Arrhythmia models: in vivo, in vitro and in silico

Remodeling of ion channel and/or intracellular calcium handling properties lies at the heart of numerous congenital and acquired cardiovascular disorders that culminate in lethal arrhythmias. Typically pathophysiological remodeling is caused by a complex interplay between electrical, mechanical, structural, metabolic, and genetic alterations which disrupt normal excitation-contraction coupling and predispose to arrhythmic triggers. Therefore, a comprehensive understanding of arrhythmia mechanisms requires a multi-faceted approach that involves studies performed at multiple levels of integration. Specifically, the development of appropriate in vivo, in vitro, and in silico models that simulate key aspects of human disease is required to dissect the complex regulatory pathways and feedback mechanisms that ultimately dictate ion channel function in both health and disease. In this section of Drug Discovery Today: Disease Models, several review articles by experts in the field are presented to illustrate the importance of using complimentary approaches for investigating arrhythmia mechanisms. As will become evident, state-of-the-art experimental and computational tools can be effectively exploited in a synergistic manner to better understand the role of altered ion channel and calcium handling properties in the genesis of complex and clinically relevant arrhythmias. The article by Sobie and Wehrens is a perfect illustration of how in vitro, in vivo, and in silico approaches have recently improved our understanding of calcium mediated arrhythmias, in general, and catecholaminergic polymorphic ventricular tachycardia, in particular. Specifically, these studies have revealed how certain mutations targeting calcium regulatory proteins can enhance diastolic calcium leak from the sarcoplasmic reticulum and generate afterdepolarization mediated triggers at the intact organ level. Calcium is a central signaling molecule, which along with its associated proteins, calmodulin, and calcium-calmodulin kinase II couple subcellular processes, modulate protein function and alter cellular electrophysiology by participating in microdomains that are coordinated by macromolecular signaling complexes. The article by Kline and Mohler highlights the role of anchoring proteins in cardiac pathophysiology. As will be revealed, these anchoring subunits not only regulate functional activities by coordinating structural interactions within large macromolecular complexes, but also exert direct effects on ion channel gating, which have been causally linked to cardiac arrhythmia phenotypes. Mechanisms by which altered subcellular function by anchoring proteins result in abnormal electrical behavior at the tissue level is perhaps best probed using multi-scale computational modeling approaches which can combine molecular details on the one hand and network properties on the other. This concept is also highlighted by Moreno and Clancy, who discuss the challenges associated with determining the relationships between subcellular perturbations and arrhythmias - since the cardiac system is so extraordinarily complex. In order to attribute an arrhythmia to a specific parameter, individual perturbations can be studied in isolation and combination, which is only possible using computational approaches, which reveal behavior in systems throughout large parameter spaces and lead to elucidation of general mechanisms. This, in fact, is the strong suit of computational approaches. The results of model simulations can also suggest predicted outcomes that can be tested in vitro and ultimately in vivo. Consistent feedback between computer based predictions and experimental outcomes allows for targeted hypothesis testing. Trayanova and Tice review anatomically based computational approaches in whole heart in silico models. The approach they describe is the complement to computer simulations aimed at discovering general mechanisms, and rather aspires to individualized model reconstructions that have the potential to revolutionize patient treatment options. Heart-specific reconstructions can be used to specifically identify pathological tissues and simulations may reveal appropriate ablation and even appropriate drug interventions on a case-by-case basis. A combined in vivo, in vitro and in silico approach can even be used to design cardiac devices, such as a biological pacemaker described in the paper by Robinson. The biological pacemaker may someday take the place of widely used implantable devices to maintain normal cardiac rhythms. The development of a biopacemaker relies on the interplay and feedback between complementary approaches to define specific biophysical traits of the ideal pacemaker and make predictions about outcomes in increasingly complex cardiac systems. ug Discovery Today: Disease Models | Cardiovascular diseases Vol. 4, No. 4 2007 It has become increasingly clear that elucidation of arrhythmia mechanisms is best accomplished by a multifaceted approach that includes in vivo, in vitro and in silico models. Continuous feedback between distinct approaches to arrhythmias allow for revelation of the physiological mechanisms that underlie emergent arrhythmias that are observed in tissues and organs. As experimental and computational model approaches become progressively more refined and increasingly sophisticated, improved understanding of what causes arrhythmias should lead to improved treatment strategies for millions of affected patients worldwide.