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1.
J Vasc Surg ; 79(5): 1179-1186.e1, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38145634

RESUMO

OBJECTIVE: Only 5% of patients with popliteal artery aneurysms (PAAs) are female. Evidence on PAA treatment and outcomes in women is therefore scarce. The POPART Registry provides one of Europe's largest data collections regarding PAA treatment. Data on clinical presentation, aneurysm morphology, and perioperative outcomes after open surgical PAA repair in women will be presented. METHODS: POPART is a multicenter, noninterventional registry for open and endovascular PAA repair, with 42 participating centers in Germany and Luxembourg. All patients aged >18 years who have been treated for PAA since 2010 are eligible for study inclusion. Data collection is based on an online electronic case report form. RESULTS: Of the 1236 PAAs, 58 (4.8%) were in women. There were no significant differences in age or cardiopulmonary comorbidities. However, female patients had a lower prevalence of contralateral PAAs and abdominal aortic aneurysms (P < .05). PAAs in women were more likely to be symptomatic before surgery (65.5% vs 49.4%; P = .017), with 19% of women presenting with acute limb ischemia (vs 11%; P = .067). Women had smaller aneurysm diameters than men (22.5 mm vs 27 mm; P = .004) and became symptomatic at smaller diameters (20 mm vs 26 mm; P = .002). Only 8.6% of women and 11.6% of men underwent endovascular aneurysm repair (P > .05); therefore, the perioperative outcome analysis focused on open surgical repair. In total, 23.5% of women and 16.9% of men developed perioperative complications (P > .05). There were no differences in major cardiovascular events (P > .05), but women showed a higher incidence of impaired wound healing (15.7% vs 7.2%; P = .05) and major amputation (5.9% vs 1.1%; P = .027). Female sex was significantly associated with the need for nonvascular reinterventions within 30 days after surgery (odds ratio: 2.48, 95% confidence interval: 1.26-4.88), whereas no significant differences in the odds for vascular reinterventions were observed (odds ratio: 1.98, 95% confidence interval: 0.68-5.77). In the multiple logistic regression model, female sex, symptomatic PAAs, poor quality of outflow vessels, and graft material other than vein graft were independently associated with perioperative reinterventions. CONCLUSIONS: Women have smaller PAAs, are more likely to be symptomatic before treatment, and are more often affected by nonvascular reinterventions in the perioperative course. As our understanding of aneurysmatic diseases in women continues to expand, sex-specific treatment strategies and screening options for women in well-selected cohorts with modified screening protocols should be continuously re-evaluated.


Assuntos
Aneurisma da Aorta Abdominal , Arteriopatias Oclusivas , Implante de Prótese Vascular , Procedimentos Endovasculares , Aneurisma da Artéria Poplítea , Masculino , Humanos , Feminino , Aneurisma da Aorta Abdominal/cirurgia , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/métodos , Implante de Prótese Vascular/efeitos adversos , Arteriopatias Oclusivas/cirurgia , Artéria Poplítea/diagnóstico por imagem , Artéria Poplítea/cirurgia , Resultado do Tratamento , Estudos Retrospectivos , Fatores de Risco
2.
Vasa ; 52(2): 119-123, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36601699

RESUMO

Background: The aim of this retrospective cross-sectional observational study was to determine differences of patients with multiple arterial aneurysms to patients with single arterial aneurysms. Patients and methods: Patients with the diagnosis of an arterial aneurysm from January 2006 to January 2016 in the department of vascular surgery Heidelberg were investigated. Excluded were patients with hereditary disorders of connective tissue or systemic inflammatory disease, as well as other arterial pathologies than true aneurysms. Patients with multiple aneurysms (defined by at least four aneurysms) were compared to patients with single aneurysms concerning age at initial diagnosis, sex and affected arterial site. To verify the findings, a replication of the study was performed at a comparable institution. Results: Of 3107 patients with arterial aneurysms, 918 were excluded. Of the resulting 2189 patients, 1238 (56.6%) patients had a single, 808 (36.9%) two or three, and 143 (6.5%) at least four aneurysms (group mult-AA). Nine hundred seventy-two patients (44.4%) had a single abdominal aortic aneurysm (group sing-AAA). Age at initial diagnosis differed between mult-AA (66.7±9.5 y) and sing-AAA (69.1±8.6 y) (p=0.0338). Within mult-AA, 138 patients (96.5%) were male, compared with 865 patients (89.0%) in sing-AAA (p=0.0041). The most frequent aneurysm localization shifted from the abdominal aorta and its branches in patients with a single aneurysm (n=1029; 83.1%) to pelvic and leg arteries in patients with at least four aneurysms (n=318; 63.2%). The replication of the study at the department of vascular surgery Frankfurt confirmed the younger age at initial diagnosis in mult-AA (67.3±12.5 y) compared to sing-AAA (70.9±9.6 y) (p=0.0259) and the distribution shift toward the arteries below the aortic bifurcation in mult-AA. Conclusions: Patients with multiple aneurysms are younger at initial diagnosis and differ concerning aneurysm localization compared to patients with a single aneurysm.


