SERCA2a gene transfer (GT) to the failing heart improves it mechanical function. The electrophysiological (EP) consequences of SERCA2a GT are less clear. We investigated the EP substrate, total (t) and phosphorylated (p) Cx43 expression in a chronic model of heart failure (HF) with & without SERCA2a GT.
Methods:
After 2 mo of aortic banding rats underwent 30min LAD occlusion & reperfusion for another 2 mo. Rats developed widespread proliferation of reactive fibrosis in ischemic & remote zones and were randomized to receive AAV9 GFP (HF) or AAV9 SERCA2a (HF treatment) at the time of LAD occlusion/reperfusion. Hearts from normal (Sham, N=6), HF (AAV9.GFP, N=7), and HF treatment (AAV9.SERCA2a, N=9) rats were studied using optical mapping. Cx43 levels (t & p) were measured.
Results:
HF rats exhibited significant APD prolongation (by 50%) & CV slowing (by 30%). More importantly APD heterogeneity was increased 2.5 fold (p=0.006). The ratio of S368 p-to-t Cx43 was reduced in the ischemic zone of HF rats where SERCA2a expression was decreased (Fig). AAV9 SERCA2a GT increased SERCA2a levels in the ischemic and remote zones. Surprisingly, APD & CV were comparable (p=NS each) in HF and HF treatment groups. In contrast SERCA2a GT reduced APD heterogeneity by 30% relative to untreated rats (p=0.03), fully restored pCx43 expression to sham levels in the ischemic zone and abolished regional differences in p-to-t Cx43 (Fig).
Conclusions:
AAV9 SERCA2a GT reverses key EP and molecular deficits that are causally related to arrhythmias in HF. This therapy, however, fails to reverse other hallmark features of HF, which are likely dependent on widespread ion channel and structural remodeling, namely fibrosis.
Loss of Fractalkine Signaling Exacerbates Axon Transport Dysfunction in a Chronic Model of Glaucoma
