The human gut contains trillions of commensal bacteria, and similar to pathogenic bacteria, the gut microbes and their products can be recognized by toll-like receptors (TLRs). It is well ...acknowledged that the interaction between gut microbiota and the local TLRs help to maintain the homeostasis of intestinal immunity. High-fat intake or obesity can weaken gut integrity leading to the penetration of gut microbiota or their bacterial products into the circulation, leading to the activation of TLRs on immune cells and subsequently low-grade systemic inflammation in host. Metabolic cells including hepatocytes and adipocytes also express TLRs. Although they are able to produce and secrete inflammatory molecules, the effectiveness remains low compared with the immune cells embedded in the liver and adipose tissue. The interaction of TLRs in these metabolic cells or organs with gut microbiota remains unclear, but a few studies have suggested that the functions of these TLRs are related to metabolism. Alteration of the gut microbiota is associated with body weight change and adiposity in human, and the interaction between the commensal gut microbiota and TLRs may possibly involve both metabolic and immunological regulation. In this review, we will summarize the current findings on the relationship between TLRs and gut microbiota with a focus on metabolic regulation and discuss how such interaction participates in host metabolism.
Chronic unresolved inflammation plays a causal role in the development of advanced atherosclerosis, but the mechanisms that prevent resolution in atherosclerosis remain unclear. Here, we use targeted ...mass spectrometry to identify specialized pro-resolving lipid mediators (SPM) in histologically-defined stable and vulnerable regions of human carotid atherosclerotic plaques. The levels of SPMs, particularly resolvin D1 (RvD1), and the ratio of SPMs to pro-inflammatory leukotriene B
(LTB
), are significantly decreased in the vulnerable regions. SPMs are also decreased in advanced plaques of fat-fed Ldlr
mice. Administration of RvD1 to these mice during plaque progression restores the RvD1:LTB
ratio to that of less advanced lesions and promotes plaque stability, including decreased lesional oxidative stress and necrosis, improved lesional efferocytosis, and thicker fibrous caps. These findings provide molecular support for the concept that defective inflammation resolution contributes to the formation of clinically dangerous plaques and offer a mechanistic rationale for SPM therapy to promote plaque stability.
As comparative data on the precision of 3D-printed anatomical models are sparse, the aim of this study was to evaluate the accuracy of 3D-printed models of vascular anatomy generated by two commonly ...used printing technologies. Thirty-five 3D models of large (aortic, wall thickness of 2 mm, n = 30) and small (coronary, wall thickness of 1.25 mm, n = 5) vessels printed with fused deposition modeling (FDM) (rigid, n = 20) and PolyJet (flexible, n = 15) technology were subjected to high-resolution CT scans. From the resulting DICOM (Digital Imaging and Communications in Medicine) dataset, an STL file was generated and wall thickness as well as surface congruency were compared with the original STL file using dedicated 3D engineering software. The mean wall thickness for the large-scale aortic models was 2.11 µm (+5%), and 1.26 µm (+0.8%) for the coronary models, resulting in an overall mean wall thickness of +5% for all 35 3D models when compared to the original STL file. The mean surface deviation was found to be +120 µm for all models, with +100 µm for the aortic and +180 µm for the coronary 3D models, respectively. Both printing technologies were found to conform with the currently set standards of accuracy (<1 mm), demonstrating that accurate 3D models of large and small vessel anatomy can be generated by both FDM and PolyJet printing technology using rigid and flexible polymers.
