Pharmacogenomics and antiarrhythmic therapy: An in silico investigation

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DESCRIPTION (provided by applicant): Pharmacological treatment of cardiac arrhythmia is a long sought and as yet elusive goal. Poor efficacy and outcomes in treating arrhythmia with drugs is due, in part, to failure to accurately predict how drugs with implicitly complex pharmacodynamics affect multi-component interactive cardiac cells and tissues. For example, a representation of drug block of cardiac ion channels as reduced current amplitude is overly simplistic and fails to predict drug effects. Rather, multiple factors including complex drug pharmacokinetics, pH dependence, voltage dependence, conformation-specific block and rate-dependent properties of drugs, as well drug interaction with the multiple mechanisms and triggers of arrhythmia must be considered for development of appropriate pharmacological intervention for arrhythmia management. These issues have been further complicated in the last decade, during which genetic advances have revealed that genes also play a role in determining arrhythmia susceptibility and effectiveness of drug treatment. As a result, it is now clear that, in addition to pharmacodynamics, genotype must be considered as a factor in pharmacological management of arrhythmia. Our goal is to develop novel theoretical approaches through the construction of detailed mathematical pathways of drug block in virtual cardiac cells and tissues to bridge this gap. The long-term purpose of our studies is to develop a framework for accurate prediction of drug interaction with cardiac ion channels, and especially, to predict the emergent effects of mutations and drug block on cellular and tissue level electrical behavior. We will address the following three specific aims: 1: To develop a theoretical framework to simulate pharmacological block of cardiac Na+- channels - A comprehensive model that includes pH dependent partitioning, membrane diffusion, conformation-state specificity of interaction and voltage dependence of Na+ channel block. 2: AIM 2: To utilize the theoretical framework in virtual cardiac cells to examine the effects of Na+ channel block of normal or arrhythmia linked mutant Na+ channels on cell activity. 3: To test, using tissue level simulations, the relationship between pharmacogenomics, drug treatment and arrhythmia. The merit of this proposal lies in the novelty of the approach to test and predict the outcomes of drug interventions intended for diagnosis and treatment of cardiac arrhythmia and represents progress towards a virtual drug testing system.