Quantification of repolarization reserve to understand interpatient variability in the response to proarrhythmic drugs: A computational analysis

doi:10.1016/j.hrthm.2011.05.023

Heart Rhythm

Volume 8, Issue 11, November 2011, Pages 1749-1755

https://doi.org/10.1016/j.hrthm.2011.05.023 Get rights and content

Background

“Repolarization reserve” is frequently invoked to explain why potentially proarrhythmic drugs cause, across a population, a range of changes to cardiac action potentials (APs). However, the mechanisms underlying this interindividual variability are not understood quantitatively.

Objective

The purpose of this study was to perform a novel analysis of mathematical models of ventricular myocytes to quantify repolarization reserve and gain insight into the factors responsible for variability in the response to proarrhythmic drugs.

Methods/Results

In several models of human or canine ventricular myocytes, variability was simulated by randomizing model parameters and running repeated simulations. With each randomly generated set of parameters, APs before and after simulated 75% block of the rapid delayed rectifier current (I_Kr) were calculated. Multivariable regression was performed to determine how much each model parameter attenuated or exacerbated the AP prolongation caused by the I_Kr-blocking drug. Simulations with a human ventricular myocyte model suggest that drug response is influenced most strongly by (1) the density of I_Kr, (2) the density of slow delayed rectifier current I_Ks, (3) the voltage dependence of I_Kr inactivation, (4) the density of L-type Ca²⁺ current, and (5) the kinetics of I_Ks activation. The analysis also identified mechanisms underlying nonintuitive behavior, such as ionic currents that prolong baseline APs but decrease drug-induced AP prolongation. Finally, the simulations provided quantitative insight into conditions that aggravate the drug response, such as silent ion channel mutations and heart failure.

Conclusion

These modeling results provide the first thorough quantification of repolarization reserve and improve our understanding of interindividual variability in adverse drug reactions.

Introduction

Increased risk of ventricular arrhythmia is a major side effect of many drugs, including antiarrhythmics and drugs intended for other purposes.1, 2 Although rare, these arrhythmias can prove fatal, and avoiding them is of paramount importance in drug development.1, 2, 3 Electrophysiologic studies have demonstrated that proarrhythmic drugs block the K⁺ channel responsible for the rapid delayed rectifier current (I_Kr), colloquially known as HERG (human ether-à-go-go related gene). HERG block lengthens action potentials (APs) in cardiac myocytes and QT intervals on electrocardiograms. Drug-induced QT prolongation, although acknowledged to be an imperfect predictor,4, 5 is therefore considered a reasonable surrogate for increased arrhythmia risk. All proarrhythmic drugs withdrawn from the market lengthen the QT interval in patients and in experimental models.²

Interindividual variability greatly complicates our understanding of drug-induced arrhythmias. “Dangerous” drugs cause arrhythmias in only a small minority of patients, and the extent of QT prolongation may vary widely among a population exposed to identical doses of a given drug.2, 6 The concept of “repolarization reserve,”⁷ or an individual's excess capacity for membrane repolarization, has been invoked by several groups to explain experimental results.8, 9, 10, 11, 12 However, repolarization reserve remains an essentially qualitative concept.¹³ Modeling studies, although invaluable for understanding the complexity of cardiac electrical activity¹⁴ and arrhythmia risk, have thus far only considered differences between a healthy myocyte and one affected by a mutation, a drug, or a disease-causing insult15, 16 and have not addressed the challenges posed by heterogeneity across a population.

Here we have used a recently developed computational methodology17, 18 to understand interpatient variability in drug-induced QT prolongation. This has allowed us to quantify, to our knowledge for the first time, how the electrophysiologic characteristics of a simulated ventricular myocyte influence the cell's response to a HERG-blocking drug. The analysis generates unexpected predictions regarding which factors are most important, thereby suggesting future experiments. Furthermore, our results quantify reduced repolarization reserve in disease and establish a rigorous, quantitative framework for understanding the factors underlying the potentially proarrhythmic effects of drugs.

