Background Oxidative/nitrosative stress and endothelial dysfunction are hypothesized to be central to cancer therapeutics-related cardiac dysfunction (CTRCD). However, the relationship between circulating arginine-nitric oxide (NO) metabolites and CTRCD remains unstudied. Objectives To examine the relationship between arginine-NO metabolites and CTRCD in a prospective cohort of 170 breast cancer patients treated with doxorubicin ± trastuzumab. Methods Plasma levels of arginine, citrulline, ornithine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and N-monomethylarginine (MMA) were quantified at baseline, 1 month, and 2 months following doxorubicin initiation. Determinants of baseline biomarker levels were identified using multivariable linear regression, and Cox regression defined the association between baseline levels and 1- or 2-month biomarker changes and CTRCD rate in 139 participants with quantitated echocardiograms at all time points. Results Age, hypertension, body mass index, and African American race were independently associated with ≥1 baseline citrulline, ADMA, SDMA, and MMA levels. Decreases in arginine and citrulline, and increases in ADMA were observed at 1 and 2 months (all P<0.05). Overall, 32 participants experienced CTRCD over a maximum follow-up of 5.4 years. Hazard ratios for ADMA and MMA at 2 months were 3.33 (95% confidence interval [CI] 1.12, 9.96) and 2.70 (95%CI 1.35, 5.41), respectively, and 0.78 (95%CI 0.64, 0.97) for arginine at 1 month. Conclusions In breast cancer patients undergoing doxorubicin therapy, early alterations in arginine-NO metabolite levels occurred, and early biomarker changes were associated with a greater CTRCD rate. Our findings highlight the potential mechanistic and translational relevance of this pathway to CTRCD.

BackgroundRecent data suggest that noninvasive liver fibrosis indexes could be useful for predicting esophageal varices (EV) in cirrhotic patients. However, thus far, the diagnostic efficacy of these indexes in predicting portal hypertension (PH) in cirrhotic patients has been poorly evaluated.AimsTo evaluate the diagnostic efficacy of noninvasive liver fibrosis indexes in the diagnosis of PH.MethodsA total of 238 cirrhotic patients underwent hepatic venous pressure gradient (HVPG) evaluation and relevant serum tests to analyze the variables associated with PH grade. Then, the diagnostic performances of seven fibrosis indexes, the aspartate aminotransferase (AST)-to-alanine aminotransferase (ALT) ratio (AAR), AST-to-platelet (PLT) ratio index (APRI), fibrosis index (FI), FIB-4, Forns index, King’s score and the Lok index, were evaluated to determine their efficacy in predicting clinically significant PH (CSPH) and severe PH (SPH). In addition, the performances of these fibrosis indexes in different subgroups were investigated.ResultsThe results of a multivariate analysis of serum markers showed that AST values, platelet (PLT) count and albumin (ALB) were associated with PH grade. Among the seven—fibrosis indexes, King’s score, APRI and the Lok index showed modest diagnostic accuracy in predicting CSPH and SPH, as indicated by AUC of 0.755 and 0.742, 0.740 and 0.742, and 0.722 and 0.717, respectively. In addition, combination of King’s score (cutoff 23.47) and Lok index (cutoff 1.30) predicted presence of CSPH, with the highest PPV (95.38%) and +LR (5.49). A subgroup analysis indicated that the noninvasive screening model may be more applicable to patients with cirrhosis of viral etiology.ConclusionsSerum liver fibrosis indexes exhibited modest diagnostic accuracy for PH in cirrhotic patients. These indexes may not be able to replace HVPG measurements for the diagnosis of PH but may be used as a first-line screening method for CSPH in liver cirrhosis patients.

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