Volumetric imaging and computation to characterize cardiac electromechanical coupling

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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.