Assuntos
Aneurisma da Aorta Abdominal , Humanos , Masculino , Feminino , Estudos Retrospectivos , Estudos Transversais , Aneurisma da Aorta Abdominal/cirurgia , Aorta Abdominal/patologia , Artérias
3.
JVS Vasc Sci ; 2: 219-234, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34778850

RESUMO

INTRODUCTION: Abdominal aortic aneurysm (AAA) is a condition that has considerable socioeconomic impact and an eventual rupture is associated with high mortality and morbidity. Despite decades of research, surgical repair remains the treatment of choice and no medical therapy is currently available. Animal models and, in particular, murine models, of AAA are a vital tool for experimental in vivo research. However, each of the different models has individual limitations and provide only partial mimicry of human disease. This narrative review addresses the translational potential of the available mouse models, highlighting unanswered questions from a clinical perspective. It is based on a thorough presentation of the available literature and more than a decade of personal experience, with most of the available models in experimental and translational AAA research. RESULTS: From all the models published, only the four inducible models, namely the angiotensin II model (AngII), the porcine pancreatic elastase perfusion model (PPE), the external periadventitial elastase application (ePPE), and the CaCl2 model have been widely used by different independent research groups. Although the angiotensin II model provides features of dissection and aneurysm formation, the PPE model shows reliable features of human AAA, especially beyond day 7 after induction, but remains technically challenging. The translational value of ePPE as a model and the combination with ß-aminopropionitrile to induce rupture and intraluminal thrombus formation is promising, but warrants further mechanistic insights. Finally, the external CaCl2 application is known to produce inflammatory vascular wall thickening. Unmet translational research questions include the origin of AAA development, monitoring aneurysm growth, gender issues, and novel surgical therapies as well as novel nonsurgical therapies. CONCLUSION: New imaging techniques, experimental therapeutic alternatives, and endovascular treatment options provide a plethora of research topics to strengthen the individual features of currently available mouse models, creating the possibility of shedding new light on translational research questions.

4.
Cells ; 10(9)2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34572082

RESUMO

Aortic diseases comprise aneurysms, dissections, and several other pathologies. In general, aging is associated with a slow but progressive dilation of the aorta, along with increased stiffness and pulse pressure. The progression of aortic disease is characterized by subclinical development or acute presentation. Recent evidence suggests that inflammation participates causally in different clinical manifestations of aortic diseases. As of yet, diagnostic imaging and surveillance is mainly based on ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI). Little medical therapy is available so far to prevent or treat the majority of aortic diseases. Endovascular therapy by the introduction of covered stentgrafts provides the main treatment option, although open surgery and implantation of synthetic grafts remain necessary in many situations. Because of the risks associated with surgery, there is a need for identification of pharmaceutical targets interfering with the pathophysiology of aortic remodeling. The participation of innate immunity and inflammasome activation in different cell types is common in aortic diseases. This review will thus focus on inflammasome activities in vascular cells of different chronic and acute aortic diseases and discuss their role in development and progression. We will also identify research gaps and suggest promising therapeutic targets, which may be used for future medical interventions.


Assuntos
Aorta , Doenças da Aorta , Inflamassomos/metabolismo , Aorta/citologia , Aorta/patologia , Aorta/fisiologia , Aneurisma Aórtico/metabolismo , Aneurisma Aórtico/fisiopatologia , Aneurisma da Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/fisiopatologia , Doenças da Aorta/metabolismo , Doenças da Aorta/fisiopatologia , Proteínas de Ligação a DNA/metabolismo , Sistemas de Liberação de Medicamentos , Células Endoteliais/metabolismo , Humanos , Imuno-Histoquímica , Inflamassomos/fisiologia , Inflamação/metabolismo , Inflamação/fisiopatologia , Interleucina-1beta/metabolismo , Linfócitos/metabolismo , Macrófagos/metabolismo , Miócitos de Músculo Liso/metabolismo , Miofibroblastos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
5.
Atherosclerosis ; 318: 8-13, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33348068

RESUMO

BACKGROUND AND AIMS: Genetic variations between C57Bl/6 mouse substrains are highly relevant to the investigation of cardiovascular disease. We here assessed whether these variations have an impact on the incidence of abdominal aortic aneurysms (AAA) in C57Bl/6J and 6 N mice. METHODS: AAA were induced by subcutaneous infusion of 1500 ng/kg*min Angiotensin-II for four weeks in six-month-old male CB57Bl/6J and 6N mice. Aortic smooth muscle cells (VSMC) were isolated from untreated animals for in vitro analysis. RESULTS: C57Bl/6J mice are more susceptible to AAA formation (76.5% vs. 7.1%, p = 0.0002). C57Bl/6J VSMC expressed more pro-inflammatory molecules such as Nlrp3, Aim2 and NF-κB. Additionally, these cells presented significantly higher levels of NADP/NADPH and oxidative DNA modifications, as indicated by 8-OHdG-staining, compared to C57Bl/6N VSMC. CONCLUSIONS: In contrast to previous reports, we present evidence that six-month-old C57BL/6J, but not C57BL/6N mice develop AAA. In accordance with the deficiency of nicotinamide-nucleotide-transhydrogenase (Nnt), C57BL/6J VSMC displayed increased oxidative stress, oxidative DNA damage and a stronger inflammatory phenotype than C57BL/6N VSMC.


