RESUMO
BACKGROUND & AIMS: Development of the portal-hypertensive syndrome is mediated by splanchnic inflammation and neoangiogenesis. Since peroxisome proliferator-activated receptor gamma (PPARγ) agonists like pioglitazone (PIO) regulate inflammatory response and inhibit angiogenesis in endothelial cells, we evaluated PIO as treatment for experimental portal hypertension. METHODS: PIO (10 mg/kg) or vehicle (VEH) was administered from day 21-28 after bile duct ligation (BDL), from day 0-7 after partial portal vein ligation (PPVL) or sham-operation (SO), respectively. After treatment, systemic hemodynamics, splanchnic blood flow (SMABF), portal pressure (PP), and portosystemic shunting (PSS) were assessed. Splanchnic and hepatic tissues were analyzed for angiogenic and inflammatory markers. RESULTS: BDL and PPVL showed significantly increased PP, SMABF, and PSS compared to SO-VEH rats. While PIO treatment did not decrease PP or SMABF, PSS was significantly reduced both in cirrhotic (BDL-VEH: 71% to BDL-PIO: 41%; p<0.001) and non-cirrhotic (PPVL-VEH: 62% to PPVL-PIO: 40%; p=0.041) rats. PIO (10 µM, in vitro) inhibited endothelial cell migration and significantly increased PPARγ activity in vivo. In BDL rats, PIO decreased hepatic mRNA levels of PPARγ (p=0.01) and PlGF (p=0.071), and splanchnic mRNA expression of PPARγ (p=0.017), PDGFß (p=0.053) and TNFα (p=0.075). Accordingly, splanchnic protein expression of PPARγ (p=0.032), VEGFR2 (p=0.035), CD31 (p=0.060) and PDGFß (p=0.066) were lower in BDL-PIO vs. BDL-VEH animals. In PPVL rats, PIO treatment decreased splanchnic gene expression of Ang2 (-12.4 fold), eNOS (-9.3 fold), PDGF (-7.0 fold), PlGF (-11.9 fold), TGFb (-8.3 fold), VEGF-A (-11.3 fold), VEGFR1 (-5.9 fold), IL1b (-14.4 fold), and IL6 (-9.6 fold). CONCLUSIONS: Pioglitazone treatment decreases portosystemic shunting via modulation of splanchnic inflammation and neoangiogenesis. Pioglitazone should be assessed for potential beneficial effects in patients with portosystemic collaterals due to portal hypertension.
Assuntos
Hipertensão Portal/tratamento farmacológico , Cirrose Hepática Experimental/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Pressão na Veia Porta/efeitos dos fármacos , Tiazolidinedionas/farmacologia , Animais , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Modelos Animais de Doenças , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipertensão Portal/imunologia , Hipertensão Portal/fisiopatologia , Hipoglicemiantes/farmacologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/fisiopatologia , Circulação Hepática/efeitos dos fármacos , Circulação Hepática/fisiologia , Cirrose Hepática Experimental/imunologia , Cirrose Hepática Experimental/fisiopatologia , Masculino , Neovascularização Patológica/imunologia , Neovascularização Patológica/fisiopatologia , PPAR gama/metabolismo , Pioglitazona , Pressão na Veia Porta/fisiologia , Ratos Sprague-Dawley , Circulação Esplâncnica/efeitos dos fármacos , Circulação Esplâncnica/imunologia , Circulação Esplâncnica/fisiologiaRESUMO
BACKGROUND: We evaluated the effects of nebivolol, a third generation beta-blocker capable of increasing NO-bioavailability on portal pressure, and on splachnic and systemic haemodynamics in a cirrhotic portal hypertensive rat model. METHODS: Male Sprague-Dawley rats underwent sham operation (SO) or bile duct ligation (BDL). When cirrhosis was fully developed, the animals were orally treated with low-dose (5 mg/kg) or high-dose (10 mg/kg) nebivolol (NEBI) or vehicle (VEH) for 7 days. Heart rate (HR), mean arterial pressure (MAP), portal pressure (PP) and superior mesenteric artery blood flow (SMABF) were measured. Portosystemic collateral blood flow (PSCBF) was quantified using radioactive microspheres. Hepatic and splanchnic NOx levels and GSH/GSSG ratios (RedOx state) were determined using commercially available kits. RESULTS: BDL-VEH rats showed increased HR, PP and PSCBF, whereas MAP was decreased compared to SO-VEH rats. Nebivolol significantly reduced HR both in SO (P < 0.001) and BDL (P < 0.001) rats. BDL-NEBI animals had significantly higher PP (15.5 vs. 12.6 mmHg; P = 0.006) and SMABF (5.3 vs. 3.7 ml/min/100g; P = 0.016) than BDL-VEH animals. The increase in PP and SMABF was noted both in low-dose and high-dose BDL-NEBI rats. While no beneficial effects on hepatic RedOx state were observed, splanchnic NOx levels were significantly increased by NEBI treatment in a dose-dependent manner. Nebivolol treatment did not affect PSCBF in SO and BDL animals. CONCLUSION: Nebivolol increases portal pressure in cirrhotic animals by increasing splanchnic blood flow via modulation of NO signalling. Portosystemic collateral blood flow remained unchanged. These data do not support the use of nebivolol for treatment of cirrhotic patients with portal hypertension.
