Bestrophin3 Deficiency in Vascular Smooth Muscle Cells Activates MEKK2/3-MAPK Signaling to Trigger Spontaneous Aortic Dissection.

BACKGROUND: Aortic dissection (AD) is a fatal cardiovascular disorder without effective medications due to unclear pathogenic mechanisms. Bestrophin3 (Best3), the predominant isoform of bestrophin family in vessels, has emerged as critical for vascular pathological processes. However, the contribution of Best3 to vascular diseases remains elusive. METHODS: Smooth muscle cell-specific and endothelial cell-specific Best3 knockout mice (Best3SMKO and Best3ECKO, respectively) were engineered to investigate the role of Best3 in vascular pathophysiology. Functional studies, single-cell RNA sequencing, proteomics analysis, and coimmunoprecipitation coupled with mass spectrometry were performed to evaluate the function of Best3 in vessels. RESULTS: Best3 expression in aortas of human AD samples and mouse AD models was decreased. Best3SMKO but not Best3ECKO mice spontaneously developed AD with age, and the incidence reached 48% at 72 weeks of age. Reanalysis of single-cell transcriptome data revealed that reduction of fibromyocytes, a fibroblast-like smooth muscle cell cluster, was a typical feature of human ascending AD and aneurysm. Consistently, Best3 deficiency in smooth muscle cells decreased the number of fibromyocytes. Mechanistically, Best3 interacted with both MEKK2 and MEKK3, and this interaction inhibited phosphorylation of MEKK2 at serine153 and MEKK3 at serine61. Best3 deficiency induced phosphorylation-dependent inhibition of ubiquitination and protein turnover of MEKK2/3, thereby activating the downstream mitogen-activated protein kinase signaling cascade. Furthermore, restoration of Best3 or inhibition of MEKK2/3 prevented AD progression in angiotensin II-infused Best3SMKO and ApoE-/- mice. CONCLUSIONS: These findings unveil a critical role of Best3 in regulating smooth muscle cell phenotypic switch and aortic structural integrity through controlling MEKK2/3 degradation. Best3-MEKK2/3 signaling represents a novel therapeutic target for AD.

Extensive Arch Repair with a Novel Two-Branched Stent Graft in Acute Type A Aortic Dissection.

PURPOSE: In this study, we compared the early results between the extensive arch repair with a novel two-branched stent graft (TSG) and the traditional technique. METHODS: Between 2013 July and 2015 March, 63 acute type A aortic dissection (ATAAD) patients from four cardiac centers with indications for extensive arch repair were included in this study. Finally, 28 patients were involved in the traditional procedure (TP) group (23 males with the age of 49.75 ± 9.26 years) and 35 patients were involved in the TSG group (29 males with the age of 53.82 ± 8.17 years). RESULTS: The operation was successful in all patients. The selective cerebral perfusion time, total operation time, and chest drainage within 24 hours after the operation in the TSG group were significantly less than those in the TP group (P ≤0.05). The mean follow-up time was 11.17 ± 1.74 months in the TP group and 11.94 ± 4.29 months in the TSG group. No statistical differences were found in aortic diameter, false lumen diameter, and true lumen diameter at the diaphragmatic level during the follow-up. CONCLUSION: Our technique with a novel TSG simplified the extensive arch repair procedure and was an effective way for the treatment of ATAAD.

[Surgical management of pregnancy-associated acute Stanford type A aortic dissection: analysis of 5 cases].

OBJECTIVE: To explore the diagnosis and treatment of pregnancy-associated acute Stanford type A aortic dissection to improve the maternal and fetal outcomes. METHODS: We analyzed the perioperative data of 5 pregnant women with acute Stanford type A aortic dissection treated between June, 2009 and February, 2017. RESULTS: The median age of the women was 30 years (range, 22-34 years) with gestational weeks of 23-38 weeks upon diagnosis. All the 5 patients received surgical interventions. Three patients underwent caesarean delivery and hysterectomy, and the fetuses survived after the surgery; 2 patients chose to continue pregnancy following the surgery, among whom one died due to postoperative complications and the other underwent termination of pregnancy. During follow-up, the surviving patients showed no endoleak in the descending aorta stent and the distal dissection remained stable. CONCLUSION: The maternal and fetal outcomes of pregnancy-associated acute Stanford type A aortic dissection can be improved by multidisciplinary cooperation and optimization of the surgical approaches according to the time of pregnancy, fetal development and conditions of the aortic lesions.

[Prophylactic antibiotics: a necessity in totally percutaneous thoracic endovascular aortic repair?].

OBJECTIVE: To study the benefit of prophylactic antibiotics (PA) in totally percutaneous aortic endovascular repair (PEVAR) in the catheterization laboratory for reducing stent-graft infection and postimplantation syndrome (PIS). METHODS: The clinical data were analyzed of patients undergoing thoracic endovascular aortic repairs. The patients were divided into non-PA group and PA group according to the use of prophylactic antibiotics before PEVAR. The diagnosis of infection was made by two senior physicians with reference to Hospital Acquired Infection Diagnostic Criteria Assessment released by the Ministry of Health of China. RESULTS: The 95 enrolled patients included 35 with PA and 60 without PA group, who were comparable for baseline characteristics. Infection-related deaths occurred in 1 case in non-PA group and retrograde Stanford type A dissection and death occurred in 1 case in PA group (1.67% vs 2.85%, P=1.00). The PA and non-PA groups showed no significant difference in the incidence of postoperative infection (5% vs 2.86%, P=1.000), hospital stay (9.30±7.21 vs 10.06±5.69, P=0.094), infection-related mortality (1.67% vs 0%, P=1.00), or postoperative fever (70.90% vs 91.43%, P=0.20). The body temperature showed significant variations at different time points after procedure (F=19.831, P<0.001) irrelevant to the use of prophylactic antibiotics (F=0.978, P=0.326). CONCLUSION: The current data do not support the benefit of PA in reducing postoperative infection and PIS in patients undergoing PEVAR, but the patients without PA may have worse clinical outcomes in the event of postoperative infections.

[Protective effect of retrograde venous perfusion of cryogenic liquid via accessory hemiazygos vein and treated with resveratrol on spinal cord injury in swine].

OBJECTIVES: To observe the protective effect of retrograde venous perfusion of cryogenic liquid via accessory hemiazygos vein and treated with resveratrol on spinal cord injury and evaluate the expression changes of microtubule-associated protein 2 (MAP-2) after spinal cord ischemia reperfusion injury (SCII) in swine. METHODS: Eighteen swine were divided into 3 groups: group I/R (n = 6, operation group), group CL (n = 6, retrograde venous perfusion of cryogenic liquid), group CL+Res (n = 6, retrograde venous perfusion of cryogenic liquid and treated with resveratrol after ischemia). In the group I/R, the aorta was clamped for 60 minutes and then removed. In the group CL and CL+Res, 9 g/L cold (4 °C) saline solution (perfusion rate, 16.65 ml/min) was infused into the accessory hemiazygos vein during ischemia.In the group CL+Res, the swine were treated with resveratrol (10 mg/kg) after spinal cord ischemia. Arterial pressure, blood gas analysis and the spinal canal and nasopharyngeal temperature changes were monitored during the surgery. Nervous function were assessed at 6 hours, 1, 2 days, 1, 2, 4 weeks and MAP-2 expression were detected at 4 weeks after reperfusion by using Western blot analysis in spinal cord tissue. RESULTS: After operation 18 swine were all survival. Behavioral scores of all groups decreased until 1 week after reperfusion and increased as time went by. The scores of group CL and CL+Res were higher than group I/R (F = 8.612, 17.276 and 11.985, P = 0.035,0.011 and 0.023) at 6 hours, 1, 2 days, group CL+Res were higher than group CL(P = 0.021) at 1 days after surgery. After descending aortic cross clamping, the spinal canal and nasopharyngeal temperature were obviously decreased in all groups and dropped to the lowest at 60 minutes after ischemia and 20 minutes after reperfusion in group I/R and the other groups respectively(F = 23.187-55.029, P < 0.01).In group CL(0.54 ± 0.26) and CL+Res (0.66 ± 0.31), the MAP-2 expression were higher than group I/R(0.37 ± 0.18) (F = 9.381, P = 0.037) , and the level in group CL+Res was higher than in group CL (P = 0.021) . CONCLUSION: Retrograde venous perfusion of cryogenic liquid via accessory hemiazygos vein and treated with resveratrol can relieve the ischemia-induced spinal cord injury in swine.

Matrine inhibits disturbed flow-enhanced migration via downregulation of ERK1/2-MLCK signaling vascular smooth muscle cells.

BACKGROUND: To investigate the effects of matrine on the vascular smooth muscle cell (VSMC) migration modulated by disturbed flow and their underlying molecular mechanisms in vitro. METHODS: Isolated rat aortic VSMCs were grown to confluence on 20- × 80-mm fibronectin-coated glass cover slides, and then, denuded zones were made at the position calculated to be the oscillating flow-reattachment zone and also in the downstream laminar flow region. VSMCs were treated with different doses of matrine (0, 10, 20, 30, and 40 mg/L), or PD98059 (30 µM), ML-7 (10 µM) combined with matrine (40 mg/L) for 30 minutes before and during the experiments. Then, the wounded monolayers were kept under static conditions or were subjected to laminar or disturbed flow for 21 hours or 10 hours. The VSMC migration was assessed by microscopic images. The extracellular signal-regulated kinase 1/2 (ERK1/2) and myosin light chain kinase (MLCK) proteins were determined by Western blot. RESULTS: Disturbed flow significantly increased phosphorylation of ERK1/2. Selective inhibition of ERK1/2 phosphorylation by inhibitor PD98059 and matrine significantly suppressed VSMC migration under disturbed flow. Disturbed flow significantly enhanced phosphorylation of MLCK, whereas both matrine and PD98059 inhibited the phosphorylation of MLCK under disturbed flow. The complete inhibition of MLCK phosphorylation using the selective MLCK inhibitor ML-7 significantly inhibited VSMC migration under disturbed flow. CONCLUSION: Matrine inhibits VSMC migration under disturbed flow, in part, by downregulation of ERK1/2-MLCK signaling pathway.

Totally percutaneous thoracic endovascular aortic repair with the preclosing technique: a case-control study.

BACKGROUND: The conventional thoracic endovascular aortic repair (TEVAR) involves groin incisions under general or epidural anesthesia. As technology moves towards less invasive procedures, a total percutaneous approach is desirable. In this study, we describe a Preclosing technique and investigate its safety and efficacy for femoral access sites management, and evaluate its advantages as compared to those of traditional surgical cutdown approaches. METHODS: The Preclosing technique involves two or multiple 6 F Perclose Proglide devices deployed in the femoral artery before upsizing to a 20-25 F sheath. The sutures were secured to close the arteriotomy at the end of the procedure. The medical records of patients who underwent thoracic endovascular aortic repairs using the Preclosing technique between December 2009 and November 2010 (group A) were compared with those using surgical femoral cutdown from January 2008 to November 2009 (group B). Outcome measures included rates of technical success, early complications, anesthesia method, procedure time, cardiac care unit (CCU) stay, time from procedure to discharge, hospital stay, procedure expense, hospital cost. RESULTS: Between the two groups, there were no significant differences in baseline characteristics, in the endograft models or profiles. The technical success rate was 100.0% (85/85) in group A vs. 97.4% (147/151) in group B (P < 0.05). There was no access-related mortality in both groups. Compared with group B, the incidence of early complications were fewer in group A, 9.4% (8/85) vs. 22.5% (34/151) (P < 0.01). Local anesthesia with conscious sedation was used more often in group A, 68.2% (58/85) vs. 51.7% (78/151) in group B (P < 0.01). The procedure duration was shorter, (96 ± 33) minutes in group A vs. (127 ± 41) minutes in group B (P < 0.01). The length of the CCU stay, the duration from procedure to discharge, and the hospital stay were both reduced in group A, (117.3 ± 88.3) hours, (7.5 ± 5.3) days and (15.3 ± 6.8) days vs. (132.7 ± 115.5) hours, (10.5 ± 5.0) days and (19.5 ± 7.8) days in group B (P < 0.01). The procedure cost was RMB (109,000 ± 30,000) Yuan in group A vs. RMB (108,000 ± 25,000) Yuan in group B (P = NS). The hospital cost was RMB (130,000 ± 35,000) Yuan in group A vs. RMB (128,000 ± 33,000) Yuan in group B (P = NS). CONCLUSIONS: Total percutaneous TEAVR with the Preclosing technique is safe and effective with meticulous technique and appropriate patient selection. The Preclosing technique decreases access-related complications, depends less on general anesthesia and the surgeon's cooperation, saves procedure time and shortens the CCU/hospital stay. With these advantages, the use of two percutaneous closure devices increases the hospital cost only slightly.

[Surgical treatment of 128 cases of constrictive pericarditis].

OBJECTIVE: To summarize the experience with surgical treatment of constrictive pericarditis. METHODS: A retrospective analysis of the post-operative clinical data was conducted in 128 surgical patients with chronic constrictive pericarditis. RESULTS: Two early postoperative death occurred in this group due to severe low cardiac output syndrome, with the mortality rate of 1.57%. The postoperative complications included low cardiac output syndrome (13.2%), arrhythmia (7.02%), acute renal insufficiency (3.9%), respiratory insufficiency (3.1%), wound infection (2.3%), postoperative chest bleeding (1.6%) and cerebral infarction (0.78%). Relapse occurred in one case because of incomplete pericardial resection. CONCLUSIONS: Constrictive pericarditis should be confirmed as soon as possible with actively surgery, and the extent of pericardial resection should be decided according to the individual conditions. Complete untethering of the diseased pericardium should be performed with active prevention of postoperative complications.

The short-term pulsatile ventricular assist device for postcardiotomy cardiogenic shock: a clinical trial in China.

Despite the recent advances in myocardial protection, surgical techniques, intra-aortic balloon therapy, and maximal pharmacological support, postoperative ventricular dysfunction continues to occur in 0.5-1.0% of all patients undergoing cardiac surgery. Ventricular assist device (VAD) is an important therapeutic adjunct in treating patients with profound ventricular dysfunction with postcardiotomy cardiogenic shock. The purpose of this report was to describe the clinical results with the China-made Luo-Ye VAD as a short-term circulatory support. From May 1998 to December 2006, 17 patients with postcardiotomy cardiogenic shock were supported by the Luo-Ye VAD. Of these patients, 10 were males and seven were females with a mean age of 49.6 years (range 36-68 years). All cases were supported by left VAD (LVAD). Mean duration of support was 46.3 h (range 13-113 h). A criteria of insertion was established to standardize implantation criteria. Among the 17 patients treated with LVAD, eight (47.1%) patients were weaned from support and seven (41.2%) patients were discharged from hospital. Ten (58.8%) patients died while on LVAD support (nine cases) or shortly after weaning (one case). The causes of death in the entire group were cardiac (40%), renal failure (20%), neurologic (10%), sepsis (10%), and multiple organ system failure (20%). The complications were represented by bleeding, renal failure, neurologic event, infection, ventricular arrhythmias, etc. The Luo-Ye VAD functioned well and proved to be useful in patients with postcardiotomy cardiogenic shock. It carries a less-postoperative anticoagulant and a low incidence of VAD-related complications. The survival rate was encouraging in our small cohort of patients.

[Endovascular repair for patients with DeBakey III aortic dissection].

OBJECTIVE: To investigate the clinical therapeutic effects of endovascular repair for patients with DeBakey III aortic dissection. METHODS: From December 2002 to June 2007, endovascular TALENT stent-graft exclusion was performed in 75 (65 males, mean age 54.4 +/- 12.6 years) patients with DeBakey III aortic dissection (1 young woman due to Ehlers-Danlos syndrome, 2 young men due to primary aldosteronism and trauma respectively). All patients were diagnosed by contrast enhanced computed tomography (CT) or MRI. Stent-grafts were deployed via femoral artery to exclude the tear of dissection. Aortic angiography was performed immediately after procedure. RESULTS: Eighty-one stent-grafts were installed in 75 patients successfully without operation related dissection. Endoleakage immediately after stent-graft deploying was evidenced in 25 patients and disappeared after stent placements (n = 6) or balloon dilation (n = 19). Two patients died from aortic rupture within 2 days after procedure. Iliac artery was torn in a female patient with Ehlers-Danlos syndrome, this patient developed hemorrhagic shock after stent-graft placement and recovered after anti-shock treatments and iliac artery replacement with synthetic artery. During the follow-up of 1 - 24 months, 2 patients (including the woman with Ehlers-Danlos syndrome) suddenly died half a year after procedure. The remaining patients were alive and well. Repeat CT during follow up showed that reduced lumen size and thrombosis in the false lumen. There was no aortic rupture, endoleak and stent migration during the follow-up period except descending aortic dissection distal of the stent-graft in 1 patient 1 year after procedure and the patient were successfully treated surgically without complication. CONCLUSIONS: Endovascular repair is a safe and effective treatment for patients with DeBakey III aortic dissection, suitable for old patients with high risk of surgery. Ehlers-Danlos syndrome should be considered in young DeBakey III aortic dissection patients without hypertension. Further studies are warranted on endovascular repair therapy for artery complication of Ehlers-Danlos syndrome.

[Anti-atherosclerotic effect of betaine in apolipoprotein E-deficient mice].

OBJECTIVE: To study the effect of betaine on the formation of atherosclerotic plaque in apolipoprotein E (ApoE)-deficient mice and explore its anti-inflammatory mechanism. METHODS: Seven-week-old ApoE-deficient mice (C57BL/6J background) were divided into four groups randomly based on body weight: model group and three betaine groups. Wild-type mice with the same age and genetic background were used as control group. The control group and model group were fed AIN-93G diet. Three betaine groups were fed AIN-93G diet supplemented with 1, 2, 4 g betaine/100 g diet, respectively. Serum tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1, lipid levels and methylation status of TNF-alpha promotor in aorta were determined at 0, 7 and 14 weeks. The percentage of aorta sinus plaque to lumen area was measured at 14-week. RESULTS: The percentage of aorta sinus plaque to lumen area of 1% and 2% betaine groups were (11.43+/-2.65)% and (12.09+/-3.07)%, respectively, which were 41% and 33% smaller than that of the model group (t=3.117, 3.010, respectively, and P<0.01). Serum TNF-alpha level of three betaine groups were (56.33+/-3.86), (63.04+/-4.67) and (65.52+/-3.97) pg/ml, respectively, which were lower than that of the model group (79.40+/-4.68) pg/ml (t=9.270, 6.571 and 5.576, respectively, P<0.001), but there was no significant difference in the methylation status of TNF-alpha promotor among all five groups. CONCLUSION: Betaine could inhibit the development of atherosclerosis via anti-inflammation.

[Clinical analysis of gastrointestinal bleeding after cardiac surgery].

OBJECTIVE: To explore early diagnosis, treatment and prevention of gastrointestinal (GI) bleeding after cardiac surgery. METHODS: In the last 13 years, cases complicated with GI bleeding after cardiac surgeries were analyzed retrospectively. RESULTS: Fourty-four GI bleeding occurred post-operatively in (6 +/- 3) d. The mortality was 23% (10/44). Thirty-eight were located in upper GI tract, of them 26 underwent conservative therapy while 4 died of other than GI bleeding cause; six underwent laparotomy while 1 and 3 died of septicemia and multi-organ failure respectively; six underwent gastric endoscopic hemostasis by electrocautery or clipping the bleeding vessel while all survived. Six were located in lower GI tract, and 2 of them underwent laparotomy without finding bleeding section and died of multi-organ failure. By multivariable logistic regression analysis, deaths were highly related to the post-operative ventilator-dependence, acute renal insufficiency, intra-aortic balloon pump (IABP) assisting and laparotomy. CONCLUSION: The mortality of GI bleeding after cardiac surgeries is very high, early gastrointestinal endoscopic examination and minimally invasive intervention can treat this complication more effectively. GI bleeding must be prevented whenever complicating post-operative ventilator-dependence, acute renal insufficiency, and IABP assisting after cardiac surgery.