Is Lymphocyte Adenosine a Diagnostic Marker of Clinical Malignant Hyperthermia? A Pilot Study

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. DESIGN:Application of lymphocytes for malignant hyperthermia diagnosis. SETTING:Hospitals and university laboratory. SUBJECTS:Malignant hyperthermia–susceptible patients (n = 13) and normal subjects (n = 11). INTERVENTIONS: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. MEASUREMENTS AND MAIN 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 subje