Mesenchymal Stem Cells Expressing eNOS and a Cav1 Mutant Inhibit Vascular Smooth Muscle Cell Proliferation in a Rat Model of Pulmonary Hypertension.

BACKGROUND: This study aimed to investigate the effect of bone marrow derived mesenchymal stem cells (rBMSCs) transduced with lentiviral vectors expressing endothelial nitric oxide synthase (eNOS) and/or a mutant caveolin-1(F92A-Cav1), on the pulmonary haemodynamics and structure in a rat model of pulmonary arterial hypertension (PAH). METHODS: Pulmonary arterial hypertension was induced with monocrotaline (MCT) in 60 adult male Wistar rats prior to delivery of lentiviral vector transduced rBMSCs expressing Cav1, eNOS and/or F92A-Cav1. Changes in pulmonary haemodynamics, right ventricular hypertrophy index (RVHI), and serum nitric oxide (NO) were evaluated. Ultrastructure changes in lung tissues were observed by transmission electron microscopy. Expression of Kruppel-like factor 4 (KLF4), p53, P21, eNOS, and alpha-smooth muscle actin were evaluated by real time PCR, western blotting or immunohistochemistry. RESULTS: Treatment of PAH rats with gene modified rBMSCs (eNOS +/- Cav1 F92A) decreased right ventricular systolic pressure and improved pulmonary haemodynamics. The protein of alpha-smooth muscle actin expression was decreased whilst KLF4, p53, P21, eNOS expression, and serum NO concentration was elevated. The survival rate of rats in the treatment groups was also improved, after 35 days of observation. CONCLUSION: Intravenous delivery of rBMSCs expressing eNOS/F92A-Cav1 to PAH rats inhibits pulmonary vascular smooth muscle cell proliferation, and improves pulmonary haemodynamics, vascular remodelling and short-term survival. Activation of KLF4-p53 signalling pathway may be involved in these beneficial effects.

Impact of peripherally established cardiopulmonary bypass on regional and systemic blood lactate levels.

BACKGROUND: To investigate blood lactate levels during and after peripherally established cardiopulmonary bypass (CPB). METHODS: In 86 patients (41 males, mean age 13.8 ± 7.2), CPB was established via femoral vein and artery cannulation for thoracoscopic closure of atrial (n=54) or ventricular septal defect (n=32). Arterial and venous blood lactate levels were measured from the cannulated limb during CPB, and from systemic circulation after CPB. RESULTS: The mean duration of CPB and cannulation of a lower extremity were 50.0 ± 10.5 min and 76.0 ± 18.5 min, respectively. The mean arterial lactate level measured from the systemic circulation remained unchanged during CPB (P>0.05). In patients with CPB for 3h or more, mean arterial lactate in the cannulated limb were higher than the baseline values (3.3 ± 0.5 vs 0.8 ± 0.2 mmol/L, P<0.05). In patients with more than 2h of CPB, mean venous lactate levels in the cannulated limb were also higher than the baseline values (3.4 ± 0.2 vs 1.1 ± 0.3 mmol/L, P<0.05). Within 6h after CPB, systemic arterial (3.0 ± 0.2 vs 0.8 ± 0.1 mmol/L, P<0.01) and venous lactate levels (6.5 ± 0.2 vs 1.0 ± 0.1 mmol/L, P<0.01) were higher than the pre-CPB values. CONCLUSIONS: Peripherally established CPB was associated with an arterial and venous lactate elevation in local and systemic circulation. The duration of CPB and lower limb cannulation appears to be related to the lactate elevation.

Effect of preoperational mechanical ventilation on short-term postoperative outcomes in patients with severe tetralogy of Fallot.

