Abstract 16325: Robust MCARDTM-mediated βARKct Expression Results in Acute Reverse Remodeling in Ovine Ischemic Cardiomyopathy
Background: The deleterious effects of the uncoupling of βARs in ischemic heart failure are associated with elevated levels of the G protein-coupled receptor kinase-2 (GRK2). Inhibition of GRK2 via βARKct gene therapy prevents and reverses heart failure in murine transgenic models. However translation into large animal models has been limited by inefficient delivery. Here we utilize molecular cardiac surgery with recirculating delivery (MCARDTM), a highly efficient, cardiac-specific translatable cardiac gene delivery platform to assess the effect of robust scAAV6-mediated βARKct cardiac gene delivery on LV remodeling in ovine ischemic cardiomyopathy.
Methods and Results: Six ovine subjects underwent MCARDTM with delivery of 1014 vg scAAV6-CMV-βARKct. After a 3 week recovery, the obtuse marginal artery (OM1) was ligated proximally. The control infarct group (n=3, no βARKct) 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), Cardiac Output (CO)] were assessed via MRI pre-infarct and 8–12 Weeks post-infarct. Isoproterenol (Iso) was infused [0.5 mcg/min] to evaluate βAR responsiveness following baseline assessment. At 8–12 Weeks, (Iso) stimulated LV contractility (dP/dt) increased in the MCARD/βARKct (ΔdP/dt max =39.0%, p<0.05) group only. In this group, LV (EDV) decreased significantly (ΔLV EDV=33.4%,p<0.05) post (Iso) infusion resulting in acute reverse remodeling (Fig.1A). Western blot analysis confirmed robust βARKct expression globally in the LV (Fig.1B). No statistically significant improvement was found in EF, Baseline EDV or CO compared to the control infarct group.
Conclusion: Robust βARKct gene expression increases inotropic reserve post infarction. However, it did not prevent progressive chronic left ventricular dilatation and the reduction in LV function in sheep after acute myocardial infarction.
- © 2010 by American Heart Association, Inc.