Plastics and cardiovascular health: phthalates may disrupt heart rate variability and cardiovascular reactivity

Abstract

Plastics have revolutionized medical device technology, transformed hematological care, and facilitated modern cardiology procedures. Despite these advances, studies have shown that phthalate chemicals migrate out of plastic products and that these chemicals are bioactive. Recent epidemiological and research studies have suggested that phthalate exposure adversely affects cardiovascular function. Our objective was to assess the safety and biocompatibility of phthalate chemicals and resolve the impact on cardiovascular and autonomic physiology. Adult mice were implanted with radiofrequency transmitters to monitor heart rate variability, blood pressure, and autonomic regulation in response to di-2-ethylhexyl-phthalate (DEHP) exposure. DEHP-treated animals displayed a decrease in heart rate variability (-17% SD of normal beat-to-beat intervals and -36% high-frequency power) and an exaggerated mean arterial pressure response to ganglionic blockade (31.5% via chlorisondamine). In response to a conditioned stressor, DEHP-treated animals displayed enhanced cardiovascular reactivity (-56% SD major axis Poincarè plot) and prolonged blood pressure recovery. Alterations in cardiac gene expression of endothelin-1, angiotensin-converting enzyme, and nitric oxide synthase may partly explain these cardiovascular alterations. This is the first study to show an association between phthalate chemicals that are used in medical devices with alterations in autonomic regulation, heart rate variability, and cardiovascular reactivity. Because changes in autonomic balance often precede clinical manifestations of hypertension, atherosclerosis, and conduction abnormalities, future studies are warranted to assess the downstream impact of plastic chemical exposure on end-organ function in sensitive patient populations. This study also highlights the importance of adopting safer biomaterials, chemicals, and/or surface coatings for use in medical devices.NEW & NOTEWORTHY Phthalates are widely used in the manufacturing of consumer and medical products. In the present study, di-2-ethylhexyl-phthalate exposure was associated with alterations in heart rate variability and cardiovascular reactivity. This highlights the importance of investigating the impact of phthalates on health and identifying suitable alternatives for medical device manufacturing.

Keywords: autonomic; cardiovascular reactivity; endocrine disruptor; heart rate variability; phthalate.

Fig. 1.

Cardiovascular (CV) reactivity to Pavlovian fear conditioning and poststress recovery (4 wk). A: Pavlovian fear conditioning (CV reactivity) protocol timeline. B: mean systolic blood pressure (SBP) monitored throughout the course of the CV reactivity protocol (30 min). A significant elevation in SBP was observed in the di-2-ethylhexyl-phthalate (DEHP)-treated group during both recovery periods after CV reactivity testing. All values are reported as means ± SE. *P < 0.05 (two-way ANOVA). C and D: Poincaré plots were computed by the first 500 beats after the first tone/shock pair during fear conditioning (the first CV reactivity session) and ensemble averaged for the control and DEHP-treated group. DEHP-treated animals have reduced variability along the major axis (SD2). CS, conditioned stimulus; US, unconditioned stimulus.

Fig. 2.

Measurement of heart rate variability and sympathetic tone under basal resting conditions (6 wk, end of study). A: SD of normal beats (SDNN) was corrected for mean RR interval. A significant decrease in SDNN was found at the end of the study in the di-2-ethylhexyl-phthalate (DEHP)-treated group compared with the control (Ctrl) group. B: high-frequency (HF) power was computed by power in the band 2.5–5 Hz corrected by squared mean RR interval. A significant decrease in HF power was found in the DEHP-treated group at 6 wk compared with the Ctrl group. C: after treatment with chlorisondamine (12 mg/kg), mean arterial pressure (MAP) of the DEHP-treated group decreased significantly compared with the Ctrl group, indicating an elevated state of sympathetic tone (means ± SE). All values reported are as means ± SE. *P < 0.05.

Fig. 3.

Heart rate (HR) and systolic blood pressure (SBP) under basal resting conditions. SBP (A–C) and HR measurements (D–F) were separated by time of day. SBP decreased marginally in the control (Ctrl) group to 96–97% of the baseline value and increased marginally in the di-2-ethylhexyl-phthalate (DEHP)-treated group to 105–109% of the baseline value (F). No significant difference in HR was observed between groups (F). All values are reported as means ± SE. BPM, beats/min.

Fig. 4.

Gene expression profiling of cardiac tissue. Shown are gene expression levels (ΔΔC_T, where C_T is threshold cycle) of cardiovascular genes involved in blood pressure regulation [angiotensin-converting enzyme (ACE), ACE2, and angiotensin II type 1 receptor (AGTR1)], autonomic receptors [α_1A-adrenoceptor (ADRA1A) and β₂-adrenoceptor (ADRB2)], cardiac contractility [nitric oxide synthase 3 NOS3)], and vasoconstriction [endothelin-1 (EDN1), endothelin receptor type A receptor (EDNRA), and endothelin receptor type B receptor (EDRNB)]. Ctrl, control; DEHP, di-2-ethylhexyl-phthalate. All values are reported as means ± SE. *P < 0.05.