Classification and management strategy of spontaneous carotid artery dissection.

OBJECTIVE: Spontaneous carotid artery dissections (sCADs) are the common cause of stroke in middle-aged and young people. There is still a lack of clinical classification to guide the management of sCAD. We reviewed our experience with 179 patients with sCAD and proposed a new classification for sCAD with prognostic and therapeutic significance. METHODS: This is a retrospective review of prospectively collected data from June 2018 to June 2023 of patients with sCAD treated at a large tertiary academic institution in an urban city in China. Based on imaging results, we categorize sCAD into four types: type Ⅰ, intramural hematoma or dissection with <70% luminal narrowing; type Ⅱ, intramural hematoma or dissection with ≥70% luminal narrowing; type Ⅲ, dissecting aneurysm; type ⅣA, extracranial carotid artery occlusion; and type ⅣB, tandem occlusion. We compared the clinical data and prognostic outcomes among various types of sCADs. RESULTS: A total of 179 patients and 197 dissected arteries met the inclusion criteria. The mean age of the 179 patients with sCAD was 49.5 years, 78% were male, and 18 patients (10%) had bilateral sCAD. According to our classification, there were 56 type Ⅰ (28.4%), 50 type Ⅱ (25.4%), 60 type Ⅲ (30.5%), and 31 type Ⅳ (15.7%) dissections. During a mean hospitalization length of 11.4 ± 47.0 days, there were nine recurrent strokes (4.6%) after medical treatment, two type Ⅲ dissections (1.0%), seven type Ⅳ dissections (3.6%), all ipsilateral, and one death. Overall, there were seven (3.6%, 1 type Ⅰ dissection, 3 type Ⅱ dissections, 2 type Ⅲ dissections, and 1 type Ⅳ dissection) recurrent strokes and three (1.5%, all type Ⅲ dissections) recurrent transient ischemic attacks in patients treated with just medical therapy during the follow-up period, all ipsilateral, with a mean follow-up of 26 months (range, 3-59 months). These patients did not undergo further intervention due to the high difficulty associated with endovascular treatment (EVT) or the mild nature of recurrent cerebral ischemic symptoms. Twenty-nine type I dissections (51.8%) were completely recanalized after antithrombotic therapy. A total of 19 type II dissections (38%) and 44 type III dissections (73%) received EVT for persistent flow-limited dissections, enlargement of dissecting aneurysms, or aggravation of neurological symptoms despite antithrombotic therapy. Type Ⅳ dissections are more likely to lead to the occurrence of ischemic stroke and presented with more severe symptoms. Eight type IVB dissections (33%) received acute phase intervention due to distal thromboembolism or aggravation of neurological symptoms after medical treatment. In terms of cerebral ischemic events and mortality, there were no statistically significant differences among the four types of sCAD (all P > .05). Favorable outcome was achieved in 168 patients (93.9%). CONCLUSIONS: This study proposed a novel and more comprehensive classification method and the modern management strategy for sCAD. Antithrombotic therapy is beneficial to reduce the risk of recurrent stroke for stable sCAD. Non-emergent EVT can be an alternative therapeutic approach for patients who meet indications as in type II to IVA dissections. Urgent procedure with neurovascular intervention is necessary for some type IVB dissections. The short-term results of EVT for sCAD are encouraging, and long-term device-related and functional outcomes should undergo further research.

Localized Elevation of Wall Shear Stress Is Linked to Recent Symptoms in Patients with Carotid Stenosis.

BACKGROUND: Estimation of symptomatic and asymptomatic carotid atherosclerosis differences can be the basis for prevention and management of carotid artery stenosis disease. In clinical practice, carotid plaque vulnerability is assessed only on the basis of luminal stenosis. However, the evolution of carotid plaque from an asymptomatic state to a symptomatic one is a complex process and the underlying hemodynamic mechanisms are unknown. We aimed to investigate the differences in hemodynamic parameters between patients with recently symptomatic carotid stenosis and asymptomatic ones. METHODS: Hemodynamic simulations were performed on 26 carotid plaques from 25 patients with carotid artery stenosis ≥50%, 16 of whom had recent cerebrovascular ischemic events. Using human-specific flow parameters and 3D reconstruction of carotid computed tomography angiography images, we assessed hemodynamic characteristics such as wall shear stress (WSS), time-averaged WSS (TAWSS), oscillatory shear index, and relative residence time (RRT) during the cardiac cycle in patients with and without symptoms. RESULTS: We found that symptomatic carotid stenosis patients had greater local TAWSS (99.59 ± 26.29 vs. 60.40 ± 20.46 dyn/cm2, p = 0.0007) and maximal WSS (116.65 ± 39.11 vs. 68.28 ± 23.67 dyn/cm2, p = 0.003), but lower RRT (0.019 ± 0.006 vs. 0.013 ± 0.069 s, p = 0.049), than asymptomatic patients, but this hemodynamic difference was not associated with carotid stenosis severity (p = 0.70). Patients with transient ischemic attack (TIA) or stroke had higher local TAWSS and WSSmax than patients with asymptomatic stenosis (p < 0.05). Subgroup analysis showed that there was no statistical difference in local hemodynamic variables between TIA and stroke patients with carotid artery stenosis. CONCLUSIONS: Patients with carotid artery stenosis are more likely to experience acute ischemic cerebrovascular accidents if they have higher WSS. Simultaneous assessment with hemodynamic parameters like WSS along with stenosis severity may aid risk stratification in patients with asymptomatic carotid artery stenosis.

