Morbidity and mortality from ischaemic heart disease (IHD) and heart failure (HF) remain significant in Europe and are increasing worldwide. Patients with IHD or HF might benefit from novel therapeutic strategies, such as cellbased therapies. We recently discussed the therapeutic potential of cell-based therapies and provided recommendations on how to improve the therapeutic translation of these novel strategies for effective cardiac regeneration and repair. Despite major advances in optimizing these strategies with respect to cell source and delivery method, the clinical outcome of cell-based therapy remains unsatisfactory. Major obstacles are the low engraftment and survival rate of transplanted cells in the harmful microenvironment of the host tissue, and the paucity or even lack of
Cardiac tissue conduction velocity (CV) is a relevant variable in the maintenance and stability of atrial fibrillation (AF). The main goal of this work is to investigate modulation of CV in human chronic AF by inter-subject variability in ionic channel properties, cellular environmental factors and tissue coupling, by using a population of mathematical models. A monodomain tissue model was developed on the basis of the Skibsbye human atrial cell model. In this model, nine parameters are varied leading to a total number of 500 tissue models (8x156 cells). Among these simulations, 126 models are found within the experimental physiological range of biomarkers obtained from 149 chronic AF patients. The resulting population of 126 tissue models covers the variability in the biomarkers observed in the experimental recordings. The specific balance between sodium current and diffusion coefficient modulates the CV, critical for arrhythmia inducibility. The developed population of tissue models establishes the basis for further research in ionic mechanisms that facilitate AF maintenance and in-silico evaluation of personalised drug treatments.
Background Cardiac ageing is associated to heart failure with preserved ejection fraction (HF-pEF) and increased senescence, hypertrophy and diastolic dysfunction. No treatments have yet proved to reduce HF-pEF morbidity and mortality. Cardiosphere-derived cells (CDCs) and their secreted extracellular vesicles (CDC-EVs) have demonstrated efficacy in old animals with cardiac dysfunction, but variability of effect and lack of adequate potency tests remain as challenges. Purpose To explore in vitro predictors of cardiac protective potency of CDC-EVs, focusing on the chronological age of the CDC-donors, CDC-senescence, and their in vitro anti-senescent and pro-angiogenic effect. Methods CDCs derived from 34 patients (age range 0–81 years old, both sexes) were characterized in terms of senescence, proliferative and migration capacities, VEGF secretion, expression of specific surface markers and cardiosphere size. CDC-EVs were purified and their in vitro anti-senescent potential (at genetic, secretory and cellular level over cardiac stromal cells) and their pro-angiogenic potential (ability to induce tube formation over endothelial cells) quantified. According to the performance in each of these tests, potency was scored and CDC-EVs were classified as potent (P-EVs) and non-potent (NP-EVs). The effect of P-EVs and NP-EVs were then tested in vivo in rats with induced cardiac aging. SD-rats received 3-months of daily intraperitoneal injections (IP) of saline (healthy control) or D-galactose. Rats in the D-Gal group were randomly allocated to receive IP saline (sham control, n=12), P-EVs (n=7) or NP-EVs (n=6) and followed-up for one month. Results Chronological age of the donor or expression of surface markers did not relate to most CDC properties nor to their in vitro potency. CDC senescence did relate to other CDC bioactive properties, but this was insufficient to predict CDC-EV anti-senescence and pro-angiogenic in vitro potency. In vivo, EV classified as P-EVs, but not NP-EVs, prevented D-gal induced hypertrophy (2.4 vs. 2.9 mg/gr, p=0.05). This finding was in parallel to the levels of galactosidase-beta 1 expression in cardiac tissue, which were increased in sham vs. P-EVs (1.22 vs. 0.73, p=0.03) but levels in NP-EVs were not significantly different to the sham group (0.86, p=0.1). P-EVs tended to reduce TGFB1 expression, while NP-EVs significantly increased cardiac fibrosis and reduced cardiac perfusion. At systemic level, while P-EVs significantly improved glucose metabolism and tended to drive total antioxidant capacity and hair growth to a healthier profile, NP-EVs did not significantly improve any of the explored parameters and significantly increased total antioxidant capacity. Conclusions After further validation, the matrix potency assay proposed here, scoring the anti-senescent and pro-angiogenic in vitro effect of CDC-EVs could be used to predict EV suitability as an allogenic product in the treatment of cardiac ageing. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Instituto de Salud Carlos III, Ministerio de Ciencia e Innovaciόn, Spain: PI16/01123; PI19/00161; Red de Terapia Celular, Tercel, (RD16.0011.0029) and CIBERCV (CB16.11.00292)
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.