Notable sex differences in autonomic functioning among trauma-exposed individuals: A prospective examination

A prospective examination of sex differences in posttraumatic autonomic functioning. Antonia V. Seligowski et al. Neurobiology of Stress, Volume 15, November 2021, 100384. https://doi.org/10.1016/j.ynstr.2021.100384

Abstract

Background: Cross-sectional studies have found that individuals with posttraumatic stress disorder (PTSD) exhibit deficits in autonomic functioning. While PTSD rates are twice as high in women compared to men, sex differences in autonomic functioning are relatively unknown among trauma-exposed populations. The current study used a prospective design to examine sex differences in posttraumatic autonomic functioning.

Methods: 192 participants were recruited from emergency departments following trauma exposure (Mean age = 35.88, 68.2% female). Skin conductance was measured in the emergency department; fear conditioning was completed two weeks later and included measures of blood pressure (BP), heart rate (HR), and high frequency heart rate variability (HF-HRV). PTSD symptoms were assessed 8 weeks after trauma.

Results: 2-week systolic BP was significantly higher in men, while 2-week HR was significantly higher in women, and a sex by PTSD interaction suggested that women who developed PTSD demonstrated the highest HR levels. Two-week HF-HRV was significantly lower in women, and a sex by PTSD interaction suggested that women with PTSD demonstrated the lowest HF-HRV levels. Skin conductance response in the emergency department was associated with 2-week HR and HF-HRV only among women who developed PTSD.

Conclusions: Our results indicate that there are notable sex differences in autonomic functioning among trauma-exposed individuals. Differences in sympathetic biomarkers (BP and HR) may have implications for cardiovascular disease risk given that sympathetic arousal is a mechanism implicated in this risk among PTSD populations. Future research examining differential pathways between PTSD and cardiovascular risk among men versus women is warranted.

Keywords: TraumaPTSDAutonomicSexCardiovascular

5. Discussion

This study used a prospective design to examine sex differences in autonomic functioning among a sample of recently traumatized men and women. Sex differences were observed and varied by biomarker. While men demonstrated significantly higher BP and rates of hypertension, women demonstrated significantly higher HR and lower HF-HRV, and these effects were strongest among women who subsequently developed PTSD. Further, acute sympathetic arousal (indexed via skin conductance response) associated with HR and HF-HRV during fear conditioning but only among women who developed PTSD.

Our findings regarding BP and hypertension are consistent with what is commonly observed in the general population, such that men are more likely than women to experience hypertension (American Heart Association, heart.org). This sex difference is known to decrease among older age groups and it is thought that decreasing estradiol levels as a result of menopause in women play a role (i.e., estradiol is cardioprotective and may explain lower rates of hypertension in pre-menopausal women; for reviews, see Colafella and Denton, 2018; Regitz-Zagrosek et al., 2016). It is important to note that the average age in our sample was 35 and thus most women were pre-menopausal. While prior studies have found that individuals with PTSD demonstrate higher BP than those without PTSD (for a review, see Buckley and Kaloupek, 2001), we did not observe an effect of PTSD status. One potential explanation is that our sample is not as highly traumatized as comparisons in prior work (e.g., most participants were in motor vehicle collisions). Similarly, BP was assessed with only one measurement and this occurred two weeks following trauma exposure. It is therefore possible that the higher levels of BP observed in prior PTSD studies were a result of more chronic PTSD symptoms and sympathetic hyperarousal, which our study did not capture.

In terms of HR and HF-HRV, our findings indicate that women experienced worse autonomic functioning during fear conditioning compared to men, and this was particularly seen in those women who subsequently developed PTSD. Specifically, trauma-exposed women demonstrated stronger sympathetic arousal and worse parasympathetic control than men during fear learning, where main effects of sex were observed, and those with PTSD demonstrated particularly worse functioning during extinction. This is consistent with prior literature implicating extinction deficits as a biomarker specific to PTSD (Jovanovic et al., 2012) and further suggests that women may be more likely than men to experience these deficits. Given that HF-HRV has been shown to be higher in healthy women compared to men (for a review, see Koenig and Thayer, 2016), our findings also highlight the importance of trauma and PTSD status in sex differences in autonomic function. The lack of sex differences in eyeblink startle (a brainstem-mediated reflex and not an autonomic indicator) suggests that there may be specificity of our sex-based findings to peripheral autonomic and cardiovascular physiology (i.e., HR and HF-HRV). Additionally, low levels of estradiol have been implicated as a contributing factor to fear inhibition and extinction deficits in women with PTSD (indexed via eyeblink startle; Glover et al., 2012, 2013) as well as healthy controls (indexed via skin conductance; Milad et al., 2010). Thus, future research is needed to determine if an interaction between PTSD status and high versus low estradiol confers greater risk for autonomic and inhibition/extinction deficits (indexed via startle) in trauma-exposed women.

