RESUMO
INTRODUCTION: The past 25 years have been witness to a revolution in how vascular care is delivered. The majority of arterial and venous interventions have converted from open surgery to minimally invasive percutaneous endovascular procedures. METHODS: This surgical innovations symposium article reviews current endovascular therapy in multiple vascular beds with a primary focus on carotid artery occlusive disease, aortic pathologies, and lower extremity arterial occlusive disease. Mesenteric arterial occlusive disease and lower extremity venous endovascular therapies are also briefly discussed. Indications for intervention, treatment examples and outcomes analysis are presented. While not reviewed in this article, endovascular therapy has also become first line in the treatment of coronary artery disease, chronic mesenteric arterial occlusive disease, superficial venous reflux, central vein occlusion, and acute venous thrombus intervention when indicated. CONCLUSION: Endovascular therapies are used in all vascular beds to treat the full spectrum of vascular pathologies. Aneurysm disease, atherosclerotic arterial occlusive disease, acute arterial and venous thrombosis, ongoing hemorrhage, and venous reflux are among the issues which can be addressed by endovascular means. The minimally invasive nature of endovascular treatments in what is largely a very co-morbid patient cohort is an attractive method of avoiding major procedural related morbidity and mortality.
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Arteriopatias Oclusivas , Procedimentos Endovasculares , Oclusão Vascular Mesentérica , Humanos , Extremidade Inferior/cirurgia , Resultado do Tratamento , VeiasRESUMO
The thrombospondins (TSPs), multifunctional matricellular proteins, are known mediators of endothelial cell (EC) angiogenesis and apoptosis. TSP-1, an antiangiogenic molecule, is important in the progression of vascular disease, in part by inducing EC apoptosis. TSP-2, although less studied, also induces EC apoptosis and inhibits angiogenesis. The effects of TSP-5 are largely unexplored in ECs, but TSP-5 is believed to be protective against arterial disease. Statin drugs have been shown to have beneficial pleiotropic effects, including decreasing EC apoptosis, increasing angiogenesis, and blocking TSP signaling. We hypothesized TSP-5 will be proangiogenic and antiapoptotic, and statin pretreatment would reverse the proapoptotic and antiangiogenic phenotype of TSP-1 and TSP-2. ECs were exposed to serum-free medium, TSP-1, TSP-2, or TSP-5 with or without fluvastatin pretreatment. Quantitative real-time polymerase chain reaction was performed on 96 apoptosis and 96 angiogenesis-related genes using microfluidic card assays. Angiogenesis was measured using Matrigel assays, while apoptosis was measured by fluorescent caspase assay. TSP-5 suppressed apoptotic genes and had a mixed effect on the angiogenic genes; however, TSP-5 did not alter apoptois but was proangiogenic. Pretreatment with fluvastatin downregulated proapoptotic genes and apoptosis and upregulated proangiogenic genes and angiogenesis. Findings indicate TSP-5 and fluvastatin have a protective effect on ECs, being proangiogenic and reversing the antiangiogenic effects of TSP-1 and TSP-2. In conclusion, TSP-5 and fluvastatin may be beneficial for inducing angiogenesis in the setting of ischemia.
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Apoptose/efeitos dos fármacos , Proteína de Matriz Oligomérica de Cartilagem/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Fluvastatina/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Aorta/citologia , Apoptose/genética , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Neovascularização Fisiológica/genética , Trombospondina 1/farmacologia , Trombospondinas/farmacologia , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND: Frailty predicts poor outcome after vascular surgery. We determined the predictive utility of the modified frailty index (mFI) after first-time revascularization and identified biomarkers of frailty predictive of outcome in veterans with peripheral arterial disease. METHODS: A retrospective study was performed of first-time revascularizations (open surgery [OS] and endovascular surgery [ES]) in male veterans (2003-2016). Preoperative mFI scores were calculated, and serum and nonserum biomarkers of frailty were recorded. The primary endpoint was 2-y incidence of reintervention, amputation, and mortality. Secondary endpoints included 30-day morbidity and readmissions. RESULTS: Four hundred and thirty one patients (OS, n = 188; ES, n = 243), mean age of 66 ± 9 y, and 16 mo of median follow-up were studied. Mean mFI was 0.39 ± 0.16 for OS and 0.38 ± 0.15 for ES (P = 0.43). 30-day complications (adjusted odds ratio, 4.89; 95% confidence interval [CI]: 1.67-14.33) and readmissions (adjusted hazard ratio [aHR] 3.32; 95% CI: 1.16-9.55) were increased in the OS versus ES group when stratified by mFI. Survival analysis showed a correlation between risk of amputation, death, and composite outcome with increasing mFI (P < 0.005) in both groups. Frailty independently predicted major amputation (aHR 2.16; 1.06-4.39), mortality (aHR 2.62; 95% CI: 1.17-5.88), and composite outcome (aHR 1.97; 95% CI: 1.06-3.68) when the groups are combined. Except for absolute neutrophil count, all preoperative lab values correlated with mFI (P < 0.5). Higher albumin was independently associated with lower risk of amputation (aHR: 0.58 [0.36-0.94]) and mortality (aHR: 0.45 [0.25-0.83]); higher hemoglobin predicted limb salvage (aHR 0.7 [0.62-0.84]). CONCLUSIONS: Frailty predicts short- and long-term outcomes after first-time revascularization in veterans. Hypoalbuminemia and anemia are associated with higher mFI and independently predict poor outcome, suggesting albumin and hemoglobin are viable biomarkers of frailty in veterans.
