Yugang Dong

The Role of Macrolide Antibiotics in Increasing Cardiovascular Risk

BACKGROUND Large cohort studies provide conflicting evidence regarding the potential for oral macrolide antibiotics to increase the risk of serious cardiac events. OBJECTIVES This 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. METHODS We 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. RESULTS Thirty-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. CONCLUSIONS Administration of macrolide antibiotics is associated with increased risk for SCD or VTA and cardiovascular death but not increased all-cause mortality.

AMPK activation enhances PPARα activity to inhibit cardiac hypertrophy via ERK1/2 MAPK signaling pathway.

Activation of adenosine monophosphate-activated protein kinase (AMPK) has been shown to inhibit cardiac hypertrophy through peroxisome proliferators-activated receptor-α (PPARα) signaling pathway, but the detailed mechanism remains unclear. A rat model of cardiac hypertrophy created by transaortic constriction (TAC) was used to investigate the mechanism involved in regulation of PPARα activity by AMPK. It was observed that treatment with AICAR (5-aminoimidazole 1 carboxamide ribonucleoside), an AMPK activator, significantly inhibited cardiac hypertrophy in vivo and in vitro. Phosphorylated extracellular signal regulated protein kinase (phospho-ERK1/2) and phospho-p38 mitogen-activated protein kinase (MAPK) protein levels were significantly up-regulated, while PPARα protein level was down-regulated in TAC rats. AICAR treatment reversed the changes of PPARα and phospho-ERK1/2, but increased phospho-p38 MAPK protein level in TAC rats. Similar changes of PPARα and phospho-ERK1/2 protein levels were observed in the hypertrophied cardiomyocytes induced by phenylephrine treatment. Epidermal growth factor (EGF, ERK1/2 activator), but not SB203580 (p38 inhibitor) blocked the up-regulation of PPARα protein level induced by AICAR. Luciferase assay showed that AICAR increased PPARα transcriptional activity which was abrogated by EGF, but not by SB203580. These results demonstrate that AMPK activation enhances the activity of PPARα to inhibit cardiac hypertrophy through ERK1/2, but not p38 MAPK, signaling pathway.

Adenosine monophosphate-activated protein kinase inhibits cardiac hypertrophy through reactivating peroxisome proliferator-activated receptor-α signaling pathway

The activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) has been shown to inhibit cardiac hypertrophy, however, the mechanism remains unclear. Rat models of cardiac hypertrophy were created with transaortic constriction (TAC) to investigate the mechanistic role of AMPK involved. RT-PCR and Western blot analyses indicated that hypertrophy marker genes ANP and beta-MHC expression were up-regulated in the myocardium of TAC rats. We also observed that the expressions of peroxisome proliferator-activated receptor-alpha (PPARalpha) and its target genes, carnitine palmitoyl transferase-capital I, Ukrainian (CPT-capital I, Ukrainian) and medium-chain acyl-COA dehydrogenases (MCAD), were down-regulated, and the fatty acid oxidation was decreased in TAC rats. Treatment of TAC animals with 5-aminoimidazole 1 carboxamide ribonucleoside (AICAR, 0.5 mg/g body wt), a specific activator of AMPK, inhibited cardiac hypertrophy in TAC and reversed PPARalpha, CPT-I and MCAD expression and fatty acid oxidation. Similar observations were made in hypertrophied cardiomyocytes induced by phenylephrine in vitro. Treatment of hypertrophied cardiomyocytes with Compound C, a specific AMPK inhibitor, showed an effect opposite to that of AICAR. The effect of AICAR on cardiac hypertrophy was blocked after PPARalpha was silenced by transfection of cardiomyocytes with PPARalpha-siRNA. Luciferase activity assay suggested that AICAR elevates PPARalpha transcriptional activity. These results indicate that AMPK plays an important role in the inhibition of cardiac hypertrophy by activating the PPARalpha signaling pathway.

The oxidation ratio of LDL: a predictor for coronary artery disease.