Early and midterm outcomes of in situ laser fenestration during thoracic endovascular aortic repair for acute and subacute aortic arch diseases and analysis of its complications.

OBJECTIVE: An analysis was conducted of early and midterm outcomes of a large series of patients treated with in situ laser fenestration (ISLF) during thoracic endovascular aortic repair (TEVAR) of acute and subacute complex aortic arch diseases, such as Stanford type A aortic dissection (TAAD), type B aortic dissection (TBAD) requiring proximal sealing at zone 2 or more proximal, thoracic aortic aneurysm or pseudoaneurysm, and penetrating aortic ulcer. We present the perioperative and follow-up outcomes and discuss the rate of complications. METHODS: This is a retrospective review of prospectively collected data from January 2017 to March 2019 of patients treated with TEVAR and ISLF of aortic arch branches at a large tertiary academic institution in an urban city in China. Preoperative, intraoperative, and follow-up clinical and radiographic data are analyzed and discussed. RESULTS: A total of 148 patients presented with symptomatic and acute or subacute TAAD, TBAD, thoracic aortic aneurysm, or penetrating aortic ulcer for a total of 183 arch vessels. There were 105 men and 43 women, 21 to 79 years of age (mean, 54.9 ± 12.9 years). Time from symptom onset to time of surgery was an average of 7 ± 3 days. Survivor follow-up duration ranged from 5 to 24 months (mean, 15 ± 5 months). Single-vessel fenestration was carried out in 124 cases, two-vessel fenestration in 13 cases, and three-vessel fenestration in 11 cases. There were four cases with technical failure to laser fenestration, with a technical success rate of 97.3%. Postoperatively, there were seven cases of endoleak (4.7%; one type IB distal from the left subclavian artery branch stent graft, three type IIIC at the fenestration site, and three type II), three retrograde dissections (2.0%), and five strokes (3.4%); death occurred in three patients with 30-day mortality of 2.9%, and two deaths occurred during follow-up for 3.4% mortality at an average 15 months of follow-up. There was no branch stent graft occlusion or spinal ischemia postoperatively or during follow-up. The distribution of arch diseases varied significantly according to the number of vessels that were laser fenestrated; TAAD was more likely to receive multivessel laser fenestrations, and TBAD was more likely to receive single-vessel fenestration (P < .001). The rate of complications was distributed differently between the three ISLF groups, with more complications occurring in multivessel fenestrations. However, a statistical weakening was observed when frequency of complications between the three groups was stratified by type of arch disease. The complication rate varied significantly between the different arch diseases, higher in TAAD than in TBAD (P = .008). CONCLUSIONS: ISLF during TEVAR for treatment of acute and subacute complex aortic arch diseases in the proximal aortic arch is safe and effective on the basis of these early to midterm follow-up data of a large cohort. However, care should be taken in intervening on TAAD using TEVAR with adjunctive multivessel laser fenestration. Continued investigation of TEVAR and adjunctive ISLF is needed to elucidate the long-term outcomes of this minimally invasive treatment for complex aortic arch disease in an urgent setting.

AngioJet Aspiration Thrombectomy Combined with Transcatheter Thrombolysis in Treatment of Acute Portal Venous Systemic Thrombosis.

