Follistatin-Like 1 Attenuates Ischemia/Reperfusion Injury in Cardiomyocytes via Regulation of Autophagy.

BACKGROUND: The cardioprotective effect of FSTL1 has been extensively studied in recent years, but its role in myocardial ischemia/reperfusion injury (IRI) is unclear. In this study, we investigated the effect of FSTL1 pretreatment on myocardial IRI as well as the possible involvement of autophagic pathways in its effects. METHODS: The effects of FSTL1 on the viability and apoptosis of rat cardiomyocytes were investigated after exposure of cardiomyocytes to hypoxia/ischemia by using the CCK-8 assay and Annexin V/PI staining. Further, western blot analysis was used to detect the effects of FSTL1 pretreatment on autophagy-associated proteins, and confocal microscopy was used to observe autophagic flux. To confirm the role of autophagy, the cells were treated with the autophagy promoter rapamycin or the autophagy inhibitor 3-methyladenine, and cell viability and apoptosis during IRI were observed. These effects were also observed after treatment with rapamycin or 3-methyladenine followed by FSTL1 administration and IRI. RESULTS: FSTL1 pretreatment significantly increased viability and reduced apoptosis in cardiomyocytes exposed to hypoxia/ischemia conditions. Further, FSTL1 pretreatment affected the levels of the autophagy-related proteins and enhanced autophagic flux during IRI. In addition, cell viability was enhanced and apoptosis was decreased by rapamycin treatment, while these effects were reversed by 3-MA treatment. However, when the myocardial cells were pretreated with rapamycin or 3-methyladenine, there was no significant change in their viability or apoptosis with FSTL1 treatment during IRI. CONCLUSIONS: FSTL1 plays a protective role in myocardial IRI by regulating autophagy.

LncRNA CASC11 improves atherosclerosis by downregulating IL-9 and regulating vascular smooth muscle cell apoptosis and proliferation.

LncRNA CASC11 is an oncogene in several types of cancer, while its role in atherosclerosis is unknown. In the present study we found that CASC11 was downregulated, while IL-9 was upregulated in plasma of atherosclerosis patients compared with healthy controls. Altered plasma levels of CASC11 and IL-9 distinguished atherosclerosis patients from healthy controls. CASC11 and IL-9 were significantly and inversely correlated in atherosclerosis patients but not in healthy controls. Exogenous IL-9 treatment failed to significantly affect expression levels of CASC11 in vascular smooth muscle cells (VSMC), while CASC11 overexpression resulted in the downregulation of IL-9. CASC11 overexpression also resulted in the downregulation of proliferation and promoted apoptosis of VSMC. Therefore, CASC11 may improve atherosclerosis by downregulating IL-9 and regulating VSMC apoptosis and proliferation.

An aorto-oesophageal fistula treated with endovascular aortic repair: the fate of untreated oesophageal lesion on endoscopic follow-up.

Oesophageal foreign body is an emergency situation. Once oesophageal perforation occurs, damage and subsequent infection involving surrounding tissue or organs may ensue. We present here a rare case of aorto-oesophageal fistula which was treated with challenges. An old lady with fishbone induced oesophageal perforation, aortic pseudoaneurysm and mediastinal haematoma was treated with great vessel stent-graft placed in aortic arch, and the fish bone was removed under endoscopy thereafter. During the early follow-up period, part of the graft stent was discovered in the oesophageal perforation with no haemorrhage. The patient is still in good condition during follow-up.

Spermine ameliorates ischemia/reperfusion injury in cardiomyocytes via regulation of autophagy.

