title: Variability in timing of spontaneous calcium release in the intact rat heart is determined by the time course of sarcoplasmic reticulum calcium load.
abstract: BACKGROUND
  Abnormalities in intracellular calcium (Ca) cycling during Ca overload can cause triggered activity because spontaneous calcium release (SCR) activates sufficient Ca-sensitive inward currents to induce delayed afterdepolarizations (DADs). However, little is known about the mechanisms relating SCR and triggered activity on the tissue scale.
  
  
  RESULTS
  Laser scanning confocal microscopy was used to measure the spatiotemporal properties of SCR within large myocyte populations in intact rat heart. Computer simulations were used to predict how these properties of SCR determine DAD magnitude. We measured the average and standard deviation of the latency distribution of SCR within a large population of myocytes in intact tissue. We found that as external [Ca] is increased, and with faster pacing rates, the average and SD of the latency distribution decreases substantially. This result demonstrates that the timing of SCR occurs with less variability as the sarcoplasmic reticulum (SR) Ca load is increased, causing more sites to release Ca within each cell. We then applied a mathematical model of subcellular Ca cycling to show that a decrease in SCR variability leads to a higher DAD amplitude and is dictated by the rate of SR Ca refilling following an action potential.
  
  
  CONCLUSIONS
  Our results demonstrate that the variability of the timing of SCR in a population of cells in tissue decreases with SR load and is dictated by the time course of the SR Ca content.
authors.affiliation: Department of Medicine (Cardiology) and Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 310 E Superior Street, Chicago, IL 60611, USA. ja-wasserstrom@northwestern.edu
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Wasserstrom
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Shiferaw
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Satvik
authors.initials: S
authors.lastname: Ramakrishna
authors.forename: Heetabh
authors.initials: H
authors.lastname: Patel
authors.forename: James E
authors.initials: JE
authors.lastname: Kelly
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: O'Toole
authors.forename: Amanda
authors.initials: A
authors.lastname: Pappas
authors.forename: Nimi
authors.initials: N
authors.lastname: Chirayil
authors.forename: Nikhil
authors.initials: N
authors.lastname: Bassi
authors.forename: Lisa
authors.initials: L
authors.lastname: Akintilo
authors.forename: Megan
authors.initials: M
authors.lastname: Wu
authors.forename: Rishi
authors.initials: R
authors.lastname: Arora
authors.forename: Gary L
authors.initials: GL
authors.lastname: Aistrup
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D013997:Time Factors
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium