Exercise-induced CRP increase

Prior to the NEEDED study, there was uncertainty about the kinetics of exercise-induced CRP, the magnitude of the CRP increase and the predictors of this response.

The clinical significance of the exercise-induced CRP response was also unknown.

We addressed these topics in Paper 4, and found an 129 % increase in CRP levels 24 hours following the North Sea Race, as compared to baseline levels, p<0.001. The magnitude was less than described following marathon-running by Weight et al., (155), but similar as described by Sherr et al. (168). We did not sample after 24 hours following exercise, however, other studies have confirmed that exercise-induced CRP levels decrease at 48-72 hours following strenuous exercise (168,210,211).

In bivariate and multiple regression analyses, physical fitness was significantly inversely associated with the magnitude of the CRP response, assessed as race duration, self-reported fitness level, number of prior endurance exercise competitions during the past 5 years and number of hours per week of endurance exercise training.

The present study did not use peak oxygen consumption to determine physical fitness; however, all measures of physical fitness were well correlated with each other.

The correlation between physical fitness and exercise-induced CRP increase might have been anticipated, as less fit subjects have smaller cardiac dimensions, less developed musculature and vasculature and a lower degree of exercise efficiency as compared with highly trained athletes. During acute exercise, contracting viable (i.e.

non-damaged) skeletal muscle serve as a secretory organ, secreting pleiotropic molecules collectively called myokines which exerts paracrine and endocrine effects on various target organs. During and shortly following physical activity, IL-6 is released from myocytes causing plasma levels to increase hundred-fold compared with baseline values (153,154). IL-6 serves as an upstream regulator of CRP production in the liver, and Scharhag et al. showed that exercise-induced CRP and IL-6 were strongly correlated (R=0.68, p<0.001) (212). This association between muscle metabolism and inflammation might also be the reason why an association

between exercise-induced CRP and CK was identified. The correlation between exercise-induced CRP and CK is in line with findings by Strachan et al. (210).

Findings from the present study confirms and extends on prior findings. Liesen et al.

found an attenuation of the exercise-induced CRP response following 9 weeks of endurance training; however, this study only included three male subjects (213).

Mündermann et al. (n=45) described a relationship between marathon performance and exercise-induced CRP, however they included male subjects only (214). The findings of the present study suggest that the beneficial effects of high degree of physical fitness might not only relate to a favourable modulation of basal inflammation, but also an improved biological response to physical stress.

There are known associations between baseline CV risk factors and CRP, and as such, the influence of CV risk factors on exercise-induced CRP was assessed in multiple regression analysis. At baseline, BMI was significantly associated with the CRP level of the present cohort. The association between BMI and exercise-induced CRP levels, however, was not significant in the present study. This is in line with findings by Mündermann et al. who also did not find an association between BMI and exercise-induced CRP (214). We wanted to assess the relationship between CV risk factors and the exercise-induced CRP response further in the 2014 cohort in order to confirm this finding, however, in this larger cohort, BMI was significantly associated with exercise-induced CRP increase (Figure 15) (215). Baseline LDL levels also had a significant bivariate correlation with exercise-induced CRP in the 2014 cohort (rho=0.12, p<0.001). Systolic blood pressure was not associated with exercise-induced CRP increase. As such, it is important to note that in small studies, and particularly studies with homogenous cohorts, certain associations are difficult to assess with certainty.

Figure 15: The association between BMI, race duration and the CRP increase during the NEEDED 2014 study (n=1002) (215).

A secondary aim of Paper 4 was to evaluate the association between the exercise-induced CRP, cTnI and BNP after strenuous exercise. No significant relationship was observed. This is in line with findings by Scherr et al., who also did not find an association between CRP and cTnT following a marathon (168). They, however, did not sample cTnT at the expected peak at 2-6 hours following exercise (168).

Scharhag et al. assessed the association between CRP and N terminal pro brain natriuretic peptide (NT-proBNP) (212). They found no association between exercise-induced CRP and NT-proBNP levels in their cohort of 14 athletes, suggesting that the exercise-induced increase in NT-proBNP was unrelated to inflammation (212).

In order to assess the significance of the exercise-induced CRP increase, data on infections and well-being at 1-week post-race was collected. Clinical events following the NEEDED 2013 study were defined as self-reported unscheduled healthcare contact (n=3), sick leave or unusual discomfort 1 week following the race (n=9). These subjects had non-significantly increased levels of CRP both prior to the race and 24 hours following the race. These findings are reassuring; however, the small sample-size of this study prevents us to conclude with certainty on the clinical significance of exercise-induced CRP. The association between exercise-induced CRP increase and clinical end events will be further assessed in the 5-year follow-up

study of the NEEDED 2014 cohort, where the primary end-pint is a composite of mortality, myocardial infarction, revascularization, sudden cardiac arrest, heart failure and stroke.