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Heart Rhythm. 2012 Dec;9(12):2034-41. doi: 10.1016/j.hrthm.2012.08.026. Epub 2012 Aug 28.

CaMKII inhibition rescues proarrhythmic phenotypes in the model of human ankyrin-B syndrome.

Author information

1
Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, USA.

Abstract

BACKGROUND:

Cardiovascular disease is a leading cause of death worldwide. Arrhythmias are associated with significant morbidity and mortality related to cardiovascular disease. Recent work illustrates that many cardiac arrhythmias are initiated by a pathologic imbalance between kinase and phosphatase activities in excitable cardiomyocytes.

OBJECTIVE:

To test the relationship between myocyte kinase/phosphatase imbalance and cellular and whole animal arrhythmia phenotypes associated with ankyrin-B cardiac syndrome.

METHODS:

By using a combination of biochemical, electrophysiological, and in vivo approaches, we tested the ability of calcium/calmodulin-dependent kinase (CaMKII) inhibition to rescue imbalance in kinase/phosphatase pathways associated with human ankyrin-B-associated cardiac arrhythmia.

RESULTS:

The cardiac ryanodine receptor (RyR(2)), a validated target of kinase/phosphatase regulation in myocytes, displays abnormal CaMKII-dependent phosphorylation (pS2814 hyperphosphorylation) in ankyrin-B(+/-) heart. Notably, RyR(2) dysregulation is rescued in myocytes from ankyrin-B(+/-) mice overexpressing a potent CaMKII-inhibitory peptide (AC3I), and aberrant RyR(2) open probability observed in ankyrin-B(+/-) hearts is normalized by treatment with the CaMKII inhibitor KN-93. CaMKII inhibition is sufficient to rescue abnormalities in ankyrin-B(+/-) myocyte electrical dysfunction including cellular afterdepolarizations, and significantly blunts whole animal cardiac arrhythmias and sudden death in response to elevated sympathetic tone.

CONCLUSIONS:

These findings illustrate the complexity of the molecular components involved in human arrhythmia and define regulatory elements of the ankyrin-B pathway in pathophysiology. Furthermore, the findings illustrate the potential impact of CaMKII inhibition in the treatment of a congenital form of human cardiac arrhythmia.

PMID:
23059182
PMCID:
PMC3630478
DOI:
10.1016/j.hrthm.2012.08.026
[Indexed for MEDLINE]
Free PMC Article

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