Assuntos
Angiotensina II , Aneurisma da Aorta Abdominal , Angiotensina II/toxicidade , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso , Fenótipo
6.
Front Cardiovasc Med ; 8: 805150, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35127865

RESUMO

Both aortic aneurysm and dissection are life threatening pathologies. In the lack of a conservative medical treatment, the only therapy consists of modifying cardiovascular risk factors and either surgical or endovascular treatment. Like many other cardiovascular diseases, in particular atherosclerosis, aortic aneurysm and dissection have a strong inflammatory phenotype. Inflammasomes are part of the innate immune system. Upon stimulation they form multi protein complexes resulting mainly in activation of interleukin-1ß and other cytokines. Considering the gathering evidence, that inflammasomes are decisively involved in the emergence and progression of aortic diseases, inflammasome targeted therapy provides a promising new treatment approach. A systematic review following the PRISMA guidelines on the current preclinical data regarding the potential role of inflammasome targeted drug therapy as novel treatment option for aortic aneurysms and dissections was performed. Included were all rodent models of aortic disease (aortic aneurysm and dissection) evaluating a drug therapy with direct or indirect inhibition of inflammasomes and a suitable control group with the use of the same aortic model without the inflammasome targeted therapy. Primary and secondary outcomes were incidence of aortic disease, aortic rupture, aortic related death, and the maximum aortic diameter. The literature search of MEDLINE (via PubMed), the Web of Science, EMBASE and the Cochrane Central Registry of Registered Trials (CENTRAL) resulted in 8,137 hits. Of these, four studies met the inclusion criteria and were therefore eligible for data analysis. In all of them, targeting of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome effectively reduced the incidence of aortic disease and aortic rupture, and additionally reduced destruction of the aortic wall. Treatment strategies aiming at other inflammasomes could not be identified. In conclusion, inflammasome targeted therapies, more precisely targeting the NLRP3 inflammasome, have shown promising results in rodent models and deserve further investigation in preclinical research to potentially translate them into clinical research for the treatment of human patients with aortic disease. Regarding other inflammasomes, more preclinical research is needed to investigate their role in the pathophysiology of aortic disease. Protocol Registration: PROSPERO 2021 CRD42021279893, https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021279893.

7.
Mol Med ; 26(1): 87, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32933486

RESUMO

BACKGROUND: Phenotypic transformation of vascular smooth muscle cells is a key element in vascular remodeling and aortic aneurysm growth. Previously, deletion of several inflammasome components decreased formation of aortic aneurysm (AA) in the Angiotensin II (AngII) -induced mouse model. We hypothesized that the inflammasome sensor Absent in melanoma 2 (Aim2) might affect the phenotype of vascular smooth muscle cells (VSMC), thereby reducing AA formation. METHODS: Aim2-/- mice and wild-type (WT) C57Bl/6 J mice were used as an animal model. VSMC were isolated from 6 months old mice and grown in vitro. Young (passage 3-5) and senescent (passage 7-12) cells were analyzed in vitro for calcification in mineralization medium by Alizarin Red S staining. Expression of calcification and inflammatory markers were studied by real-time RT-PCR and Western blotting, release of cytokines was determined by ELISA. To induce AA, osmotic mini-pumps loaded with AngII (1500 ng/kg bodyweight/min) were implanted for 28 days in male mice at 6 months of age. RESULTS: Compared with VSMC from WT mice, VSMC isolated from Aim2-/- mice were larger, less viable, and underwent stronger calcification in mineralization medium, along with induction of Bmp4 and repression of Tnfsf11/Rankl gene expression. In addition, Aim2 deficiency was associated with reduced inflammasome gene expression and release of Interleukin-6. Using the mouse model of AngII induced AA, Aim2 deficiency reduced AA incidence to 48.4% (15/31) in Aim2-/- mice versus 76.5% (13/17) in WT mice. In contrast to Aim2-/- mice, AA from WT mice expressed significantly increased levels of alpha-smooth muscle actin/Acta2, indicating tissue remodeling. Reduced cell proliferation in Aim2-/- mice was indicated by significantly increased p16ink4a/Cdkn2a expression in untreated and AngII-infused aortas, and by significantly lower amounts of proliferating (Ki67 positive) VSMC in AngII-infused Aim2-/- mice. CONCLUSIONS: Our results suggest a role for Aim2 in regulating VSMC proliferation and transition to an osteoblast-like or osteoclast-like phenotype, thereby modulating the response of VSMC in aortic remodeling and AA formation.