BACKGROUND: This study is designed to investigate the effect of preoperational mechanical ventilation on the short-term postoperative outcomes following corrective surgery for severe tetralogy of Fallot (TOF). METHODS: Ninety-two patients (58 males, mean age 20.5±8.5 months) with severe TOF were randomised into study and control groups. In the study group, mechanical ventilation was performed in PEEP/PRVC mode in the intensive care unit to correct blood gas imbalances for the corrective surgery. In the control group, preoperative oxygen supply was provided via face mask or nasal tubes. RESULTS: The postoperative mechanical ventilation time (14.3±1.9 vs 22.5±2.2h, p=0.02), intensive care stay (2.3±1.2 vs 4.7±1.1d, p=0.03) and duration for positive inotropic drug administration (2.5±1.1 vs 4.8±1.2d, p=0.04) in the study group were shorter than those in the control group. The postoperative capillary leak syndrome in the study group was lower than that in the control group (4.3% vs 23.9%, p=0.006). There was no statistically significant difference in the postoperative mortality between the study and control groups (2.1% vs 6.5%, p=0.606). CONCLUSIONS: Preoperational mechanical ventilation in patients with severe forms of TOF was associated with improved short-term outcomes following the corrective surgery. The effect of the preoperational ventilation on postoperative mortality requires further investigation.

Left Ventricular Aneurysm Repair: Off-pump Linear Plication versus On-pump Patch Plasty.

OBJECTIVE: The study aimed to compare the clinical outcomes of simplified linear plication and classic patch plasty in patients with left ventricular aneurysm (LVA). METHODS: We retrospectively reviewed 282 patients undergoing LVA repair between 2006 and 2016. After propensity score matching, 45 pairs of patients receiving LVA surgery were divided into either a patch group (on-pump endoventricular patch plasty) or a plication group (off-pump linear plication). Then, their early surgical outcomes and long-term survival were compared in two matched groups. RESULTS: The heart function improvement at discharge was similar in the two matched groups, while patients in the patch group more commonly suffered from low cardiac output syndrome (P=0.042) with higher proportion of intra-aortic balloon pumping assistance (P=0.034) than patients in the plication group. Compared with patients in the patch group, the patients in the plication group had shorter recovery times, regarding to mechanical ventilation, intensive care unit stay, and hospital stay (P<0.001, P<0.001, and P=0.001, respectively). No significant difference was found in the long-term survival (P=0.62). CONCLUSIONS: Off-pump linear plication presented acceptable results in terms of early outcomes and long-term survival. For high-risk patients, the simplified LVA repair technique may be an option.

Application of medical adhesive inhibits intimal hyperplasia involving the downregulation of ERK1/2 and eNOS levels.

Vein graft remains the most broadly applied vascular material in coronary artery bypass surgery. However, the restenosis rate of the vein bridge following angioplasty is high. The present study investigated the effect of medical adhesive on vascular intimal hyperplasia, in addition to the signal transduction mechanism. A total of 36 New Zealand white rabbits were divided into three groups at random, including the normal group, the surgery group and the medical adhesive spray group. Following surgery for transplantation of the left external jugular vein to the ipsilateral common carotid artery for 4 weeks, the thickness and area of the intima and media of the vessel were measured on formalin­fixed, paraffin wax­embedded pathological sections using hematoxylin­eosin staining, and alterations in the expression of proliferating cell nuclear antigen (PCNA), platelet endothelial cell adhesion molecule 1 (PECAM­1), vascular cell adhesion protein 1 (VCAM­1), extracellular signal­regulated kinase (ERK)1/2, and endothelial nitric oxide synthase (eNOS) were detected by immunohistochemical staining, reverse transcription­quantitative polymerase chain reaction analysis and western blotting. The levels of intimal hyperplasia in the medical adhesive spray group were markedly decreased compared with the surgery group. Consistently, PCNA, PECAM­1 and VCAM­1 were underexpressed in the medical adhesive spray group compared with the surgery group. ERK1/2 and eNOS were underexpressed in the medical adhesive spray group compared with the surgery group. Therefore, the application of medical adhesive may inhibit intimal hyperplasia, which may be associated with the restriction of the over­distension of the vein graft by downregulating the ERK1/2 and eNOS levels, reducing injury to the vascular intima and inhibiting the signaling pathway involved in intimal hyperplasia.

Effect of interleukin-6 on myocardial regeneration in mice after cardiac injury.

