Publications by authors named "Fragiska Sigala"

84 Publications

Adenosine-to-inosine Alu RNA editing controls the stability of the pro-inflammatory long noncoding RNA NEAT1 in atherosclerotic cardiovascular disease.

J Mol Cell Cardiol 2021 Jul 21;160:111-120. Epub 2021 Jul 21.

Biosciences Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK; Department of Cardiology, Freeman Hospital, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; Vascular Inflammation and RNA Metabolism Laboratory, Institute for Vascular Signalling, JW Goethe University Frankfurt, Frankfurt am Main, Germany. Electronic address:

Long non-coding RNAs (lncRNAs) have emerged as critical regulators in human disease including atherosclerosis. However, the mechanisms involved in the post-transcriptional regulation of the expression of disease-associated lncRNAs are not fully understood. Gene expression studies revealed that Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) lncRNA expression was increased by >2-fold in peripheral blood mononuclear cells (PBMCs) derived from patients with coronary artery disease (CAD) or in carotid artery atherosclerotic plaques. We observed a linear association between NEAT1 lncRNA expression and prevalence of CAD which was independent of age, sex, cardiovascular traditional risk factors and renal function. NEAT1 expression was induced by TNF-α, while silencing of NEAT1 profoundly attenuated the TNF-α-induced vascular endothelial cell pro-inflammatory response as defined by the expression of CXCL8, CCL2, VCAM1 and ICAM1. Overexpression of the RNA editing enzyme adenosine deaminase acting on RNA-1 (ADAR1), but not of its editing-deficient mutant, upregulated NEAT1 levels. Conversely, silencing of ADAR1 suppressed the basal levels and the TNF-α-induced increase of NEAT1. NEAT1 lncRNA expression was strongly associated with ADAR1 in CAD and peripheral arterial vascular disease. RNA editing mapping studies revealed the presence of several inosines in close proximity to AU-rich elements within the AluSx3/AluJo double-stranded RNA complex. Silencing of the stabilizing RNA-binding protein AUF1 reduced NEAT1 levels while silencing of ADAR1 profoundly affected the binding capacity of AUF1 to NEAT1. Together, our findings propose a mechanism by which ADAR1-catalyzed A-to-I RNA editing controls NEAT1 lncRNA stability in ASCVD.
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http://dx.doi.org/10.1016/j.yjmcc.2021.07.005DOI Listing
July 2021

Regulation of Long Non-Coding RNAs by Statins in Atherosclerosis.

Biomolecules 2021 04 22;11(5). Epub 2021 Apr 22.

First Propaedeutic Department of Surgery, Division of Vascular Surgery, Hippokration Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece.

Despite increased public health awareness, atherosclerosis remains a leading cause of mortality worldwide. Significant variations in response to statin treatment have been noted among different populations suggesting that the efficacy of statins may be altered by both genetic and environmental factors. The existing literature suggests that certain long noncoding RNAs (lncRNAs) might be up- or downregulated among patients with atherosclerosis. LncRNA may act on multiple levels (cholesterol homeostasis, vascular inflammation, and plaque destabilization) and exert atheroprotective or atherogenic effects. To date, only a few studies have investigated the interplay between statins and lncRNAs known to be implicated in atherosclerosis. The current review characterizes the role of lncRNAs in atherosclerosis and summarizes the available evidence related to the effect of statins in regulating lncRNAs.
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http://dx.doi.org/10.3390/biom11050623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143454PMC
April 2021

Hybrid Repair of a Common Carotid Pseudoaneurysm and Concomitant Internal Carotid Stenosis With Retrograde Stenting and Carotid Endarterectomy.

Vasc Endovascular Surg 2021 Aug 11;55(6):627-630. Epub 2021 Mar 11.

First Propaedeutic Department of Surgery, National and Kapodistrian University of Athens, Hippocration Hospital, Athens, Greece.

This report aims to present a rare case of a common carotid artery (CCA) pseudoaneurysm with a concomitant internal carotid artery (ICA) stenosis that were treated with a hybrid technique. This strategy included the retrograde placement of a CCA covered stent under ICA clamping followed by standardized carotid endarterectomy. The technique will be discussed and compared with other possible treatments.
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http://dx.doi.org/10.1177/1538574421992935DOI Listing
August 2021

Mapping the Endothelial Cell -Sulfhydrome Highlights the Crucial Role of Integrin Sulfhydration in Vascular Function.

Circulation 2021 Mar 14;143(9):935-948. Epub 2020 Dec 14.

Institute for Vascular Signalling (S-I.B., J.H., J.W., M.K.D., V.R., F.D.L., B.F., S.Z., A.K., A.F.O.J., I.F.), Goethe University, Frankfurt am Main, Germany.

Background: In vascular endothelial cells, cysteine metabolism by the cystathionine γ lyase (CSE), generates hydrogen sulfide-related sulfane sulfur compounds (HS), that exert their biological actions via cysteine -sulfhydration of target proteins. This study set out to map the "-sulfhydrome" (ie, the spectrum of proteins targeted by HS) in human endothelial cells.

Methods: Liquid chromatography with tandem mass spectrometry was used to identify -sulfhydrated cysteines in endothelial cell proteins and β3 integrin intraprotein disulfide bond rearrangement. Functional studies included endothelial cell adhesion, shear stress-induced cell alignment, blood pressure measurements, and flow-induced vasodilatation in endothelial cell-specific CSE knockout mice and in a small collective of patients with endothelial dysfunction.