Myocardial infarction could result in high morbidity and mortality and heart diseases of children have becoming prevalent. Functions of spermine administration on cardiomyocytes remain unknown. The present study was designed to investigate the role of spermine pretreatment on myocardial ischemia/reperfusion injury (IRI). A cell model of simulated ischemia/reperfusion injury was established by incubating neonatal Sprague-Dawley rat cardiomyocytes in ischemia medium and re-cultured in normal medium. Of note, spermine pretreatment significantly reduced apoptosis and increased viability of immature cardiomyocytes. Spermine pretreatment enhanced autophagic flux as determined by confocal microscopy and transmission electron microscopy. Furthermore, proteins of mammalian target of rapamycin (mTOR) pathway were significantly reduced in response to spermine pretreatment during IRI, while proteins related to autophagy were up-regulated. The cell viability was enhanced and apoptosis decreased by rapamycin after spermine pretreatment, while these were reversed by 3-methyladenine. However, when immature cardiomyocytes were pretreated with rapamycin or 3-methyladenine, followed by IRI and spermine administration, no significant changes of viability and apoptosis were observed. In conclusion, this study suggests that spermine is a potential novel approach for preventing IRI, especially in children.

Protective function of tocilizumab in human cardiac myocytes ischemia reperfusion injury.

OBJECTIVE: To investigate the protective function of tocilizumab in human cardiac myocytes ischemia-reperfusion injury. METHODS: The human cardiac myocytes were treated by tocilizumab with different concentrations(1.0 mg/mL, 3.0 mg/mL, 5.0 mg/mL) for 24 h, then cells were cultured in ischemia environment for 24 h and reperfusion environment for 1 h. The MTT and flow cytometry were used to detect the proliferation and apoptosis of human cardiac myocytes, respectively. The mRNA and protein expressions of Bcl-2 and Bax were measured by qRT-PCR and western blot, respectively. RESULTS: Compared to the negative group, pretreated by tocilizumab could significantly enhance the proliferation viability and suppress apoptosis of human cardiac myocytes after suffering ischemia reperfusion injury (P<0.05). The expression of Bcl-2 in tocilizumab treated group were higher than NC group (P<0.05), while the Bax expression were lower (P<0.05). CONCLUSIONS: Tocilizumab could significantly inhibit apoptosis and keep the proliferation viability of human cardiac myocytes after suffering ischemia reperfusion injury. Tocilizumab may obtain a widely application in the protection of ischemia reperfusion injury.

Anterolateral minithoracotomy versus median sternotomy for mitral valve disease: a meta-analysis.

OBJECTIVE: Mitral valve disease tends to be treated with anterolateral minithoracotomy (ALMT) rather than median sternotomy (MS), as ALMT uses progressively smaller incisions to promote better cosmetic outcomes. This meta-analysis quantifies the effects of ALMT on surgical parameters and post-operative outcomes compared with MS. METHODS: One randomized controlled study and four case-control studies, published in English from January 1996 to January 2013, were identified and evaluated. RESULTS: ALMT showed a significantly longer cardiopulmonary bypass time (P=0.001) and aortic cross-clamp time (P=0.05) compared with MS. However, the benefits of ALMT were evident as demonstrated by a shorter length of hospital stay (P<0.00001). According to operative complications, the onset of new arrhythmias following ALMT decreased significantly as compared with MS (P=0.05); however, the incidence of peri-operative mortality (P=0.62), re-operation for bleeding (P=0.37), neurologic events (P=0.77), myocardial infarction (P=0.84), gastrointestinal complications (P=0.89), and renal insufficiency (P=0.67) were similar to these of MS. Long-term follow-up data were also examined, and revealed equivalent survival and freedom from mitral valve events. CONCLUSIONS: Current clinical data suggest that ALMT is a safe and effective alternative to the conventional approach and is associated with better short-term outcomes and a trend towards longer survival.

Hybrid perventricular device closure of doubly committed subarterial ventricular septal defects: mid-term results.

BACKGROUND: Doubly committed Subarterial ventricular septal defect (VSD) is a specific anatomic type of VSD located just beneath the aortic valve. The purpose of this study was to evaluate the safety and feasibility of using minimal invasive perventricular device closure in managing this type of VSD. METHODS: During Dec 2008 and Aug 2010, 34 Pediatric patients with doubly committed subarterial VSD who met the inclusion criteria for device closure were enrolled in this study. Perventricular closure was attempted using a unique design eccentric device under the guidance of real-time transesophageal echocardiography. Complications such as residual shunt, valve regurgitation, arrhythmias were all recorded in postoperative period and during follow-up. RESULT: Perventricular device closure was successfully done in 28 patients (82%). 6 patients converted to open surgical repair due to residual shunt >3mm (1 patient), more than mild degree aortic regurgitation (3 patients) and device mal-position (2 patients). Complete closure rate was achieved in 93% at discharge and 100% during 20 months follow-up. No severe complications such as device embolism, significant arrhythmias and noticeable valve regurgitation were noted during follow-up. Procedure induced trivial grade aortic valve regurgitation was noted in five (18%) patients after procedure while only one (4%) persisted during midterm follow-up. CONCLUSION: Perventricular closure of doubly committed subarterial VSDs appears to be a safe and effective minimally invasive technique with good mid-term outcomes.

