Sex influences susceptibility to methamphetamine cardiomyopathy in mice

Abstract

In this study, we 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 2 or 5 months during two study periods. 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.

Keywords: Cardiomyopathy; gender; methamphetamine; transcription.

Figure 1

Survival curve of male PBS‐ and Meth‐treated mice (all females survived either treatment). (A) 5‐month PBS (n = 4F, n = 6M) and Meth (n = 7F, n = 16M) treated mice. The only premature mortality was seen in Meth‐treated male mice.

Figure 2

Average HW to BW ratios of PBS‐ and Meth‐treated mice. (A) 2‐month trial showed significant difference between female PBS (n = 3) and Meth (n = 5) treated mice. Conversely, Meth‐treated males (n = 6) had a greater average HW to BW ratio than PBS‐treated controls (n = 3). (B) In the 5‐month trial, a small but not statistically significant difference was found between Meth‐treated females (n = 7) and PBS controls (n = 4). The HW to BW ratio in Meth (n = 16) treated males was substantially higher than in males treated with PBS (n = 6).

Figure 3

Female 5‐month echocardiography data. (A,B) EF and FS during the 5‐month studies. (C,D) LVID; d and LVID;s measurements at similar time intervals.

Figure 4

Male 5‐month echocardiography data. (A,B) EF and FS during the 5‐month studies. (C,D) LVID;d and LVID;s measurements at similar time intervals.

Figure 5

Histology of mouse hearts stained with picrosirius red. Panel B compared to A shows minimal fibrosis in Meth‐treated female mouse heart, whereas the single male mouse that survived 5 months of treatment (panel D) had substantial fibrosis.

Figure 6

Real‐time confirmation expression patterns of selected highly dysregulated genes from 5‐month chronic Meth‐treated female and male mice. **P < 0.01, ***P < 0.001.