Roles and Mechanisms of miRNAs in Abdominal Aortic Aneurysm: Signaling Pathways and Clinical Insights.

PURPOSE OF REVIEW: Abdominal aortic aneurysm refers to a serious medical condition that can cause the irreversible expansion of the abdominal aorta, which can lead to ruptures that are associated with up to 80% mortality. Currently, surgical and interventional procedures are the only treatment options available for treating abdominal aortic aneurysm patients. In this review, we focus on the upstream and downstream molecules of the microRNA-related signaling pathways and discuss the roles, mechanisms, and targets of microRNAs in abdominal aortic aneurysm modulation to provide novel insights for precise and targeted drug therapy for the vast number of abdominal aortic aneurysm patients. RECENT FINDINGS: Recent studies have highlighted that microRNAs, which are emerging as novel regulators of gene expression, are involved in the biological activities of regulating abdominal aortic aneurysms. Accumulating studies suggested that microRNAs modulate abdominal aortic aneurysm development through various signaling pathways that are yet to be comprehensively summarized. A total of six signaling pathways (NF-κB signaling pathway, PI3K/AKT signaling pathway, MAPK signaling pathway, TGF-ß signaling pathway, Wnt signaling pathway, and P53/P21 signaling pathway), and a total of 19 miRNAs are intimately associated with the biological properties of abdominal aortic aneurysm through targeting various essential molecules. MicroRNAs modulate the formation, progression, and rupture of abdominal aortic aneurysm by regulating smooth muscle cell proliferation and phenotype change, vascular inflammation and endothelium function, and extracellular matrix remodeling. Because of the broad crosstalk among signaling pathways, a comprehensive analysis of miRNA-mediated signaling pathways is necessary to construct a well-rounded upstream and downstream regulatory network for future basic and clinical research of AAA therapy.

Development and Validation of a Nomogram of Persistent Pulmonary Hypertension in Adult Pretricuspid Shunts After Correction.

BACKGROUND: Pretricuspid shunts have been associated with poorer survival rates in patients with Eisenmenger syndrome compared with postricuspid shunts and complex lesions. However, the risk stratification for persistent pulmonary hypertension (PH) in this population remains uncertain. METHODS AND RESULTS: We retrospectively enrolled 103 patients with pretricuspid shunts with high total pulmonary resistance >4.5 Wood units (estimated pulmonary vascular resistance ≥3 Wood units). During a mean±SD follow-up of 20.95±24.84 months, 32 patients developed postoperative persistent PH after shunt correction. We identified 3 significant predictors of postoperative persistent PH, including mean pulmonary artery pressure after inhaled oxygen ≥40.5 mm Hg (odds ratio [OR], 7.78 [95% CI, 2.02-30.03]; P<0.01), total pulmonary resistance after inhaled oxygen ≥6.5 Wood units (estimated pulmonary vascular resistance ≥5 Wood units; OR, 12.23 [95% CI, 2.12-70.46]; P<0.01), and artery oxygen saturation at rest <95% (OR, 3.34 [95% CI, 1.07-10.44]; P=0.04). We established the prediction model with the C-statistics of 0.85 (95% CI, 0.77-0.93; P<0.01), and the C-statistic was 0.83 (95% CI, 0.80-0.86) after bootstrapping 10 000 times with a good performance of the nomogram calibration curve for predicting persistent PH. CONCLUSIONS: Our study presents a multivariable risk stratification model for persistent PH after shunt correction in adults with pretricuspid shunts. This model, based on 3 hemodynamic predictors after inhaled oxygen, may assist in identifying individuals at higher risk of persistent PH after shunt correction.

HSPB6 Deficiency Promotes the Development of Aortic Dissection and Rupture.

To better understand the pathogenesis of acute type A aortic dissection, high-sensitivity liquid chromatography-tandem mass spectrometry/mass spectrometry (LC-MS/MS)-based proteomics and phosphoproteomics approaches were used to identify differential proteins. Heat shock protein family B (small) member 6 (HSPB6) in aortic dissection was significantly reduced in human and mouse aortic dissection samples by real-time PCR, western blotting, and immunohistochemical staining techniques. Using an HSPB6-knockout mouse, we investigated the potential role of HSPB6 in ß-aminopropionitrile monofumarate-induced aortic dissection. We found increased mortality and increased probability of ascending aortic dissection after HSPB6 knockout compared with wild-type mice. Mechanistically, our data suggest that HSPB6 deletion promoted vascular smooth muscle cell apoptosis. More importantly, HSPB6 deletion attenuated cofilin activity, leading to excessive smooth muscle cell stiffness and eventually resulting in the development of aortic dissection and rupture. Our data suggest that excessive stiffness of vascular smooth muscle cells caused by HSPB6 deficiency is a new pathogenetic mechanism leading to aortic dissection.

