Vaccine-induced inflammation attenuates the vascular responses to mental stress
Introduction
There is converging evidence that acute mental stress can precipitate myocardial infarction (MI). For example, survivors of MI have identified emotional stress as a trigger for their MI (Strike and Steptoe, 2005) and epidemiological studies have reported elevated MI incidence following stressful events, such as earthquakes, onset of wars, and even following international soccer matches (for review see Strike and Steptoe (2005)). Even though the underlying mechanisms are not yet fully understood, studies suggest that the effects of inflammation on the vasculature may play a role in stress-induced MI (Paine et al., 2012). Serological markers of inflammation and vasoconstriction were elevated in patients admitted for MI during the Football World Cup, compared to those admitted during a control period (Wilbert-Lampen et al., 2010). Similarly, laboratory studies have revealed that cardiac patients exhibiting mental stress-induced ischaemia (a laboratory proxy for MI) have higher basal inflammatory levels (Shah et al., 2006), and poorer vascular responses to mental stress (Burg et al., 2009, Goldberg et al., 1996, Jain et al., 1998).
Associations between inflammation and endothelial function have been studied in vivo. Endothelial function is assessed by measuring the vasodilatory response to a standardised stimulus (Sandoo et al., 2010), such as increases in blood flow. A reduced ability to vasodilate to such stimuli, i.e., endothelial dysfunction (Sandoo et al., 2010), is an indicator of atherosclerosis (Lerman and Zeiher, 2005), which is evident in patients with increased levels of inflammation (e.g., coronary artery disease (Fichtlscherer et al., 2004) and rheumatoid arthritis (Vaudo et al., 2004)). Transient endothelial dysfunction can also manifest in apparently healthy populations where inflammation has been induced by direct infusion of inflammatory cytokines (Bhagat and Vallance, 1997) or vaccination (Clapp et al., 2004, Hingorani et al., 2000, Kharbanda, 2002). Interestingly, in people without proven endothelial dysfunction, mental stress reliably causes vasodilation, indexed by increased blood flow (Joyner and Casey, 2009). However, stress-induced vasodilation is attenuated in those at risk for CVD (Hamer et al., 2007) and in those with heart failure (Middlekauff et al., 1997, Santos et al., 2005). Thus, it is important to examine the role of inflammation on stress-induced vasodilation, given that inflammation is evident in those with endothelial dysfunction and that endothelial dysfunction can lead to poorer vascular responses to stress (Sherwood et al., 1999).
To our knowledge only two studies have examined the influence of inflammation on vascular responses to mental stress. Rheumatoid arthritis patients with high-grade systemic inflammation displayed increased vascular resistance in response to mental stress, which was not evident in patients with low-grade inflammation (Veldhuijzen van Zanten et al., 2008). A second study, involving a healthy population, observed that eccentric exercise-induced increases in IL-6 resulted in reduced calf, but not forearm, blood flow during mental stress (Paine et al., 2013a), further suggesting a possible role for inflammation in attenuating the vascular responses to mental stress.
However, one criticism of utilising an eccentric exercise protocol is that it typically yields increases in IL-6, but not other inflammatory markers (Febbraio and Pedersen, 2002, Steensberg et al., 2001, Steensberg et al., 2002). Other experimental paradigms are available, such as typhoid vaccination, which can induce elevations in other pro-inflammatory markers (e.g., TNF-α (Paine et al., 2013b)), which have been implicated in the development of atherosclerosis and subsequent cardiovascular disease (Anker and von Haehling, 2004, Blake and Ridker, 2002). Critically, the typhoid vaccination does not induce changes in mood, physical symptoms or sickness behaviour (Brydon et al., 2009, Paine et al., 2013b). However, this finding is not universal, with others demonstrating a relationship between mood and vaccination (Harrison et al., 2009a, Harrison et al., 2009b), as well as others demonstrating changes in mood as a result of vaccination administration (Strike et al., 2004, Wright et al., 2005). Therefore, the use of the typhoid vaccination allows us to use a vaccination paradigm whereby relatively substantial increases in inflammation are observed without altering these other psychological factors, allowing us to examine only the physiological alteration of blood flow in response to stress.
Therefore, the aim of the current study was to examine whether vaccination-induced inflammation, induced by the administration of the Salmonella typhi (typhoid) vaccination, influences the vascular responses to mental stress in healthy participants. It was hypothesised that inflammation would attenuate the vasodilatory response to mental stress.
Section snippets
Participants and study design
A total of 23 male university students were recruited, and randomised into one of two intervention groups: vaccination and saline. All participants completed two stress reactivity sessions scheduled at least 7 days apart — one in a ‘control’ condition, the other in an ‘intervention’ condition (vaccination or saline). In the intervention condition, participants completed a stress reactivity session having either received a typhoid vaccination or a saline injection. These were administered 6 h
Inflammatory response to vaccination (S. typhi polysaccharide vaccine)
Table 1 displays the measures of inflammation at baseline in the intervention and control conditions in those who received the vaccination. A series of 2 Condition (Control, Intervention) ANOVAs confirmed that the vaccination induced an inflammatory response in those who received the vaccination intervention: TNF-α, IL-6, and granulocytes were all elevated during the vaccination intervention condition compared to the control condition (Table 1). No increases in IL-6, TNF-α or granulocytes would
Discussion
The aim of this study was to examine the impact of vaccine-induced inflammation on the vascular responses to mental stress. The S. typhi vaccination induced a systemic inflammatory response, evidenced by increased TNF-α, IL-6 and granulocytes. Elevated inflammation attenuated the vasodilatory response to mental stress. These findings are in line with previous findings where inflammation, induced through eccentric exercise, also induced an attenuation in the vascular response to mental stress (
Acknowledgements
The authors would like to acknowledge the valuable contributions of Oliver Dixon, Jessica Russell, Harpavan Shergill, Lucie Vickers and Alex Wadley in recruiting and testing participants, and Dr David McIntyre for technical assistance.
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