Assuntos
Angiotensina II/genética , Aneurisma Aórtico/etiologia , Aneurisma Aórtico/patologia , Calcinose/etiologia , Proteínas de Ligação a DNA/deficiência , Miócitos de Músculo Liso/metabolismo , Angiotensina II/metabolismo , Animais , Calcinose/metabolismo , Calcinose/patologia , Proliferação de Células , Sobrevivência Celular , Senescência Celular/genética , Modelos Animais de Doenças , Suscetibilidade a Doenças , Inflamassomos/metabolismo , Camundongos , Camundongos Knockout , Miócitos de Músculo Liso/patologia
8.
Inflamm Res ; 68(4): 337-345, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30758522

RESUMO

OBJECTIVE AND DESIGN: Abdominal aortic aneurysm (AAA) is heavily infiltrated with leukocytes, expressing the DNA sensor absent in melanoma 2 (AIM2) and other inflammasome components. METHODS: Using multicolour flow cytometry, we here compared the expression of the inflammasome components AIM2, NLRP3, and ASC in different peripheral immune cells derived from AAA patients with those from non-AAA patients in a case-control study. In parallel, peripheral blood mononuclear cells (PBMC) of AAA patients and controls were stimulated in vitro with poly-dA:dT or lipopolysaccharide (LPS) to analyze inflammasome activation. RESULTS: AIM2 expression was significantly increased in peripheral granulocytes (P = 0.026), monocytes (P = 0.007), B lymphocytes (P < 0.0001), and T lymphocytes (P = 0.004) of AAA patients. Expression of other inflammasome components did not differ between the groups. Following in vitro stimulation with foreign DNA, PBMC derived from AAA patients released significantly more IL-1ß (P = 0.022) into the supernatant than PBMC from control patients. In contrast, IL-1ß release upon LPS stimulation did not differ between the PBMC groups. CONCLUSION: The data indicate the increased activation of an AIM2 inflammasome in peripheral immune cells of AAA patients and point to a systemic AIM2-associated immune response to AAA.


Assuntos
Aneurisma da Aorta Abdominal/imunologia , Proteínas de Ligação a DNA/imunologia , Inflamassomos/imunologia , Leucócitos Mononucleares/imunologia , Idoso , DNA/imunologia , Feminino , Humanos , Interferon beta/sangue , Interleucina-1beta/sangue , Leucócitos Mononucleares/citologia , Masculino , Pessoa de Meia-Idade
9.
Eur Surg Res ; 60(1-2): 13-23, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30726831

RESUMO

BACKGROUND/PURPOSE: To establish a high-quality vascular biomaterial bank to serve vascular research teams and act as a basis for translational medicine. The aim was to collect and store material so that investigation into the pathogenesis of vascular disease would be possible employing methods based on histopathology and/or molecular biology. METHODS: The Vascular Biomaterialbank Heidelberg (VBBH) evolved as part of an established, partly accredited biobank complex at the University of Heidelberg (BioMaterialBank Heidelberg - BMBH). The BMBH provided infrastructure regarding legal and quality issues as well as safety, protocols for specimen collection, data management, and publication of results. Protocols were modified where necessary to accommodate specific needs of vascular tissue research. Correct identification of vascular biomaterial is controlled by certified vascular surgeons and pathologists at biobank entry and exit. Pseudonymized clinical data are attached to every specimen. RESULTS: The VBBH provides standardized operating procedures (SOP) regulating the request, processing, and delivery of material to researchers, as well as project tracking. Tissue samples for a research project are requested by filling out an online application form. Within 3-5 working days, a scientific board, including a member of the VBBH and a member of the BMBH, decide upon acceptance or rejection of the research project. Criteria determining acceptance include whether enough samples are available for the particular investigation and whether planned methods are judged adequate to successfully complete the research project. Through tracking of all ongoing studies involving specimens from the VBBH, methods for tissue conservation are continually being optimized. The VBBH platform has supported numerous high-ranking publications involving diverse medical departments and reflects a gain in translational medicine. CONCLUSIONS: SOPs and controls by certified specialists ensure the high quality of specimens obtained through the VBBH. Research performed by vascular surgeons can be facilitated by using the VBBH.