B-cell maturation antigen chimeric antigen receptor-T therapy alleviated heart failure in patients with multiple myeloma.

Patients with multiple myeloma (MM) are likely to achieve poor therapeutic response when organs are involved. We produced anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cells, which are in a trial for patients with relapsed/refractory MM. One enrolled patient developed severe heart failure, highly suspected as light chain cardiac amyloidosis. He exhibited increased N-terminal pro-brain natriuretic peptide with a peak of 32 299 ng/mL and heart failure with an ejection fraction of 30%. Anti-BCMA CAR-T cells were administered following lymphodepletion. The patient achieved cardiac response within 1 week with a decrease in N-terminal pro-brain natriuretic peptide by 80%, an increase in ejection fraction from 30% to 56%, and a haematological response with negative minimal residual disease at 1 month and a complete response at 1 year. To date, this patient has maintained good health without heart failure or haematological relapse. Herein, we show the efficacy of anti-BCMA CAR-T cells in patients with MM and severe heart failure.

Roles and mechanisms of umbilical cord mesenchymal stem cells in the treatment of diabetic foot: A review of preclinical and clinical studies.

AIMS: Growing preclinical and clinical evidence has suggested the potential method of umbilical cord mesenchymal stem cell (UCMSC) therapy for diabetic foot. Thus, the authors provided an outline of the application of UCMSCs in the treatment of diabetic foot and further summarized the roles and mechanisms of this therapy. DATA SYNTHESIS: With no time limitations, the authors searched the Web of Science, Cochrane Central Register of Controlled Trials, and PubMed (MEDLINE) databases. 14 studies were included, including 9 preclinical experiments and 5 clinical trials (3 RCTs and 2 single-arm trials). CONCLUSIONS: The UCMSCs are of great efficacy and safety, and function mainly by reducing inflammation, regulating immunity, promoting growth factors, and enhancing the functions of vascular endothelial cells, fibroblasts, and keratinocytes. As a result, ulcer healing-related biological processes ensue, which finally lead to diabetic foot ulcer healing and clinical symptom improvement. UCMSC treatment enhances diabetic foot ulcer healing and has a safety profile. They function mainly by modulating immunity, promoting growth factor secretion, and enhancing cellular functions. More well-designed preclinical and clinical studies are needed to provide the most optimal protocol, the comprehensive molecular mechanisms, as well as to further evaluate the efficiency and safety profile of UCMSC treatment in diabetic foot patients.

Surgical Outcome of Proximal Isolated Subclavian Artery Aneurysms: A Single-Center Retrospective Observational Study.

OBJECTIVE: The objective of this study was to introduce our institutional experience of treatment strategies (cervical subclavian artery reconstruction, thoracotomy subclavian artery reconstruction and endovascular treatment) for proximal isolated subclavian artery aneurysms (PISAAs). METHODS: we retrospectively analyzed 15 consecutive patients with PISAAs treated by different treatment strategies (cervical reconstruction, thoracotomy reconstruction and endovascular treatment) in our institution from May 2016 to May 2022. Baseline data, surgery-related data, postoperative information and long-term follow-up were assessed. RESULTS: A total of 17 PISAAs in 15 consecutive patients were treated in our institution. The success rates of subclavian artery reconstruction in the cervical reconstruction, the thoracotomy reconstruction and the endovascular treatment were 100%, 100 and 83.33%, respectively. About the involved vertebral artery, the reconstruction rates in the cervical reconstruction, the thoracotomy reconstruction, and the endovascular treatment were 80%, 75%, and 0, respectively. The intraoperative blood loss in the thoracotomy reconstruction was significantly higher than that in the cervical reconstruction and the endovascular treatment (p<0.05). The total operation time of the thoracotomy reconstruction was significantly longer than that of the cervical reconstruction and the endovascular treatment (p<0.05). In terms of postoperative ventilator use time, total postoperative drainage fluid, total postoperative drainage time, and ICU duration, both the thoracotomy reconstruction and the cervical reconstruction were significantly more than the endovascular treatment (p<0.05). During the follow-up, one patient in the endovascular treatment underwent re-intervention 22 months after surgery due to in-stent occlusion. CONCLUSIONS: For patients with PISAAs, different treatment strategies are recommended depending on the size of the aneurysms and whether the involved vertebral arteries require reconstruction. CLINICAL IMPACT: This article is the largest study on the treatment strategies of PISAAs. By comparing the prognosis and complications of endovascular treatment with those of open surgery, it provides a certain reference basis for the choice of treatment for patients with PISAAs. For patients with aneurysms' diameter of >50 mm, the thoracotomy subclavian artery reconstruction is recommended; for patients with aneurysms' diameter of <30 mm requiring reconstruction of the involved vertebral arteries, the cervical subclavian artery reconstruction is recommended; for patients with aneurysms' diameter of <30 mm not requiring reconstruction of the involved vertebral arteries, the endovascular treatment is recommended.