Assuntos
Antagonistas Adrenérgicos beta/toxicidade , Benzopiranos/toxicidade , Etanolaminas/toxicidade , Hipertensão Portal/etiologia , Cirrose Hepática Experimental/tratamento farmacológico , Artéria Mesentérica Superior/efeitos dos fármacos , Óxido Nítrico/metabolismo , Pressão na Veia Porta/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Circulação Esplâncnica/efeitos dos fármacos , Administração Oral , Antagonistas Adrenérgicos beta/administração & dosagem , Animais , Benzopiranos/administração & dosagem , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Circulação Colateral/efeitos dos fármacos , Ducto Colédoco/cirurgia , Relação Dose-Resposta a Droga , Etanolaminas/administração & dosagem , Glutationa/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Hipertensão Portal/metabolismo , Hipertensão Portal/fisiopatologia , Ligadura , Fígado/irrigação sanguínea , Fígado/efeitos dos fármacos , Fígado/metabolismo , Circulação Hepática/efeitos dos fármacos , Cirrose Hepática Experimental/complicações , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/fisiopatologia , Masculino , Artéria Mesentérica Superior/metabolismo , Artéria Mesentérica Superior/fisiopatologia , Nebivolol , Oxirredução , Ratos , Ratos Sprague-Dawley , Regulação para CimaRESUMO
BACKGROUND/AIMS: Angiogenesis plays a key role in development of portal hypertension (PHT) and represents a potential therapeutic target. We aimed to evaluate the molecular effects of sorafenib, a multiple tyrosine kinase inhibitor, on splanchnic hemodynamics in rats with partial portal vein ligation (PPVL). METHODS: The following four groups of rats were treated orally with sorafenib (10mg/kg per day; SORA group) or placebo (PLAC group) for 7 days, beginning at the day of PPVL or sham operation (SO): (1) PPVL-SORA, (2) PPVL-PLAC, (3) SO-SORA and (4) SO-PLAC. Measurements of mean arterial pressure (MAP), portal pressure (PP), and superior mesenterial artery blood flow (SMABF) were performed. Portosystemic collateral blood flow (PSCBF) was determined by radioactive microspheres. Splanchnic protein expression of CD31, alpha-smooth muscle actin (alphaSMA), phospho-extracellular signal-regulated kinase (pERK), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), tumor necrosis factor alpha (TNFalpha), and endothelial nitric oxide synthetase (eNOS) was assessed by Western blot. Gene expression was studied by angiogenesis-focused real-time reverse transcription polymerase chain reaction microarray. RESULTS: PP, SMABF, and PSCBF were significantly higher in PPVL rats than in SO rats. MAP and heart rate were similar in all groups. Treatment with sorafenib resulted in a significant decrease of PP (p<0.001) and SMABF (p<0.05) in PPVL-SORA rats compared to PPVL-PLAC rats. PPVL-SORA rats had markedly less PSCBF than PPVL-PLAC rats (p<0.001). Superior mesenteric artery resistance (SMAR) was significantly lower in both PPVL groups compared to both SO groups, but PPVL-SORA rats showed significantly higher SMAR than PPVL-PLAC rats (p<0.05). The increased protein expression of CD31, alphaSMA, pERK, VEGF, PDGF, TNFalpha, and eNOS in rats with PHT was markedly decreased by sorafenib treatment. Sorafenib decreased mRNA levels of TNFalpha, VEGF receptor 2, VEGF receptor 1, transforming growth factor beta, cyclooxygenase 1, and expression of various genes that are involved in pathways of cellular proliferation, fibrogenesis, tissue remodeling, inflammation, and angiogenesis. CONCLUSIONS: Treatment with sorafenib reduced PP, SMABF, and PSCBF in noncirrhotic rats with prehepatic PHT, without affecting systemic hemodynamics. Additional antiproliferative, anti-inflammatory, and antiangiogenic effects of sorafenib were identified.