ABSTRACT
Human neutrophil elastase impacts on atherosclerotic plaque stability by inducing apoptosis in endothelial cells. Our aim was to investigate the proapoptotic mechanism of elastase on ...endothelial cells and to evaluate the presence of elastase in human plaque material. Human endothelial cells were treated with purified human neutrophil elastase. Apoptosis was assayed by capsase‐3/7 activation, TUNEL, and sub‐G1 assay. Activation of unfolded protein response (UPR) effector molecules binding Ig protein, soluble X‐binding protein‐1, protein kinase RNA‐like ER kinase (PERK), and C/EBP‐homologous protein (CHOP) was analyzed by RT‐PCR, immunocytochemistry, and Western blot. Genetic silencing of CHOP was achieved by small interfering RNA. Elastase induces autophagic–apoptotic forms of endothelial cell death in a time‐ and dose‐dependent manner, in conjunction with a significant increase in phosphorylation/expression of the canonical UPR‐activation markers PERK and CHOP. By using CHOP knockdown, we identified CHOP as a key mediator of elastase‐induced endothelial cell death. Immunohistochemical analysis of human rupture‐prone plaque specimens confirmed the presence of elastase and colocalization with apoptosis. We have demonstrated for the first time that the PERK‐CHOP branch of the UPR is causally involved in elastase‐induced apoptosis of endothelial cells. Ex vivo analysis of human rupture‐prone plaques confirmed the presence of elastase and its colocalization with markers of apoptosis. This novel role of elastase underlines the potential of combined targeting of elastase and endoplasmic reticulum stress in the prevention of plaque progression and cardiovascular events.—Grechowa, I., Horke, S., Wallrath, A., Vahl, C.‐F., Dorweiler, B. Human neutrophil elastase induces endothelial cell apoptosis by activating the PERK‐CHOP branch of the unfolded protein response. FASEB J. 31, 3868–3881 (2017). www.fasebj.org—Grechowa, Irina, Horke, Sven, Wallrath, Anja, Vahl, Christian‐Friedrich, Dorweiler, Bernhard Human neutrophil elastase induces endothelial cell apoptosis by activating the PERK‐CHOP branch of the unfolded protein response. FASEB J. 31, 3868–3881 (2017)
Purpose
Navigating with continuous X-ray provides visual guidance, but exposes both surgeon and patient to ionizing radiation, which is associated with serious health risks. Interleaving fluoro ...snapshots with electromagnetic tracking (EMT) potentially minimizes radiation.
Methods
We propose hybrid EMT + X-ray (HEX), a research framework for navigation with an emphasis on safe experimentation. HEX is based on several hardware and software components that are orchestrated to allow for safe and efficient data acquisition.
Results
In our study, hybrid navigation reduces radiation by
71
%
with cubic, and by
40
%
with linear error compensation while achieving submillimeter accuracy. Training points for compensation can be reduced by half while keeping a similar accuracy–radiation trade-off.
Conclusion
The HEX framework allows to safely and efficiently evaluate the hybrid navigation approach in simulated procedures. Complementing intraoperative X-ray with EMT significantly reduces radiation in the OR, increasing the safety of patients and surgeons.
Dysbiosis of gut microbiota plays an important role in cardiovascular diseases but the molecular mechanisms are complex. An association between gut microbiome and the variance in HDL-C (high-density ...lipoprotein-cholesterol) level was suggested in a human study. Besides, dietary fat was shown to increase both HDL-C and LDL-C (low-density lipoprotein-cholesterol) levels. We speculate that certain types of gut bacteria responding to dietary fat may help to regulate HDL-C level and potentially affect atherosclerotic development.
We aimed to investigate whether and how high-fat diet (HFD)-associated gut microbiota regulated HDL-C level.
We found that HFD increased gut flagellated bacteria population in mice. The increase in HDL-C level was adopted by mice receiving fecal microbiome transplantation from HFD-fed mouse donors. HFD led to increased hepatic but not circulating flagellin, and deletion of TLR5 (Toll-like receptor 5), a receptor sensing flagellin, suppressed HFD-stimulated HDL-C and ApoA1 (apolipoprotein A1) levels. Overexpression of TLR5 in the liver of TLR5-knockout mice was able to partially restore the production of ApoA1 and HDL-C levels. Mechanistically, TLR5 activation by flagellin in primary hepatocytes stimulated ApoA1 production through the transcriptional activation responding to the binding of NF-κB (nuclear factor-κB) on
promoter region. Furthermore, oral supplementation of flagellin was able to stimulate hepatic ApoA1 production and HDL-C level and decrease atherosclerotic lesion size in apolipoprotein E-deficient (
) mice without triggering hepatic and systemic inflammation. The stimulation of ApoA1 production was also seen in human ApoA1-transgenic mice treated with oral flagellin.
Our finding suggests that commensal flagellated bacteria in gut can facilitate ApoA1 and HDL-C productions in liver through activation of TLR5 in hepatocytes. Hepatic TLR5 may be a potential drug target to increase ApoA1.
