Antiarrhythmic Effect of Reverse Ventricular Remodeling Induced by Cardiac Resynchronization Therapy The InSync ICD (Implantable Cardioverter-Defibrillator) Italian Registry

Objectives: We investigated whether the reverse remodeling after cardiac resynchronization therapy (CRT) might reduce the occurrence of ventricular arrhythmias (VAs). Background: It is currently debated whether CRT has an effect on the burden of VAs. Methods: The study included 398 patients treated with a CRT defibrillator and with a follow-up of at least 12 months. Spontaneous VAs detected by the device were reviewed and validated. Results: A significant reduction in VA episodes and shock therapies was evident during the follow-up with greater decrease after 1 month. After 6 months of CRT, 227 patients (57%) showed a reduction in end-systolic volume of ≥10% and were defined as "responders." The baseline characteristics were similar between the responders and the nonresponders. Nonetheless, the proportion of patients with recurrence of VA after 1 month of CRT was significantly lower in responders (32% vs. 43%, p = 0.024). Among baseline variables no parameters emerged as predictors of tachyarrhythmia recurrence. However, receiver-operating curve analysis recognized a reduction of left ventricular end-systolic volume at 6 months of 13% as the best cutoff to identify the reduction of VAs (with a sensitivity of 58% and a specificity of 54%). Conclusions: In patients treated with CRT defibrillators, a reduction in ventricular arrhythmic events occurs during the initial 12 months after implant and is correlated with the degree of ventricular remodeling induced by the therapy. Patients demonstrating reverse remodeling at midterm follow-up show a reduction in arrhythmias soon after the implant, pronounced improvements at long-term, and a better survival. © 2008 American College of Cardiology Foundation

Modified antimetabolites-loaded lipid nanocapsules to enhance antitumor immunity

Introduction : Myeloid­derived suppressor cells (MDSCs) are critical players of tumor­induced immunosuppression in mouse models and cancer patients. They accumulate in the spleen and cancers of tumor­bearing hosts where they suppress T­cell activation, proliferation and cytotoxic function [1]. Previous studies demonstrated that some anticancer agents, in addition to their cytotoxic effects on tumor cells, were able to affect MDSCs. This occurs for antimetabolites like 5­fluorouracile (5­FU) and Gemcitabine (Gem) [2]. In this work, the potential activity of novel lipophilic 5­FU and Gem derivatives encapsulated into lipid nanocapsules (LNCs) to target monocytic (M­)MDSC subset and tumor cells (pancreatic B6KPC3) was assessed. The aim was to study the immunogenic and anticancer properties of innovative nanosystems. Methods: Gem and 5­FU were modified to obtain mono­lauroyl­derivatives (Gem­C12 and 5­FU­C12). The derivatives were purified by chromatography on silica column and characterized by nuclear magnetic resonance. Blank and loaded­LNCs were prepared using the phase inversion process [3]. Physico­chemical characterization (size, dispersity, zeta potential and encapsulation efficiency) was performed. To study the in vitro induction of M­MDSCs, the immunosuppressive activity and internalization assays of GemC­12­loaded LNCs, mouse bone marrow cells cultured in presence of GM­CSF and IL­6 were used. To investigate the efficacy of 5­FU­C12­loaded LNCs, B6KPC3 cells were employed. Finally, as a preliminary in vivo study, the biodistribution of fluorescent­loaded LNCs (i.v. or s.c.) using tumor­bearing mice (EG7­OVA subcutaneous model) was evaluated. Results: Lipophilic derivatives, 5FU­C12 and Gem­C12, were synthetized. The yield of the products recovered was 60% and 40% for 5FU­C12 and Gem­C12, respectively. Blank, 5FU­C12 and Gem­C12­loaded LNCs showed an average size of 60 nm, dispersity index below 0.1 and neutral surface charge. The encapsulation efficiency of drugs was close to 100%. In vitro and in vivo studies highlighted that Gem­C12­loaded LNCs were internalized and depleted selectively M­MDSCs. Using K6PC3, we demonstrated that 5­FU­C12­loaded LNCs exerted a toxic effect comparable to the commercial 5FU­solution. In vivo studies following i.v. or s.c. administration of fluorescent­loaded LNCs showed that LNCs reached peripheral tissues. As compared with i.v., following s.c. injection, fluorescent signal increased with time in the spleen, suggesting a slow LNCs absorption. Conclusions : In the present study, lipophilic 5­FU­C12 and Gem­C12­loaded LNC were obtained. Gem­C12­ loaded LNCs were able to target M­MDSCs in vivo and in vitro. Besides, 5­FU­C12­loaded LNCs showed efficacy as anticancer drug in a pancreatic cell line. Further in vitro and in vivo therapeutic evaluations would disclose the full potential of these novel LNCs.