Perventricular device closure of residual muscular ventricular septal defects after repair of complex congenital heart defects in pediatric patients.

Residual muscular ventricular septal defects are surgical challenges, especially after the repair of complex congenital heart defects. We investigated perventricular device closure as a salvage technique in pediatric patients who had postoperative residual muscular ventricular septal defects. From February 2009 through June 2011, 14 pediatric patients at our hospital had residual muscular ventricular septal defects after undergoing surgical repair of complex congenital heart defects. Ten patients met our criteria for perventricular device closure of the residual defects: significant left-to-right shunting (Qp/Qs >1.5) or substantial hemodynamic instability (a defect ≥2 mm in size). The patients' mean age was 20.4 ± 13.5 months, and their mean body weight was 10 ± 3.1 kg. The median diameter of the residual defects was 4.2 mm (range, 2.5-5.1 mm). We deployed a total of 11 SQFDQ-II Muscular VSD Occluders (Shanghai Shape Memory Alloy Co., Ltd.; Shanghai, China) in the 10 patients, in accord with conventional techniques of perventricular device closure. The mean procedural duration was 31.1 ±9.1 min. We recorded the closure and complication rates perioperatively and during a 12-month follow-up period. Complete closure was achieved in 8 patients; 2 patients had persistent trivial residual shunts. No deaths, conduction block, device embolism, or other complications occurred throughout the study period. We conclude that perventricular device closure is a safe, effective salvage treatment for postoperative residual muscular ventricular septal defects in pediatric patients. Long-term studies with larger cohorts might further confirm this method's feasibility.

Long-term leukocyte filtration should be avoided during extracorporeal circulation.

Filtration during extracorporeal circulation (ECC) not only removes but also activates leukocytes; therefore, long-term leukocyte filtration may cause adverse effects. In the present study, we tested this hypothesis by priming ECC with 300 mL of canine blood and examining filtration effects in 3 groups (n = 6 each) during 60 min ECC. In the control group (Group C) blood was filtrated with an arterial filter for 60 min; in long-term (Group L) and short-term (Group S) groups, blood was filtrated with a leukocyte filter for 60 and 5 min. We found that about 90% of leukocytes were removed after 5 min of filtration in both Groups L and S. Although leukocyte count continued to reduce, mean fluorescent intensities of CD11/CD18, free hemoglobin, and neutrophil elastase increased in Group L and were higher than those in Groups C and S at 60 min. Leukocyte rupture, cytoplasmic leakage, and circulating naked nuclei were also found in Group L. The data support our hypothesis that long-term filtration can induce inflammation and lead to leukocyte destruction.

[Establishment and evaluation of extracorporeal circulation model in rats].

OBJECTIVE: To establish an extracorporeal circulation (ECC) rat model, and evaluate the inflammatory response and organ injury induced in the model. METHODS: SD rats were anesthetized and cannulated from right common carotid artery to left femoral vein to establish the bypass of extracorporeal circulation. Then the rats were randomly divided into ECC group and sham group. The rats in ECC group were subjected to extracorporeal circulation for 2 hours and then rest for 2 hours, while the rats in sham group were only observed for 4 hours without extracorporeal circulation. After that, blood routine examination, blood gas analysis, the measurement of pro-inflammatory factors in bronchoalveolar lavage fluid and lung tissue were performed to evaluate the lung injury induced by ECC. Circulating endothelial cells were also calculated by flow cytometry to assess the vascular endothelial injury. RESULTS: At 2 hours after ECC, red blood cell counts in both groups kept normal, while leukocyte and neutrophil counts, plasmatic tumor necrosis factor-a level and neutrophil elastase level, circulating endothelial cells in the rats of ECC group were significantly higher than those in sham group. Tumor necrosis factor-alpha in bronchoalveolar lavage fluid and water content in lung of the ECC rats were also significantly higher, while the oxygenation index was significantly lower. Neutrophil infiltration was also observed in lung tissues with increased thickness of alveolar membrane in ECC group. CONCLUSION: The ECC model established from right common carotid artery to left femoral vein in our study can successfully induce systemic inflammatory response, and acute lung injury associated with inflammation.