Objective: Oxidized LDL cholesterol (ox-LDL-C) is considered to be a key factor of initiating and accelerating atherosclerosis (AS). The purpose of this study is to elucidate the sensitivity and specificity of ox-LDL and oxidation ratio of LDL in the diagnosis of coronary artery disease (CAD). For the first time, we investigated the ratio of ox-LDL to ALB(ox-LDL/ALB). Methods and results: Blood ox-LDL, total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglyceride (TG) and albumin (ALB) were measured in patients with acute myocardial infarction (AMI, n = 80), unstable angina pectoris (UAP, n = 80), stable angina pectoris (SAP, n = 80), normal control (n = 60), and dyslipidemia control (n = 60). Ox-LDL was measured by competitive ELISA. The level of ox-LDL and oxidation ratio of LDL(ox-LDL/TC, ox-LDL/HDL-C, ox-LDL/ LDL-C and ox-LDL/ALB) were significantly higher in each diseased group than controls (P < 0.001). In CAD group, ox-LDL and oxidation ratio of LDL in subjects complicated with hypertension (HT) and/or diabetes mellitus (DM) increased further (P < 0.001). Ox-LDL/ALB in the AMI group was 7 times higher than normal control group (0.068 ± 0.017 vs 0.009 ± 0.007, P < 0.001). The area under the curve (AUC) of receiver operating characteristic curve (ROC curve) is a criterium to evaluate the accuracy of diagnosing a disease. The AUC of ROC curve of ox-LDL/TC, ox-LDL/HDL-C, ox-LDL, ox-LDL/ALB and ox-LDL/ LDL-C for diagnosing CAD were 0.975, 0.975, 0.966, 0.966, 0.957 respectively (P < 0.001). When ox-LDL/TC = 0.175, the sensitivity and specificity of diagnosing CAD were 0.917 and 0.925, which were almost equal to each other, indicating that the rates of missed diagnosis and misdiagnosis for CAD were the lowest. Conclusions: The level of ox-LDL and the ratio of ox-LDL/TC, ox-LDL/LDL-C, ox-LDL/HDL-C and ox-LDL/ALB are better biomarkers than TC, TG, HDL-C and LDL-C for discriminating between patients with coronary artery disease and healthy subjects. And patients who have a high ratio of ox-LDL /TC may have a higher risk for CAD.

Poor sleep quality, stress status, and sympathetic nervous system activation in nondipping hypertension.

ObjectiveIt has been reported that poor sleep quality is associated with nondipping hypertension, but the underlying mechanisms were not reported. This study was carried out to evaluate whether poor sleep quality is associated with stress status and sympathetic nervous system activation in nondippers. Materials and methodsA total of 307 Chinese essential hypertensive patients were defined as dippers or nondippers by ambulatory blood pressure monitoring. Sleep quality was assessed by Pittsburgh Sleep Quality Index (PSQI), and stress status was assessed by Perceived Stress Scale (PSS). The levels of epinephrine and norepinephrine were examined to investigate the underlying mechanisms. ResultsA total of 204 (66.4%) and 103 cases (33.6%) were found to be dippers and nondippers, respectively. Nondippers were with poorer sleep quality (P<0.05), more stressful status (P<0.05), and with an increased activity of sympathetic nervous system (P<0.01). The decline of systolic BP (SBP) and diastolic BP (DBP) at night was inversely related with the PSQI score (r=−0.469, P<0.01 and r=−0.421, P<0.01), PSS score (r=−0.432, P<0.01 and r=−0.404, P<0.01), epinephrine (r=−0.304, P<0.05 and r=−0.293, P<0.05), and norepinephrine (r=−0.321, P<0.05 and r=−0.357, P<0.05). Multiple logistic regression analyses showed that older age [odds ratio (OR): 1.69; 95% confidence interval (CI): 1.22–2.43], PSQI score (OR: 2.78; 95% CI: 1.65–6.87), and PSS score (OR: 2.43; 95% CI: 1.56–5.93) were independently correlated with the nondipping pattern. ConclusionPoor sleep quality and stressful status were closely associated with higher activation of sympathetic nervous system, and they are independent predictors of nondipping hypertension.

Activation of AMPK inhibits cardiomyocyte hypertrophy by modulating of the FOXO1/MuRF1 signaling pathway in vitro

AbstractAim:To examine the inhibitory effects of adenosine monophosphate-activated protein kinase (AMPK) activation on cardiac hypertrophy in vitro and to investigate the underlying molecular mechanisms.Methods:Cultured neonatal rat cardiomyocytes were treated with the specific AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) and the specific AMPK antagonist Compound C, and then stimulated with phenylephrine (PE). The Muscle RING finger 1 (MuRF1)-small interfering RNA (siRNA) was transfected into cardiomyocytes using Lipofectamine 2000. The surface area of cultured cardiomyocytes was measured using planimetry. The protein degradation was determined using high performance liquid chromatography (HPLC). The expression of β-myosin heavy chain (β-MHC) and MuRF1, as well as the phosphorylation levels of AMPK and Forkhead box O 1 (FOXO1), were separately measured using Western blot or real-time polymerase chain reaction.Results:Activation of AMPK by AICAR 0.5 mmol/L inhibited PE-induced increase in cardiomyocyte area and β-MHC protein expression and PE-induced decrease in protein degradation. Furthermore, AMPK activation increased the activity of transcription factor FOXO1 and up-regulated downstream atrogene MuRF1 mRNA and protein expression. Treatment of hypertrophied cardiomyocytes with Compound C 1 μmol/L blunted the effects of AMPK on cardiomyocyte hypertrophy and changes to the FOXO1/MuRF1 pathway. The effects of AICAR on cardiomyocyte hypertrophy were also blocked after MuRF1 was silenced by transfection of cardiomyocytes with MuRF1-siRNA.Conclusion:The present study demonstrates that AMPK activation attenuates cardiomyocyte hypertrophy by modulating the atrophy-related FOXO1/MuRF1 signaling pathway in vitro.

