Sudden infant death syndrome in mice with an inherited mutation in RyR2

Xander H.T. Wehrens, Nitin Mathur, Subeena Sood, Sufen Wang, Ralph J. Van Oort, Satyam Sarma, Na Li, Darlene G. Skapura, J. Henri Bayle, Miguel Valderrábano

Research output: Contribution to journalArticle

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Abstract

Background-Mutations in the cardiac ryanodine receptor gene (RyR2) have been recently identified in victims of sudden infant death syndrome. The aim of this study was to determine whether a gain-of-function mutation in RyR2 increases the propensity to cardiac arrhythmias and sudden death in young mice. Methods and Results-Incidence of sudden death was monitored prospectively in heterozygous knock-in mice with mutation R176Q in RyR2 (R176Q/+). Young R176Q/+ mice exhibited a higher incidence of sudden death compared with wild-type littermates. Optical mapping of membrane potentials and intracellular calcium in 1- to 7-day-old R176Q/+ and wild-type mice revealed an increased incidence of ventricular ectopy and spontaneous calcium releases in neonatal R176Q/+ mice. Surface ECGs in 3- to 10-day-old mice showed that R176Q/+ mice developed more ventricular arrhythmias after provocation with epinephrine and caffeine. Intracardiac pacing studies in 12- to 18-day-old mice revealed the presence of an arrhythmogenic substrate in R176Q/+ compared with wild-type mice. Reverse transcription-polymerase chain reaction and Western blotting showed that expression levels of other calcium handling proteins were unaltered, suggesting that calcium leak through mutant RyR2 underlies arrhythmogenesis and sudden death in young R176Q/+ mice. Conclusions-Our findings demonstrate that a gain-of-function mutation in RyR2 confers an increased risk of cardiac arrhythmias and sudden death in young mice and that young R176Q/+ mice may be used as a model for elucidating the complex interplay between genetic and environmental risk factors associated with sudden infant death syndrome. (Circ Arrhythm Electrophysiol. 2009;2:677-685.)

Original languageEnglish (US)
Pages (from-to)677-685
Number of pages9
JournalCirculation: Arrhythmia and Electrophysiology
Volume2
Issue number6
DOIs
StatePublished - Dec 1 2009

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Ryanodine Receptor Calcium Release Channel
Sudden Infant Death
Mutation
Sudden Death
Calcium
Cardiac Arrhythmias
Incidence
Caffeine
Membrane Potentials
Epinephrine
Reverse Transcription
Electrocardiography
Western Blotting

Keywords

  • Calcium
  • Focal activity
  • Ryanodine receptors
  • Sudden infant death syndrome
  • Ventricular arrhythmias

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Wehrens, X. H. T., Mathur, N., Sood, S., Wang, S., Van Oort, R. J., Sarma, S., ... Valderrábano, M. (2009). Sudden infant death syndrome in mice with an inherited mutation in RyR2. Circulation: Arrhythmia and Electrophysiology, 2(6), 677-685. https://doi.org/10.1161/CIRCEP.109.894683

Sudden infant death syndrome in mice with an inherited mutation in RyR2. / Wehrens, Xander H.T.; Mathur, Nitin; Sood, Subeena; Wang, Sufen; Van Oort, Ralph J.; Sarma, Satyam; Li, Na; Skapura, Darlene G.; Bayle, J. Henri; Valderrábano, Miguel.

In: Circulation: Arrhythmia and Electrophysiology, Vol. 2, No. 6, 01.12.2009, p. 677-685.

Research output: Contribution to journalArticle

Wehrens, XHT, Mathur, N, Sood, S, Wang, S, Van Oort, RJ, Sarma, S, Li, N, Skapura, DG, Bayle, JH & Valderrábano, M 2009, 'Sudden infant death syndrome in mice with an inherited mutation in RyR2', Circulation: Arrhythmia and Electrophysiology, vol. 2, no. 6, pp. 677-685. https://doi.org/10.1161/CIRCEP.109.894683
Wehrens, Xander H.T. ; Mathur, Nitin ; Sood, Subeena ; Wang, Sufen ; Van Oort, Ralph J. ; Sarma, Satyam ; Li, Na ; Skapura, Darlene G. ; Bayle, J. Henri ; Valderrábano, Miguel. / Sudden infant death syndrome in mice with an inherited mutation in RyR2. In: Circulation: Arrhythmia and Electrophysiology. 2009 ; Vol. 2, No. 6. pp. 677-685.
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