Statin-induced Ca(2+) release was increased in B lymphocytes in patients who showed elevated serum creatine kinase during statin treatment.
OBJECTIVE
Statins are effective in lowering cholesterol levels, but cause fatal rhabdomyolysis in susceptible individuals. Because it has been hypothesized that muscle damage could result from alterations in Ca(2+) homeostasis in muscle cells, we tested whether measuring statin-induced changes in intracellular calcium ([Ca(2+)](i)) is useful for predicting susceptibility to statin-muscle damage, using human CD19+ primary B lymphocytes.


METHODS
Statin-induced alterations in [Ca(2+)](i) were studied using the human THP-1 cell line and CD19+ primary B lymphocytes. Changes in [Ca(2+)](i) were measured directly in fluo-3- loaded cells using either single or dual-color flow cytometry.


RESULTS
The Ca(2+) release study suggested that statin-induced changes in [Ca(2+)](i) were due to Ca(2+) release from ryanodine-sensitive Ca(2+) stores and mitochondrial compartments. Further, statin users who experienced elevated creatine kinase (n=8) exhibited significantly greater statin-induced Ca(2+) release in B cells than healthy volunteers (n=45) and statin users without elevated creatine kinase (n=16), while no difference was seen between the latter two groups.


CONCLUSIONS
Statin-induced Ca(2+) release from ryanodine-sensitive stores and mitochondria may contribute to myotoxicity. The laboratory test for Ca(2+) release using CD19+ primary B lymphocytes may be useful to predict susceptibility to statin-induced muscle toxicity prior to statin use.
Hattori
Takayuki
T
Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Japan.
Saito
Kuniaki
K
Takemura
Masao
M
Ito
Hiroyasu
H
Ohta
Hirotoshi
H
Wada
Hisayasu
H
Sei
Yoshitatsu
Y
Kawamura
Mitsunobu
M
Seishima
Mitsuru
M
D000328:Adult; D000368:Aged; D018941:Antigens, CD19 / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D003402:Creatine Kinase / Q000097:blood* / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D005456:Fluorescent Dyes / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism
D018941:Antigens, CD19; D005456:Fluorescent Dyes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019837:Ryanodine Receptor Calcium Release Channel; D003402:Creatine Kinase; D002118:Calcium