title: Increased leakage of sarcoplasmic reticulum Ca2+ contributes to abnormal myocyte Ca2+ handling and shortening in sepsis.
abstract: OBJECTIVE
  Changes in cardiac function due to sepsis have been widely reported. However, the underlying mechanisms remain poorly understood. In the mammalian heart, myocyte function and intracellular calcium homeostasis are closely coupled. In this study we tested the hypothesis that alterations in cardiac calcium homeostasis due to sepsis underlie the observed myocyte dysfunction.
  
  
  METHODS
  Randomized prospective animal study.
  
  
  METHODS
  Research laboratory.
  
  
  METHODS
  Male Sprague-Dawley rats weighing 250-275 g.
  
  
  METHODS
  We induced sepsis by cecal ligation and puncture in the rat, which mimics the type of infection caused by perforation of the intestine in humans.
  
  
  RESULTS
  Forty-eight hours after cecal ligation and puncture, isolated cardiac ventricular cardiomyocytes demonstrated a 57% decreased peak systolic [Ca]. The time constant of the Ca transient increased 71% and 57% in myocytes obtained 24 hrs and 48 hrs after cecal ligation and puncture, respectively. The average shortening of cardiomyocytes 48 hrs after cecal ligation and puncture was significantly decreased. To investigate the cellular mechanisms of altered Ca transients and myocyte shortening, we measured Ca sparks, the spontaneous local Ca release events in cardiomyocytes at resting states. The Ca spark frequency progressively increased in myocytes 24 hrs and 48 hrs after cecal ligation and puncture. The total activity of sparks also increased compared with sham-operated animals. The overall leakage of sarcoplasmic reticulum Ca in resting states was increased in sepsis and resulted in reduced sarcoplasmic reticulum Ca content.
  
  
  CONCLUSIONS
  Abnormal Ca leakage from the sarcoplasmic reticulum contributes significantly to the depressed myocyte shortening in sepsis. In the future, modalities that prevent this Ca leakage may prove beneficial in the treatment of sepsis-induced myocyte shortening.
authors.affiliation: Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Xinsheng
authors.initials: X
authors.lastname: Zhu
authors.forename: Oliver Y
authors.initials: OY
authors.lastname: Bernecker
authors.forename: Naveen S
authors.initials: NS
authors.lastname: Manohar
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Judith
authors.initials: J
authors.lastname: Hellman
authors.forename: Fumito
authors.initials: F
authors.lastname: Ichinose
authors.forename: Héctor H
authors.initials: HH
authors.lastname: Valdivia
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D003600:Cytosol / Q000378:metabolism; D006706:Homeostasis; D008297:Male; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000648:ultrastructure; D011446:Prospective Studies; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D018805:Sepsis / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D002118:Calcium