Source:http://linkedlifedata.com/resource/pubmed/id/17209005
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
5
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pubmed:dateCreated |
2007-5-9
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pubmed:abstractText |
Patients with mutations in the mitochondrial very-long-chain acyl-CoA dehydrogenase (VLCAD) gene are at risk for cardiomyopathy, myocardial dysfunction, ventricular tachycardia (VT), and sudden cardiac death. The mechanism is not known. Here we report a novel mechanism of VT in mice lacking VLCAD (VLCAD(-/-)). These mice exhibited polymorphic VT and increased incidence of VT after isoproterenol infusion. Polymorphic VT was induced in 10 out of 12 VLCAD(-/-) mice (83%) when isoproterenol was used. One out of 10 VLCAD(-/-) mice with polymorphic VT had VT with the typical bidirectional morphology. At the molecular level, VLCAD(-/-) cardiomyocytes showed increased levels of cardiac ryanodine receptor 2, phospholamban, and calsequestrin with increased [(3)H]ryanodine binding in heart microsomes. At the single cardiomyocyte level, VLCAD(-/-) cardiomyocytes showed significant increase in diastolic indo 1 and fura 2 fluorescence, with increased Ca(2+) transient amplitude. These changes were associated with altered Ca(2+) dynamics, to include: faster sarcomere contraction, larger time derivative of the upstroke, and shorter time-to-minimum sarcomere length compared with VLCAD(+/+) control cells. The L-type Ca(2+) current characteristics were not different under voltage-clamp conditions in the two VLCAD genotypes. Sarcoplasmic reticulum Ca(2+) load measured as normalized integrated Na(+)/Ca(2+) exchange current after rapid caffeine application was increased by 48% in VLCAD(-/-) cells. We conclude that intracellular Ca(2+) handling represents a possible molecular mechanism of arrhythmias in mice and perhaps in VLCAD-deficient humans.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical | |
pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
0363-6135
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pubmed:author |
pubmed-author:AndersonMark EME,
pubmed-author:AschnerMichaelM,
pubmed-author:BaudenbacherFranzF,
pubmed-author:DzhuraIgorI,
pubmed-author:ExilVernat JVJ,
pubmed-author:FleischerSidneyS,
pubmed-author:JeyakumarLoice HLH,
pubmed-author:KannankerilPrince JPJ,
pubmed-author:LeGroneAlisonA,
pubmed-author:MilatovicDejanD,
pubmed-author:StraussArnold WAW,
pubmed-author:WerdichAndreas AAA
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pubmed:issnType |
Print
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pubmed:volume |
292
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
H2202-11
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pubmed:dateRevised |
2007-12-3
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pubmed:meshHeading |
pubmed-meshheading:17209005-Acyl-CoA Dehydrogenase, Long-Chain,
pubmed-meshheading:17209005-Animals,
pubmed-meshheading:17209005-Calcium,
pubmed-meshheading:17209005-Calcium Signaling,
pubmed-meshheading:17209005-Female,
pubmed-meshheading:17209005-Heart Ventricles,
pubmed-meshheading:17209005-Male,
pubmed-meshheading:17209005-Mice,
pubmed-meshheading:17209005-Mice, Knockout,
pubmed-meshheading:17209005-Tachycardia, Ventricular
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pubmed:year |
2007
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pubmed:articleTitle |
Polymorphic ventricular tachycardia and abnormal Ca2+ handling in very-long-chain acyl-CoA dehydrogenase null mice.
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pubmed:affiliation |
Division of Cardiology, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232-0001, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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