Wu-Tao Zeng

The Role of Macrolide Antibiotics in Increasing Cardiovascular Risk

BACKGROUNDnLarge cohort studies provide conflicting evidence regarding the potential for oral macrolide antibiotics to increase the risk of serious cardiac events.nnnOBJECTIVESnThis study performed a meta-analysis to examine the link between macrolides and risk of sudden cardiac death (SCD) or ventricular tachyarrhythmias (VTA), cardiovascular death, and death from any cause.nnnMETHODSnWe performed a search of published reports by using MEDLINE (January 1, 1966, to April 30, 2015) and EMBASE (January 1, 1980, to April 30, 2015) with no restrictions. Studies that reported relative risk (RR) estimates with 95% confidence intervals (CIs) for the associations of interest were included.nnnRESULTSnThirty-three studies involving 20,779,963 participants were identified. Patients taking macrolides, compared with those who took no macrolides, experienced an increased risk of developing SCD or VTA (RR: 2.42; 95% CI: 1.61 to 3.63), SCD (RR: 2.52; 95% CI: 1.91 to 3.31), and cardiovascular death (RR: 1.31; 95% CI: 1.06 to 1.62). No association was found between macrolides use and all-cause death or any cardiovascular events. The RRs associated with SCD or VTA were 3.40 for azithromycin, 2.16 for clarithromycin, and 3.61 for erythromycin, respectively. RRs for cardiovascular death were 1.54 for azithromycin and 1.48 for clarithromycin. No association was noted between roxithromycin and adverse cardiac outcomes. Treatment with macrolides is associated with an absolute risk increase of 118.1 additional SCDs or VTA, and 38.2 additional cardiovascular deaths per 1 million treatment courses.nnnCONCLUSIONSnAdministration of macrolide antibiotics is associated with increased risk for SCD or VTA and cardiovascular death but not increased all-cause mortality.

Chronic angiotensin-(1–7) administration improves vascular remodeling after angioplasty through the regulation of the TGF-β/Smad signaling pathway in rabbits☆

OBJECTIVEnAngiotensin-(1-7) [ANG-(1-7)] has been reported to attenuate neointimal formation after vascular injury and stent implantation in rats, but the mechanism remains mostly unresolved. Interestingly, the levels of circulating transforming growth factor-beta1 (TGF-beta1) after myocardial infarction were suppressed by ANG-(1-7), which suggests a possible downstream target for the anti-remodeling action of ANG-(1-7). Our study focused on the effects of ANG-(1-7) on vascular remodeling, including neointimal formation and collagen synthesis, and determining whether or not these effects were dependent upon the TGF-beta signaling pathway.nnnMETHODSnThirty-two New Zealand white rabbits underwent sham surgery or angioplasty in abdominal aorta. The animals were divided into four groups, which were sham, control, ANG-(1-7), and ANG-(1-7)+A-779. Subsequently, an osmotic minipump was implanted to deliver saline, ANG-(1-7) (576 microg kg(-1)d(-1)) or ANG-(1-7)+A-779 (576 microg kg(-1)d(-1)) for 4 weeks.nnnRESULTSnThe ANG-(1-7) group displayed a significant reduction in neointimal thickness (207.51+/-16.70 microm vs. 448.08+/-15.30 microm, P<0.001), neointimal area (0.266+/-0.009 mm(2) vs. 0.408+/-0.002 mm(2), P<0.001), and restenosis rate (28.13+/-2.74% vs. 40.13+/-2.74%, P<0.001) when compared to the control group. ANG-(1-7) also inhibited collagen synthesis by significantly decreasing the mRNA expression of Collagen I and Collagen III (vs.nnnCONTROL GROUPn0.2190+/-0.0036 vs. 0.3852+/-0.0212, P<0.001 and 1.1328+/-0.0554 vs. 1.7378+/-0.1164, P<0.001, respectively). Furthermore, the expression of TGF-beta1 and phosphor-Smad2 (p-Smad2) were significantly suppressed by ANG-(1-7) (vs.nnnCONTROL GROUPn1.21+/-0.07 vs. 1.54+/-0.08, P<0.001 and 0.31+/-0.01 vs. 0.43+/-0.02, P<0.001, respectively), but no effect on p38 phosphorylation was observed. [d-Ala(7)]-ANG-(1-7) (A-779), showed a tendency to attenuate the anti-remodeling effects of ANG-(1-7).nnnCONCLUSIONnANG-(1-7) decreases the amount of vascular remodeling, including a reduction in neointimal formation and collagen synthesis, after angioplasty in rabbits. The responsible mechanism may function through the possible down-regulation of TGF-beta1 levels and inhibition of the Smad2 pathway.

