Sustained inflammation and high cortisol reactivity following an coronary event
Authors: Mahmood Z , Skoglund C , Back M , Jonasson L 
Published: May 2023

Abstract

Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): Heart and lung foundation Sweden.

Background
Over the last decades, significant improvements have been made in medical and lifestyle managements of patients with coronary artery disease (CAD). Nonetheless, "residual inflammatory risk" for recurrent cardiovascular events is high in this patient group and remains a diagnostic and therapeutic challenge. Activation of the NLRP3 inflammasome, involving release of interleukin (IL)-1β and IL-18 followed by their downstream target IL-6, is considered a major component of the inflammatory process in atherosclerosis. One major immunomodulator is the hypothalamic–pituitary–adrenal (HPA) axis. Interestingly, there is increasing evidence that cortisol exerts proinflammatory effects through the induction of NLRP3 expression.

Purpose
We investigated whether sustained inflammation was associated with altered HPA stress reactivity in patients with CAD. From 4 weeks up to 6 months after a coronary event, we measured systemic inflammation, with focus on inflammasome-related cytokines, and HPA axis hormones (ACTH and cortisol) before and after acute physical stress.

Method
We included 81 patients (mean age 62 years, 77 % males) and 30 controls (mean age 69 years, 67 % males). Patients underwent a standardized submaximal exercise stress test at 4 weeks (visit A) and 3-6 months after the coronary event (visit B) while controls performed one test only. Free cortisol was measured in saliva before, directly and 30 min after exercise. IL-18, IL-Ra (as a surrogate for IL-1 β), IL-6, ACTH and total cortisol were measured in plasma before and 30 min after exercise.

Results
At visit A, plasma levels of CRP (baseline only) and IL-6 did not differ between patients and controls while IL-18 and IL-1Ra were significantly higher in patients both before and after exercise, 500 (391-632) vs 386 (295-493), p=0.002; and 179 (141-267) vs 147 (117- 182), p=0.005, respectively(table 1). At visit B, CRP decreased while IL-18 and IL-1Ra levels remained at higher levels than controls. At both visits, patients showed a heightened cortisol reactivity (i.e. significant increase directly after exercise) while this did not occur in controls (Figure 1). At visit B, the relative increase in cortisol directly after exercise was even higher than at visit A (p=0.024). At both visits, ACTH decreased significantly after exercise in patients (p&lt;0.01), probably due to negative feedback, while no change in ACTH was observed in controls.

Conclusion
Sustained elevations in IL-18 and IL-1Ra in CAD patients following a coronary event may indicate enhanced activity of NLRP3 inflammasome. Furthermore, patients exhibited a heightened cortisol stress reactivity, a phenomenon which has been associated with atherosclerosis progression and sedentary lifestyle in the population. It may be speculated that HPA axis alteration is directly associated with NLRP3 inflammasome activation in CAD, thus opening doors to new insights in prevention. However, this remains to be further investigated.