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Abstract Background Telmisartan is a well-established angiotensin II type 1 receptor blocker that improves insulin sensitivity in animal models of obesity and insulin resistance, as well as in humans. Telmisartan has been reported to function as a partial agonist of the peroxisome proliferator-activated receptor (PPAR) γ, which is also targeted by the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase (SIRT1). Here, we investigated the pathways through which telmisartan acts on skeletal muscle, in vitro as well as in vivo. Methods Nine-week-old male db/db mice were fed a 60% high-fat diet, with orally administrated either vehicle (carboxymethyl-cellulose, CMC), 5 mg/kg telmisartan, or 5 mg/kg telmisartan and 1 mg/kg GW9662, a selective irreversible antagonist of PPARγ, for 5 weeks. Effects of telmisartan on Sirt1 mRNA, AMPK phosphorylation, and NAD+/NADH ratio were determined in C2C12 cultured myocytes. Results and discussion Telmisartan treatment improved insulin sensitivity in obese db/db mice fed a high-fat diet and led to reduction in the size of hypertrophic pancreatic islets in these mice. Moreover, in vitro treatment with telmisartan led to increased expression of Sirt1 mRNA in C2C12 skeletal muscle cells; the increase in Sirt1 mRNA in telmisartan-treated C2C12 myoblasts occurred concomitantly with an increase in AMPK phosphorylation, an increase in NAD+/NADH ratio, and increases in the mRNA levels of PGC1α, FATP1, ACO, and GLUT4. Conclusions Our results indicate that telmisartan acts through a PPARγ-independent pathway, but at least partially exerts its effects by acting directly on skeletal muscle AMPK/SIRT1 pathways.

Abstract Background Growing evidence suggests that epicardial adipose tissue (EAT) may contribute to the development of coronary artery disease (CAD). In this study, we explored gender disparities in EAT volume (EATV) and its impact on coronary atherosclerosis. Methods The study population consisted of 90 consecutive subjects (age: 63 ± 12 years; men: 47, women: 43) who underwent 256-slice multi-detector computed tomography (MDCT) coronary angiography. EATV was measured as the sum of cross-sectional epicardial fat area on CT images, from the lower surface of the left pulmonary artery origin to the apex. Subjects were segregated into the CAD group (coronary luminal narrowing > 50%) and non-CAD group. Results EATV/body surface area (BSA) was higher among men in the CAD group than in the non-CAD group (62 ± 13 vs. 33 ± 10 cm3/m2, p < 0.0001), but did not differ significantly among women in the 2 groups (49 ± 18 vs. 42 ± 9 cm3/m2, not significant). Multivariate logistic analysis showed that EATV/BSA was the single predictor for >50% coronary luminal narrowing in men (p < 0.0001). Predictors excluded were age, body mass index, hypertension, diabetes mellitus, and hyperlipidemia. Conclusions Increased EATV is strongly associated with coronary atherosclerosis in men.

Multiple murine models have proven useful in studying the natural history of neovessel development in the tissue engineering of vascular grafts. Nevertheless, to better understand longitudinal changes in the biomechanics of such neovessels, we must first quantify native tissue structure and properties. In this paper, we present the first biaxial mechanical data for, and nonlinear constitutive modeling of, the inferior vena cava from two models used in tissue engineering: wild-type C57BL/6 and immunodeficient CB-17 SCID/bg mice. Results show that inferior vena cava from the latter are significantly stiffer in the circumferential direction, both materially (as assessed by a stored energy function) and structurally (as assessed by the compliance), despite a lower intramural content of fibrillar collagen and similar wall thickness. Quantifying the natural history of neovessel development in different hosts could lead to increased insight into the mechanisms by which cells fashion and maintain extracellular matrix in order to match best the host stiffness while ensuring sufficient vascular integrity. [ABSTRACT FROM AUTHOR]

Introduction and Importance: Elderly and frail patients with thoracic aortic aneurysms (TAAs) near to origins of cervical arteries present facing challenges with aortic arch replacement with cardiopulmonary bypass, and traditional tube-type stent-grafts are also inadequate for transcatheter endovascular aortic repair (TEVAR). Thus, necessitating precise treatment with fenestrated stent-grafts from zone 0. This approach is crucial for achieving favorable postoperative outcomes without compromising activities of daily living (ADL)., Case Presentations: An 85-year-old-man admitted to the hospital for treatment of a large TAA. While arch replacement is a definitive procedure, it is highly invasive, and the postoperative ADL are expected to be significantly lower than preoperative levels. Therefore, we performed a debranching TEVAR from Zone 0 with fenestrated stent-graft. The patient was discharged from the hospital on the 11th postoperative day., Clinical Discussion: In frail and elderly patients for whom conventional surgery may not be viable, TEVAR emerges as a preferred alternative. However, TEVAR of TAA proximal to the aortic arch continues to pose challenges, necessitating meticulous attention to the cervical branches in the intervention strategy. While surgical intervention in these patients necessitates careful consideration of its suitability, including the potential for postoperative enhancement in ADL, the use of fenestrated stent-grafts from Zone 0 emerges as one of the treatment modalities., Conclusion: The authors present a very elderly case in which fenestrated stent-grafts were used to avoid aortic arch replacement for a large aortic arch aneurysm, resulting in a good postoperative course with no decline in ADL., Competing Interests: Not applicable., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

