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In cirrhosis, portal vein thrombosis (PVT) could be a cause or a consequence of the progression of liver disease. We analyzed data from a prospective trial of ultrasound screening for hepatocellular carcinoma in order to identify risk factors for and the impact of PVT in patients with cirrhosis. In all, 1,243 adults with cirrhosis without PVT were enrolled from 43 liver units in France and Belgium between June 2000 and March 2006. The mean follow-up was 47 months. Doppler ultrasonography was used to check the portal vein. Progression of liver disease was defined by the development of: ascites, hepatic encephalopathy, variceal bleeding, prothrombin <45%, serum bilirubin >45 lmol/L, albumin <28 g/L, and/or creatinine >115 lmol/L. G20210A prothrombin and factor V gene mutations were assessed in sera stored at three large centers. The 5-year cumulative incidence of PVT was 10.7%. PVT was mostly partial and varied over time. The development of PVT was independently associated with baseline esophageal varices (P 5 0.01) and prothrombin time (P 5 0.002), but not with disease progression before PVT, or prothrombotic mutations. Disease progression was independently associated with baseline age (hazard ratio [HR] 1.55; 95% confidence interval [CI]: 1.11-2.17), body mass index (HR 1.40; 95% CI: 1.01-1.95), prothrombin time (HR 0.79; 95% CI: 0.70-0.90), serum albumin (HR 0.97; 95% CI: 0.94-0.99), and esophageal varices (HR 1.70; 95% CI: 1.21-2.38) but not with the prior development of PVT (HR 1.32; 95% CI: 0.68-2.65). Conclusion: In patients with cirrhosis, the development of PVT is associated with the severity of liver disease at baseline, but does not follow a recent progression of liver disease. There is no evidence that the development of PVT is responsible for further progression of liver disease. (HEPATOLOGY 2015;61:660-667)

Beta-blockers may have a negative impact on survival in patients with cirrhosis and refractory ascites. The aim of this study was to evaluate the effect of the administration of betablockers on long-term survival in patients with cirrhosis and refractory ascites. We performed a single-center, observational, case-only, prospective study of patients with cirrhosis and refractory ascites who did or did not receive beta-blockers for the prevention of gastrointestinal bleeding; 151 patients were included. The mean Model for End-Stage Liver Disease score was 18.8 6 4.1. All patients regularly underwent large-volume paracentesis and intravenous albumin administration. Seventy-seven patients (51%) were treated with propranolol (113 6 46 mg/day). The median follow-up for the whole group was 8 months. The median survival time was 10 months [95% confidence interval (CI) 5 8-12 months]. The probability of survival at 1 year was 41% (95% CI 5 33%-49%). The clinical characteristics and laboratory values at enrolment were not significantly different between patients who were receiving propranolol and those who were not. The median survival time was 20.0 months (95% CI 5 4.8-35.2 months) in patients not treated with propranolol and 5.0 months (95% CI 5 3.5-6.5 months) in those treated with propranolol (P 5 0.0001). The 1-year probability of survival was significantly lower in patients who received propranolol [19% (95% CI 5 9%-29%)] versus those who did not [64% (95% CI 5 52%-76%), P < 0.0001]. The independent variables of mortality were Child-Pugh class C, hyponatremia and renal failure as causes of refractory ascites, and beta-blocker therapy. Conclusion: The use of beta-blockers is associated with poor survival in patients with refractory ascites. These results suggest that betablockers should be contraindicated in these patients.

