Drug‐induced shortening of the electromechanical window is an effective biomarker for in silico prediction of clinical risk of arrhythmias

Abstract

Background and PurposeEarly identification of drug‐induced cardiac adverse events is key in drug development. Human‐based computer models are emerging as an effective approach, complementary to in vitro and animal models. Drug‐induced shortening of the electromechanical window has been associated with increased risk of arrhythmias. This study investigates the potential of a cellular surrogate for the electromechanical window (EMw) for prediction of pro‐arrhythmic cardiotoxicity, and its underlying ionic mechanisms, using human‐based computer models.Experimental ApproachIn silico drug trials for 40 reference compounds were performed, testing up to 100‐fold the therapeutic concentrations (EFTPCmax) and using a control population of human ventricular action potential (AP) models, optimised to capture pro‐arrhythmic ionic profiles. EMw was calculated for each model in the population as the difference between AP and Ca2+ transient durations at 90%. Drug‐induced changes in the EMw and occurrence of repolarisation abnormalities (RA) were quantified.Key ResultsDrugs with clinical risk of Torsade de Pointes arrhythmias induced a concentration‐dependent EMw shortening, while safe drugs lead to increase or small change in EMw. Risk predictions based on EMw shortening achieved 90% accuracy at 10× EFTPCmax, whereas RA‐based predictions required 100× EFTPCmax to reach the same accuracy. As it is dependent on Ca2+ transient, the EMw was also more sensitive than AP prolongation in distinguishing between pure hERG blockers and multichannel compounds also blocking the calcium current.Conclusion and ImplicationsThe EMw is an effective biomarker for in silico predictions of drug‐induced clinical pro‐arrhythmic risk, particularly for compounds with multichannel blocking action.

A Population Modelling Approach to Studying Age-Related Effects on Excitation-Contraction Coupling in Human Cardiomyocytes

“…Using the methodology developed by B. Rodriguez group [3,4,1,2], we constructed a control population of human ventricular electro-mechanical models based on the above TNNP+M model with a reference set of parameters. We varied randomly nine model parameters, having chosen, as suggested in [1], eight parameters for the conductances of main transmembrane ionic currents: fast Na + current (G Na ), transient outward K + current (G to ), rapid and slow delayed rectifier K + currents (G Kr and G Ks ), inward rectifier K + current (G K1 ), the L-type Ca 2+ current (G CaL ); and the Na + − K + (NKX) and Na + − Ca 2+ (NCX) exchangers (P NaK , K NaCa ).…”

“…A set of several AP and Ca 2+ transient biomarkers were calculated to compare model simulations with experimental data: AP duration at 40%, 50%, and 90% of repolarisation (APD 40 , APD 50 , and APD 90 ); AP triangulation, defined as the difference between APD 90 and APD 40 (Tri 90−40 ); maximum upstroke velocity (dV/dt max ); peak voltage (V peak ); resting membrane potential (V rest ); and Ca 2+ transient duration at 50% and 90% of repolarisation (CTD 50 and CTD 90 ). The population was then filtered by experimental biomarkers derived from the AP and Ca 2+ transient recordings in isolated cells from undiseased human hearts as described in [2,10].…”

“…As in virtual arrhythmogenic drug testing [2], we checked the occurrence of the age-related effects on AP generation and Ca 2+ handling associated with adverse events in the intact heart, particularly with the risk of TdP [19,20].…”

“…Recently, populations of human ventricular in silico action potential (AP) models were used to predict the clinical drug-induced arrhythmic risk of Torsade de Pointes (TdP) arrhythmia. The occurrence of cellular repolarisation abnormalities (RA) and the shortening of the electromechanical window (EMw), reflecting the difference between the durations of the electrical and mechanical systole, was evaluated in model populations and showed a high accuracy (close to 90%) in predicting TdP risk for a number of reference compounds [1,2]. These in silico trials demonstrated a challenging promise of such analysis as a valuable tool for cardiotoxicity prediction.…”

“…In this paper, we apply the experimentally calibrated population-of-models methodology [3,4,1,2] o investigating variability in the response of cardiomyocytes to age-related changes in the parameters of the molecular and cellular mechanisms of excitation-contraction coupling. Besides, it is used for predicting the pro-arrhythmogenic effects of age-related cellular remodelling using human electro-mechanical cellular models developed by our research group [5].…”