BACKGROUND: This study set out to assess the feasibility, effectiveness, and safety of percutaneous AngioJet aspiration thrombectomy combined with transcatheter thrombolysis for treating acute portal venous systemic thrombosis (APVST). METHODS: Clinical data of 13 patients with APVST who were treated by AngioJet aspiration thrombectomy combined with transcatheter thrombolysis from March 2017 to July 2018 were analyzed retrospectively. The effect of portal venous recanalization was evaluated by intraoperative angiography and postoperative surveillance of clinical findings, portal venous ultrasound, or computed tomography. RESULTS: Successful puncture of the portal vein (PV) was performed in all patients. The PV was punctured successfully in 7 patients via the transjugular intrahepatic route, 2 patients failed to be punctured and then had successful percutaneous transhepatic puncture, and 4 patients underwent percutaneous transhepatic PV puncture directly. The duration of thrombus aspiration was 238.46 ± 89.89 sec (range, 120-360), and the amount of urokinase in thrombus aspiration was 353,000 ± 87,700 IU (range, 200,000-400,000). Portal venous thrombosis was dissolved by the AngioJet thrombectomy device (Boston Scientific, Marlborough, MA) in all patients. After aspiration, angiography showed that grade III lysis was achieved in 8 patients, grade II lysis in 1 patient, and grade I lysis in 4 patients. The length of transcatheter thrombolysis was 3.07 ± 1.75 days (range, 1-7), and the total urokinase dose via an indwelling catheter was 1,230,000 ± 706,000 IU (range, 200,000-2,800,000). Four patients had a transjugular intrahepatic portosystemic shunt, 1 patient with stenosis of the superior mesenteric vein (SMV) achieved balloon angioplasty, and 1 patient with stenosis of the SMV was stented. Operative complications were transient hematuria (4 patients), palpitation (1 patient), and bowel resection (1 patient). No patients died within 30 days. Patients were discharged at 12.00 ± 5.83 days (range, 6-27) after admission. All patients survived, and no recurrence developed during the follow-up of 9.15 ± 3.18 months (range, 4-15). CONCLUSIONS: Percutaneous AngioJet aspiration thrombectomy combined with thrombolytic therapy is feasible and effective for APVST. This treatment is beneficial for APVST in dissolving thrombus, improving SMV flow, and relieving symptoms of PV hypertension.

Aortic Valve Replacement with Bovine Pericardium in Patients with Aortic Valve Regurgitation.

This study aimed to analyze the early and mid-term outcomes of aortic valve replacement with bovine pericardium in the treatment of aortic valve regurgitation.From January 2015 to March 2018, 36 patients (19 men; mean ± standard deviation [SD] age, 46.70 ± 16.60 years) underwent aortic valve replacement with bovine pericardium. The bovine pericardium was intraoperatively measured and shaped using an Ozaki template, according to the shape and size of the individual patient's aortic valve leaflets. Additional procedures were performed, including ventricular septal defect repair in 5 cases, mitral valve reconstruction in 6 cases, tricuspid valve reconstruction in 6 cases, and coronary artery bypass grafting in 3 cases.There were no perioperative deaths. One elderly patient with postoperative respiratory failure recovered after symptomatic treatment. One patient with frequent ventricular tachycardia after intraoperative cardiac re-jump underwent intra-aortic balloon counterpulsation (IABP), and the IABP device was successfully removed on the second postoperative day. Within the first 6 months of follow-up, there were no death events, no reoperation events, and no additional thromboembolic events. Follow-up echocardiography was performed for 6 months, with average left ventricular ejection fraction of 62.01 ± 3.21%, mean transvalvular pressure gradient of 11.17 ± 4.90 mmHg, and mean aortic valve velocity of 1.60 ± 0.58 m/s. Compared with the preoperative transthoracic echocardiography findings, the results at the six-month follow-up were statistically significant (P < 0.05). Mild aortic valve regurgitation occurred in 2 patients (5.56%), whereas other patients had no or only minimal aortic valve regurgitation (n = 34, 94.44%). Moderate aortic valve regurgitation occurred in one patient at 9 months after the initial operation. This was found to be due to infective endocarditis, and a biological valve was finally implanted.Aortic valve replacement with bovine pericardium in the treatment of aortic valve regurgitation is feasible, and good early and mid-term results are achieved. Long-term results need to be followed up in the future.

Pulmonary artery closure in combination with patch technique for treating congenital heart disease combined with large patent ductus arteriosus: A clinical study of 9 cases.