Actin filament reorganization is a key step in lung inflammation induced by systemic inflammatory response syndrome.

Acute lung injury (ALI) induced by systemic inflammatory response syndrome (SIRS) is characterized by deterioration in pulmonary function and leukocyte-associated lung inflammation. Actin fragment (F-actin) reorganization is required for leukocyte activation, adhesion, and transcription of inflammatory factors. We tested the hypothesis that F-actin plays a central role in SIRS-induced ALI. ALI was produced in a rat model with extracorporeal circulation. Cytochalasin B (CB) pretreatment to block F-actin reorganization improved oxygenation and reduced BAL inflammatory factors and pulmonary neutrophil sequestration, but did not reduce the adhesive molecules of blood leukocytes. We challenged blood neutrophils with TNF-α in vitro to explore the underlying mechanisms. Upon activation, neutrophils became polarized and formed a protrusive leading edge, with an aggregation of CD11b molecules. This effect could be blocked by CB, leading to reduced neutrophil adhesion. In addition, after LPS challenge, we observed F-actin reorganization and the up-regulation of inflammatory factors in pulmonary monocytes, which could also be blocked by CB pretreatment. F-actin reorganization initiates lung inflammation via increased blood neutrophil adhesion and migration, and by the production of inflammatory factors by pulmonary monocytes. Thus, blocking F-actin reorganization may potentially prevent and treat SIRS-induced ALI.

Anterolateral minithoracotomy versus median sternotomy for the treatment of congenital heart defects: a meta-analysis and systematic review.

BACKGROUND: Anterolateral Minithoracotomy (ALMT) for the radical correction of Congenital Heart Defects is an alternative to Median Sternotomy (MS) due to reduce operative trauma accelerating recovery and yield a better cosmetic outcome after surgery. Our purpose is to conduct whether ALMT would bring more short-term benefits to patients than conventional Median Sternotomy by using a meta-analysis of case-control study in the published English Journal. METHODS: 6 case control studies published in English from 1997 to 2011 were identified and synthesized to compare the short-term postoperative outcomes between ALMT and MS. These outcomes were cardiopulmonary bypass time, aortic cross-clamp time, intubation time, intensive care unit stay time, and postoperative hospital stay time. RESULTS: ALMT had significantly longer cardiopulmonary bypass times (8.00 min more, 95% CI 0.36 to 15.64 min, p = 0.04). Some evidence proved that aortic cross-clamp time of ALMT was longer, yet not significantly (2.38 min more, 95% CI -0.15 to 4.91 min, p = 0.06). In addition, ALMT had significantly shorter intubation time (1.66 hrs less, 95% CI -3.05 to -0.27 hrs, p = 0.02). Postoperative hospital stay time was significantly shorter with ALMT (1.52 days less, 95% CI -2.71 to -0.33 days, p = 0.01). Some evidence suggested a reduction in ICU stay time in the ALMT group. However, this did not prove to be statistically significant (0.88 days less, 95% CI -0.81 to 0.04 days, p = 0.08). CONCLUSION: ALMT can bring more benefits to patients with Congenital Heart Defects by reducing intubation time and postoperative hospital stay time, though ALMT has longer CPB time and aortic cross-clamp time.

Perventricular device closure of patent ductus arteriosus: a secondary chance.

