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.

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 subjects to correctly appreciate the clinical utility of the novel lymphocyte-adenosine protocol for malignant hyperthermia testing.

• Authors: Saiid Bina, John Capacchione, Bayarsaikhan Munkhuu, Sheila Muldoon, Rolf Bünger
• Journal: Critical care medicine (Crit Care Med) Vol. 43 Issue 3 Pg. 584-93 (Mar 2015) ISSN: 1530-0293 [Electronic] United States
• PMID: 25479114 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Anesthetics, Inhalation
• Biomarkers
• Cresols
• Ryanodine Receptor Calcium Release Channel
• chlorocresol
• Adenosine
• Calcium
• Halothane

Topics

• Adenosine (blood, metabolism)
• Anesthetics, Inhalation (pharmacology)
• Biomarkers
• Calcium (metabolism)
• Cresols (metabolism)
• Female
• Halothane (pharmacology)
• Humans
• Lymphocytes (metabolism)
• Male
• Malignant Hyperthermia (diagnosis, physiopathology)
• Muscle, Skeletal (metabolism)
• Phenotype
• Pilot Projects
• ROC Curve
• Ryanodine Receptor Calcium Release Channel (metabolism)
• Sarcoplasmic Reticulum (metabolism)