OBJECTIVE: To document clinical experience of treating congenital heart disease combined with large patent ductus arteriosus with pulmonary artery closure in combination with patch technique. METHODS: Thirty-six patients (8 males and 28 females) who suffered from congenital heart disease and underwent hybrid surgery in the First Affiliated Hospital of Zhengzhou University from October 2010 to February 2014 were selected for this study. They aged 14 to 39 years and weighed 32.20 to 61.50 kg. Diameter of arterial duct was between 10 mm and 13 mm; 28 cases were tube type, 4 cases were funnel type and four cases were window type. All patients had moderate or severe pulmonary arterial hypertension; besides, there were 28 cases of ventricular septal defect, 16 cases of atrial septal defect, eight cases of aortic insufficiency, four cases of mitral stenosis and insufficiency and four cases of infectious endocarditis. Cardz Pulmonary Bypass (CPB) was established after chest was opened along the middle line. With the help of Transesophageal echocardiography, large patent ductus arteriosus was blocked off through pulmonary artery. Pulmonary artery was cut apart after blocking of heart. Large patent ductus arteriosus on the side of pulmonary artery was strengthened with autologous pericardial patch. RESULTS: Of 36 patients, 32 patients had patent ductus arteriosus closure device and four patients had atrial septal defect closure device. Pulmonary arteries of 36 cases were all successfully closed. Systolic pressure declined after closure ((54.86±19.23) mmHg vs (96.05±23.07) mmHg, p<0.05); average pulmonary arterial pressure also declined after closure ((39.15±14.83) mmHg vs (72.88±15.76) mmHg, p<0.05). The patients were followed up for one to fifty one months (average 11.5 months). Compared to before surgery, left atrial diameter, left ventricular diameter and pulmonary artery diameter all narrowed after surgery. Besides, clinical symptoms were relieved and cardiac function of the patients also improved. CONCLUSION: Hybrid surgery is feasible and safe in treating patients with large patent ductus arteriosus and congenital heart disease, which decreases surgical problems, shortens surgical time and lowers the incidence of complications.

Cross-talk between α7 nAChR-mediated cholinergic pathway and acylation stimulating protein signaling in 3T3-L1 adipocytes: role of NFκB and STAT3.

Inflammation is a key feature in adipose tissue, especially in association with obesity comorbidies. The novel adipokine acylation stimulating protein (ASP) is one factor implicated in the inflammatory response. The disruption of the α7 nicotine acetylcholine receptor (α7nAChR), an important component of the endogenous non-neural cholinergic defense system, may exacerbate sustained inflammatory phenotype. We examined cholinergic regulation of ASP-initiated inflammatory response in 3T3-L1 adipocytes. Our results show that preincubation of 3T3-L1 cells with α7nAChR agonist GTS-21 significantly reduces ASP-mediated chemokine MCP-1 secretion, which is regulated though nuclear factor κB (NFκB) and signal transducer and activator of transcription 3 (STAT3). Treatment of 3T3-L1 cells with GTS-21 significantly reduced NFκB activation by DNA binding and STAT3 activation by disturbing post-translational modification.

M3 muscarinic acetylcholine receptor dysfunction inhibits Rac1 activity and disrupts VE-cadherin/ß-catenin and actin cytoskeleton interaction.

The objective was to investigate whether M3 muscarinic acetylcholine receptor (mAChR) dysfunction disrupts the linkage between the vascular endothelial (VE)-cadherin in the adherens junctional complex and the actin-based cytoskeleton, increasing vascular permeability in atherosclerosis. Western blotting revealed that a selective M3 receptor antagonist, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), and M3 receptor siRNA decrease VE-cadherin and ß-catenin in Triton X-100-insoluble fractions, indicating that M3 receptor inhibition weakens the linkage between the VE-cadherin/ß-catenin complex and the actin cytoskeleton. Co-immunoprecipitation assays showed that M3 receptor inhibition reduces Rac1 activity and the association of IQ motif-containing GTPase-activating protein 1 (IQGAP1) with Ras-related C3 botulinum toxin substrate 1 (Rac1), while increasing the interaction between IQGAP1 and ß-catenin. Using IQGAP1 siRNA, we found that IQGAP1 is required for stable interaction between VE-cadherin/ß-catenin and the actin cytoskeleton in quiescent endothelial cells; IQGAP1 siRNA augments the M3 receptor inhibition-induced dissociation between them. Moreover, S-nitroso-N-acetylpenicillamine (SNAP), a nitric oxide (NO) donor, attenuates this disassociation and Rac1 activity inhibition. The M3 receptor facilitates interaction of the VE-cadherin-based adherens junctional complex and the actin-based cytoskeleton by maintaining Rac1 activity, which regulates the interaction between IQGAP1/Rac1 and IQGAP1/ß-catenin, and may contribute to endothelial barrier function under physiological conditions.

Combined use of transmyocardial laser revascularization and endothelial progenitor cells enhances neovascularization and regional contractility in a canine model of ischemic hearts.

