title: Cardiac ryanodine receptors control heart rate and rhythmicity in adult mice.
abstract: OBJECTIVE
  The molecular mechanisms controlling heart function and rhythmicity are incompletely understood. While it is widely accepted that the type 2 ryanodine receptor (Ryr2) is the major Ca(2+) release channel in excitation-contraction coupling, the role of these channels in setting a consistent beating rate remains controversial. Gain-of-function RYR2 mutations in humans and genetically engineered mouse models are known to cause Ca(2+) leak, arrhythmias, and sudden cardiac death. Embryonic stem-cell derived cardiomyocytes lacking Ryr2 display slower beating rates, but no supporting in vivo evidence has been presented. The aim of the present study was to test the hypothesis that RYR2 loss-of-function would reduce heart rate and rhythmicity in vivo.
  
  
  RESULTS
  We generated inducible, tissue-specific Ryr2 knockout mice with acute ∼50% loss of RYR2 protein in the heart but not in other tissues. Echocardiography, working heart perfusion, and in vivo ECG telemetry demonstrated that deletion of Ryr2 was sufficient to cause bradycardia and arrhythmia. Our results also show that cardiac Ryr2 knockout mice exhibit functional and structural hallmarks of heart failure, including sudden cardiac death.
  
  
  CONCLUSIONS
  These results illustrate that the RYR2 channel plays an essential role in pacing heart rate. Moreover, we find that RYR2 loss-of-function can lead to fatal arrhythmias typically associated with gain-of-function mutations. Given that RYR2 levels can be reduced in pathological conditions, including heart failure and diabetic cardiomyopathy, we predict that RYR2 loss contributes to disease-associated bradycardia, arrhythmia, and sudden death.
authors.affiliation: Cardiovascular Research Group, Life Sciences Institute,  University of British Columbia, 5358 Life Sciences Building, 2350 Health Sciences Mall, Vancouver, BC,  Canada V6T 1Z3.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bround
authors.forename: Parisa
authors.initials: P
authors.lastname: Asghari
authors.forename: Rich B
authors.initials: RB
authors.lastname: Wambolt
authors.forename: Lubos
authors.initials: L
authors.lastname: Bohunek
authors.forename: Claire
authors.initials: C
authors.lastname: Smits
authors.forename: Marjolaine
authors.initials: M
authors.lastname: Philit
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kieffer
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lakatta
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Boheler
authors.forename: Edwin D W
authors.initials: ED
authors.lastname: Moore
authors.forename: Michael F
authors.initials: MF
authors.lastname: Allard
authors.forename: James D
authors.initials: JD
authors.lastname: Johnson
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D001683:Biological Clocks; D001919:Bradycardia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002302:Cardiac Output; D016757:Death, Sudden, Cardiac / Q000209:etiology; D015536:Down-Regulation; D015716:Electrocardiography, Ambulatory / Q000379:methods; D056966:Excitation Contraction Coupling; D006339:Heart Rate; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013686:Telemetry; D013997:Time Factors; D014463:Ultrasonography; D016276:Ventricular Function
chemical_list: D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel