Dynamics of Period Doubling Bifurcation in Myocyctes

Dynamics of cellular electrical activation in the heart is exquisitely choreographed and repeats reliably billions of times, in certain circumstances, however, the dynamics diverges, i.e. bifurcates, from the operating point to result in period doubling bifurcation (PDB). Such bifurcation is manifest as beat by beat alternation in the shape of the T wave of the ECG. This behavior, referred to as alternans, is perhaps the best predictor of degeneration of electrical rhythm into lethal arrhythmia. Contemporary theory regarding the dynamics of PDB focuses on the restitution function, which is relation between repolarization interval, i.e. duration of action potential, APO, and the interval between previous beats, Le. diastolic interval, 01, and the functional dependence of an APD on previous APOs, called the memory effect. Our proposed study has a focus on the role that restitution and memory play in this dynamical phenomenon. We have five objectives: 1. To determine contribution of accumulative memory in onset threshold and amplitude of PDB. We will use a novel feedback based pacing protocol to maintain 01 preceding each activation invariant and independent of APO to determine effects of memory on onset of POB. 2. To determine the contribution of restitution dependent effects in amplitude of PDB. We will compare amplitude of PDB, measured along the length of linear strands of tissue when OIs are maintained invariant at one end to determine the contribution of restitution dependent effects. 3. To identifY factors that enhance effects of residual memory in restitution of A PD. We will manipulate select potassium and calcium ion currents and concentrations during sinusoidal changes in DI and quantify the effect of these manipulations on residual memory, i.e. hysteresis, in restitution of APO. 4. To determine if enhanced residual memory in restitution increases stability of a perturbation. We will determine trajectory of an electrical perturbation in intact and perfused hearts to determine whether increased hysteresis increases stability of a perturbation. 5. To develop portable feedback based pacing control approach that can be implemented with ease in diverse electrophysiology laboratories. We will modifY and further develop our feedback based pacing control approach for ease of use and make it available for download from our website. Intellectual merit: The theoretical basis of studies that have and continue to use measures based on restitution and memory to predict and investigate causes of PDB is that for POB to occur, there exists a causal link between DJ and APD, i.e., a change in DI is the cause of change in APD. We challenge this widely accepted link and propose an alternate theory: in terms of what causes POB to occur, we propose that the change in DI is, in fact, an effect of change in APD and not a cause as believed for over four decades. We have developed a novel experimental tool that makes it possible to obtain empirical proof of our alternate theory. The developed approach provides a new avenue for unmasking the causes of POB that have eluded us despite a long history of exploration. We propose to investigate dynamics of PDB within the above stated entirely different theoretical framework, and expect to reveal a more clearer role of restitution and memory in this phenomenon. Our study will open a new path of investigation towards the objective of unraveling the dynamics of PDB in ventricular cells. Broader impact: The experimental approach that we have developed is nove] and unique in the sense that not only it allows one to verify the alternate theory, importantly, it permits explicit isolation of cause and effects in tissue, thereby allowing investigation of the dynamics of PBO by removing a critical confound of restitution that is present in virtually all previous studies of electrical POB in ventricular myocytes. Wide availability of this experimental approach will facilitate investigation of the causes of this important phenomenon. As a part of our proposed study we will develop engineering tools to implement the approach such that it becomes portable and easy to use. We will then use the internet to make these tools available to researchers working in this area. Dissemination of these to the research community at large, therefore, will broaden the impact of our proposed studies. We will partner with a specialized magnet program for exceptionally talented high school students in our community that focuses on mathematics, science and technology. We will recruit students from this program to work in the proposed activity with special emphasis on recruiting under-represented and women candidates. We have recently implemented a University Scholars Program at our institute which allows highly qualified undergraduates to initiate graduate studies in our program overlapping with the senior year in their undergraduate engineering curriculum. This pool of talented undergraduates will be our target for recruitment to work on the proposed research activity as well. We anticipate that student involvement in the proposed project will include high school juniors and seniors, undergraduate seniors, and graduate students.