The purpose of this study was to determine the combined effect of transmyocardial laser revascularization (TMLR) and the implantation of endothelial progenitor cells (EPCs) on cardiac function of ischemic hearts in canines. The left anterior descending artery (LAD) was occluded to establish the canine model of acute myocardial infarct (AMI). Four weeks later, the animals were randomly divided into four groups: TMLR group, in which transmyocardial laser-induced channels were established at the ischemic region; EPCs+TMLR group, in which EPCs were locally transplanted into laser-induced channels at the ischemic region; EPCs group, in which the EPCs were injected into the ischemic region; control group, in which the AMI animals received neither TMLR nor EPCs. The peripheral blood (50 mL) was sampled in all groups. Mononuclear cells from the peripheral blood were separated and cultured to obtain spindle-shaped attaching (AT) cells in vitro. AT cells were labeled with 1, 1'-dioctadecyl-1 to 3,3, 3',3'-tetramethyl-indocarbocyanine perchlorate (DiI) before injecting into the laser-induced channels or ischemic region. Four weeks after the first operation, TMLR was performed in the TMLR group and EPCs+TMLR group, and at the same time, the EPCs originating from the AT cells were mixed with calcium alginate (CA). Then the EPCs-CA composites were implanted into myocardial channels induced by laser in the EPCs+TMLR group, and into the myocardial infarct area in the EPCs group. All dogs underwent echocardiography at second month after LAD occlusion. Finally the samples of myocardium around the LAD were subjected to histochemical and immunohistologic examinations. The results showed there was no significant difference in the diameter of left atrium and ventricle before treatment among all groups (P>0.05). Eight weeks after modeling, the regional contractility in the LAD territory in the EPCs+TMLR group was increased as compared with control group and TMLR group, but there was no significant difference between control group and TMLR group. Neoangiogenesis was observed in the EPCs+TMLR group, and the fibrosis was seen in the TMLR group. There was no significant difference in neoangiogenesis around the channels induced by laser among EPCs+TMLR, EPCs and TMLR groups. It was concluded that TMLR combined with EPCs could improve the regional and global cardiac function in AMI, and augment neovascularizaiton in channels of ischemic myocardium induced by laser.

Identifying vulnerable plaques: A 3D carotid plaque radiomics model based on HRMRI.

Background: Identification of vulnerable carotid plaque is important for the treatment and prevention of stroke. In previous studies, plaque vulnerability was assessed qualitatively. We aimed to develop a 3D carotid plaque radiomics model based on high-resolution magnetic resonance imaging (HRMRI) to quantitatively identify vulnerable plaques. Methods: Ninety patients with carotid atherosclerosis who underwent HRMRI were randomized into training and test cohorts. Using the radiological characteristics of carotid plaques, a traditional model was constructed. A 3D carotid plaque radiomics model was constructed using the radiomics features of 3D T1-SPACE and its contrast-enhanced sequences. A combined model was constructed using radiological and radiomics characteristics. Nomogram was generated based on the combined models, and ROC curves were utilized to assess the performance of each model. Results: 48 patients (53.33%) were symptomatic and 42 (46.67%) were asymptomatic. The traditional model was constructed using intraplaque hemorrhage, plaque enhancement, wall remodeling pattern, and lumen stenosis, and it provided an area under the curve (AUC) of 0.816 vs. 0.778 in the training and testing sets. In the two cohorts, the 3D carotid plaque radiomics model and the combined model had an AUC of 0.915 vs. 0.835 and 0.957 vs. 0.864, respectively. In the training set, both the radiomics model and the combination model outperformed the traditional model, but there was no significant difference between the radiomics model and the combined model. Conclusions: HRMRI-based 3D carotid radiomics models can improve the precision of detecting vulnerable carotid plaques, consequently improving risk classification and clinical decision-making in patients with carotid stenosis.

Comparative outcomes of anticoagulation alone versus anticoagulation plus endovascular intervention in adults with isolated renal vein thrombosis.