eSense has previously demonstrated utility in predicting PTSD status and symptom trajectory when used to measure skin conductance in recently traumatized individuals in emergency departments (Hinrichs et al., 2019). Our findings suggest it may have additional, and perhaps more specific utility among women, such that eSense skin conductance levels were significantly associated with future HR and HF-HRV only in women who developed PTSD. Given that autonomic deficits have been implicated in the increased risk of cardiovascular disease in PTSD, future research testing eSense as a predictor of autonomic functioning and subsequent cardiac events could be extremely useful in determining which trauma-exposed individuals are at highest risk for developing cardiovascular disease. Findings from the current study indicate that this may be a particularly useful tool among women, though replication is needed.

Our findings regarding sex differences in autonomic functioning may have clinical implications. Specifically, men and women differed in their sympathetic arousal, with men demonstrating higher BP and women demonstrating higher HR. Further, women demonstrated lower parasympathetic function than men. As mentioned above, autonomic deficits have been implicated in the increased risk of cardiovascular disease in PTSD. Our findings suggest that the specific autonomic mechanisms through which cardiovascular disease develops could differ for men versus women with PTSD. For example, there is preliminary evidence that blockade of the renin-angiotensin system (responsible for BP regulation) via ace-inhibitors and angiotensin receptor blockers is associated with decreased likelihood of PTSD diagnosis (Khoury et al., 2012; Seligowski et al., 2021). We recently observed a sex effect such that the protective effects of these medications may be greater among men versus women (Seligowski et al., 2021). Thus, medications targeting BP may be more effective in men versus women with PTSD because men are more likely to experience hypertension and therefore see an effect of such medications. Prospective trials of antihypertensive medications for PTSD are needed to further explore sex differences in their effects. Another possible avenue for future trials is to determine if the autonomic deficits we observed during extinction in women with PTSD translate to clinical outcomes (e.g., do women with PTSD experience less symptom reduction from exposure treatments than men?). Thus far, sex differences in exposure-based treatments have not been reported, but we are not aware of any trials that examined sex differences in autonomic functioning during these treatments.

While capturing acute trauma reactions with a prospective design is a strength of this study, an important limitation is that our sample is not as highly symptomatic as comparisons from the literature. For example, we did not see main effects of PTSD status on BP, HR, of HF-HRV and this may be due to the recency of trauma exposure and the absence of severe PTSD symptoms in this cohort. Another limitation relates to trauma type, such that the index trauma for most participants was a motor vehicle collision and the incidence of PTSD in that population is lower than that of other trauma types, such as interpersonal violence and combat exposure (Kessler et al., 2017). Additionally, while we used a recommended cutoff for provisional PTSD diagnosis (Bovin et al., 2016) at 8-weeks, the current study relied on self-reported symptoms and did not include a structured clinical interview of PTSD. Future studies with more robust PTSD assessment among individuals with a broader range of trauma exposure will be needed to replicate and extend our findings. Despite these limitations, this study adds to a very scant literature regarding both 1) prospective assessments of posttraumatic autonomic functioning and 2) sex differences in posttraumatic autonomic functioning.

The current study identified sex differences in multiple domains of autonomic functioning among a recently traumatized sample. Our findings suggest that men and women demonstrate different patterns of sympathetic arousal, with men exhibiting higher BP and women exhibiting higher HR. Women also exhibited worse parasympathetic function as indicated by lower HF-HRV during fear conditioning, as was particularly seen in women who developed PTSD. Acute sympathetic arousal indexed by skin conductance in the emergency department was associated with HR and HF-HRV among women who developed PTSD, suggesting it may be a useful biomarker of subsequent autonomic functioning in this population. Additional studies examining subsequent sex differences in cardiovascular risk as a result of differential autonomic mechanisms are warranted.