3D Imaging Technology
Optical imaging utilizing voltage-sensitive dyes has become a powerful tool for the analysis of cardiac excitation. Until recently, it has been primarily used for fluorescence surface recordings, where only the subsurface layers beneath the epicardial surface were shown to contribute to the optical signal. However, the myocardial wall can be up to 1 cm thick and imaging of the heart's electrical activity throughout the thickness of the ventricular muscle would greatly add to the understanding of the mechanisms underlying cardiac arrhythmias.
Voltage-sensitive dyes (e.g. di-4-ANEPPS) have been widely and successfully used as probes for mapping membrane potential changes in cardiac cells and tissues for over 25 years. However, their utility has been somewhat limited because their excitation wavelengths have been restricted to the 450-550 nm range. We are developing near-infrared (NIR) membrane voltage probes because absorption and scattering in cardiac tissue are weaker for NIR light. In optical mapping applications, reduced absorption and scattering result in improved recordings from deeper tissue layers. The new NIR voltage-sensitive dyes are being developed in close collaboration with Dr. L.Loew's group.
Ion Channel Expression
Proper expression of ion channel genes is responsible for maintaining the electrical properties of cardiac tissue. Ion channel expression changes across different areas of the heart. These changes allow myocytes to specialize in signal propagation, contraction, or pace-making. Further alterations in ion channel transcriptional expression are associated with diseases such as atrial fibrillation. We study the regulation of ion channel gene expression at the transcriptional level using bioinformatic data mining approaches to analyze the core promoter of ion channel genes. Our effexpression patterns may lead to novel drug targets in treating cardiovasorts to predict ion channel cular arrhythmias and disease.
We work to find mechanistic explanations for the genesis and maintenance of cardiac arrhythmias. Cardiac arrhythmias are a major cause of death, particularly self-sustained arrhythmias like fibrillation. The excitation patterns underlying self-sustained arrhythmias are spiral waves (see Figure) and their three-dimensional counterparts, scroll waves. We study the dynamics of spiral waves and scroll waves in tissue and in computer simulations.
We try to better understand the mechanisms underlying defibrillation. A major unresolved question is how defibrillation shocks manage to eliminate reentrant activity from the deeper layers of the myocardium in which the shock effects should be small according to common theory. Figure shows how a shock can indirectly eliminate reentrant activity even from the center of a preparation. A shock causes an initially straight filament to detach from the surfaces of the preparation. Afterwards, the filament assumes a new shape that is in certain situations unstable, so that the scroll wave eventually disappears.