Section snippets

Methods

The goal of this study was to understand possible causes of interindividual variability in the response to HERG-blocking drugs. Mathematical modeling was combined with multivariable regression techniques to correlate cellular electrophysiologic parameters with AP properties measured before and after block (75%) of the rapid delayed rectifier current I_Kr.17, 18 This technique was used with the ventricular myocyte models developed by (1) ten Tusscher et al¹⁹ (ten Tusscher-Noble-Noble-Panfilov

Results

We used mathematical models to understand variability in the response to HERG-blocking drugs using a technique of parameter randomization followed by multivariable regression described in the Methods section and elsewhere.17, 18 Figures 1A and 1B respectively illustrate the procedure and show an especially relevant result obtained with the TNNP model.¹⁹ Two sets of randomly chosen parameters (Trials 97 and 270) result in baseline action potential durations (APDs) extremely similar to those

Summary of results

Repolarization reserve7, 13 is generally considered the main reason for interpatient variability in the response to HERG block.² This phrase expresses the idea that several ionic currents are involved in the repolarization phase of the AP, and thus a defect in any single channel or accessory protein potentially can be compensated by the others. A corollary is that the effect of blocking any particular current (eg, I_Kr) depends not just on the density of that channel but also on the other ionic

Conclusion

Our study provides, to the best of our knowledge, the first thorough quantification of repolarization reserve. In doing so, we were able not only to confirm that the biological context within which the HERG channel is placed matters but also to specify the extent to which other channels contribute to the response to HERG block. Such an understanding is critical to determine why different individuals exhibit divergent responses to the same drug. Because the pharmaceutical industry has been

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This chapter considers mechanisms of torsades de pointes (TdP) linked to delayed ventricular repolarization. Major ionic conductances contributing to action potential repolarization are summarized. The key role of I_Kr as an anti-target in drug-induced long QT syndrome (diLQTS) is considered, as is more recent evidence implicating late Na current (I_Na,L) enhancement as an additional mechanism by which chronic drug exposure can prolong ventricular action potentials. Factors influencing repolarization reserve, heterogeneity (dispersion) of repolarization and formation of early afterdepolarizations (EADs) are described. Evidence for TdP triggers and maintenance mechanisms from models of congenital LQTS variants 1–3 is discussed. Models of and issues pertaining to evaluation of TdP in diLQTS are then considered, including the use of surrogate measures as exemplified by the TRiAD model. Across the different forms of LQTS considered, EADs are strongly implicated as trigger events for TdP, whilst dispersion of repolarization is a likely maintenance substrate.
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Citation Excerpt :
Therefore, different models can exhibit very different responses to the same channel blocker (54) (see Fig. S2 for the different responses of the seven AP models to the same blocker). One way to interpret this is to consider this variability as physiological diversity between cells or between individuals (30,55–57). On the other hand, some of these differences may be due to the caveats of the models themselves.
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: Supported by National Institutes of Health Grant GM071558 and a Grant-in-Aid from the American Heart Association, Heritage Affiliate (10GRNT4170020).

View full text

ExperimentalQuantification of repolarization reserve to understand interpatient variability in the response to proarrhythmic drugs: A computational analysis

Background

Objective

Methods/Results

Conclusion

Introduction

Section snippets

Methods

Results

Summary of results

Conclusion

Pharmacol Ther

Heart Rhythm

Heart Rhythm

J Am Coll Cardiol

J Mol Cell Cardiol

Biophys J

Biophys J

J Mol Cell Cardiol

J Mol Cell Cardiol

Prog Biophys Mol Biol

Drug-induced torsades de pointes and implications for drug development

J Cardiovasc Electrophysiol

Drug-induced long QT syndrome

Pharmacol Rev

Instability and triangulation of the action potential predict serious proarrhythmia, but action potential duration prolongation is antiarrhythmic

Circulation

Taking the “idio” out of “idiosyncratic”: predicting torsades de pointes

Pacing Clin Electrophysiol

Sex, age, and regional differences in L-type calcium current are important determinants of arrhythmia phenotype in rabbit hearts with drug-induced long QT type 2

Circ Res

Potassium channel subunit remodeling in rabbits exposed to long-term bradycardia or tachycardia: discrete arrhythmogenic consequences related to differential delayed-rectifier changes

Circulation

Reduction of repolarization reserve unmasks the proarrhythmic role of endogenous late Na+ current in the heart

Am J Physiol Heart Circ Physiol

Experimental
Quantification of repolarization reserve to understand interpatient variability in the response to proarrhythmic drugs: A computational analysis

Reduction of repolarization reserve unmasks the proarrhythmic role of endogenous late Na⁺ current in the heart