Assuntos
Benzenossulfonatos/uso terapêutico , Hipertensão Portal/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Animais , Proliferação de Células/efeitos dos fármacos , Citocinas/genética , Regulação para Baixo/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Hipertensão Portal/etiologia , Hipertensão Portal/genética , Hipertensão Portal/fisiopatologia , Ligadura , Masculino , Neovascularização Patológica/prevenção & controle , Niacinamida/análogos & derivados , Óxido Nítrico Sintase Tipo III/metabolismo , Compostos de Fenilureia , Veia Porta , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Sorafenibe , Circulação Esplâncnica/efeitos dos fármacosRESUMO
BACKGROUND/AIMS: Budd-Chiari syndrome (BCS) mainly affects women of childbearing age. We aimed to clarify whether pregnancy, a thrombotic risk factor, should be contraindicated in patients with known and treated BCS. METHODS: A retrospective study of pregnancy in women with known and treated BCS. RESULTS: Sixteen women had 24 pregnancies. Nine women had undergone surgical or radiological treatment. Anticoagulation was administered during 17 pregnancies. Seven fetuses were lost before gestation week 20. Deliveries occurred between week 20 and 31 in two patients, week 32 and 36 in eleven and after week 37 in four. There was one stillbirth, but 16 infants did well. Factor II gene mutation was a factor for a poor outcome of pregnancies. In two patients, symptomatic thrombosis recurred during pregnancy or postpartum. All patients were alive after a median follow-up of 34 months after the last delivery. Bleeding at delivery, although non-lethal, occurred only on anticoagulation therapy. CONCLUSIONS: When known and treated BCS is well controlled, pregnancy should not be contraindicated as maternal outcome, and fetal outcome beyond gestation week 20, are good. The risk-benefit ratio of anticoagulant therapy needs to be further clarified. Patients should be fully informed of the persistent risks of such pregnancies.
Assuntos
Síndrome de Budd-Chiari/complicações , Complicações na Gravidez , Adolescente , Adulto , Anticoagulantes/uso terapêutico , Síndrome de Budd-Chiari/terapia , Feminino , Humanos , Pessoa de Meia-Idade , Gravidez , Complicações na Gravidez/terapia , Resultado da Gravidez , Estudos RetrospectivosRESUMO
BACKGROUND AND AIMS: Transjugular intrahepatic portosystemic shunts (TIPS) are used in patients with cirrhosis for the prevention of variceal rebleeding. METHODS: We retrospectively evaluated re-bleeding rate, patency, mortality, and transplant-free survival (TFS) in cirrhotic patients receiving TIPS implantation for variceal bleeding between 1994-2014. RESULTS: 286 patients received TIPS (n = 119 bare metal stents, n = 167 polytetrafluorethylene (PTFE)-covered stents) for prevention of variceal re-bleeding. Mean age was 55.1 years, median MELD was 11.8, and the main etiology of cirrhosis was alcoholic liver disease (70%). Median follow-up was 821 days. 67 patients (23%) experienced at least one re-bleeding event. Patients with PTFE-TIPS were at significantly lower risk for variceal re-bleeding than patients with bare metal stents (14% vs. 37%, OR:0.259; p<0.001) and had less need for stent revision (21% vs. 37%; p = 0.024). Patients with PTFE stent grafts showed lower mortality than patients with bare stents after 1 year (19% vs. 31%, p = 0.020) and 2 years (29% vs. 40%; p = 0.041) after TIPS implantation. Occurrence of hepatic encephalopathy after TIPS was similar between groups (20% vs. 24%, p = 0.449). CONCLUSIONS: PTFE-TIPS were more effective at preventing variceal re-bleeding than bare metal stents due to better patency. Since this tended to translate in improved survival, only covered stents should be implemented for bleeding prophylaxis when TIPS is indicated.
