Authors: Singh DP et al.
Journal: Anesthesiology, December 5, 2025. DOI: 10.1097/ALN.0000000000005882
Summary
This exploratory validation study evaluated a novel diagnostic approach for malignant hyperthermia (MH) susceptibility using a single muscle fiber calcium wave frequency assay (CaWFa). Given the limitations of the current gold standard in-vitro contracture test (IVCT), including invasiveness, tissue requirements, and indirect measurement of calcium handling, the investigators sought to assess whether CaWFa could directly and reliably distinguish malignant hyperthermia–susceptible (MHS) from malignant hyperthermia–negative (MHN) muscle.
Muscle biopsies obtained during routine IVCT testing from 30 patients were used to isolate mechanically skinned single muscle fibers. Calcium release from ryanodine receptors (RyR1) was assessed using calcium-dependent fluorescence and confocal microscopy following graded exposure to halothane and caffeine. Diagnostic performance was evaluated by comparing calcium wave onset and frequency between MHS and MHN fibers and benchmarking results against IVCT classification.
Exposure to halothane triggered markedly more frequent regenerative calcium waves in fibers from MHS patients compared with MHN patients, both in terms of the proportion of responsive fibers and overall wave frequency. In contrast, caffeine exposure did not differentiate between groups, indicating specificity of the assay to anesthetic-triggered RyR1 dysfunction. A diagnostic threshold combining halothane exposure at 1 mM with a calcium wave frequency cutoff of 1.57 waves per minute achieved high sensitivity and specificity, comparable to IVCT performance.
Overall, the findings suggest that CaWFa directly interrogates the pathogenic calcium release mechanism underlying MH and may provide a less invasive, tissue-sparing alternative to traditional contracture testing.
Key Points
-
CaWFa directly measures RyR1-mediated calcium release at the single-fiber level.
-
Halothane-induced calcium wave frequency clearly distinguishes MHS from MHN muscle.
-
Diagnostic performance approached that of the IVCT with 92% sensitivity and 88% specificity.
-
Caffeine responses did not differentiate MH status, supporting assay specificity.
-
The assay requires a much smaller muscle sample than IVCT.
-
CaWFa shows promise as a minimally invasive future diagnostic tool for MH susceptibility.
Thank you for allowing us to use this article from Anesthesiology.