Applications of Dynamic Clamp to Cardiac Arrhythmia Research: Role in Drug Target Discovery and Safety Pharmacology Testing.

Francis A Ortega,Eleonora Grandi,Trine Krogh-Madsen,David J Christini

doi:10.3389/fphys.2017.01099

Francis A Ortega, Eleonora Grandi + Show 2 more

Open Access

https://doi.org/10.3389/fphys.2017.01099

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Abstract

Dynamic clamp, a hybrid-computational-experimental technique that has been used to elucidate ionic mechanisms underlying cardiac electrophysiology, is emerging as a promising tool in the discovery of potential anti-arrhythmic targets and in pharmacological safety testing. Through the injection of computationally simulated conductances into isolated cardiomyocytes in a real-time continuous loop, dynamic clamp has greatly expanded the capabilities of patch clamp outside traditional static voltage and current protocols. Recent applications include fine manipulation of injected artificial conductances to identify promising drug targets in the prevention of arrhythmia and the direct testing of model-based hypotheses. Furthermore, dynamic clamp has been used to enhance existing experimental models by addressing their intrinsic limitations, which increased predictive power in identifying pro-arrhythmic pharmacological compounds. Here, we review the recent advances of the dynamic clamp technique in cardiac electrophysiology with a focus on its future role in the development of safety testing and discovery of anti-arrhythmic drugs.

Highlights

The search for successful anti-arrhythmia therapeutics is rooted in the voltage clamp and current clamp techniques, which have provided the mechanistic details behind the ionic membrane currents that compose the cardiac action potential (AP)
Computational modeling readily allows for the precise perturbation of particular parameters individually or in controlled combinations, but results are reliant on the accuracy of the model and its many components
Dynamic clamp studies on the cardiac L-type Ca2+ current (ICaL) by Madhvani et al identified arrhythmia mechanisms, which could potentially be targeted by anti-arrhythmic drugs (Madhvani et al, 2011, 2015)

Summary

INTRODUCTION

The search for successful anti-arrhythmia therapeutics is rooted in the voltage clamp and current clamp techniques, which have provided the mechanistic details behind the ionic membrane currents that compose the cardiac action potential (AP). We focus on a specific configuration of this technique, called the dynamic model clamp (referred hereafter as dynamic clamp), where a mathematically based model of a conductance is injected to the cell in real-time This mathematical model describes a specific voltage and time-dependent membrane current determined by a set of differential equations. Accurate and rapid sampling of the membrane potential and computation of the virtual conductance is required to mimic sufficiently a biological conductance (Bettencourt et al, 2008) The works discussed here predominately use two software platforms— DynaClamp (Berecki et al, 2005, 2006) and the Real-Time eXperimental Interface (RTXI, www.rtxi.org; Ortega et al, 2014; Patel et al, 2017). We discuss how investigators have used the dynamic clamp technique to test theoretical drug targets, validate and improve existing cardiac mathematical models, and design assays for cardiotoxicity testing

Drug Target Identification

Improvement of Cardiac Computational Models

DRUG SAFETY TESTING PLATFORMS

Findings

CONCLUSION