Assuntos
Varizes Esofágicas e Gástricas/complicações , Hemorragia Gastrointestinal/prevenção & controle , Derivação Portossistêmica Transjugular Intra-Hepática , Adulto , Idoso , Feminino , Hemorragia Gastrointestinal/etiologia , Humanos , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de SobrevidaRESUMO
BACKGROUND: Early implantation (<72h) of a transjugular intrahepatic portosystemic shunt (TIPS) after acute variceal bleeding (AVB) improves survival in highly selected patients. METHODS: We retrospectively assessed bleeding control and survival of unselected cirrhotic patients undergoing early TIPS implantation within 72h. We compared the outcomes to patients meeting early TIPS criteria but receiving late TIPS within 3-28days after AVB and endoscopic/medical treatment. RESULTS: Forty-nine patients were included. Mean MELD was 14.4 (±4.4). Thirteen patients (26.5%) presented characteristics that were exclusion criteria in previous early TIPS trials (age>75, CPS>13, HCC>Milan, previous beta-blocker/band-ligation, renal insufficiency). Bare metal and PTFE-covered stents were used in n=32 (65.3%) and n=17 (34.7%) patients, respectively, and showed similar early re-bleeding rates (9.9% vs. 7.1%; p=0.6905) and bleeding-related mortality (25.0% vs. 23.5%; p=0.9906). However, overall re-bleeding rate was lower with PTFE-TIPS (7.7% vs. 64.2%; p=0.0044) over a median follow-up of 18.5 months with a tendency towards improved survival (median 70.5 vs. 13.8 months; p=0.204). Additional 68 patients meeting stringent criteria but receiving late TIPS also showed a favorable bleeding-related mortality (8.8%), which was not achieved in similar n=34 patients by a medical/endoscopic strategy with bleeding-related mortality of 35.7%. CONCLUSIONS: An early TIPS strategy using covered stents and implementation of 'stringent criteria' results in a favorable outcome in patients with acute variceal bleeding.
Assuntos
Varizes Esofágicas e Gástricas/complicações , Hemorragia Gastrointestinal/mortalidade , Hipertensão Portal/etiologia , Cirrose Hepática/cirurgia , Derivação Portossistêmica Transjugular Intra-Hepática/efeitos adversos , Áustria , Varizes Esofágicas e Gástricas/etiologia , Feminino , Hemorragia Gastrointestinal/etiologia , Humanos , Ligadura , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Stents , Resultado do TratamentoRESUMO
Portal hypertension is an almost unavoidable complication of cirrhosis, and it is responsible for the more lethal complications of this syndrome. Appearance of these complications represents the major cause of death and liver transplantation in patients who have cirrhosis. This article highlights treatment modalities in use for managing portal hypertension and those that may be available in the future.
Assuntos
Hipertensão Portal/terapia , Varizes Esofágicas e Gástricas/etiologia , Varizes Esofágicas e Gástricas/prevenção & controle , Varizes Esofágicas e Gástricas/terapia , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/prevenção & controle , Hemorragia Gastrointestinal/terapia , Humanos , Hipertensão Portal/complicações , Hipertensão Portal/tratamento farmacológico , Derivação Portossistêmica Transjugular Intra-Hepática , RecidivaRESUMO
Implantation of a transjugular intrahepatic portosystemic shunt (TIPS) for therapy of portal hypertension has been available in Vienna, Austria, since 1991. Ten years of experience with this technique led the Vienna TIPS Study Group to retrospectively analyse characteristics and outcome of all patients undergoing TIPS in Vienna between 1991 and 2001. Survival and subgroup analyses were performed using Mann Whitney U-tests, log-rank tests, Spearman's correlation and Kaplan-Meier analyses. A total of 523 patients underwent TIPS; 23 for acute variceal bleeding, 350 for prevention of variceal bleeding, and 109 for therapy of refractory ascites. Portal hypertension was caused by cirrhosis in 503 patients; 20 presented with other diseases. 253 patients died within the study period, median follow-up was 5.07 years, median survival 4.51 years. The 3-month, 1-year, 3-year, and 5-year survival rates were 83%, 71%, 57%, and 49%, respectively. Etiology of cirrhosis had no effect on survival; patients with TIPS for refractory ascites had poorer survival rates than those undergoing TIPS for prevention of rebleeding. TIPS is a safe and effective therapy for patients with portal hypertension. The first decade of TIPS in Vienna has shown, in line with other publications, that good criteria for patient selection, effective post-interventional management, and close cooperation between internists, interventional radiologists and liver-transplant centers are the key for a good outcome.