Interventional Occlusion of Large Patent Ductus Arteriosus in Adults with Severe Pulmonary Hypertension.

(1) Background: the indications for transcatheter closure of large patent ductus arteriosus (PDA) with severe pulmonary hypertension (PH) are still unclear, and scholars have not fully elucidated the factors that affect PH prognosis. (2) Methods: we retrospectively enrolled 134 consecutive patients with a PDA diameter ≥10 mm or a ratio of PDA and aortic >0.5. We collected clinical data to explore the factors affecting follow-up PH. (3) Results: 134 patients (mean age 35.04 ± 10.23 years; 98 women) successfully underwent a transcatheter closure, and all patients had a mean pulmonary artery pressure (mPAP) >50 mmHg. Five procedures were deemed to have failed because their mPAP did not decrease, and the patients experienced uncomfortable symptoms after the trial occlusion. The average occluder (pulmonary end) size was almost twice the PDA diameter (22.33 ± 4.81 mm vs. 11.69 ± 2.18 mm). Left ventricular end-diastolic dimension (LVEDD), mPAP, and left ventricular ejection fraction (LVEF) significantly reduced after the occlusion, and LVEF recovered during the follow-up period. In total, 42 of the 78 patients with total pulmonary resistance >4 Wood Units experienced clinical outcomes, and all of them had PH in the follow-up, while 10 of them had heart failure, and 4 were hospitalized again because of PH. The results of a logistic regression analysis revealed that the postoperative mPAP had an independent risk factor (odds ratio = 1.069, 95% confidence interval: 1.003 to 1.140, p = 0.040) with a receiver operating characteristic curve cut-off value of 35.5 mmHg (p < 0.001). (4) Conclusions: performing a transcatheter closure of large patent ductus arteriosus is feasible, and postoperative mPAP was a risk factor that affected the follow-up PH. Patients with a postoperative mPAP >35.5 mmHg should be considered for targeted medical therapy or should undergo right heart catheterization again after the occlusion.

Is Revascularization of V1 Segment of Vertebral Artery Combined with Ipsilateral Carotid Endarterectomy Safe?

BACKGROUND: The recommendation of the European Society for Vascular Surgery (ESVS) is that vertebral revascularization combined with ipsilateral CEA (carotid endarterectomy) should not be performed in the same operation. ESVS believes that vertebral revascularization combined with ipsilateral CEA increases perioperative death/stroke rates. In our opinion, revascularization of the first segment of vertebral artery (V1) combined with ipsilateral CEA is safe compared to vertebral V1 revascularization in the perioperative period. The purpose of this study is to prove that revascularization of V1 segment of vertebral artery combined with ipsilateral CEA is secure in the perioperative period. METHODS: We describe our experience with homochronous revascularization of V1 segment of vertebral artery with ipsilateral CEA (group B) and simple revascularization of V1 segment of vertebral artery (group A) in 48 consecutive patients during a 5-year period. O.Y. (Ouyang) incisions were used in both groups. We compare the results of the 2 procedures with aspects of mortality, stroke, morbidity, incident rates of complications, and so on. RESULTS: There was no significant difference between patients in group A and group B in terms of red blood cell reduction, postoperative ventilator using time, postoperative drainage volume, postoperative drainage days, postoperative hospitalize duration, and incident rates of postoperative complications. The postoperative complications include death, stroke, Horner syndrome, vocal paralysis, hypoglossal nerve paralysis, wound hematomas, and lymphatic leakage. CONCLUSIONS: Revascularization of vertebral artery combined with ipsilateral CEA should be divided into revascularization of V1 segment of vertebral artery combined with ipsilateral CEA and revascularization of V3 segment of vertebral artery with ipsilateral CEA. Revascularization of V1 segment of vertebral artery combined with ipsilateral CEA is safe; it can be performed for suitable patients who are fit for indications. O.Y. incisions can fully expose the target blood vessels and simplify the procedures without transecting the sternocleidomastoid muscles in operations.

