Targeted SERCA2a Gene Delivery to Restore Electrical Stability in the Failing Heart
Background—Recently, we reported that SERCA2a, the pump responsible for re-uptake of cytosolic calcium during diastole, plays a central role in the molecular mechanism of cardiac alternans. Heart failure (HF) is associated with impaired myocardial calcium handling, deficient SERCA2a, and increased susceptibility to cardiac alternans. Therefore, we hypothesized that restoring deficient SERCA2a by gene transfer will significantly reduce arrhythmogenic cardiac alternans in the failing heart.
Methods and Results—Adult guinea pigs that were divided into 3 groups: 1) Control, 2) HF and 3) HF + AAV9.SERCA2a gene transfer. HF resulted in a decrease in LV fractional shortening compared to controls (p<0.001). As expected, isolated HF myocytes demonstrated slower SR calcium uptake, decreased Ca2+ release and increase diastolic Ca2+ (p<0.05) compared to controls. Moreover, SERCA2a, cardiac ryanodine receptor (RyR2) and sodium calcium exchanger (NCX) protein expression were decreased in HF when compared to control (p<0.05). As predicted, HF increased susceptibility to cardiac alternans as evidenced by decreased heart rate thresholds for both Vm-ALT and Ca-ALT compared to controls (p<0.01). Interestingly, in vivo gene transfer of AAV9.SERCA2a in the failing heart improved LV contractile function (p<0.01), suppressed cardiac alternans (p<0.01) and reduced RyR2 Po secondary to reduction of RyR2-PS2814 (p<0.01). This ultimately resulted in a decreased incidence inducible ventricular arrhythmias (p=0.05).
Conclusions—These data show that SERCA2a gene transfer in the failing heart not only improves contractile function but it directly restores electrical stability through the amelioration of key arrhythmogenic substrate (i.e. cardiac alternans) and triggers (i.e. SR Ca2+ leak).
- Received October 5, 2011.
- Accepted August 10, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited