Reduced Arrhythmia Inducibility With Calcium/Calmodulin-dependent Protein Kinase II Inhibition in Heart Failure Rabbits.
- Author(s): Hoeker, Gregory S
- Hanafy, Mohamed A
- Oster, Robert A
- Bers, Donald M
- Pogwizd, Steven M
- et al.
Published Web Locationhttp://ovidsp.tx.ovid.com/sp-3.21.0a/ovidweb.cgi?QS2=434f4e1a73d37e8c0a3e3482ebd1207500e52cedc60ccc97e0541cca82ccd5cf351bc6f610aeb5601a76efcb5c8370d19eae9327af3f0e6496635a0cb016a85eff3de67d553d6f52bd4d659d25fffeadf58149ae6b743e06de060ccdcb8aaf1b5703b0064d0dd23643f8043f4133977d79c3cd34b0e1ab9c71211528867adc89be29cf95e1f836377597630cd28e90c5cd7a184cdf570919cbbbc1f78dff27c24a03ca3dd9bdd8f2677b569714b012126d415595e946dfed873809d75a09e4bd980d5248455912f995ce89083f33c70394472675b5b428aca24c9f4d98622ef
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.To evaluate the effect of CaMKII inhibition on ventricular tachycardia (VT) induction in conscious HF and naive rabbits.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.KN-93 significantly reduced arrhythmia inducibility and slowed initiation of VT, suggesting that CaMKII inhibition may have antiarrhythmic effects in the failing human heart.