Shortened Ca2+ signaling refractoriness underlies cellular arrhythmogenesis in a postinfarction model of sudden cardiac death.

Abstract

RATIONALE:

Diastolic spontaneous Ca(2+) waves (DCWs) are recognized as important contributors to triggered arrhythmias. DCWs are thought to arise when [Ca(2+)] in sarcoplasmic reticulum ([Ca(2+)](SR)) reaches a certain threshold level, which might be reduced in cardiac disease as a consequence of sensitization of ryanodine receptors (RyR2s) to luminal Ca(2+).

OBJECTIVE:

We investigated the mechanisms of DCW generation in myocytes from normal and diseased hearts, using a canine model of post-myocardial infarction ventricular fibrillation (VF).

METHODS AND RESULTS:

The frequency of DCWs, recorded during periodic pacing in the presence of a β-adrenergic receptor agonist isoproterenol, was significantly higher in VF myocytes than in normal controls. Rather than occurring immediately on reaching a final [Ca(2+)](SR), DCWs arose with a distinct time delay after attaining steady [Ca(2+)](SR) in both experimental groups. Although the rate of [Ca(2+)](SR) recovery after the SR Ca(2+) release was similar between the groups, in VF myocytes the latency to DCWs was shorter, and the [Ca(2+)](SR) at DCW initiation was lower. The restitution of depolarization-induced Ca(2+) transients, assessed by a 2-pulse protocol, was significantly faster in VF myocytes than in controls. The VF-related alterations in myocyte Ca(2+) cycling were mimicked by the RyR2 agonist, caffeine. The reducing agent, mercaptopropionylglycine, or the CaMKII inhibitor, KN93, decreased DCW frequency and normalized restitution of Ca(2+) release in VF myocytes.

CONCLUSIONS:

The attainment of a certain threshold [Ca(2+)](SR) is not sufficient for the generation of DCWs. Postrelease Ca(2+) signaling refractoriness critically influences the occurrence of DCWs. Shortened Ca(2+) signaling refractoriness due to RyR2 phosphorylation and oxidation is responsible for the increased rate of DCWs observed in VF myocytes and could provide a substrate for synchronization of arrhythmogenic events at the tissue level in hearts prone to VF.

• Authors: Andriy E Belevych, Dmitry Terentyev, Radmila Terentyeva, Hsiang-Ting Ho, Inna Gyorke, Ingrid M Bonilla, Cynthia A Carnes, George E Billman, Sandor Györke
• Journal: Circulation research (Circ Res) Vol. 110 Issue 4 Pg. 569-77 (Feb 17 2012) ISSN: 1524-4571 [Electronic] United States
• PMID: 22223353 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adrenergic beta-Agonists
• Benzylamines
• Calcium Channel Agonists
• Protein Kinase Inhibitors
• Reducing Agents
• Ryanodine Receptor Calcium Release Channel
• Sulfonamides
• KN 93
• Caffeine
• Tiopronin
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Isoproterenol

Topics

• Adrenergic beta-Agonists
• Animals
• Benzylamines (pharmacology)
• Caffeine (pharmacology)
• Calcium Channel Agonists (pharmacology)
• Calcium Signaling (drug effects)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (antagonists & inhibitors, metabolism)
• Cardiac Pacing, Artificial
• Death, Sudden, Cardiac (etiology)
• Disease Models, Animal
• Dogs
• Excitation Contraction Coupling
• Female
• Isoproterenol
• Male
• Myocardial Infarction (complications, metabolism, physiopathology)
• Myocytes, Cardiac (drug effects, metabolism)
• Oxidation-Reduction
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Reaction Time
• Reducing Agents (pharmacology)
• Ryanodine Receptor Calcium Release Channel (drug effects, metabolism)
• Sarcoplasmic Reticulum (metabolism)
• Sulfonamides (pharmacology)
• Time Factors
• Tiopronin (pharmacology)
• Ventricular Fibrillation (etiology, metabolism, physiopathology)