In silico evaluation of cell therapy in acute versus chronic infarction: role of automaticity, heterogeneity and Purkinje in human.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Myocardial Infarction*/therapy ; Myocardial Infarction*/pathology ; Myocardial Infarction*/physiopathology ; Computer Simulation* ; Cell- and Tissue-Based Therapy*/methods; Humans ; Arrhythmias, Cardiac/therapy ; Arrhythmias, Cardiac/physiopathology ; Models, Cardiovascular ; Chronic Disease ; Male ; Purkinje Fibers/physiopathology ; Electrocardiography ; Acute Disease ; Female ; Middle Aged

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.
(© 2024. The Author(s).)

Circulation. 2000 Jun 27;101(25):2981-8. (PMID: 10869273)
Heart Rhythm. 2010 Jan;7(1):127-35. (PMID: 19939742)
Herzschrittmacherther Elektrophysiol. 2018 Mar;29(1):62-69. (PMID: 29392412)
Front Physiol. 2017 Sep 12;8:668. (PMID: 28955244)
Trends Mol Med. 2016 Feb;22(2):99-114. (PMID: 26776094)
PLoS One. 2016 Mar 02;11(3):e0149342. (PMID: 26934736)
Front Pharmacol. 2021 Mar 15;12:604713. (PMID: 33841140)
Circ Arrhythm Electrophysiol. 2015 Feb;8(1):76-86. (PMID: 25527678)
Elife. 2022 Jan 25;11:. (PMID: 35076018)
Biophys J. 2020 May 19;118(10):2596-2611. (PMID: 32298635)
Int J Numer Method Biomed Eng. 2018 Feb;34(2):. (PMID: 28636811)
Circulation. 2000 Jun 13;101(23):E215-20. (PMID: 10851218)
J Electrocardiol. 2018 Jul - Aug;51(4):607-612. (PMID: 29996998)
J Mol Cell Cardiol. 2020 May;142:24-38. (PMID: 32251669)
Circ Res. 2003 Jul 11;93(1):32-9. (PMID: 12791707)
Circ Res. 2003 Sep 5;93(5):381-3. (PMID: 12958139)
Circulation. 1987 Feb;75(2):379-86. (PMID: 3802441)
Europace. 2021 Mar 4;23(23 Suppl 1):i143-i152. (PMID: 33751088)
Front Physiol. 2022 Apr 25;13:877428. (PMID: 35547576)
Front Toxicol. 2022 Oct 05;4:992650. (PMID: 36278026)
Circulation. 2021 May 18;143(20):1991-2006. (PMID: 33648345)
Front Physiol. 2020 Sep 16;11:1145. (PMID: 33041850)
CPT Pharmacometrics Syst Pharmacol. 2021 Aug;10(8):804-825. (PMID: 34102034)
Am J Emerg Med. 2009 Jul;27(6):734-46. (PMID: 19751632)
Heart Rhythm. 2009 Dec;6(12):1782-9. (PMID: 19959130)
Nat Med. 2006 Apr;12(4):452-8. (PMID: 16582915)
Methods. 2021 Jan;185:120-127. (PMID: 31991193)
Clin Med Insights Cardiol. 2014 Sep 25;8(Suppl 1):1-13. (PMID: 25368538)
Cardiovasc Res. 2022 Mar 25;118(5):1247-1261. (PMID: 33881518)
Front Physiol. 2019 Aug 27;10:1103. (PMID: 31507458)
Open Heart. 2021 Jun;8(1):. (PMID: 34099530)
Elife. 2019 Dec 24;8:. (PMID: 31868580)
Heart Rhythm. 2021 Jun;18(6):954-961. (PMID: 33515714)
Annu Rev Biomed Eng. 2005;7:223-53. (PMID: 16004571)
J Mol Cell Cardiol. 2000 Apr;32(4):621-30. (PMID: 10756118)
PLoS One. 2013 Jul 02;8(7):e68872. (PMID: 23844245)
PLoS Comput Biol. 2022 Apr 1;18(4):e1010030. (PMID: 35363778)