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Procedimentos Endovasculares/mortalidade , Fragilidade/complicações , Doença Arterial Periférica/cirurgia , Complicações Pós-Operatórias/epidemiologia , Idoso , Biomarcadores/sangue , Fragilidade/sangue , Humanos , Masculino , Pessoa de Meia-Idade , New York/epidemiologia , Doença Arterial Periférica/complicações , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Resultado do Tratamento , Veteranos/estatística & dados numéricosRESUMO
BACKGROUND: Thrombospondin-1 (TSP-1) is functionally important to intimal hyperplasia (IH) development. Statin drugs have beneficial pleiotropic effects, including reduced IH; however, the effect of statins on IH in a TSP-1-independent setting is unknown. HYPOTHESIS: Statins will be less effective in attenuating IH after vascular injury in TSP-1-null (Thbs1-/-) mice compared with wild-type (WT) mice. MATERIALS AND METHODS: Carotid artery ligation was performed on WT and Thbs1-/- mice. Each strain was divided into two groups: no statin control or standard chow containing fluvastatin (10 or 40 mg/kg/d). After 28 d, analysis included morphometric analysis and real-time quantitative reverse transcription polymerase chain reaction on the arteries and enzyme-linked immunosorbent assay on plasma (TSP-1 WT, TSP-2 WT, and Thbs1-/-). Comparisons were made by analysis of variance, with P < 0.05 considered significant. RESULTS: In no statin controls, WT mice had more IH than Thbs1-/- mice (0.46 ± 0.09 versus 0.15 ± 0.04). Fluvastatin reduced IH in the WT (0.46 ± 0.09 versus 0.23 ± 0.06), but not in Thbs1-/- groups (0.15 ± 0.04 versus 0.22 ± 0.07). No difference in IH existed between Thbs1-/- no statin controls and fluvastatin WT and Thbs1-/- groups. Statin dose did not affect IH. TSP-1 plasma levels were increased in fluvastatin WT. TSP-2 levels were decreased in fluvastatin WT and elevated in fluvastatin Thbs1-/-. Fluvastatin had no effect on tissue Thbs1 or Thbs2 gene expression. CONCLUSIONS: TSP-1 is necessary for robust IH after arterial injury. Because fluvastatin had no effect on IH in Thbs1-/-, the data suggest that the statin effect on IH may be largely TSP-1 dependent. Both statins and the presence of TSP-1 affect TSP-1 and TSP-2 plasma levels.
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Artérias Carótidas/patologia , Ácidos Graxos Monoinsaturados/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperplasia/prevenção & controle , Indóis/uso terapêutico , Trombospondina 1/metabolismo , Túnica Íntima/patologia , Animais , Biomarcadores/metabolismo , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/metabolismo , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Ácidos Graxos Monoinsaturados/farmacologia , Fluvastatina , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hiperplasia/metabolismo , Indóis/farmacologia , Masculino , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Trombospondina 1/deficiência , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/metabolismoRESUMO
Thrombospondin-1 (TSP-1) is an important regulator of vascular smooth muscle cell (VSMC) physiology and gene expression. MicroRNAs (microRNA), small molecules that regulate protein translation, have emerged as potent regulators of cell function. MicroRNAs have been shown to be involved in intimal hyperplasia, atherosclerosis, and upregulated in the vasculature in diabetes. The purpose of this study was to identify microRNAs regulated by TSP-1 in vascular smooth muscle cells (VSMCs). Human VSMCs were treated for 6 h with basal media or TSP-1 both supplemented with 0.2% FBS. Cells were then snap frozen and RNA extracted. An Affymetrix GeneChip microRNA array analysis was performed in triplicate on three separate collections. Confirmatory qrtPCR was performed. Data were analyzed by ANOVA or t test, with significance set at p < 0.05. MicroRNAs identified were subjected to KEGG pathway analysis using the DIANA tools miRPath online tool. TSP-1 upregulated 22 microRNAs and downregulated 18 microRNAs in VSMCs (p < 0.05). The most upregulated microRNA was miR-512-3p (45.12 fold). The microRNA most downregulated by TSP-1 was miR-25-5p, which was decreased by 9.61. Of note, five members of the mir-17-92 cluster were downregulated. KEGG analysis revealed that thirty-three cellular signaling pathways were impacted by these microRNAs and that nine pathways were relevant to vascular disease. MicroRNAs regulate protein expression at the level of translation and may represent a significant mechanism by which TSP-1 regulates VSMC function. Several of the microRNAs identified have a role in vascular function. The miR-17-92 cluster family, which was found to exhibit reduced expression in this study, is known to be involved in angiogenesis and vascular function. TSP-1 regulates multiple microRNAs in VSMCs adding a new layer of complexity to TSP-1 regulation of VSMC function.