Assuntos
Derivação Portossistêmica Transjugular Intra-Hepática , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ascite/terapia , Criança , Pré-Escolar , Interpretação Estatística de Dados , Varizes Esofágicas e Gástricas/complicações , Feminino , Seguimentos , Hemorragia Gastrointestinal/prevenção & controle , Hemorragia Gastrointestinal/terapia , Humanos , Hipertensão Portal/complicações , Lactente , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Estudos Retrospectivos , Fatores de TempoRESUMO
In November 2004, the Austrian Society of Gastroenterology and Hepatology (ÖGGH) held for the first time a consensus meeting on the definitions and treatment of portal hypertension and its complications in the Billroth-Haus in Vienna, Austria (Billroth I-Meeting). This meeting was preceded by a meeting of international experts on portal hypertension with some of the proponents of the Baveno consensus conferences (http://www.oeggh.at/videos.asp). The consensus itself is based on the Baveno III consensus with regard to portal hypertensive bleeding and the suggestions of the International Ascites Club regarding the treatment of ascites. Those statements were modified by new knowledge derived from the recent literature and also by the current practice of medicine as agreed upon by the participants of the consensus meeting. In October 2011, the ÖGGH organized the second consensus meeting on portal hypertension and its complications in Vienna (Billroth II-Meeting). The Billroth II-Guidelines on the definitions and treatment of portal hypertension and its complications take into account the developments of the last 7 years, including the Baveno-V update and several key publications.
Assuntos
Varizes Esofágicas e Gástricas/diagnóstico , Varizes Esofágicas e Gástricas/terapia , Gastroenterologia/normas , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/terapia , Hipertensão Portal/diagnóstico , Hipertensão Portal/terapia , Varizes Esofágicas e Gástricas/etiologia , Hemorragia Gastrointestinal/etiologia , Humanos , Hipertensão Portal/complicaçõesRESUMO
This article overviews principles of portal hypertension and the role of implantation of a transjugular intrahepatic postosystemic shunt (TIPS) in its management. Since TIPS is available for over 30 years, technical achievements have been made and knowledge about indications, contraindications and patient selection has been improved. Recent studies and guidelines may lead to an increase in TIPS implantation rates. This review aims to commemorate the merits and demerits of TIPS in current clinical practice.
Assuntos
Síndrome de Budd-Chiari/terapia , Hipertensão Portal/terapia , Derivação Portossistêmica Transjugular Intra-Hepática , Varizes Esofágicas e Gástricas/etiologia , Varizes Esofágicas e Gástricas/terapia , Humanos , Hipertensão Portal/etiologia , Hepatopatias/complicações , Pressão na Veia Porta , Derivação Portossistêmica Transjugular Intra-Hepática/métodosRESUMO
PURPOSE: Hypoxic hepatitis (HH) is a form of hepatic injury following arterial hypoxemia, ischemia, and passive congestion of the liver. We investigated the incidence and the prognostic implications of HH in the medical intensive care unit (ICU). METHODS: A total of 1,066 consecutive ICU admissions at three medical ICUs of a university hospital were included in this prospective cohort study. All patients were screened prospectively for the presence of HH according to established criteria. Independent risk factors of mortality in this cohort of critically ill patients were identified by a multivariate Poisson regression model. RESULTS: A total of 118 admissions (11%) had HH during their ICU stay. These patients had different baseline characteristics, longer median ICU stay (8 vs. 6 days, p < 0.001), and decreased ICU survival (43 vs. 83%, p < 0.001). The crude mortality rate ratio of admissions with HH was 4.62 (95% CI 3.63-5.86, p < 0.001). Regression analysis demonstrated strong mortality risk for admissions with HH requiring vasopressor therapy (adjusted rate ratio 4.91; 95% CI 2.51-9.60, p < 0.001), whereas HH was not significantly associated with mortality in admissions without vasopressor therapy (adjusted rate ratio 1.79, 95% CI 0.52-6.23, p = 0.359). CONCLUSIONS: Hypoxic hepatitis (HH) occurs frequently in the medical ICU. The presence of HH is a strong risk factor for mortality in the ICU in patients requiring vasopressor therapy.
