Reduced Arrhythmia Inducibility With Calcium/Calmodulin-dependent Protein Kinase II Inhibition in Heart Failure Rabbits

作者：Hoeker Gregory S; Hanafy Mohamed A; Oster Robert A; Bers Donald M; Pogwizd Steven M^*

来源：Journal of Cardiovascular Pharmacology, 2016, 67(3): 260-265.

DOI：10.1097/FJC.0000000000000343

• norepinephrine
• arrhythmia
• heart failure
• antiarrhythmic drugs
• calcium/calmodulin-dependent protein kinase II

Rationale:
Calcium/calmodulin-dependent protein kinase II (CaMKII) is activated in heart failure (HF) and can contribute to arrhythmias induced by beta-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 mu g/kg); VT was induced by infusion of increasing doses of norepinephrine (1.56-25 mu g center dot kg(-1)center dot 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 mu g center dot kg(-1)center dot min(-1) norepinephrine in naive rabbits (P = 0.06). Pretreatment with KN-93 significantly increased VT threshold in HF and naive rabbits (median = 25 mu g center dot kg(-1)center dot 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.

• 出版日期2016-3