@article{SchusterJohannsenIsbaryetal.2018,
  author    = {Schuster, Frank and Johannsen, Stephan and Isbary, Susanne and T{\"u}rkmeneli, Ismail and Roewer, Norbert},
  title     = {In vitro effects of levosimendan on muscle of malignant hyperthermia susceptible and non-susceptible swine},
  series = {BMC Anesthesiology},
  volume    = {18},
  journal   = {BMC Anesthesiology},
  number    = {182},
  doi       = {10.1186/s12871-018-0644-z},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176991},
  year      = {2018},
  abstract  = {Background: The calcium sensitizer levosimendan is increasingly used to improve hemodynamics in patients with acutely decompensated heart failure. By binding to cardiac troponin C the conformation of the calcium-troponin C complex is stabilized, which leads to acceleration of actin-myosin crossbrigde formation and increased force generating capacity of muscle fibers. Besides indications in cardiac failure, beneficial effects of levosimendan in skeletal muscle disorders are currently evaluated. The aim of this study was to investigate differential effects of levosimendan on skeletal muscle of pigs with and without susceptibility to malignant hyperthermia (MH) in order to identify possible risks of this emerging drug for patients with predisposition to MH. Methods: Muscle bundles of 17 pigs (9 MH susceptible (MHS); 8 MH non-susceptible (MHN)) were excised under general anesthesia and examined in the tissue bath with increasing concentrations of levosimendan (0.065; 0.125; 0.5; 1.0; 10 and 50 μg/ml). Baseline tension and twitch force were monitored continuously. Data are presented as median and interquartile range. Statistical evaluation was performed using D'Agostino \& Pearson test for normal distribution and student's t test and 2-way ANOVA for differences between the groups. P < 0.05 was considered significant. Results: There were no differences between the groups concerning length, weight, initial twitch force and pre-drug resting tension of the investigated muscle strips. After an initial decrease in both groups, twitch amplitude was significantly higher in MHN (- 3.0 [- 5.2-0.2] mN) compared to MHS (- 7.5 [- 10.8- -4.5] mN) (p = 0.0034) muscle at an applied levosimendan concentration of 50 μg/ml. A marked increase in resting tension was detected following levosimendan incubation with 50 μg/ml in MHS muscle bundles (3.3 [0.9-6.1] mN) compared to MHN (- 0.7 [- 1.3-0.0] mN) (p < 0.0001). Conclusions: This in vitro investigation revealed the development of significant contractures in muscle bundles of MHS pigs after incubation with levosimendan. However, the effect appeared only at supra-therapeutic concentrations and further research is needed to determine the impact of levosimendan on MHS individuals in vivo.},
  language  = {en}
}
@article{KlinglerHeiderichGirardetal.2014,
  author    = {Klingler, Werner and Heiderich, Sebastian and Girard, Thierry and Gravino, Elvira and Heffron, James J. A. and Johannsen, Stephan and Jurkat-Rott, Karin and R{\"u}ffert, Henrik and Schuster, Frank and Snoeck, Marc and Sorrentino, Vincenzo and Tegazzin, Vincenzo and Lehmann-Horn, Frank},
  title     = {Functional and genetic characterization of clinical malignant hyperthermia crises: a multi-centre study},
  series = {Orphanet Journal of Rare Diseases},
  volume    = {9},
  journal   = {Orphanet Journal of Rare Diseases},
  number    = {8},
  issn      = {1750-1172},
  doi       = {10.1186/1750-1172-9-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117630},
  year      = {2014},
  abstract  = {Background: Malignant hyperthermia (MH) is a rare pharmacogenetic disorder which is characterized by life-threatening metabolic crises during general anesthesia. Classical triggering substances are volatile anesthetics and succinylcholine (SCh). The molecular basis of MH is excessive release of Ca2+ in skeletal muscle principally by a mutated ryanodine receptor type 1 (RyR1). To identify factors explaining the variable phenotypic presentation and complex pathomechanism, we analyzed proven MH events in terms of clinical course, muscle contracture, genetic factors and pharmocological triggers. Methods: In a multi-centre study including seven European MH units, patients with a history of a clinical MH episode confirmed by susceptible (MHS) or equivocal (MHE) in vitro contracture tests (IVCT) were investigated. A test result is considered to be MHE if the muscle specimens develop pathological contractures in response to only one of the two test substances, halothane or caffeine. Crises were evaluated using a clinical grading scale (CGS), results of IVCT and genetic screening. The effects of SCh and volatile anesthetics on Ca2+ release from sarcoplasmic reticulum (SR) were studied in vitro. Results: A total of 200 patients met the inclusion criteria. Two MH crises (1\%) were triggered by SCh (1 MHS, 1 MHE), 18\% by volatile anesthetics and 81\% by a combination of both. Patients were 70\% male and 50\% were younger than 12 years old. Overall, CGS was in accord with IVCT results. Crises triggered by enflurane had a significantly higher CGS compared to halothane, isoflurane and sevoflurane. Of the 200 patients, 103 carried RyR1 variants, of which 14 were novel. CGS varied depending on the location of the mutation within the RyR1 gene. In contrast to volatile anesthetics, SCh did not evoke Ca2+ release from isolated rat SR vesicles. Conclusions: An MH event could depend on patient-related risk factors such as male gender, young age and causative RyR1 mutations as well as on the use of drugs lowering the threshold of myoplasmic Ca2+ release. SCh might act as an accelerant by promoting unspecific Ca2+ influx via the sarcolemma and indirect RyR1 activation. Most MH crises develop in response to the combined administration of SCh and volatile anesthetics.},
  language  = {en}
}