Vulnerability to stress-induced inflammation has been linked to a dysfunctional hypothalamus–pituitary–adrenal (HPA) axis. In the present study, patients with known or suspected coronary artery disease (CAD) were assessed with respect to inflammatory and HPA axis response to acute physical exercise. An exercise stress test was combined with SPECT myocardial perfusion imaging. Plasma and saliva samples were collected before and 30 min after exercise. Interleukin (IL)-6 and adrenocorticotropic hormone (ACTH) were measured in plasma, while cortisol was measured in both plasma and saliva. In total, 124 patients were included of whom 29% had a prior history of CAD and/or a myocardial perfusion deficit. The levels of exercise intensity and duration were comparable in CAD and non-CAD patients. However, in CAD patients, IL-6 increased after exercise (p = 0.019) while no differences were seen in HPA axis variables. Conversely, patients without CAD exhibited increased levels of ACTH (p = 0.003) and cortisol (p = 0.004 in plasma, p = 0.006 in saliva), but no change in IL-6. We conclude that the IL-6 response to acute physical exercise is exaggerated in CAD patients and may be out of balance due to HPA axis hypoactivity. It remains to be further investigated whether this imbalance is a potential diagnostic and therapeutic target in CAD.
BackgroundLow-grade systemic inflammation is a predictor of recurrent cardiac events in patients with coronary artery disease (CAD). Plasma proteins such as matrix metalloproteinase (MMP)-9 and myeloperoxidase (MPO) have been shown to reflect basal as well as stress-induced inflammation in CAD. Measurements of MMP-9 and MPO in saliva might pose several advantages. Therefore, we investigated whether salivary levels of MMP-9 and MPO corresponded to plasma levels in patients with coronary artery disease (CAD), both at rest and after acute physical exercise.MethodsA bicycle ergometer test was used as a model for stress-induced inflammation. Twenty-three CAD patients performed the test on two occasions 3–6 months apart. Whole unstimulated saliva was collected before, directly after and 30 min after exercise while plasma was collected before and after 30 min. MMP-9 and MPO in saliva and plasma were determined by Luminex.ResultsMMP-9 and MPO levels were 2- to 4-fold higher in saliva than in plasma. Amongst the saliva samples, and also to a great extent amongst the plasma samples, the levels of both types of protein showed strong intercorrelations between the levels at rest and after exercise during the two visits. However, there were no (or weak) correlations between salivary and plasma MMP-9 and none between salivary and plasma MPO.ConclusionWe conclude that salivary diagnostics cannot be used to assess systemic levels of MMP-9 and MPO in CAD patients, neither at rest nor after acute physical exercise.
22 Background 23 Low-grade systemic inflammation is a predictor of recurrent cardiac events in patients with coronary 24 artery disease (CAD). Plasma proteins such as matrix metalloproteinase (MMP)-9 and 25 myeloperoxidase (MPO) have been shown to reflect basal as well as stress-induced inflammation in 26 CAD. Measurements of MMP-9 and MPO in saliva might pose several advantages. Therefore, we 27 investigated whether salivary levels of MMP-9 and MPO corresponded to plasma levels in patients 28 with CAD, both at rest and after acute physical exercise. 29 Methods 30 An acute bout of physical exercise on a bicycle ergometer was used as a model for stress-induced 31 inflammation. Twenty-three CAD patients performed the test on two occasions 3-6 months apart. 32 Whole unstimulated saliva was collected before, directly after and 30 min after exercise while plasma 33 was collected before and after 30 min. MMP-9 and MPO in saliva and plasma were determined by 34 Luminex. 35 Results 36 MMP-9 and MPO levels were 2-to 4-fold higher in saliva than in plasma. Within the saliva 37 compartment, and also to a great extent within the plasma compartments, MMP-9 and MPO showed 38 strong intercorrelations at all time points. However, there were no (or weak) correlations between 39 salivary and plasma MMP-9 and none between salivary and plasma MPO. 40 Conclusion 41 We conclude that salivary diagnostics cannot be used to assess systemic levels of MMP-9 and MPO in 42 CAD patients, neither at rest nor after acute physical exercise. 43 44 Key words 45 Coronary artery disease; inflammation; matrix metalloproteinase-9; myeloperoxidase; saliva 46 3 47 Introduction 48 49 Inflammation is an important component of atherosclerosis, from the formation of atherosclerotic 50 plaques to plaque destabilization eventually leading to plaque rupture and atherothrombotic events, 51 such as myocardial infarction [1]. Systemic levels of inflammatory markers can be useful to assess 52 cardiovascular risk and monitor disease activity and over the years, great efforts have been made to 53 identify relevant and easily available markers. The predictive value of markers like C-reactive protein 54 (CRP) and interleukin (IL)-6 in determining the risk of myocardial infarction is well-documented [2].55 Moreover, a number of epidemiological and clinical studies have shown that neutrophil-associated 56 proteins in plasma, such as matrix metalloproteinase (MMP)-9 and myeloperoxidase (MPO), predict 57 cardiovascular outcome [3, 4] and also relate to the extent and severity of atherosclerosis [5]. Overall, 58 there is emerging evidence that the presence of low-grade systemic inflammation should be considered 59 in clinical praxis when assessing a patient´s risk of recurrent cardiovascular events. 60 61 Low-grade inflammation is however not always detectable in plasma measures taken at rest. As has 62 been shown in various settings, stress provocation tests may add important information on the 63 individual´s susceptibility to inflammatory response [6][7][8][9]. A gr...
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<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.
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