Abstract Wed142: Myocardium in a Dish: Organotypic Slice Culture as a Translational Platform for Pharmacological Testing and Mechanistic Insights

In vitro models that maintain the complexity and function of adult myocardium are critical for basic and translational research. We developed and optimized an organotypic culture technique for precision-cut myocardial slices from human and animal hearts, enabling stable contractile performance for several weeks. Human myocardial slices remain functional for up to four months. This is achieved by physiological preload, medium agitation, and continuous electrical stimulation, which preserve tissue viability, structure, and contractility. The approach allows repeated electrophysiological, mechanical, metabolic, optical and other measurements over time, permitting detailed study of acute and chronic effects, for instance of drugs or genetic modifications. This presentation shall provide insights into this emerging technique and demonstrate studies that successfully utilized the novel approach. In failing human myocardium, cultivation with dexamethasone enhances inotropy by increasing contractile force, changing force–frequency relationships, and upregulating key ion channels such as CACNA1c, SERCA, Kv4.3, and Kir2.x. Dexamethasone also preserves Ca 2+ transient kinetics and increases beta-adrenergic responsiveness, suggesting that glucocorticoid signaling may counteract functional deterioration often seen in heart failure. Other studies in human cardiac slices demonstrate the effectiveness of anti-sense oligonucleotides or cardiac contractility modulation. Extending this technique to rabbit myocardial slices required additional adaptations. During early culture, transient application of electro-mechanical uncouplers and supplementation with physiological levels of cortisol minimized tissue damage and stabilized function, thereby preserving force generation and Ca 2+ handling over at least one week. Effects of thyroid hormones on beta-adrenergic response and metabolic rate were evident. Moreover, the technique effectively detects drug-induced cardiotoxicity by integrating electrophysiological endpoints (e.g., Na + , Ca 2+ , hERG, channel block), with contractility and structural evaluation, as shown in pig myocardial slices. This robust, biomimetic myocardial slice culture model thus provides a powerful tool to investigate drug targets, gene functions, electrophysiological mechanisms, and tissue remodeling in healthy or failing myocardium across multiple species with the potential to bridge critical gaps between basic science studies and clinical applications.