Original ArticleReduced Arrhythmia Inducibility With Calcium/Calmodulin-dependent Protein Kinase II Inhibition in Heart Failure RabbitsHoeker, Gregory S. PhD; Hanafy, Mohamed A. MD; Oster, Robert A. PhD; Bers, Donald M. PhD; Pogwizd, Steven M. MDAuthor Information *Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL; †Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; ‡Division of Preventive Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; and §Department of Pharmacology, University of California Davis, Davis, CA. Reprints: Steven M. Pogwizd, MD, Department of Medicine, University of Alabama at Birmingham, VH B140, 1670 University Boulevard, Birmingham, AL 35294 (e-mail: [email protected]). Supported by an American Heart Association Predoctoral Fellowship (G.S.H.) and grants from the NIH (S.M.P. and D.M.B., P01-HL80101; R.A.O., UL1TR001417) and Fondation LeDucq (S.M.P. and D.M.B., 08CVD01). The authors report no conflicts of interest. Received July 23, 2015 Accepted October 26, 2015 Journal of Cardiovascular Pharmacology: March 2016 - Volume 67 - Issue 3 - p 260-265 doi: 10.1097/FJC.0000000000000343 Buy Metrics Abstract Rationale: Calcium/calmodulin-dependent protein kinase II (CaMKII) is activated in heart failure (HF) and can contribute to arrhythmias induced by β-adrenergic receptor-mediated sarcoplasmic reticulum calcium leak. Objective: To evaluate the effect of CaMKII inhibition on ventricular tachycardia (VT) induction in conscious HF and naive rabbits. Methods and Results: Nonischemic HF was induced by aortic insufficiency and constriction. Electrocardiograms were recorded in rabbits pretreated with vehicle (saline) or the CaMKII inhibitor KN-93 (300 μg/kg); VT was induced by infusion of increasing doses of norepinephrine (1.56–25 μg·kg−1·min−1) in naive (n = 8) and HF (n = 7) rabbits. With saline, median VT dose threshold in HF was 6.25 versus 12.5 μg·kg−1·min−1 norepinephrine in naive rabbits (P = 0.06). Pretreatment with KN-93 significantly increased VT threshold in HF and naive rabbits (median = 25 μg·kg−1·min−1, P < 0.05 vs. saline for both groups). Mean cycle length of VT initiation was shorter in HF (221 ± 20 milliseconds) than naive (296 ± 23 milliseconds, P < 0.05) rabbits with saline; this difference was not significant after treatment with KN-93. Conclusions: KN-93 significantly reduced arrhythmia inducibility and slowed initiation of VT, suggesting that CaMKII inhibition may have antiarrhythmic effects in the failing human heart. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.