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

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

Altered Ca2+ and Na+ Homeostasis in Human Hypertrophic Cardiomyopathy: Implications for Arrhythmogenesis

Hypertrophic cardiomyopathy (HCM) is the most common mendelian heart disease, with a prevalence of 1/500. HCM is a primary cause of sudden death, due to an heightened risk of ventricular tachyarrhythmias that often occur in young asymptomatic patients. HCM can slowly progress toward heart failure, either with preserved or reduced ejection fraction, due to worsening of diastolic function. Accumulation of intra-myocardial fibrosis and replacement scars underlies heart failure progression and represents a substrate for sustained arrhythmias in end-stage patients. However, arrhythmias and mechanical abnormalities may occur in hearts with little or no fibrosis, prompting toward functional pathomechanisms. By studying viable cardiomyocytes and trabeculae isolated from inter-ventricular septum samples of non-failing HCM patients with symptomatic obstruction who underwent myectomy operations, we identified that specific abnormalities of intracellular Ca2+ handling are associated with increased cellular arrhytmogenesis and diastolic dysfunction. In HCM cardiomyocytes, diastolic Ca2+ concentration is increased both in the cytosol and in the sarcoplasmic reticulum and the rate of Ca2+ transient decay is slower, while the amplitude of Ca2+-release is preserved. Ca2+ overload is the consequence of an increased Ca2+ entry via L-type Ca2+-current [due to prolongation the action potential (AP) plateau], combined with a reduced rate of Ca2+-extrusion through the Na+/Ca2+ exchanger [due to increased cytosolic (Na+)] and a lower expression of SERCA. Increased late Na+ current (INaL) plays a major role, as it causes both AP prolongation and Na+ overload. Intracellular Ca2+ overload determines an higher frequency of Ca2+ waves leading to delayed-afterdepolarizations (DADs) and premature contractions, but is also linked with the increased diastolic tension and slower relaxation of HCM myocardium. Sustained increase of intracellular [Ca2+] goes hand-in-hand with the increased activation of Ca2+/calmodulin-dependent protein-kinase-II (CaMKII) and augmented phosphorylation of its targets, including Ca2+ handling proteins. In transgenic HCM mouse models, we found that Ca2+ overload, CaMKII and increased INaL drive myocardial remodeling since the earliest stages of disease and underlie the development of hypertrophy, diastolic dysfunction and the arrhythmogenic substrate. In conclusion, diastolic dysfunction and arrhythmogenesis in human HCM myocardium are driven by functional alterations at cellular and molecular level that may be targets of innovative therapies

Effects of ranolazine on the arrhythmic substrate in hypertrophic cardiomyopathy

Introduction: Hypertrophic cardiomyopathy (HCM) is a leading cause of lethal arrhythmias in the young. Although the arrhythmic substrate has been hypothesised to be amenable to late Na+ block with ranolazine, the specific mechanisms are not fully understood. Therefore, this study aimed to investigate the substrate mechanisms of safety and antiarrhythmic efficacy of ranolazine in HCM. Methods: Computational models of human tissue and ventricles were used to simulate the electrophysiological behaviour of diseased HCM myocardium for variable degrees of repolarisation impairment, validated against in vitro and clinical recordings. S1-S2 pacing protocols were used to quantify arrhythmic risk in scenarios of (i) untreated HCM-remodelled myocardium and (ii) myocardium treated with 3µM, 6µM and 10µM ranolazine, for variable repolarisation heterogeneity sizes and pacing rates. ECGs were derived from biventricular simulations to identify ECG biomarkers linked to antiarrhythmic effects. Results: 10µM ranolazine given to models manifesting ventricular tachycardia (VT) at baseline led to a 40% reduction in number of VT episodes on pooled analysis of >40,000 re-entry inducibility simulations. Antiarrhythmic efficacy and safety were dependent on the degree of repolarisation impairment, with optimal benefit in models with maximum JTc interval <370 ms. Ranolazine increased risk of VT only in models with severe-extreme repolarisation impairment. Conclusion: Ranolazine efficacy and safety may be critically dependent upon the degree of repolarisation impairment in HCM. For moderate repolarisation impairment, reductions in refractoriness heterogeneity by ranolazine may prevent conduction blocks and re-entry. With severe-extreme disease substrates, reductions of the refractory period can increase re-entry sustainability

T-Tubular Electrical Defects Contribute to Blunted &#946;-Adrenergic Response in Heart Failure.

Alterations of the β-adrenergic signalling, structural remodelling, and electrical failure of T-tubules are hallmarks of heart failure (HF). Here, we assess the effect of β-adrenoceptor activation on local Ca2+ release in electrically coupled and uncoupled T-tubules in ventricular myocytes from HF rats. We employ an ultrafast random access multi-photon (RAMP) microscope to simultaneously record action potentials and Ca2+ transients from multiple T-tubules in ventricular cardiomyocytes from a HF rat model of coronary ligation compared to sham-operated rats as a control. We confirmed that β-adrenergic stimulation increases the frequency of Ca2+ sparks, reduces Ca2+ transient variability, and hastens the decay of Ca2+ transients: all these effects are similarly exerted by β-adrenergic stimulation in control and HF cardiomyocytes. Conversely, β-adrenergic stimulation in HF cells accelerates a Ca2+ rise exclusively in the proximity of T-tubules that regularly conduct the action potential. The delayed Ca2+ rise found at T-tubules that fail to conduct the action potential is instead not affected by β-adrenergic signalling. Taken together, these findings indicate that HF cells globally respond to β-adrenergic stimulation, except at T-tubules that fail to conduct action potentials, where the blunted effect of the β-adrenergic signalling may be directly caused by the lack of electrical activity