More Favorable Response to Cardiac Resynchronization Therapy in Women Than in Men

Background—Data on sex difference in response to cardiac resynchronization therapy (CRT) remain controversial. We conducted a meta-analysis to summarize all published studies to determine whether sex-based differences in response to CRT exist. Methods and Results—We performed a literature search using MEDLINE (source PubMed; January 1966 to March 2014) and EMBASE (January 1980 to March 2014) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis. Seventy-two studies involving 33 434 patients were identified. Overall, female patients had better outcomes from CRT compared with male patients, with a significant 33% reduction in the risk of death from any cause (hazard ratio, 0.67; 95% confidence interval, 0.61–0.74; P<0.001), 20% reduction in death or hospitalization for heart failure (hazard ratio, 0.80; 95% confidence interval, 0.71–0.90; P<0.001), 41% reduction in cardiac death (hazard ratio, 0.59; 95% confidence interval, 0.42–0.84; P<0.001), and 41% reduction in ventricular arrhythmias or sudden cardiac death (hazard ratio, 0.59; 95% confidence interval, 0.49–0.70; P<0.001). These more favorable responses to CRT in women were consistently associated with greater echocardiographic evidence of reverse cardiac remodeling in women than in men. Conclusions—Women obtained greater reductions in the risk of death from any cause, cardiac cause, death or hospitalization for heart failure, and ventricular arrhythmias or sudden cardiac death with CRT therapy compared with men, with consistently greater echocardiographic evidence of reverse cardiac remodeling in women than in men. Further studies are needed to investigate the exact reasons for these results and determine whether indications for CRT in women should be different from men.

Risk of Thromboembolic Events in Atrial Fibrillation With Chronic Kidney Disease

Background and Purpose— Chronic kidney disease may increase the risk for ischemic stroke or systemic embolism in patients with nonvalular atrial fibrillation (AF). We conducted a meta-analysis to summarize all published studies to investigate the link between chronic kidney disease and risk of thromboembolic events in AF. Methods— We performed a literature search using MEDLINE (source PubMed, 1966 to July, 2014) and EMBASE (1980 to July 2014) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis. Results— Eighteen studies involving 538 479 patients and 41 719 incident thromboembolic events were identified. From the pooled analysis, AF patients with estimated glomerular filtration rate <60 mL/min compared with those with estimated glomerular filtration rate ≥60 mL/min experienced a significantly increased risk for developing thromboembolic events (relative risk, 1.62 [95% confidence interval, 1.40–1.87; P<0.001]). The annual rate of thromboembolic events increased by 0.41% (95% confidence interval, 0.17%–0.65%) for a 10 mL/min decrease in renal function. Addition of renal impairment to CHADS2 slightly improved the stroke risk stratification. Conclusions— Impaired renal function is an independent predictor of stroke or systemic embolism in patients with nonvalvular AF. Consideration of renal function may improve stroke risk stratification in patients with AF.

Impairment of Cardiac Function and Remodeling Induced by Myocardial Infarction in Rats are Attenuated by the Nonpeptide Angiotensin‐(1–7) Analog AVE 0991

AIMSnWe evaluated effects of the nonpeptide angiotensin (ANG)-(1-7) analog AVE 0991 (AVE) on cardiac function and remodeling as well as transforming growth factor-beta1 (TGF-β1)/tumor necrosis factor-alpha (TNF-α) expression in myocardial infarction rat models.nnnMETHODS AND RESULTSnSprague-Dawley rats underwent either sham surgery or coronary ligation. They were divided into four groups: sham, control, AVE, and AVE+A-779 [[D-Ala(7) ]-ANG-(1-7), a selective antagonist for the ANG-(1-7)] group. After 4 weeks of treatment, the AVE group displayed a significant elevation in left ventricular fractional shorting (LVFS) (25.5 ± 7.3% vs. 18.4 ± 3.3%, P < 0.05) and left ventricular ejection fraction (LVEF) (44.8 ± 7.6% vs. 32.7 ± 6.5%, P < 0.05) when compared to the control group, but no effects on the left ventricular end-diastolic and end-systolic diameters (LVDd and LVDs, respectively) were observed. In addition, we found that the myocyte diameter (18 ± 2 μm vs. 22 ± 4 μm, P < 0.05), infarct size (42.6 ± 3.6% vs. 50.9 ± 4.4%, P < 0.001) and collagen volume fraction (CVF) (16.4 ± 2.2% vs. 25.3 ± 3.2%, P < 0.001) were significantly reduced in the AVE group when compared to the control group. There were no differences in LVFS, LVEF, myocyte diameter, and infarct size between the control and AVE+A-779 groups. AVE also markedly attenuated the increased mRNA expression of collagen I (P < 0.001) and collagen III (P < 0.001) and inhibited the overexpression of TGF-β1 (P < 0.05) and TNF-α (P < 0.05) compared to the control group.nnnCONCLUSIONnAVE could improve cardiac function and attenuate ventricular remodeling in MI rat models. It may involve the inhibition of inflammatory factors TGF-β1/TNF-α overexpression and the action on the specific receptor Mas of ANG-(1-7).

