Mechanisms of ischaemia-induced arrhythmias in hypertrophic cardiomyopathy: a large-scale computational study

Author:

Coleman James A1ORCID,Doste Ruben1ORCID,Ashkir Zakariye2ORCID,Coppini Raffaele3ORCID,Sachetto Rafael4,Watkins Hugh5ORCID,Raman Betty2ORCID,Bueno-Orovio Alfonso1ORCID

Affiliation:

1. Department of Computer Science, University of Oxford , Oxford , UK

2. Oxford Centre for Clinical Magnetic Resonance Research (OCMR), Radcliffe Department of Medicine, Division of Cardiovascular Medicine, University of Oxford , Oxford , UK

3. Department of NeuroFarBa, University of Florence , Florence , Italy

4. Department of Computer Science, Federal University of São João del-Rei , São João del-Rei, Minas Gerais , Brazil

5. Radcliffe Department of Medicine, Division of Cardiovascular Medicine, University of Oxford , Oxford , UK

Abstract

Abstract 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.

Funder

UK Engineering and Physical Sciences Research Council

British Heart Foundation

Swiss National Supercomputing Centre, Switzerland

University of Oxford Advanced Research Computing

Publisher

Oxford University Press (OUP)

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