To date, there has been limited investigation of bioabsorbable atrial septal defect (ASD) or patent foramen ovale (PFO) closure devices using clinically relevant large animal models. The purpose of this study is to explore the function and safety of a bioabsorbable ASD occluder (BAO) system for PFO and/or secundum ASD transcatheter closure. Using a sheep model, the intra-atrial septum was evaluated by intracardiac echo (ICE). If a PFO was not present, atrial communication was created via transseptal puncture. Device implantation across the intra-atrial communication was performed with fluoroscopic and ICE guidance. Our 1st generation device consisted of a main structure of thin Poly(L-lactide-co-epsilon-caprolactone) (PLCL) fibers, and an internal Poly glycolic acid (PGA) fabric. Four procedures validated procedure feasibility. Subsequently, device design was modified for improved transcatheter delivery. The 2nd generation device has a two-layered structure and was implanted in six sheep. Results showed procedural success in 9/10 (90%) animals. With deployment, the 1st generation device did not reform into its original disk shape and did not conform nicely along the atrial septum. The 2nd generation device was implanted in six animals, 3 out of 6 survived out to 1 year. At 1 year post implantation, ICE confirmed no residual shunting. By necropsy, biomaterials had partially degraded, and histology of explanted samples revealed significant device endothelialization and biomaterial replacement with a collagen layer. Our results demonstrate that our modified 2nd generation BAO can be deployed via minimally invasive percutaneous transcatheter techniques. The BAO partially degrades over 1 year and is replaced by host native tissues. Future studies are needed prior to clinical trials., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: The molecular mechanisms underlying post-operative pericardial adhesions remain poorly understood. We aimed to unveil the temporal molecular and cellular mechanisms underlying tissue dynamics during adhesion formation, including inflammation, angiogenesis, and fibrosis., Methods and Results: We visualized cell-based tissue dynamics during pericardial adhesion using histological evaluations. To determine the molecular mechanism, RNA-seq was performed. Chemical inhibitors were administered to confirm the molecular mechanism underlying adhesion formation. A high degree of adhesion formation was observed during the stages in which collagen production was promoted. Histological analyses showed that arterioles excessively sprouted from pericardial tissues after the accumulation of neutrophils on the heart surface in mice as well as humans. The combination of RNA-seq and histological analyses revealed that hyperproliferative endothelial and smooth muscle cells with dedifferentiation appeared in cytokine-exposed sprouting vessels and adhesion tissue but not in quiescent vessels in the heart. SMAD2/3 and ERK activation was observed in sprouting vessels. The simultaneous abrogation of PI3K/ERK or TGF-β/MMP9 signaling significantly decreased angiogenic sprouting, followed by inhibition of adhesion formation. Depleting MMP9-positive neutrophils shortened mice survival and decreased angiogenic sprouting and fibrosis in the adhesion. Our data suggest that TGF-β/matrix metalloproteinase-dependent tissue remodeling and PI3K/ERK signaling activation might contribute to unique angiogenesis with dedifferentiation of vascular smooth muscle cells from the contractile to the synthetic phenotype for fibrosis in the pericardial cavity., Conclusions: Our findings provide new insights in developing prevention strategies for pericardial adhesions by targeting the recruitment of vascular cells from heart tissues., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Namiguchi, Sakaue, Okazaki, Kanno, Komoda, Shikata, Kurata, Ota, Kubota, Kurobe, Nishimura, Masumoto, Higashiyama and Izutani.)

