search was performed up to April, 2015. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated employing random-effects models. Three models were used to assess the association between myopia and risk of DR: axial length (AL) (per millimetre increase) and DR; myopia (myopia versus non-myopia) and DR; refractive error (RE) (per D decrease) and DR. Publication bias of the literature was evaluated using Begg's funnel plots and Egger's test. RESULTS: A total of 11 studies that met the predefined criteria were included in this meta-analysis. Overall, longer AL (per millimetre increase) was associa-ted with a significantly decreased risk of DR (combined OR, 0.75; 95% CI, 0.65-0.86; p < 0.001); myopic eyes (myopia versus non-myopia) showed a lower risk of DR (combined OR, 0.70; 95% CI, 0.58-0.85; p < 0.001). A greater degree of myopic RE (per D decrease) also revealed a significantly decreased risk of DR (combined OR, 0.89; 95% CI, 0.85-0.93; p < 0.001). The sensitivity analyses and cumulative meta-analysis showed similar results. No publication bias was detected in any of the three models. CONCLUSIONS: This meta-analysis suggests that both myopic refraction and longer AL are associated with a lower risk of DR. Further studies are needed to determine exact mechanisms underpinning the protective effect of myopia against DR.

Effects of add-on lipid-modifying therapy on top of background statin treatment on major cardiovascular events: A meta-analysis of randomized controlled trials.

BACKGROUND: In patients at high risk of atherosclerotic cardiovascular diseases (ASCVDs), residual cardiovascular risk persists despite the achievement of target LDL cholesterol levels with statin therapy. It is still unclear whether adding lipid-modifying agent to statin treatment can further improve clinical outcomes. METHODS: Randomized controlled trials (RCTs) in terms of adding lipid-modifying agent to statin versus statin monotherapy in patients at high risk of ASCVD were identified by electronic and manual searches. Results were expressed as relative risk (RR) with 95% confidence intervals (CIs). RESULTS: Eleven RCTs with 109,244 patients were included in this meta-analysis. Overall, the incidences of major adverse cardiovascular events (MACEs) were 9.70% in the statin combination groups and 9.92% in the statin monotherapy groups. No significant difference was observed in the risk of MACEs either in overall (RR 0.99, 95% CI 0.93-1.05, P=0.76) or subgroup analysis (CETP inhibitor: RR 1.07, 95% CI 0.93-1.23, P=0.37; niacin: RR 1.03, 95% CI 0.85-1.25, P=0.79; n-3 fatty acid: RR 0.98, 95% CI 0.88-1.09, P=0.70; fenofibrate: RR 0.93, 95% CI 0.80-1.09, P=0.38), with the exception of the statin/ezetimibe combination subgroup (RR 0.92, 95% CI 0.87-0.97, P=0.004). Adding lipid-modifying agent to statin significantly increased liver injury risk. Adding ezetimibe to statin did not alter side effect profile. CONCLUSION: Adding niacin, CETP inhibitors, n-3 fatty acid or fibrates to statin therapy has all failed to achieve a clinical benefit. Adding ezetimibe to statin therapy further lowers LDL-cholesterol safely and translates into a clinical benefit in patients at high risk of ASCVD.

Role of pre-procedural C-reactive protein level in the prediction of major adverse cardiac events in patients undergoing percutaneous coronary intervention: a meta-analysisof longitudinal studies.

Numerous studies have reported the relation between pre-procedural C-reactive protein (CRP) levels and the risk of major adverse cardiac events (MACEs) in patients undergoing percutaneous coronary intervention (PCI). However, the results across the studies were inconsistent. The aim of this study was to evaluate the predictive effect of pre-procedural CRP levels and the risk of MACEs in patients undergoing PCI. Longitudinal studies on the association between pre-procedural CRP levels and MACEs were identified by electronic and manual searches. Summary risk ratios (RRs) and 95 % confidence intervals (CI) were calculated employing an inverse variance random-effects model irrespective of between-study heterogeneity. Thirty-three studies involving 34,367 patients with 4119 MACEs were included in this study. High CRP level was associated with increased incidences of MACEs, all-cause death, myocardial infarction, coronary revascularization, and clinical restenosis, with pooled RRs of 1.97 (95 % CI, 1.65, 2.35), 2.88 (95 % CI, 2.15, 3.86), 1.81 (95 % CI, 1.48, 2.21), 1.31 (95 % CI, 1.11, 1.56), and 1.45 (95 % CI, 1.07, 1.96), respectively. Dose-response analysis showed that every 1 mg/L increment in pre-procedural serum CRP level was associated with a significant 12 % increase in the risk of MACEs. In spite of heterogeneity across the included studies, this meta-analysis suggests that pre-procedural serum CRP level is a valuable predictor of MACEs in patients undergoing PCI.

