5F peptide promotes endothelial differentiation of bone marrow stem cells through activation of ERK1/2 signaling.

Synthetic apolipoprotein A-I (apoA-I) mimetic peptide 5F exhibits anti-atherosclerotic ability with largely unknown mechanism(s). Bone marrow (BM)-derived endothelial progenitor cells (EPCs) play a critical role in vascular integrity and function. The objective of the present study was to evaluate the effect of 5F on endothelial differentiation of BM stem cells and related mechanisms. Murine BM multipotent adult progenitor cells (MAPCs) were induced to differentiate into endothelial cells in vitro with or without 5F. The expression of endothelial markers vWF, Flk-1 and CD31 was significantly increased in the cells treated with 5F with enhanced in vitro vascular tube formation and LDL uptake without significant changes on proliferation and stem cell maker Oct-4 expression. Phosphorylated ERK1/2, not Akt, was significantly increased in 5F-treated cells. Treatment of MAPCs with PD98059 or small interfering RNA against ERK2 substantially attenuated ERK1/2 phosphorylation, and effectively prevented 5F-induced enhancement of endothelial differentiation of MAPCs. In vivo studies revealed that 5F increased EPCs number in the BM in mice after acute hindlimb ischemia that was effectively prevented with PD98059 treatment. These data supported the conclusion that 5F promoted endothelial differentiation of MAPCs through activation of ERK1/2 signaling.

Incidence and predictors of left atrial thrombus in patients with atrial fibrillation prior to ablation in the real world of China.

BACKGROUND: The present study was to evaluate the value of CHADS2 and CHA2DS2VASC scores on predicting left atrial (LA) or left atrial appendage (LAA) thrombus in atrial fibrillation (AF) patients prior to ablation in the real world of China. METHODS AND RESULTS: A total of 397 patients with non-valvular AF were analyzed to determine the relationship between CHADS2 and CHA2DS2VASC scores and LA/LAA thrombus identified on transesophageal echocardiography prior to radiofrequency ablation(RFA). LA/LAA thrombus was present in 38 patients (9.6%). There was a strong association between higher CHADS2 score or CHA2DS2VASC score and LA/LAA thrombus. No thrombus was identified in patients with CHA2DS2VASC score of 0 regardless of anticoagulation status. However, LA/LAA thrombus was detected in 2.9% patients with CHADS2 score of 0 without adequate anticoagulation, while no thrombus was present in the patients with CHADS2 score of 0 with adequate anticoagulation. Univariate analysis showed that heart failure (LVEF＜50%), LA≥40 mm, diabetes mellitus, previous stroke or TIA, CAD, hypertension, inadequate anticoagulation therapy, CHADS2 score of ≥2 and CHA2DS2VASC score of ≥2 were significantly associated with LA/LAA thrombus. Multivariable Cox regression analysis demonstrated that CHA2DS2VASC score of ≥2 (p = 0.02) and previous stroke or TIA (p = 0.04) were independently associated with LA/LAA thrombus regardless of anticoagulation status. ROC curve analysis showed that higher CHADS2 score and CHA2DS2VASC score could be similarly used to predict the presence of LA thrombus. CONCLUSIONS: Both higher CHA2DS2VASC and CHADS2 scores were associated with LA/LAA thrombus in non-valvular AF patients prior to ablation. Although CHA2DS2VASC score and CHADS2 score had similar value to predict LA/LAA thrombus, CHA2DS2VASc score was better to identify low-risk patients for LA/LAA thrombus than CHADS2 score without anticoagulation. There will be a possibility of performing AF ablation or cardioversion in patients with a CHA2DS2VASC of 0 without TEE or anticoagulation therapy. The safety need to be verified by more multicentre randomized controlled clinical trails.

Spontaneous scar-based reentrant atrial flutter: Electrophysiologic characteristics and ablation outcome in a retrospective analysis.

