Amiodarone-induced ultrastructural changes in canine myocardial fibers

Chronic clinical toxicity with amiodarone, a unique antiarrhythmic drug, is associated with intracellular myelinoid inclusion bodies in skin, cornea, lung, liver and lymph nodes. The present study was designed to develop a canine animal model to study amiodarone concentration and onset of formation of myelinoid inclusion bodies in the cardiac tissue. Amiodarone was given intravenously in a single dose (40 mg/kg body weight) or multiple doses (40 mg/kg IV + 10 mg/kg IV X 7 days). Amiodarone concentration in the heart was high after a single dose but electron microscopic examination showed a normal ultrastructure. Numerous myelinoid inclusion bodies were found in the myofibrils of the left atria and right and left ventricles after only 7 days of amiodarone treatment. Myelinoid inclusion bodies were identified in several subcellular locations including intercalated disc but most were in close proximity of the mitochondria, sometimes touching and indenting the mitochondrial membrane. The antiarrhythmic effect of the schedule of intravenous amiodarone for 7 days used in this study was minimal, and this correlated with unexpectedly low myocardial levels of the drug and its metabolite. The results are consistent with our previous data of an antiarrhythmic effect with a single intravenous dose of 40 mg/kg body weight associated with high myocardial levels of amiodarone. We conclude that a single large dose of amiodarone with high tissue level may not cause myelinoid inclusion bodies, but they can be readily identified in all heart chambers after only 1 week of amiodarone treatment. This model would be useful to study amiodarone-induced ultrastructural changes in the heart.