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(Circulation. 2008;118:2225-2234.)
© 2008 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Proarrhythmic Defects in Timothy Syndrome Require Calmodulin Kinase II

William H. Thiel, BS; Biyi Chen, PhD; Thomas J. Hund, PhD; Olha M. Koval, PhD; Anil Purohit, MD, PhD; Long-Sheng Song, MD; Peter J. Mohler, PhD; Mark E. Anderson, MD, PhD

From Vanderbilt University, Nashville, Tenn (W.H.T.), and University of Iowa, Iowa City (W.H.T., B.C., T.J.H., O.M.K., A.P., L.-S.S., P.J.M., M.E.A.).

Correspondence to Mark E. Anderson, University of Iowa, Department of Internal Medicine, 285 Newton Rd, Iowa City, IA 52242. E-mail mark-e-anderson{at}uiowa.edu

Received April 23, 2008; accepted September 8, 2008.

Background— Timothy syndrome (TS) is a disease of excessive cellular Ca²⁺ entry and life-threatening arrhythmias caused by a mutation in the primary cardiac L-type Ca²⁺ channel (Ca_V1.2). The TS mutation causes loss of normal voltage-dependent inactivation of Ca_V1.2 current (I_Ca). During cellular Ca²⁺ overload, the calmodulin-dependent protein kinase II (CaMKII) causes arrhythmias. We hypothesized that CaMKII is a part of the proarrhythmic mechanism in TS.

Methods and Results— We developed an adult rat ventricular myocyte model of TS (G406R) by lentivirus-mediated transfer of wild-type and TS Ca_V1.2. The exogenous Ca_V1.2 contained a mutation (T1066Y) conferring dihydropyridine resistance, so we could silence endogenous Ca_V1.2 with nifedipine and maintain peak I_Ca at control levels in infected cells. TS Ca_V1.2–infected ventricular myocytes exhibited the signature voltage-dependent inactivation loss under Ca²⁺ buffering conditions, not permissive for CaMKII activation. In physiological Ca²⁺ solutions, TS Ca_V1.2–expressing ventricular myocytes exhibited increased CaMKII activity and a proarrhythmic phenotype that included action potential prolongation, increased I_Ca facilitation, and afterdepolarizations. Intracellular dialysis of a CaMKII inhibitory peptide, but not a control peptide, reversed increases in I_Ca facilitation, normalized the action potential, and prevented afterdepolarizations. We developed a revised mathematical model that accounts for CaMKII-dependent and CaMKII-independent effects of the TS mutation.

Conclusion— In TS, the loss of voltage-dependent inactivation is an upstream initiating event for arrhythmia phenotypes that are ultimately dependent on CaMKII activation.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2008 118: 2219-2220. [Extract] [Full Text]

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