Yong Sun

Anoxic preconditioning: A way to enhance the cardioprotection of mesenchymal stem cells

OBJECTIVE We hypothesized that anoxic preconditioning (AP) could enhance the cardioprotective effect of mesenchymal stem cells (MSCs). METHODS Myocardial infarction (MI) was set up in Sprague-Dawley rats and left ventricles were randomly injected with the following: DMEM, MSCs and AP-MSCs. Cardiac function was assessed by echocardiography 4 weeks after transplantation, hematoxylin-eosin staining and Masson trichrome were performed subsequently. RESULTS Increased fractional shortening, ejection fraction and decreased infarct size were observed most obviously in AP-MSCs group, accompanied by increased arteriole density and cell survival. CONCLUSIONS AP enhanced the capacity of MSCs to repair infarcted myocardium, attributable to increased cell survival and angiogenesis.

Heat shock protein 90 protects rat mesenchymal stem cells against hypoxia and serum deprivation-induced apoptosis via the PI3K/Akt and ERK1/2 pathways

Mesenchymal stem cell (MSC) transplantation has shown a therapeutic potential to repair the ischemic and infracted myocardium, but the effects are limited by the apoptosis and loss of donor cells in host cardiac microenvironment. The aim of this study is to explore the cytoprotection of heat shock protein 90 (Hsp90) against hypoxia and serum deprivation-induced apoptosis and the possible mechanisms in rat MSCs. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was assessed by Hoechst 33258 nuclear staining and flow cytometric analysis with annexin V/PI staining. The gene expression of Toll-like receptor-4 (TLR-4) and V-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ErbB2) was detected by real-time polymerase chain reaction (PCR). The protein levels of cleaved caspase-3, Bcl-2, Bcl-xL, Bax, total-ERK, phospho-ERK, total-Akt, phospho-Akt, and Hsp90 were detected by Western blot. The production of nitric oxide was measured by spectrophotometric assay. Hsp90 improves MSC viability and protects MSCs against apoptosis induced by serum deprivation and hypoxia. The protective role of Hsp90 not only elevates Bcl-2/Bax and Bcl-xL/Bax expression and attenuates cleaved caspase-3 expression via down-regulating membrane TLR-4 and ErbB2 receptors and then activating their downstream PI3K/Akt and ERK1/2 pathways, but also enhances the paracrine effect of MSCs. These findings demonstrated a novel and effective treatment strategy against MSC apoptosis in cell transplantation.

Safety and efficacy of intracoronary hypoxia-preconditioned bone marrow mononuclear cell administration for acute myocardial infarction patients: The CHINA-AMI randomized controlled trial

BACKGROUND Pre-clinical studies have shown that hypoxia preconditioning can enhance stem cell therapeutic potential for myocardial repair. We sought to investigate the safety and feasibility of intracoronary administration of hypoxia-preconditioned bone marrow mononuclear cells (HP-BMCs) for acute ST segment elevation myocardial infarction (STEMI). METHODS We randomized 22 patients with acute STEMI to receive intracoronary administration of normoxia bone marrow mononuclear cells (N-BMCs) (n=11) or HP-BMCs (n=11) following successful reperfusion. Another 14 patients receiving standard therapy were recruited as control (n=14). RESULTS There were no differences in the occurrence of major adverse cardiovascular events at 30 days and 1 year among three groups. There were significant improvement in the change of left ventricular end-diastolic volume (LVEDV) and end-systolic volume (LVESV) in HP-BMC group both at 6 and 12 months compared with N-BMCs or control group (P<0.05). No differences were observed in the change of left ventricular ejection fraction (LVEF), or wall motion score index (WMSI) among three groups. Nevertheless, WMSI was improved in HP-BMCs and N-BMC group (P<0.05, within group), but not in control. The ratio of myocardial perfusion defect determined by SPECT was significantly decreased in HP-BMCs and N-BMC groups at 6months compared with baseline (P<0.05, within group), but no significant differences were observed among three groups. CONCLUSIONS Our results provide the first-in-man evidence that intracoronary administration of HP-BMCs following acute MI appears to be safe and feasible. These results provide the basis for future prospective randomized clinical trials in a larger patient cohort. CLINICAL TRIAL REGISTRATION INFORMATION NCT01234181 (http://clinicaltrials.gov/ct2/show/NCT01234181?term=NCT01234181&rank=1).

