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 (RyR2), a validated target of kinase/phosphatase regulation in myocytes, displays abnormal CaMKII-dependent phosphorylation (pS2814 hyperphosphorylation) in ankyrin-B+/- heart. Notably, RyR2 dysregulation is rescued in myocytes from ankyrin-B+/- mice overexpressing a potent CaMKII-inhibitory peptide (AC3I), and aberrant RyR2 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.
Original language | English (US) |
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Pages (from-to) | 2034-2041 |
Number of pages | 8 |
Journal | Heart Rhythm |
Volume | 9 |
Issue number | 12 |
DOIs | |
State | Published - Dec 2012 |
Externally published | Yes |
Keywords
- Ankyrin
- Arrhythmia
- CaMKII
- Ryanodine receptor
- Spectrin
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)