Results: Three paired sample sets were compared: (1) native human endothelial cells isolated from plaque-free mesenteric arteries (CSE activity high) and plaque-containing carotid arteries (CSE activity low); (2) cultured human endothelial cells kept under static conditions or exposed to fluid shear stress to decrease CSE expression; and (3) cultured endothelial cells exposed to shear stress to decrease CSE expression and treated with solvent or the slow-releasing HS donor, SG1002. The endothelial cell "-sulfhydrome" consisted of 3446 individual cysteine residues in 1591 proteins. The most altered family of proteins were the integrins and focusing on β3 integrin in detail we found that -sulfhydration affected intraprotein disulfide bond formation and was required for the maintenance of an extended-open conformation of the β leg. β3 integrin -sulfhydration was required for endothelial cell mechanotransduction in vitro as well as flow-induced dilatation in murine mesenteric arteries. In cultured cells, the loss of -sulfhydration impaired interactions between β3 integrin and Gα13 (guanine nucleotide-binding protein subunit α 13), resulting in the constitutive activation of RhoA (ras homolog family member A) and impaired flow-induced endothelial cell realignment. In humans with atherosclerosis, endothelial function correlated with low HS generation, impaired flow-induced dilatation, and failure to detect β3 integrin -sulfhydration, all of which were rescued after the administration of an HS supplement.

Conclusions: Vascular disease is associated with marked changes in the -sulfhydration of endothelial cell proteins involved in mediating responses to flow. Short-term HS supplementation improved vascular reactivity in humans highlighting the potential of interfering with this pathway to treat vascular disease.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051877DOI Listing
March 2021

Utility of viscoelastic coagulation testing in liver surgery: a systematic review.

HPB (Oxford) 2021 Mar 21;23(3):331-343. Epub 2020 Nov 21.

Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA. Electronic address:

Background: The objective of the current study was to summarize and evaluate all published evidence regarding viscoelastic testing in the field of liver surgery.

Methods: A systematic search of the literature was performed using Medline/PubMed, Scopus, Cochrane Library Central, Google Scholar, and clinicaltrials.gov databases. The following keywords were used:"Thromboelastography", "Thromboelastometry", "Viscoelastic tests OR testing", "Sonoclot Devices", "Point-of-care tests OR testing", "Coagulation OR Haemostasis OR Hemostasis", "Liver OR Hepatic Surgery", "Cirrhosis."

Results: A total of 12 studies analyzing 348 patients who underwent viscoelastic testing of coagulation during liver surgery for benign or malignant diseases were included; 7 (58.3%) studies reported on the use of thromboelastography (TEG), and 5 (41.7%) reported on rotational thromboelastometry (ROTEM). Viscoelastic testing (TEG and ROTEM) identified normo-, hyper- and hypo-coagulable status in 77% (n = 268/348), 18.4% (n = 64/348), and 4.6% (n = 16/348) of patients, respectively. In contrast, conventional coagulation tests indicated normo-coagulability in 111 patients (34.2% out of 325) and hypo-coagulability in 214 (65.8% out of 325) patients following liver resection. No patient (0% out of 291) experienced postoperative hemorrhage, whereas 5.8% (n = 17/291) experienced postoperative thromboembolic events.

Conclusions: Global viscoelastic testing may be a reasonable adjunct to conventional coagulation testing to provide a more robust assessment of the coagulation status of patients undergoing liver surgery.
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http://dx.doi.org/10.1016/j.hpb.2020.10.023DOI Listing
March 2021

The TAXINOMISIS Project: A multidisciplinary approach for the development of a new risk stratification model for patients with asymptomatic carotid artery stenosis.

Eur J Clin Invest 2020 Dec 2;50(12):e13411. Epub 2020 Oct 2.

Department of Materials Science and Engineering, Unit of Medical Technology and Intelligent Information Systems, University of Ioannina, Ioannina, Greece.

Introduction: Asymptomatic carotid artery stenosis (ACAS) may cause future stroke and therefore patients with ACAS require best medical treatment. Patients at high risk for stroke may opt for additional revascularization (either surgery or stenting) but the future stroke risk should outweigh the risk for peri/post-operative stroke/death. Current risk stratification for patients with ACAS is largely based on outdated randomized-controlled trials that lack the integration of improved medical therapies and risk factor control. Furthermore, recent circulating and imaging biomarkers for stroke have never been included in a risk stratification model. The TAXINOMISIS Project aims to develop a new risk stratification model for cerebrovascular complications in patients with ACAS and this will be tested through a prospective observational multicentre clinical trial performed in six major European vascular surgery centres.

Methods And Analysis: The risk stratification model will compromise clinical, circulating, plaque and imaging biomarkers. The prospective multicentre observational study will include 300 patients with 50%-99% ACAS. The primary endpoint is the three-year incidence of cerebrovascular complications. Biomarkers will be retrieved from plasma samples, brain MRI, carotid MRA and duplex ultrasound. The TAXINOMISIS Project will serve as a platform for the development of new computer tools that assess plaque progression based on radiology images and a lab-on-chip with genetic variants that could predict medication response in individual patients.

Conclusion: Results from the TAXINOMISIS study could potentially improve future risk stratification in patients with ACAS to assist personalized evidence-based treatment decision-making.
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http://dx.doi.org/10.1111/eci.13411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757200PMC
December 2020

Quality Versus Costs Related to Gastrointestinal Surgery: Disentangling the Value Proposition.

J Gastrointest Surg 2020 12 23;24(12):2874-2883. Epub 2020 Jul 23.

Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, 395 W. 12th Ave., Suite 670, Columbus, OH, USA.

Background: There has been a dramatic increase in worldwide health care spending over the last several decades. Operative procedures and perioperative care in the USA represent some of the most expensive episodes per patient. In view of both the rising cost of health care in general and the rising cost of surgical care specifically, policymakers and stakeholders have sought to identify ways to increase the value-improving quality of care while controlling (or diminishing) costs. In this context, we reviewed data relative to achieving the "value proposition" in the delivery of gastrointestinal surgical care.