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MicroRNAs/fisiologia , Músculo Liso Vascular/metabolismo , Trombospondina 1/fisiologia , Células Cultivadas , Humanos , Músculo Liso Vascular/citologia , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo RealRESUMO
INTRODUCTION: The thrombospondins (TSPs) are matricellular proteins that exert multifunctional effects by binding cytokines, cell-surface receptors and other proteins. TSPs play important roles in vascular pathobiology and are all expressed in arterial lesions. The differential effects of TSP-1, -2, and -5 represent a gap in knowledge in vascular smooth muscle cell (VSMC) physiology. Our objective is to determine if structural differences of the TSPs imparted different effects on VSMC functions critical to the formation of neointimal hyperplasia. We hypothesize that TSP-1 and -2 induce similar patterns of migration, proliferation and gene expression, while the effects of TSP-5 are different. METHODS: Human aortic VSMC chemotaxis was tested for TSP-2 and TSP-5 (1-40 µg/mL), and compared to TSP-1 and serum-free media (SFM) using a modified Boyden chamber. Next, VSMCs were exposed to TSP-1, TSP-2 or TSP-5 (0.2-40 µg/mL). Proliferation was assessed by MTS assay. Finally, VSMCs were exposed to TSP-1, TSP-2, TSP-5 or SFM for 3, 6 or 24 h. Quantitative real-time PCR was performed on 96 genes using a microfluidic card. Statistical analysis was performed by ANOVA or t-test, with p < 0.05 being significant. RESULTS: TSP-1, TSP-2 and TSP-5 at 20 µg/mL all induce chemotaxis 3.1 fold compared to serum-free media. TSP-1 and TSP-2 induced proliferation 53% and 54% respectively, whereas TSP-5 did not. In the gene analysis, overall, cardiovascular system development and function is the canonical pathway most influenced by TSP treatment, and includes multiple growth factors, cytokines and proteases implicated in cellular migration, proliferation, vasculogenesis, apoptosis and inflammation pathways. CONCLUSIONS AND RELEVANCE: The results of this study indicate TSP-1, -2, and -5 play active roles in VSMC physiology and gene expression. Similarly to TSP-1, VSMC chemotaxis to TSP-2 and -5 is dose-dependent. TSP-1 and -2 induces VSMC proliferation, but TSP-5 does not, likely due conservation of N-terminal domains in TSP-1 and -2. In addition, TSP-1, -2 and -5 significantly affect VSMC gene expression; however, little overlap exists in the specific genes altered. This study further delineates TSP-1, -2 and -5's contributions to processes related to VSMC physiology.
Assuntos
Miócitos de Músculo Liso/fisiologia , Trombospondina 1/fisiologia , Trombospondinas/fisiologia , Proteína de Matriz Oligomérica de Cartilagem/genética , Proteína de Matriz Oligomérica de Cartilagem/farmacologia , Proteína de Matriz Oligomérica de Cartilagem/fisiologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Células Cultivadas , Quimiotaxia/efeitos dos fármacos , Quimiotaxia/fisiologia , Expressão Gênica/efeitos dos fármacos , Humanos , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Neointima/etiologia , Trombospondina 1/genética , Trombospondina 1/farmacologia , Trombospondinas/genética , Trombospondinas/farmacologiaRESUMO
UNLABELLED: Dyslipidemia is a risk factor for intimal hyperplasia (IH). Key to IH is vascular smooth muscle cell (VSMC) migration. Thrombospondin-1 (TSP-1) is a matricellular protein that stimulates VSMC migration. HYPOTHESIS: HDL will inhibit and LDL will augment TSP-1-induced VSMC chemotaxis. VSMC chemotaxis will be inhibited by the HDL moiety, S1P, through the S1PR1 receptor, and augmented by the LDL component, LPA, through the LPAR1 receptor. The goal of this study was to determine the effect of HDL and LDL and their receptors on TSP-1-induced VSMC chemotaxis. For VSMC chemotaxis to TSP-1 cells received the following pretreatments: low (25 µg/ml) or optimal (75 µg/ml) concentration of HDL, S1P, optimal (75 µg/ml) or high (175 µg/ml) concentration of LDL, or LPA. For the receptor studies, VSMCs were transfected with siRNA to S1PR1, S1PR3, LPAR1, LPAR2, LPAR3, or a S1PR2 receptor antagonist. The TSP-1-induced chemotaxis results were (1) HDL (25 µg/ml) or LDL (75 µg/ml) exhibited no effect on chemotaxis; (2) HDL (75 µg/ml) inhibited chemotaxis by 50.9 ± 8 % and S1P by 43.4 ± 11.6 %; (3) LDL (175 µg/ml) augmented chemotaxis by 30 ± 10.4 % and LPA by 25.6 ± 12.3 %; (4) S1PR1 and S1PR3 knockdown and S1PR2 antagonist-treated cells augmented chemotaxis; and (5) LPAR1 and LPAR2 knockdown inhibited and LPAR3 knockdown had no effect on chemotaxis. In conclusion, HDL/S1P inhibits, while LDL/LPA stimulates TSP-1-induced VSMC chemotaxis. The HDL/S1P effect is mediated by the S1PR1-3 receptors. The LDL/LPA effects are mediated by the LPAR1 and LPAR2 receptors, but not LPAR3. Therefore, lipids have significant effects on TSP-1-induced VSMC chemotaxis.