Assuntos
Hepatite/mortalidade , Hipóxia/mortalidade , Unidades de Terapia Intensiva/estatística & dados numéricos , Vasoconstritores/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Áustria/epidemiologia , Atestado de Óbito , Hepatite/tratamento farmacológico , Hepatite/etiologia , Hepatite/fisiopatologia , Humanos , Hipóxia/complicações , Hipóxia/tratamento farmacológico , Hipóxia/fisiopatologia , Tempo de Internação/estatística & dados numéricos , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Estudos Prospectivos , Análise de Regressão , Fatores de Risco , Taxa de Sobrevida , Vasoconstritores/uso terapêutico , Adulto JovemRESUMO
PURPOSE: Hypoxic hepatitis (HH) is a frequent cause of acute hepatocellular damage at the intensive care unit. Although mortality is reported to be high, risk factors for mortality in this population are unknown. METHODS: One-hundred and seventeen consecutive patients with HH were studied prospectively at three medical intensive care units of a university hospital. RESULTS: The main causes of hypoxic hepatitis were low cardiac output and septic shock, and most patients (74%) had more than one underlying factor. Peak aspartate transaminase (P = 0.02), lactate dehydrogenase (P = 0.03), INR (P < 0.001) and lactate (P < 0.01) were higher in non-survivors. Prolonged duration of HH caused higher overall mortality rate (P = 0.03). INR > 2 (P = 0.02), septic shock (P = 0.01) and SOFA score >10 (P = 0.04) were risk factors of mortality in the regression model. CONCLUSIONS: Hypoxic hepatitis is the consequence of multiorgan injury. Outcome is influenced by the severity of liver impairment and the etiology and severity of the basic disease.
Assuntos
Hepatite/mortalidade , Hipóxia/mortalidade , Idoso , Áustria/epidemiologia , Estado Terminal/mortalidade , Feminino , Hepatite/etiologia , Hepatite/fisiopatologia , Hospitais Universitários , Humanos , Hipoglicemia , Hipóxia/etiologia , Hipóxia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Choque SépticoRESUMO
BACKGROUND: Recent studies have shown the presence of vascular endothelial growth factor (VEGF)-dependent splanchnic angiogenesis in experimental models of portal hypertension, and the role of such neovascularisation on the development of both portosystemic collaterals and hyperdynamic splanchnic circulation. However, the mechanisms modulating angiogenesis in portal hypertension are unknown. Experimental evidence indicates that NAD(P)H oxidase is required for VEGF-induced angiogenesis. Interestingly, we have recently shown that splanchnic NAD(P)H oxidase activity is significantly increased in portal hypertensive rats. Therefore, it could be possible that activated NAD(P)H oxidases modulate angiogenesis in portal hypertension. AIM: To determine the effects of chronic NAD(P)H oxidase inhibition on angiogenesis and splanchnic haemodynamics in portal hypertensive rats. METHODS: Partial portal vein-ligated and sham-operated rats were treated with the NAD(P)H oxidase inhibitor apocynin, or with vehicle for 5 days. Then, the expression of angiogenesis markers (western blotting), the formation of portosystemic collaterals (radioactive microspheres) and the production of superoxide anion (lucigenin-enhanced chemiluminescence) were determined. Mean arterial pressure, portal pressure, and superior mesenteric arterial blood flow and resistance were also measured. RESULTS: In portal hypertensive rats, NAD(P)H oxidase blockade significantly decreased portosystemic collateral formation, and superior mesenteric arterial flow. It also reduced the splanchnic expression of VEGF, VEGF receptor-2 and CD31, and attenuated the increased production of superoxide, compared with vehicle. CONCLUSIONS: NAD(P)H oxidase plays an important role in experimental portal hypertension, modulating splanchnic angiogenesis, the formation of portosystemic collaterals and the development of splanchnic hyperdynamic circulation. These results suggest that NAD(P)H oxidase may represent a new target in the treatment of portal hypertension.
