Angpt1 binding to Tie1 regulates the signaling required for lymphatic vessel development in zebrafish.

Development of the vascular system is regulated by multiple signaling pathways mediated by receptor tyrosine kinases (RTKs). Among them, angiopoietin (Ang)/Tie signaling regulates lymphatic and blood vessel development in mammals. Of the two Tie receptors, Tie2 is well known as a key mediator of Ang/Tie signaling, but unexpectedly, recent studies reveal that the Tie2 locus has been lost in many vertebrate species, while the Tie1 gene is more commonly present. However, Tie1-driven signaling pathways, including ligands and cellular functions, are not well understood. Here, we performed comprehensive mutant analyses of angiopoietins and Tie receptors in zebrafish and found that only angpt1 and tie1 mutants show defects in trunk lymphatic vessel development. Among zebrafish angiopoietins, only Angpt1 binds to Tie1 as a ligand. We indirectly monitored Ang1/Tie1 signaling and detected Tie1 activation in sprouting endothelial cells (ECs), where Tie1 inhibits nuclear import of EGFP-Foxo1a. Angpt1/Tie1 signaling functions in EC migration, proliferation, and lymphatic specification during early lymphangiogenesis, at least in part by modulating Vegfc/Vegfr3 signaling. Thus, we show Angpt1/Tie1 signaling to constitute an essential signaling pathway for lymphatic development in zebrafish.

Staged repair of a ruptured thoracoabdominal aortic aneurysm: a case report.

BACKGROUND: A ruptured thoracoabdominal aortic aneurysm (rTAAA) represents a considerable challenge for surgeons. To date, endovascular procedures have not been able to completely replace open repair when debranching is required. CASE PRESENTATION: A 73-year-old man was admitted to our hospital after complaining of left lateral abdominal pain. Enhanced computed tomography revealed a left retroperitoneal hematoma and a large, ruptured Crawford type IV TAAA. We first performed emergency resuscitative surgery to close the lacerated foramen. A graft replacement was performed 1 month after the initial surgery when the patient had stabilized. At 5 years postoperatively, neither occlusion nor anastomotic pseudoaneurysm was noted on computed tomography. CONCLUSIONS: We provide an update on the perioperative management of patients undergoing open rTAAA repair. This procedure can be considered to ensure complete repair of an rTAAA.

Evaluation of flow dynamics in distal stent graft-induced new entry using 4D flow MRI.

Distal stent graft-induced new entry may occur after stent grafting for aortic dissection. Four-dimensional magnetic resonance imaging is useful for predicting outcomes, showing accelerated flow and increased wall shear stress, indicating further false lumen expansion.

Long-term results of etiology-based thoracic endovascular aortic repair: a single-center experience.

The use of thoracic endovascular aortic repair (TEVAR) for thoracic aortic aneurysm (TAA) and Stanford type B aortic dissection (TBAD) has been increasing; however, in terms of etiology, the differences of long term after TEVAR outcomes remain unexplored. Thus, we investigated etiology-specific long-term results of TEVAR for TAA and TBAD. A total of 421 TEVAR procedures were performed at our institution from July 2007 to December 2021; 249 TAA cases and 172 TBAD cases were included. Traumatic aortic dissection and aortic injury cases were excluded. The mean observation duration was 5.7 years. The overall 30-day mortality rate was 1.4% (n = 6), with 1.2% (n = 3) in the TAA group and 1.7% (n = 3) in the TBAD group. The overall incidence of postoperative stroke was 0.9% (n = 4), with 1.2% (n = 3) and 0.6% (n = 1) in the TAA and TBAD groups, respectively (p = 0.90). Paraplegia developed in 1.7% (n = 7) of patients, with 2.4% (n = 6) in the TAA group and 0.6% (n = 1) in the TBAD group. Freedom from aortic-related death was not significantly different between the two etiologies; however, thoracic reintervention was more common in the TBAD group (p = 0.003), with endoleak being the most common indication for reintervention. Additionally, retrograde type A aortic dissection occurred in four TBAD cases, while migration occurred in three TAA cases. The perioperative results of TEVAR for TAA and TBAD were satisfactory. The long-term results were unfavorable owing to the occurrence of etiology-specific and common complications. In terms of the high frequency of reintervention, the long-term complications associated with TEVAR are etiology specific.