PLoS One. 2012;7(7):e40288. (PMID: 22815737)
Sci Rep. 2019 Nov 14;9(1):16803. (PMID: 31728039)
Adv Ther (Weinh). 2020 Mar;3(3):. (PMID: 33665356)
J Physiol. 2023 Jul;601(13):2733-2749. (PMID: 37014103)
Sci Rep. 2023 Jul 21;13(1):11788. (PMID: 37479707)
Front Physiol. 2022 Sep 15;13:966046. (PMID: 36187798)
J Pharmacol Toxicol Methods. 2022 Nov-Dec;118:107228. (PMID: 36273536)
Cardiovasc Res. 2011 Mar 1;89(4):744-53. (PMID: 20962103)
Comput Biol Med. 2023 Mar;154:106550. (PMID: 36701966)
Nat Cell Biol. 2022 May;24(5):659-671. (PMID: 35550611)
Circ Arrhythm Electrophysiol. 2020 Apr;13(4):e007792. (PMID: 32191131)
Sci Rep. 2019 Jun 25;9(1):9238. (PMID: 31239508)
Mol Ther. 2018 Jul 5;26(7):1644-1659. (PMID: 29606507)
Med Image Anal. 2024 May;94:103108. (PMID: 38447244)
Biophys J. 1970 Apr;10(4):345-63. (PMID: 5436883)
Am J Physiol. 1985 Dec;249(6 Pt 2):H1228-31. (PMID: 3000199)
Nat Cardiovasc Res. 2024 Feb;3(2):145-165. (PMID: 39196193)
Theranostics. 2017 May 17;7(7):2067-2077. (PMID: 28638487)
Front Cardiovasc Med. 2018 Jun 11;5:52. (PMID: 29942806)
PLoS Comput Biol. 2011 May;7(5):e1002061. (PMID: 21637795)
Cell Stem Cell. 2023 Apr 6;30(4):396-414.e9. (PMID: 37028405)
Am J Cardiol. 2007 Apr 15;99(8):1109-14. (PMID: 17437737)
Am J Physiol Heart Circ Physiol. 2011 Nov;301(5):H2006-17. (PMID: 21890694)
Cardiovasc Res. 2015 Oct 1;108(1):188-96. (PMID: 26209251)
IEEE Trans Biomed Eng. 2011 Aug;58(8):. (PMID: 21536529)
Stem Cell Reports. 2019 May 14;12(5):967-981. (PMID: 31056479)
Ann Biomed Eng. 1994 Jan-Feb;22(1):34-44. (PMID: 8060025)
Int J Cardiol. 2020 Feb 15;301:14-20. (PMID: 31761400)
Nature. 2014 Jun 12;510(7504):273-7. (PMID: 24776797)
Circulation. 1987 Oct;76(4):860-74. (PMID: 3652425)
Int J Numer Method Biomed Eng. 2019 Apr;35(4):e3185. (PMID: 30721579)

(R39207/CN063) Oxford-Bristol Myers Squibb Fellowship; icp019 Partnership for Advanced Computing in Europe AISBL (PRACE); BB/V509395/1 RCUK | Biotechnology and Biological Sciences Research Council (BBSRC); 214290/Z/18/Z Wellcome Trust (Wellcome); NC/P001076/1 National Centre for the Replacement Refinement and Reduction of Animals in Research (NC3Rs); grant agreements No. 675451 CompBioMed project (European Commission Horizon 2020 research and innovation programme); (EP/X019446/1) EPSRC project CompBioMed X; United Kingdom WT_ Wellcome Trust; PRACE-ICEI icp013 Partnership for Advanced Computing in Europe AISBL (PRACE); R67719/CN001 AstraZeneca; RE/13/1/30181 BHF Centre of Research Excellence, Oxford (BHF Centre of Research Excellence in Oxford); No. 823712 CompBioMed project (European Commission Horizon 2020 research and innovation programme)

Date Created: 20240916 Date Completed: 20240916 Latest Revision: 20241026

20250114

PMC11405404

10.1038/s41598-024-67951-5

39284812