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Biology subjects

Shrier, A.

Publications and source records attributed to Shrier, A..

3 recordsLinked to original sources

RhythmWriter: GPU-accelerated Contractility Quantification for Large Datasets

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been considered optimal model systems for use in cardiac safety testing, yet their adoption remains low, largely because of technical limitations in the analysis methodology. RhythmWriter (RW) is an open-source GPU plugin for ImageJ developed to quantify contractile motion over extended periods of time. RW compensates for baseline drift, is time-scale invariant and is capable of very rapid data analysis. As a consequence, RW is capable of generating simultaneous high-resolution contraction restitution curves from multiple aggregates of hiPSC-CMs derived from premature-stimulus (S1S2) and dynamic-ramp restitution protocols. The aggregates exhibit brief refractory periods, which allow the induction of S2 beats at coupling intervals down to 130 ms and 1:1 entrainment during periodic stimulation down to a cycle length of 245 ms. Simulations confirm the ability of RW to track programmed contractile strength and stimulation intervals even at rapid pacing rates. This makes possible, for the first time, high-throughput functional assessment of hiPSC-CM aggregates for contractility drug screening and maturation.

physiology↗

Phase resetting in human stem cell derived cardiomyocytes explains complex cardiac arrhythmias

Phase resetting of cardiac oscillators underlies some complex arrhythmias. Here we use optogenetic stimulation to construct phase response curves (PRC) for spheroids of human induced pluripotent stem cell derived cardiomyocytes (iPSC-CM) and a computational cardiomyocyte model to identify ionic mechanisms shaping the PRC. The clinical utility of the human PRCs is demonstrated by adding a patient-based conduction delay to the same equations to explain complex multi-day Holter ECG dynamics and cardiac arrhythmias. Periodic stimulation of these patient-based models and the computational model of human iPSC-CM reveal similar bifurcation patterns and entrainment zones. Cell therapy by injecting iPSC-CM into diseased hearts can induce ectopic foci-based engraftment arrhythmias. The PRC analysis offers a potential strategy to entrain these foci in a parameter space that avoids such arrhythmias.

physiology↗

KHz-rate volumetric voltage imaging of the whole zebrafish heart

Fast volumetric imaging is essential for understanding the function of excitable tissues such as those found in the brain and heart. Measuring cardiac voltage transients in tissue volumes with spatial and temporal resolutions needed to give insight to cardiac function has so far been impossible. We introduce a new imaging modality based on simultaneous illumination of multiple planes in the tissue and parallel detection with multiple cameras, avoiding compromises inherent in any scanning approach. The system enables imaging of voltage transients in-situ, allowing us, for the first time, to map voltage activity in the whole heart volume at KHz rates. The unprecedented spatio-temporal resolution of our method enabled the observation of novel dynamics of electrical propagation through the zebrafish atrioventricular canal.

physiology↗