Long-term efficacy and safety of statin treatment beyond six years: a meta-analysis of randomized controlled trials with extended follow-up.

Large-scale randomized controlled trials (RCTs) have well demonstrated the beneficial effects of cholesterol-lowering treatment with statins in patients at high risk of vascular disease. However, large statin RCTs were usually restricted to the typical 5-6 years. Moreover, non-cardiovascular events, especially the risk of cancer, probably failed to emerge within a restricted period of 6 years. The aim of this study was to evaluate the long-term efficacy and safety of statin treatment by performing a meta-analysis of statin RCTs with extended follow-up beyond 6 years. Six RCTs with post-trial follow-up were eligible for inclusion, involving 47,296 patients with total follow-up ranging from 6.7 to 14.7 years. During the post-trial period, all the surviving participants were advised to take a statin and the cholesterol level were almost identical between the original statin group and the original placebo group. Over the entire 6.7-14.7 years of follow-up, a significant reduction in the rates of all-cause mortality (relative risk 0.90, 95% confidence interval 0.85-0.96; P=0.0009), cardiovascular mortality (0.87, 0.81-0.93; P<0.0001) and major coronary events (0.79, 0.72-0.86; P<0.00001) was observed in favour of the original statin group. During 2-year post-trial period, further reduction in all-cause mortality (0.83, 0.74-0.93; P=0.001), cardiovascular mortality (0.81, 0.69-0.95; P=0.01) and major coronary events (0.77, 0.63-0.95; P=0.01) was observed among initially statin-treated patients. Over the entire follow-up period, statin treatment did not increase the incidence of cancers (0.99, 0.95-1.04; P=0.79), deaths from cancers (1.00, 0.93-1.07; P=0.98) and non-cardiovascular mortality (0.95, 0.90-1.00; P=0.07). In conclusion, statin treatment beyond 6 years is effective and safe in patients at high risk of vascular events. Moreover, earlier treatment with statin may not only preserve the initial benefit but also have further survival benefit for additional 2 years. Further studies are called for to explore the underlying mechanisms.

Antiproteinuric effect of angiotensin receptor blockers in normotensive patients with proteinuria: a meta-analysis of randomized controlled trials.

INTRODUCTION: The objective of this article is to evaluate the antiproteinuric effect of angiotensin receptor blockers (ARBs) in normotensive patients with proteinuria. MATERIALS AND METHODS: We reviewed randomized controlled trials assessing ARBs treatment in patients with normotension and proteinuria. Data concerning the study design, patient characteristics, and outcomes were extracted. Ratio of means was calculated by using the generalized inverse variance method. RESULTS: Eight trials involving 866 patients were included in this study. Compared with a control group, ARBs group was associated with a significant reduction in urinary protein excretion (ratio of means 0.53, 95% CI 0.44-0.64). Subgroup analysis shows that ARBs therapy resulted in a significant decrease in urinary protein excretion in diabetic patients with microalbuminuria or nondiabetic nephropathy with overt proteinuria (ratio of means 0.57, 95% CI 0.47-0.69 and 0.46, 95% CI 0.26-0.83, respectively), in a Western population or an Asian population (ratio of means 0.61, 95% CI 0.54-0.69 and 0.49, 95% CI 0.37-0.64, respectively), and in patients followed up for one to three months or three to 12 months (ratio of means 0.62, 95% CI 0.54-0.70 and 0.49, 95% CI 0.38-0.63, respectively). CONCLUSIONS: The data suggest that ARBs may have beneficial effects in preventing the progression of proteinuria in normotensive patients with renal disease.

Triple antithrombotic therapy versus double antiplatelet therapy after percutaneous coronary intervention with stent implantation in patients requiring chronic oral anticoagulation: a meta-analysis.

