The long-term goal of this project is to develop new and non-invasive screening methods for malignant hyperthermia (MH), a frequently fatal complication of anesthesia seen in genetically susceptible patients. The MH crisis can be triggered in a susceptible individual with virtually any potent inhalational agent (most commonly with halothane) and/or succinylcholine (a widely used muscle relaxant) in the operating room. Currently, the only test for MH involves the gross surgical biopsy of a substantial piece of muscle. The effect of halothane (and other known potentiators such as caffeine or succinylcholine) is then tested on the in vitro contractility of the biopsied specimen. This is not only a stressful test for the subjects, but also laborious and time consuming procedure. Only about a dozen hospitals in the United States can perform such a test. The PI proposed the new hypothesis that the sarcoplasmic reticulum (SR) may play an important role in Mh. He found that in MH-pig SR, both (i) the fluidity of the membrane and (ii) the calcium release phenomenon were more remarkably enhanced by halothane than in control pig SR, and that these halothane effects were inhibited by dantrolene (an effective therapeutic drug against MH). Applying these results to the study of blood, he made the exciting discovery that in MH patients, both (1) the fluidity of the red cell membranes as measured by an EPR-spin probe technique, and (2) the calcium release phenomenon in platelets are more remarkably enhanced by halothane than in normal red cells or platelets. Close similarity between the SR and these blood components strongly suggests that the membranes of red cells and platelets are also affected by the same gene (or genes) which cause MH. This opens up the new possibility of diagnosing MH through blood tests. Preliminary results were encouraging. At the Univ. of Calgary, MH susceptibility of individuals was determined by muscle biopsy. Then their blood samples were sent to the PI without disclosing their MH susceptibility. The PI tested with EPR technique. Out of 14 specimens (7 positives), the PI was able to correctly diagnose 13. This method can also be easily used with infants. Thus, the success of this project will greatly benefit suspected MH individuals, both by eliminating the need for a painful biopsy and by removing the hesitation to test. This is the first practical screening method for MH.
