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

Area of Science:

• Computational biology
• Cardiovascular research
• Medical imaging

Background:

• Lethal arrhythmias in hypertrophic cardiomyopathy (HCM) are linked to myocardial ischemia and fibrosis.
• The precise mechanisms by which these factors increase arrhythmic risk are not fully understood.
• Invasive mapping is not standard practice for HCM patients, limiting current understanding.

Purpose of the Study:

• To investigate the mechanisms of increased arrhythmic risk in HCM using multiscale digital twin technologies.
• To simulate the effects of myocardial ischemia on HCM cardiac cells and tissue.
• To explore how ischemia interacts with fibrosis to influence arrhythmia generation in HCM.

Main Methods:

• Developed multiscale computational models of human HCM cardiomyocytes, tissue, and ventricles.
• Simulated acute myocardial ischemia and its effects on cellular electrophysiology.
• Validated cellular model predictions with patch-clamp studies.
• Incorporated patient-specific ischemia distributions from perfusion scans into ventricular models.
• Quantified arrhythmic risk using S1-S2 pacing protocols under various conditions (ischemia, impaired repolarization, fibrosis).

Main Results:

• HCM cardiomyocytes showed abnormal action potential and shortened refractory periods in response to ischemia.
• Simulations indicated that HCM's cellular response facilitates arrhythmia induction at lower ischemia levels than in healthy hearts.
• Larger refractoriness gradients in HCM promote conduction block, enabling re-entry.
• Transmural ischemia posed a higher risk for sustained arrhythmias than subendocardial ischemia.
• Fibrosis interacted with ischemia to create asymmetric re-entry patterns, leading to sustained ventricular tachycardia.

Conclusions:

• HCM ventricles demonstrate an elevated risk for both non-sustained and sustained re-entrant arrhythmias.
• This increased risk is primarily driven by an impaired cellular electrophysiological response to ischemia.
• Deleterious interactions between ischemia and the diffuse fibrotic substrate significantly contribute to arrhythmia susceptibility.