Gender determines susceptibility to methamphetamine cardiomyopathy in mice

In this study, we have created a mouse model of methamphetamine cardiomyopathy that reproduces the chronic, progressive dosing commonly encountered in addicted subjects. We gradually increased the quantity of methamphetamine given to C57Bl/6 mice from 5 to 40 mg/kg over five months. At the fifth month, heart weight was increased, echocardiograms showed a dilated cardiomyopathy and survival was lower in males, with less effect in females. Interestingly, these findings correspond to previous observations in human patients, suggesting greater male susceptibility to the effects of methamphetamine on the heart.Transcriptional analysis showed changes in genes dysregulated in previous methamphetamine neurological studies as well as many that likely play a role in cardiac response to this toxic stress. We expect that a deeper understanding of the molecular biology of methamphetamine exposure in the heart will provide insights into the mechanism of cardiomyopathy in addicts and potential routes to more effective treatment. Male and female C57BL/6 mice were given intraperitoneal injections of methamphetamine hydrochloride (Sigma Aldrich, St. Louis, MO) dissolved in sterile phosphate buffered saline (PBS) once per week for 5 months. The dose was gradually increased 2mg per week over the 20 week study period to achieve a final dose of 40mg/kg. Control mice were injected with sterile PBS on the same schedule. After 5 months, hearts were excised, and heart tissue RNA was extracted. Two independent experiments were preformed for the males, and one experiment was performed for the females. Whole genome microarrays were performed on the heart tissueRNA from 2-4 methamphetamine-treated mice and 2-3 PBS-treated controls from the male and female groups of Trial 1. Trial 2 included only male mice, and arrays were performed on 2 methamphetamine-treated males and 2 PBS-treated controls. Transcripts dysregulated in the hearts of male and female mice in response to methamphetamine exposure were identified as well as transcripts differentially dysregulated between the genders.