Integrative cardiac mechanobiology: Tools for probing electrophysiology and mechanotransduction in heart health and disease

Cardiac function emerges from an integrated loop of electrical activity, calcium signaling, and mechanical contraction. Yet, most in vitro studies continue to treat these processes as distinct, limiting our ability to model and understand key regulatory phenomena such as mechano-electric feedback. In this thesis, I address this challenge by studying how substrate stiffness and mechanical signaling influence electromechanical behavior in human iPSC-derived cardiomyocytes and cardiac fibroblasts.The thesis begins with a comprehensive review of cardiac mechanobiology, emphasizing the interplay between stiffness and the excitation-contraction coupling. This review identifies discrepancies in how stiffness is measured and modeled across studies, highlighting the need for standardized tools and frameworks in the field.To study how mechanical cues affect electrophysiology, the first requirement is to reliably quantify the electrophysiological response of cardiac cells. Calcium imaging serves as the most widely used proxy for this purpose, offering insight into the timing and magnitude of cellular excitation. To this end, I developed the “Heart-on-a-Miniscope,” a compact, low-cost optical platform that integrates calcium imaging and electrical stimulation in a single, modular, and adjustable unit. Designed to overcome the complexity and cost of traditional imaging setups, this system enabled functional recordings in 3D cardiac organoids and supported the development of a custom analysis pipeline for automated extraction of calcium transient parameters.Having established a platform to measure cellular response, the next challenge was to deliver mechanical input in a physiologically relevant and tunable manner. To address this, I developed a dual-crosslinked PDMS substrate with photopatternable stiffness control across a cardiac-relevant range (3–35 kPa). This system allowed spatial control over mechanical cues and revealed that localized stiffness gradients could induce differential cytoskeletal organization, nuclear deformation, and YAP localization in cardiac fibroblasts.With both sensing and stimulation platforms in place, I next examined how mechanical input affects cellular output in an integrated system. By combining calcium imaging and traction force microscopy in hiPSC-CMs cultured on mechanically-defined substrates, I found that substrate stiffness modulates not only contractile force but also calcium transient amplitude, duration, and kinetics. These findings highlight that mechanical feedback actively shapes electrophysiological behavior, and that inhibiting force generation pharmacologically may mask critical features of cellular response.Together, these studies contribute novel tools and mechanistic insight into how the physical microenvironment governs cardiac function. The findings underscore the importance of mechanical context in cardiac modeling and lay the groundwork for more predictive in vitro platforms for disease modeling and drug screening

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