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Ibandronate and Ventricular Arrhythmia Risk
Author(s) -
BONILLA INGRID M.,
VARGASPINTO PEDRO,
NISHIJIMA YOSHINORI,
PEDRAZATOSCANO ADRIANA,
HO HSIANGTING,
LONG VICTOR P.,
BELEVYCH ANDRIY E.,
GLYNN PATRIC,
HOUMSSE MAHMOUD,
RHODES TROY,
WEISS RAUL,
HUND THOMAS J.,
HAMLIN ROBERT L.,
GYÖRKE SANDOR,
CARNES CYNTHIA A.
Publication year - 2014
Publication title -
journal of cardiovascular electrophysiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.193
H-Index - 138
eISSN - 1540-8167
pISSN - 1045-3873
DOI - 10.1111/jce.12327
Subject(s) - medicine , afterdepolarization , proarrhythmia , qt interval , repolarization , calcium , in vivo , cardiology , ryanodine receptor , calcium in biology , endocrinology , pharmacology , electrophysiology , microbiology and biotechnology , biology
Ibandronate‐Induced Proarrhythmia Introduction Bisphosphonates, including ibandronate, are used in the prevention and treatment of osteoporosis. Methods and Results We report a case of suspected ibandronate‐associated arrhythmia, following a single dose of ibandronate in a 55‐year‐old female. ECG at presentation revealed frequent ectopy and QT/QTc interval prolongation; at follow‐up 9 months later the QT/QTc intervals were normalized. Proarrhythmic potential of ibandronate was assessed with a combination of in vivo and in vitro approaches in canines and canine ventricular myocytes. We observed late onset in vivo repolarization instability after ibandronate treatment. Myocytes superfused with ibandronate exhibited action potential duration (APD) prolongation and variability, increased early afterdepolarizations (EADs) and reduced I to (P < 0.05), with no change in I Kr . Ibandronate‐induced APD changes and EADs were prevented by inhibition of intracellular calcium cycling. Ibandronate increased sarcoplasmic reticulum calcium load; during washout there was an increase in calcium spark frequency and spontaneous calcium waves. Computational modeling was used to examine the observed effects of ibandronate. While reductions in I to alone had modest effects on APD, when combined with altered RyR inactivation kinetics, the model predicted effects on APD and SR Ca 2+ load consistent with observed experimental results. Conclusion Ibandronate may increase the susceptibility to ventricular ectopy and arrhythmias. Collectively these data suggest that reduced I to combined with abnormal RyR calcium handling may result in a previously unrecognized form of drug‐induced proarrhythmia.