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 naïve 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 (NE, 1.56-25 µg/kg/min) in naïve (n = 8) and HF (n = 7) rabbits. With saline, median VT dose threshold in HF was 6.25 versus 12.5 µg/kg/min NE in naïve rabbits (p = 0.06). Pretreatment with KN-93 significantly increased VT threshold in HF and naïve rabbits (median = 25 µg/kg/min, p <0.05 versus saline for both groups). Mean cycle length of VT initiation was shorter in HF (221 ± 20 ms) than naïve (296 ± 23 ms, 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.
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine