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Ying Zhuge,1,* Huan-Er Ni,1,* Yu-Jie Wang,2 Mu-Ye He,2 Jun-Shan Wang,3 Feng Gao,2,4 Fang Wang1 1Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200800, People’s Republic of China; 2Department of Pharmaceutics, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, People’s Republic of China; 3Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University, Shanghai 200072, People’s Republic of China; 4Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai 200237, People’s Republic of China *These authors contributed equally to this work Aims: To determine whether use of radiofrequency catheter ablation (RFCA) combined with intravenously administered liposomal doxorubicin (L-DOX) facilitates a reduction in the recovery of post-ablation electrical conduction. Methods: Circumferential ablation was performed on the epicardial surface of the left atrial appendage (LAA) in New Zealand White rabbits, and L-DOX was then administered intravenously. Fluorescence spectrophotometry was used to assess reagent bio-distribution, while Western blots and immunohistochemistry were used to assess the localization of the apoptotic markers Bcl-2, Bax, and cleaved CASP3 in the LAA. Liver, kidney, and cardiac functions were also measured to evaluate the safety of this approach. Results: At 1 week and 1 month after RFCA, a pacing electrocardiogram could not be detected in most of the rabbits that had received the combined RFCA and L-DOX therapy. L-DOX began to target the LAA on the second day after RFCA. L-DOX treatment increased the apoptosis of cardiomyocytes in the regions peripheral to the necrotic area induced by RFCA. Doxorubicin had some effect on liver and kidney function, but these effects were reversible and did not affect survival. Conclusion: The present results provide evidence that L-DOX treatment can reduce the recovery of electrical conduction after RFCA therapy owing to L-DOX-induced apoptosis of cardiomyocytes in the ablated area and the proximal transition zone of the LAA. Keywords: doxorubicin, liposome, radiofrequency catheter ablation, atrial fibrillation, recovered electrical conduction

Ying Zhuge,1,* Zhi-Feng Zheng,1,* Mu-Qing Xie,2 Lin Li,2 Fang Wang,1 Feng Gao2,3 1Department of Cardiology, Shanghai First People’s Hospital of Nanjing Medical University, 2Department of Pharmaceutics, School of Pharmacy, 3Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai, People’s Republic of China*These authors contributed equally to this workAbstract: The objective of this study was to develop an amiodarone hydrochloride (ADHC)-loaded liposome (ADHC-L) formulation and investigate its potential for cardiomyocyte targeting after cardiac radiofrequency ablation (CA) in vivo. The ADHC-L was prepared by thin-film method combined with ultrasonication and extrusion. The preparation process was optimized by Box–Behnken design with encapsulation efficiency as the main evaluation index. The optimum formulation was quantitatively obtained with a diameter of 99.9±0.4 nm, a zeta potential of 35.1±10.9 mV, and an encapsulation efficiency of 99.5%±13.3%. Transmission electron microscopy showed that the liposomes were spherical particles with integrated bilayers and well dispersed with high colloidal stability. Pharmacokinetic studies were investigated in rats after intravenous administration, which revealed that compared with free ADHC treatment, ADHC-L treatment showed a 5.1-fold increase in the area under the plasma drug concentration–time curve over a period of 24 hours (AUC0–24 h) and an 8.5-fold increase in mean residence time, suggesting that ADHC-L could facilitate drug release in a more stable and sustained manner while increasing the circulation time of ADHC, especially in the blood. Biodistribution studies of ADHC-L demonstrated that ADHC concentration in the heart was 4.1 times higher after ADHC-L treatment in CA rat model compared with ADHC-L sham-operated treatment at 20 minutes postinjection. Fluorescence imaging studies further proved that the heart-targeting ability of ADHC-L was mainly due to the CA in rats. These results strongly support that ADHC-L could be exploited as a potential heart-targeting drug delivery system with enhanced bioavailability and reduced side effects for arrhythmia treatment after CA.Keywords: liposomes, cardiomyocyte targeting, amiodarone hydrochloride, cardiac radiofrequency ablation

Background Plasma ammonia has been shown to be an independent prognostic factor for patients with liver cirrhosis. Aim We aimed to investigate the discrimination and calibration of a new prognostic model (aCTP) based on plasma ammonia (Amm) replacing hepatic encephalopathy (HE) in the Child-Turcotte-Pugh (CTP) score. Design Diagnostic test, paired design. Methods Baseline Amm levels were corrected to the upper limit of normal (Amm-ULN). We designed the new model based on the cut-off value of Amm-ULN in the observational cohort of 554 clinically stable cirrhotic patients from January 2012 to July 2019. External validation was carried out using prospective data from 185 patients with liver cirrhosis. Results Our analysis showed that each 1-point increase in Amm-ULN was associated with a 2-fold increase in the likelihood of mortality [hazard ratio (HR), 2.06; 95% CI: 1.81–2.36, P  < 0.001]. In the aCTP score, Amm-ULN < 1.0 was defined as a score of 1, 1.0 ≤ Amm-ULN < 1.4 as 2 and ≥1.4 as 3. The survival curves among three aCTP grades were significantly different (P  < 0.0001). The aCTP score showed the better agreements between predicted and observed events in the validating cohorts than the CTP score (C -statistics: 0.75 and 0.69, P  < 0.001). The aCTP score showed inspiring power to predict acute decompensation (C -statistics: 0.76; 95% CI: 0.71–0.81) and acute-on-chronic liver failure (C -statistics: 0.81; 95% CI: 0.77–0.86). Conclusion This study demonstrates the feasibility and the potential for plasma Amm replacing HE (aCTP) to enhance the prognostication of transplant-free survival provided by the CTP score for patients with decompensated cirrhosis. [ABSTRACT FROM AUTHOR]

Identification of the association between molecular markers and quality traits would promote the efficient utilization, conservation and management of the tall fescue germplasm. Thus, 59 tall fescue accessions from different origins (16 cultivars; 19 from America; 15 from Europe; 2from Africa and 7 from Asia), were evaluated for quality traits and genetic diversity with 90 simple sequence repeat (SSR) markers. Significant variations were observed among 59 tall fescue accessions in dry matter (DM), crude protein (CP), crude fat (CF),and CP were negatively correlated with DM (r=0.269) and CF (r=0.254), respectively. Three sub-populations were identified within the collections but no obvious relative kinship (K) was found. The GLM model was used to describe the association between SSR markers and quality traits. 41 SSR markers associated with quality traits were observed. In addition, 26 markers were significantly associated with CP; 12 markers with CF and 4 markers with DW. Notably, M100 marker was significantly both associated with CF and DM. Moreover, six significant associations were observed between CP and M213, M214, M215, M217, M218, and M216 markers, and the explained ratio of genetic variation were exceed 20 %. These identified marker alleles associated with quality traits could provide important information and markers for molecular-assisted breeding in tall fescue. [ABSTRACT FROM AUTHOR]