Transcatheter closure of inferior sinus venosus defect using a patent ductus arteriosus occluder following simulation with a 3D-printed model.

Background: Transcatheter closure of inferior sinus venosus defect (ISVD) is still contraindication. To explore whether transcatheter closure with patent ductus arteriosus (PDA) occluders is possible for ISVD. Methods: From June 2014 to March 2021, 12 patients were recruited diagnosed as <25 mm ISVD. The three-dimensional printing (3DP) heart model was produced based on multi-slice computed tomography (MSCT) scans. Preoperative closure simulation was planned on the personalized 3D model for each patient. Follow-up including electrocardiography (ECG), transthoracic echocardiography (TTE), and X-ray was traced. Results: 3DP models of 12 patients were successfully printed. Twelve patients had been diagnosed with <25 mm ISVD and 4 of them had another secundum atrial septal defect (ASD). All patients were produced interventional therapy successfully. PDA occluder was implanted to closed ISVD, and ASD was closed using ASD occluder simultaneously. The average diameter of ISVD measured by TTE was (12.67±3.80), and the average diameter of sagittal axes and longitudinal axes measured by the 3D-printed model was (17.08±3.20) and (18.42±4.62) mm, respectively. The average size of PDA (diameter of pulmonary artery side) was (28.17±3.35) mm. Compared with the preoperative, the X-ray cardiothoracic ratio (0.51±0.04 vs. 0.47±0.06, P=0.007) and the right ventricle anterior-posterior diameter (31.17±5.65 vs. 24.58±3.75 mm, P<0.001) of postoperative was significantly decreased. During the average (47.75±27.52) months follow-up, it has achieved satisfying results, and there were no severe adverse events such as device transposition, death, and pericardial tamponade occurred. Conclusions: Assisting by 3D heart model, transcatheter closure of ISVD with PDA occluder had an excellent outcome. This method provides a new considerable treatment strategy for ISVD.

Vascular smooth muscle cell-derived hydrogen sulfide promotes atherosclerotic plaque stability via TFEB (transcription factor EB)-mediated autophagy.

Vascular smooth muscle cells (VSMCs) contribute to plaque stability. VSMCs are also a major source of CTH (cystathionine gamma-lyase)-hydrogen sulfide (H2S), a protective gasotransmitter in atherosclerosis. However, the role of VSMC endogenous CTH-H2S in pathogenesis of plaque stability and the mechanism are unknown. In human carotid plaques, CTH expression in ACTA2+ cells was dramatically downregulated in lesion areas in comparison to non-lesion areas. Intraplaque CTH expression was positively correlated with collagen content, whereas there was a negative correlation with CD68+ and necrotic core area, resulting in a rigorous correlation with vulnerability index (r = -0.9033). Deletion of Cth in VSMCs exacerbated plaque vulnerability, and were associated with VSMC autophagy decline, all of which were rescued by H2S donor. In ox-LDL treated VSMCs, cth deletion reduced collagen and heightened apoptosis association with autophagy reduction, and vice versa. For the mechanism, CTH-H2S mediated VSMC autophagosome formation, autolysosome formation and lysosome function, in part by activation of TFEB, a master regulator for autophagy. Interference with TFEB blocked CTH-H2S effects on VSMCs collagen and apoptosis. Next, we demonstrated that CTH-H2S sulfhydrated TFEB at Cys212 site, facilitating its nuclear translocation, and then promoting transcription of its target genes such as ATG9A, LAPTM5 or LDLRAP1. Conclusively, CTH-H2S increases VSMC autophagy by sulfhydration and activation of TFEB, promotes collagen secretion and inhibits apoptosis, thereby attenuating atherogenesis and plaque vulnerability. CTH-H2S may act as a warning biomarker for vulnerable plaque.Abbreviations ATG9A: autophagy related 9A; CTH: cystathionine gamma-lyase; CQ: chloroquine; HASMCs: human aortic smooth muscle cells; H2S: hydrogen sulfide; LAMP1: lysosomal associated membrane protein 1; LAPTM5: lysosomal protein transmembrane 5; NaHS: sodium hydrosulfide hydrate; ox-LDL: oxidized-low density lipoprotein; PPG: DL- propagylglycine; TFEB: transcription factor EB; 3-MA: 3-methyladenine; VSMCs: vascular smooth muscle cells.