Assuntos
Quimiotaxia/efeitos dos fármacos , Dislipidemias/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Trombospondina 1/farmacologia , Células Cultivadas , Dislipidemias/genética , Dislipidemias/patologia , Humanos , Lipoproteínas HDL/farmacologia , Lipoproteínas LDL/farmacologia , Lisofosfolipídeos/farmacologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Interferência de RNA , Receptores de Ácidos Lisofosfatídicos/genética , Receptores de Ácidos Lisofosfatídicos/metabolismo , Receptores de Lisoesfingolipídeo/genética , Receptores de Lisoesfingolipídeo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esfingosina/análogos & derivados , Esfingosina/farmacologia , Receptores de Esfingosina-1-Fosfato , Fatores de Tempo , TransfecçãoRESUMO
INTRODUCTION: Vascular smooth muscle cells are important in intimal hyperplasia. Thrombospondin-1 is a matricellular protein involved in the vascular injury response. Statins are cholesterol lowering drugs that have beneficial cardiovascular effects. Statis have been shown to inhibit smooth muscle migration through the mevalonate pathway. This effect is thought to be mediated by small G protein Ras and Rho turnover which requires many hours. While many patients undergoing treatment for vascular disease are on statins, many are not. Thus immediate pretreatment with statins before surgery may be beneficial. We hypothesized that statins have effects independent of the mevalonate pathway and thus have an immediate effect. METHODS: Human vascular smooth muscle cells were pretreated for 20 h (long-term) or 20 min (short-term) with fluvastatin, or mevalonolactone plus fluvastatin. Thrombospondin-1-induced migration, activation of p42/p44 extracellular signal-regulated kinase, c-Src, focal adhesion kinase and PI3 kinase was determined. The effect of fluvastatin on thrombospondin-1-induced expression of THBS1, FOS, HAS2 and TGFB2 was examined. RESULTS: Both treatments inhibited thrombospondin-1-induced chemotaxis back to the control group. Mevalonolactone reversed the long-term statin effect by increasing migration but had no effect on the short-term statin response. p42/p44 extracellular signal-regulated kinase was activated by thrombospondin-1 and both treatments augmented activation. Neither treatment affected c-Src activity, but both inhibited focal adhesion kinase and PI3 kinase activity. Only long-term statin treatment inhibited THBS1 expression while both treatments inhibited FOS and TGFB2 expression. Neither treatment affected HAS2. FOS knockdown inhibited thrombospondin-1-induced HAS2 but not TGFß2 gene expression. CONCLUSION: Long-term fluvastatin inhibited thrombospondin-1-induced chemotaxis through the mevalonate pathway while short-term fluvastatin inhibited chemotaxis through an alternate mechanism. Short-term stains have immediate effects independent of the mevalonate pathway. Acute local treatment with statins followed by longer term therapy may limit the vascular response to injury.
RESUMO
Angioplasty causes local vascular injury, leading to the release of thrombospondin-1 (TSP-1), which stimulates vascular smooth muscle cell (VSMC) migration and proliferation, important steps in the development of intimal hyperplasia. Transforming growth factor beta 2 (TGF-ß2) and hyaluronic acid synthase (HAS) are two pro-stenotic genes upregulated in VSMCs by TSP-1. We hypothesized that inhibition of TGF-ß2 or HAS would inhibit TSP-1-induced VSMC migration, proliferation, and TSP-1 signaling. Our data demonstrate that Inhibition of either TGF-ß2 or HAS inhibited TSP-1-induced VSMC migration and proliferation. Activation of ERK 1 was decreased by TGF-ß2 inhibition and unaffected by HAS inhibition. TGF-ß2 and HAS are not implicated in TSP-1-induced thbs1 expression, while they are each implicated in TSP-1-induced expression of their own gene. In summary, TSP-1-induced VSMC migration and proliferation rely on intact TGF-ß2 signaling and HAS function. TSP-1 activation of ERK 1 is dependent on TGF-ß2. These data further expand our understanding of the complexity of TSP-1 cellular signaling and the involvement of TGF-ß2 and HAS.
