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(Circulation. 2006;114:1352-1359.)
© 2006 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Death, Cardiac Dysfunction, and Arrhythmias Are Increased by Calmodulin Kinase II in Calcineurin Cardiomyopathy

Michelle S.C. Khoo, BCh, MB; Jingdong Li, MD, PhD; Madhu V. Singh, PhD; Yingbo Yang, MD, PhD; Prince Kannankeril, MD; Yuejin Wu, PhD; Chad E. Grueter, MS; Xiaoqun Guan, PhD; Carmine V. Oddis, MD, PhD; Rong Zhang, MD, PhD; Lisa Mendes, MD; Gemin Ni, MD; Ernest C. Madu, MD; Jinying Yang, RN; Martha Bass, BS; Rey J. Gomez, BS; Brian E. Wadzinski, PhD; Eric N. Olson, PhD; Roger J. Colbran, PhD; Mark E. Anderson, MD, PhD

From the Departments of Medicine (M.S.C.K., Y.Y., C.V.O., R.Z., L.M.), Pediatrics (P.K.), Molecular Physiology and Biophysics (C.E.G., M.B., R.J.C.), and Pharmacology (R.J.G., B.E.W.), Vanderbilt University, Nashville, Tenn; Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PRC (J.L.); Departments of Medicine (M.V.S., Y.W., X.G., G.N., J.L., J.Y., M.E.A.) and Physiology and Biophysics (M.E.A.), Carver College of Medicine, University of Iowa, Iowa City; Division of Cardiovascular Medicine (E.M.), Heart Institute of the Caribbean, Kingston, Jamaica; and Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Tex (E.N.O.).

Correspondence to Mark E. Anderson, MD, PhD, University of Iowa Hospitals and Clinics, 200 Hawkins Dr, Room E315 GH, Iowa City, IA 52242-1081. E-mail mark-e-anderson{at}uiowa.edu

Received January 5, 2006; received de novo June 8, 2006; revision received July 6, 2006; accepted July 21, 2006.

Background— Activation of cellular Ca²⁺ signaling molecules appears to be a fundamental step in the progression of cardiomyopathy and arrhythmias. Myocardial overexpression of the constitutively active Ca²⁺-dependent phosphatase calcineurin (CAN) causes severe cardiomyopathy marked by left ventricular (LV) dysfunction, arrhythmias, and increased mortality rate, but CAN antagonist drugs primarily reduce hypertrophy without improving LV function or risk of death.

Methods and Results— We found that activity and expression of a second Ca²⁺-activated signaling molecule, calmodulin kinase II (CaMKII), were increased in hearts from CAN transgenic mice and that CaMKII-inhibitory drugs improved LV function and suppressed arrhythmias. We devised a genetic approach to "clamp" CaMKII activity in CAN mice to control levels by interbreeding CAN transgenic mice with mice expressing a specific CaMKII inhibitor in cardiomyocytes. We developed transgenic control mice by interbreeding CAN transgenic mice with mice expressing an inactive version of the CaMKII-inhibitory peptide. CAN mice with CaMKII inhibition had reduced risk of death and increased LV and ventricular myocyte function and were less susceptible to arrhythmias. CaMKII inhibition did not reduce transgenic overexpression of CAN or expression of endogenous CaMKII protein or significantly reduce most measures of cardiac hypertrophy.

Conclusions— CaMKII is a downstream signal in CAN cardiomyopathy, and increased CaMKII activity contributes to cardiac dysfunction, arrhythmia susceptibility, and longevity during CAN overexpression.

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