In the mixed model, time after exercise was a significant factor for the decrease in serum YKL-40 overall (P<0.0001), but no difference in YKL-40 decrease over time could be demonstrated between the two groups (P=0.12). There was no difference of the effect of time on YKL-40 between the groups (P=0.76), as illustrated in Fig. 3.
In this study, we investigated the effect of exercise on the inflammatory biomarker serum YKL-40 in patients with CAD versus controls. We found that serum YKL-40 was higher at baseline for the CAD patients compared with the controls, and in both groups serum YKL-40 decreased after exercise with a slightly steeper decrease for the CAD patients than the controls. Time after exercise was a significant factor for decrease in serum YKL-40 overall, but we did not observe a difference in serum YKL-40 decrease over time between the two groups, indicating that exercise has a beneficial effect on the inflammatory level independent of atherosclerotic degree.
Serum YKL-40 is a new inflammatory biomarker, which potentially could be of interest in monitoring treatment efficacy, and as a prognostic factor in patients with CAD. Earlier studies suggest that serum YKL-40 could be a new biomarker of acute and chronic inflammation in patients with stable CAD. Circulating serum YKL-40 may reflect the total burden of coronary atherosclerosis or identify high-risk atherosclerosis with ongoing inflammation and atherosclerotic plaque formation.
In this study, it was interesting that we did not see a difference between CAD patients and controls with respect to YKL-40 decrease after exercise. It has already been established that the formation of fatty streaks and atherosclerosis begins early in life 28,29 and advanced atherosclerotic lesions may already appear in young adulthood 29,30. Our control group had a mean age of 53.5 years and were therefore likely to have developed atherosclerosis despite the fact that they did not have stenosis nor coronary artery calcification on CT angiography. Inflammation plays a central role in atherosclerosis 2, and this could explain why we observed a decrease in both groups and why exercise had a positive effect on inflammation in both CAD patients and controls.
A recent study demonstrated increasing plasma YKL-40 and muscle tissue YKL-40 mRNA values after 1 h of intensive exercise 23. Another recent study showed that marathon running increased the levels of circulating YKL-40 by 56% 31. However, yet another study observed no effect on serum YKL-40 after physical exercise 32. It is possible that a higher intensity and/or a longer duration are necessary for induction of increases in circulating YKL-40 levels in response to exercise. However, none of the mentioned studies considered the changes in YKL-40 after exercise as did the present study.
Inflammation is an important factor in the pathogenesis of atherosclerosis, and several markers of inflammation have been associated with an increased risk of cardiovascular events. Physical activity may lower the risk for CAD by decreasing inflammation. Other studies have shown that exercise decreases inflammation by decreasing inflammatory markers such as C-reactive protein and VCAM-1 33. In a study of 177 inactive patients and overweight patients, a single measurement of the inflammatory marker high-sensitivity C-reactive protein was inversely correlated to physical fitness independent of other cardiovascular risk factors. The authors conclude that this indicates the beneficial effects of physical activity on inflammation 34.
To our knowledge, this is the first study to compare serial measurements of serum YKL-40 after exercise in a population of patients with documented CAD and a control group with suspected stable angina but with normal coronary arteries. The cohort was consecutively collected and was representative of CAD patients. Some important limitations in this study need to be addressed. First of all, there were a limited number of participants, which has an impact on the possible generalizability of the results. The borderline significant difference in age between the two groups represents a possible confounder, as age is known to be associated with serum concentrations of YKL-40. The choice of the control group can also be discussed, as these were referred because of stable angina pectoris and possible CAD, but were found to have no stenosis nor calcification on CT angiography. Ideally, the control group should be free from symptoms, and it is possible that the control group could represent a population with stable microvascular disease causing them to have angina pectoris. Furthermore, coronary artery pathology was assessed with different methods in the CAD patients and the controls, because of different a-priori risk for CAD. This, however, represents a daily clinical practice scenario, and a CT angiography has a high negative predictive value and therefore it is unlikely that the difference method has affected the results.
Serum YKL-40 was higher in CAD patients compared with controls, but both groups experienced declining values after exercise, indicating that exercise has an anti-inflammatory effect independent of the degree of the atherosclerotic burden.
The authors thank the Department of Cardiology at Hillerød Hospital Copenhagen University Hospital, Denmark where the examinations have taken place. They thank Ulla Kjærulff-Hansen, Dorthe Mogensen, and Marianne Sørensen, Department of Medicine, Herlev Hospital for excellent technical assistance with the serum YKL-40 analysis. Last but not least, they also thank the participants for their willingness to contribute to the research.
There are no conflicts of interest.
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