An investigation of vago-regulatory and health-behavior accounts for increased inflammation in posttraumatic stress disorder

Highlights

• Fasting serum cytokine levels of young adults with and without PTSD were assessed.

• PTSD symptom severity was positively associated with CRP, TNF-α, IL-10, and TARC.

• Smoking, alcohol dependence, and RSA each independently mediated that association.

• The effects of smoking and alcohol dependence were larger than that of RSA.

• All three mediators accounted for 95% of the link between PTSD and cytokine levels.

Abstract

Objective

Posttraumatic stress disorder (PTSD) has been linked to chronic inflammation, a condition that poses a risk for cardiovascular disease. Attenuated vagal activity has been proposed as a potential mediator of PTSD and inflammation, although associated behavioral health risks—namely cigarette smoking and alcohol dependence—might also account for that link.

Methods

Inflammation was quantified by fasting serum concentrations of C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interleukin (IL)-10, and thymus- and activation-regulated chemokine (TARC)/CCL17 collected from 85 participants with PTSD and 82 without PTSD. Latent variable modeling was used to assess the relationship between PTSD symptom severity and inflammation along with potential mediators vagal activity (respiratory sinus arrhythmia; RSA), smoking status, and lifetime alcohol dependence.

Results

PTSD symptom severity was associated with increased inflammation (β = .18, p = .02). However, this association was reduced in models that adjusted for RSA, smoking status, and lifetime alcohol dependence. Independent mediation effects were deemed significant via bootstrapping analyses. Together, RSA, smoking status, and lifetime alcohol dependence accounted for 95% of the effect of PTSD symptom severity on inflammation.

Conclusion

Although RSA accounted for a modest proportion of the association between posttraumatic stress and pro-inflammatory responses, behavioral factors—specifically cigarette smoking and alcohol dependence—proved to be larger mediators. The benefits of PTSD treatment may be enhanced by additional interventions aimed at modifying these health behaviors.

Introduction

Posttraumatic stress disorder (PTSD) is a chronic condition precipitated by exposure to a traumatic event. It is characterized by intrusive re-experiencing of the traumatic event, avoidance of stimuli evocative of that event, negative alterations in cognitions and mood, and hyperarousal [1]. PTSD also frequently conveys physical health symptoms, perhaps most notably cardiovascular disease [2]. For instance, PTSD has been prospectively associated with coronary heart disease [3] and cardiovascular mortality [4]. Although the pathway from posttraumatic stress to cardiovascular risk is not well understood, emerging evidence suggests that inflammation may play a key role [5].

Under conditions of heightened threat or stress, the sympathetic nervous system activates a “fight or flight” response, characterized by increased cardiovascular and metabolic activity. The immune system also responds in kind, presumably to stave off infections resulting from injuries sustained during such fight or flight. The initial immune response is fast and generalized, during which numbers of phagocytes, including neutrophils and macrophages, are mobilized. Macrophages in turn release pro-inflammatory communication factors (cytokines), including interleukin (IL)-1, IL-6, C-reactive protein (CRP), and tumor necrosis factor alpha (TNF-α), which cause fever and inflammation while contributing to healing. A second, more specific immune response is also initiated in which lymphocytes become activated upon attaching to chemically matched pathogens, thereby initiating lymphocyte expansion and cytokine release. These cytokines include the pro-inflammatory IL-2 and interferon gamma (IFN-γ) as well as the anti-inflammatory IL-4, IL-10, and thymus- and activation-regulated chemokine (TARC/CLL17), which regulate lymphocyte activity.

Over the past two decades, a number of studies have found that psychological stress is associated with elevated cytokine levels, reflecting heightened inflammation [6]. For instance, several studies have found that exposure to trauma in childhood [7], [8], [9] and in adulthood [10] is subsequently predictive of increased inflammation. One study even found that increased cytokine levels post-trauma were predictive of later development of PTSD [11]. In fact, with the exception of a few studies [12], [13], [14], [15], PTSD is generally associated with increased cytokine levels [16], [17], [18], [19], [20], [21], [22], even above and beyond the effect of trauma exposure [23], [24].

The link between PTSD and inflammation is complex but may be partially explained by behavioral risk factors associated with PTSD [22]. For instance, individuals with PTSD are more likely than those without PTSD to smoke and do so heavily [25], be obese [26], and abuse alcohol [27]. Each of these risk factors is independently associated with inflammation [28], [29], [30]. Autonomic dysfunction may also partially account for the association between PTSD and inflammation. Individuals with PTSD exhibit suppressed heart-rate variability (HRV) [31], [32], [33], which is likely due to attenuated vagal regulation of sympathetic arousal [34]. Given the central role of the vagus nerve in inhibiting generalized immune response [35], [36], [37], vagal dysregulation has been proposed as a pathway by which PTSD is associated with chronic inflammation [38].

Although behavioral risk factors and depressed vagal activity have been suggested as potential mechanisms linking PTSD and inflammation, no research has verified this let alone compared their relative mediation effects. Thus, the purpose of the present study was to determine whether the association between PTSD symptom severity and inflammation is partially mediated by vagal activity, smoking status, and history of alcohol dependence, and, if so, which mediator accounts for the largest portion of that association. As such, fasting serum concentrations of CRP, TNF-α, IL-10, and TARC were assayed from a sample of young (i.e., < 40 years of age), largely trauma-exposed adults. Latent variable modeling was used to model inflammation via the four cytokines en route to testing three sets of hypotheses: 1) PTSD symptom severity is positively associated with inflammation; 2) PTSD symptom severity is associated with reduced vagal activity, greater smoking, and higher rates of lifetime alcohol dependence; and 3) vagal activity, smoking status, and lifetime alcohol dependence partially mediate the association between PTSD symptom severity and inflammation.