Statins alter intracellular calcium homeostasis in malignant hyperthermia susceptible individuals.
OBJECTIVE
Statines, HMG-CoA reductase inhibitors, are widely used to treat hypercholesterinemia. These substances are well tolerated, but myotoxic effects have been reported. The exact mechanisms of the induced myotoxicity are unknown but an involvement of intracellular calcium handling is suspected. Individuals susceptible to malignant hyperthermia (MH) have an impaired calcium homeostasis. An in vitro test measuring contracture responses of isolated muscle bundles is used to investigate cellular processes of MH. Aim of this study was to investigate if statins modify the contracture response of isolated muscle bundles from MH susceptible (MHS) and nonsusceptible (MHN) pigs.


METHODS
With approval of the local ethics committee muscle biopsies of 18 MH susceptible and 12 nonsusceptible pigs were performed. Muscle bundles were mounted on an isometric force transducer, preloaded, and electrically stimulated. After establishment of a stable baseline, muscle bundles were exposed to simvastatin, atorvastatin, gemfibrocil, and the pure solvent. Baseline tension was measured and analyzed for changes with P < 0.05 considered to be significant.


RESULTS
There were no differences in weight, length, and predrug baseline tension between the groups. Both simvastatin and atorvastatin induced significant contractures in muscle bundles from MHS pigs. Gemfibrocil and the solvent methanol showed no effect. In MHN muscle bundles, none of the tested substances induced a contracture. Statines induce contractures only in MHS muscle bundles.


CONCLUSIONS
We therefore conclude that the underlying mechanism may be a pathologic influence on intracellular calcium handling that is absent in MHN. A preexisting impairment of the calcium homeostasis seems to be necessary for this behavior because muscle bundles of MHN pigs showed no pathologic reaction. A higher muscle cell vulnerability toward statins is assumed in MHS patients. Statins ought to be used with caution in these individuals. Analogous a diagnostic workup for MH should be considered for patients with statin-induced rhabdomyolyis.
Metterlein
T
T
Department of Anesthesiology, University Hospital Wuerzburg, Wuerzburg, Germany. tom.metterlein@gmx.net
Schuster
F
F
Tadda
L
L
Hager
M
M
Roewer
N
N
Anetseder
M
M
D000818:Animals; D000069059:Atorvastatin; D001706:Biopsy; D002118:Calcium / Q000378:metabolism*; D004558:Electric Stimulation; D005260:Female; D015248:Gemfibrozil / Q000494:pharmacology; D005838:Genotype; D006538:Heptanoic Acids / Q000633:toxicity*; D006706:Homeostasis; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects*; D008297:Male; D008305:Malignant Hyperthermia / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D010641:Phenotype; D011758:Pyrroles / Q000633:toxicity*; D012206:Rhabdomyolysis / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D019821:Simvastatin / Q000633:toxicity*; D013552:Swine; D013997:Time Factors
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin; D019821:Simvastatin; D015248:Gemfibrozil; D002118:Calcium