BACKGROUND: Limited therapeutic strategies are available for adults with isolated renal vein thrombosis (RVT). In the present study, we explore and compare the efficacy of anticoagulation therapy alone vs anticoagulation plus endovascular intervention in the treatment of this rare disease. METHODS: In the present study, we analyzed the clinical data of RVT patients treated in a tertiary referral center in urban China from April 2012 to April 2022. These patients were classified into anticoagulation therapy (best medical treatment [BMT]) and endovascular intervention (endovascular-based treatment [EBT]) groups. The primary end points, including thrombus clearance and renal function changes, were evaluated by measuring the serum creatinine levels and glomerular filtration rates (GFRs). RESULTS: A total of 40 consecutive patients with RVT (25 men and 15 women) were included in the present study, with a median age of 37 years (range, 18-72 years). Some patients developed symptoms, including 12 with low back pain (30%), 11 with lower extremity edema (28%), and 10 with abdominal pain (30%). Nephrotic syndrome was the underlying etiology for most patients (30 of 40; 75%). Additionally, 28 patients (70%) developed unilateral RVT, including 18 cases of left RVT (45%). Of the 40 patients, 17 had received BMT (42%) and 23 had received EBT (58%). In the acute phase of RVT, defined as <14 days from symptom onset, the EBT group had higher thrombus clearance and better improvement of creatinine and GFR after treatment compared with the BMT group (P < .05). In the subacute phase, defined as 14 to 30 days after symptom onset, thrombus clearance was higher in the EBT group than in the BMT group (P < .05). However, the improvement in creatinine and GFR were insignificantly different between the two groups (P > .05). CONCLUSIONS: The etiologies of RVT can and should be investigated. In the present study, RVT was primarily caused by nephrotic syndrome in young patients and also was attributed to malignancy and lupus nephritis. In addition to anticoagulation therapy, endovascular intervention, including catheter-directed thrombolysis and mechanical thrombectomy, contributed to the improvement of renal function in patients with acute RVT. Endovascular intervention markedly promoted thrombus clearance in patients in the subacute phase but did not improve renal function. Therefore, endovascular intervention should be considered if RVT is diagnosed in the acute phase.

Pneumonia After Cardiovascular Surgery: Incidence, Risk Factors and Interventions.

Postoperative pneumonia (POP) is prevalent in patients undergoing cardiovascular surgery, associated with poor clinical outcomes, prolonged hospital stay and increased medical costs. This article aims to clarify the incidence, risk factors, and interventions for POP after cardiovascular surgery. A comprehensive literature search was performed to identify previous reports involving POP after cardiovascular surgery. Current situation, predictors and preventive measures on the development of POP were collected and summarized. Many studies showed that POP was prevalent in various cardiovascular surgical types, and predictors varied in different studies, including advanced age, smoking, chronic lung disease, chronic kidney disease, cardiac surgery history, cardiac function, anemia, body mass index, diabetes mellitus, surgical types, cardiopulmonary bypass time, blood transfusion, duration of mechanical ventilation, repeated endotracheal intubation, and some other risk factors. At the same time, several targeted interventions have been widely reported to be effective to reduce the risk of POP and improve prognosis, including preoperative respiratory physiotherapy, oral care and subglottic secretion drainage. Through the review of the current status, risk factors and intervention measures, this article may play an important role in clinical prevention and treatment of POP after cardiovascular surgery.

Novel Loss-of-Function Mutations in NPR2 Cause Acromesomelic Dysplasia, Maroteaux Type.

Acromesomelic dysplasia, Maroteaux type (AMDM) is a rare skeletal dysplasia characterized by severe disproportionate short stature, short hands and feet, normal intelligence, and facial dysmorphism. Homozygous or compound heterozygous mutations in the natriuretic peptide receptor 2 (NPR2) gene produce growth-restricted phenotypes. The current study was designed to identify and characterize NPR2 loss-of-function mutations in patients with AMDM and to explore therapeutic responses to recombinant growth hormone (rhGH). NPR2 was sequenced in two Chinese patients with AMDM via next generation sequencing, and in silico structural analysis or transcript analysis of two novel variants was performed to examine putative protein changes. rhGH treatment was started for patient 1. Three NPR2 mutations were identified in two unrelated cases: two compound heterozygous mutations c.1112G>A p.(Arg371Gln) and c.2887+2T>C in patient 1 and a homozygous mutation c.329G>A p.(Arg110His) in patient 2, yielding distinct phenotypes. RNA extracted from peripheral blood cells of patient 1 showed alternatively spliced transcripts not present in control cells. Homology modeling analyses suggested that the c.1112G>A p.(Arg371Gln) mutation disrupted the binding of NPR-B homodimer to its ligand (C-type natriuretic peptide) in the extracellular domain as a result of global allosteric effects on homodimer formation. Thus, c.2887+2T>C and c.1112G>A p.(Arg371Gln) in NPR2 were loss-of-function mutations. Furthermore, rhGH therapy in patient 1 increased the patient's height by 0.6SDS over 15 months without adversely affecting the trunk-leg proportion. The short-term growth-promoting effect was equivalent to that reported for idiopathic short stature. Overall, our findings broadened the genotypic spectrum of NPR2 mutations in individuals with AMDM and provided insights into the efficacy of rhGH in these patients.

