Abstract 5341: Spatial Heterogeneity Of The Mitochondrial Membrane Potential Underlying Arrhythmias In Pressure Overload Hypertrophy
Increased production and/or impaired scavenging of reactive oxygen species (ROS) are a hallmark of mitochondrial dysfunction in structural heart disease. Previously, we demonstrated a mechanism by which depolarization of the mitochondrial membrane potential (mitoVm) caused by ROS release through the mitochondrial benzodiazepine receptor (mBZR) promotes conduction failure. Since pressure overload hypertrophy (PoH) is a major risk factor for sudden death, we hypothesized that instability of mitoVm in PoH predisposes to arrhythmias.
Methods: PoH was produced in rats by ascending aortic banding for 4 weeks. LV dysfunction characteristic of PoH was confirmed in vivo using M mode 2D echocardiography. Ultrahigh resolution optical imaging was performed in ex vivo perfused hearts from PoH (n=6) and normal (n=3) rats. Normalized mitoVm was measured using a novel quantitative technique of TMRM imaging with subcellular resolution during a protocol of ischemia (for 7min) and reperfusion. Mean and SD mitoVm across 6400 sites were compared as was the expression of the mBZR gene (PKBS) using western blot analysis.
Results: Aortic banding for 4 weeks resulted in a significant increase in LV anteroseptal and posterior wall dimensions consistent with structural remodeling in PoH. Ischemia reperfusion related ventricular fibrillation (VF) was observed in 5/6 PoH and 1/3 normal hearts. Average mitoVm was surprisingly greater in PoH compared to normal hearts during both ischemia (17%, p=0.012) and reperfusion (24%, p=0.004). However, spatial heterogeneity of mitoVm indexed by SD was markedly greater in PoH during ischemia (0.42 vs 0.11, p=0.00007) but not reperfusion (p=0.15). Analysis of mitoVm in susceptible (VF+) versus resistant (VF−) rats revealed a 4X increase in mitoVm heterogeneity in ischemia (p=0.0004) but not reperfusion (p=0.12) in the VF+ group. There were no differences in overall protein content of PKBS between groups indicating that altered mitoVm dynamics are independent of PKBS expression.
Conclusions: These data demonstrate that increased spatial heterogeneity of mitoVm during ischemia in PoH promotes VF. Strategies aimed at preventing the desynchronization of mitoVm may form a novel therapeutic approach for combating malignant arrhythmias.
This research has received full or partial funding support from the American Heart Association, AHA National Center.