Assuntos
Quimiotaxia/fisiologia , Glucuronosiltransferase/metabolismo , Miócitos de Músculo Liso/metabolismo , Trombospondina 1/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Angioplastia com Balão/efeitos adversos , Degranulação Celular , Proliferação de Células , Ativação Enzimática , Glucuronosiltransferase/antagonistas & inibidores , Humanos , Hialuronan Sintases , Himecromona/farmacologia , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiologia , Miócitos de Músculo Liso/fisiologia , Transdução de Sinais , Fator de Crescimento Transformador beta2/antagonistas & inibidores , Lesões do Sistema Vascular/metabolismoRESUMO
Sarcoidosis is a chronic granulomatous disorder characterized by unknown etiology, undetermined mechanisms, and non-specific therapies except TNF blockade. To improve our understanding of the pathogenicity and to predict the outcomes of the disease, the identification of new biomarkers and molecular endotypes is sorely needed. In this study, we systematically evaluate the biomarkers identified through Omics and non-Omics approaches in sarcoidosis. Most of the currently documented biomarkers for sarcoidosis are mainly identified through conventional "one-for-all" non-Omics targeted studies. Although the application of machine learning algorithms to identify biomarkers and endotypes from unbiased comprehensive Omics studies is still in its infancy, a series of biomarkers, overwhelmingly for diagnosis to differentiate sarcoidosis from healthy controls have been reported. In view of the fact that current biomarker profiles in sarcoidosis are scarce, fragmented and mostly not validated, there is an urgent need to identify novel sarcoidosis biomarkers and molecular endotypes using more advanced Omics approaches to facilitate disease diagnosis and prognosis, resolve disease heterogeneity, and facilitate personalized medicine.
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Doença Granulomatosa Crônica , Sarcoidose , Humanos , Biomarcadores , Algoritmos , Aprendizado de Máquina , Sarcoidose/diagnóstico , Sarcoidose/genéticaRESUMO
Atherosclerosis is a chronic inflammatory condition of the blood vessel wall that can lead to arterial narrowing and subsequent vascular compromise. Although there are a variety of open and endovascular procedures used to alleviate the obstructions caused by atherosclerotic plaque, blood vessel instrumentation itself can lead to renarrowing of the vessel lumen through intimal hyperplasia, wound contracture, or a combination of the two. While the cell types involved in both atherosclerosis and vessel renarrowing after surgical intervention are largely characterized, current research has shown that components of the extracellular matrix are also important in the pathogenesis of the aforementioned processes. One such component is hyaluronic acid (HA). The objective of this review, therefore, is to examine the involvement of HA in these pathologic processes. Literature on the structure and function of HA was reviewed, with particular attention given to the role of HA in the processes of atherogenesis, intimal hyperplasia, and wound contracture after blood vessel instrumentation. HA interacts with vascular smooth muscle cells (VSMCs), endothelial cells (ECs), and platelets to promote atherogenesis. In particular, VSMCs manufacture large amounts of HA that form "cable-like" structures important for leukocyte adhesion and rolling. Additionally, transmigration of leukocytes across the EC layer is mediated by HA. Platelets cleave large molecules of HA into fragments that up-regulate leukocyte production of chemokines and cytokines. HA also has a role in both intimal hyperplasia and wound contracture, the two processes most responsible for vessel renarrowing after vascular instrumentation. HA has a complex, and sometimes conflicting, role in the pathologic processes of atherogenesis and vessel wall renarrowing after surgical intervention.
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Aterosclerose/etiologia , Reestenose Coronária/etiologia , Ácido Hialurônico/fisiologia , Animais , Aterosclerose/terapia , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/biossíntese , Ácido Hialurônico/química , Hiperplasia/etiologia , Túnica Íntima/patologiaAssuntos
Angioplastia com Balão , Artérias Carótidas/efeitos dos fármacos , Lesões das Artérias Carótidas/tratamento farmacológico , Ácidos Graxos Monoinsaturados/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Indóis/farmacologia , Neointima , Sinvastatina/farmacologia , Administração Oral , Animais , Artérias Carótidas/patologia , Lesões das Artérias Carótidas/etiologia , Lesões das Artérias Carótidas/patologia , Modelos Animais de Doenças , Ácidos Graxos Monoinsaturados/administração & dosagem , Fluvastatina , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hiperplasia , Indóis/administração & dosagem , Masculino , Ratos Sprague-Dawley , Ratos Zucker , Sinvastatina/administração & dosagem , Especificidade da EspécieRESUMO
INTRODUCTION: The Vascular Surgery Board (VSB) of the American Board of Surgery sought to answer the following questions: what is the scope of contemporary vascular surgery practice? Do current vascular surgery residents obtain training that is appropriate for their future career expectations and for successful Board certification? How effectively do practicing vascular surgeons incorporate emerging technologies and procedures into practice? METHODS: We analyzed the operative logs submitted to the VSB by recent vascular surgery residents applying for the Vascular Surgery Qualifying Examination (QE; 2006-2009) or by practicing vascular surgeons applying for the Vascular Surgery Recertification Examination (RE; 1995-2009). The relationship between reported operative experience and performance of the QE and RE was examined. RESULTS: There has been a threefold increase in the mean number of primary cases reported by both RE and QE applicants over the past 15 years and the increase in case volume has been driven largely by an increase in the number of endovascular procedures. Endovascular procedures have been broadly incorporated into the practice of most vascular surgeons applying for recertification. The number of major open surgical cases reported by recent QE applicants has remained unchanged over the period of observation. For QE applicants, the number of endovascular aneurysm repairs (EVARs) has reached a plateau at approximately 50 cases, whereas the mean number of open infrarenal aneurysm repairs has decreased for both QE and RE applicants, reflecting national trends favoring EVAR. There was a significant association between case volume and performance on the QE but not on the RE. CONCLUSION: Over the past 15 years, there has been a significant increase in the total number of operative cases reported to the VSB by both QE and RE applicants. Contrary to popular belief, the volume of major open vascular surgery reported by recent vascular surgery residents has remained relatively stable since 1994. Over the same time period, endovascular procedures have been rapidly incorporated into clinical practice by the majority of vascular surgeons applying for recertification by the VSB. Current vascular surgery residents receive a rich operative experience in both open and endovascular procedures that is reflective of contemporary practice.
Assuntos
Competência Clínica , Educação de Pós-Graduação em Medicina , Procedimentos Endovasculares/educação , Internato e Residência , Procedimentos Cirúrgicos Vasculares/educação , Certificação , Distribuição de Qui-Quadrado , Competência Clínica/estatística & dados numéricos , Educação de Pós-Graduação em Medicina/estatística & dados numéricos , Procedimentos Endovasculares/estatística & dados numéricos , Humanos , Internato e Residência/estatística & dados numéricos , Sistemas de Informação em Salas Cirúrgicas , Sociedades Médicas , Fatores de Tempo , Estados Unidos , Procedimentos Cirúrgicos Vasculares/estatística & dados numéricosRESUMO
BACKGROUND: Thrombospondin-1 (TSP-1) induces vascular smooth muscle cell (VSMC) migration and is important in the development of intimal hyperplasia. HMG-CoA reductase inhibitors, such as lovastatin, reduce the incidence of vascular restenosis after angioplasty by both cholesterol lowering and pleiotropic effects. Inhibition of the mevalonate pathway is largely responsible for these pleiotropic properties. This inhibition prevents isoprenylation of the small G proteins, Rho and Ras, by geranylgeranyl and farnesyl pyrophosphate, respectively. Isoprenylation is required for Ras and Rho activation, which is relevant for cell migration. HYPOTHESIS: Lovastatin inhibits TSP-1-induced VSMC chemotaxis by inhibiting small G proteins via the mevalonate pathway. METHODS: Chemotaxis was assessed using a modified Boyden chamber. Quiescent VSMCs were pretreated with serum free media (SFM), lovastatin with or without mevalonate farnesyl (FTI), geranylgeranyl transferase inhibitors (GGTI), farnesyl transferase inhibitor (FPT), or the Rho kinase inhibitor (Y-27632). Chemoattractants were SFM or TSP-1. Comparisons were made by ANOVA followed by post-hoc testing (P<0.05). The effect of lovastatin on Ras activation was evaluated using cells pretreated with SFM or lovastatin, with or without mevalonate prior to TSP-1 exposure. Western blot for Ras activation was performed. RESULTS: Lovastatin dose-dependently inhibited TSP-1-induced chemotaxis, which was reversed by mevalonate. Mevalonate did not induce chemotaxis independently. FTI and FPT, but not GGTI or Y-27632, inhibited TSP-1-induced Ras activation and TSP-1-induced chemotaxis. Lovastatin inhibition of Ras activation was reversed with mevalonate. CONCLUSION: Ras, not Rho, is relevant for TSP-1-induced VSMC chemotaxis. These data suggest that lovastatin suppresses TSP-1-induced chemotaxis by inhibition of Ras.
Assuntos
Quimiotaxia/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lovastatina/farmacologia , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Trombospondina 1/metabolismo , Animais , Bovinos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ácido Mevalônico/farmacologia , Modelos Animais , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Túnica Íntima/citologia , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/metabolismo , Túnica Média/citologia , Túnica Média/efeitos dos fármacos , Túnica Média/metabolismo , Proteínas ras/metabolismoRESUMO
OBJECTIVE: Diabetes is associated with a more aggressive form of atherosclerosis. Thrombospondin-1 (TSP-1), an extracellular matrix protein, is an acute-phase reactant that induces vascular smooth muscle (VSMC) migration and proliferation in areas of vascular injury and is also up-regulated in VSMCs exposed to hyperglycemia. This study tested the hypothesis that hyperglycemia amplifies the expression of genes induced by TSP-1 in VSMCs. METHODS: Human aortic VSMCs were cultured in Dulbecco Modified Eagle's Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 1% antibiotics. Cells were used between passages three and five. VSMCs were preincubated in DMEM containing 0.2% FBS with 5 mM glucose (normoglycemia), 25 mM glucose (hyperglycemia), 25 mM mannose (osmotic control), TSP-1 (20 microg/mL), 25 mM glucose + TSP-1 (20 microg/mL), or 25 mM mannose + TSP-1 (20 microg/mL). Total RNA was extracted. Microarray analysis was performed and analyzed by analysis of variance. P < .05 was considered significant. Quantitative real-time polymerase chain reaction (rtPCR) was used to confirm selected up-regulated genes. RESULTS: Microarray analysis revealed: (1) hyperglycemia altered 30 genes; (2) TSP-1 altered 212 genes, of which 8 were altered similarly to VSMCs exposed to 25 mM glucose; (3) TSP-1 up-regulated 10 genes associated with atherosclerosis and 4 others with diabetic vascular disease; (4) hyperglycemia combined with TSP-1 altered expression of 2822 genes. The three genes most up-regulated by TSP-1 in a normoglycemic environment were uridine 5'-diphosphoglucose (UDP-glucose) dehydrogenase (UGDH, 127%), transforming growth factor beta-2 (TGFbeta2, 116%), and hyaluronan synthase 2 (HAS2, 113%). Further, TSP-1 altered the expression of genes in 13 canonical pathways; however, when combined with hyperglycemia, 53 canonical pathways were affected. CONCLUSION: Quantitative rtPCR confirmed that genes in several of these pathways for TSP-1 and hyperglycemia combined with TSP-1 were up-regulated. These findings suggest that TSP-1 may be germane to the progression of atherosclerosis and may have a large effect with concurrent hyperglycemia.
Assuntos
Glucose/farmacologia , Hiperglicemia , Músculo Liso Vascular/metabolismo , Trombospondinas/genética , Regulação para Cima/genética , Análise de Variância , Animais , Aterosclerose/genética , Aterosclerose/fisiopatologia , Bovinos , Movimento Celular/genética , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Músculo Liso Vascular/fisiologia , Análise de Sequência com Séries de Oligonucleotídeos , Valores de Referência , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Trombospondinas/metabolismoRESUMO
Intimal hyperplasia (IH) is a pathologic process that leads to restenosis after treatment for peripheral arterial disease. Heat shock protein 90 (HSP90) is a molecular chaperone that regulates protein maturation. Activation of HSP90 results in increased cell migration and proliferation. 17Nallylamino17demethoxygeldanamycin (17AAG) and 17dimethylaminoethylamino17demethoxygeldanamycin (17DMAG) are low toxicity Food and Drug Association approved HSP90 inhibitors. The current study hypothesized that HSP90 inhibition was predicted to reduce vascular smooth muscle cell (VSMC) migration and proliferation. In addition, localized HSP90 inhibition may inhibit postangioplasty IH formation. For proliferation, VSMCs were treated with serumfree media (SFM), 17DMAG or 17AAG. The selected proliferative agents were SFM, platelet derived growth factor (PDGF) or fibronectin. After three days, proliferation was measured. For migration, VSMCs were treated with SFM, 17AAG or 17DMAG with SFM, PDGF or fibronectin as chemoattractants. Balloon injury to the carotid artery was performed in rats. The groups included in the present study were the control, saline control, 17DMAG in 20% pluronic gel delivered topically to the adventitia or intraluminal delivery of 17DMAG. After 14 days, arteries were fixed and sectioned for morphometric analysis. Data was analyzed using ANOVA or a student's ttest. P<0.05 was considered to indicate a statistically significant difference. The results revealed that 17AAG and 17DMAG had no effect on cell viability. PDGF and fibronectin also increased VSMC proliferation and migration. Furthermore, both 17AAG and 17DMAG decreased cell migration and proliferation in all agonists. Topical adventitial treatment with 17DMAG after balloon arterial injury reduced IH. HSP90 inhibitors suppressed VSMC proliferation and migration without affecting cell viability. Topical treatment with a HSP90 inhibitor (DMAG) decreased IH formation after arterial injury. It was concluded that 17DMAG may be utilized as an effective therapy to prevent restenosis after revascularization.
Assuntos
Angioplastia/efeitos adversos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Túnica Íntima/patologia , Animais , Benzoquinonas/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fibronectinas/farmacologia , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Hiperplasia , Lactamas Macrocíclicas/farmacologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Fator de Crescimento Derivado de Plaquetas/farmacologia , Ratos Sprague-DawleyRESUMO
The collapse or compression of a thoracic endograft represents a potentially fatal complication that normally requires endovascular or open surgical correction. We present the first report of a compressed thoracic endograft that spontaneously re-expanded without surgical or endovascular intervention. The possible mechanism for the compression and re-expansion of the endograft will be discussed. The unique behavior of this endograft offers insight into an important failure modality for thoracic endografts.
Assuntos
Acidentes de Trânsito , Aorta Torácica/lesões , Aorta Torácica/cirurgia , Implante de Prótese Vascular/instrumentação , Prótese Vascular , Falha de Prótese , Ferimentos não Penetrantes/cirurgia , Angioplastia com Balão/instrumentação , Aorta Torácica/diagnóstico por imagem , Aortografia/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Pressão , Desenho de Prótese , Stents , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Recusa do Paciente ao Tratamento , Ferimentos não Penetrantes/diagnóstico por imagem , Ferimentos não Penetrantes/etiologiaRESUMO
Pulmonary embolism remains an endemic challenge for public health care. The first line of treatment for venous thromboembolic disorder has been anticoagulation; however, in the absence of appropriate pharmacologic treatment, because of failure or contraindication, caval filter placement has been widely performed in the prevention of pulmonary embolism. Initially an open surgical procedure, technological advancements have allowed filter placement to be done percutaneously. Bedside filter placement in the intensive care unit with ultrasonographic imaging has been reported to be safe, effective, and reliable. In this report, we present an example, discuss our technique, and review the literature.
