Exploring protein biomarkers of physical activity and cardiovascular disease

Abstract

Abstract Background The beneficial effects of physical activity on cardiovascular risk are well documented. Yet, the underlying mechanisms by which physical activity prevents cardiovascular disease remain unclear (1). Advancements of omics technology enables us to explore novel biomarkers of this complex molecular relationship and potentially unravel underlying molecular mechanisms involved in the progression of cardiovascular events. Purpose To investigate associations between long term physical activity and plasma proteins. As a second step investigate associations between identified plasma proteins and future myocardial infarction and mortality. Methods In the population based prospective cohort Uppsala Longitudinal Study of Adult Men (ULSAM), men were repeatedly investigated with a validated questionnaire on physical activity at ages 50, 60 and 70. 720 plasma proteins were analyzed at age 70 (n=782) with follow up on mortality data for 30 years. In the case-cohort MIMI (Markers of Imminent Myocardial Infarction study) the same plasma proteins were measured in disease-free individuals from six European cohorts. Individuals with acute myocardial infarction within 6 months from baseline were defined as cases (n=420) and up tto four cohort representatives per case were defined as controls (n=1598). Results Higher level of physical activity during 20 years was significantly associated with 12 plasma proteins, in a linear regression model adjusted for age, education and smoking after Bonferroni correction for multiple testing (p<0.000069). After additional adjustment for known cardiovascular risk factors (education, smoking status, BMI, blood pressure, low-density lipoprotein, diabetes diagnosis, and hypertensive-, lipid- or diabetes-treatment), all 12 proteins remained negatively associated with higher level of physical activity in the ULSAM cohort (p<0,05). Two proteins of the 12 proteins associated with physical activity were also significantly associated with future myocardial infarction in the MIMI study (FGF21 and IL6, p<0.05 for both) and 10 proteins were associated with increased mortality risk in the ULSAM cohort (p<0.05 for all). Moreover, proteins that were more negatively associated with physical activity were generally more positively associated with the risk of myocardial infarction in MIMI (Figure). Conclusion Multiple novel associations were found between long-term physical activity and plasma proteins. Some proteins were also associated with future myocardial infarction in an independent cohort which could suggest that the cardioprotective effects of physical activity to some degree may be mediated via the circulating proteome. Our findings encourage additional studies in order to understand the underlying causal mechanisms of these associations.