Mechanisms of toxic cardiomyopathy

Background: Dilated cardiomyopathy is a frequent disease responsible for 40-50% of cases of heart failure. Idiopathic cardiomyopathy is a primary disorder often related to familial/genetic predisposition. Before the diagnosis of idiopathic cardiomyopathy is made, clinicians must not only rule out viral and immune causes, but also toxic causes such as drugs, environmental agents, illicit substances and natural toxins.

Objective: The objective of this review is to present recent data on the mechanisms underlying toxic cardiomyopathy.

Methods: The US National Library of Medicine Pubmed database was searched from 1980 to December 2017 utilizing the combinations of the search terms "toxic cardiomyopathy", "drugs", "anticancer drugs", "azidothymidine", "rosiglitazone", "carbon monoxide", "alcohol", "illicit drugs", "cocaine", "metamfetamine", "metals", "venom". A total of 339 articles were screened and papers that dealt with the pathophysiology of toxic cardiomyopathy, either in animal models or in clinical practice were selected, with preference being given to more recently published papers, which left 92 articles. Anticancer drugs: The mechanisms of anthracycline-induced cardiotoxicity are primarily related to their mechanisms of action as anticancer drugs, mainly the inhibition of topoisomerase II β and DNA cleavage. Additional metabolic or oxidative stress factors may play a part, together with interference with iron metabolism. The more recent drugs, trastuzumab and imatinib, also influence stress pathways. Antiretroviral agents: Azidothymidine is cardiotoxic as a result of mitochondrial toxicity. In addition to energy depletion, azidothymidine also increases the production of mitochondrial reactive oxygen species (ROS). Antidiabetic drugs: The cardiotoxicity of thiazolidinedione antidiabetic drugs is still under investigation, though interference with mitochondrial respiration or oxidative stress is suspected. Cocaine: Among the multiple mechanisms involved in cocaine-related cardiotoxicity, excessive sympathetic stimulation with increased myocardial oxygen consumption is well documented in the acute form of left ventricular dysfunction. As for cocaine-related cardiomyopathy, the role of apoptosis and ROS is under investigation. Ethanol: The aetiology of ethanol-related cardiotoxicity is multifactorial, with individual susceptibility being important. It involves apoptosis, alterations of the excitation-contraction coupling in cardiac myocytes, structural and functional alterations of the mitochondria and sarcoplasmic reticulum, changes in cytosolic calcium flows, changes in calcium sensitivity of myofilaments, alterations of mitochondrial oxidation, deregulation of protein synthesis, decrease of contractile proteins and disproportion between the different types of myofibrils, changes in the regulation of myosin ATPase, up-regulation of the L-type calcium channels, increase of oxidative stress, and induction of ANP and p21 mRNA expression in ventricular myocardium. Metamfetamines: Catecholamine-mediated toxicity is the probable cause, with a possible role for genetic susceptibility. Carbon monoxide: In addition to hypoxic injury, carbon monoxide is also directly toxic to the mitochondria, with impairment of mitochondrial respiratory chain at the cytochrome c oxidase level, decrease of glutathione concentrations and of ATP production. There is no evidence for a delayed dilated cardiomyopathy in survivors of an acute exposure. Metals: Cobalt-related cardiomyopathy probably results from interference with energy production and contractile mechanisms, but additional factors (nutrition, hypothyroidism) are often required. Antimony may cause lethal oxidative stress and cell death mediated by elevation in intra-cellular calcium. Proposed mechanisms for mercury toxicity include glutathione depletion, production of ROS, and interruption in selenium-dependent endogenous enzymatic reactions. The existence of a lithium-induced cardiomyopathy is still debated. Scorpion venom: Catecholamine release is the probable cause of acute cardiomyopathy following scorpion envenomation.

Conclusions: The mechanisms behind toxic cardiomyopathy are complex and multifactorial but include interference with myocardial cell bioenergetics and intracellular calcium handling, the generation of ROS, neurohormonal stress, and induction of apoptosis.