Department of Physiology and Biophysics, Rush University Medical Center, Chicago, IL, USA.
Malignant Hyperthermia Investigation Unit of the University Health Network, Toronto, ON, Canada; Department of Anaesthesia & Pain Management, Toronto General Hospital, University of Toronto, Toronto, ON, Canada.
Br J Anaesth. 2019 Jan;122(1):32-41. doi: 10.1016/j.bja.2018.08.009. Epub 2018 Sep 20.
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 and F, respectively). Patients with above-threshold F or F 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 Ca signalling related to excitation-contraction coupling in myotubes.
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 [Ca], frequency of spontaneous cytosolic Ca events, Ca waves, and cell-wide Ca spikes after electrical stimulation.
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 [Ca] and spontaneous event frequency as the defining HH characteristics.
These findings suggest that HH pathogenesis stems from excess Ca 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.
恶性高热（MH）是一种钙信号紊乱的疾病，其临床表现多变，这给其诊断和治疗带来了困难。诊断依赖于咖啡因-氟烷收缩试验，即测量肌肉暴露于咖啡因或氟烷时的收缩力（分别为 F 和 F）。F 或 F 值超过阈值的患者被诊断为 MH 易感。许多患者仅对氟烷呈阳性（称为“HH”）。我们的目的是确定这些 HH 患者的特征，包括他们的临床症状和与肌原纤维兴奋-收缩耦联相关的胞质 Ca 信号的特征。
在获得机构伦理委员会批准后，从多伦多 MH 中心接受收缩试验的招募患者被分为三组：HH 组、双重阳性（HS）组和阴性（HN）组。从肌肉骨骼症状和体征中收集了一个临床指数。类似的钙指数总结了培养的肌原纤维中的四个测量值：静息[Ca]、胞质 Ca 事件的频率、Ca 波和电刺激后的细胞全钙峰。
两个指数的最高值均出现在 HH 组；钙指数在 HH 组和其他组之间的差异具有统计学意义。主成分分析证实了 HH 组独特的细胞水平特征，并确定了升高的静息[Ca]和自发事件频率是 HH 的特征。
这些发现表明，HH 的发病机制源于肌浆网通道的钙泄漏过多。这将 HH 确定为一个独立的诊断组，并根据对病理生理机制的理解为其提供治疗方法。
