AuthorsA. Tveito, G. T. Lines, P. Li and A. D. McCulloch
TitleOn Defining Candidate Drug Characteristics for Long-QT
AfilliationCenter for Biomedical Computing (SFF), Scientific Computing, Scientific Computing
Project(s)Center for Biomedical Computing (SFF)
StatusPublished
Publication TypeJournal Article
Year of Publication2011
JournalMathematical Biosciences and Engineering
Volume8
Number3
Pagination861-873
Abstract

Mutations of the SCN5A gene can significantly alter the function of cardiac myocyte sodium channels leading to increased risk of ventricular arrhythmia. Several gain-of-function mutations associated with long QT intervals result in a persistent late current that prolongs the cardiac action potential. Over the past decade, Markov models of the action potential of wild type and mutant cardiac cells have been developed. The effects of drugs on mutant cells have also been incorporated into some of these models. It is the purpose of this paper to predict the effects on sodium currents and whole cell action potentials of theoretical drugs targeting the mutant sodium channel. Our aim is to compute advantageous properties of a hypothetical drug by deriving Markov model parameters of the drug action that: (a) restores the steady-state open probability of the mutant channel to that of normal wildtype channels; and (b) minimizes the difference between whole cell currents in drugged mutant and wildtype cells. The difference in the electrochemical state vector of the cell can be measured in a norm taking all components and their dynamical properties into account. Measured with this norm, the difference between the state of the mutant and wild type cell was reduced by a factor of 36 after the drug was introduced and by factors of 4 over mexitiline and 25 over lidocaine. The results suggest the potential to synthesize more effective drugs based on mechanisms of action of existing compounds.

Citation KeySimula.SC.644