Alpha Omega Alpha Honor Medical Society

2011 Research Abstract

Changes in Heart Failure Markers After Myocardial Gene Transfer Using Cardiac Surgery

Investigator: Catherine E. Tomasulo, UMDNJ—Robert Wood Johnson Medical School

Mentor: Charles R. Bridges, MD, ScD, University of Pennsylvania School of Medicine

Heart disease is the leading cause of death in the United States. The Bridges Molecular Cardiac Surgery Research Group has developed a clinically translatable method for cardiac-specific global recombinant adeno-associated virus (rAAV)-mediated delivery of a therapeutic transgene for the treatment of heart failure. This involves cardiopulmonary bypass (CPB) with complete surgical isolation of the heart coupled with recombinant AAV gene delivery allowing for stable transduction of the majority of cardiac myocytes in situ (“Molecular Cardiac Surgery with Recirculating Delivery” (MCARD)). Robust transgene expression has already been proven in a large animal model, but an effective therapeutic transgene must be coupled to MCARD. The aim of this study was to utilize real-time polymerase chain reaction (RT-PCR) to assess molecular markers of heart failure in failing sheep ventricular tissue to determine if there was molecular rescue of the phenotype due to therapeutic transgene sarcoplasmic reticulum Ca2+ ATPase 2a (SERCA2a). Standard marker mRNA, brain natriuretic peptide (BNP), known to change in heart failure and normalize in “rescued” myocardium, was analyzed. Western blots were also performed to confirm SERCA2a expression. BNP marker results support the hypothesis that heart failure marker levels will be reduced in sheep receiving an infarct followed by the MCARD procedure for AAV-mediated delivery of SERCA2a when compared to levels in control infarct sheep. While not statistically significant, the lateral wall of the SERCA2a sheep hearts show decreased BNP expression when compared to the controls, demonstrating the ability of SERCA2a to rescue the failing myocardium. The SERCA2a sheep also had statistically significantly increased ejection fraction, cardiac index, infarct zone contraction and enhanced stroke volume as compared to controls, reinforcing the BNP data. Studies with a larger sample size should be conducted to normalize variability and further test the hypothesis.

Updated on July 13, 2012.

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