BACKGROUND: The understanding of spontaneous scar-based reentrant atrial arrhythmia is limited. We aim to characterize the electrophysiologic and mapping features of spontaneous scar-based atrial flutter (AFL) and outcomes of catheter ablation. METHODS: Consecutive patients with a diagnosis of AFL who underwent catheter ablation from January 2012 to June 2015 were screened. Scars were detected in 12 patients and were included in this study. All had negative coronary angiography. These patients were divided into right AFL (seven patients) and left AFL groups (five patients) based on electrophysiologic mappings. RESULTS: Compared to patients with right AFL, the size of right atrium (RA) was smaller and left atrium (LA) was larger in the left AFL group. The proportion of the scar area was 11.1 ± 11.7 % in the RA AFL group and 7.8 ± 2.8 % in the LA AFL group. The difference was significant (P = 0.001). The acute success rates of ablation were 85.7% and 100%, respectively, in patients with right and left AFL (P = 0.304). During the follow-up, expansion of the scar area was noted in three patients with recurrent right AFL. No scar expansion was noted in one patient with recurrent left AFL. In addition, three patients with right AFL required permanent pacemaker implantation for sinus node dysfunction, and no one required pacemaker in patients with left AFL. CONCLUSIONS: Spontaneous scar could serve as substrate for AFL in RA or LA. Compared to left AFL, there was a higher rate of recurrence and pacemaker implantation in patients with right AFL.

Potential role of MG53 in the regulation of transforming-growth-factor-ß1-induced atrial fibrosis and vulnerability to atrial fibrillation.

Atrial fibrosis plays a critical role in atrial fibrillation (AF) by the transforming growth factor (TGF)-ß1/Smad pathway. The disordered differentiation, proliferation, migration and collagen deposition of atrial fibroblasts play significant roles in atrial fibrosis. Mitsugumin (MG)53 is predominantly expressed in myocardium of rodents and has multiple biological functions. However, the role of MG53 in cardiac fibrosis remains unclear. This study provided clinical and experimental evidence for the involvement of MG53 in atrial fibrosis in humans and atrial fibrosis phenotype in cultured rat atrial fibroblasts. In atrial tissue from patients we demonstrated that MG53 was expressed in human atrium. Expression of MG53 increased with the extent of atrial fibrosis, which could induce AF. In cultured atrial fibroblasts, depletion of MG53 by siRNA caused down-regulation of the TGF-ß1/Smad pathway, while overexpression of MG53 by adenovirus up-regulated the pathway. MG53 regulated the proliferation and migration of atrial fibroblasts. Besides, exogenous TGF-ß1 suppressed expression of MG53. In conclusion, we demonstrated that MG53 was expressed in human atrium, and may be a potential upstream of the TGF-ß1/Smad pathway in human atrium and rat atrial fibroblasts. This suggests that MG53 is a potential regulator of atrial fibrosis induced by the TGF-ß1/Smad pathway in patients with AF.

A Simple Method to Differentiate Atrioventricular Node Reentrant Tachycardia from Orthodromic Reciprocating Tachycardia.

Discrimination between atrioventricular node reentry tachycardia (AVNRT) and orthodromic reciprocating tachycardia (ORT) during an electrophysiological study is sometimes challenging. This study aimed to investigate if the difference in the local VA (ventricle-atrium) interval during ventricular entrainment pacing and during tachycardia (DVA, defined as the shortest local VA interval of coronary sinus [CS] during entrainment minus the shortest local VA interval of CS during tachycardia) was different in patients with AVNRT and patients with ORT.Diagnoses of AVNRT or ORT through a concealed accessory pathway (AP) were made according to conventional electrophysiological criteria and ablation results. Entrainment by right ventricular (RV) pacing was performed in each patient before ablation and patients with successful entrainment were included in the study. The DVA was compared between patients with AVNRT and patients with ORT. The DVA in patients with AVNRT was significantly longer than that in patients with ORT (120 ± 20 versus 5.7 ± 9; P < 0.001). In each patient with AVNRT of slow-fast type, fast-slow type, and slow-slow type, the DVA was more than 48 ms. In each patient with ORT using a left free wall accessory pathway (AP), right free wall AP, and septal AP, the DVA was less than 20 ms.DVA was found to be a rapid, useful test in distinguishing patients with AVNRT from those with ORT.

Ambient Fine Particulate Matter Suppresses In Vivo Proliferation of Bone Marrow Stem Cells through Reactive Oxygen Species Formation.