Transcatheter closure is the mainstay of treatment for patent ductus arteriosus (PDA) in the pediatric patient but it is technically challenging and does not always succeed, especially in a younger age child with a large PDA. We present a technique of using a transesophageal echocardiogram-guided minimally invasive perventricular closure for the pediatric patient with a large PDA who failed transcatheter closure.

Intra-operative device closure of multiple atrial septal defects facilitated by a unique atrial septum remodeling technique: initial results and experience in 11 patients.

OBJECTIVE: We introduced a new atrial septum remodeling technique and further investigated the feasibility of this method in facilitating the intra-operative device closure (IODC) of multiple atrial septal defects (ASDs). METHODS: Adult patients with multiple nearby ASDs, which were not eligible for transcatheter closure, were enrolled in this study. Transesophageal echocardiogram (TEE) was applied for intra-operative evaluation. The multiple ASDs were divided into three different types according to its morphology. Based on the concept of breaking the rim between multiple ASDs and making it feasible for single device closure, atrial septum remodeling procedure was carried out via pre-atrial approach using special clamp under the guidance of TEE. IODC was then attempted for reshaped ASD. Successful rate and perioperative complications were then noted. RESULTS: Eleven patients were enrolled in this study, with mean age being 23.4 ± 5.3 years and mean weight 51.6 ± 8.0 kg. Among them, seven patients have double ASDs and four have triple ASDs. Mean diameter of isolated ASD was 10.4 ± 3.8 mm with a mean distance of 3.2 ± 1.2 mm between each other. Atrial septum remodeling procedure was successfully done in all patients. One device was then used for each patient. Mean ASD diameter after remodeling procedure was 20.6 ± 3.9 mm with mean device size 23.5 ± 4.0 mm. Complete closure of multiple ASDs was achieved in nine patients immediately after the procedure; two patients had trivial grade shunt after device deployment that resolved within the 3-month follow-up. No severe complications were noticed during the perioperative period and the 3-month follow-up. CONCLUSIONS: Atrial septum remodeling technique seems to be a safe and effective method that could largely facilitate the successful IODC of multiple ASDs.

Successful repair of a traumatic ventricular septal defect using an amplatzer occluder guided by three-dimensional transesophageal echocardiography.

Transesophageal echocardiogram (TEE) guided perventricular cardiac intervention has gained popularity in recent years. We present a special case of perventricular closure conducted for a traumatic apical muscular ventricular septal defect (mVSD) under the guidance of three-dimensional (3D) TEE with an Amplatzer mVSD occluder and further discuss the important role of 3D TEE in perventricular cardiac intervention.

Blood hibernation: a novel strategy to inhibit systemic inflammation and coagulation induced by cardiopulmonary bypass.

BACKGROUND: Inflammation and coagulation are two intimately cross-linked defense mechanisms of most, if not all organisms to injuries. During cardiopulmonary bypass (CPB), these two processes are activated and interact with each other through several common pathways, which may result in subsequent organ dysfunction. In the present study, we hypothesized that the addition of nitric oxide, prostaglandin E1 (PGE1), and aprotinin to the systemic circulation, hereby referred to as blood hibernation, would attenuate the inflammation and coagulation induced by CPB. METHODS: Thirty adult mongrel dogs were equally divided into five groups, anesthetized and placed on hypothermic CPB (32 degrees C). Each group received respectively the following treatments: (1) inhalation of 40 ppm nitric oxide; (2) intravenous infusion of 20 ng x kg(-1) x min(-1) of PGE1; (3) 80,000 kallikrein inhibitor units (KIU)/kg of aprotinin; (4) the combination of all three agents (blood hibernation group); and (5) no treatment (control group) during CPB. Activation of leukocyte, platelet, endothelial cell, and formation of thrombin were assessed after CPB. RESULTS: As compared with the other four groups, leukocyte counts were higher, while plasma elastase, interleukin-8, CD11b mRNA expression, myeloperoxidase activities and lung tissue leukocyte counts were lower in the blood hibernation group (P < 0.05 versus other four groups after CPB). Plasma prothrombin fragment (PTF)1+2, and platelet activation factors were lower, while platelet counts were higher in the blood hibernation group (P < 0.05 versus other four groups at 6 and 12 hours after CPB). Electron microscopy showed endothelial pseudopods protrusion, with cell adherence in all four groups except the blood hibernation group where endothelial cells remained intact. CONCLUSION: Blood hibernation, effected by the addition of nitric oxide, PGE1 and aprotinin to the circulating blood during extra-corporeal circulation, was observed to attenuate the inflammation and coagulation induced by cardiopulmonary bypass, most likely by inhibiting the important common intermediates between the two cross-linked processes.

