Journal article
Mechanisms of ischaemia-induced arrhythmias in hypertrophic cardiomyopathy: a large-scale computational study
- Abstract:
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Aims: Lethal arrhythmias in hypertrophic cardiomyopathy (HCM) are widely attributed to myocardial ischaemia and fibrosis. How these factors modulate arrhythmic risk remains largely unknown, especially as invasive mapping protocols are not routinely used in these patients. By leveraging multiscale digital twin technologies, we aim to investigate ischaemic mechanisms of increased arrhythmic risk in HCM.
Methods and results: Computational models of human HCM cardiomyocytes, tissue, and ventricles were used to simulate outcomes of Phase 1A acute myocardial ischaemia. Cellular response predictions were validated with patch-clamp studies of human HCM cardiomyocytes (n = 12 cells, N = 5 patients). Ventricular simulations were informed by typical distributions of subendocardial/transmural ischaemia as analysed in perfusion scans (N = 28 patients). S1-S2 pacing protocols were used to quantify arrhythmic risk for scenarios in which regions of septal obstructive hypertrophy were affected by (i) ischaemia, (ii) ischaemia and impaired repolarization, and (iii) ischaemia, impaired repolarization, and diffuse fibrosis. HCM cardiomyocytes exhibited enhanced action potential and abnormal effective refractory period shortening to ischaemic insults. Analysis of ∼75 000 re-entry induction cases revealed that the abnormal HCM cellular response enabled establishment of arrhythmia at milder ischaemia than otherwise possible in healthy myocardium, due to larger refractoriness gradients that promoted conduction block. Arrhythmias were more easily sustained in transmural than subendocardial ischaemia. Mechanisms of ischaemia–fibrosis interaction were strongly electrophysiology dependent. Fibrosis enabled asymmetric re-entry patterns and break-up into sustained ventricular tachycardia.
Conclusion: HCM ventricles exhibited an increased risk to non-sustained and sustained re-entry, largely dominated by an impaired cellular response and deleterious interactions with the diffuse fibrotic substrate.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 1.2MB, Terms of use)
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- Publisher copy:
- 10.1093/cvr/cvae086
Authors
- Publisher:
- Oxford University Press
- Journal:
- Cardiovascular Research More from this journal
- Volume:
- 120
- Issue:
- 8
- Pages:
- 914–926
- Place of publication:
- England
- Publication date:
- 2024-04-22
- Acceptance date:
- 2024-03-17
- DOI:
- EISSN:
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1755-3245
- ISSN:
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0008-6363
- Pmid:
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38646743
- Language:
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English
- Keywords:
- Pubs id:
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1992273
- Local pid:
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pubs:1992273
- Deposit date:
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2024-05-09
Terms of use
- Copyright holder:
- Coleman et al.
- Copyright date:
- 2024
- Rights statement:
- © The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
- Notes:
- For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript (AAM) version arising from this submission.
- Licence:
- CC Attribution (CC BY)
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