Mono(2-Ethylhexyl)Phthalate Exposure Alters Electrical Restitution Curve In Isolated Hearts

Medical devices are frequently manufactured with polyvinyl chloride (PVC) plastic, in combination with phthalate plasticizers to impart flexibility to otherwise rigid PVC. Since phthalate plasticizers are not covalently bound, these chemicals migrate out of the plastic device and into lipophilic solutions, including blood, parenteral nutrition, and pharmacological agents. As an example, Di(2‐ethylhexyl) phthalate (DEHP) can make up to 80% by weight of flexible medical devices, including: blood storage bags, medical tubing, and cardiopulmonary bypass and ECMO circuitry. Phthalate leaching from these devices presents a significant intravenous route of exposure to patient populations. Our previously published in vitro studies have indicated that phthalate plasticizer exposure inhibits electrical conduction in isolated cardiac cells.ObjectiveTo investigate the impact of phthalate plasticizer exposure on electrical restitution in isolated whole hearts.MethodsAll animal protocols were approved by the Children's National Institutional Animal Care and Use Committee. Adult rat hearts were excised, the aorta cannulated, and transferred to a Langendorff‐perfusion system. Hearts were perfused with oxygenated Krebs‐Heinslett buffer, and electrodes were placed on the epicardial surface. Mechanical contraction was inhibited with 5 uM Blebbistatin, and hearts were loaded with 200 nM RH237 to optically map action potentials. Hearts were subjected to a ventricular pacing protocol, and action potentials were recorded using an Andor iXon camera (> 500 fps). Electrical signals were collected using Iox2 software (EMKA technologies) and analyzed using custom MatLab scripts.ResultsExposure to clinically relevant concentrations of mono(2‐ethylhexyl) phthalate (MEHP), the main metabolite of di(2‐ethylhexyl) phthalate plasticizer, resulted in a steeper monophasic electrical restitution curve (slope = 1.8) compared with biphasic control (slope = 2.1, plateau slope = 0.1). MEHP‐exposed hearts were also more susceptible to alternans at shorter cycle lengths, compared with control.ConclusionThe effect of phthalate plasticizers on cardiac electrical restitution has important clinical implications. Alterations in action potential duration restitution and the presence of electrical alternans are arrhythmogenic factors. Additional studies are necessary to resolve the impact of plastic chemical contaminant exposure in patients, and the impact on cardiac function.Support or Funding InformationThis study was supported by the National Institutes of Health (R00ES023477 to NGP, UL1TR000075, KL2TR000076), Children's Research Institute: Divisions of Cardiology and Cardiac Surgery.