Perventricular device closure of perimembranous ventricular septal defects in 61 young children: early and midterm follow-up results.

OBJECTIVES: Perventricular device closure of perimembranous ventricular septal defect as a novel technique has recently been described in several small series with initial experience. Further studies with larger cohorts and longer-term follow-up are needed to confirm the validity of this new approach. This report describes our recent experience with perventricular device closure of perimembranous ventricular septal defects on beating hearts in 61 young children with over 1 year of follow-up. METHODS: Between April 2007 and April 2008, 61 patients with perimembranous ventricular septal defects were enrolled for a prospective study of perventricular device closure of their defects. The hospital course and the immediate and midterm complications during follow-up were herein reported. RESULTS: The defects were closed successfully with devices in 57 (93.4%) patients without mortality or major morbidity. Four (6.6%) patients were converted to surgical repair when device closure was deemed unsuccessful; the failure of device closure was associated with the subaortic rim (odds ratio = 21.471; P = .038). Residual shunt was observed in 4 (6.6%) patients during the procedure. One of them was converted into surgical repair, and the residual shunt of the other 3 resolved during the 6-month follow-up period. Two (3.3%) patients had complete atrioventricular block develop in the operating room or during follow-up. One was converted into surgical repair and the other patient converted to sinus rhythm after treatment with steroids. CONCLUSIONS: Perventricular device closure of ventricular septal defect is a safe and efficacious treatment option with acceptable midterm outcomes. For infants with poor vascular access, it might be the procedure of choice.

Modified cavoatrial anastomosis in Warden procedure.

The Warden procedure was introduced for surgical repair of partial anomalous pulmonary venous connection to the higher portion of the superior vena cava in an attempt to decrease the incidence of postoperative sinoatrial node dysfunction and pulmonary venous obstruction. However, postoperative cavoatrial channel stenosis and obstruction up to 20% and 10%, respectively, requiring catheter intervention has been reported. In this article, we describe a modified cavoatrial anastomotic technique to avoid postprocedural superior vena cava stenosis.

Aprotinin combined with nitric oxide and prostaglandin E1 protects the canine kidney from cardiopulmonary bypass-induced injury.

OBJECTIVE: Aprotinin is frequently used to reduce blood loss during cardiac surgery; however, it also causes renal injury. Since aprotinin reduces nitric oxide (NO) and prostaglandin I(2) (PGI(2)), and both cause vasodilation and inhibit activation of neutrophils and platelets, their reduction may be responsible for the injury. This study was to determine whether the combination of aprotinin with NO and prostaglandin E(1) (PGE(1), an analogue of PGI(2)) can attenuate renal injury associated with aprotinin during cardiopulmonary bypass (CPB). METHODS: Thirty mongrel dogs were equally divided into five groups, with each group receiving CPB and aprotinin, NO, PGE(1), a combination of the three or no treatment (control). Serum creatinine and creatinine clearance were determined. To elucidate the mechanism, neutrophil, platelet and thrombin activations were also assessed. RESULTS: After CPB, serum creatinine increased and creatinine clearance decreased in all dogs. These changes were similar among the NO, PGE(1), aprotinin and control groups, but were significantly smaller in the combination group. Similarly, myeloperoxidase activities in tissues, CD11b expression, plasma elastase, prothrombin fragment (PTF) 1+2 and platelet activation factor were lower, whereas neutrophil and platelet counts were higher in the combination group than in the other groups (P<0.05). CONCLUSIONS: Aprotinin combined with NO and PGE(1) produced synergistic protective effects and improved renal function, due partly to inhibition of platelet and neutrophil activation and suppression of thrombin formation.