Reduced Arrhythmia Inducibility with Calcium/Calmodulin-Dependent Protein Kinase II Inhibition in Heart Failure Rabbits

Gregory S. Hoeker, Mohamed A. Hanafy, Robert A. Oster, Donald M Bers, Steven M. Pogwizd

Research output: Contribution to journalArticle

11 Scopus citations

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 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.

Original languageEnglish (US)
JournalJournal of Cardiovascular Pharmacology
DOIs
StateAccepted/In press - Nov 21 2015

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

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