Ventricular fibrillation (VF) is a disordered and chaotic state, but it begins with a more orderly stage, Wiggers' stage I, that has been shown by the investigators of Project 2 to be a spiral wave (or pair), which then breaks down into the multi-spiral disordered VF state. Anti-arrhythmic drug development has focused on the initiation of the reentrant spiral wave, which led directly to Class I and Class III anti-arrhythmic drugs. The failure of these drugs, as documented in the CAST and SWORD trials, has created a crisis in the pharmacologic approach to VF. This SCOR is based on the idea that understanding how and why the spiral wave breaks down into fibrillation offers a new paradigm for anti-fibrillatory drug design. In the initial funding period of this SCOR, the investigators found that fibrillation shows all the signs of being a specific form of """"""""deterministic chaos,"""""""" one that arises through a series of pre-fibrillatory oscillations in what is called 'the quasiperodic transition to chaos.' The investigators' research has led them to think that the key factors responsible for the transition to chaos and spiral wave breakup are the Action Potential Duration and Conduction Velocity Restitution properties of the tissue, which determine how the tissue responds to a stimulus when it has not yet fully recovered from the previous activation. The investigators have found that restitution properties alone can cause spiral wave breakup and a transition to fibrillation in computer models, even in perfectly homogeneous tissue. But the real heart is not homogeneous, and many researchers believe that natural and pathological inhomogeneities are the key factors responsible for destabilizing the wave of electrical activation. The investigators are now testing this hypothesis, using improvements in cardiac cell modeling, and in models of cardiac tissue, as well as in cardiac tissue (jointly with Projects 2 and 3). Computer power has now evolved to the point where it is reasonable to test these hypotheses in realistic models. The investigators will use computer modeling and mathematical analysis to determine the relative importance of, and the interactions between, dynamical factors and anatomical ones in the genesis and maintenance of VF. The goal is to find properties that are modifiable by drugs or stimulation protocols that will prevent the breakdown into fibrillation.
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