A mechanism for sudden infant death syndrome (SIDS): Stress-induced leak via ryanodine receptors

Tester, David J.; Důra, Miroslav; Carturan, Elisa; Reiken, Steven; Wronska, Anetta; Marks, Andrew R.; Ackerman, Michael J.

doi:10.1016/j.hrthm.2007.02.026

Cited by 165 publications

(110 citation statements)

References 44 publications

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“…Channelopathies are dysfunctional myocyte ion channels that result in abnormal movement of electrolytes into and/or out of the cell and predispose the heart to arrhythmia. [492][493][494][495][496][497][498][499][500][501] Mutations causing cardiac ion channelopathies are found in 2% to 10% of victims [492][493][494][495][496][497][498] and in 14% to 20% of young adults with sudden death in whom the cause of death is not evident in a routine autopsy. 499 -501 Clinical and laboratory (eg, ECG, molecular-genetic screening) investigations of first-and second-degree relatives of patients with sudden unexplained death reported inherited, arrhythmogenic disease in 22% to 53% of families.…”

Section: Sudden Unexplained Deathsmentioning

confidence: 99%

Part 14: Pediatric Advanced Life Support

Kleinman¹,

Chameides²,

Schexnayder³

et al. 2010

Circulation

915

304

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Section: Sudden Unexplained Deathsmentioning

confidence: 99%

Part 14: Pediatric Advanced Life Support

Kleinman¹,

Chameides²,

Schexnayder³

et al. 2010

Circulation

915

304

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“…CPVT patients experience syncope and sudden cardiac death (SCD) from the toddler to adult ages, and by 35 years age the mortality is up to 50% (13,16,17).…”

Section: Introductionmentioning

confidence: 99%

Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice

Lehnart

Mongillo²,

Bellinger³

et al. 2008

J. Clin. Invest.

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272

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The Ca 2+ release channel ryanodine receptor 2 (RyR2) is required for excitation-contraction coupling in the heart and is also present in the brain. Mutations in RyR2 have been linked to exercise-induced sudden cardiac death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). CPVT-associated RyR2 mutations result in "leaky" RyR2 channels due to the decreased binding of the calstabin2 (FKBP12.6) subunit, which stabilizes the closed state of the channel. We found that mice heterozygous for the R2474S mutation in Ryr2 (Ryr2-R2474S mice) exhibited spontaneous generalized tonic-clonic seizures (which occurred in the absence of cardiac arrhythmias), exercise-induced ventricular arrhythmias, and sudden cardiac death. Treatment with a novel RyR2-specific compound (S107) that enhances the binding of calstabin2 to the mutant Ryr2-R2474S channel inhibited the channel leak and prevented cardiac arrhythmias and raised the seizure threshold. Thus, CPVT-associated mutant leaky Ryr2-R2474S channels in the brain can cause seizures in mice, independent of cardiac arrhythmias. Based on these data, we propose that CPVT is a combined neurocardiac disorder in which leaky RyR2 channels in the brain cause epilepsy, and the same leaky channels in the heart cause exerciseinduced sudden cardiac death. IntroductionPharmacological seizure models have implicated abnormalities in intracellular Ca 2+ cycling of inhibitory interneurons and/or astrocytes as a mechanism of seizure generation (1, 2), and the inositol 1,4,5-trisphosphate receptor (IP3R), an intracellular calcium release channel on the ER, has been associated with seizures in mice (3). However, a causal relationship between defective intracellular calcium release channels and seizures has not been reported. Calcium stored within the ER contributes to neuronal signaling and is controlled by intracellular Ca 2+ release channels, in particular ryanodine receptors (RyRs) (4-6) and IP3Rs (7,8). To explore the underlying mechanism for seizures in CPVT we generated mice that harbor a missense mutation (RyR2-R2474S) that has been linked to exercise-induced cardiac arrhythmias in humans (9-12).More than 50 distinct RYR2 mutations have been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), an arrhythmogenic cardiomyopathy (13-15). CPVT patients experience syncope and sudden cardiac death (SCD) from the toddler to adult ages, and by 35 years age the mortality is up to 50% (13,16,17).

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“…6 While the pathophysiological mechanisms underlying most of these tragic deaths remain elusive, heritable cardiac arrhythmia syndromes such as long QT syndrome (LQTS), Brugada syndrome (BrS), and catecholoaminergic polymorphic ventricular tachycardia (CPVT) appear to account for 10-15% of SIDS, with the majority of SIDS related mutations being identified in the SCN5A-encoded cardiac sodium channel alpha subunit (Nav1.5) or its interacting proteins. [7][8][9][10][11][12][13][14][15] In 2002, Splawski and colleagues reported on the common African American-specific polymorphism S1103Y-SCN5A (denoted previously as S1102Y) with a prevalence of 13% among African Americans and associated with an increased risk for arrhythmia susceptibility, particularly in the context of other acquired risk factors such as medications, hypokalemia or structural heart disease. 16 Subsequently, Burke and colleagues observed an overrepresentation of S1103Y among African American adolescents and adults whose deaths were classified as autopsy negative sudden unexplained death (SUD).…”

Section: Introductionmentioning

confidence: 99%

Overrepresentation of the proarrhythmic, sudden death predisposing sodium channel polymorphism S1103Y in a population-based cohort of African-American sudden infant death syndrome

Norstrand¹,

Tester²,

Ackerman³

2008

Heart Rhythm

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A mechanism for sudden infant death syndrome (SIDS): Stress-induced leak via ryanodine receptors

Abstract: BACKGROUND-Sudden infant death syndrome (SIDS) is the leading cause of postneonatal mortality in the United States. Mutations in the RyR2-encoded cardiac ryanodine receptor cause the highly lethal catecholaminergic polymorphic ventricular tachycardia (CPVT1) in the young.

Cited by 165 publications

References 44 publications

Part 14: Pediatric Advanced Life Support

Part 14: Pediatric Advanced Life Support

Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice

Overrepresentation of the proarrhythmic, sudden death predisposing sodium channel polymorphism S1103Y in a population-based cohort of African-American sudden infant death syndrome

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