In silico evaluation of cell therapy in acute versus chronic infarction: role of automaticity, heterogeneity and Purkinje in human
Human-based modelling and simulation offer an ideal testbed for novel medical therapies to guide experimental and clinical studies. Myocardial infarction (MI) is a common cause of heart failure and mortality, for which novel therapies are urgently needed. Although cell therapy offers promise, electrophysiological heterogeneity raises pro-arrhythmic safety concerns, where underlying complex spatio-temporal dynamics cannot be investigated experimentally. Here, after demonstrating credibility of the modelling and simulation framework, we investigate cell therapy in acute versus chronic MI and the role of cell heterogeneity, scar size and the Purkinje system. Simulations agreed with experimental and clinical recordings from ionic to ECG dynamics in acute and chronic infarction. Following cell delivery, spontaneous beats were facilitated by heterogeneity in cell populations, chronic MI due to tissue depolarisation and slow sinus rhythm. Subsequent re-entrant arrhythmias occurred, in some instances with Purkinje involvement and their susceptibility was enhanced by impaired Purkinje-myocardium coupling, large scars and acute infarction. We conclude that homogeneity in injected ventricular-like cell populations minimises their spontaneous beating, which is enhanced by chronic MI, whereas a healthy Purkinje-myocardium coupling is key to prevent subsequent re-entrant arrhythmias, particularly for large scars.
Authors
- Rodrigo Weber dos Santos (ORCID: https://orcid.org/0000-0002-0633-1391)
- Rafael Sachetto Oliveira (ORCID: https://orcid.org/0000-0003-0800-5984)
- Lucas Arantes Berg (ORCID: https://orcid.org/0000-0002-8777-0125)
- Jacopo Biasetti (ORCID: https://orcid.org/0000-0001-7180-7889)
- Leto Luana Riebel (ORCID: https://orcid.org/0000-0002-5774-2406)
- Hector Martinez‐Navarro (ORCID: https://orcid.org/0000-0003-0234-2605)
- Zhinuo Jenny Wang (ORCID: https://orcid.org/0000-0001-5325-909X)
- Julià Camps (ORCID: https://orcid.org/0000-0002-6491-2565)
- Xin Zhou (ORCID: https://orcid.org/0000-0003-2814-3399)
- Cristian Trovato (ORCID: https://orcid.org/0000-0002-2593-290X)
- Rubén Doste (ORCID: https://orcid.org/0000-0003-4187-4970)
- Blanca Rodríguez (ORCID: https://orcid.org/0000-0002-3435-7388)
Institutions
- Universidade Federal de Juiz de Fora (BR)
- AstraZeneca (United Kingdom) (GB)
- Federal University of São João del-Rei (BR)
- University of Oxford (GB)
- AstraZeneca (Sweden) (SE)
Publication Details
- Journal
- Scientific Reports
- Published
- 2024-09-16
- DOI
- https://doi.org/10.1038/s41598-024-67951-5
- Citations
- 16
- Primary Topic
- Cardiac electrophysiology and arrhythmias
- Type
- article
- Field-Weighted Citation Impact
- 6.43
Funders
- Bristol-Myers Squibb
- AstraZeneca
- Wellcome
- Wellcome Trust
- British Heart Foundation
- European Commission
- Partnership for Advanced Computing in Europe AISBL
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Fundação de Amparo à Pesquisa do Estado de Minas Gerais
- BHF Centre of Research Excellence, Oxford
- Universidade Federal de Juiz de Fora
- National Centre for the Replacement Refinement and Reduction of Animals in Research
- Universidade Federal de São João del-Rei
- Centro Svizzero di Calcolo Scientifico
- National Supercomputing Centre Singapore
- Engineering and Physical Sciences Research Council
- Biotechnology and Biological Sciences Research Council