PROJECT SUMMARY / ABSTRACT
Volumetric imaging and computation to characterize cardiac electromechanical coupling
Approximately 450,000 individuals in the United States die suddenly from cardiac arrhythmias every year. Many
widely used medications such as antiarrhythmic agents, antimicrobials, anticancer drugs, and psychotropic drugs
can cause or exacerbate a variety of arrhythmias. However, the fundamental mechanisms of most clinical
arrhythmias remain poorly understood. The ability to prospectively identify potentially arrhythmogenic
compounds would be clinically valuable. Recent advances demonstrate that zebrafish are a productive model
system to screen small molecules that function as arrhythmic compounds in humans. However, much remains
unknown about the involved excitation-contraction coupling abnormalities and mechanisms of arrhythmias
associated with specific drugs. Despite the new zebrafish lines gained in past decades, technical difficulties
including motion artifact, frame rate, penetration depth, and signal-to-noise ratio limits the in-depth investigation
of aberrant calcium activities and contractile dysfunction. For this reason, we seek to integrate our 4-dimensional
(4D, 3D spatial + 1D temporal) volumetric imaging with computational model to investigate whether a common
mechanism of action underlies drug-induced excitation-contraction coupling abnormalities. In collaboration with
Dr. Kelli Carroll (developmental biology), Dr. Catherine Makarewich (calcium signaling), and Dr. Jay Kuo
(machine learning), we will test the hypothesis that small molecule-induced bradycardia activates distinct EC
coupling abnormalities responsible for various arrhythmias. In Aim 1, we will reveal the 4D calcium activities
across the intact heart with high spatiotemporal resolution via our custom-built structured-illumination light-field
microscope. In Aim 2, we will elucidate the electromechanical interaction among neighboring cardiomyocytes
during 5~10 cardiac cycles. In Aim 3, we will assess the excitation-contraction coupling abnormalities induced
by small molecule compounds. In this context, success of this research will establish a new holistic strategy to
in vivo investigate sophisticated electromechanical interaction, providing an entry point to further study the
underlying mechanism of arrhythmias and prospectively identify arrhythmogenic compounds.