Objective In thoracoabdominal aortic aneurysms (TAAAs), a paradigm shift is observed from open surgery toward total endovascular aortic repair using fenestrated and branched endografts. Whereas ...outcome after open replacement in terms of mortality and paraplegia has been evaluated extensively, no studies exist addressing long-term patency of visceral and renal vessels. To enable comparison of target vessel patency between open and endovascular treatment, we analyzed our series of open TAAA replacements. Methods Our vascular surgery database was screened for patients who received open TAAA replacement between 1998 and 2012, and patient records were analyzed retrospectively. All available imaging scans (computed tomography and magnetic resonance angiography: preoperative, postoperative, and follow-up) were evaluated for graft and vessel patency. Results We identified 62 patients (mean age, 66 ± 10 years; 40 men) who had been operated on for aneurysms of Crawford types I (8), II (13), III (13), and IV (24) and Safi type V (4). A total of 181 vessels were revascularized by either patch inclusion (n = 147) or selective revascularization (bypass or transposition, n = 34); 48 survived the procedure, resulting in a number of vessels available for follow-up of 154 (patch, 126; selective revascularization, 28). The respective patency rates for overall, patch, and selective revascularization were 95.2%, 94.2%, and 100% at 5 years and 83.7%, 81.3%, and 100% at 10 years, respectively. In addition, a trend for better performance of selective revascularization (bypass or transposition) was evident as all vessel occlusions were observed in cases of patch inclusion, whereas all selectively revascularized vessels were patent. The respective patency rates for the celiac trunk, superior mesenteric artery, and left and right renal artery were 100%, 97.5%, 92.3%, and 90.3% at 5 years. Conclusions In our series of open thoracoabdominal aortic replacement, excellent patency rates for revascularized renal and visceral vessels were observed during long-term follow-up. We were able to provide a reference value of long-term target vessel patency that can and should be taken into account to judge the efficacy of endovascular repair in TAAA.
ABSTRACT
The first ATP‐competitive p38a MAPK/MAPK14 inhibitor with excellent in vivo efficacy and selectivity, skepinone‐L, is now available. We investigated the impact of selective p38a MAPK/MAPK14 ...inhibition on enzymatically modified LDL (eLDL) stimulated human monocytes with its implications for atherosclerosis. Among the different p38 MAPK isoforms, p38a/MAPK14 was the predominantly expressed and activated isoform in isolated human peripheral blood monocytes. Moreover, eLDL colocalized with macrophages positive for p38a MAPK/ MAPK14 in human carotid endarterectomy specimens. Using the human leukemia cell line THP‐1 and/or primary monocyte‐derived macrophages, skepinone‐L inhibited eLDL‐induced activation of the p38 MAPK pathway, inhibited eLDL induced expression of both cluster of differentiation 36 (CD36) and ATP‐binding cassette, subfamily A, member 1 (ABCA1), without a net effect on foam cell formation, had a cell‐and time‐dependent effect on eLDLtriggered apoptosis, and inhibited eLDL‐stimulated secretion of IL‐8 and MIP‐1b/CCL4 (macrophage inflammatory protein‐1b/chemokine, CC motif, ligand 4). Inhibition of a key signaling molecule of the p38 MAPK pathway, p38a MAPK/MAPK14, by selective inhibitors like skepinone‐L, conclusively facilitates elucidation of the impact of the complex network of p38 MAPK signaling on atherogenesis and might provide a promising therapeutic tool to prevent inflammatory cascades in atherosclerosis.—Cheng, F., Twardowski, L., Fehr, S., Aner, C., Schaeffeler, E., Joos, T., Knorpp, T., Dorweiler, B., Laufer, S., Schwab, M., Torzewski, M. Selective p38a MAP kinase/MAPK14 inhibition in enzymatically modified LDL‐stimulated human monocytes: implications for atherosclerosis. FASEB J. 31, 674–686 (2017). www.fasebj.org
To assess outcomes of a low-profile thoracic stent-graft in the treatment of thoracic aortic pathologies.
A retrospective analysis of all consecutive patients with aortic thoracic pathologies treated ...with the RelayPro device in two university hospitals between October 2018 and July 2019.
23 patients (65% men; mean age 63.4 ± 15 years) were treated. Pathologies included aortic dissections (n = 10), 5 residual type A (22%) and 5 type B (22%), 6 degenerative aortic aneurysms (26%), 4 penetrating aortic ulcers (17%), and aortic erosion, intramural hematoma and aortic rupture (n = 1 and 4% in each case). Two cases (9%) were emergent and two urgent. Proximal landing was achieved in zones 0 (4%), 1 (4%), 2 (43%), and 3 (26%). Five grafts were frozen elephant trunk extensions. Technical success was 100% with accurate device deployment in the intended landing zone of the aortic arch in all 23 patients and with no Ia/III endoleaks and three (13%) type II endoleaks. Apposition was adequate in 96%. Two patients had post-implantation syndromes (one fever, one leukocytosis). Mean follow-up was 11.6 ± 3.7 months (range, 2-16) with no other complications, secondary interventions or conversions to open surgery. There was no 30-day mortality and no aortic-related mortality; all-cause mortality was 4% during follow-up.
A 3-4 French reduced profile in the current generation of stent-grafts facilitates TEVAR particularly in patients with smaller vessels access. Early safety and effectiveness outcomes are favorable, even in endpoints such as deployment accuracy and apposition which may be surrogates for longer-term clinical success and durability.
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