ArticleCirculation. Arrhythmia and electrophysiology2012
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.
Article in Circulation. Arrhythmia and electrophysiology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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27 citing papers in PubMed, 43 citations in OpenAlex.
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- Targeting Calpain for Heart Failure Therapy: Implications From Multiple Murine Models.JACC. Basic to translational science · 2018Article
- Role of Stress Kinase JNK in Binge Alcohol-Evoked Atrial Arrhythmia.Journal of the American College of Cardiology · 2018Article
- Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial Arrhythmogenesis.Circulation research · 2018Article
- Calcium-Dependent Arrhythmogenic Foci Created by Weakly Coupled Myocytes in the Failing Heart.Circulation research · 2017Article
- MG53 is dispensable for T-tubule maturation but critical for maintaining T-tubule integrity following cardiac stress.Journal of molecular and cellular cardiology · 2017Article
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- Nebivolol suppresses cardiac ryanodine receptor-mediated spontaneous Ca2+ release and catecholaminergic polymorphic ventricular tachycardia.The Biochemical journal · 2016Article
- Suppression of ryanodine receptor function prolongs Ca2+ release refractoriness and promotes cardiac alternans in intact hearts.The Biochemical journal · 2016Article
- R4496C RyR2 mutation impairs atrial and ventricular contractility.The Journal of general physiology · 2016Article
- A novel cardiac ryanodine receptor gene (RyR2) mutation in an athlete with aborted sudden cardiac death: a case of adult-onset catecholaminergic polymorphic ventricular tachycardia.Heart and vessels · 2015Article
- Mitochondrial oxidative stress promotes atrial fibrillation.Scientific reports · 2015Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
backgroundCatecholaminergic 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. METHODS AND
resultsWe 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.
conclusionsOur 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.
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