In situ confocal imaging in intact heart reveals stress-induced Ca(2+) release variability in a murine catecholaminergic polymorphic ventricular tachycardia model of type 2 ryanodine receptor(R4496C+/-) mutation

Biyi Chen; Ang Guo; Zhan Gao; Sheng Wei; Yu-Ping Xie; S R Wayne Chen; Mark E Anderson; Long-Sheng Song

doi:10.1161/CIRCEP.111.969733

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In situ confocal imaging in intact heart reveals stress-induced Ca(2+) release variability in a murine catecholaminergic polymorphic ventricular tachycardia model of type 2 ryanodine receptor(R4496C+/-) mutation

Journal article

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Peer reviewed

In situ confocal imaging in intact heart reveals stress-induced Ca(2+) release variability in a murine catecholaminergic polymorphic ventricular tachycardia model of type 2 ryanodine receptor(R4496C+/-) mutation

Biyi Chen, Ang Guo, Zhan Gao, Sheng Wei, Yu-Ping Xie, S R Wayne Chen, Mark E Anderson and Long-Sheng Song

Circulation. Arrhythmia and electrophysiology, Vol.5(4), pp.841-849

08/01/2012

DOI: 10.1161/CIRCEP.111.969733

PMCID: PMC3421047

PMID: 22722659

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Abstract

Catecholaminergic polymorphic ventricular tachycardia is directly linked to mutations in proteins (eg, type 2 ryanodine receptor [RyR2](R4496C)) responsible for intracellular Ca(2+) homeostasis in the heart. However, the mechanism of Ca(2+) release dysfunction underlying catecholaminergic polymorphic ventricular tachycardia has only been investigated in isolated cells but not in the in situ undisrupted myocardium. We investigated in situ myocyte Ca(2+) dynamics in intact Langendorff-perfused hearts (ex vivo) from wild-type and RyR2(R4496C+/-) mice using laser scanning confocal microscopy. We found that myocytes from both wild-type and RyR2(R4496C+/-) hearts displayed uniform, synchronized Ca(2+) transients. Ca(2+) transients from beat to beat were comparable in amplitude with identical activation and decay kinetics in wild-type and RyR2(R4496C+/-) hearts, suggesting that excitation-contraction coupling between the sarcolemmal Ca(2+) channels and mutated RyR2(R4496C+/-) channels remains intact under baseline resting conditions. On adrenergic stimulation, RyR2(R4496C+/-) hearts exhibited a high degree of Ca(2+) release variability. The varied pattern of Ca(2+) release was absent in single isolated myocytes, independent of cell cycle length, synchronized among neighboring myocytes, and correlated with catecholaminergic polymorphic ventricular tachycardia. A similar pattern of action potential variability, which was synchronized among neighboring myocytes, was also revealed under adrenergic stress in intact hearts but not in isolated myocytes. Our studies using an in situ confocal imaging approach suggest that mutated RyR2s are functionally normal at rest but display a high degree of Ca(2+) release variability on intense adrenergic stimulation. Ca(2+) release variability is a Ca(2+) release abnormality, resulting from electric defects rather than the failure of the Ca(2+) release response to action potentials in mutated ventricular myocytes. Our data provide important insights into Ca(2+) release and electric dysfunction in an established model of catecholaminergic polymorphic ventricular tachycardia.

Myocardial Contraction

Genetic Predisposition to Disease

Excitation Contraction Coupling

Adrenergic Agonists - pharmacology

Action Potentials

Microscopy, Confocal

Phenotype

Tachycardia, Ventricular - physiopathology

Animals

Myocytes, Cardiac - drug effects

Ryanodine Receptor Calcium Release Channel - genetics

Calcium Signaling - drug effects

Mice, Mutant Strains

Perfusion

Tachycardia, Ventricular - metabolism

Electrocardiography

Myocytes, Cardiac - metabolism

Tachycardia, Ventricular - genetics

Mice

Kinetics

Mutation

In Vitro Techniques

Epinephrine - pharmacology

Disease Models, Animal

Details

Title: Subtitle: In situ confocal imaging in intact heart reveals stress-induced Ca(2+) release variability in a murine catecholaminergic polymorphic ventricular tachycardia model of type 2 ryanodine receptor(R4496C+/-) mutation
Creators: Biyi Chen - Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Ang Guo
Zhan Gao
Sheng Wei
Yu-Ping Xie
S R Wayne Chen
Mark E Anderson
Long-Sheng Song
Resource Type: Journal article
Publication Details: Circulation. Arrhythmia and electrophysiology, Vol.5(4), pp.841-849
DOI: 10.1161/CIRCEP.111.969733
PMID: 22722659
PMCID: PMC3421047
NLM abbreviation: Circ Arrhythm Electrophysiol
eISSN: 1941-3084
Grant note: R01 HL113001 / NHLBI NIH HHS 2R01HL075210 / NHLBI NIH HHS R01 HL079031 / NHLBI NIH HHS R01 HL070250 / NHLBI NIH HHS R01 HL096652 / NHLBI NIH HHS R01 HL70250 / NHLBI NIH HHS R01 HL075210 / NHLBI NIH HHS R01 HL62494 / NHLBI NIH HHS R01 HL090905 / NHLBI NIH HHS R01 HL062494 / NHLBI NIH HHS
Language: English
Date published: 08/01/2012
Academic Unit: Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984094588102771

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