Membrane vesicles released in the extracellular space are composed of a lipid bilayer enclosing soluble cytosolic material and nuclear components. Extracellular vesicles include apoptotic bodies, exosomes, and microvesicles (also known previously as microparticles). Originating from different subcellular compartments, the role of extracellular vesicles as regulators of transfer of biological information, acting locally and remotely, is now acknowledged. Circulating vesicles released from platelets, erythrocytes, leukocytes, and endothelial cells contain potential valuable biological information for biomarker discovery in primary and secondary prevention of coronary artery disease. Extracellular vesicles also accumulate in human atherosclerotic plaques, where they affect major biological pathways, including inflammation, proliferation, thrombosis, calcification, and vasoactive responses. Extracellular vesicles also recapitulate the beneficial effect of stem cells to treat cardiac consequences of acute myocardial infarction, and now emerge as an attractive alternative to cell therapy, opening new avenues to vectorize biological information to target tissues. Although interest in microvesicles in the cardiovascular field emerged about 2 decades ago, that for extracellular vesicles, in particular exosomes, started to unfold a decade ago, opening new research and therapeutic avenues. This Review summarizes current knowledge on the role of extracellular vesicles in coronary artery disease, and their emerging potential as biomarkers and therapeutic agents.

Rationale for Study: MicroRNAs (miRNAs) are small noncoding RNAs that regulate protein expression at post-transcriptional level. We hypothesized that a specific pool of endothelial miRNAs could be selectively regulated by flow conditions and inflammatory signals, and as such be involved in the development of atherosclerosis. Objective: To identify miRNAs, called atheromiRs, which are selectively regulated by shear stress and oxidized low-density lipoproteins (oxLDL), and to determine their role in atherogenesis. Methods and Results: Large-scale miRNA profiling in HUVECs identified miR-92a as an atheromiR candidate, whose expression is preferentially upregulated by the combination of low shear stress (SS) and atherogenic oxLDL. Ex vivo analysis of atheroprone and atheroprotected areas of mouse arteries and human atherosclerotic plaques demonstrated the preferential expression of miR-92a in atheroprone low SS regions. In Ldlr −/− mice, miR-92a expression was markedly enhanced by hypercholesterolemia, in particular in atheroprone areas of the aorta. Assessment of endothelial inflammation in gain- and loss-of-function experiments targeting miR-92a expression revealed that miR-92a regulated endothelial cell activation by oxLDL, more specifically under low SS conditions, which was associated with modulation of Kruppel-like factor 2 (KLF2), Kruppel-like factor 4 (KLF4), and suppressor of cytokine signaling 5. miR-92a expression was regulated by signal transducer and activator of transcription 3 in SS- and oxLDL-dependent manner. Furthermore, specific in vivo blockade of miR-92a expression in Ldlr −/− mice reduced endothelial inflammation and altered the development of atherosclerosis, decreasing plaque size and promoting a more stable lesion phenotype. Conclusions: Upregulation of miR-92a by oxLDL in atheroprone areas promotes endothelial activation and the development of atherosclerotic lesions. Therefore, miR-92a antagomir seems as a new atheroprotective therapeutic strategy.

Autophagy, or cellular self-digestion, is a cellular pathway crucial for development, differentiation, survival, and homeostasis. Its implication in human diseases has been highlighted during the last decade. Recent data show that autophagy is involved in major fields of hepatology. In liver ischemia reperfusion injury, autophagy mainly has a prosurvival activity allowing the cell for coping with nutrient starvation and anoxia. During hepatitis B or C infection, autophagy is also increased but subverted by viruses for their own benefit. In hepatocellular carcinoma, the autophagy level is decreased. In this context, autophagy has an anti-tumor role and therapeutic strategies increasing autophagy, as rapamycin, have a beneficial effect in patients. Moreover, in hepatocellular carcinoma, Beclin-1 level, an autophagy protein, has a prognostic significance. In α-1-antitrypsin deficiency, the aggregation-prone ATZ protein accumulates in the endoplasmic reticulum. This activates the autophagic response which aims at degrading mutant ATZ. Some FDA-approved drugs which enhance autophagy and the disposal of aggregation-prone proteins may be useful in α-1-antitrypsin deficiency. Following alcohol consumption, autophagy is decreased in liver cells, likely due to a decrease in intracellular 5'-AMP-activated protein kinase (AMPk) and due to an alteration in vesicle transport in hepatocytes. This decrease in autophagy contributes to the formation of Mallory-Denk bodies and to liver cell death. Hepatic autophagy is defective in the liver in obesity and its upregulation improves insulin sensitivity.

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