Objective : To evaluate the relationship between systemic inflammatory biomarkers and efficacy of surgical treatment of primary varicose veins of the lower extremities. Methods : Total 12 patients who underwent endovenous laser ablation or stripping of varicose veins and six healthy subjects were enrolled. Structural and molecular changes of varices were assessed by immunohistochemical staining with anti-monocyte chemotactic protein-1 (MCP-1). MCP-1 and interleukin-6 (IL-6) levels in systemic antecubital blood were measured before and at 12 weeks after treatment. Results : Immunohistochemical staining revealed prominent manifestation of MCP-1-positive endothelial cells in the walls of varices. Preoperative serum MCP-1 and IL-6 levels in the patients were significantly higher than those in the control (166±12 pg/mL vs 99±10 pg/mL, p=0.003; 5.1±0.95 pg/mL vs 0.0±0.0 pg/mL, p=0.001, respectively). The values were significantly correlated with the severity of chronic venous insufficiency (CVI). Postoperative serum MCP-1 level significantly decreased compared with the preoperative level (152±10 pg/mL vs 166±12 pg/mL, p=0.048). The values after endovenous laser ablation did not significantly decrease compared with those after stripping. Conclusion : Varicose veins with CVI increase inflammatory biomarker levels in the local tissue and systemic blood. Appropriate treatment of symptomatic varicose veins decreases inflammatory biomarker levels., Competing Interests: Disclosure StatementWe have no conflict of interest to disclose., (Copyright © 2019 Annals of Vascular Diseases.)

Electrospinning is commonly used to generate polymeric scaffolds for tissue engineering. Using this approach, we developed a small-diameter tissue engineered vascular graft (TEVG) composed of poly-ε-caprolactone-co-l-lactic acid (PCLA) fibers and longitudinally assessed its performance within both the venous and arterial circulations of immunodeficient (SCID/bg) mice. Based on in vitro analysis demonstrating complete loss of graft strength by 12 weeks, we evaluated neovessel formation in vivo over 6-, 12- and 24-week periods. Mid-term observations indicated physiologic graft function, characterized by 100% patency and luminal matching with adjoining native vessel in both the venous and arterial circulations. An active and robust remodeling process was characterized by a confluent endothelial cell monolayer, macrophage infiltrate, and extracellular matrix deposition and remodeling. Long-term follow-up of venous TEVGs at 24 weeks revealed viable neovessel formation beyond graft degradation when implanted in this high flow, low-pressure environment. Arterial TEVGs experienced catastrophic graft failure due to aneurysmal dilatation and rupture after 14 weeks. Scaffold parameters such as porosity, fiber diameter, and degradation rate informed a previously described computational model of vascular growth and remodeling, and simulations predicted the gross differential performance of the venous and arterial TEVGs over the 24-week time course. Taken together, these results highlight the requirement for in vivo implantation studies to extend past the critical time period of polymer degradation, the importance of differential neotissue deposition relative to the mechanical (pressure) environment, and further support the utility of predictive modeling in the design, use, and evaluation of TEVGs in vivo. STATEMENT OF SIGNIFICANCE: Herein, we apply a biodegradable electrospun vascular graft to the arterial and venous circulations of the mouse and follow recipients beyond the point of polymer degradation. While venous implants formed viable neovessels, arterial grafts experienced catastrophic rupture due to aneurysmal dilation. We then inform a previously developed computational model of tissue engineered vascular graft growth and remodeling with parameters specific to the electrospun scaffolds utilized in this study. Remarkably, model simulations predict the differential performance of the venous and arterial constructs over 24 weeks. We conclude that computational simulations should inform the rational selection of scaffold parameters to fabricate tissue engineered vascular grafts that must be followed in vivo over time courses extending beyond polymer degradation., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

A 78-year-old man with no history of allergy, underwent endovascular aortic repair for abdominal aortic aneurysm rupture. Postoperatively, he had low-grade fever and persistently raised white blood cell counts, but tests showed no infection. A skin rash appeared on the trunk and upper arms; we suspected a drug allergy. Despite withdrawal and/or change of medications, the symptoms remained. Finally, a patch test for nickel showed a strongly positive result. Oral prednisone 5 mg·day -1 was started, and the clinical findings resolved thereafter. No recurrence of allergy, infection, or exacerbation of the treated abdominal aortic aneurysm was noted at the 2-year follow-up.