Our aim was to investigate the role of interleukin-6 (IL-6) in myocardial regeneration from mice after cardiac injury. The newborn mice were divided into the following 4 groups (16 in each group): sham group, model group, IL-6-/- group (IL-6 knockout) and IL-6 group (IL-6 overexpression). Electrocardiography was performed on all mice and found higher LVEDD, LVESD and IVST and lower LVEF and LVFS in the IL-6 group compared with the sham group. Using HE staining, severe myocardial injury combined with infarction and fibrosis were observed in the IL-6-/- group, while the damaged myocardial tissue was repaired to some extent in the IL-6 group. The expression of IL-6 in the IL-6 group were significantly up-regulated. BrdU immunofluorescence found that the IL-6-/- group had the least number of BrdU positive cells, while the IL-6 group had more BrdU positive cells than the model group and the IL-6-/- group. Expressions of IL-6, cyclinD1 and Bcl-2 in the IL-6 group were up-regulated compared with other groups. In conclusion, IL-6 overexpression could enhance cardiomyocyte proliferation and relevant protein expression in mice myocardium, thus promoting cardiac regeneration.

Collagen External Scaffolds Mitigate Intimal Hyperplasia and Improve Remodeling of Vein Grafts in a Rabbit Arteriovenous Graft Model.

Objectives. The aim of this study was to test the effects of collagen external scaffold (CES) in intimal hyperplasia of vein grafts and explore its underlying mechanisms. Methods. Thirty-six New Zealand white rabbits were randomized into no-graft group, graft group, and CES group. The rabbit arteriovenous graft model was established. In CES group, the vein graft was wrapped around with CES. The hemodynamic parameters of vein grafts were measured intraoperatively and 4 weeks after operation by ultrasonic examination. Histological characteristics of vein grafts were also evaluated 4 weeks later. The mRNA and protein levels of proliferating cell nuclear antigen (PCNA), active cleaved-caspase-3 (ClvCasp-3), and smooth muscle 22 alpha (SM22α) were measured 4 weeks later by quantitative real-time PCR and western blot. Results. CES significantly improved the hemodynamic stability of vein grafts, with higher blood velocity and blood flow. Similarly, CES also markedly mitigated intimal hyperplasia and inhibited dilatation of vein grafts. In CES group, the upexpression of PCNA and ClvCasp-3 and the downexpression of SM22α were inhibited. Conclusion. CES exerts beneficial effects in mitigating intimal hyperplasia and improving remodeling of autogenous vein grafts, which may be associated with reducing the proliferation and apoptosis and preserving the phenotype of VSMCs.

Left ventricular aneurysm repair: off-pump linear plication versus on-pump patch plasty

Abstract Objective: The study aimed to compare the clinical outcomes of simplified linear plication and classic patch plasty in patients with left ventricular aneurysm (LVA). Methods: We retrospectively reviewed 282 patients undergoing LVA repair between 2006 and 2016. After propensity score matching, 45 pairs of patients receiving LVA surgery were divided into either a patch group (on-pump endoventricular patch plasty) or a plication group (off-pump linear plication). Then, their early surgical outcomes and long-term survival were compared in two matched groups. Results: The heart function improvement at discharge was similar in the two matched groups, while patients in the patch group more commonly suffered from low cardiac output syndrome (P=0.042) with higher proportion of intra-aortic balloon pumping assistance (P=0.034) than patients in the plication group. Compared with patients in the patch group, the patients in the plication group had shorter recovery times, regarding to mechanical ventilation, intensive care unit stay, and hospital stay (P<0.001, P<0.001, and P=0.001, respectively). No significant difference was found in the long-term survival (P=0.62). Conclusions: Off-pump linear plication presented acceptable results in terms of early outcomes and long-term survival. For high-risk patients, the simplified LVA repair technique may be an option.

Effect of prostaglandin E1 on pulmonary arterial hypertension following corrective surgery for congenital heart disease.

