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

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.

Keywords: Arrhythmic risk; Hypertrophic cardiomyopathy; Ischaemia; Modelling and simulation.

Graphical Abstract

Figure 1

Cellular HCM response to ischaemia. (A) Simulated populations of non-ischaemic control (n = 228) and HCM (n = 228) human AP models. (B) ERPs among the populations under basal, hyperkalaemic (K_o = 8 mM), and hypoxic (f_KATP = 0.09) conditions, showing abnormal hyperkalaemic and enhanced hypoxic ERP shortening in HCM. (C) Representative simulated AP traces during hyperkalaemia (K_o = 8 mM; solid) compared to basal conditions (dashed). Arrows denote change in ERP due to hyperkalaemia. (D) Representative simulated AP traces during hypoxia (f_KATP = 0.09; solid) compared to basal conditions (dashed). Arrows denote change in ERP due to hypoxia. (E) Representative simulated AP traces with HCM remodelling except in I_NaL and I_Kr during ischaemia (hyperkalaemia, hypoxia, and acidosis; solid) compared to basal conditions (dashed). Arrow denotes change in ERP due to hyperkalaemia. (F) The difference in ERP during ischaemia with respect to basal conditions (ΔERP) among populations with full HCM ionic remodelling, HCM except I_NaL upregulation, HCM except I_Kr downregulation, HCM except both I_NaL and I_Kr remodelling, and control electrophysiology. (G) Representative patch-clamp human AP traces during hyperkalaemia (K_o = 9 mM; solid) compared to basal conditions (dashed) paced at 0.5 Hz (n = 12 HCM cells from N = 5 patients; n = 7 control cells from N = 3 patients). (H) The difference in APD90 during hyperkalaemia (K_o = 9 mM) with respect to basal conditions (ΔAPD90) vs. basal APD90 in patch-clamp experiments, compared to the simulated AP models paced at 0.5 Hz. Patch-clamp experiments confirmed the relationship between basal APD and hyperkalaemic APD decreases in control and HCM (both P < 0.001).

Figure 2

In-tissue characterization of HCM ischaemic arrhythmic risk. (A) Schematics of in-tissue acute myocardial ischaemia domains, with control electrophysiology (left) and regional HCM electrophysiology (right), for which arrhythmic risk was measured in 50 randomly sampled AP models. Domains consist of a CZ subject uniformly to the full extent of ischaemia, a BZ where ischaemic parameters (K_o, f_KATP, and I_CaL, I_Na inhibition) are linearly varied towards baseline values away from the CZ (left-hand side diagrams), and a normal zone (NZ) unaffected by ischaemia. The positions of sinus rhythm activation (S1) and the ectopic stimulus (S2) are denoted. (B) Summary statistics of arrhythmic risk over the hypoxia/hyperkalaemia parameter space for the 50 AP models in tissue, as characterized using ectopic S1-S2 pacing protocols. (C) Representative in-tissue simulations at K_o = 7 mM and f_KATP = 0.06 following application of S2 demonstrate how conduction block is infrequent in ischaemic control myocardium (left), but common in ischaemic HCM myocardium (right) due to repolarization impairment. Subsequent re-entries occur in HCM. The circular ischaemic region has visibly less negative resting membrane potential. Arrows and crosses indicate direction of wavefront propagation and locations of conduction block, respectively. Time elapsed (ms) following S2 is denoted in each frame. K_o, extracellular K⁺ concentration (mM); f_KATP, fraction of activated K-ATP channels; I_CaL, I_Na, L-type Ca²⁺ and fast Na⁺ currents.

Figure 3

Diffuse fibrosis modulates arrhythmic risk during ischaemia in HCM. Representative in-tissue simulations following application of S2 demonstrate how the presence of diffuse fibrosis affects re-entry inducibility in ischaemic HCM myocardium, through three different mechanisms. Conduction impairment at increased fibrosis density leads to (A) retrograde propagation block at the CZ, preventing re-entrant cycles, or (B) retrograde propagation delay at the CZ, enabling re-entrant cycles by allowing NZ to recover excitability. (C) The fibrotic microstructure leads to asymmetric retrograde propagation, such that the re-entrant wavefront interacts with the refractory wavetail and forms a stable rotor, anchored to the ischaemic–fibrotic region. Arrows and crosses indicate direction of wavefront propagation and locations of conduction block, respectively. Time elapsed (ms) following S2 is denoted in each frame.

Figure 4

Clinical perfusion imaging data from HCM patients. (A) Number of segments with wall thickness >15 mm, demonstrating predominant septal involvement of hypertrophy. (B) Number of segments with MPRI < 1, showing that perfusion impairment is diffuse in HCM. (C) Comparison of MPRI between patients with and without a history of ventricular tachycardia (n = 5, 23 respectively), where an association was observed between inferoseptal perfusion impairment and ventricular tachycardia (P < 0.01). (D) Colour perfusion scan showing large septal perfusion defects in an HCM patient. MPRI, myocardial perfusion reserve index; VT, ventricular tachycardia.

Figure 5

Transmural extent of ischaemia modulates arrhythmic risk in HCM. (A) Outcomes (either ectopic failure, no re-entry induced, single re-entry, or multiple cycles of re-entry) of the S1-S2 pacing protocol applied to the ischaemic biventricular HCM mesh, for the range of S1-S2 time intervals tested, with the minimum and maximum S1-S2 time denoted for each of the six ectopic positions. Subendocardial ischaemia (left) enabled wider windows of vulnerability to single re-entries, whereas transmural ischaemia (right) promoted increasingly sustained arrhythmia in HCM. At this low extent of ischaemia, re-entry was only inducible with regional HCM repolarization impairment. (B) Representative single cycle of re-entry in subendocardial ischaemia following the application of S2, compared with (C) multiple cycles of re-entry in transmural ischaemia, as viewed from the right ventricular cavity. Arrows and crosses indicate direction of wavefront propagation and locations of conduction block, respectively. Time elapsed (ms) following S2 is denoted in each frame.

Figure 6

Effect of fibrosis on arrhythmic risk during ischaemia is electrophysiology dependent in HCM. Outcomes (either ectopic failure, no re-entry induced, single re-entry, or multiple cycles of re-entry) of the S1-S2 pacing protocol applied to the transmurally ischaemic biventricular HCM mesh with mid-wall (left) and transmural (right) diffuse fibrosis, for the range of S1-S2 time intervals tested, with the minimum and maximum S1-S2 time denoted for each of the six ectopic positions. (A) When using the default ToR-ORd AP model, multiple re-entrant cycles that were previously possible in the non-fibrotic case were interrupted by both mid-wall and transmural fibrosis by bidirectional conduction block. (B) In an alternative AP model from the populations, for which re-entry was not inducible under non-fibrotic conditions, mid-wall and transmural fibrosis enabled sustained re-entries to be induced by delaying conduction. (C) Representative sustained re-entry formation following the application of S2 for the alternative AP model in the transmurally ischaemic and fibrotic biventricular HCM mesh, where fibrosis forces a re-entry to emerge asymmetrically, which sets up a large sustained rotor anchored to the diseased myocardium. Arrows and crosses indicate direction of wavefront propagation and locations of conduction block, respectively. Time elapsed (ms) following S2 is denoted in each frame.