Methods: The National Library of Medicine online repository (PubMed) was text searched for human studies including "cost," "quality," "outcomes," "health care," "surgery," and "value." Results from this literature framed by the Donabedian conceptual model (identifying structures, processes, and outcomes), and the resulting impact of efforts to improve quality on costs.

Results: The relationship between quality and costs was nuanced. Better quality care, though associated with better outcomes, was not always reported as concomitant with low costs. Moreover, some centers reported higher costs of surgical care commensurate with higher quality. Conversely, higher costs in health care delivery were not always linked to improved outcomes. While higher quality surgical care can lead to lower costs, higher costs of care were not necessarily associated with better outcomes. Strategies to improve quality, reduce cost, or achieve both simultaneously included regionalization of complex operations to high-volume centers of excellence, overall reduction in complications, introducing evidence-based improvements in perioperative care pathways including as enhanced recovery after surgery (ERAS), and elimination of inefficient or low-value care.

Conclusions: The relationship between quality and cost following gastrointestinal surgical procedure is complex. Data from the current study should serve to highlight the various means available to improve the value proposition related to surgery, as well as encourage surgeons to become more engaged in the national conversation around the Triple Aim of better health care quality, lower costs, and improved health care outcomes.
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http://dx.doi.org/10.1007/s11605-020-04748-7DOI Listing
December 2020

Epithelioid hemangioendothelioma of the retroperitoneum - a rare vascular tumor.

Vasa 2021 Jul 22;50(4):312-316. Epub 2020 Jul 22.

First Department of Propedeutic Surgery, National Kapodistrian University of Athens, Hippocration Hospital, Athens, Greece.

Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor, affecting the liver, the lungs and the bones most frequently. It has a heterogenous clinical presentation and there is no consensus on optimal treatment. This report aims to present a rare case of a retroperitoneal EHE and to discuss on proper management.
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http://dx.doi.org/10.1024/0301-1526/a000898DOI Listing
July 2021

Carotid Disease and Ageing: A Literature Review on the Pathogenesis of Vascular Senescence in Older Subjects.

Curr Gerontol Geriatr Res 2020 13;2020:8601762. Epub 2020 Jun 13.

First Department of Propaedeutic Surgery, Hippocration General Hospital, School of Medicine, National Kapodistrian University of Athens, Athens, Greece.

Aging is a natural process that affects all systems of the human organism, leading to its inability to adapt to environmental changes. Advancing age has been correlated with various pathological conditions, especially cardiovascular and cerebrovascular diseases. Carotid artery (CA) is mainly affected by age-induced functional and morphological alterations causing atheromatous disease. The evolvement of biomedical sciences has allowed the elucidation of many aspects of this condition. Symptomatic carotid disease (CD) derives from critical luminar stenosis or eruption of an atheromatous plaque due to structural modifications of the vessels, such as carotid intima-media thickening. At a histologic level, the aforementioned changes are mediated by elastin fragmentation, collagen deposition, immune cell infiltration, and accumulation of cytokines and vasoconstrictors. Underlying mechanisms include chronic inflammation and oxidative stress, dysregulation of cellular homeostatic systems, and senescence. Thus, there is an imbalance in components of the vessel wall, which fails to counteract exterior stress stimuli. Consequently, arterial relaxation is impaired and atherosclerotic lesions progress. This is a review of current evidence regarding the relationship of aging with vascular senescence and CD. A deeper understanding of these mechanisms can contribute to the production of efficient prevention methods and targeted therapeutic strategies.
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http://dx.doi.org/10.1155/2020/8601762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306882PMC
June 2020

Conditioning attenuates kidney and heart injury in rats following transient suprarenal occlusion of the abdominal aorta.

Sci Rep 2020 03 19;10(1):5040. Epub 2020 Mar 19.

First Department of Propaedeutic Surgery, Hippocration General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Suprarenal aortic clamping during abdominal aortic aneurysm (AAA) repair results in ischemia-reperfusion injury (IRI) in local (i.e. kidney) and distant (i.e. heart) tissue. To investigate perioperative approaches that mitigate IRI-induced tissue damage, Wistar rats underwent suprarenal aortic clamping either alone or in combination with short cycles of ischemic conditioning before and/or after clamping. Serum analysis revealed significant reduction in key biochemical parameters reflecting decreased tissue damage at systemic level and improved renal function in conditioned groups compared to controls (p < 0.05), which was corroborated by histolopathological evaluation. Importantly, the levels of DNA damage, as reflected by the biomarkers 8-oxo-G, γH2AX and pATM were reduced in conditioned versus non-conditioned cases. In this setting, NADPH oxidase, a source of free radicals, decreased in the myocardium of conditioned cases. Of note, administration of 5-HD and 8-SPT blocking key protective signaling routes abrogated the salutary effect of conditioning. To further understand the non-targeted effect of IRI on the heart, it was noted that serum TGF-β1 levels decreased in conditioned groups, whereas this difference was eliminated after 5-HD and 8-SPT administration. Collectively, conditioning strategies reduced both renal and myocardial injury. Additionally, the present study highlights TGF-β1 as an attractive target for manipulation in this context.
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http://dx.doi.org/10.1038/s41598-020-61268-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081351PMC
March 2020

Utilization of low-temperature helium plasma (J-Plasma) for dissection and hemostasis during carotid endarterectomy.

J Vasc Surg Cases Innov Tech 2020 Mar 3;6(1):152-155. Epub 2020 Mar 3.

