Reduced arrhythmia inducibility with calcium/ calmodulin-dependent protein kinase II inhibition in heart failure rabbits
- Author(s): Hoeker, GS
- Hanafy, MA
- Oster, RA
- Bers, DM
- Pogwizd, SM
- et al.
Published Web Locationhttp://ovidsp.tx.ovid.com/sp-3.21.0a/ovidweb.cgi?QS2=434f4e1a73d37e8c0a3e3482ebd1207500e52cedc60ccc97e0541cca82ccd5cf351bc6f610aeb5601a76efcb5c8370d19eae9327af3f0e6496635a0cb016a85eff3de67d553d6f52bd4d659d25fffeadf58149ae6b743e06de060ccdcb8aaf1b5703b0064d0dd23643f8043f4133977d79c3cd34b0e1ab9c71211528867adc89be29cf95e1f836377597630cd28e90c5cd7a184cdf570919cbbbc1f78dff27c24a03ca3dd9bdd8f2677b569714b012126d415595e946dfed873809d75a09e4bd980d5248455912f995ce89083f33c70394472675b5b428aca24c9f4d98622ef
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Rationale: Calcium/calmodulin-dependent protein kinase II (CaMKII) is activated in heart failure (HF) and can contribute to arrhythmias induced by b-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 mg/kg); VT was induced by infusion of increasing doses of norepinephrine (1.56-25 mgkg21min21) in naive (n = 8) and HF (n = 7) rabbits. With saline, median VT dose threshold in HF was 6.25 versus 12.5 mgkg21min21 norepinephrine in naive rabbits (P = 0.06). Pretreatment with KN-93 significantly increased VT threshold in HF and naive rabbits (median = 25 mgkg21min21, P , 0.05 vs. saline for both groups). Mean cycle length of VT initiation was shorter in HF (221 6 20 milliseconds) than naive (296 6 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.
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