David Paterson D.Phil, D.Sc.
The Tangling of Three Dynamical Systems in the Heart: Interactions of the Electrical, the Ca2+ Signaling, and the Contractile Systems
Ye Chen-Izu M.S. Ph.D.
Cardiac excitation-contraction is controlled by three dynamic systems – the electrical system, the Ca2+ signaling system, and the contractile system. In the classic paradigm, electrical excitation controls Ca2+ signaling which, in turn, controls muscle contraction. Early work focused on investigating each dynamic system in isolation. However, recent studies show that defects in the contractile system can feedback to disrupt Ca2+ signaling system and cause electrical arrhythmias. We have developed innovative techniques and new methods to study the interaction of these dynamic systems. (1) The action potential (AP)-clamp sequential dissection method enables recording of multiple ionic currents under AP-clamp in the ...Read More
Patrick Y. Jay M.D., Ph.D.
C. William Balke M.D., F.A.C.P., F.A.H.A.
Sándor Györke Ph.D.
Mark Anderson M.D., Ph.D.
Omer Berenfeld Ph.D.
Atrial fibrillation (AF) is the most common sustained arrhythmia with alarming increase in its prevalence. We take an integrative approach to discuss the manner in which nonlinear electrical waves self-organize in the form of rotors and drive the arrhythmia. Using cellular electrophysiology, numerical simulations as well as analytical mapping approaches we study the ionic mechanisms and dynamics of such patterns of excitation. Analysis of activation data in the frequency and phase domains reveals that local excitation frequencies during AF are hierarchically distributed throughout the atria with the highest frequency colocalizing with a sustained reentrant activity that drives the arrhythmia.
Ralph J. Damiano Jr., M.D.
Ursula Ravens M.D., Ph.D., F.E.S.C., F.A.H.A.
Steven C. George M.D., Ph.D.
Tissue engineering holds enormous potential to not only replace or restore function to a wide range of tissues, but also to capture and control 3D physiology in vitro (e.g., microphysiological systems). The latter has important applications in the fields of drug development, toxicity screening, and repairing damaged cardiac (heart) muscle. In order to replicate the complex 3D arrangement of cells and extracellular matrix (ECM), new human microphysiological systems must be developed, and must include a vascular supply. The vasculature not only provides the necessary convective transport of nutrients and waste in 3D culture, it also couples and integrates the response ...Read More
Late Sodium Current, a Mechanism for Angina, Heart Failure, and Arrhythmia, is Controlled by Nitrosylation Mechanisms Within the Cardiac Sodium Channel Complex
Jonathan C. Makielski M.D.
Late sodium current is a residual flow normally representing less than 1% of the peak current, but increasing to 3% or more under many conditions such as heart failure, ischemia, and long QT arrhythmia LQT) mutations. Despite the small size, it affects action potential duration and calcium loading, and plays a role in the pathogenesis of the clinical manifestations of angina, heart failure, and arrhythmia, and therefore represents an attractive therapeutic target. Sodium current flow through a multiprotein complex that regulates the channel. Mutations in two of these interacting proteins, syntrophin alpha 1 and caveolin 3 cause LQT syndromes LQT12 ...Read More
Jeanne Nerbonne Ph.D.
Gerald W. Dorn M.D.