Mechanisms of pro-arrhythmic abnormalities in ventricular repolarisation and anti-arrhythmic therapies in human hypertrophic cardiomyopathy

Abstract

IntroductionHypertrophic cardiomyopathy (HCM) is a cause of sudden arrhythmic death, but the understanding of its pro-arrhythmic mechanisms and an effective pharmacological treatment are lacking. HCM electrophysiological remodelling includes both increased inward and reduced outward currents, but their role in promoting repolarisation abnormalities remains unknown. The goal of this study is to identify key ionic mechanisms driving repolarisation abnormalities in human HCM, and to evaluate anti-arrhythmic effects of single and multichannel inward current blocks.MethodsExperimental ionic current, action potential (AP) and Ca2 +-transient (CaT) recordings were used to construct populations of human non-diseased and HCM AP models (n = 9118), accounting for inter-subject variability. Simulations were conducted for several degrees of selective and combined inward current block.ResultsSimulated HCM cardiomyocytes exhibited prolonged AP and CaT, diastolic Ca2 + overload and decreased CaT amplitude, in agreement with experiments. Repolarisation abnormalities in HCM models were consistently driven by L-type Ca2 + current (ICaL) re-activation, and ICaL block was the most effective intervention to normalise repolarisation and diastolic Ca2 +, but compromised CaT amplitude. Late Na+ current (INaL) block partially abolished repolarisation abnormalities, with small impact on CaT. Na+/Ca2 + exchanger (INCX) block effectively restored repolarisation and CaT amplitude, but increased Ca2 + overload. Multichannel block increased efficacy in normalising repolarisation, AP biomarkers and CaT amplitude compared to selective block.ConclusionsExperimentally-calibrated populations of human AP models identify ICaL re-activation as the key mechanism for repolarisation abnormalities in HCM, and combined INCX, INaL and ICaL block as effective anti-arrhythmic therapies also able to partially reverse the HCM electrophysiological phenotype.

Blinded In Silico Drug Trial Reveals the Minimum Set of Ion Channels for Torsades de Pointes Risk Assessment

“…By using human ventricular cell models of electrophysiology, we were able to provide mechanistic explanations of the increased inducibility of RAs under hERG block. Our results showed that I CaL re-activation was the key mechanism of RAs under hERG block, which was consistent with the mechanism revealed by sheep Purkinje fiber experiments (January et al, 1988;January and Riddle, 1989) and previous modeling investigations (Zeng and Rudy, 1995;Passini et al, 2016). Therefore, if calcium block effect is not considered, the TdP risk of a compound may be overestimated.…”

“…The baseline model used in this study is the O'Hara-Rudy dynamic (ORd) human endocardial ventricular AP model (O'Hara et al, 2011), developed using data from over 100 human hearts, with modifications to the fast sodium channel (Passini et al, 2016). It includes detailed representation of the potassium, sodium and calcium sarcolemmal currents, as well as intracellular calcium handling (including SERCA pump and c a l c i u m -i n d u c e d c a l c i u m r e l e a s e m e c h a n i s m ) .…”

Fibrosis and wall thickness affect ventricular repolarization dynamics in hypertrophic cardiomyopathy

“…In experimental studies, the prolongation of ventricular repolarization in HCM is the result of pathologies on many levels. The action potential is prolonged as the net repolarizing current is diminished by increased late‐type Na and Ca 2+ currents ( I NaL and I CaL ) and selective down regulation of the outward rectifying current ( I Kr )(Coppini et al., ; Crocini et al., ; Passini et al., ). The repolarization in the myocardium is also delayed due to hypertrophy (Badran et al., ) and global repolarization is spatially dispersed due to the asymmetric location of hypertrophy (Sakata et al., ).…”

Logistic regression analysis of populations of electrophysiological models to assess proarrythmic risk

“…Population-based approaches have been widely adopted in the recent years in the field of computational cardiac electrophysiology [1], [2], [3], [4], [5], [6], [7], [8]. The classical analysis performed with a single action potential (AP) model has been extended to the study of the properties emerging in a broad group of models (called “population”).…”

“…We use here the same value of σ (0.1) for all the parameters. Alternatively, different standard deviations can be used to reproduce the degree of variability experimentally determined for each parameter [6], [7], [23]. Note that while this choice does not alter the subsequent steps of this analysis, when increasing the range of variability of the model parameter, one needs to (i) discard non-physiological models; and (ii) ensure representative coverage of the parameter space (convergence of sensitivity coefficients upon stable values) by increasing the number of model variants [2].…”