The molecular mechanism of acylation stimulating protein regulation of adipophilin and perilipin expression: involvement of phosphoinositide 3-kinase and phospholipase C.

The novel adipokine acylation stimulating protein (ASP) is involved in lipid metabolism and obesity-related disorders. Adipophilin and perilipin, two members of the lipid droplet protein family, participate not only in fat storage within adipocytes, but also in ectopic lipid deposition in the form of cytoplasmic triglyceride (TG) droplets within many types of mammalian cells. During differentiation to mature adipocytes, mechanisms controlling the synthesis and turnover of these lipid droplet proteins are only partially understood, the mechanisms regulating gene/protein expression as yet unidentified. In our previous study, ASP has been shown to regulate adipophilin and perilipin expression to facilitate TG synthesis during 3T3-L1 cell differentiation. Our aim in this study was to provide insight into the physiological importance of phosphoinositide 3-kinase (PI3K) and phospholipase C (PLC) in ASP-triggered alteration of adipophilin and perilipin expression. We found that acute (2.5 h) inhibition of PLC or PI3K results in a decrease in mRNA and protein of perilipin and adipophilin at any time during differentiation. The fact that there is such a rapid change even with mRNA levels suggests a rapid turnover of both mRNA and protein independent of a direct ASP effect. Also, the presence of these inhibitors blocked the ASP stimulatory effects with a maximal decrease in gene and protein expression of adipophilin (-45% and -60%, respectively, P < 0.01) and perilipin (-96% and -63%, respectively, P < 0.01 and P < 0.05). These findings provide further understanding of the adipogenic properties of ASP in adipocytes.

Roles of human epicardial adipose tissue in coronary artery atherosclerosis.

This study examined the adipocytokine-vascular interactions and link between epicardial adipose tissue and coronary artery atherosclerosis. Thirty-four patients undergoing open heart surgery were chosen randomly, and divided into group I (non-coronary artery disease group) and group II (coronary artery disease group). Blood samples were taken through peripheral vein prior to surgery. Plasma levels of a panel of proteins (adiponectin, IL-10, TNF-α) were detected by using ELISA. Epicardial adipose tissue was taken near the proximal tract of the right coronary artery and subcutaneous adipose was taken from the leg before cardiopulmonary bypassing, adiponectin and CD68 + were detected by using RT-PCR and immunohistochemistry. Our results showed that plasma adiponectin level was significantly lower in the group II as compared with group I (P<0.05). There were no differences in plasma concentration (IL-10, TNF-α, tatal-chol, HDL-chol, LDL-chol) between group I and group II. The number of CD68+ cells in epicardial adipose tissue of group II was significantly higher than that in subcutaneous adipose tissue. Adiponectin mRNA expression was 6 fold higher in subcutaneous adipose tissue than in epicardial adipose tissue of group II (P<0.01). Furthermore, the level of adiponectin mRNA in the epicardial adipose tissue in group II was also significantly lower than in group I (P<0.05). We are led to conclude that inflammation that occurs locally in epicardial adipose tissue of CAD contributes to the pathogenesis of coronary artery disease.

Endovascular treatment for left innominate vein aneurysm: Case report and literature review.

Innominate vein aneurysms originating from the mediastinum are very rare. Previous treatments for this condition often required thoracotomy. We report a case of a 43-year-old male who presented a mediastinal mass by chest radiography. Contrast-enhanced CT and venography confirmed the diagnosis of left innominate vein aneurysm. The patient underwent endovascular treatment with stent placement and coil embolization of the left innominate vein. The patient remains well 18 months after surgery. The objective of this report is to discuss the diagnosis and endovascular treatment results of innominate vein aneurysm and to review the relevant literature to enhance and expand the pool of knowledge for this abnormality.

Cholinergic activation suppresses palmitate-induced macrophage activation and improves acylation stimulating protein resistance in co-cultured adipocytes.