Assuntos
Materiais Biocompatíveis , Bancos de Espécimes Biológicos , Pesquisa Translacional Biomédica , Procedimentos Cirúrgicos Vasculares , Bancos de Espécimes Biológicos/legislação & jurisprudência , Bancos de Espécimes Biológicos/normas , Gerenciamento de Dados , Humanos , Manejo de Espécimes/métodos , Manejo de Espécimes/normas , Doenças Vasculares/etiologia
10.
Biochem Biophys Res Commun ; 511(2): 343-349, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30782482

RESUMO

Abdominal aortic aneurysm (AAA) is a multi-factorial progressive vascular disease with life-threatening complications. Increasing evidence suggests that smooth muscle cell (SMC) dysfunction and cell death contribute to dilatation and rupture of the aorta by inducing an inflammatory response. The exact mechanism of this response however, is incompletely understood. We here investigated in vitro the capacity of autologous necrotic cell debris (CD) to induce inflammasome components and inflammatory mediators in aortic SMC (AAA-SMC) isolated from patients with AAA undergoing surgical repair. AAA-SMCs were additionally primed with Interferon- γ (IFN-γ) before treatment with CD in order to mimic the proinflammatory status caused by higher IFN-γ concentrations that have been demonstrated in the wall of AAAs. Real-time RT-PCR revealed that CD significantly increased NLRP3 and IL1B mRNA expression in different SMC cultures within 6 h of exposure. Priming of the AAA-SMC with IFN-γ significantly increased expression of NLRP3, AIM2, IFI16 and CASP1 mRNAs, whereas IL1B mRNA was reduced. Additional exposure of IFN-γ-primed AAA-SMC to CD for 6-24 h, further augmented expression of AIM2, NLRP3, and Caspase-1 protein levels. Analysis of the SMC supernatants by ELISA revealed CD-induced release of the senescence-associated cytokines IL-6 and MCP-1 in native and IFN-γ-primed SMC, whereas no secretion of Interleukin-(IL) 1α and IL-1ß secretion were observed. Our results implicate a role of necrotic cell debris derived from dead neighboring cells in SMC dysfunction and in inflammatory response of AAA tissue.


Assuntos
Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/patologia , Inflamassomos/imunologia , Miócitos de Músculo Liso/patologia , NF-kappa B/imunologia , Aorta Abdominal/citologia , Aorta Abdominal/imunologia , Aneurisma da Aorta Abdominal/complicações , Aneurisma da Aorta Abdominal/imunologia , Células Cultivadas , Humanos , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/imunologia , Necrose/complicações , Necrose/imunologia , Necrose/patologia
11.
Vasa ; 48(2): 186-192, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30421661

RESUMO

BACKGROUND: The enzyme glyoxalase1 (GLO1) is the main opponent in the degradation of the reactive metabolite methylglyoxal (MG), which by glycation of macromolecules is involved in atherogenesis. Reduced GLO1-activity in atherosclerotic tissue is known to be associated with diabetes. It has been shown that treatment of patients with type 2 diabetes with metformin leads to increased GLO1-activity in peripheral-blood-cells. The aim of this study was to evaluate whether metformin treatment increases GLO1-activity in atherosclerotic lesions of patients with type 2 diabetes. PATIENTS AND METHODS: Patients with type 2 diabetes and carotid artery disease were included into the study prospectively. Type of diabetes-medication was documented upon admission along with demographic and clinical history. Using shock frozen endarterectomy-derived carotid artery plaques, GLO1-activity as well as protein expression was measured by a spectophotometric assay and western-blotting respectively. RESULTS: 33 patients (76 % male, mean age 71 years) were included into the study and were divided according to treatment with metformin or not (15 vs. 18 patients). GLO1-activity was increased by the factor 1.36 when treated with metformin - however, not significantly (0.86 vs. 0.63 U/mg, p = 0.056). Normalisation of GLO1-activity onto GLO1-expression level lead to a significant increase by more than twofold (8.48 vs. 3.85, p = 0.044) while GLO1-protein levels did not differ significantly. GLO1-activity correlated positively with increasing HbA1c, especially under metformin treatment. CONCLUSIONS: Treatment with metformin in patients with type 2 diabetes is associated with enhanced GLO1-activity in atherosclerotic lesions. Regarding the macro- and microvascular complications in these patients further studies are needed to gain more insight into the effect of metformin on the GLO/MG system.


Assuntos
Aterosclerose , Diabetes Mellitus Tipo 2 , Metformina/uso terapêutico , Idoso , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Humanos , Lactoilglutationa Liase , Masculino , Respeito
12.
Langenbecks Arch Surg ; 403(1): 73-82, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28493145

RESUMO

PURPOSE: The relationship between the body mass index (BMI) of kidney transplant recipients and outcomes after kidney transplantation (KT) is not fully understood and remains controversial. We studied the influence of BMI on clinically relevant outcomes in kidney transplant recipients. METHODS: In this retrospective single-centre study, all patients who underwent kidney transplantation at our institution between January 2007 and December 2012 were included. Demographic data and BMI were correlated with the clinical course of the disease, rejection rates, delayed graft function rates, and graft and patient survival. RESULTS: During the study period, 384 single KTs (130 women and 254 men) were performed. Seventeen percent of the transplants were transplanted within the Eurotransplant Senior Programme (ESP). Most of the transplants were performed using organs that were obtained from donors after brain death (DBD), and living donor kidney transplants were performed in 22.4% of all transplants. The median BMI of the recipients was 25.9 kg/m2. Additionally, 13.5% of the recipients had a BMI of 30-34.9 kg/m2 and 3.9% had a BMI >35 kg/m2. A BMI >30 kg/m2 was significantly associated with primary non-function of the kidney (p = 0.047), delayed graft function (p = 0.008), and a higher rate of loss of graft function (p = 0.015). The glomerular filtration rate 12 months after KT was significantly lower in recipients with a BMI >30 kg/m2. Multivariate analysis revealed that recipient BMI, among other factors, was an independent risk factor for delayed graft function and graft survival. Patients with a BMI >30 kg/m2 had an almost four times higher risk for surgical site infection than did recipients with a lower BMI. CONCLUSIONS: Increased BMI at kidney transplantation is a predictor of adverse outcomes, including delayed graft function. These findings demonstrate the importance of the careful selection of patients and pre-transplant weight reduction, although the role of weight reduction for improving graft function is not clear.


Assuntos
Nefropatias/complicações , Nefropatias/cirurgia , Transplante de Rim/efeitos adversos , Obesidade/complicações , Complicações Pós-Operatórias/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Função Retardada do Enxerto/epidemiologia , Feminino , Taxa de Filtração Glomerular , Rejeição de Enxerto/epidemiologia , Sobrevivência de Enxerto , Humanos , Nefropatias/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
13.
J Cardiovasc Surg (Torino) ; 59(1): 4-13, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28946735

RESUMO

Challenging iliac anatomy is a major limitation of endovascular repair for aortic aneurysms. Stenotic lesions, excessive calcification, tortuosity, and aneurysmal dilatation jeopardize technical success of device implantation and long-term success. This review addresses technical options in treating patients with stenotic or aneurysmatic iliac arteries. Endovascular solutions and hybrid procedures are included to demonstrate the wide scope of endovascular therapy that may be offered to patients with unfavorable iliac anatomy.


Assuntos
Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/cirurgia , Procedimentos Endovasculares , Aneurisma Ilíaco/patologia , Aneurisma Ilíaco/cirurgia , Artéria Ilíaca/patologia , Artéria Ilíaca/cirurgia , Prótese Vascular , Implante de Prótese Vascular , Humanos , Complicações Pós-Operatórias , Fatores de Risco
14.
Mol Med ; 22: 505-518, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27474483

RESUMO

Male sex is a risk factor for abdominal aortic aneurysm (AAA). Within the AAA adventitia, infiltrating leukocytes express high levels of inflammasome components. To further elucidate the role of inflammatory cells in the pathogenesis of AAA, we here addressed expression and functionality of inflammasome components in peripheral blood mononuclear cells (PBMC) of AAA patients in association with sex. PBMC and plasma were isolated from 100 vascular patients, including 34 pairs of AAA patients and age/sex-matched non-AAA patients. Male PBMC were found to express significantly higher mRNA levels of AIM2, NLRP3, ASC (PYCARD), CASP1, CASP5, and IL1B (all P < 0.0001) than female PBMC. Within the male patients, PBMC of AAA patients displayed increased mRNA levels of NLRP3 (P = 0.044), CASP1 (P = 0.032) and IL1B (P = 0.0004) compared to matched non-AAA PBMC, whereas there was no difference between female AAA and non-AAA patients. The relative protein level of NLRP3 was significantly lower in PBMC lysates from all AAA patients than in matched controls (P = 0.038), whereas AIM2 and active Caspase-1 (p10) protein levels were significantly increased (P = 0.014 and P = 0.049). ELISA revealed significantly increased IL-1α (mean = 6.34 vs 0.01 pg/ml) and IL-1ß plasma levels (mean = 12.07 vs. 0.04 pg/ml) in AAA patients. The data indicate that male PBMC display a systemic proinflammatory state with primed inflammasomes that may contribute to AAA-pathogenesis. The AAA-specific inflammasome activation pattern suggests differential regulation of the sensors AIM2 and NLRP3 in inflammatory cells of AAA patients.

15.
Langenbecks Arch Surg ; 401(3): 289-98, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27055854

RESUMO

BACKGROUND: Ruptured abdominal aortic aneurysm (rAAA) represents one of the most challenging emergencies in surgery. Open repair (OR) is associated with relevant morbidity and mortality and has not been reduced significantly over the last decade. The introduction of endovascular aneurysm repair (EVAR) and its meanwhile common use in the treatment of rAAA has raised the demand for randomised controlled trials (RCTs) in order to resolve a potential superiority of either OR or EVAR. PURPOSE: This review discusses the current treatment strategies in rAAA repair including diagnostics, peri-operative management and results of OR and EVAR, focussing on RCTs comparing both modalities. RESULTS: Thirty-day mortality after OR and EVAR shows no significant difference in published RCTs. In particular with respect to OR, 30-day mortality was much lower than anticipated throughout all RCTs ranging from 18 to 37 %. EVAR for rAAA resulted in reduced in-hospital stay. Limitations of all except one RCT are low patient recruitment and exclusion of haemodynamically unstable patients. CONCLUSIONS: OR and EVAR need to be provided for rAAA. Despite lacking evidence, EVAR is the first choice treatment in experienced high-volume vascular centres. Low mortality rates in all RCTs raise the question if aortic surgery should be centralised.


