Cell biology

Biology

Cardiac hypertrophy

Endocrinology

Fibrosis

Cardiology

Meth-

Cardiac fibrosis

Polymer

Heart failure

Cardiac dysfunction

Organic chemistry

Masson's trichrome stain

Acrylate

Methamphetamine

Internal medicine

Mitochondrion

Cardiomyopathy

Medicine

Chemistry

Monomer

Muscle hypertrophy

Pathology

Sirius Red

Circulation Research

Introduction: Methamphetamine (METH) is one of the most commonly abused illicit drugs in the United States, exerting a range of adverse effects upon multiple organ systems. Cardiovascular complications are among the major causes of death in METH users. METH-induced cardiomyopathy is a poorly characterized disease entity as METH-induced molecular perturbations, and histopathological changes in the heart remain under-explored. Objectives: We studied histopathology in the hearts of human METH users. We also observed the histological alteration and changes in mitochondrial function in mice that received ‘binge’ administration of METH. Methods and Results: We obtained 32 autopsy heart samples from humans with positive toxicology for chronic METH use and performed Sirius Red and Masson’s Trichrome (MT) staining on left ventricular (LV) sections. Notably, chronic METH user hearts showed intense perivascular and interstitial fibrosis in LVs. ‘Binge’ METH administration in mice for 4 weeks showed an increase in heart weight-to-tibia length and increase in myocyte cross-sectional area in WGA stained LVs compared to saline-treated mice. Sirius red and MT staining also showed an increase in perivascular and interstitial fibrosis in METH mice heart. Isolated mitochondria from METH-treated mice heart showed suppressed mitochondrial bioenergetics measured by Seahorse Analyzer. Immunoblotting in heart lysates and mitochondrial fractions showed altered mitochondrial dynamics regulatory proteins expression in METH mice compared to control saline group. METH-treated cultured neonatal rat ventricular cardiomyocytes also showed suppression of mitochondrial respiration and mitochondrial network disorganization indicating a direct effect of METH on cardiomyocytes. Conclusions: We report that maladaptive cardiac fibrotic remodeling is typical in a human and pre-clinical mouse model of METH abuse. ‘Binge’ METH exposure in mice induces cardiac hypertrophy, cardiac fibrosis, and suppression of mitochondrial respiration. Thus, chronic METH use induces maladaptive cardiac remodeling associated with mitochondrial dysfunction.

Abstract 120: Methamphetamine-induced Cardiomyopathy Associated With Mitochondrial Dysfunction, Cardiac Fibrosis and Hypertrophy