• J. Thorac. Cardiovasc. Surg. · Mar 2012

    AAV6-βARKct gene delivery mediated by molecular cardiac surgery with recirculating delivery (MCARD) in sheep results in robust gene expression and increased adrenergic reserve.

    • Michael G Katz, Anthony S Fargnoli, JaBaris D Swain, Catherine E Tomasulo, Michele Ciccarelli, Z Maggie Huang, Joseph E Rabinowitz, and Charles R Bridges.
    • Division of Cardiovascular Surgery, Department of Surgery, the University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
    • J. Thorac. Cardiovasc. Surg. 2012 Mar 1; 143 (3): 720-726.e3.

    ObjectiveGenetic modulation of heart function is a novel therapeutic strategy. We investigated the effect of molecular cardiac surgery with recirculating delivery (MCARD)-mediated carboxyl-terminus of the β-adrenergic receptor kinase (βARKct) gene transfer on cardiac mechanoenergetics and β-adrenoreceptor (βAR) signaling.MethodsAfter baseline measurements, sheep underwent MCARD-mediated delivery of 10(14) genome copies of self-complimentary adeno-associated virus (scAAV6)-βARKct. Four and 8 weeks after MCARD, mechanoenergetic studies using magnetic resonance imaging were performed. Tissues were analyzed with real-time quantitative polymerase chain reaction (RT-qPCR) and Western blotting. βAR density, cyclic adenosine monophosphate levels, and physiologic parameters were evaluated.ResultsThere was a significant increase in dP/dt(max) at 4 weeks: 1384 ± 76 versus 1772 ± 182 mm Hg/s; and the increase persisted at 8 weeks in response to isoproterenol (P < .05). Similarly, the magnitude of dP/dt(min) increased at both 4 weeks and 8 weeks with isoproterenol stimulation (P < .05). At 8 weeks, potential energy was conserved, whereas in controls there was a decrease in potential energy (P < .05) in response to isoproterenol. RT-qPCR confirmed robustness of βARKct expression throughout the left ventricle and undetectable expression in extracardiac tissues. Quantitative Western blot data confirmed higher expression of βARKct in the left ventricle: 0.46 ± 0.05 versus 0.00 in lung and liver (P < .05). Survival was 100% and laboratory parameters of major organ function were within normal limits.ConclusionsMCARD-mediated βARKct delivery is safe, results in robust cardiac-specific gene expression, enhances cardiac contractility and lusitropy, increases adrenergic reserve, and improves energy utilization efficiency in a preclinical large animal model.Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

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