Assuntos
Aneurisma da Aorta Abdominal/cirurgia , Ruptura Aórtica/cirurgia , Implante de Prótese Vascular , Procedimentos Endovasculares , Humanos , Resultado do Tratamento
16.
J Diabetes Res ; 2016: 2981639, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26788517

RESUMO

Objective. Glyoxalase-1 is an enzyme detoxifying methylglyoxal (MG). MG is a potent precursor of advanced glycation endproducts which are regarded to be a key player in micro- and macrovascular damage. Yet, the role of Glo1 in atherosclerosis remains unclear. In this study, the effect of Glo1 on mouse metabolism and atherosclerosis is evaluated. Methods. Glo1 knockdown mice were fed a high fat or a standard diet for 10 weeks. Body weight and composition were investigated by Echo MRI. The PhenoMaster system was used to measure the energy expenditure. To evaluate the impact of Glo1 on atherosclerosis, Glo1(KD) mice were crossed with ApoE-knockout mice and fed a high fat diet for 14 weeks. Results. Glo1 activity was significantly reduced in heart, liver, and kidney lysates derived from Glo1(KD) mice. Yet, there was no increase in methylglyoxal-derived AGEs in all organs analyzed. The Glo1 knockdown did not affect body weight or body composition. Metabolic studies via indirect calorimetry did not show significant effects on energy expenditure. Glo1(KD) mice crossed to ApoE(-/-) mice did not show enhanced formation of atherosclerosis. Conclusion. A Glo1 knockdown does not have major short term effects on the energy expenditure or the formation of atherosclerotic plaques.


Assuntos
Doenças da Aorta/enzimologia , Aterosclerose/enzimologia , Metabolismo Energético , Lactoilglutationa Liase/deficiência , Animais , Doenças da Aorta/genética , Doenças da Aorta/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/genética , Aterosclerose/patologia , Calorimetria Indireta , Dieta Hiperlipídica , Modelos Animais de Doenças , Metabolismo Energético/genética , Predisposição Genética para Doença , Rim/enzimologia , Lactoilglutationa Liase/genética , Fígado/enzimologia , Imageamento por Ressonância Magnética , Masculino , Camundongos Knockout , Miocárdio/enzimologia , Fenótipo , Placa Aterosclerótica , Aldeído Pirúvico/metabolismo
17.
Immun Ageing ; 12: 15, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26448778

RESUMO

BACKGROUND: Chronic low-grade inflammation is considered a driver of many age-related disorders, including vascular diseases (inflammaging). Inhibition of autophagic capacity with ageing was postulated to generate a pro-inflammatory condition via activation of inflammasomes, a group of Interleukin-1 activating intracellular multi-protein complexes. We thus investigated gene expression of inflammasome components in PBMC of 77 vascular patients (age 22-82) in association with age. FINDINGS: Linear regression of real-time qRT-PCR data revealed a significant positive association of gene expression of each of the inflammasome components with age (Pearson correlation coefficients: AIM2: r = 0.245; P = 0.032; NLRP3: r = 0.367; P = 0.001; ASC (PYCARD): r = 0.252; P = 0.027; CASP1: r = 0.296; P = 0.009; CASP5: r = 0.453; P = 0.00003; IL1B: r = 0.247; P = 0.030). No difference in gene expression of AIM2, NLRP3, ASC CASP1, and CASP5 was detected between PBMC of patients with advanced atherosclerosis and other vascular patients, whereas IL1B expression was increased in PBMC of the latter group (P = 0.0005). CONCLUSION: The findings reinforce the systemic pro-inflammatory phenotype reported in elderly by demonstrating an increased phase-1 activation of inflammasomes in PBMC of vascular patients.