Assuntos
Cateterismo Periférico/instrumentação , Sistemas Automatizados de Assistência Junto ao Leito , Embolia Pulmonar/prevenção & controle , Ultrassonografia Doppler Dupla , Filtros de Veia Cava , Veia Cava Inferior/diagnóstico por imagem , Tromboembolia Venosa/terapia , Acidentes de Trânsito , Estado Terminal , Humanos , Masculino , Veículos Off-Road , Embolia Pulmonar/etiologia , Resultado do Tratamento , Ultrassonografia de Intervenção , Tromboembolia Venosa/complicações , Tromboembolia Venosa/diagnóstico por imagem , Adulto JovemRESUMO
The American Board of Surgery (ABS) has more than 80 years of both direct and indirect involvement in US surgical education, with its primary role being certification of graduates of Accreditation Council for Graduate Medical Education-approved surgical training programs. The ABS's impact on education has been at multiple levels, including the development of the content and administration of qualifying and certifying examinations; original education research based on the Board's unique data sets; and surgical training and education-related initiatives in partnership with multiple regulatory bodies and surgical societies. Within these efforts, by incremental steps, the specialty of vascular surgery attained recognition as a primary specialty of the ABS, and the Vascular Surgery Board of the ABS was established 20 years ago, in 1998. The 2 decades that followed have witnessed significant transformations in the evaluation and treatment of vascular disease, the paradigms for training vascular and endovascular surgeons, and the Vascular Surgery Board has partnered with stakeholder organizations to continually ensure quality education for the evolving vascular surgical workforce. Looking forward, while surgical education remains outside of its primary mission, the ABS and Vascular Surgery Board will continue as key stakeholders and leaders in the complex network of professional societies and training institutions that will guide the evolution of vascular surgery training.
Assuntos
Educação de Pós-Graduação em Medicina/métodos , Conselhos de Especialidade Profissional , Cirurgiões/educação , Procedimentos Cirúrgicos Vasculares/educação , Competência Clínica , Currículo , Educação de Pós-Graduação em Medicina/história , Educação de Pós-Graduação em Medicina/normas , História do Século XX , História do Século XXI , Humanos , Conselhos de Especialidade Profissional/história , Conselhos de Especialidade Profissional/normas , Cirurgiões/história , Cirurgiões/normas , Estados Unidos , Procedimentos Cirúrgicos Vasculares/história , Procedimentos Cirúrgicos Vasculares/normasRESUMO
INTRODUCTION: Oral statins reduce intimal hyperplasia (IH) after arterial injury by only â¼25%. Alternative drug delivery systems have gained attention as carriers for hydrophobic drugs. We studied the effects of simvastatin (free vs hyaluronic acid-tagged polysialic acid-polycaprolactone micelles) on vascular smooth muscle cell (VSMC) migration, VSMC proliferation and intimal hyperplasia. We hypothesized both free and micelle containing simvastatin would inhibit VSMC chemotaxis and proliferation, and local statin treatment would be more effective than oral in reducing IH in rats following carotid balloon injury. METHODS: VSMCs pretreated with free simvastatin (20 minutes or 20 hours) or simvastatin-loaded micelles underwent chemotaxis and proliferation to platelet-derived growth factor. Next, rats that underwent balloon injury of the common carotid artery received statin therapy-intraluminal simvastatin-loaded micelles prior to injury, periadventitial pluronic gel following injury, or combinations of gel, micelle, and oral simvastatin. After 14 days, morphometric analysis determined the -intimal to medial ratio. Findings were compared to controls receiving oral simvastatin or no statin therapy. Statistical analysis was by analysis of variance for the in vitro experiments and a factorial general linear model for the in vivo experiments. RESULTS: The simvastatin-loaded micelles and free simvastatin inhibited VSMC chemotaxis (54%-60%). IH was induced in all injured vessels. Simvastatin in pluronic gel or micelles reduced IH compared to untreated controls (0.208 ± 0.04 or 0.160 ± 0.03 vs 0.350 ± 0.03, respectively); however, neither gel nor simvastatin-loaded micelles were superior to oral statins (0.261 ± 0.03). Addition of oral statins or combining both local therapies did not provide additional benefit. Micelles were the single greatest contributing factor in IH attenuation. CONCLUSIONS: Intraluminally or topically delivered statins reduced IH. The efficacy of single-dose, locally delivered statin alone may lead to novel treatments to prevent IH. The different routes of administration may allow for treatment during endovascular procedures, without the need for systemic therapy.