First Department of Propaedeutic Surgery, National and Kapodistrian University of Athens, Hippocration Hospital, Athens, Greece.

Herein we report nine cases of carotid endarterectomy in which we used a cold atmospheric helium plasma device (J-Plasma; Apyx Medical Corporation, Clearwater, Fla). Although clinical reports are limited, experimental data indicate that this technology could be used for dissection and coagulation during surgery, yielding limited adjacent tissue damage. As a result, it could be extremely useful in procedures like carotid endarterectomy that necessitate careful dissection and coagulation with limited damage of adjacent neurovascular structures.
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http://dx.doi.org/10.1016/j.jvscit.2020.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056604PMC
March 2020

Vascular complications during transcatheter aortic valve implantation: The role of the vascular surgeon.

Vascular 2020 Aug 20;28(4):421-429. Epub 2020 Feb 20.

First Propedeutic Department of Surgery, National and Kapodistrian University of Athens, Hippocration Hospital, Athens, Greece.

Introduction: This study compares the incidence of vascular complications and other major outcomes between patients undergoing transcatheter aortic valve implantation, with and without a standardized preoperative vascular surgeon consultation.

Methods: This retrospective study evaluated all patients scheduled for transcatheter aortic valve implantation during a five-year period at a Hellenic University Hospital. Two main periods were evaluated: Group A (early period (2014-2015), without a standardized preoperative vascular surgeon consultation) and Group B (late period (2016-2018), with a standardized preoperative vascular surgeon consultation). All vascular complications as well as other major outcomes (early death, stroke, myocardial infarction, and treatment) were recorded. Univariate and multivariate analyses were also conducted.

Results: Overall, 382 transcatheter aortic valve implantation procedures were conducted (Group A:  = 115; duration = 19 months; Group B:  = 267; duration = 41 months). Overall, 58 vascular complications were recorded (21 patients in Group A and 37 patients in Group B (18.3% versus 13.9%;  = 0.279)). However, vascular complications that necessitated a vascular surgeon's interference were more frequent during the first period (13% versus 4.9%;  = 0.009). Among patients with a vascular complication, early mortality was higher during the first period (14.3% versus 0%;  = 0.034) although stroke and myocardial infarction rates were similar. Age >80 years (OR = 1.856 [1.134-3.452];  = 0.03) and preoperative vascular surgeon consultation (OR = 0.345 [0.132-0.756];  = 0.015) were the only independent predictors for vascular complications.

Conclusions: A standardized preoperative evaluation by a vascular surgeon may decrease the risk for vascular complications that necessitate a repair as well as early mortality among patients undergoing transcatheter aortic valve implantation procedures.
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http://dx.doi.org/10.1177/1708538120902659DOI Listing
August 2020

Small abdominal aortic aneurysms: Has anything changed so far?

Trends Cardiovasc Med 2020 11 26;30(8):500-504. Epub 2019 Nov 26.

First Propedeutic Department of Surgery, National and Kapodistrian University of Athens, Hippocration Hospital, 114 Vasilissis Sofias Avenue, 11527 Athens, Greece.

The proper management of small abdominal aortic aneurysms (AAAs), namely those under the threshold of 5.5 cm in diameter, has been under investigation for years. Risk of rupture for this group of AAAs is higher than the general population, although it remains low enough not to require a repair. However, specific factors have been associated with increased expansion or rupture rate, and these factors could identify potential candidates for earlier intervention. This review aims to collect and present all available data on the development and progress of small AAAs. Moreover, recommendations on proper management are discussed as well.
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http://dx.doi.org/10.1016/j.tcm.2019.11.006DOI Listing
November 2020

Shear stress regulates cystathionine γ lyase expression to preserve endothelial redox balance and reduce membrane lipid peroxidation.

Redox Biol 2020 01 13;28:101379. Epub 2019 Nov 13.

Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany; German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany. Electronic address:

Cystathionine γ lyase (CSE) is the major source of hydrogen sulfide-derived species (HS) in endothelial cells and plays an important role in protecting against atherosclerosis. Here we investigated the molecular mechanisms underlying the regulation of CSE expression in endothelial cells by fluid shear stress/flow. Fluid shear stress decreased CSE expression in human and murine endothelial cells and was negatively correlated with the transcription factor Krüppel-like factor (KLF) 2. CSE was identified as a direct target of the KLF2-regulated microRNA, miR-27b and high expression of CSE in native human plaque-derived endothelial cells, was also inversely correlated with KLF2 and miR-27b levels. One consequence of decreased CSE expression was the loss of Prx6 sulfhydration (on Cys47), which resulted in Prx6 hyperoxidation, decamerization and inhibition, as well as a concomitant increase in endothelial cell reactive oxygen species and lipid membrane peroxidation. HS supplementation in vitro was able to reverse the redox state of Prx6. Statin therapy, which is known to activate KLF2, also decreased CSE expression but increased CSE activity by preventing its phosphorylation on Ser377. As a result, the sulfhydration of Prx6 was partially restored in samples from plaque containing arteries from statin-treated donors. Taken together, the regulation of CSE expression by shear stress/disturbed flow is dependent on KLF2 and miR-27b. Moreover, in murine and human arteries CSE acts to maintain endothelial redox balance at least partly by targeting Prx6 to prevent its decamerization and inhibition of its peroxidase activity.
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http://dx.doi.org/10.1016/j.redox.2019.101379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880097PMC
January 2020

Iatrogenic Vascular Injuries of the Abdomen and Pelvis: The Experience at a Hellenic University Hospital.

Vasc Endovascular Surg 2019 Oct 27;53(7):541-546. Epub 2019 Jun 27.

1 First Propedeutic Department of Surgery, Hippocration Hospital, National and Kapodistrian University of Athens, Athens, Greece.

