UCLA

This dissertation is dedicated to understanding the dynamical mechanisms underlying early afterdepolarization (EAD)-mediated arrhythmias. EADs are a richly mined area of research that has resulted in little therapeutic benefit at the bedside since their first description in the early 1980's. In an effort to provide a fresh perspective on EADs, I take an experimental and computational non-linear dynamics approach to studying these arrhythmias that plague millions worldwide and are associated with significant cost burden and high mortality. Here, I show that the dual Hopf-homoclinic bifurcation mechanism for generating EADs may be responsible for EAD-mediated arrhythmias in cardiac disease, providing new therapeutic targets and expanding the current concept of reduced repolarization reserve. Also, I provide evidence that certain pathological cardiac tissue substrates may exhibit the unique dynamical property of bistability (ie. switch-like behavior) in the form of biexcitability, the ability to switch between INa- and ICa-mediated propagation. This unique property of biexcitability may provide significant mechanistic insight into the seemingly paradoxical properties of certain EAD-mediated arrhythmias such as Torsades de Pointes (TdP), that is uniquely characterized by a slow rate and undulating QRS complexes on ECG. Lastly, I show that activation of KATP channels (inward rectifying K channels that open when cellular ATP levels fall) "flips the switch" from ICa- to INa-mediated propagation. Consistent with clinical observations of TdP and polymorphic ventricular tachycardia (PVT), the majority of ICa-dependent reentries spontaneously terminate following KATP channel activation, with a minority of ICa-dependent reentries converting to INa-dependent reentries. These results suggest that in the clinical setting, KATP channels may serve as an "emergency repolarization reserve" to spontaneously terminate most episodes of ICa-dependent arrhythmias such as PVT and TdP, but may also facilitate the occasional degeneration of these arrhythmias to INa-dependent VT/VF. These findings provide a fresh perspective on EAD-mediated arrhtyhmias that may lead to novel therapeutics at the bedside.