OBJECTIVE: To evaluate the therapeutic effects of prostaglandin E(1) (PGE(1)) on residual pulmonary arterial hypertension (PAH) after corrective surgery for congenital heart disease. METHODS: Thirty-one patients with postoperational PAH were randomly divided into control group (n = 15) and PGE(1) group (n = 16, 6 courses of intravenous PGE(1) plus conventional therapy). Mean pulmonary arterial pressure (MPAP), right ventricular ejection fraction (RVEF), and left ventricular ejection fraction (LVEF) were measured by echocardiography before and 3, 6, and 12 months after the treatment. Arterial oxygen pressure (Pao (2)) was monitored. RESULTS: In both groups, MPAP decreased and RVEF, LVEF, and Pao (2) increased at 6 and 12 months following surgery. In the PGE(1) group, the MPAP (32.2 ± 5.2 vs 40.2 ± 5.1 mm Hg; P = .008) was lower and RVEF (66.6% ± 6.5% vs 54.9% ± 2.1%; P = .019), LVEF (65.9% ± 3.9% vs 53.5% ± 5.1%; P = .031), and Pao (2) (94.3% ± 11.2% vs 93.1% ± 11.3%; P = .009) was higher than in the control group 12 months after the surgery. Four patients (26.7%) in the control group died of pulmonary hypertension crisis, but there was no death in the PGE(1) group (P = .029). Cumulative survival rate in the control group were 86.7%, 80%, 73.3%, and 73.3% at 1, 2, 3, and 5 years, respectively. CONCLUSIONS: Intravenous PGE(1) therapy after corrective surgery for congenital heart disease was associated with a reduction in mean pulmonary arterial pressure and a lower risk of death.

Thoracoscopic closure of ventricular septal defect in young children: technical challenges and solutions.

OBJECTIVES: To investigate the feasibility and safety of totally thoracoscopic repair of ventricular septal defects (VSDs) in young children. METHODS: VSD repair was conducted in 36 children (21 boys, mean age 2.5 ± 1.7 years, range 2-5, mean body weight 17.4 ± 2.1 kg) by a totally thoracoscopic approach. Cardiopulmonary bypass (CPB) was achieved peripherally. Through three port incisions in the right chest wall, pericardiotomy, atriotomy and VSD repair were performed under the direct view of a thoracoscopy. Forty patients who were treated with a traditional VSD closure through a sternotomy were selected as a control group. RESULTS: There was no statistically significant difference in age, sex or types of VSD between the study and control group (P > 0.05). In the study group, CPB was established through femoral vessels in 28 (77.8%) patients, and through both the right internal jugular vein and the femoral vessels in eight (22.2%). The aortic cross-clamp time (32 ± 6 vs 29 ± 3 min, P = 0.06) and CPB time (46 ± 11 vs 48 ± 4 min, P = 0.107) were similar between the study and control groups. However, the total operation time, mechanical ventilation time, intensive care stay and overall hospital stay in the study group were shorter than in the control group (P < 0.05). Transthoracic echocardiography 3 months after the operation showed no residual shunt in the ventricular septum. CONCLUSIONS: Thoracoscopic closure of VSDs in young children appears feasible and safe.

Anticoagulation therapy with combined low dose aspirin and warfarin following mechanical heart valve replacement.

INTRODUCTION: This study was designed to evaluate safety and efficacy of combined low dose aspirin and warfarin therapy following mechanical heart valve replacement. METHODS: A total of 1496 patients (686 males, mean age 35±8.5 years) undergoing mechanical heart valvular replacement were randomly divided into study (warfarin plus 75-100 mg aspirin) or control (warfarin only) group. International normalized ratio (INR) and prothrombin time was maintained at 1.8-2.5 and 1.5-2.0 times of the normal value, respectively. Thromboembolic events and major bleedings were registered during follow up. RESULTS: Patients were followed up for 24±9 months. The average dose of warfarin in the study and control group was 2.92±0.87 mg and 2.89±0.79 mg, respectively (p>0.05). The overall thromboembolic events in study group were lower than in control group (2.1% vs. 3.6%, p=0.044). No statistically significant differences were found in hemorrhage events (3.5% vs. 3.7%, p>0.05) or mortality (0.3% vs 0.4%, p>0.05) between the two groups. CONCLUSIONS: Following mechanical valve replacement, combined low dose aspirin and warfarin therapy was associated with a greater reduction in thromboembolism events than warfarin therapy alone. This combined treatment was not associated with an increase in the rate of major bleeding or mortality.