Background: The aim of this study is to present the experience of a Vascular Division at a Hellenic University hospital concerning the management of iatrogenic vascular injuries (IVIs) of the abdomen or pelvis.

Patients And Methods: This is a retrospective study evaluating all IVIs reported during a 10-year period in our institution. Only injuries warranting a vascular surgeon consultation were included in the study. Non-iatrogenic injuries were not included. Mortality and major complications within 30 days were evaluated.

Results: Overall, 70 cases were recorded, with 41% being venous and 59% being arterial injuries. Iliac arteries (51%) were the most common location and rupture/lacerations (73%) were the most common type of injury. General surgery (61.5%) and cardiology (30%) procedures were the most frequently involved procedures. A 30-day mortality was 5.7%, with 30% of cases treated conservatively. Synthetic bypass grafting (odds ratio [OR] = 65.0; 95% confidence interval [CI], 4.022-1050.358; = .003) and male gender (OR = 83.77; 95% CI, 4.040-1736.738; = .004) were associated with death.

Conclusions: Iatrogenic vascular injuries of the abdomen or pelvis are usually associated with general surgery and endovascular procedures. When vascular consultation is requested early, mortality could remain low. However, a selected number of stable patients with retroperitoneal or pelvic hematomas could be treated conservatively, yielding satisfying results.
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http://dx.doi.org/10.1177/1538574419858809DOI Listing
October 2019

Levosimendan prevents doxorubicin-induced cardiotoxicity in time- and dose-dependent manner: implications for inotropy.

Cardiovasc Res 2020 03;116(3):576-591

National and Kapodistrian University of Athens, Laboratory of Pharmacology, Faculty of Pharmacy, Panepistimiopolis, Zografou, Athens 15771, Greece.

Aims: Levosimendan (LEVO) a clinically-used inodilator, exerts multifaceted cardioprotective effects. Case-studies indicate protection against doxorubicin (DXR)-induced cardiotoxicity, but this effect remains obscure. We investigated the effect and mechanism of different regimens of levosimendan on sub-chronic and chronic doxorubicin cardiotoxicity.

Methods And Results: Based on preliminary in vivo experiments, rats serving as a sub-chronic model of doxorubicin-cardiotoxicity and were divided into: Control (N/S-0.9%), DXR (18 mg/kg-cumulative), DXR+LEVO (LEVO, 24 μg/kg-cumulative), and DXR+LEVO (acute) (LEVO, 24 μg/kg-bolus) for 14 days. Protein kinase-B (Akt), endothelial nitric oxide synthase (eNOS), and protein kinase-A and G (PKA/PKG) pathways emerged as contributors to the cardioprotection, converging onto phospholamban (PLN). To verify the contribution of PLN, phospholamban knockout (PLN-/-) mice were assigned to PLN-/-/Control (N/S-0.9%), PLN-/-/DXR (18 mg/kg), and PLN-/-/DXR+LEVO (ac) for 14 days. Furthermore, female breast cancer-bearing (BC) mice were divided into: Control (normal saline 0.9%, N/S 0.9%), DXR (18 mg/kg), LEVO, and DXR+LEVO (LEVO, 24 μg/kg-bolus) for 28 days. Echocardiography was performed in all protocols. To elucidate levosimendan's cardioprotective mechanism, primary cardiomyocytes were treated with doxorubicin or/and levosimendan and with N omega-nitro-L-arginine methyl ester (L-NAME), DT-2, and H-89 (eNOS, PKG, and PKA inhibitors, respectively); cardiomyocyte-toxicity was assessed. Single bolus administration of levosimendan abrogated DXR-induced cardiotoxicity and activated Akt/eNOS and cAMP-PKA/cGMP-PKG/PLN pathways but failed to exert cardioprotection in PLN-/- mice. Levosimendan's cardioprotection was also evident in the BC model. Finally, in vitro PKA inhibition abrogated levosimendan-mediated cardioprotection, indicating that its cardioprotection is cAMP-PKA dependent, while levosimendan preponderated over milrinone and dobutamine, by ameliorating calcium overload.

Conclusion: Single dose levosimendan prevented doxorubicin cardiotoxicity through a cAMP-PKA-PLN pathway, highlighting the role of inotropy in doxorubicin cardiotoxicity.
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http://dx.doi.org/10.1093/cvr/cvz163DOI Listing
March 2020

Pleiotropic effects of laminar flow and statins depend on the Krüppel-like factor-induced lncRNA MANTIS.

Eur Heart J 2019 08;40(30):2523-2533

Institute for Cardiovascular Physiology, Goethe University, Theodor-Stern-Kai 7, Frankfurt, Germany.

Aims: To assess the functional relevance and therapeutic potential of the pro-angiogenic long non-coding RNA MANTIS in vascular disease development.

Methods And Results: RNA sequencing, CRISPR activation, overexpression, and RNAi demonstrated that MANTIS, especially its Alu-element, limits endothelial ICAM-1 expression in different types of endothelial cells. Loss of MANTIS increased endothelial monocyte adhesion in an ICAM-1-dependent manner. MANTIS reduced the binding of the SWI/SNF chromatin remodelling factor BRG1 at the ICAM-1 promoter. The expression of MANTIS was induced by laminar flow and HMG-CoA-reductase inhibitors (statins) through mechanisms involving epigenetic rearrangements and the transcription factors KLF2 and KLF4. Mutation of the KLF binding motifs in the MANTIS promoter blocked the flow-induced MANTIS expression. Importantly, the expression of MANTIS in human carotid artery endarterectomy material was lower compared with healthy vessels and this effect was prevented by statin therapy. Interestingly, the protective effects of statins were mediated in part through MANTIS, which was required to facilitate the atorvastatin-induced changes in endothelial gene expression. Moreover, the beneficial endothelial effects of statins in culture models (spheroid outgrowth, proliferation, telomerase activity, and vascular organ culture) were lost upon knockdown of MANTIS.

