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.

Cannabidiol Attenuates Methamphetamine-Induced Cardiac Inflammatory Response and Necrosis through The PKA/CREB Signaling Pathway

“…Various autopsy reports have revealed that cardiomyopathy, coronary artery stenosis, valvular heart disease, and in ammatory heart disease are involved in many MA-toxicity deaths, with myocyte hypertrophy, myocarditis, endocarditis, pericarditis, perivascular and interstitial brosis, ber necrosis, collagen deposition, and subendocardial myocardial infarction found via microscopic examination (Nishida et al, 2003, Darke et al, 2017, Darke et al, 2018, Abdullah et al, 2020. The nonspeci c cardiac histopathology observed in our study following MA exposure is similar with that reported in autopsy studies and animal models (Islam et al, 2009, Marcinko et al, 2019, Abdullah et al, 2020. Notably, in ammatory response, brosis, and necrosis of myocardial tissue were con rmed by H&E staining, ELISA analysis, Masson's trichrome staining, and western blotting.…”

“…Relative heart weight, calculated as the heart-to-body weight ratio, increased signi cantly in the MA group compared to the control group (Fig. 2C), consistent with that found in mice (i.e., increased 4-5 mg/week for 8 weeks at 35 mg/kg MA and 2 mg/week after 20 weeks at 40 mg/kg) (Marcinko et al, 2019). In contrast, other research has reported no signi cant differences in relative heart weight in rats after an acute dose of 50 mg/kg MA or in mice after 10 days of exposure to 2 mg/kg MA (Islam et al, 2009, Garcia-Carmona et al, 2018.…”

Methamphetamine-induced changes in myocardial gene transcription are sex-dependent

“…It should be noted that not all methamphetamine-induced cardiac effects occur exclusively in female hearts. Some investigators have reported that males are more susceptible than females to methamphetamine-induced cardiomyopathy [ 47 , 48 ]. Additional work is needed to understand the mechanism by which methamphetamine induces sex-dependent effects in the myocardium.…”

Methamphetamine induces cardiomyopathy by Sigmar1 inhibition-dependent impairment of mitochondrial dynamics and function

“…Acute and chronic METH treatment in rodents showed the evidence of METH-induced cardiotoxicity [18][19][20] . Findings from these studies suggest that METH causes mitochondrial dysfunction, increases oxidative stress, alters intracellular Ca 2+ dynamics, enhances inflammatory marker, and adversely affects cardiac contractility [20][21][22] . However, the molecular targets and mechanisms of METH-induced cardiomyopathy remain elusive.…”