Mid- and long-term results of open repair for chronic type B aortic dissection in endovascular era.

Medical management is the standard treatment of chronic type B aortic dissection (CTBAD). However, the roles of open surgical repair (OSR) and thoracic endovascular repair (TEVAR) in patients with CTBAD remain controversial. Thus, this study aimed to assess and compare the mid- and long-term clinical outcomes of OSR via left thoracotomy with that of TEVAR for CTBAD. The data of 85 consecutive patients who underwent surgery for CTBAD from April 2007 to May 2021 were retrospectively reviewed. The patients were divided into two groups: Group G, which included patients who underwent OSR, and Group E, which included patients who underwent TEVAR. Groups G and E comprised 33 and 52 patients, respectively. Preoperative and postoperative computed tomography (CT) studies were retrospectively analyzed for the maximum diameter. The mean duration of the follow-up period was 5.8 years. Operative mortality did not occur. There was no difference in complications, such as stroke (G: 2 vs. E: 0, p = 0.30), paraplegia (G: 1 vs. E: 1, p = 0.66), and respiratory failure (G: 2, vs. E: 0, p = 0.30). The difference in preoperative factors was observed, including the intervals between onset and operation (G; 4.9 years vs. E; 1.9 years, p < 0.01), maximum diameter in preoperative CT (G; 59.0 mm vs. E; 50.5 mm, p < 0.001), and maximum false lumen diameter (G; 35.5 mm vs. E; 29.0 mm, p < 0.01). There was no significant difference in the mid- and long-term survival rates (p = 0.49), aorta-related deaths (p = 0.33), and thoracic re-intervention rates (p = 0.34). Postoperative adverse events occurred in Group E: four cases of retrospective type A aortic dissection, two cases of aorto-bronchial fistula, and one case of aorto-esophagus fistula. Aorta-related death and re-intervention rates crossed over in both groups after seven years postoperatively. Although endovascular repair of CTBAD is less invasive, the rate of freedom from re-intervention was unsatisfactory. Some fatal complications were observed in the endovascular group, and the mid- and long-term outcomes were reversed compared with those in the OSR group. Although OSR is an invasive procedure, it could be performed safely without perioperative complications. OSR has more feasible mid- and long-term outcomes.

Safety of intranasal insulin administration in patients undergoing cardiovascular surgery: An open-label, nonrandomized, dose-escalation study.

Objective: This study aimed to determine the maximum safe dose of intranasal insulin administration during cardiac surgery. Methods: This open-label, Phase 1, single-center, dose-escalation clinical trial recruited patients scheduled to undergo elective cardiac surgery or major vascular surgery requiring cardiopulmonary bypass between February and September 2021. They were grouped into 5 dose-escalation cohorts and administered 0, 40, 80, 160, and 240 IU insulin (n = 6 in each group) via a metered nasal dispenser after the induction of general anesthesia. Blood samples were collected at 10-minute intervals for the first 60 minutes and at 30-minute intervals thereafter. Hypoglycemia was defined as a blood glucose level <70 mg/dL. Patient recruitment was terminated after hypoglycemia was observed in 2 patients in any of the groups. Results: In total, 27 of 29 enrolled patients were administered intranasal insulin or saline. Hypoglycemia was not observed after the administration of intranasal insulin in the 0, 40, 80, or 160 IU groups; however, it was observed in 2 of 3 patients in the 240 IU group. The serum insulin concentration was elevated in the 160-IU group, but the C-peptide concentration was not elevated in any of the groups. Conclusions: The administration of up to 160 IU intranasal insulin did not induce clinically significant hypoglycemia. However, 160 IU intranasal insulin should be administered cautiously because insulin can enter the systemic circulation in a dose-dependent manner.

Melanocortin-4 receptor in macrophages attenuated angiotensin II-induced abdominal aortic aneurysm in mice.

