In Vitro Cardiac Device for Assessing Proarrhythmic Risk

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DESCRIPTION (provided by applicant): Electrical conductance in the heart is important for coordinating the chambers and controlling heart rate. Master electrical signals originate in specialized tissues and then propagate along the myocardium, where cardiac myocytes depolarize and contract. Some therapeutic agents acutely disrupt the generation and/or propagation of these electrical signals, leading to uncoordinated or incorrectly paced contraction in the atria and ventricles called arrhythmia. This serious adverse effect is cause to terminate clinical development of new compounds, recall approved products, and restrict marketing indications. Preclinical animal models are inadequate for assessing cardiotoxic risk and too often provide conflicting data across different species that confuse translation of findings into man. Recent interest in developing engineered heart tissue for a number of medical and R&D applications has resulted in systems for in vitro cultivation of cardiac myocytes and study of their electromechanical properties. Although some of these in vitro systems can be used to assess proarrhythmic risk of pharmaceutical products, none are ideally suited for assessing drug-induced adverse effects on electrical or mechanical cardiac function simultaneously. This STTR application proposes to develop microarrays of cardiomyocytes on proprietary, flexible, electrically-active material, in which propagation of electrical impulses can be studied in the presence of test chemicals and findings related to coupled mechanical function. The proposed device combines the best features of current systems with novel material technology to offer precisely controlled interrogation of integrated cellular function and precisely applied external factors that promote long-term survival of myocytes are reuse of devices - ultimately an important issue for human devices. Phase I studies aim to achieve proofs of feasibility and principle using rat cardiomyocytes and extend the system to canine myocytes. In Phase II, a prototype device will be constructed and a human cardiomyocyte device added to complete the panel.