BACKGROUND: Whether an addition of OAC to double antiplatelet therapy for patients with an indication of chronic oral anticoagulation undergoing PCI-S may improve clinical outcomes is still debated. This meta-analysis aimed to update and re-compare the benefits and risks of triple antithrombotic therapy (TT) with double anti-platelet therapy (DAPT) after in patients who requiring oral anticoagulation after percutaneous coronary interventions with stenting (PCI-s). METHODS: Ten reports of observational retrospective or prospective studies were retrieved, including a total of 6296 patients, follow-up period ranging from 1 year to 2 years. RESULTS: Baseline characteristics were similar in both groups. The main finding of this study is the overall incidence of major adverse cardiovascular events (MACE), myocardial infarction (MI) and stent thrombosis was comparable between two groups. Patients with TT was associated with significant reduction in ischemic stroke (OR: 0.27; 95%CI: 0.13 - 0.57; P = 0.0006) as compared to DAPT. We reaffirmed triple therapy significantly increased the risk of major bleeding (OR: 1.47; 95%CI: 1.22 - 1.78; P < 0.0001) and minor bleeding (OR: 1.55; 95%CI: 1.07 - 2.24; P = 0.02). CONCLUSIONS: Triple therapy is more efficacious in reducing the occurrence of ischemic stroke in PCI-s patients with an indication of chronic oral anticoagulation (OAC), compared with DAPT. However, it significantly increased major and minor risk of bleeding. It is imperative that further prospective randomized controlled trials are required to defne the best therapeutic strategy for patients with an indication of chronic OAC undergoing PCI-s.

Angiotensin II receptor blocker attenuates intrarenal renin-angiotensin-system and podocyte injury in rats with myocardial infarction.

The mechanisms and mediators underlying common renal impairment after myocardial infarction (MI) are still poorly understood. The present study aimed to test the hypothesis that angiotensin II type 1 receptor blockers (ARBs) provides renoprotective effects after MI by preventing augmented intrarenal renin-angiotensin-system (RAS)-induced podocyte injury. Sprague-Dawley rats that underwent ligation of their coronary arteries were treated with losartan (20 mg/kg/d) or vehicle for 3 or 9 weeks. Renal function, histology and molecular changes were assessed. The current study revealed that MI-induced glomerular podocyte injury was identified by increased immunostaining for desmin and p16(ink4a), decreased immunostaining for Wilms' tumor-1 and podocin mRNA expression, and an induced increase of blood cystatin C at both 3 and 9 weeks. These changes were associated with increased intrarenal angiotensin II levels and enhanced expressions of angiotensinogen mRNA and angiotensin II receptor mRNA and protein. These changes were also associated with decreased levels of insulin-like growth factor (IGF-1) and decreased expressions of IGF-1 receptor (IGF-1R) protein and mRNA and phosphorylated(p)-Akt protein at 9 weeks, as well as increased expressions of 8-hydroxy-2'-deoxyguanosine at both time points. Treatment with losartan significantly attenuated desmin- and p16(ink4a)-positive podocytes, restored podocin mRNA expression, and decreased blood cystatin C levels. Losartan also prevented RAS activation and oxidative stress and restored the IGF-1/IGF-1R/Akt pathway. In conclusion, ARBs prevent the progression of renal impairment after MI via podocyte protection, partially by inhibiting the activation of the local RAS with subsequent enhanced oxidative stress and an inhibited IGF-1/IGF-1R/Akt pathway.

Protection of renal impairment by angiotensin II type 1 receptor blocker in rats with post-infarction heart failure.

Renal impairment is a frequent accompaniment post-myocardial infarction (MI) heart failure. However, the mechanisms and predictors are yet poorly understood. The present study aimed to explore early markers for renal impairment and to test the hypothesis that angiotensin II type 1 receptor (AT1R) blocker exerted renoprotection by regulating local angiotensin II receptors post-MI heart failure. Sprague-Dawley rats underwent ligation of the left descending coronary artery and were treated with losartan (20 mg/kg/day) or vehicle for 3 or 9 weeks. Samples of urine, blood, and kidney were collected for assessment of renal function, histology, and protein changes. The current study revealed that blood cystatin C, rather than serum creatinine and blood urea nitrogen, as well as urine proteins, increased post-MI heart failure significantly. These changes were associated with increased immunohistochemical staining of AT1R and AT2R proteins, accompanied by increased renal fibrosis, tubular necrosis, and inflammatory cell infiltration. Treatment with losartan for MI rats significantly attenuated upregulated AT1R but not AT2R. Losartan also decreased blood cystatin C levels and attenuated renal fibrosis, tubular necrosis, and inflammatory cell infiltration. In conclusion, blood cystatin C may be a better marker for early renal impairment. AT1R blockers modulated local angiotensin II receptors, as well as inflammatory reaction and profibrotic effects, providing potential clinical application in the setting of cardiorenal syndrome post-MI.