18.
Antioxid Redox Signal ; 22(11): 938-50, 2015 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-25647640

RESUMO

AIMS: Mitochondrial thioredoxin reductase (Txnrd2) is a central player in the control of mitochondrial hydrogen peroxide (H2O2) abundance by serving as a direct electron donor to the thioredoxin-peroxiredoxin axis. In this study, we investigated the impact of targeted disruption of Txnrd2 on tumor growth. RESULTS: Tumor cells with a Txnrd2 deficiency failed to activate hypoxia-inducible factor-1α (Hif-1α) signaling; it rather caused PHD2 accumulation, Hif-1α degradation and decreased vascular endothelial growth factor (VEGF) levels, ultimately leading to reduced tumor growth and tumor vascularization. Increased c-Jun NH2-terminal Kinase (JNK) activation proved to be the molecular link between the loss of Txnrd2, an altered mitochondrial redox balance with compensatory upregulation of glutaredoxin-2, and elevated PHD2 expression. INNOVATION: Our data provide compelling evidence for a yet-unrecognized mitochondrial Txnrd-driven, regulatory mechanism that ultimately prevents cellular Hif-1α accumulation. In addition, simultaneous targeting of both the mitochondrial thioredoxin and glutathione systems was used as an efficient therapeutic approach in hindering tumor growth. CONCLUSION: This work demonstrates an unexpected regulatory link between mitochondrial Txnrd and the JNK-PHD2-Hif-1α axis, which highlights how the loss of Txnrd2 and the resulting altered mitochondrial redox balance impairs tumor growth as well as tumor-related angiogenesis. Furthermore, it opens a new avenue for a therapeutic approach to hinder tumor growth by the simultaneous targeting of both the mitochondrial thioredoxin and glutathione systems.


Assuntos
Proliferação de Células , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Mitocôndrias/metabolismo , Neovascularização Patológica/metabolismo , Tiorredoxina Redutase 2/genética , Animais , Células Cultivadas , Técnicas de Silenciamento de Genes , Xenoenxertos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Camundongos , Camundongos Transgênicos , Transplante de Neoplasias , Espécies Reativas de Oxigênio/metabolismo
19.
Biochem Soc Trans ; 42(2): 528-33, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24646273

RESUMO

Glo1 (glyxoalase I) is a cytosolic protein expressed in all mammalian cells. Its physiological function is the detoxification of MG (methylglyoxal), which is a potent precursor of AGEs (advanced glycation end-products). Although the impact of AGEs on different forms of vascular diseases has been intensively investigated, the evidence for the involvement of Glo1 and MG is still scarce. Recently, several studies have provided significant evidence for Glo1 having a protective effect on microvascular complications in diabetic patients, such as retinopathy and nephropathy. Regarding macrovascular complications, especially atherosclerotic lesions, the impact of Glo1 is even less clear. In the present article, we review the latest findings regarding the role of Glo1 and MG in vascular biology and the pathophysiology of micro- and macro-vascular disease.


Assuntos
Aterosclerose/enzimologia , Lactoilglutationa Liase/metabolismo , Doenças Vasculares/enzimologia , Animais , Aterosclerose/metabolismo , Humanos , Doenças Vasculares/metabolismo
20.
Circ Res ; 113(4): 408-17, 2013 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-23770613

RESUMO

RATIONALE: Growing evidence indicates that oxidative stress contributes markedly to endothelial dysfunction. The selenoenzyme glutathione peroxidase 4 (Gpx4) is an intracellular antioxidant enzyme important for the protection of membranes by its unique activity to reduce complex hydroperoxides in membrane bilayers and lipoprotein particles. Yet a role of Gpx4 in endothelial cell function has remained enigmatic. OBJECTIVE: To investigate the role of Gpx4 ablation and subsequent lipid peroxidation in the vascular compartment in vivo. METHODS AND RESULTS: Endothelium-specific deletion of Gpx4 had no obvious impact on normal vascular homeostasis, nor did it impair tumor-derived angiogenesis in mice maintained on a normal diet. In stark contrast, aortic explants from endothelium-specific Gpx4 knockout mice showed a markedly reduced number of endothelial branches in sprouting assays. To shed light onto this apparent discrepancy between the in vivo and ex vivo results, we depleted mice of a second antioxidant, vitamin E, which is normally absent under ex vivo conditions. Therefore, mice were fed a vitamin E-depleted diet for 6 weeks before endothelial deletion of Gpx4 was induced by 4-hydroxytamoxifen. Surprisingly, ≈80% of the knockout mice died. Histopathological analysis revealed detachment of endothelial cells from the basement membrane and endothelial cell death in multiple organs, which triggered thrombus formation. Thromboembolic events were the likely cause of various clinical pathologies, including heart failure, renal and splenic microinfarctions, and paraplegia. CONCLUSIONS: Here, we show for the first time that in the absence of Gpx4, sufficient vitamin E supplementation is crucial for endothelial viability.


Assuntos
Glutationa Peroxidase/deficiência , Glutationa Peroxidase/genética , Trombose/etiologia , Trombose/mortalidade , Deficiência de Vitamina E/complicações , Vitamina E/genética , Animais , Apoptose/fisiologia , Pressão Sanguínea/fisiologia , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Feminino , Glutationa Peroxidase/metabolismo , Frequência Cardíaca/fisiologia , Peroxidação de Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neovascularização Patológica/fisiopatologia , Estresse Oxidativo/fisiologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Trombose/fisiopatologia , Vitamina E/metabolismo , Deficiência de Vitamina E/metabolismo , Deficiência de Vitamina E/fisiopatologia
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