Obesity is recognized as an independent risk factor for abdominal aortic aneurysm (AAA). While mutations in the melanocortin-4 receptor (MC4R) gene is the most common cause of obesity caused by mutations in a single gene, the link between MC4R function and vascular disease has still remained unclear. Here, by using melanocortin-4 receptor (MC4R) deficient mice, we confirmed MC4R deficiency promotes AAA and atherosclerosis. We demonstrated the contribution of two novel factors towards vascular vulnerability in this model: leptin signaling in vascular smooth muscle cells (VSMCs) and loss of MC4R signaling in macrophages. Leptin was shown to promote vascular vulnerability via PI3K-dependent upregulation of Spp1 expression in VSMC. Additionally, Ang II-induced AAA incidence was significantly reduced when MC4R gene expression was myeloid cell-specifically rescued in MC4R deficient (MC4RTB/TB) mice. Ex vivo analysis showed a suppression in NF-κB activity in bone marrow-derived macrophages from LysM(+);MC4RTB/TB mice compared to LysM(-);MC4RTB/TB mice, which exaggerates with endogenous MC4R ligand treatment; α-MSH. These results suggest that MC4R signaling in macrophages attenuates AAA by inhibiting NF-κB activity and subsequent vascular inflammation.

A possible mechanism and predictors of forming looped guidewire between the right subclavian and brachiocephalic artery during coronary angiography with right radial artery access: An original paper.

OBJECTIVES: Guidewire occasionally creates a loop-like appearance between the right subclavian artery and brachiocephalic artery when performing coronary angiography (CAG) with right radial artery (RtRA) access. We called this occurrence a looped guidewire at the brachiocephalic artery (looped GW at BA). It is associated with difficulties in catheter manipulation. This study aimed to assess the predictors of forming a looped GW at the BA. METHODS: We examined 175 (mean age, 71.3 ± 9.5 years; 74.9% men) consecutive patients who underwent elective CAG with the RtRA access. Looped GW at the BA was defined as a loop-like appearance of the 0.035-inch GW between the right subclavian and brachiocephalic artery on a frontal view or left anterior oblique. To identify the predictors of looped GW at BA, patient characteristics and examination data obtained before CAG were compared between patients with and without looped GW at the BA. RESULTS: The prevalence of looped GW at BA was 10.9%. The cardio-ankle vascular index (CAVI), which reflects arterial stiffness, was significantly different in patients with or without looped GW at BA (9.8 ± 1.0 vs. 8.9 ± 1.5, p = 0.0092). The area under the receiver-operating characteristic curve of CAVI to predict looped GW at BA was 0.745, with 0.94 sensitivity and 0.57 specificity in a cutoff point of CAVI ≥9.0. CONCLUSIONS: Looped GW at BA can be ruled out by CAVI and is associated with high arterial stiffness.

Systolic anterior motion due to morphology changes in constrictive pericarditis.

Systolic anterior motion (SAM) can be caused by multifactorial mechanisms, including structural, morphological and functional factors. We report an unusual case of a 76-year-old woman presenting with SAM associated with constrictive pericarditis. Echocardiography showed no septal hypertrophy but SAM and left ventricular outflow tract obstruction and moderate mitral regurgitation. The restoration of diastolic function after complete pericardiectomy successfully eliminated it.

Structures on the ventricular side of the prosthetic valve in extremely late mitral paravalvular leak: a case report.