Conclusion: MANTIS is tightly regulated by the transcription factors KLF2 and KLF4 and limits the ICAM-1 mediated monocyte adhesion to endothelial cells and thus potentially atherosclerosis development in humans. The beneficial effects of statin treatment and laminar flow are dependent on MANTIS.
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http://dx.doi.org/10.1093/eurheartj/ehz393DOI Listing
August 2019

Regarding "Outcomes after elective abdominal aortic aneurysm repair in obese versus nonobese patients".

J Vasc Surg 2019 06;69(6):2008

First Department of Propedeutic Surgery, National and Kapodistrian University of Athens Medical School, Hippocration Hospital, Athens, Greece.

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http://dx.doi.org/10.1016/j.jvs.2018.12.053DOI Listing
June 2019

Weekend effect among patients undergoing elective vascular surgery.

J Vasc Surg 2019 12 27;70(6):2038-2045. Epub 2019 May 27.

First Department of Propaedeutic Surgery, National and Kapodistriakon University of Athens, Hippocration Hospital, Athens, Greece.

Objective: Several studies have described a higher mortality among patients admitted or operated during the weekend for various diseases. However, pooled data on patients undergoing elective vascular surgery procedures are sparse.

Methods: The PubMed, Embase, Scopus, and Cochrane Library databases were systematically searched to identify eligible studies. Studies comparing short-term mortality (≤30 days) between patients undergoing elective vascular surgery during the weekend and working days were included. When studies included patients undergoing mixed types of surgery, only the vascular surgery subgroups were evaluated. Urgent/emergency vascular procedures were excluded according to certain definitions provided by each study. Data were analyzed by using the StatsDirect Statistical software (Version 2.8.0, StatsDirect Ltd, Cambridge, UK).

Results: Overall, four retrospective studies including 131,201 patients undergoing elective vascular surgery (on working days, n = 130,163; on the weekend, n = 1038) were evaluated. The pooled short-term mortality risk was higher among patients operated during the weekend compared with working days (odds ratio [OR], 2.41; 95% confidence interval [CI], 1.58-3.67; P = .0004). This weekend effect was more evident among patients undergoing abdominal aortic aneurysm repair and carotid surgery (OR, 3.62 [95% CI, 1.49-8.82; P = .0046] and OR, 3.48 [95% CI, 1.15-10.54; P = .027], respectively). In the United States, the weekend effect was more evident among patients undergoing aortic aneurysm repair (OR, 3.61; 95% CI, 1.99-6.53; P < .0001). However, data from Canada originated from one study on patients undergoing carotid and peripheral arterial surgery only.

Conclusions: Elective vascular surgery is associated with a higher short-term mortality risk when conducted over the weekend. Improvement of perioperative management during these days may be necessary to improve outcomes.
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http://dx.doi.org/10.1016/j.jvs.2019.03.020DOI Listing
December 2019

Autologous Platelet-Rich Plasma for Nonhealing Ulcers: A Comparative Study.

Vasc Specialist Int 2019 Mar;35(1):22-27

First Department of Propedeutic Surgery, Hippocration General Hospital, National Kapodistrian University of Athens, Athens, Greece.

Purpose: The use of platelet-rich plasma (PRP) for the treatment of nonhealing ulcers is a relatively new technique. Although it seems to result in a satisfying level of healing and low complication rates, data regarding its effectiveness remain sparse. This study aims to evaluate the potential therapeutic effects of PRP on chronic nonhealing ulcers.

Materials And Methods: This was a prospectively designed study comparing outcomes between patients treated with PRP (Group A, n=15) and patients treated conventionally (Group B, n=12) for different types of nonhealing ulcers. In Group A, PRP was produced from the patients' own peripheral blood samples and was applied on the ulcer once every week. In Group B, patients were treated conventionally, without applying PRP. The total treatment period was 5 weeks.

Results: Both groups were similar regarding age, sex, comorbidities, and time of treatment. In Group A, patients showed a nonsignificant reduction of 4.5 mm in ulcer area (P=0.190) and a reduction of more than 1 mm in depth (P=0.0006), while Group B showed an increase of 108±80.5 mm in ulcer area after 5 weeks (P=0.016). The healing rate (HR) in Group A was stable and positive throughout the treatment period, while HR in Group B was initially negative but became positive after the 3rd week.

Conclusion: PRP application once a week promotes the healing of chronic ulcers. It improves the ulcer's depth and HR, although its effect on ulcer area seems to be nonsignificant. However, larger comparative series are still needed to confirm these findings.
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http://dx.doi.org/10.5758/vsi.2019.35.1.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453601PMC
March 2019

Letter by Galyfos et al Regarding Article, "Weekend Effect in Carotid Endarterectomy".

Stroke 2019 04;50(4):e110

First Department of Propedeutic Surgery, National and Kapodistrian University of Athens Medical School Hippocration Hospital, Athens, Greece.

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http://dx.doi.org/10.1161/STROKEAHA.118.024303DOI Listing
April 2019

Re: "Editor's Choice - Cerebral Hyperperfusion Syndrome after Carotid Artery Stenting: A Systematic Review and Meta-analysis".

Eur J Vasc Endovasc Surg 2019 06 16;57(6):892. Epub 2019 Feb 16.

First Department of Propedeutic Surgery, National and Kapodistrian University of Athens Medical School, Hippocration Hospital, Athens, Greece.