Influence of genetic polymorphisms in cytochrome P450 oxidoreductase on the variability in stable warfarin maintenance dose in Han Chinese.

PurposeThe aim of this study was to investigate whether any of the single-nucleotide polymorphisms (SNPs) in the POR gene were significantly associated with CYP activity and expression, and could contribute to the total variability in stable warfarin maintenance doses in Han Chinese.MethodsA total of 408 patients treated at the First Affiliated Hospital of Sun Yat-Sen University were eligible for the study and had attained a stable warfarin maintenance dose at the start of the investigation. Demographics, warfarin maintenance doses, and concomitant medications were documented. Genomic DNA was extracted from peripheral blood samples and genotyped for ten SNPs (CYP 2C9*2 and *3, CYP4F2 rs2108622, VKORC1 −1639C>T, and potential POR genes of rs10239977, rs3815455, rs41301394, rs56256515, rs1057868, and rs2286823) using the Sequenom MassARRAY genotyping system.ResultsA predictive model of warfarin maintenance dose was established and indicated that age, gender, body surface area, aspirin use, CYP2C9*3, CYP4F2 rs2108622, VKORC1 −1639C>T, and POR*37 831–35C>T accounted for 42.4 % of dose variance in patients undergoing anticoagulant treatment. The contribution of POR*37 831–35C>T to warfarin dose variation was only 3.9 %.ConclusionsFor the first time, the SNP POR*37 831–35C>T was confirmed as a minor but statistically significant factor associated with interindividual variation in warfarin maintenance dose in Han Chinese. The POR*37 gene polymorphism should be considered in future algorithms for faster and more reliable achievement of stable warfarin maintenance doses.

Protective effect of angiotensin-(1-7) against hyperglycaemia-induced injury in H9c2 cardiomyoblast cells via the PI3K̸Akt signaling pathway Corrigendum in /10.3892/ijmm.2017.3322

Angiotensin-(1-7) [Ang-(1-7)], a heptapeptide mainly generated from cleavage of AngI and AngII, possesses physiological and pharmacological properties, including anti-inflammatory and antidiabetic properties. Activation of the phosphoinositide 3-kinase and protein kinase B (PI3K/Akt) signaling pathway has been confirmed to participate in cardioprotection against hyperglycaemia-induced injury. The aim of the present study was to test the hypothesis that Ang-(1-7) protects H9c2 cardiomyoblast cells against high glucose (HG)-induced injury by activating the PI3K/Akt pathway. To examine this hypothesis, H9c2 cells were treated with 35 mmol/l (mM) glucose (HG) for 24 h to establish a HG-induced cardiomyocyte injury model. The cells were co-treated with 1 μmol/l (μM) Ang-(1-7) and 35 mM glucose. The findings of the present study demonstrated that exposure of H9c2 cells to HG for 24 h markedly induced injury, as evidenced by an increase in the percentage of apoptotic cells, generation of reactive oxygen species and level of inflammatory cytokines, as well as a decline in cell viability and mitochondrial luminosity. These injuries were significantly attenuated by co-treatment of the cells with Ang-(1-7) and HG. In addition, PI3K/Akt phosphorylation was suppressed by HG treatment, but this effect was abolished when the H9c2 cells were co-treated with Ang-(1-7) and HG. Furthermore, the cardioprotection of Ang-(1-7) against HG-induced injury in H9c2 cardiomyoblasts was highly attenuated in the presence of either D-Ala7-Ang-(1-7) (A-779, an antagonist of the Mas receptor) or LY294002 (an inhibitor of PI3K/Akt). In conclusion, the present study provided new evidence that Ang-(1-7) protects H9c2 cardiomyoblasts against HG-induced injury by activating the PI3K/Akt signaling pathway.

Human induced pluripotent stem cell‑derived mesenchymal stem cells alleviate atherosclerosis by modulating inflammatory responses

The transplantation of mesenchymal stem cells (MSCs) has been a reported method for alleviating atherosclerosis (AS). Because the availability of bone marrow-derived MSCs (BM-MSCs) is limited, the authors used this study to explore the use of a new type of MSC, human induced pluripotent stem cell-derived MSCs (iPSC-MSCs), to evaluate whether these cells could alleviate AS. iPSC-MSCs were intravenously administered to ApoE knock out mice fed on a high-fat diet (HFD) for 12 weeks. It was reported that systematically administering iPSC-MSCs clearly reduced the size of plaques. In addition, the numbers of macrophages and lipids in plaques were lower in the HFD + iPSC-MSCs group than in the HFD group. Furthermore, iPSC-MSCs attenuated AS-associated inflammation by decreasing the levels of inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, in serum. In addition, the expression of Notch1 was higher in the HFD group, and injecting iPSC-MSCs reversed this effect. In conclusion, the current study provides the first evidence indicating that iPSC-MSCs may be a new optional MSC-based strategy for treating AS.