Evaluation of the safety and efficacy of transcatheter aortic valve implantation in patients with a severe stenotic bicuspid aortic valve in a Chinese population

ObjectiveThe purpose of this study is to evaluate the safety and efficacy of transcatheter aortic valve implantation (TAVI) in patients with a severe stenotic bicuspid aortic valve (BAV) in a Chinese population. While several groups have reported the feasibility, efficacy, and safety of TAVI for patients with a BAV, worldwide experience of the technique is still limited, especially in China.MethodsFrom March 2013 to November 2014, high surgical risk or inoperable patients with symptomatic severe aortic stenosis (AS) who had undergone TAVI at our institution were selected for inclusion in our study. Results were compared between a BAV group and a tricuspid aortic valve (TAV) group.ResultsForty patients were included in this study, 15 (37.5%) of whom were identified as having a BAV. In the BAV group, the aortic valve area was smaller ((0.47±0.13) vs. (0.59±0.14) cm2), the ascending aortic diameter was larger ((40.4±4.4) vs. (36.4±4.3) mm), and the concomitant aortic regurgitation was lower. No significant differences were found between the groups in the other baseline characteristics. No differences were observed either in the choice of access or valve size. The procedural success achieved in this study was 100%. There were no differences between groups in device success (86.7% vs. 88.0%), 30-d mortality (6.7% vs. 8.0%), or 30-d combined end point (13.3% vs. 12.0%). The incidences of new pacemaker implantation, paravalvular regurgitation and other complications, recovery of left ventricle ejection fraction and heart function were similar in both groups.ConclusionsPatients with a severely stenotic BAV can be treated with TAVI, and their condition after treatment should be similar to that of people with a TAV.摘要目的评估经导管主动脉瓣置入术在中国人群二叶式主动脉瓣重度狭窄中的安全性和有效性。创新点首次在中国人群比较经导管主动脉瓣置入术在二叶式和三叶式主动脉瓣重度狭窄中的安全性和有效性。方法选取2013年3月至2014年9月行经导管主动脉瓣置入术的40位主动脉瓣狭窄的患者, 分二叶式和三叶式主动脉瓣两组, 比较基线水平、 手术以及随访1月结果的差别。结论经导管主动脉瓣置入术在中国人群中二叶式主动脉瓣重度狭窄中的应用是安全有效的。

Complex coronary lesions and rotational atherectomy: one hospital’s experience

ObjectiveTo evaluate the safety and effectiveness of rotational atherectomy followed by drug eluting stent (DES) implantation in patients with complex coronary lesions.MethodsFrom August 2006 to August 2012, 253 consecutive patients with 289 lesions and who underwent rotational atherectomy in our center were enrolled in this study.ResultsThe overall procedure success rate was 98% with the cost of two (0.8%) coronary perforations, three (1.2%) dissections, five (2.0%) slow flows or no flows, three (1.2%) peri-procedure myocardial infarctions, and two (0.8%) in hospital deaths. During follow-up (mean three years), one (0.4%) patient died, two (0.8%) patients had acute myocardial infarction, 14 (5.5%) had restenosis, and target lesion revascularization occurred in eight patients (3.2%).ConclusionsRotational atherectomy followed by DES implantation is a safe and effective technique for patients with complex coronary lesions, especially calcified and non-dilatable lesions.

