Colchicine added to standard therapy further reduces fibrosis in pigs with myocardial infarction

Background: The anti-inflammatory drug colchicine improves the outcome of patients with myocardial infarction (MI). As an intense inflammatory and fibrotic response after MI may lead to scar expansion and left ventricular (LV) remodeling, the clinical benefit of colchicine could be related to a positive effect on the infarct scar and LV remodeling. Methods: Pigs underwent left anterior descending artery occlusion through an angioplasty balloon for 90 min and were then randomized into two groups: standard therapy [ACE inhibitor, beta blocker, mineralocorticoid receptor antagonist (MRA), aspirin] plus colchicine (n = 14) or standard therapy alone (n = 13). The pigs were treated for 30 days and underwent two cardiac magnetic resonance (CMR) scans at 72 h and 30 days. The pigs were then sacrificed the day after the second CMR. The primary efficacy end point was the extent of fibrosis in the infarct zone (calculated on eight samples from this zone and averaged). Results: In the hearts explanted after 31 days, pigs in the colchicine group had less fibrosis in the infarct zone than the other animals [41.6% (20.4-51.0) vs. 57.4% (42.9-66.5); P = 0.022]. There was a trend toward a higher myocardial salvage index (MSI; an index of the efficacy of revascularization) in pigs on colchicine (P = 0.054). Conversely, changes in LV volumes, ejection fraction and mass did not differ between groups. Conclusion: Colchicine therapy for 1 month after reperfused MI further reduces myocardial fibrosis when added to standard therapy, while it does not have additional effects on LV remodeling

Intrapericardial cardiosphere-derived cells hinder epicardial dense scar expansion and promote electrical homogeneity in a porcine post-infarction model

The arrhythmic substrate of ventricular tachycardias in many structural heart diseases is located in the epicardium, often resulting in poor outcomes with currently available therapies. Cardiosphere-derived cells (CDCs) have been shown to modify myocardial scarring. A total of 19 Large White pigs were infarcted by occlusion of the mid-left anterior descending coronary artery for 150 min. Baseline cardiac magnetic resonance (CMR) imaging with late gadolinium enhancement sequences was obtained 4 weeks post-infarction and pigs were randomized to a treatment group (intrapericardial administration of 300,000 allogeneic CDCs/kg), (n = 10) and to a control group (n = 9). A second CMR and high-density endocardial electroanatomical mapping were performed at 16 weeks post-infarction. After the electrophysiological study, pigs were sacrificed and epicardial optical mapping and histological studies of the heterogeneous tissue of the endocardial and epicardial scars were performed. In comparison with control conditions, intrapericardial CDCs reduced the growth of epicardial dense scar and epicardial electrical heterogeneity. The relative differences in conduction velocity and action potential duration between healthy myocardium and heterogeneous tissue were significantly smaller in the CDC-treated group than in the control group. The lower electrical heterogeneity coincides with heterogeneous tissue with less fibrosis, better cardiomyocyte viability, and a greater quantity and better polarity of connexin 43. At the endocardial level, no differences were detected between groups. Intrapericardial CDCs produce anatomical and functional changes in the epicardial arrhythmic substrate, which could have an anti-arrhythmic effect.This study was supported by the Instituto de Salud Carlos III, Madrid, Spain (PI18/01895 and DTS21/00064); Red de Terapia Celular from the Instituto de Salud Carlos III, Madrid, Spain (RD16/0011/0029); Ricors-Red de Investigación Cooperativa Orientada a Resultados en Salud-RICORS TERAV (RD21.0017.0002), European Union's H2020 Program under grant agreement No. 874827 (BRAVE), and the Sociedad Española de Cardiología, Madrid, Spain

Effectiveness of a single-dose mass dengue vaccination in Cebu, Philippines: A case-control study.