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http://dx.doi.org/10.1016/j.ejvs.2018.11.022DOI Listing
June 2019

Prognostic Factors in Patients Treated with Drug-Coated Balloon Angioplasty for Symptomatic Peripheral Artery Disease.

Vasc Specialist Int 2018 Dec 31;34(4):94-102. Epub 2018 Dec 31.

First Department of Surgery, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Thessaloniki, Greece.

Purpose: Aim of this study is to report real-life experience on the treatment of peripheral artery disease (PAD) with a specific drug-coated balloon (DCB), and to evaluate potential prognostic factors for outcomes.

Materials And Methods: This is a retrospective study reporting outcomes in patients with PAD who were treated with the Lutonix DCB during a four-year period. Major outcomes included: all-cause mortality, amputation, clinical improvement, wound healing and target lesion revascularization (TLR). Mean follow-up was 24.2±2.3 months.

Results: Overall, 149 patients (mean age: 68.6±8.3 years; 113 males) were treated, either for intermittent claudication (IC) (n=86) or critical limb ischemia (CLI) (n=63). More than half the target lesions (n=206 in total) were located in the superficial femoral artery and 18.0% were below-the-knee lesions. CLI patients presented more frequently with infrapopliteal (P=0.002) or multilevel disease (P=0.0004). Overall, all-cause mortality during follow-up was 10.7%, amputation-free survival was 81.2% and TLR-free survival was 96.6%. CLI patients showed higher all-cause mortality (P=0.007) and total amputation (P=0.0001) rates as well as lower clinical improvement (P=0.0002), compared to IC patients. Coronary artery disease (CAD), gangrene and infrapopliteal disease were found to be predictors for death whereas CLI and gangrene were found to be predictors for amputation, during follow-up.

Conclusion: PAD treatment with Lutonix DCBs seems to be an efficient and safe endovascular strategy yielding promising results. However, CAD, gangrene, CLI and infrapopliteal lesions were found to be independent predictors for adverse outcomes. Larger series are needed to identify additional prognostic factors.
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http://dx.doi.org/10.5758/vsi.2018.34.4.94DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340698PMC
December 2018

Rivaroxaban versus Clopidogrel for Peripheral Artery Disease: A Clinico-Economic Approach of the COMPASS Trial.

Curr Pharm Des 2018 ;24(38):4516-4517

First Department of Propaedeutic Surgery, Vascular Unit, National and Kapodistrian University of Athens, Athens, Greece.

Peripheral artery disease (PAD) is the third most common manifestation of atherosclerosis after coronary artery (CAD) and cerebrovascular disease (CVD). People with PAD have plaque findings in other vascular territories as well and, thus, are at increased risk of major adverse cardiovascular or cerebrovascular events (MACCE), including myocardial infarction, and stroke. In that context, the COMPASS multicenter, randomized controlled trial showed that the risk of MACCE was significantly reduced by 24% in the rivaroxaban plus aspirin arm compared with aspirin alone (4.1% vs 5.4% respectively; HR: 0.76, 95% CI: 0.66 to 0.86). Interestingly, the rivaroxaban/aspirin arm also showed a reduction in cardiovascular death (HR: 0.78; 95% CI: 0.64-0.96]) and allcause mortality (HR: 0.82; 95% CI: 0.71-0.96) by 22% and 18%, respectively. Recently, the FDA approved the use of the dual pathway approach, rivaroxaban 2.5 mg twice daily plus aspirin 75-100mg once daily, to reduce the risk of major cardiovascular (CV) events, such as CV death, myocardial infarction and stroke, in people with CAD as well as PAD. In comparing rivaroxaban plus aspirin versus aspirin alone, a preliminary economic analysis showed that saving per patient was USD 462 for events and USD 220 for procedures with a total reduction of USD 682 per participant in the US with the combination group (rivaroxaban plus aspirin). The data from COMPASS trial suggest that low dose rivaroxaban plus aspirin may be a preferred treatment strategy in PAD patients in whom the bleeding risk is deemed to be favourable.
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http://dx.doi.org/10.2174/1381612825666190101100832DOI Listing
November 2019

Regarding "The effect of preoperative cognitive impairment and type of vascular surgery procedure on postoperative delirium with associated cost implications".

J Vasc Surg 2018 11;68(5):1615-1616

First Department of Propaedeutic Surgery, University of Athens Medical School, Hippocration Hospital, Athens, Greece.

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http://dx.doi.org/10.1016/j.jvs.2018.07.032DOI Listing
November 2018

Cystathionine γ Lyase Sulfhydrates the RNA Binding Protein Human Antigen R to Preserve Endothelial Cell Function and Delay Atherogenesis.

Circulation 2019 01;139(1):101-114

Institute for Vascular Signalling, Centre for Molecular Medicine (S.-I.B., J. Hu, S.Z., V.R., J.W., M.S., D.S., B.L., R.A.M., I.F.), Goethe University, Frankfurt am Main, Germany.

Background: Hydrogen sulfide (HS), generated by cystathionine γ lyase (CSE), is an important endogenous regulator of vascular function. The aim of the present study was to investigate the control and consequences of CSE activity in endothelial cells under physiological and proatherogenic conditions.

Methods: Endothelial cell CSE knockout mice were generated, and lung endothelial cells were studied in vitro (gene expression, protein sulfhydration, and monocyte adhesion). Mice were crossed onto the apolipoprotein E-deficient background, and atherogenesis (partial carotid artery ligation) was monitored over 21 days. CSE expression, HS bioavailability, and amino acid profiling were also performed with human material.