Background: Mechanisms of paravalvular leak (PVL) after mitral valve replacement have not been fully delineated. Herein, we report a case of structures on the ventricular side of the mitral valve in a patient with an extremely late PVL. Case summary: A 68-year-old female underwent aortic and mitral valve replacement with a mechanical valve 29 years ago. She was in good health for 28 years. However, exertional dyspnoea appeared 8 months ago. She was admitted to our hospital for congestive heart failure and haemolytic anaemia. Echocardiography showed severe regurgitation due to PVL of the mitral valve. The fluoroscopy showed that a circular calcification was found below the mitral prosthesis. The operation was performed through a median sternotomy. After the aortic cross-clamp, the aortic mechanical valve was removed. The ventricular side of the mitral valve was inspected with the endoscope through the aortic annulus before manoeuvers were performed in the mitral valve. A gap was seen between the prosthetic valve and annular tissue and subvalvular calcification. A bioprosthetic valve was placed with a modified collar-reinforcement technique using a xenopericardium strip. The postoperative course was uneventful. PVL and haemolysis completely disappeared. Discussion: The ventricular side of the prosthetic valve could be observed before the mitral valve was removed. Not only the protruding circular calcification and displacement of the prosthetic valve to the atrial side but also the loss of adhesion and adhesive nature of the annular tissue played a definitive role in the late PVL occurrence and recurrence after percutaneous or surgical repair.

Svep1 is a binding ligand of Tie1 and affects specific aspects of facial lymphatic development in a Vegfc-independent manner.

Multiple factors are required to form functional lymphatic vessels. Here, we uncover an essential role for the secreted protein Svep1 and the transmembrane receptor Tie1 during the development of subpopulations of the zebrafish facial lymphatic network. This specific aspect of the facial network forms independently of Vascular endothelial growth factor C (Vegfc) signalling, which otherwise is the most prominent signalling axis in all other lymphatic beds. Additionally, we find that multiple specific and newly uncovered phenotypic hallmarks of svep1 mutants are also present in tie1, but not in tie2 or vegfc mutants. These phenotypes are observed in the lymphatic vasculature of both head and trunk, as well as in the development of the dorsal longitudinal anastomotic vessel under reduced flow conditions. Therefore, our study demonstrates an important function for Tie1 signalling during lymphangiogenesis as well as blood vessel development in zebrafish. Furthermore, we show genetic interaction between svep1 and tie1 in vivo, during early steps of lymphangiogenesis, and demonstrate that zebrafish as well as human Svep1/SVEP1 protein bind to the respective Tie1/TIE1 receptors in vitro. Since compound heterozygous mutations for SVEP1 and TIE2 have recently been reported in human glaucoma patients, our data have clinical relevance in demonstrating a role for SVEP1 in TIE signalling in an in vivo setting.

In situ follicular neoplasm discovered as an enlarging pulmonary nodule complicated by pulmonary aspergillosis.

In situ follicular B cell neoplasm, previously known as follicular lymphoma in situ, is a neoplastic proliferation of follicular lymphoma-like B cells confined to the germinal centers. Herein, we report a case of a woman in her 70s who initially presented with several enlarged abdominal lymph nodes. Seven months later during follow-up, a solitary pulmonary nodule was detected. As it was close to the hilum, lobectomy was performed. The intraoperative frozen section showed fibrosis and a collection of lymphocytes and macrophages. Therefore, the lymph nodes were sampled. Station 4 and 10 lymph nodes exhibited similar tumor cells and were immunohistochemically positive for CD10 and BCL2. Thus, the patient was diagnosed with in situ follicular neoplasm and is currently under observation. In situ follicular neoplasm is typically a slowly progressive neoplasm; however, it can present as a rapidly enlarging pulmonary nodule complicated by pulmonary aspergillosis.

A case of Candida parapsilosis bioprosthetic valve endocarditis.

Fungal bioprosthetic valve endocarditis is regarded as a rare, fatal disease. Severe aortic valve stenosis due to vegetation in bioprosthetic valves was also rare. Because biofilm formation is a factor related to persistent infection, the best outcomes for endocarditis are achieved in patients treated surgically with concomitant antifungal medicine.

Effect of Pemafibrate on Hemorheology in Patients with Hypertriglyceridemia and Aggravated Blood Fluidity Associated with Type 2 Diabetes or Metabolic Syndrome.