Drug delivery to tumours using a novel 5-FU derivative encapsulated into lipid nanocapsules

In this work, a novel lipophilic 5-fluorouracil (5-FU) derivative was synthesised and encapsulated into lipid nanocapsules (LNC). 5-FU was modified with lauric acid to give a lipophilic mono-lauroyl-derivative (5-FU-C12, MW of about 342 g/mol, yield of reaction 70%). 5-FU-C12 obtained was efficiently encapsulated into LNC (encapsulation efficiency above 90%) without altering the physico-chemical characteristics of LNC. The encapsulation of 5-FU-C12 led to an increased stability of the drug when in contact with plasma being the drug detectable until 3 h following incubation. Cytotoxicity assay carried out using MTS on 2D cell culture showed that 5-FU-C12-loaded LNC had an enhanced cytotoxic effect on glioma (9L) and human colorectal (HTC-116) cancer cell line in comparison with 5-FU or 5-FU-C12. Then, HCT-116 tumour spheroids were cultivated and the reduction of spheroid volume was measured following treatment with drug-loaded LNC and drugs alone. Similar reduction on spheroids volume was observed following the treatment with drug-loaded LNC, 5-FU-C12 and 5-FU alone, while blank LNC displayed a reduction in cell viability only at high concentration. Globally, our data suggest that the encapsulation increased the activity of the 5-FU-C12. However, in-depth evaluations of LNC permeability into spheroids are needed to disclose the potential of these nanosystems for cancer treatment

Effectiveness of cardiac resynchronization therapy in heart failure patients with valvular heart disease: comparison with patients affected by ischaemic heart disease or dilated cardiomyopathy. The InSync/InSync ICD Italian Registry

AimsTo analyse the effectiveness of cardiac resynchronization therapy (CRT) in patients with valvular heart disease (a subset not specifically investigated in randomized controlled trials) in comparison with ischaemic heart disease or dilated cardiomyopathy patients.Methods and resultsPatients enrolled in a national registry were evaluated during a median follow-up of 16 months after CRT implant. Patients with valvular heart disease treated with CRT (n = 108) in comparison with ischaemic heart disease (n = 737) and dilated cardiomyopathy (n = 635) patients presented: (i) a higher prevalence of chronic atrial fibrillation, with atrioventricular node ablation performed in around half of the cases; (ii) a similar clinical and echocardiographic profile at baseline; (iii) a similar improvement of LVEF and a similar reduction in ventricular volumes at 6-12 months; (iv) a favourable clinical response at 12 months with an improvement of the clinical composite score similar to that occurring in patients with dilated cardiomyopathy and more pronounced than that observed in patients with ischaemic heart disease; (v) a long-term outcome, in term of freedom from death or heart transplantation, similar to patients affected by ischaemic heart disease and basically more severe than that of patients affected by dilated cardiomyopathy.ConclusionIn 'real world' clinical practice, CRT appears to be effective also in patients with valvular heart disease. However, in this group of patients the outcome after CRT does not precisely overlap any of the two other groups of patients, for which much more data are currently available

Long-term safety and efficacy of Eculizumab in Aquaporin-4 IgG-positive NMOSD

Objective During PREVENT (NCT01892345), eculizumab significantly reduced relapse risk versus placebo in patients with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD). We report an interim analysis of PREVENT's ongoing open-label extension (OLE; NCT02003144) evaluating eculizumab's long-term safety and efficacy. Methods Patients who completed PREVENT could enroll in the OLE to receive eculizumab (maintenance dose = 1,200 mg/2 weeks, after a blinded induction phase). Safety and efficacy data from PREVENT and its OLE (interim data cut, July 31, 2019) were combined for this analysis. Results Across PREVENT and the OLE, 137 patients received eculizumab and were monitored for a median (range) of 133.3 weeks (5.1–276.9 weeks), for a combined total of 362.3 patient-years (PY). Treatment-related adverse event (AE) and serious adverse event (SAE) rates were 183.5 in 100 PY and 8.6 in 100 PY, respectively. Serious infection rates were 10.2 in 100 PY in eculizumab-treated patients versus 15.1 in 100 PY in the PREVENT placebo group. No patient developed a meningococcal infection. At 192 weeks (3.7 years), 94.4% (95% confidence interval [CI], 88.6–97.3) of patients remained adjudicated relapse-free. The adjudicated annualized relapse rate was 0.025 (95% CI = 0.013–0.048) in all eculizumab-treated patients versus 0.350 (95% CI = 0.199–0.616) in the PREVENT placebo group. During the OLE, 37% of patients (44 of 119 patients) stopped or decreased background immunosuppressive therapy use. Interpretation This analysis demonstrates that eculizumab's long-term safety profile in NMOSD is consistent with its established profile across other indications. This analysis also demonstrated the sustained ability of long-term eculizumab treatment to reduce relapse risk in patients with AQP4-IgG+ NMOSD. ANN NEUROL 2021;89:1088–109

BIVENTRICULAR PACING IN PATIENTS CANDIDATE TO AN ICD

EUROPEAN HEART JOURNA