Results: The endothelial cell-specific deletion of CSE selectively increased the expression of CD62E and elevated monocyte adherence in the absence of an inflammatory stimulus. Mechanistically, CD62E mRNA was more stable in endothelial cells from CSE-deficient mice, an effect attributed to the attenuated sulfhydration and dimerization of the RNA-binding protein human antigen R. CSE expression was upregulated in mice after partial carotid artery ligation and in atheromas from human subjects. Despite the increase in CSE protein, circulating and intraplaque HS levels were reduced, a phenomenon that could be attributed to the serine phosphorylation (on Ser377) and inhibition of the enzyme, most likely resulting from increased interleukin-1β. Consistent with the loss of HS, human antigen R sulfhydration was attenuated in atherosclerosis and resulted in the stabilization of human antigen R-target mRNAs, for example, CD62E and cathepsin S, both of which are linked to endothelial cell activation and atherosclerosis. The deletion of CSE from endothelial cells was associated with the accelerated development of endothelial dysfunction and atherosclerosis, effects that were reversed on treatment with a polysulfide donor. Finally, in mice and humans, plasma levels of the CSE substrate l-cystathionine negatively correlated with vascular reactivity and HS levels, indicating its potential use as a biomarker for vascular disease.

Conclusions: The constitutive S-sulfhydration of human antigen R (on Cys13) by CSE-derived HS prevents its homodimerization and activity, which attenuates the expression of target proteins such as CD62E and cathepsin S. However, as a consequence of vascular inflammation, the beneficial actions of CSE-derived HS are lost owing to the phosphorylation and inhibition of the enzyme.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.034757DOI Listing
January 2019

Oxidized phospholipids regulate amino acid metabolism through MTHFD2 to facilitate nucleotide release in endothelial cells.

Nat Commun 2018 06 12;9(1):2292. Epub 2018 Jun 12.

Institute for Cardiovascular Physiology, Goethe University, Frankfurt am Main, 60590, Germany.

Oxidized phospholipids (oxPAPC) induce endothelial dysfunction and atherosclerosis. Here we show that oxPAPC induce a gene network regulating serine-glycine metabolism with the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) as a causal regulator using integrative network modeling and Bayesian network analysis in human aortic endothelial cells. The cluster is activated in human plaque material and by atherogenic lipoproteins isolated from plasma of patients with coronary artery disease (CAD). Single nucleotide polymorphisms (SNPs) within the MTHFD2-controlled cluster associate with CAD. The MTHFD2-controlled cluster redirects metabolism to glycine synthesis to replenish purine nucleotides. Since endothelial cells secrete purines in response to oxPAPC, the MTHFD2-controlled response maintains endothelial ATP. Accordingly, MTHFD2-dependent glycine synthesis is a prerequisite for angiogenesis. Thus, we propose that endothelial cells undergo MTHFD2-mediated reprogramming toward serine-glycine and mitochondrial one-carbon metabolism to compensate for the loss of ATP in response to oxPAPC during atherosclerosis.
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http://dx.doi.org/10.1038/s41467-018-04602-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997752PMC
June 2018

Cytokines as biomarkers of inflammatory response after open versus endovascular repair of abdominal aortic aneurysms: a systematic review.

Acta Pharmacol Sin 2018 Jul 17;39(7):1164-1175. Epub 2018 May 17.

Department of Surgery, Duke University Medical Center, Durham, USA, NC.

The repair of an abdominal aortic aneurysm (AAA) is a high-risk surgical procedure related to hormonal and metabolic stress-related response with an ensuing activation of the inflammatory cascade. In contrast to open repair (OR), endovascular aortic aneurysm repair (EVAR) seems to decrease the postoperative stress by offering less extensive incisions, dissection, and tissue manipulation. However, these beneficial effects may be offset by the release of cytokines and arachidonic acid metabolites during intra-luminal manipulation of the thrombus using catheters in endovascular repair, resulting in systemic inflammatory response (SIR), which is clinically called post-implantation syndrome. In this systematic review we compared OR with EVAR in terms of the post-interventional inflammatory response resulting from alterations in the circulating cytokine levels. We sought to summarize all the latest evidence regarding post-implantation syndrome after EVAR. We searched Medline (PubMed), ClinicalTrials.gov and the Cochrane library for clinical studies reporting on the release of cytokines as part of the inflammatory response after both open/conventional and endovascular repair of the AAA. We identified 17 studies examining the cytokine levels after OR versus EVAR. OR seemed to be associated with a greater SIR than EVAR, as evidenced by the increased cytokine levels, particularly IL-6 and IL-8, whereas IL-1β, IL-10 and TNF-α showed conflicting results or no difference between the two groups. Polyester endografts appear to be positively correlated with the incidence of post-implantation syndrome after EVAR. Future large prospective studies are warranted to delineate the underlying mechanisms of the cytokine interaction in the post-surgical inflammatory response setting.
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http://dx.doi.org/10.1038/aps.2017.212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289472PMC
July 2018

Critical evaluation on proper antithrombotic treatment in different groups of patients undergoing vascular surgery.

Hellenic J Cardiol 2018 Nov - Dec;59(6):313-316. Epub 2018 Apr 30.

First Department of Propedeutic Surgery, Hippocration Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece. Electronic address:

Antithrombotic treatment including anticoagulants and antiplatelets has evolved during the last decades, and several recommendations have been included in the latest guidelines regarding the proper management of patients undergoing vascular surgery. However, there are significant differences compared to older recommendations, and indications vary among patients with peripheral artery disease, carotid disease, and abdominal aortic aneurysm. In this mini review, we critically evaluate all these data to produce useful conclusions for everyday clinical practice.
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http://dx.doi.org/10.1016/j.hjc.2018.04.006DOI Listing
July 2019
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