Assuntos
Hiperemia/enzimologia , Hipertensão Portal/enzimologia , NADPH Oxidases/fisiologia , Neovascularização Patológica/enzimologia , Circulação Esplâncnica , Acetofenonas/farmacologia , Indutores da Angiogênese/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Circulação Colateral/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Hiperemia/fisiopatologia , Hiperemia/prevenção & controle , Hipertensão Portal/patologia , Hipertensão Portal/fisiopatologia , Masculino , Artéria Mesentérica Superior/fisiopatologia , NADPH Oxidases/antagonistas & inibidores , Neovascularização Patológica/fisiopatologia , Neovascularização Patológica/prevenção & controle , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/efeitos dos fármacos , Circulação Esplâncnica/efeitos dos fármacos , Superóxidos/metabolismoRESUMO
BACKGROUND/AIMS: The pathophysiological significance of heme oxygenase-1 up-regulation in portal hypertension is not completely understood. In this study, we determined the role of heme oxygenase-1 on oxidative stress, inflammation, angiogenesis, and splanchnic hemodynamics in rats with portal hypertension induced by partial portal vein ligation. METHODS: Rats were treated with the heme oxygenase inhibitor SnMP or vehicle for 7 days. Then, oxidative stress was quantified by superoxide anion production, and inflammatory response was assessed by immunofluorescence. Expression of angiogenesis mediators was determined by western blotting, and the extent of portosystemic collaterals by radioactive microspheres. Hemodynamic studies were performed by flowmetry. RESULTS: Oxidative stress was significantly increased in the mesentery of portal hypertensive rats, as compared with sham-operated controls. In portal hypertensive rats, chronic heme oxygenase inhibition (1) potentiated oxidative stress and inflammation, (2) significantly decreased VEGF expression, without modifying the extent of collaterals or the splanchnic neovascularization, and (3) significantly decreased superior mesenteric artery blood flow and portal pressure. CONCLUSIONS: This study demonstrates that heme oxygenase plays an important (beneficial) role attenuating oxidative stress and inflammation, but it also plays a detrimental role in stimulating VEGF production, and contributing to the development of hyperdynamic splanchnic circulation in rats with portal hypertension.
Assuntos
Heme Oxigenase-1/fisiologia , Hipertensão Portal/enzimologia , Inflamação/enzimologia , Estresse Oxidativo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Heme Oxigenase-1/antagonistas & inibidores , Masculino , Metaloporfirinas/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Protoporfirinas/farmacologia , Ratos , Ratos Sprague-Dawley , Regulação para CimaRESUMO
BACKGROUND/AIMS: Portal hypertension is characterized by the development of a hyperdynamic splanchnic circulation. To determine whether this process is angiogenesis-dependent, we assessed the effects of SU5416, a specific inhibitor of VEGF receptor-2, in portal hypertensive rats. METHODS: Rats with portal hypertension induced by partial portal vein ligation were treated with SU5416 or vehicle during 5 days. Then, hemodynamic studies were performed using radioactive microspheres. Protein expressions of CD31, VEGF receptor-2 and VEGF were also determined by Western blotting. RESULTS: Treatment of portal hypertensive rats with SU5416 resulted in a significant and marked decrease (by 44%) in portal venous inflow, and increases in splanchnic arteriolar resistance (by 68%) and portal venous resistance (by 93%). In addition, SU5416 administration significantly inhibited the formation of portal-systemic collateral vessels (52% inhibition), as well as the splanchnic CD31 and VEGF receptor-2 protein expressions in portal hypertensive rats, compared with those receiving vehicle. CONCLUSIONS: This study demonstrates that the development of hyperdynamic splanchnic circulation and the formation of portal-systemic collateral vessels in portal hypertensive rats are angiogenesis-dependent processes that can be markedly inhibited by blockade of the VEGF signaling pathway. Therefore, modulation of angiogenesis may represent a potential target in the treatment of portal hypertension.
