Abnormal calcium signalling and the caffeine-halothane contracture test

Background: The variable clinical presentation of malignant hyperthermia (MH), a disorder of calcium signalling, hinders its diagnosis and management. Diagnosis relies on the caffeine-halothane contracture test, measuring contraction forces upon exposure of muscle to caffeine or halothane (F-C and F-H, respectively). Patients with above-threshold FC or FH are diagnosed as MH susceptible. Many patients test positive to halothane only (termed 'HH'). Our objective was to determine the characteristics of these HH patients, including their clinical symptoms and features of cytosolic Ca2+ signalling related to excitation-contraction coupling in myotubes. Methods: After institutional ethics committee approval, recruited patients undergoing contracture testing at Toronto's MH centre were assigned to three groups: HH, doubly positive (HS), and negative patients (HN). A clinical index was assembled from musculoskeletal symptoms and signs. An analogous calcium index summarised four measures in cultured myotubes: resting [Ca2+](cytosol), frequency of spontaneous cytosolic Ca2+ events, Ca2+ waves, and cell-wide Ca2+ spikes after electrical stimulation. Results: The highest values of both indexes were found in the HH group; the differences in calcium index between HH and the other groups were statistically significant. The principal component analysis confirmed the unique cell-level features of the HH group, and identified elevated resting [Ca2+](cytosol) and spontaneous event frequency as the defining HH characteristics. Conclusions: These findings suggest that HH pathogenesis stems from excess Ca2+ leak through sarcoplasmic reticulum channels. This identifies HH as a separate diagnostic group and opens their condition to treatment based on understanding of pathophysiological mechanisms.