Abstract 2796: AAV2/1/SERCA2a Delivered via the Percutaneous Cardiac Recirculation Improves Left Ventricular Function in an Ovine Pacing Model of Heart Failure.
Background: Heart failure is a progressive disorder with complex pathophysiology. The molecular basis of heart failure has been increasingly characterised, particularly with regard to the factors causing progressive contractile failure. Amongst these decreased expression of SERCA2a is well documented, potentially providing a valid target for clinical intervention using gene therapy. As such, restoration of SERCA2a by AAV2/1SERCA2a has recently been shown in experimental HF models. In this study we aimed to evaluate the effect of AAV2/1SERCA2a delivery via closed loop cardiac recirculation (V Focus) on left ventricular function and myocardial BNP expression in an ovine model (rapid pacing) of heart failure.
Methods: AAV2/1SERCA2a was delivered to sheep with pacing induced heart failure using either the V-Focus cardiac delivery system (V-Focus, 1 x 1013 drp, n=7) or direct intra-coronary infusion (IC, 2.5 x 1013 drp, n=6), while a control group received vehicle buffer via IC. Left ventricular (LV) hemodynamics (+dp/dtmax) was measured prior to delivery. Gene delivery was well tolerated, with no evidence of arrhythmias or clinically significant ST segment changes during administration. Following administration animals were paced for a further six weeks at which time LV hemodynamics were recorded and left ventricular tissue collected for quantitative PCR analysis of BNP.
Results: There was no significant change in LV +dp/dtmax between the IC and control animals (control -18 ± 75, IC 119 ± 121 mmHg/s; p<0.05) following six weeks of additional pacing, while the V-Focus group of animals had significantly improved LV + dp/dtmax max (287 ± 104 mmHg/s; p<0.05) compared the control group. In conjunction, tissue BNP mRNA (real-time PCR) was significantly reduced in animals receiving AAV2/1SERCA2a via cardiac recirculation compared to IC AAV2/1SERCA2a treated animals: (ΔΔct compared to vehicle: V-Focus -2.62 ± 0.86 vs IC 1.45 ± 0.85; p<0.05)
Conclusions: These results suggest that AAV2/1SERCA2a improves LV function and with favourable effects on gene expression in HF. Further, this study suggest gene therapy for HF may be optimally delivered using a cardiac recirculation approach.