TNFR2 Stimulation Promotes Mitochondrial Fusion via Stat3- and NF-kB-Dependent Activation of OPA1 Expression

Rationale: Mitochondria are important cellular organelles and play essential roles in maintaining cell structure and function. Emerging evidence indicates that in addition to having proinflammatory and proapoptotic effects, TNF&agr; (tumor necrosis factor &agr;) can, under certain circumstances, promote improvements in mitochondrial integrity and function, phenomena that can be ascribed to the existence of TNFR2 (TNF&agr; receptor 2). Objective: The present study aimed to investigate whether and how TNFR2 activation mediates the effects of TNF&agr; on mitochondria. Methods and Results: Freshly isolated neonatal mouse cardiac myocytes treated with shRNA targeting TNFR1 were used to study the effects of TNFR2 activation on mitochondrial function. Neonatal mouse cardiac myocytes exhibited increases in mitochondrial fusion, a change that was associated with increases in mitochondrial membrane potential, intracellular ATP levels, and oxygen consumption capacity. Importantly, TNFR2 activation–induced increases in OPA1 (optic atrophy 1) protein expression were responsible for the above enhancements, and these changes could be attenuated using siRNA targeting OPA1. Moreover, both Stat3 and RelA bound to the promoter region of OPA1 and their interactions synergistically upregulated OPA1 expression at the transcriptional level. Stat3 acetylation at lysine 370 or lysine 383 played a key role in the ability of Stat3 to form a supercomplex with RelA. Meanwhile, p300 modulated Stat3 acetylation in HEK293T (human embryonic kidney 293T) cells, and p300-mediated Stat3/RelA interactions played an indispensable role in OPA1 upregulation. Finally, TNFR2 activation exerted beneficial effects on OPA1 expression in an in vivo transverse aortic constriction model, whereby TNFR1-knockout mice exhibited better outcomes than in mice with both TNFR1 and TNFR2 knocked out. Conclusions: TNFR2 activation protects cardiac myocytes against stress by upregulating OPA1 expression. This process was facilitated by p300-mediated Stat3 acetylation and Stat3/RelA interactions, leading to improvements in mitochondrial morphology and function.

Electron leak from NDUFA13 within mitochondrial complex I attenuates ischemia-reperfusion injury via dimerized STAT3

Significance Reactive oxygen species (ROS) generation due to electron leak from the mitochondria may be involved in physiological or pathological processes. NDUFA13 is an accessory subunit of mitochondria complex I with a unique molecular structure and is located close to FeS clusters with low electrochemical potentials. Here, we generated cardiac-specific conditional NDUFA13 heterozygous knockout mice. At the basal state, a moderate down-regulation of NDUFA13 created a leak within complex I, resulting in a mild increase in cytoplasm localized H2O2, but not superoxide. The resultant ROS served as a second messenger and was responsible for the STAT3 dimerization and, hence, the activation of antiapoptotic signaling, which eventually significantly suppressed the superoxide burst and decreased the infarct size during the ischemia-reperfusion process. The causative relationship between specific mitochondrial molecular structure and reactive oxygen species (ROS) generation has attracted much attention. NDUFA13 is a newly identified accessory subunit of mitochondria complex I with a unique molecular structure and a location that is very close to the subunits of complex I of low electrochemical potentials. It has been reported that down-regulated NDUFA13 rendered tumor cells more resistant to apoptosis. Thus, this molecule might provide an ideal opportunity for us to investigate the profile of ROS generation and its role in cell protection against apoptosis. In the present study, we generated cardiac-specific tamoxifen-inducible NDUFA13 knockout mice and demonstrated that cardiac-specific heterozygous knockout (cHet) mice exhibited normal cardiac morphology and function in the basal state but were more resistant to apoptosis when exposed to ischemia-reperfusion (I/R) injury. cHet mice showed a preserved capacity of oxygen consumption rate by complex I and II, which can match the oxygen consumption driven by electron donors of N,N,N′,N′-tetramethyl-p-phenylenediamine (TMPD)+ascorbate. Interestingly, at basal state, cHet mice exhibited a higher H2O2 level in the cytosol, but not in the mitochondria. Importantly, increased H2O2 served as a second messenger and led to the STAT3 dimerization and, hence, activation of antiapoptotic signaling, which eventually significantly suppressed the superoxide burst and decreased the infarct size during the I/R process in cHet mice.