AIMS: Some environmental insults, such as fine particulate matter (PM) exposure, significantly impair the function of stem cells. However, it is unknown if PM exposure could affect the population of bone marrow stem cells (BMSCs). The present study was to investigate the effects of PM on BMSCs population and related mechanism(s). MAIN METHEODS: PM was intranasally distilled into male C57BL/6 mice for one month. Flow cytometry with antibodies for BMSCs, Annexin V and BrdU ware used to determine the number of BMSCs and the levels of their apoptosis and proliferation in vivo. Phosphorylated Akt (P-Akt) level was determined in the BM cells with western blotting. Intracellular reactive oxygen species (ROS) formation was quantified using flow cytometry analysis. To determine the role of PM-induced ROS in BMSCs population, proliferation, and apotosis, experiments were repeated using N-acetylcysteine (NAC)-treated wild type mice or a triple transgenic mouse line with overexpression of antioxidant network (AON) composed of superoxide dismutase (SOD)1, SOD3, and glutathione peroxidase-1 with decreased in vivo ROS production. KEY FINDINGS: PM treatment significantly reduced BMSCs population in association with increased ROS formation, decreased P-Akt level, and inhibition of proliferation of BMSCs without induction of apoptosis. NAC treatment or AON overexpression with reduced ROS formation effectively prevented PM-induced reduction of BMSCs population and proliferation with partial recovery of P-Akt level. SIGNIFICANCE: PM exposure significantly decreased the population of BMSCs due to diminished proliferation via ROS-mediated mechanism (could be partially via inhibition of Akt signaling).

Ambient fine particulate matter induces apoptosis of endothelial progenitor cells through reactive oxygen species formation.

BACKGROUND/AIMS: Bone marrow (BM)-derived endothelial progenitor cells (EPCs) play a critical role in angiogenesis and vascular repair. Some environmental insults, like fine particulate matter (PM) exposure, significantly impair cardiovascular functions. However, the mechanisms for PM-induced adverse effects on cardiovascular system remain largely unknown. The present research was to study the detrimental effects of PM on EPCs and explore the potential mechanisms. METHODS: PM was intranasal-distilled into male C57BL/6 mice for one month. Flow cytometry was used to measure the number of EPCs, apoptosis level of circulating EPCs and intracellular reactive oxygen species (ROS) formation. Serum TNF-α and IL-1ß were measured using ELISA. To determine the role of PM-induced ROS in EPC apoptosis, PM was co-administrated with the antioxidant N-acetylcysteine (NAC) in wild type mice or used in a triple transgenic mouse line (TG) with overexpression of antioxidant enzyme network (AON) composed of superoxide dismutase (SOD)1, SOD3, and glutathione peroxidase (Gpx-1) with decreased in vivo ROS production. RESULTS: PM treatment significantly decreased circulating EPC population, promoted apoptosis of EPCs in association with increased ROS production and serum TNF-α and IL-1ß levels, which could be effectively reversed by either NAC treatment or overexpression of AON. CONCLUSION: PM exposure significantly decreased circulating EPCs population due to increased apoptosis via ROS formation in mice.

[CHADS2versus CHA2DS2-VASc scoring systems for predicting left atrial thrombus in patients with nonvalvular atrial fibrillation].

OBJECTIVE: To assess the correlation of CHADS2and CHA2DS2-VASc scores for left atrial thrombus in patients with nonvalvular atrial fibrillation and the differences in the results between the two scoring systems. METHODS: A total of 397 patients with nonvalvular atrial fibrillation were enrolled in this study. The CHADS2and CHA2DS2-VASc scoring systems were used for evaluating the risk of left atrial thrombus and their differences in the scores and risk stratifications were compared. The correlation of CHADS2 and CHA2DS2-VASc scores with left atrial thrombus was analyzed. RESULTS: The average score of CHA2DS2-VASc was significantly higher than that of CHADS2in these patients (1.37 ± 1.19 vs 0.63 ± 0.78, P<0.001). The proportion of high-risk group was significantly higher (P<0.001) while that of low-risk group significantly lower as stratified by CHA2DS2-VASc scores than by CHADS2scores (P<0.001). Transesophageal echocardiography detected left atrial thrombus in 44 of the total patients. The prevalence of left atrial thrombus increased significantly with a higher risk stratification by CHADS2or CHA2DS2-VASc scores (P<0.05). Univariate analysis showed that female gender, age ≥ 65 years, left atrium diameter ≥ 38 mm, left ventricular ejection fraction ≤ 40%, hypertension, diabetes, coronary heart disease, stroke history, CHADS2≥ 2, and CHA2DS2-VASc ≥ 2 were all correlated with left atrial thrombus, but multivariate logistic analysis identified only CHA2DS2-VASc ≥ 2 as the independent risk factor for left atrial thrombus (OR=9.85, 95% CI: 2.178-44.542, P < 0.01). CONCLUSION: The average score of CHA2DS2-VASc is higher than that of CHADS2and has better predictive ability for left atrial thrombus.