Objective: Hesperidin, an abundant flavonoid in citrus fruit, and its aglycone, hesperetin, have been reported to possess various physiological activities, including antioxidant, anti-inflammatory, hypolipidemic, and antihypertensive activities. In this study, we investigated whether α-glucosyl hesperidin and water-dispersible hesperetin have protective effects on atherosclerotic progression in apolipoprotein E knockout (Apo-E KO) mice., Methods: Ten-week-old male Apo-E KO mice were randomly assigned a regular high-fat diet, a high-fat diet with 0.5% α-glucosyl hesperidin, or a high-fat diet with 0.1% water-dispersible hesperetin for 12 weeks. Measurement of plasma total cholesterol levels, histological staining of aortic root, and immunohistochemistry for macrophages were performed to evaluate atherosclerotic plaque formation. Vascular reactivity of mouse aortic rings was also measured., Results: Both α-glucosyl hesperidin and water-dispersible hesperetin reduced plasma total cholesterol level. They also reduced plaque formation area, adipose deposition, and macrophage infiltration into atherosclerotic lesion. Vascular-endothelium-dependent relaxation in response to acetylcholine was improved in both experimental diet groups compared to the high-fat diet group., Conclusions: Our study suggests that both α-glucosyl hesperidin and water-dispersible hesperetin exert protective effects on atherosclerotic progression in Apo-E KO mice because they exhibit hypolipidemic activity, reduce inflammation through macrophages, and prevent endothelial dysfunction.

Objectives: Tissue-engineered vascular grafts (TEVGs) have demonstrated potential for treating congenital heart disease (CHD); however, quantitative imaging for tracking functional and structural remodeling of TEVGs has not been applied. Therefore, we evaluated the potential of magnetic resonance (MR) imaging for assessing TEVG wall shear stress (WSS) and wall thickness in a large animal model., Methods: Cell-seeded (n = 3) or unseeded (n = 3) TEVGs were implanted as inferior vena cava interposition grafts in juvenile lambs. Six months following implantation, two-dimensional phase-contrast MR imaging was performed at 3 slice locations (proximal, middle, and distal) to assess normalized WSS (i.e., WSS-to-cross sectional area). T2-weighted MR imaging was performed to assess TEVG wall thickness. Histology was qualitatively assessed, whereas immunohistochemistry was semiquantitatively assessed for smooth muscle cells (αSMA), macrophage lineage cells (CD11b), and matrix metalloproteinase activity (MMP-2 and MMP-9). Picrosirius Red staining was performed to quantify collagen content., Results: TEVG wall thickness was significantly higher for proximal, middle, and distal slices in unseeded versus cell-seeded grafts. Significantly higher WSS values existed for proximal versus distal slice locations for cell-seeded TEVGs, whereas no differences in WSS existed between slices for unseeded TEVGs. Additionally, no differences in WSS existed between cell-seeded and unseeded groups. Both groups demonstrated elastin formation, without vascular calcification. Unseeded TEVGs possessed greater content of smooth muscle cells when compared with cell-seeded TEVGs. No differences in macrophage, MMP activity, or collagen content existed between groups., Conclusion: MR imaging allows for in vivo assessment of functional and anatomical characteristics of TEVGs and may provide a nonionizing approach that is clinically translatable to children undergoing treatment for CHD.

Objective: This study aimed to determine the perioperative predictors of contrast medium-induced nephropathy (CIN) after endovascular aortic repair (EVAR)., Materials and Methods: The data of 203 consecutive patients who underwent elective EVAR for thoracic and abdominal aortic aneurysm between January 2014 and September 2014 were retrospectively analyzed. CIN was defined according to the diagnostic criteria of the European Society of Urogenital Radiology., Results: Fourteen patients (6.9%) developed CIN after EVAR. Contrast medium volume (CV), preoperative serum creatinine, estimated glomerular filtration rate (eGFR), and the CV/eGFR ratio were significantly related with CIN development after EVAR. The CV/eGFR ratio was significantly higher in patients with CIN than those without CIN. Receiver operator characteristic curve analysis showed that the area under the curve of the CV/eGFR ratio was 0.782, indicating that it was the most important predictor. The appropriate CV/eGFR ratio cutoff was 1.62. Sensitivity and specificity were 85.7% and 65.6%, respectively., Conclusions: The CV/eGFR ratio was a useful predictor of contrast medium-induced nephropathy after EVAR. It is possible that the score can be used in patients when managing the EVAR techniques and contrast medium volume. J. Med. Invest. 65:116-121, February, 2018.

Aim: Surgical management of pediatric extrahepatic portal vein obstruction requires meso-Rex bypass using autologous or synthetic grafts. Tissue-engineered vascular grafts (TEVGs) provide an alternative, but no validated animal models using portal TEVGs exist. Herein, we preclinically assess TEVGs as portal vein bypass grafts., Materials & Methods: TEVGs were implanted as portal vein interposition conduits in SCID-beige mice, monitored by ultrasound and micro-computed tomography, and histologically assessed postmortem at 12 months., Results: TEVGs remained patent for 12 months. Histologic analysis demonstrated formation of neovessels that resembled native portal veins, with similar content of smooth muscle cells, collagen type III and elastin., Conclusion: TEVGs are feasible portal vein conduits in a murine model. Further preclinical evaluation of TEVGs may facilitate pediatric clinical translation.