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Chronic passive venous congestion drives hepatic fibrogenesis via sinusoidal thrombosis and mechanical forces.

ABSTRACT: UNLABELLED:Chronic passive hepatic congestion (congestive hepatopathy) leads to hepatic fibrosis; however, the mechanisms involved in this process are not well understood. We developed a murine experimental model of congestive hepatopathy through partial ligation of the inferior vena cava (pIVCL). C57BL/6 and transgenic mice overexpressing tissue factor pathway inhibitor (SM22?-TFPI) were subjected to pIVCL or sham. Liver and blood samples were collected and analyzed in immunohistochemical, morphometric, real-time polymerase chain reaction, and western blot assays. Hepatic fibrosis and portal pressure were significantly increased after pIVCL concurrent with hepatic stellate cell (HSC) activation. Liver stiffness, as assessed by magnetic resonance elastography, correlated with portal pressure and preceded fibrosis in our model. Hepatic sinusoidal thrombosis as evidenced by fibrin deposition was demonstrated both in mice after pIVCL as well as in humans with congestive hepatopathy. Warfarin treatment and TFPI overexpression both had a protective effect on fibrosis development and HSC activation after pIVCL. In vitro studies show that congestion stimulates HSC fibronectin (FN) fibril assembly through direct effects of thrombi as well as by virtue of mechanical strain. Pretreatment with either Mab13 or Cytochalasin-D, to inhibit ?-integrin or actin polymerization, respectively, significantly reduced fibrin and stretch-induced FN fibril assembly. CONCLUSION:Chronic hepatic congestion leads to sinusoidal thrombosis and strain, which in turn promote hepatic fibrosis. These studies mechanistically link congestive hepatopathy to hepatic fibrosis.

SUBMITTER: Simonetto DA

PROVIDER: S-EPMC4303520 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Chronic passive venous congestion drives hepatic fibrogenesis via sinusoidal thrombosis and mechanical forces.

Simonetto Douglas A DA Yang Hui-yin HY Yin Meng M de Assuncao Thiago M TM Kwon Jung Hee JH Hilscher Moira M Pan Shuchong S Yang Liu L Bi Yan Y Beyder Arthur A Cao Sheng S Simari Robert D RD Ehman Richard R Kamath Patrick S PS Shah Vijay H VH

Hepatology (Baltimore, Md.) 20150105 2

<h4>Unlabelled</h4>Chronic passive hepatic congestion (congestive hepatopathy) leads to hepatic fibrosis; however, the mechanisms involved in this process are not well understood. We developed a murine experimental model of congestive hepatopathy through partial ligation of the inferior vena cava (pIVCL). C57BL/6 and transgenic mice overexpressing tissue factor pathway inhibitor (SM22α-TFPI) were subjected to pIVCL or sham. Liver and blood samples were collected and analyzed in immunohistochemic ...[more]

PMID: 25142214

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Project description:BackgroundIn hepatectomy, the preservation of portal perfusion and venous drainage in the remnant liver is important for securing postoperative hepatic function. Right hepatectomy is generally indicated when a hepatic tumor involves the right hepatic vein (RHV). However, if a sizable inferior RHV (IRHV) exists, hepatectomy with preservation of the IRHV territory may be another option. In this case, we verified the clinical feasibility of anatomical bisegmentectomy 7 and 8 with RHV ligation, averting the right hepatic parenchyma from venous congestion, utilizing the presence of the IRHV.Case presentationA 70-year-old man was presented with a large hepatic tumor infiltrating the RHV on computed tomography during a medical checkup. The patient was diagnosed with hepatocellular carcinoma (HCC), T2N0M0, stage III. Right hepatectomy was first considered, but multi-detector computed tomography (MDCT) also revealed a large IRHV draining almost all of segments 5 and 6, suggesting that IRHV-preserving liver resection may be another option. The calculated future remnant liver volumes were 382 mL (26.1% of the total volume) after right hepatectomy and 755 mL (51.7% of the total volume) after anatomical bisegmentectomy 7 and 8; therefore, we scheduled IRHV-preserving anatomical bisegmentectomy 7 and 8 considering the prevention of postoperative liver failure and increased chance of performing repeat resections in cases of recurrence. Preoperative three-dimensional simulation using MDCT clearly revealed the portal perfusion area and venous drainage territories by the RHV and IRHV. There was an issue with invisibility of the anatomical resection line of segments 7 and 8, which was completely dissolved by intraoperative ultrasonography using Sonazoid and the portal dye injection technique with counter staining. The postoperative course in the patient was uneventful, without recurrence of HCC, for 30 months after hepatectomy.ConclusionsIRHV-preserving anatomical bisegmentectomy 7 and 8 is a safe and feasible procedure utilizing the three-dimensional simulation of the portal perfusion area and venous drainage territories and the portal dye injection technique.

Project description:BackgroundVenous excess ultrasound (VExUS) is a novel ultrasound technique previously reported as a noninvasive measure of venous congestion and predictor of cardiorenal acute kidney injury.Research questionAre there associations between VExUS grade and cardiac pressures measured by right heart catheterization (RHC) and cardiac biomarkers and clinical outcomes in patients undergoing RHC?Study design and methodsWe conducted a prospective cohort study at the Denver Health Medical Center from December 20, 2022, to March 25, 2023. All patients undergoing RHC underwent a blinded VExUS assessment prior to their procedure. Multivariable regressions were conducted to assess relationships between VExUS grade and cardiac pressures, biomarkers, and changes in weight among patients with heart failure, a proxy for diuretic success. Receiver operating characteristic curve and area under the curve (AUC) were derived for VExUS, inferior vena cava (IVC) diameter, and IVC collapsibility index (ICI) to predict right atrial pressure (RAP) > 10 and < 7 mm Hg.ResultsAmong 81 patients, 45 of whom were inpatients, after adjusting for age, sex, and Charlson Comorbidity Index, there were significant relationships between VexUS grade of 2 (β = 4.8; 95% CI, 2.6-7.1; P < .01) and 3 (β = 11; 95% CI, 8.9-14; P < .01) and RAP, VExUS grade of 2 (β = 6.8; 95% CI, 0.16-13; P = .045) and 3 (β = 15; 95% CI, 7.3-22; P < .01) and mean pulmonary artery pressure, and VExUS grade of 2 (β = 7.0; 95% CI, 3.9-10; P < .01) and 3 (β = 13; 95% CI, 9.5-17; P < .01) and pulmonary capillary wedge pressure. AUC values for VExUS, IVC diameter, and ICI as predictors of RAP > 10 mm Hg were 0.9 (95% CI, 0.83-0.97), 0.77 (95% CI, 0.68-0.88), and 0.65 (95% CI, 0.52-0.78), respectively. AUC values for VExUS, IVC diameter, and ICI as predictors of RAP < 7 mm Hg were 0.79 (95% CI, 0.70-0.87), 0.74 (95% CI, 0.64-0.84), and 0.62 (95% CI, 0.49-0.76), respectively. In a subset of 23 patients with heart failure undergoing diuresis, there was a significant association between VExUS grade 3 and change in weight between time of RHC and discharge (P = .025).InterpretationAlthough more research is required, VExUS has the potential to increase diagnostic and therapeutic capabilities of physicians at the bedside and increase our understanding of the underappreciated problem of venous congestion.

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Chronic passive venous congestion drives hepatic fibrogenesis via sinusoidal thrombosis and mechanical forces.

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Chronic passive venous congestion drives hepatic fibrogenesis via sinusoidal thrombosis and mechanical forces.

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