Abstract 454: Plasticizer Interaction With the Heart: Chemicals Used in Plastic Medical Devices Can Interfere With Cardiac Electrophysiology

Abstract

Background: Phthalates are employed as plasticizers in the manufacturing of flexible, plastic medical products. Patients can be subjected to high phthalate exposure through contact with plastic medical devices. We aimed to investigate the cardiac safety and biocompatibility of mono-2-ethylhexyl phthalate (MEHP), a phthalate with documented exposure in intensive care patients. Methods and Results: Optical mapping of transmembrane voltage and pacing studies were performed on isolated, Langendorff-perfused rat hearts to assess cardiac electrophysiology after MEHP exposure compared with controls. MEHP dose was chosen based on reported blood concentrations following an exchange transfusion procedure. 30-min exposure to MEHP increased the atrioventricular node (147 vs. 107msec) and ventricular (117 vs. 77.5msec) effective refractory periods, compared with controls. Optical mapping revealed prolonged action potential duration (APD) at slower pacing cycle lengths, akin to reverse use-dependence. The plateau phase of the APD restitution curve steepened and became monophasic in MEHP-exposed hearts (0.18 vs. 0.06 slope). APD lengthening occurred during late-phase repolarization resulting in triangulation (70.3 vs. 56.6 msec). MEHP-exposure also slowed epicardial conduction velocity (35 vs. 60 cm/sec), which may be partly explained by inhibition of Na v 1.5 (874 μM and 231 μM IC50, fast and late sodium current). Conclusions: This study highlights the impact of acute MEHP exposure, using a clinically-relevant dose, on cardiac electrophysiology in the intact heart. Heightened clinical exposure to plasticized medical products may have cardiac safety implications – given that action potential triangulation and electrical restitution modifications are a risk factor for early after depolarizations and cardiac arrhythmias.

Optocardiography and Electrophysiology Studies of Ex Vivo Langendorff-perfused Hearts

“…Accordingly, high spatial resolution images (in the described setup 1240 x 1024 total, or 620 x 512 per channel, 6.5 µm pixel size) are often spatially binned during or post-acquisition ( Figure 5C). Image processing can be performed to generate activation and repolarization maps using custom algorithms 23,33,43,45 (Figure 3D), with the activation time of each pixel on the heart was defined as the maximum derivative of the action potential or calcium transient upstroke. Example of epicardial pacing at cycle length of 400 ms (S1−S1), which was used for imaging experiments.…”

“…6. After temporal parameters are calculated, generate isochronal maps to depict aspects of a single action potential or calcium transient across the entire imaged epicardial surface using custom algorithms23,33,43,45,46…”

Bisphenols and phthalates: Plastic chemical exposures can contribute to adverse cardiovascular health outcomes

“…To further characterize the effect of phthalates on cardiac electrophysiology, our laboratory selected a dose of MEHP (60 μM) comparable to patient plasma levels after exchange transfusion for isolated, Langendorff‐perfused heart studies (Jaimes et al, 2019; Sjoberg et al, 1985). In this study, we observed that MEHP‐treatment slowed sinus node recovery time, increased atrioventricular conduction time, and slowed epicardial conduction velocity (Jaimes et al, 2019). Effects on conduction time may be partly attributed to inhibitory effects on voltage‐gated sodium channels, as voltage‐clamp studies in HEK 293 cells revealed a reduction in fast and late sodium current, albeit at relatively high MEHP concentrations (IC 50 874 and 231 μmol/L, respectively).…”

“…Although, it is important to note that both chemicals exert biological effects through multiple mechanisms of action. Once inside the body, bisphenol and phthalate chemicals may interact with nuclear receptors, hormone receptors, transcription factors, ion channels and disrupt intracellular signaling pathways (Ben‐Jonathan & Steinmetz, 1998; Ito, Kamijima, & Nakajima, 2019; Jaimes et al, 2019; La Merrill et al, 2020; MacKay & Abizaid, 2018; Mariana et al, 2016; Moriyama et al, 2002; Nadal et al, 2000; Rowdhwal & Chen, 2018; Singh & Li, 2012; Sohoni & Sumpter, 1998; Soriano et al, 2016; Wetherill et al, 2007; Ye et al, 2017). Many of these interactions can result in acute and rapid consequences.…”

Phthalates Implications in the Cardiovascular System

“…Langendorff-perfused rat hearts were isolated and analyzed by electrophysiology experiments and optical mapping. The results showed that MEHP-treated hearts had slow atrioventricular conduction, increased atrioventricular and ventricular refractory periods, and also exhibited a triangulated action potential and a steeper electrical restitution curve [ 56 ]. These results confirm that DEHP and its metabolite MEHP are associated with the development of arrhythmias.…”