The novel hybrid polycarbonate polyurethane / polyester three-layered large-diameter artificial blood vessel.

BACKGROUND: The most common materials of artificial blood vessels are polyethylene terephthalate and polytetrafluoroethylene. But polycarbonate polyurethane (PCU) is an ideal material for vascular prostheses because of their excellent characteristics. As far as we know, our artificial blood vessel is the first type of hybrid PCU/polyester three-layered large-diameter artificial blood vessel in the world. OBJECTIVE: The purpose of this preclinical animal experiment is to evaluate the hemocompatibility, histocompatibility, effectiveness, and safety of the three-layered large-diameter artificial blood vessel in sheep. METHODS: The artificial blood vessels took place of the initial segments of the sheep's thoracic aorta by end-to-end anastomosis. RESULTS: All of the 14 sheep are male, their average body weight (BW) was 30.57 ± 3.95 kg. All 14 artificial blood vessels successfully replaced the thoracic aortas. 5 sheep did not survive to the end of the experiment, while the remaining 9 sheep did. After the surgery, the blood biochemical and blood routine indicators fluctuate slightly within the normal range. The angiography showed that the implanted artificial blood vessels were unobstructed without obvious stenosis or expansion. 24 weeks after surgery, the lumen surfaces of the artificial blood vessels were covered by endothelia in different degrees, and the average endothelialization rate was 69.44% (range: 20% to 100%). CONCLUSIONS: This artificial blood vessel is the first to use PCU in large-diameter artificial vascular grafts. It has excellent blood compatibility, wonderful biocompatibility, high endothelialization rate, and 100% patency.

Transcatheter Closure of Patent Ductus Arteriosus via Different Approaches.

Background: There have been marked advances in devices such as Amplatzer Duct Occluder II (ADO-II) or vascular plug through 5Fr delivery sheath for closure of patent ductus arteriosus (PDA) in the past five decades, making it possible for cardiologists to deliver occluders via different approaches. However, comparisons of these different approaches have not been reported. Therefore, the aim of this study was to summarize and compare the advantages of different approaches for PDA closure, and to guide clinical strategies. Methods: This retrospective study included all patients undergoing transcatheter closure of PDA from 2019 to 2020. Patients were matched by 1:1 propensity score matching (PSM). The retrograde femoral artery approach (FAA) and simple vein approach (SVA) groups were compared with the conventional arteriovenous approach (CAA). Results: The average age of the 476 patients was 21.05 ± 21.15 years. Their average weight was 38.23 ± 24.1 kg and average height was 130.14 ± 34.45 cm. The mean diameter of the PDA was 4.29 ± 2.25 mm. There were 127 men and 349 women, comprising 205 adults and 271 children. Among them, 197 patients underwent CAA, 223 underwent SVA, and 56 underwent retrograde FAA. The diameter in the FAA group was smaller than that in the other two groups, but was similar in adults and children. In the PSM comparison of CAA and SVA, 136 patients with CAA and 136 patients with SVA were recruited. Simple vein approach was associated with markedly reduced length of hospital stay, length of operation, and contrast medium usage as compared with CAA (all P < 0.05). In the PSM comparison of FAA and CAA, 30 patients with CAA and 30 patients with FAA were recruited. The operation duration was longer in the CAA than in the FAA group. There were no significant differences in postoperative complications among groups. Conclusion: Patent ductus arteriosus closure by using the SVA and FAA is safe and effective, and has certain advantages in some respects as compared with CAA.