Winning Abstracts from the 2012 Medical Student Abstract Competition: Molecular Cardiac Surgery with Retrograde Delivery (Mcard) in the Treatment of Heart Failure
Author: Armen Henderson, Meharry Medical College, Class of 2013
Introduction: Vector mediated cardiac gene therapy is a translatable platform for treating many cardiovascular diseases. However, in spite of development of adeno-associated viral (AAV) vector serotypes with significant trophism for the heart, these results have not yet been confirmed using an intravenous delivery route in small or large animals in situ.
The quest for more efficient, cardiac gene delivery methods is currently a critically important, rate-limiting challenge in cardiac gene therapy. MCARD is proven to serve as a solution to this problem and the efficacy of a probable gene is explored.
Methods: Six ovine subjects underwent MCARDTM with delivery of 1014 vg scAAV6-CMV-▀ARKct. After a 3 week recovery, the obtuse marginal artery (OM1) was ligated proximally. The control infarct group (n=3, no ▀ARKct) underwent OM1 ligation only. All nine animals survived to euthanasia at 8-12 weeks. LV function [Dp/dtmax, End diastolic volume (EDV), End systolic volume (ESV), Ejection Fraction (EF), Cardiac Output (CO)] was assessed via MRI pre-infarct and 8-12 Weeks post-infarct. Isoproterenol (Iso) was infused [0.5 mcg/min] to evaluate ▀AR responsiveness following baseline assessment.
Results: At 8-12 Weeks, (Iso) stimulated LV contractility (dP/dt) increased in the MCARD/▀ARKct group only. In this group, LV (EDV) decreased significantly post isoproterenol infusion resulting in an acute reverse remodeling. Western blot analysis confirmed robust ▀ARKct expression globally in the LV and there results are confirmed with RT-qPCR. No statistically significant improvement was found in EF, Baseline EDV or CO compared to the control infarct group. In comparing control infarct sheep with the creation of infarct followed by subsequent MCARD treatment using BARKct sheep, there was no significant difference between the two groups.
Conclusion: Robust ▀ARKct gene expression increases inotropic reserve post infarction. However, it did not prevent progressive left ventricular dilatation and the reduction in LV function associated with ovine ischemic cardiomyopathy.
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