Persistent high serum triglyceride (TG) and free fatty acid (FFA) levels, which are common in metabolic syndrome and type 2 diabetes, are risk factors for cardiovascular events because of exacerbated hemorheology. To explore the effects of pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, on hemorheology, we performed a single-center, nonrandomized, controlled study in patients with type 2 diabetes (HbA1c 6-10%) or metabolic syndrome, with fasting TG levels of ≥ 150 mg/dL and a whole blood transit time of > 45 s on a microarray channel flow analyzer (MCFAN). Patients were divided into a study group, receiving 0.2 mg/day of pemafibrate (n = 50) for 16 weeks, and a non-pemafibrate control group (n = 46). Blood samples were drawn 8 and 16 weeks after entry to the study to evaluate whole blood transit time as a hemorheological parameter, leukocyte activity by MCFAN, and serum FFA levels. No serious adverse events were observed in either of the groups. After 16 weeks, the pemafibrate group showed a 38.6% reduction in triglycerides and a 50.7% reduction in remnant lipoproteins. Pemafibrate treatment did not significantly improve whole blood rheology or leukocyte activity in patients with type 2 diabetes mellitus or metabolic syndrome complicated by hypertriglyceridemia and exacerbated hemorheology.

Prognostic evaluation of preoperative serum tumor marker-negative cases in non-small cell lung cancer: A retrospective study.

BACKGROUND: The role of various serum tumor markers (TMs) has been reported in non-small cell lung cancer (NSCLC). However, the prognosis of patients with multiple TM-negative NSCLC remain unclear. AIMS: This study aimed to describe the characteristics and outcomes of patients with NSCLC undergoing surgery and to investigate their prognostic association with preoperative serum TM-negative cases. METHODS AND RESULTS: We retrospectively evaluated 442 patients who underwent complete resection of stage I NSCLC between January 2004 and December 2019. These 442 patients were classified into a group whose preoperative serum levels of carcinoembryonic antigen (CEA), cytokeratin-19 fragment (CYFRA21-1), carbohydrate antigen 19-9 (CA19-9), and squamous cell carcinoma antigen (SCC Ag) were all negative (TM-negative group; n = 249, 56%) and a group with at least one positive marker (TM-positive group; n = 193, 44%). Among all patients, the TM-negative group showed higher 5-year recurrence-free survival (RFS) (92.6% vs. 79.1%; p < .01), and overall survival (OS) rates (86.3% vs. 68.6%; p < .01). After propensity score matching, patients in the TM-negative group still exhibited good 5-year RFS (92.1% vs. 81.4%; p = .01) and OS rates (87.6% vs. 72.6%; p < .01). CONCLUSION: Our study suggests that NSCLC patients who are preoperatively negative for all serum TMs, such as CEA, CYFRA21-1, CA19-9, and SCC Ag, represent a subgroup with a particularly good prognosis.

Endoderm-derived islet1-expressing cells differentiate into endothelial cells to function as the vascular HSPC niche in zebrafish.

Endothelial cells (ECs) line blood vessels and serve as a niche for hematopoietic stem and progenitor cells (HSPCs). Recent data point to tissue-specific EC specialization as well as heterogeneity; however, it remains unclear how ECs acquire these properties. Here, by combining live-imaging-based lineage-tracing and single-cell transcriptomics in zebrafish embryos, we identify an unexpected origin for part of the vascular HSPC niche. We find that islet1 (isl1)-expressing cells are the progenitors of the venous ECs that constitute the majority of the HSPC niche. These isl1-expressing cells surprisingly originate from the endoderm and differentiate into ECs in a process dependent on Bmp-Smad signaling and subsequently requiring npas4l (cloche) function. Single-cell RNA sequencing analyses show that isl1-derived ECs express a set of genes that reflect their distinct origin. This study demonstrates that endothelial specialization in the HSPC niche is determined at least in part by the origin of the ECs.

Fenestrated Fontan-like circulation under durable left-ventricular assist device support in fulminant myocarditis.

Fulminant myocarditis is a fatal development from profound biventricular heart failure and often requires both right- and left-ventricular assistance to maintain hemodynamics, even at the risk of increased mortality and morbidity. Here, we present a 42-year-old female with profound biventricular failure due to fulminant myocarditis, resolved by an isolated durable left-ventricular assist device support under a fenestrated, Fontan-like circulation and managed low-pulmonary vascular resistance.