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.

MG132 treatment attenuates cardiac remodeling and dysfunction following aortic banding in rats via the NF-κB/TGFβ1 pathway

Although MG132, a proteasome inhibitor, is suggested to impede secondary cardiac remodeling after hypertension, the mechanism and optimal duration of treatment remain unknown. This study was designed to investigate the effects and possible mechanism of MG132 on hypertension-induced cardiac remodeling. Male Sprague-Dawley rats subjected to abdominal aortic constriction (AAC) or sham operation received an intraperitoneal injection of MG132 (0.1mgkg(-1)day(-1)) or vehicle over a 2- or 8-week period. In the end, left ventricular (LV) function was evaluated with echocardiography and pressure tracing. Collagen deposition within the LV myocardium was assessed with Massons trichrome staining. Ubiquitin-proteasome system (UPS), NF-κB, I-κB, TGFβ1 and Smad2 within the LV tissue were evaluated. In addition, angiotensin II within both plasma and LV tissue was also examined. Compared with the sham groups, the vehicle-treated AAC group exhibited a higher angiotensin II level, LV/body weight ratio, septal and posterior wall thicknesses, and a markedly reduced cardiac function (P<0.05). Treatment with MG132 for 8 weeks attenuated these cardiac remodeling parameters and improved cardiac function (P<0.01). 2- and 8-week hypertension led to activation of UPS, which was followed by activation of NF-κB and increased expression of TGFβ1 and Smad2 (P<0.01). MG132 significantly inhibited NF-κB activity and down-regulate the levels of TGFβ1 and Smad2 expression by 2 and still at 8 weeks (P<0.01). Short- and long-term treatment with MG132 significantly attenuated hypertension-induced cardiac remodeling and dysfunction, which may be mediated by the NF-κB/TGFβ1 signaling pathway.

Effects of insulin-like growth factor-1 on the properties of mesenchymal stem cells in vitro.

ObjectiveTo explore the effects of insulin-like growth factor-1 (IGF-1) on migration, proliferation and differentiation of mesenchymal stem cells (MSCs).MethodsMSCs were obtained from Sprague-Dawley rats by a combination of gradient centrifugation and cell culture techniques and treated with IGF-1 at concentrations of 5–20 ng/ml. Proliferation of MSCs was determined as the mean doubling time. Expression of CXC chemokine receptor 4 (CXCR4) and migration property were determined by flow cytometry and transwell migration essay, respectively. mRNA expression of GATA-4 and collagen II was determined by reverse transcription-polymerase chain reaction (RT-PCR).ResultsThe mean doubling time of MSC proliferation was decreased, and the expression of CXCR4 on MSCs and migration of MSCs were increased by IGF-1, all in a dose-dependent manner, while the optimal concentration of IGF-1 on proliferation and migration was different. IGF-1 did not affect the expression of GATA-4 or collagen II mRNA.ConclusionsIGF-1 dose-dependently stimulated the proliferation of MSCs, upregulated the expression of CXCR4, and accelerated migration. There was no apparent differentiation of MSCs to cardiomyocytes or chondrocytes after culturing with IGF-1 alone.

Effectiveness and Safety of Warfarin in Dialysis Patients With Atrial Fibrillation: A Meta-Analysis of Observational Studies

AbstractIn routine practice, warfarin is widely used in dialysis patients with atrial fibrillation (AF) for stroke prevention though the ratio of risks to benefits remains unclear. Recent cohort studies investigating the association between warfarin use and the risks of stroke and bleeding in dialysis patients with AF present conflicting results.The objective of this study was to assess the effectiveness and safety of warfarin use in patients with AF undergoing dialysis.Three databases PubMed, EMBASE, and OVID were searched from their inception to August 2015.Observational studies which assessed the ischemic stroke or bleeding risk of warfarin use in dialysis patients with AF were included. Two reviewers independently extracted data and assessed methodological quality based on the Newcastle–Ottawa Scale score. Combined hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the random-effects model and heterogeneity was assessed based on the Cochrane Q-statistic test and the I2 statistic. Metaregression analyses were performed to explore the source of heterogeneity.A total of 11 eligible studies with 25,407 patients were included in the analysis. Warfarin use, in comparison with no-warfarin use, was not associated with a lower risk for ischemic stroke (HR 0.95, 95% CI 0.66–1.35). Sensitivity analyses found results to be robust. Metaregression analysis showed that demographic feature, clinical characteristics, or study-level variable had no impact of warfarin use on stroke risk. In addition, warfarin use was associated with a 27% higher risk for bleeding (95% CI 1.04–1.54). Overall, warfarin use did not have a significant association with reduced mortality (95% CI 0.96–1.11).It appears that warfarin use is not beneficial in reducing stroke risk, but with a high risk for bleeding in dialysis patients with AF. Randomized trials are needed to determine the risk-benefit ratio of warfarin in dialysis patients with AF.