BACKGROUND: Dengue fever is an important public health problem in the Philippines. In April 2016, the Department of Health launched a three-dose school based dengue vaccination program of nine- to fourteen-year-old children in three regions with the highest number of dengue cases using CYD-TDV (Dengvaxia, Sanofi Pasteur). In July 2017, a community-based dengue vaccination program was implemented in Cebu province. The program was discontinued in December 2017 amidst public controversy, after the first dose had been administered. We assessed the effectiveness of a single dose of CYD-TDV against hospitalized virologically confirmed dengue (VCD). METHODS: We conducted a case-control study in Cebu province following the dengue mass vaccination. Children who were nine to fourteen years of age during the mass vaccination and subsequently admitted to any of four participating public hospitals with suspected dengue were enrolled in the study as cases. Blood for RT-PCR and clinical and socio-demographic information were obtained. To estimate the level of vaccine protection, vaccination status was compared between children with hospitalized virologically confirmed dengue and controls of the same six-year age-group as the cases, matched on sex, neighborhood and time of occurrence of cases. FINDINGS: We enrolled 490 cases and 980 controls. Receipt of one dose of CYD-TDV was associated with 26% (95 % CI, -2 to 47%; p = 0 0675) overall protection against hospitalized virologically confirmed dengue and 51% (95 % CI, 23 to 68; p = 0 0016) protection against dengue with warning signs. INTERPRETATION: A single dose of CYD-TDV given to nine to fourteen-year-old children through a community-based mass vaccination program conferred protection against dengue with warning signs and severe dengue but we were unable to conclude on protection against milder illness

Dose-dependent improvement of cardiac function in a swine model of acute myocardial infarction after intracoronary administration of allogeneic heart-derived cells

Allogeneic cardiac-derived progenitor cells (CPC) without immunosuppression could provide an effective ancillary therapy to improve cardiac function in reperfused myocardial infarction. We set out to perform a comprehensive preclinical feasibility and safety evaluation of porcine CPC (pCPC) in the infarcted porcine model, analyzing biodistribution and mid-term efficacy, as well as safety in healthy non-infarcted swine.This work was mainly supported by the European FP7-HEALTH-2009-1.4-3, Grant Agreement 242038. In addition, it was partially supported by FEDER funds and grants from the Ministerio de Economia industria y Competitividad ISCIII (PI16/01172) co-funded by ERDF/ESF, “Investing in your future” and Junta de Extremadura Consejeria de Economía e Infraestructuras (IB16201) to VC, and the Spanish Ministry of Science and Innovation (SAF2015-70882-R; AEI/FEDER, UE) and the Instituto de Salud Carlos III (RETICS-RD12/0019/0018) to AB.Peer reviewe

Personalized tissue-engineered veins – long term safety, functionality and cellular transcriptome analysis in large animals

Tissue engineering is a promising methodology to produce advanced therapy medicinal products (ATMPs). We have developed personalized tissue engineered veins (P-TEV) as an alternative to autologous or synthetic vascular grafts utilized in reconstructive vein surgery. Our hypothesis is that individualization through reconditioning of a decellularized allogenic graft with autologous blood will prime the tissue for efficient recellularization, protect the graft from thrombosis, and decrease the risk of rejection. In this study, P-TEVs were transplanted to vena cava in pig, and the analysis of three veins after six months, six veins after 12 months and one vein after 14 months showed that all P-TEVs were fully patent, and the tissue was well recellularized and revascularized. To confirm that the ATMP product had the expected characteristics one year after transplantation, gene expression profiling of cells from P-TEV and native vena cava were analyzed and compared by qPCR and sequencing. The qPCR and bioinformatics analysis confirmed that the cells from the P-TEV were highly similar to the native cells, and we therefore conclude that P-TEV is functional and safe in large animals and have high potential for use as a clinical transplant graft.CC BY 3.0First published 13 Apr [email protected] study was supported by Vinnova project CAMP (contract no. 2017-02130), a common call by VINNOVA and Vetenskapsrådet: Biologcal pharmaseuticals (Dnr 2017-02983), by University of Skövde under grants from the Swedish Knowledge Foundation [#2016-0330, #2020-0014] and Västra Götalandsregionen (consultant check). The company VERIGRAFT AB holds a patent on peripheral whole blood perfusion of decellularized tissues and did also finance the project. We want to acknowledge the staff at the Department of Experimental Biomedicine at Gothenburg University. The swine studies in Spain were conducted by the ICTS ‘NANBIOSIS’, specifically Units 21, 22, and 24 of the CCMIJU. Graphical Abstract image created with BioRender.com.</p