Rapidly growing proliferative pulmonary chondroma: A case report.

INTRODUCTION: Pulmonary chondroma, a component of Carney's triad, is commonly unilateral and multiple, and progresses slowly. Herein, we report a case of a chondrogenic tumour that grew and proliferated during follow-up. PRESENTATION OF CASE: A female patient in her 20s presenting with a cough was found to have a 1.4-cm nodule in the left lung on computed tomography (CT). After 18 months' follow-up, CT revealed that the original nodule had increased to 2.2 cm, and a new 1.3-cm nodule had appeared. She was then referred to our hospital and underwent a robot-assisted lower lobectomy of the left lung. The tumour was diagnosed as a chondrogenic tumour. She had no problems after the surgery or during follow-up; other signs of the Carney's triad were ruled out. Twenty-six months postoperatively, there was no evidence of recurrence. DISCUSSION: One report suggests that the growth of pulmonary chondroma is slow, but the present case showed an increase in both the size and number of tumours within 2 years without any symptoms. The chondroma did not recur after the surgery, though her pulmonary tumours had grown and proliferated rapidly. Furthermore, it has been reported that an average of 8.4 years is needed for another sign of Carney's triad to appear; therefore, careful follow-up should be continued. CONCLUSION: This report suggests that pulmonary chondroma can grow and proliferate rapidly and asymptomatically, and can be controlled by complete resection.

Reversal flow in the left anterior descending artery after internal thoracic artery grafting.

BACKGROUND: The flow capacity of the in situ internal thoracic artery (ITA) is not necessarily sufficient and can be a cause of hypoperfusion syndrome. We present a catastrophic case of in situ ITA grafting for an isolated left main trunk obstruction 13 years after the modified Bentall operation. CASE PRESENTATION: A 33-years-old woman had undergone the modified Bentall operation. Coronary angiography showed a critical stenosis in the left coronary artery. The patient underwent emergency off-pump coronary artery bypass graft with the left ITA to the left anterior descending artery (LAD). On the 7th day, the patient had severe dyspnoea and hypotension. Catheter angiography showed that the ITA was patent; however, blood flow from the in situ ITA was delayed, and reversal flow from the apex to the proximal LAD was found. The patient underwent implantation of a left ventricular assist device. CONCLUSIONS: Concomitant aortocoronary bypass to the circumflex branch will minimise the risk of hypoperfusion, especially for young patients without atherosclerotic disease.

Lepidic growth component as a favorable prognostic factor in non-small cell lung cancer of ≤3 cm.

BACKGROUND: Many non-small cell lung cancer (NSCLC) tumors present complex histology with various components. The effects of the lepidic growth component (LGC) on the prognosis of NSCLC have not been investigated. Here, we investigated whether an LGC is a relevant prognostic factor for NSCLC. METHODS: This study retrospectively investigated the clinicopathologic characteristics of 379 patients with NSCLC ≤3 cm who underwent complete surgical resection between 2004 and 2016 at the University of Yamanashi Hospital. The histologic subtypes were classified into NSCLC with or without an LGC. We evaluated the effect of an LGC on the clinicopathologic features and 5-year overall survival of patients with NSCLC. RESULTS: On final pathology, 214 (56%) of 379 patients had an LGC, and 165 (44%) did not. Sex, smoking history, ground-glass opacity component, pathologic invasive size, lymph node metastasis, pleural invasion, vessel invasion, pathologic stage, and histologic type were significantly different between the groups. Multivariate analysis of 5-year overall survival, identified age (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.035-1.105; p < 0.001), pathologic invasive size (HR, 1.548; 95% CI, 1.088-2.202; p = 0.015) and LGC (HR, 2.11; 95% CI, 1.099-4.051; p = 0.025) as independent prognostic factors. When the pathologic invasive size was matched, the 5-year overall survival of the LGC and non-LGC groups was 93% and 77%, respectively (p = 0.006). CONCLUSIONS: LGC is a significantly favorable prognostic factor for NSCLC with a pathologic invasive size of ≤3 cm.