title: Is lymphocyte adenosine a diagnostic marker of clinical malignant hyperthermia? A pilot study.
abstract: OBJECTIVE
  Malignant hyperthermia is a pharmacogenetic disorder typically triggered by potent inhalation anesthetics and/or the depolarizing muscle relaxant succinylcholine in malignant hyperthermia-susceptible individuals. Since lymphocytes express the same Ca channel mutation found in malignant hyperthermia-susceptible muscle, we investigated agonist-induced adenosine formation in lymphocytes as an index of sarcoplasmic reticulum Ca-release-induced adenosine 5'-triphosphate turnover as a potential minimally invasive functional malignant hyperthermia assay.
  
  
  METHODS
  Application of lymphocytes for malignant hyperthermia diagnosis.
  
  
  METHODS
  Hospitals and university laboratory.
  
  
  METHODS
  Malignant hyperthermia-susceptible patients (n = 13) and normal subjects (n = 11).
  
  
  METHODS
  Adenosine formation due to malignant hyperthermia-triggering agent halothane or the ryanodine receptor Ca channels agonist 4-chloro-m-cresol was compared in blood lymphocytes from malignant hyperthermia-susceptible patients and normal subjects.
  
  
  RESULTS
  Cai and adenosine were measured in fresh or immortalized blood lymphocytes incubated with 0-10 mM 4-chloro-m-cresol or 0-10.7 mM halothane. Cai levels were significantly higher in immortalized malignant hyperthermia-susceptible B cells treated with 0.75 mM 4-chloro-m-cresol relative to controls. Similarly, at 1 mM 4-chloro-m-cresol or 0.96 mM halothane, adenosine levels were significantly higher in malignant hyperthermia-susceptible lymphocytes or immortalized B cells relative to controls. Receiver-operating characteristic analyses showed areas under the 4-chloro-m-cresol receiver-operating characteristic curves near more than or equal to 0.96 (p ≈ 0.0001), suggesting that 4-chloro-m-cresol-induced adenosine could readily distinguish between malignant hyperthermia-susceptible and normal controls cells.
  
  
  CONCLUSIONS
  Both 4-chloro-m-cresol and halothane caused adenosine accumulation in blood lymphocytes. Adenosine accumulation was markedly increased in malignant hyperthermia-susceptible lymphocytes compared with controls reflecting higher than normal adenosine 5'-triphosphate degradation in the malignant hyperthermia-susceptible cells. Although 4-chloro-m-cresol receiver-operating characteristic curves revealed that adenosine accumulation could readily distinguish between normal and malignant hyperthermia-susceptible lymphocytes, independent confirmation is required with a substantially larger number of enrolled subjects to correctly appreciate the clinical utility of the novel lymphocyte-adenosine protocol for malignant hyperthermia testing.
authors.affiliation: 1Department of Anesthesiology, Uniformed Services University of the Health Sciences, Bethesda, MD. 2Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD.
authors.forename: Saiid
authors.initials: S
authors.lastname: Bina
authors.forename: John
authors.initials: J
authors.lastname: Capacchione
authors.forename: Bayarsaikhan
authors.initials: B
authors.lastname: Munkhuu
authors.forename: Sheila
authors.initials: S
authors.lastname: Muldoon
authors.forename: Rolf
authors.initials: R
authors.lastname: Bünger
mesh_terms: D000241:Adenosine / Q000097:blood* / Q000378:metabolism; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D015415:Biomarkers; D002118:Calcium / Q000378:metabolism; D003408:Cresols / Q000378:metabolism; D005260:Female; D006221:Halothane / Q000494:pharmacology; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D008305:Malignant Hyperthermia / Q000175:diagnosis* / Q000503:physiopathology*; D018482:Muscle, Skeletal / Q000378:metabolism*; D010641:Phenotype; D010865:Pilot Projects; D012372:ROC Curve; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
chemical_list: D018685:Anesthetics, Inhalation; D015415:Biomarkers; D003408:Cresols; D019837:Ryanodine Receptor Calcium Release Channel; C006984:chlorocresol; D000241:Adenosine; D002118:Calcium; D006221:Halothane