Cardiac Conduction through Engineered Tissue

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DESCRIPTION (provided by applicant): Disruption of cardiac atrioventricular (AV) impulse propagation is a serious clinical problem in infants and children as well as adults. Congenital complete heart block or AV block due to ischemic heart disease, endocarditis, maternal autoimmune disease during pregnancy, or surgery is currently treated by implanting an artificial pacemaker device. While the efficacy of pacemakers as a palliative therapy cannot be disputed, and the range of indications requiring intervention with these devices continues to expand; their long-term performance remains unsatisfactory, especially in pediatric patients. Children implanted with cardiac pacemakers have a substantially higher incidence of re-operation compared with adults due to limited battery life, lead fractures and failure, cardiac perforation, valve dysfunction, diminished ventricular function, and thrombus formation. In addition, the size of newborn and small children frequently requires the pacemaker leads to be positioned epicardially, rather than transvenously, which results in even greater failure rates and rising capture thresholds. Consequently, there is an pressing need for advancement of innovative, lasting pacing therapies designed specifically for pediatric patients. In view of that, we have been developing an engineered tissue construct that can function as an electrical conduit between the atria and ventricles for eventual use in children that lack normal AV node function. To be clinically applicable, we have focused our efforts on developing tissue that can be autologously-derived, is easy to fabricate and implant, and poses no risk of tumor development or arrhythmogenic potential. Ideally, the engineered tissue would account for patient growth, function for the lifespan of the individual, respond to autonomic stimuli, and allow for the orderly and sequential spread of electrical impulses from the upper to lower chambers of the heart through the insulating barrier formed by the fibrous annulus of the AV valves. A multi-disciplinary group has been assembled to address the following aims: 1) improve the conduction characteristics of a previously developed construct by optimizing it's cellularity and composition as well as identifying cells in muscle and bone marrow that approximate the electrical behavior of the AV node, 2) evaluate these improvements in Lewis rat hearts by implanting constructs that contain muscle- and marrow-derived cells, and 3) examine autologously-derived engineered tissue in an ovine model of pediatric complete AV conduction block.