Physiologically relevant cardiac tissue culture model for drug testing and disease modeling

University Of Louisville, Louisville KY

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Abstract

Human tissue modelling in culture is a major challenge for drug discovery and screening, and disease modeling. The ideal cardiac tissue culture model (CTCM) should accurately recreate the critical organ-level structure and function. The success of CTCM depends on ability to mimic what occurs in the human body in physiological and pathophysiological conditions. The heart is a unique organ that is subject to continuous cycles of alternating pressure and stretch due to hemodynamic loading and unloading. These hemodynamic stressors are of critical importance to cardiac function and metabolism in health and disease. Changes in stress within physiologic range result in physiological remodeling, whereas significant changes (e.g., hypertension, ischemia, valve disease) result in adverse pathological remodeling leading to cardiovascular dysfunction. We recently developed a system to culture 300µM thick human heart slices that fully maintains their functionality for over 12 days through providing the precise-cardiac-cycle hemodynamic pressures, stresses and electrical stimulation. This technology provides access to complete 3D multicellular system that is highly similar to human heart tissue and emulates physiological or pathological conditions, both functionally and structurally. Within our CTCM, we can control electrical stimulation (current amplitude and frequency) as well as the critical mechanical parameters including preload, afterload, pressures, rate of pressure change, and heart rate (HR) to accurately model normal and pathological diseased conditions. We hypothesize that establishment of physiologically relevant Human cardiac Tissue Culture Model needs continuous functional monitoring of the human heart tissue that undergo a replication of all in vivo–like structural and functional adaptation during health and disease. Through continuous monitoring of any changes on cardiac function, this system will be able to accurately assess drug toxicity and efficacy in healthy and diseased cardiac tissue. We will validate To test this hypothesis, we propose the following aims: Specific Aim 1: (a) Incorporation of real-time monitoring of contractile force, strain, and electrophysiological properties in culture for 12 days, and (b) validate the CTCM with real-time monitoring to accurately predict drug cardiotoxicity (12 cardiotoxins. Specific Aim 2: Modeling cardiac pathology using CTCM and testing for testing drug efficacy. Successful completion of this project will validate our CTCM system and fulfill a significant need by the pharmaceutical industry and regulatory bodies for a medium throughput, tissue culture technology that faithfully replicates the human cellular and pathophysiology and is highly sensitive for cardiotoxicity responses to drugs for drug discovery and screening. Such a system will enable better mechanistic understanding of heart failure therapies, minimize drug related adverse effects in patients and enable faster, and more cost-effective drug development and screening and enhance the confidence in a candidate drug by regulatory bodies (eg. FDA).