Efficacy and Safety of Uninterrupted Low-Intensity Warfarin for Radiofrequency Catheter Ablation of Atrial Fibrillation in the Elderly: A Pilot Study

Background: No previous studies exist investigating the optimal intensity of uninterrupted anticoagulation with warfarin during radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF) in the elderly. Objective: Evaluate the efficacy and safety of continuous low-intensity warfarin therapy throughout the periprocedural period of RFCA for AF in the elderly. Methods: This is a prospective randomized study. We enrolled AF patients (age ≥ 70 years) who underwent first-time RFCA for AF. Enrolled patients were randomized to group A and group B. The international normalized ratios before ablation were maintained at 1.5 to 2.0 and 2.0 to 2.5 in group A and B, respectively. Primary end points were periprocedural thromboembolic complications and major bleeding. Secondary end points included periprocedural asymptomatic cerebral emboli (ACE) and minor bleeding. Results: A total of 101 patients were enrolled in our study (group A: 52; group B: 49). Baseline characteristics were well balanced between the 2 groups. Only 1 patient suffered from stroke in group B. No major bleeding events occurred in either group. The incidence of new ACE lesions was comparable between the 2 groups (11.5% vs 8.2%, P = 0.82). Minor bleeding occurred in 1 of 52 (1.9%) patients in group A and in 5 of 49 (10.2%) patients in group B (P = 0.10). Conclusions: Uninterrupted low-intensity warfarin for RFCA of AF might be as effective as standard-intensity warfarin in preventing periprocedural thromboembolic complications and might be associated with fewer bleeding events in the elderly.

Segmental radiofrequency ablation of pulmonary vein ostia for patients with refractory paroxysmal atrial fibrillation using multi-slice spiral computed tomography guidance

Objective: To evaluate the safety and clinical efficacy of segmental radiofrequency ablation of pulmonary vein (PV) ostia for patients with refractory paroxysmal atrial fibrillation (AF) under multi-slice spiral computed tomography (MSCT) guidance before the procedure. Methods: A series of 58 consecutive patients with refractory paroxysmal AF were enrolled to undergo segmental radiofrequency ablation of PV ostia. The 36 male and 22 female patients with mean age of (57.4±9.5) (32:_79) years and no obvious organic heart disease. Before ablation, patients received MSCT to generate 3-dimentional image of the left atrium (LA) and proximal PVs. Patients then underwent segmental radiofrequency ablation of PV ostia using PV circular mapping catheter manipulated several times to ensure complete isolation between PVs and LA. Results: No complications occurred during the procedure. One patient developed delayed cardiac tamponade, which was drained percutaneously. The mean follow-up time was (17.1±9.3) months. Forty-one patients (95%) experienced improved quality of life one month after the procedure. Thirty-six patients (83%) showed stable sinus rhythm, while 10 patients (23%) required additional anti-arrhythmic drugs. AF returned≥1 time in 6 (14%) patients who underwent anti-arrhythmic drug therapy, but the number of episodes was less than that before the procedure. However, one patient experienced recurrent episodes of atrial flutter. Conclusion: It is safe and effective to perform segmental radiofrequency ablation of PV ostia for patients with refractory paroxysmal AF using MSCT guidance mappening.

Efficacy and safety of uninterrupted low-intensity warfarin for cryoballoon ablation of atrial fibrillation in the elderly: A pilot study

Uninterrupted warfarin during cryoballoon ablation (CB‐A) of atrial fibrillation (AF) has been widely accepted. However, to our knowledge, no previous studies exist investigating the optimal intensity of anticoagulation with warfarin for CB‐A. This study aimed to evaluate the efficacy and safety of uninterrupted low‐intensity warfarin for CB‐A of AF in the elderly.