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(Circulation. 2008;118:2219-2220.)
© 2008 American Heart Association, Inc.

Clinical Summaries

An extract of the first 250 words of the full text is provided, because this article has no abstract.

	Proarrhythmic Defects in Timothy Syndrome Require Calmodulin Kinase II

 
Timothy syndrome (TS) is a genetic disorder causing excessive cellular Ca²⁺ entry resulting from defective voltage-dependent inactivation of the predominant myocardial L-type Ca²⁺ channel (Ca_V1.2) current (I_Ca). TS patients die on average at 2.5 years of age as a result of malignant cardiac arrhythmias. TS is a "model" disease whereby a concise biophysical defect in I_Ca activates a cellular signaling cascade that is required for the cardiac disease phenotypes. Our studies showed that loss of voltage-dependent inactivation leads to cellular arrhythmias by recruiting activity of the calmodulin-dependent protein kinase II (CaMKII). The role of CaMKII was not anticipated by previous computer models that relied on data obtained from nonexcitable, heterologous cells. Our studies show that the TS voltage-dependent inactivation defect activated CaMKII and that CaMKII was the feed-forward signal required for the proarrhythmic cellular phenotypes in TS. These findings have potentially broad implications for other pathological phenotypes in TS such as autism and for other genetic diseases affecting Ca²⁺ channels such as migraine headache, myasthenia, ataxia, and malignant hyperthermia. Diseases associated with excitable cells in which ion channels frequently constitute a final common pathway require careful consideration of the connections between ion channel gating and signaling cascades to more comprehensively understand the underlying mechanisms. See p 2225.

	Association Between Intraoperative and Early Postoperative Glucose Levels and Adverse Outcomes After Complex Congenital Heart Surgery

 
Hyperglycemia occurs commonly and has been associated with increased morbidity and mortality in critically ill adults, including those undergoing cardiac surgery. The use of insulin to achieve strict glycemic control may improve outcomes in these patients. The aim of this . . . [Full Text of this Article]

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