Impact of Phthalates on Cardiac Function
Open AccessDi(2-ethylhexyl) phthalate (DEHP) is a commonly used plasticizer additive that is combined with polyvinyl chloride (PVC) to create flexible plastics, including medical plastic devices. Since DEHP is a lipophilic chemical that is not covalently bound to PVC, it is prone to leach or migrate into blood21. Consequently, studies have shown that phthalates may contribute to cardiovascular mortality.65 However, it is still unclear if phthalates directly contribute to adverse health complications, particularly among intensive care and cardiac intensive care patients who may experience arrhythmias, low cardiac output, and longer hospital stays59 post exposure. Unfortunately, it is difficult to assess the direct cardiotoxic effects of DEHP in a clinical setting. Fortunately, experimental animal models can be used to better understand the direct effects of phthalate exposure on cardiac function. Likewise, this study aims to investigate the direct effects of DEHP exposure on cardiac electrophysiology. In this study, animal hearts were excised, the aorta cannulated, and the tissue retrograde perfused with a crystalloid buffer. Electrophysiology (EP) studies were performed in the presence or absence of 250 µM DEHP, over the course of 60 minutes. Flow rate and electrocardiograms (ECGs) were monitored continuously. Over 60 minutes, cardiac function remained stable during control buffer perfusion (heart rate - baseline: 322 BPM, 60 min: 318 BPM, n=8; coronary flow rate - baseline: 6.19 mL/min, 60 min: 5.67 mL/min, n=8; sinus node recovery time (SNRT) – baseline: 211 ms, 60 min: 209 ms, n=9). However, 60 minutes of DEHP exposure resulted in a steep decrease in cardiac function, with a 52% decrease in heart rate (baseline: 330 BPM, 60 min: 158 BPM) (n=10), a 63% decrease in flow rate (baseline: 4.62 mL/min, 60 min: 1.70 mL/min) (n=10), and a 53% increase in SNRT (baseline: 184 ms, 60 min: 282 ms, n=5). DEHP exposure also impaired atrioventricular (AV) conduction, with a 53% increase in the PR interval (baseline: 43 ms, 60 min: 66 ms) (n=5), and 82% increase in PR segment (baseline: 28 ms, 60 min: 51 ms) (n=5), 92% increase in Wenckebach Cycle Length (WBCL) (baseline: 87 ms, 60 min: 167 ms) (n=8), and a 106% increase in the atrioventricular node effective refractory period (AVNERP) (baseline: 79 ms, 60 min: 163 ms) (n=8). By comparison, only a slight increase in AV conduction time was observed in time control studies (PR interval; baseline: 34 ms, 60 min: 40 ms; n=8, PR segment; baseline: 20 ms, 60 min: 24 ms; n=8, WBCL; baseline: 87 ms, 60 min: 92 ms; n=10, AVNERP; baseline: 71 ms, 60 min: 75 ms; n=10). Finally, atrial action potential duration (APD) shortened after DEHP exposure, APD 30 (baseline: 22 ms, 60 min: 16 ms, baseline n=6, 60 min n=3), APD 80 (baseline: 50 ms, 60 min: 28 ms, baseline n=6, 60 min n=3). Comparatively, no changes were observed in the ventricular APD after DEHP exposure, APD 30 (baseline: 19 ms, 60 min: 19 ms, baseline n=6, 60 min n=3), APD 80 (baseline: 49 ms, 60 min: 52 ms, baseline n=6, 60 min n=3). Studies suggest that DEHP may exert cardiotoxic effects by activating the muscarinic acetylcholine (M2) receptor, which is highly expressed in nodal and atrial cells.24 Muscarinic agonists have been shown to decrease cardiac automaticity,9 precipitate vasoconstriction of the coronary arteries,46 delay AV conduction,67 and shorten atrial action potential duration (APD).28 Additional studies are necessary to fully interpret the mechanistic effects of DEHP of cardiac physiology, and future work will investigate the use of muscarinic antagonists to circumvent phthalate-induced cardiac depression.
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