Acylation-stimulating protein (ASP), produced through activation of the alternative complement immune system, modulates lipid metabolism. Using a trans-well co-culture cell model, the mitigating role of α7-nicotinic acetylcholine receptor (α7nAChR)-mediated cholinergic pathway on ASP resistance was evaluated. ASP signaling in adipocytes via its receptor C5L2 and signaling intermediates Gαq, Gß, phosphorylated protein kinase C-α, and protein kinase C-ζ were markedly suppressed in the presence of TNFα or medium from palmitate-treated RAW264.7 macrophages, indicating ASP resistance. There was no direct effect of α7nAChR activation in 3T3-L1 cell culture. However, α7nAChR activation almost completely reversed the ASP resistance in adipocytes co-cultured with palmitate-treated RAW264.7 macrophages. Further, α7nAChR activation could suppress the production of pro-inflammatory molecules TNFα and interleukin-6 produced from palmitate-treated co-cultured macrophages. These results suggest that macrophages play a significant role in the pathogenesis of ASP resistance and α7nAChR activation secondarily improves adipose ASP resistance through suppression of inflammation in macrophages. Impact statement 1. Adipocyte-macrophage interaction in acylation-stimulating protein (ASP) resistance 2. Lipotoxicity induced inflammatory response in ASP resistance 3. A vicious circle between lipotoxicity and inflammatory response in ASP resistance 4. Cholinergic modulation of inflammatory response in adipocyte and macrophage.

Right coronary artery fistula misdiagnosed as right atrial cardiac myxoma: A case report.

The current study describes a case of right coronary artery fistula (CAF) misdiagnosed as right atrial myxoma (RAM). A 33-year-old man presented with a 13-year history of intermittent chest pain, and aggravation for 3 days. Echocardiography revealed an occupying lesion in the right atrium producing a partial dynamic tricuspid obstruction. The initial diagnosis was RAM, which causes partial right ventricular inflow tract obstruction. During cardiopulmonary bypass surgery, a giant mass was detected in the anterior wall of the right ventricle and an abnormal vascular fistula was observed at the bottom of the mass. Successful excision of the mass and closure of the fistula completely relieved the patient's presenting symptoms. The disease was subsequently diagnosed as right CAF draining to the myocardial void. The surgical management and misdiagnosis of the case are discussed herein.

Nicotinic α7 receptor inhibits the acylation stimulating protein­induced production of monocyte chemoattractant protein­1 and keratinocyte­derived chemokine in adipocytes by modulating the p38 kinase and nuclear factor­κB signaling pathways.

Obesity is associated with chronic low­grade inflammation, which is characterized by increased infiltration of macrophages into adipose tissue. Acylation stimulating protein (ASP) is an adipokine derived from the immune complement system, which constitutes a link between adipocytes and macrophages, and is involved in energy homeostasis and inflammation. The purpose of the present study was to preliminarily investigate in vitro, whether functional α7nAChR in adipocytes may suppress ASP­induced inflammation and determine the possible signaling mechanism. Studies have reported associations between the expression of α7 nicotinic acetylcholine receptor (α7nAChR) and obesity, insulin resistance and diabetes. Additionally, α7nAChRs are important peripheral mediators of chronic inflammation, which is a key contributor to health problems in obesity. The primary aim of the present study was to evaluate the impact of exogenous ASP and α7nAChR on macrophage infiltration in adipose tissue and to examine the potential underlying molecular mechanism. Western blot analysis revealed that recombinant ASP increased the expression levels of monocyte chemoattractant protein­1 (MCP­1) and keratinocyte­derived chemokine (KC) by 3T3­L1 adipocytes. However, nicotine significantly inhibited the production of ASP­induced cytokines via the stimulation of α7nAChR. It was also found that α7nAChR inhibited the ASP­induced activation of p38 kinase and nuclear factor­κB (NF­κB), and the production of MCP­1 and KC. These data indicated that α7nAChR caused the inhibition of ASP­induced activation of p38 kinase and NF­κB to inhibit the production of MCP­1 and KC.

Type 3 muscarinic acetylcholine receptor stimulation is a determinant of endothelial barrier function and adherens junctions integrity: role of protein-tyrosine phosphatase 1B.

The main purpose of this study was to investigate whether type 3 muscarinic acetylcholine receptor (M3R) dysfunction induced vascular hyperpermeability. Transwell system analysis showed that M3R inhibition by selective antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) and small interfering RNA both increased endothelial permeability. Using coimmunoprecipitation and Western blot assay, we found that M3R inhibition increased VE-cadherin and ß-catenin tyrosine phosphorylation without affecting their expression. Using PTP1B siRNA, we found that PTP1B was required for maintaining VE-cadherin and ß-catenin protein dephosphorylation. In addition, 4-DAMP suppressed PTP1B activity by reducing cyclic adenosine monophosphate (cAMP), but not protein kinase Cα (PKCα). These data indicate that M3R preserves the endothelial barrier function through a mechanism potentially maintaining PTP1B activity, keeping the adherens junction proteins (AJPs) dephosphorylation.