Abstract
In this paper, we illustrate how advanced computational modelling and simulation can be used to investigate drug-induced effects on cardiac electrophysiology and on specific biomarkers of pro-arrhythmic risk. To do so, we first perform a thorough literature review of proposed arrhythmic risk biomarkers from the ionic to the electrocardiogram levels. The review highlights the variety of proposed biomarkers, the complexity of the mechanisms of drug-induced pro-arrhythmia and the existence of significant animal species differences in drug-induced effects on cardiac electrophysiology. Predicting drug-induced pro-arrhythmic risk solely using experiments is challenging both preclinically and clinically, as attested by the rise in the cost of releasing new compounds to the market. Computational modelling and simulation has significantly contributed to the understanding of cardiac electrophysiology and arrhythmias over the last 40 years. In the second part of this paper, we illustrate how state-of-the-art open source computational modelling and simulation tools can be used to simulate multi-scale effects of drug-induced ion channel block in ventricular electrophysiology at the cellular, tissue and whole ventricular levels for different animal species. We believe that the use of computational modelling and simulation in combination with experimental techniques could be a powerful tool for the assessment of drug safety pharmacology.
Highlights
Anti-arrhythmic drugs are routinely used to treat heart rhythm disorders by directly interfering with cardiac ion channel activity
Excessive action potential (AP) prolongation caused by a high dosage of class III anti-arrhythmic drugs is suspected to be the cause of a variety of forms of triggered activity at the cellular level—including early after depolarizations (EAD)—that may degenerate into life-threatening forms of arrhythmia
The first part of this paper provides a thorough review of the biomarkers of druginduced arrhythmic risk proposed in the literature from the ionic to the ECG level
Summary
Anti-arrhythmic drugs (classes I, III and IV) are routinely used to treat heart rhythm disorders by directly interfering with cardiac ion channel activity. A large body of research has provided insight into the impact that alterations in specific ion channel properties has at the cellular, tissue and ECG levels These investigations have resulted in the identification of a number of biomarkers, which could be key to the diagnosis of pathological pro-arrhythmic states. We review the main biomarkers identified for each of the ionic currents, providing examples of the impact of specific anti-arrhythmic or pro-arrhythmic drugs on those biomarkers. Class I anti-arrhythmic drugs are known to alter Na+ channel properties, resulting in depressed maximal rate of rise of cardiac APs, slowing of conduction velocity and alterations in refractoriness. Flecainide and lidocaine are examples of class Ia, Ib and Ic drugs, respectively, that have shown pro-arrhythmic potential as described below. ST elevation of no less than 0.2 mV and late potentials have
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Schedule a callMore From: Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences
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