Bernardino González de la Presa

Cerium oxide nanoparticles reduce steatosis, portal hypertension and display anti-inflammatory properties in rats with liver fibrosis

BACKGROUND & AIMS Cerium oxide nanoparticles (CeO2NPs) have proven to behave as free radical scavengers and/or anti-inflammatory agents. The aim of the study was to determine whether CeO2NPs display hepatoprotective properties in experimental chronic liver disease. METHODS Systemic and hepatic effects of nanoparticles were assessed in CCl4-treated rats receiving CeO2NPs or vehicle twice weekly for two weeks and CCl4 treatment was continued for 8 additional weeks. Thereafter, mean arterial pressure and portal pressure (PP) were assessed and serum samples obtained to measure standard hepatic and renal function tests. Organ and subcellular distribution of NPs were assessed using mass spectrometry (ICP-MS) and transmission electron microscopy. Liver samples were obtained to evaluate steatosis, α-SMA expression, macrophage infiltration, apoptosis and mRNA expression of oxidative stress, inflammatory or vasoactive related genes. RESULTS Most CeO2NPs were located in the liver and it reduced hepatic steatosis, ameliorated systemic inflammatory biomarkers and improved PP without affecting mean arterial pressure. In addition, a marked reduction in mRNA expression of inflammatory cytokines (TNFα, IL1β, COX-2, iNOS), ET-1 and messengers related to oxidative (Epx, Ncf1, Ncf2) or endoplasmic reticulum (Atf3, Hspa5) stress signaling pathways was observed in the liver of rats receiving CeO2NPs. This was associated with reduced macrophage infiltration and reduced abundance of caspase-3, α-SMA and inflammatory cytokines. CONCLUSIONS CeO2NPs administration to CCl4-treated rats protects against chronic liver injury by reducing liver steatosis and portal hypertension and markedly attenuating the intensity of the inflammatory response, thereby suggesting that CeO2NPs may be of therapeutic value in chronic liver disease.

Vasopressin 1a receptor partial agonism increases sodium excretion and reduces portal hypertension and ascites in cirrhotic rats

Patients and rats with cirrhosis and ascites have portal hypertension and circulatory dysfunction. Synthetic arginine vasopressin (AVP) receptor agonists able to induce systemic and mesenteric vasoconstriction have shown their usefulness in reducing portal pressure (PP) in this condition. We assessed the potential therapeutic value of a new V1a‐AVP receptor partial agonist with a preferential splanchnic vasoconstrictor effect (FE 204038) in rats with cirrhosis and ascites. The hemodynamic effects of cumulative intravenous doses of FE 204038, terlipressin, or vehicle were investigated. Mean arterial pressure and PP were continuously recorded and cardiac output and systemic vascular resistance (SVR) assessed at 30‐minute intervals for 90 minutes. Urine volume, urine osmolality, and urinary excretion of sodium and creatinine were measured in basal conditions and following twice‐daily subcutaneous doses of FE 204038 or vehicle. PP, mean arterial pressure, cardiac output, SVR, and ascites volume were also measured after 6 days. The expression of an array of vasoactive genes was assessed in the thoracic aorta and the mesenteric circulation of control rats and rats with cirrhosis and ascites. FE 204038 dose‐dependently decreased PP, did not modify mean arterial pressure, and increased SVR. The effect of the V1a‐AVP receptor partial agonist on PP was associated with an improvement in urine volume and urinary excretion of sodium during the first day of treatment. SVR was higher and cardiac output and ascites volume were lower in rats with cirrhosis and ascites treated with FE 204038. V1a‐AVP receptor expression in rats with cirrhosis and ascites was markedly enhanced in the mesenteric circulation compared to the thoracic aorta. Conclusion: FE 204038 increases sodium excretion and reduces portal hypertension and ascites in experimental cirrhosis. V1a‐AVP receptor partial agonism could be a useful pharmacological treatment in decompensated patients with cirrhosis. (Hepatology 2016;63:207–216)

The GALA study: relationship between galectin-3 serum levels and short- and long-term outcomes of patients with acute heart failure

Abstract Objective: We tested the hypothesis that early measurement of galectin-3 at the emergency department (ED) during an episode of acute heart failure (AHF) allows predicting short- and long-term outcomes. Methods: We performed an exploratory study including 115 patients consecutively diagnosed with AHF in a single ED. Clinical and analytical variables were recorded. The primary endpoint was 30-day all-cause mortality, and secondary endpoints were 30-day composite outcome (death, rehospitalization or ED reconsultation, whichever first) and 1-year mortality. Results: Seven patients (6.1%) died within 30 days and 43 (37.4%) within 1 year. The 30-day composite endpoint was observed in 21.1% of patients. Galectin-3 was correlated with NT-proBNP and the glomerular filtration rate but not with age and s-cTnI. Measured at time of ED arrival, galectin-3 showed good discriminatory capacity for 30-day mortality (AUC ROC: 0.732; 95% CI 0.512–0.953; p = 0.041) but not for 1-year mortality (0.521; 0.408–0.633; p = 0.722). Patients with galectin-3 concentrations >42 μg/L had an OR = 7.67(95%CI = 1.57-37.53; p = 0.012) for 30-day mortality. Conversely, NT-proBNP only showed predictive capacity for 1-year mortality (0.642; 0.537–0.748; p = 0.014). Patients with NT-proBNP concentrations >5400 ng/L had an OR = 4.34 (95%CI = 1.93-9.77; p < 0.001) for 1-year mortality. These increased short- (galectin-3) and long-term (NT-proBNP) risks remained significant after adjustment for age or renal function. s-cTnI failed in both short- and long term death prediction. No biomarker predicted the short-term composite endpoint. Conclusion: These results suggest that galectin-3 could help to monitor the risk of short-term mortality in unselected patients with AHF attended in the ED.

Prognostic value of plasma apelin concentrations at admission in patients with ST-segment elevation acute myocardial infarction

BACKGROUND The use of plasma biomarkers is relevant for the prognosis of ST-segment elevation myocardial infarction (STEMI) patients. Apelin, an adipocytokine, plays a pivotal role in the pathophysiology of both ischemia/reperfusion injury and its potential subsequent heart failure. We evaluated apelin concentrations at admission as a biomarker to assess risk of 6-month mortality. METHODS Consecutive patients with STEMI were recruited from January 2012 to January 2013 (n=250). Plasma apelin, brain natriuretic peptide (BNP) and sensitive troponin I (sTnI) were assessed in EDTA-plasma samples obtained at admission. Clinical, hemodynamic and other laboratory variables were also registered. All-cause mortality was assessed at 6-month follow-up. RESULTS Increased plasma apelin concentrations at admission were predictive of 6- month mortality, after adjustment for age, diabetes, systolic blood pressure, heart rate, glomerular filtration rate, Killip class, left ventricular ejection fraction, BNP and sTnI. The combination of apelin with BNP and sTnI further improved the apelin predictive value. Finally, apelin concentrations were associated with markers of ischemic heart failure severity, but not with markers of ischemic insult severity. CONCLUSIONS Increased plasma concentrations of apelin at admission in patients with STEMI were associated with a higher risk of mortality at 6months, adding prognostic value to the provided by BNP. Moreover, apelin levels were also related to markers of ischemic heart failure severity, but not markers of ischemia severity.