Combination of C-reactive protein and cardiac troponin I for predicting adverse cardiac events after sirolimus-eluting stent implantation.

AIMS: We assessed the predictive value of a combination of C-reactive protein (CRP) and cardiac troponin I (cTnI) in a 2-year prospective study in patients undergoing sirolimus-eluting stents (SES) implantation. METHODS AND RESULTS: CRP and cTnI levels were examined 1 day before and after SES implantation in 322 patients. CRP level greater than 3.0 mg/l (defining the high serum CRP levels) and cTnI level greater than 1.0 microg/l (defining the high serum cTnI levels) were considered abnormal. Major adverse cardiac events were defined as nonfatal myocardial infarction (MI), target vessel revascularization (TVR), and cardiac death. After 2+/-0.2 years of follow-up, there were 11 MI, 19 TVR, and 11 cardiac deaths. After adjustment for relevant risk factors, the combination of high CRP and cTnI remained predictive of adverse cardiac events, with the presence of both elevated CRP and cTnI associated with the highest risks of MI [relative risk (RR): 4.0, 95% confidence interval (CI): 2.3-6.4], TVR (RR: 3.3, 95% CI: 2.8-5.3), and cardiac death (RR: 4.2, 95% CI: 2.6-6.0). The presence of either a high CRP or cTnI was associated with an intermediated risk of MI (RR: 1.7, 95% CI: 1.2-2.2), TVR (RR: 1.5, 95% CI: 1.2-2.7), and cardiac death (RR: 2.8, 95% CI: 2.2-3.6). CONCLUSION: The combination of elevated CRP and cTnI increased the risk of adverse cardiac events, demonstrating the additive impacts of active inflammation and myocardial injury on prognosis after SES implantation.

[Elevated serum high sensitivity C-reactive protein and endothelial dysfunction in silent myocardial ischemia].

OBJECTIVE: To explore the association between silent myocardial ischemia (SMI) and high sensitivity C-reactive protein (hsCRP) and endothelial dysfunction. METHODS: 148 asymptomatic patients (103 men and 45 women) with known CAD were recruited. According to the results of ambulatory electrocardiography recording (AECG), patients were divided into two groups: SMI group and non-SMI group. All the patients underwent assessment of endothelial dependent flow mediated dilation (FMD) with high resolution ultrasound for the evaluation of endothelial function and 24-hour three-lead ambulatory electrocardiography recording for the detection of SMI. Serum hsCRP, blood glucose, HDL cholesterol, LDL cholesterol and triglycerides were measured. RESULTS: Sixty of the 148 patients had SMI, with a relatively high prevalence of 40.5%. The serum concentration of hsCRP in SMI group was higher than that in non-SMI group (1.86 +/- 0.52 vs 0.91 +/- 0.36, P < 0.05) and FMD was lower in SMI group than that in non-SMI group (3.02 +/- 1.46 vs 6.36 +/- 3.79, P < 0.05). In logistic regression analysis, SMI was found to be related only to FMD (beta = -0.452, P = 0.046, OR = 1.572) and hsCRP (beta = 1.233, P = 0.036, OR = 1.632). CONCLUSIONS: SMI shows a relatively high prevalence in patients with known stable CAD; it is suggested that this population still needs to be carefully evaluated with risk stratification. SMI may be caused by inflammation and endothelial dysfunction. FMD and hsCRP may serve as the surrogate markers in screening SMI in patients with known CAD.