Assuntos
Circulação Colateral , Hipertensão Portal/complicações , Hipertensão Portal/fisiopatologia , Neovascularização Patológica/etiologia , Sistema Porta/fisiopatologia , Circulação Esplâncnica , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Inibidores da Angiogênese/farmacologia , Animais , Arteríolas/fisiopatologia , Circulação Colateral/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Indóis/farmacologia , Masculino , Molécula-1 de Adesão Celular Endotelial a Plaquetas/efeitos dos fármacos , Veia Porta/fisiopatologia , Inibidores de Proteínas Quinases/farmacologia , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/efeitos dos fármacos , Circulação Esplâncnica/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Resistência Vascular/efeitos dos fármacosRESUMO
In patients with liver cirrhosis, implantation of a transjugular intrahepatic shunt (TIPS) leads to reduction of portal pressure, but not of mortality compared with other therapies. The high stenosis rates of conventional bare stents causes high reintervention rates and costs and may be correlated with poor survival. ePTFE-covered stentgrafts provide much improved patency rates, but their impact on survival is unclear. All suitable patients receiving either bare TIPS (419/466) or undergoing implantation of ePTFE endoprostheses (89/100) in several centers in Austria up to 2002 were included in this retrospective analysis. Both patient groups were compared regarding survival with Kaplan-Meier and Cox regression analysis. Unmatched and 1:1-matched survival analyses were performed. Patients undergoing ePTFE stentgraft implantation had significantly higher survival rates in all analyses. The 3-month, 1-year, and 2-year survival rates were 93%, 88%, and 76% for the ePTFE-group and 83%, 73%, and 62% for conventional TIPS patients, respectively. The matched survival analyses validated these findings. The model of the stent, patient age, and Child-Pugh Class (CPC) were independent predictors of survival. In conclusion, patients undergoing ePTFE-endoprosthesis implantation had higher survival rates within 2 years after TIPS-implantation. This may be the result of improved patency rates after correct placement (up to the inferior caval vein [ICV]) of the ePTFE stentgraft. These data should be validated in a prospective series.
Assuntos
Politetrafluoretileno , Derivação Portossistêmica Transjugular Intra-Hepática/mortalidade , Stents , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Análise de SobrevidaRESUMO
PURPOSE: To determine whether transjugular intrahepatic portosystemic shunt (TIPS) revisions with the Hemobahn stent-graft or the Viatorr endoprosthesis increase secondary patency rates. METHODS: Between 1998 and June 1999, Hemobahn endoprostheses (W.L. Gore, Flagstaff, AZ, USA) were used for the revision of obstructed TIPS in seven patients, 51-67 years of age (mean 59 years). From June 1999 to 2000, the Viatorr endoprosthesis (W.L. Gore, Flagstaff, AZ, USA) was used for revision of obstructed TIPS in nine patients, 33-64 years of age (mean 49 years). Follow-up included duplex ultrasound, clinical assessment and venous portography. RESULTS: The technical success rate of TIPS revision with the Hemobahn stent-graft was 100%. The pressure gradient decreased from a mean of 20 mmHg to 10 mmHg. The mean follow-up was 407 days (range 81-868 days). In two patients TIPS occlusion occurred at 62 and 529 days after stent-graft placement, respectively; in another two patients outflow tract stenosis occurred at 275 and 393 days, respectively. The technical success rate of TIPS revision with the Viatorr endoprosthesis was also 100%. The pressure gradient decreased from a mean of 27 mmHg to 11 mmHg. At a mean follow-up of 201 days (range 9-426 days), all Viatorr endoprostheses are still patent without in-graft stenosis, but angioplasty was required in two patients to treat a portosystemic pressure gradient > 15 mmHg. Four of the nine patients in the Viatorr group suffered from new encephalopathy after TIPS revision. CONCLUSION: The Viatorr endoprosthesis yielded optimal results with 100% in-graft patency rates at follow-up but had a high incidence of new encephalopathy, whereas the use of Hemobahn stent-graft for TIPS revision did not appear to improve the secondary patency rates in our series.
Assuntos
Angioplastia com Balão/instrumentação , Oclusão de Enxerto Vascular/terapia , Derivação Portossistêmica Transjugular Intra-Hepática/efeitos adversos , Stents/efeitos adversos , Idoso , Feminino , Seguimentos , Humanos , Hipertensão Portal/cirurgia , Masculino , Pessoa de Meia-Idade , Politetrafluoretileno , Estudos Prospectivos , ReoperaçãoRESUMO
The authors report the role of transjugular intrahepatic portosystemic shunts (TIPS) and consecutive interventions, including brachytherapy (n = 2) and stent-graft placement (n = 3), to increase secondary patency and consequently postpone orthotopic liver transplantation (OLT) in the treatment of Budd-Chiari syndrome in eight patients. Two patients (with hematologic diseases) died 2 weeks after the TIPS procedure. Median follow-up in the six survivors was 42.5 months (range, 11-79 mo). Multiple TIPS occlusions occurred in three patients (range, 2-7 revisions). Reocclusions occurred despite brachytherapy and Hemobahn stent-graft placement and necessitated OLT in one patient. Revision-free patency was achieved in the other two patients after VIATORR stent-graft placement (16 and 32 months after TIPS creation). All patients with stable TIPS (n = 5) are without ascites, no liver failure occurred, and no patients are currently on the transplant list.