on August 19, 2002
Published online before print August 19, 2002, doi: 10.1161/01.CIR.0000027583.73268.E7
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Submitted on May 7, 2002
From the Departments of Internal Medicine (Y.W., R.Z., I.D., R.T., D.M.R., M.E.A.), Pediatrics (J.T.), Pharmacology (W.Z., D.M.R., M.E.A.), and Molecular Physiology and Biophysics (R.J.C.), Vanderbilt University, Nashville, Tenn, and Department of Molecular Biology (R.P., E.N.O.), The University of Texas Southwestern Medical Center at Dallas, Tex. * To whom correspondence should be addressed. E-mail: mark.anderson{at}vanderbilt.edu.
Background—Calmodulin kinase (CaMK) II is linked to arrhythmia mechanisms in cellular models where repolarization is prolonged. CaMKII upregulation and prolonged repolarization are general features of cardiomyopathy, but the role of CaMKII in arrhythmias in cardiomyopathy is unknown. Methods and Results—We studied a mouse model of cardiac hypertrophy attributable to transgenic (TG) overexpression of a constitutively active form of CaMKIV that also has increased endogenous CaMKII activity. ECG-telemetered TG mice had significantly more arrhythmias than wild-type (WT) littermate controls at baseline, and arrhythmias were additionally increased by isoproterenol. Arrhythmias were significantly suppressed by an inhibitory agent targeting endogenous CaMKII. TG mice had longer QT intervals and action potential durations than WT mice, and TG cardiomyocytes had frequent early afterdepolarizations (EADs), a hypothesized mechanism for triggering arrhythmias. EADs were absent in WT cells before and after isoproterenol, whereas EAD frequency was unaffected by isoproterenol in TG mice. L-type Ca2+ channels (LTTCs) can activate EADs, and LTCC opening probability (Po) was significantly higher in TG than WT cardiomyocytes before and after isoproterenol. A CaMKII inhibitory peptide equalized TG and WT LTCC Po and eliminated EADs, whereas a peptide antagonist of the Na+/Ca2+ exchanger current, also hypothesized to support EADs, was ineffective. Conclusions—These findings support the hypothesis that CaMKII is a proarrhythmic signaling molecule in cardiac hypertrophy in vivo. Cellular studies point to EADs as a triggering mechanism for arrhythmias but suggest that the increase in arrhythmias after ß-adrenergic stimulation is independent of enhanced EAD frequency.
Revised on June 11, 2002
Accepted on June 11, 2002
Calmodulin Kinase II and Arrhythmias in a Mouse Model of Cardiac Hypertrophy
Yuejin Wu PhD,
Key words: arrhythmia • calcium • signal transduction
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