Abstract 19050: Inhibition of CaMKII blocks Inducible Ventricular Tachycardia/Fibrillation and Triggered Activity in a Canine Model of Myocardial Ischemia
Introduction: Ventricular tachycardia or fibrillation (VT/VF) of focal origin due to triggered activity (TA) from delayed afterdepolarizations is reproducibly inducible after anterior coronary artery occlusion in the dog. Calcium/Calmodulin Dependent Protein Kinase II (CaMKII) has been implicated in arrhythmias in small animal models. Here, we investigated the effect of inhibition of CaMKII on inducible VT/VF in our model.
Methods: 25 chloralose anesthetized dogs received either an inhibitor of CaMKII, KN-93 at 2 mcg/kg IV, or saline for time controls. Endocardium from ischemic sites (3-D mapping utilizing customized Matlab 7.11 software) was sampled for oxidized CaMKII or studied in vitro with standard microelectrode techniques. Results (mean ± SE, *=p<0.05): VT/VF was blocked by KN-93 in 5/10* experiments vs by saline in 1/12 time controls; all VT/VFs blocked had focal mechanisms. Reentry VT/VF was not blocked in 6 and 7 experiments, resp. KN-93 did not promote inducible VT/VF in 3 dogs without prior VT/VF. There was no evidence of conduction alteration in ischemic zones with KN-93. KN-93 given IV produced transient reflex sinus tachycardia from cycle length 414±57 to 280±9*msec. In vitro, TA induction was blocked by KN-93 (10-9 M) without altering action potentials; KN-93 at 10-8M decreased action potential amplitude from 67±4 to 51±10* mV and at 10-7M decreased resting membrane potential from -78±4 to -74±6* mV. Oxidized CaMKII was measured comparing data from untreated normal zones; ischemia increased oxidized CaMKII 7.4 fold, but with KN-93 the increase was only 1.5 fold, no different than normal.
Conclusion: In ischemic VT/VF, KN-93 specifically blocked all inducible focal VT/VF due to TA without evidence of conduction or refractory period change in our large animal model of ischemia.
- Ischemic heart disease
- Ventricular tachycardia
- Ventricular fibrillation
Author Disclosures: J.B. Martins: None. A.K. Chaudhary: None. M.A. Kwofie: None. E.D. Luczak: None. M.E. Anderson: Ownership Interest; Significant; Allosteros Therapeutics,. Other; Significant; inventor on intellectual property claiming to treatmyocardial infarction by CaMKII inhibition.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.