Ca(2+)-related signaling and protein phosphorylation abnormalities play central roles in a new experimental model of electrical storm.

Abstract

BACKGROUND:

Electrical storm (ES), characterized by recurrent ventricular tachycardia/fibrillation, typically occurs in implantable cardioverter-defibrillator patients and adversely affects prognosis. However, the underlying molecular basis is poorly understood. In the present study, we report a new experimental model featuring repetitive episodes of implantable cardioverter-defibrillator firing for recurrent ventricular fibrillation (VF), in which we assessed involvement of Ca(2+)-related protein alterations in ES.

METHODS AND RESULTS:

We studied 37 rabbits with complete atrioventricular block for ≈80 days, all with implantable cardioverter-defibrillator implantation. All rabbits showed long-QT and VF episodes. Fifty-three percent of rabbits developed ES (≥3 VF episodes per 24-hour period; 103±23 VF episodes per rabbit). Expression/phosphorylation of Ca(2+)-handling proteins was assessed in left ventricular tissues from rabbits with the following: ES; VF episodes but not ES (non-ES); and controls. Left ventricular end-diastolic diameter increased comparably in ES and non-ES rabbits, but contractile dysfunction was significantly greater in ES than in non-ES rabbits. ES rabbits showed striking hyperphosphorylation of Ca(2+)/calmodulin-dependent protein kinase II, prominent phospholamban dephosphorylation, and increased protein phosphatase 1 and 2A expression versus control and non-ES rabbits. Ryanodine receptors were similarly hyperphosphorylated at Ser2815 in ES and non-ES rabbits, but ryanodine receptor Ser2809 and L-type Ca(2+) channel α-subunit hyperphosphorylation were significantly greater in ES versus non-ES rabbits. To examine direct effects of repeated VF/defibrillation, VF was induced 10 times in control rabbits. Repeated VF tissues showed autophosphorylated Ca(2+)/calmodulin-dependent protein kinase II upregulation and phospholamban dephosphorylation like those of ES rabbit hearts. Continuous infusion of a calmodulin antagonist (W-7) to ES rabbits reduced Ca(2+)/calmodulin-dependent protein kinase II hyperphosphorylation, suppressed ventricular tachycardia/fibrillation, and rescued left ventricular dysfunction.

CONCLUSIONS:

ES causes Ca(2+)/calmodulin-dependent protein kinase II activation and phospholamban dephosphorylation, which can explain the vicious cycle of arrhythmia promotion and mechanical dysfunction that characterizes ES.

• Authors: Yukiomi Tsuji, Mayumi Hojo, Niels Voigt, Ali El-Armouche, Yasuya Inden, Toyoaki Murohara, Dobromir Dobrev, Stanley Nattel, Itsuo Kodama, Kaichiro Kamiya
• Journal: Circulation (Circulation) Vol. 123 Issue 20 Pg. 2192-203 (May 24 2011) ISSN: 1524-4539 [Electronic] United States
• PMID: 21555709 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channels, L-Type
• Calcium-Binding Proteins
• Enzyme Inhibitors
• Intracellular Signaling Peptides and Proteins
• Ryanodine Receptor Calcium Release Channel
• Sulfonamides
• phospholamban
• protein phosphatase inhibitor-1
• W 7
• Calcium-Calmodulin-Dependent Protein Kinase Type 2

Topics

• Animals
• Calcium Channels, L-Type (metabolism)
• Calcium Signaling (drug effects, physiology)
• Calcium-Binding Proteins (metabolism)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (antagonists & inhibitors, metabolism)
• Defibrillators, Implantable
• Disease Models, Animal
• Electrocardiography
• Enzyme Inhibitors (pharmacology)
• Female
• Heart Block (metabolism)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Phosphorylation (drug effects, physiology)
• Rabbits
• Recurrence
• Ryanodine Receptor Calcium Release Channel (metabolism)
• Sulfonamides (pharmacology)
• Tachycardia, Ventricular (diagnosis, metabolism, therapy)
• Ventricular Fibrillation (diagnosis, metabolism, therapy)