Evidence for the cardiodepressive effects of the plasticizer di-2-ethylhexylphthalate (DEHP)

Abstract

Background: Di(2)ethylhexylphthalate (DEHP) is commonly used in the manufacturing of plastic materials, including intravenous bags, blood storage bags, and medical grade tubing. Prior studies demonstrated that DEHP can leach from plastic medical products, which can result in inadvertent patient exposure. Further, in vitro studies suggest that DEHP may act as a cardiodepressive agent by slowing the beating rate of isolated cardiomyocytes. Objective: In this study, we investigated the direct effects of acute DEHP exposure on cardiac electrophysiology. Methods: DEHP concentrations were measured in red blood cell (RBC) units stored between 7 and 42 days (23 to 119 ug/mL). Using these concentrations as a guide, Langendorff-perfused heart preparations were exposed to DEHP (15 to 90 minutes) and the impact on cardiac electrophysiology metrics were quantified. Secondary studies used human induced pluripotent stem cell derived cardiomyocytes (hiPSCCM) to measure the effect of DEHP exposure on conduction velocity over a prolonged period of time (15 to 180 minutes). Results: In intact rat heart preparations, sinus activity remained stable following acute exposure to lower doses of DEHP (25 to 50 ug/mL), but sinus rate declined by 43% and sinus node recovery time prolonged by 56.5% following 30 minute exposure 100 ug/ml DEHP. DEHP exposure also exerted a negative dromotropic response, as indicated by a 69.4% longer PR interval, 108.5% longer Wenckebach cycle length, and increased incidence of atrioventricular uncoupling. Pretreatment with doxycycline, a matrix metalloproteinase inhibitor, partially rescued the effects of DEHP on sinus activity, but did not ameliorate the effects on atrioventricular conduction. DEHP exposure prolonged the ventricular action potential and effective refractory period but had no measurable effect on intracellular calcium transient duration. Follow-up studies using hiPSCCM demonstrated that DEHP slows electrical conduction in a time (15 min to 3 hours) and dose-dependent manner (10 to 100 ug/mL). Discussion: DEHP exposure perturbs cardiac electrophysiology in a dose- and time-dependent manner. Future studies are warranted to investigate the impact of DEHP exposures on human health, with special consideration for clinical procedures that employ plastic materials.

Red Blood Cell Metabolism In Vivo and In Vitro

“…From these studies, it is emerging that donor habits, such as smoking or other nicotine exposures, consumption of alcohol, coffee and caffeinated, taurine-rich beverages, all impact RBC energy and redox metabolism in a way that affects storage biology and, potentially, post-transfusion performance, especially when combined with invasive processing such as RBC unit irradiation [ 195 , 196 , 197 , 198 ]. While phthalate plasticizers were historically added to polyvinylchloride bags to decrease the rigidity of the blood bag, these compounds leach from the unit and intercalate into the RBC membranes, resulting in an erythrocyte with altered deformability, decreased hemolytic propensity [ 199 , 200 ], and altered increased risk for toxicity (e.g., infertility, cardiodepression), especially in certain categories of recipients such as pediatric patients [ 201 ]. Controversial reports on the detection of metabolites of professional exposures such as Perfluoroalkyl and Polyfluoroalkyl Substances (PFAS) in high-fidelity recurring donors such as firefighters have been described [ 202 ], though the potential toxicity profiles of these compounds in transfusion recipients remain to be assessed.…”