Association of Physical Activity with Bioactive Lipids, BMI, and Risk of Future, Cardiovascular Events: Mediation Analysis from the Vitamin D and Omega-3 Trial (VITAL) and Jupiter Studies

Principal Investigator: Samia Mora

Authors: Rosangela Akemi Hoshi*, Yanyan Liu*, Yanjun Guo, Saumya Tiwari, Heike Luttmann-Gibson, Allen M. Andres, Jeramie D. Watrous, Nancy R. Cook, Trisha Copeland, Karen H. Costenbader, Olivia I. Okereke, Paul M Ridker, JoAnn E. Manson, I-Min Lee, Susan Cheng, Mohit Jain†, Olga Demler†, Samia Mora†
Lay Abstract

Lipid metabolism produces small molecules fundamental in immune regulation, inflammation, and internal body control of many organic processes. Increments or decrements in these molecules, named bioactive lipids, can influence, or be influenced, by the practice of frequent physical activity. Although it is known that physical activity is a healthy behavior and can protect from cardiovascular diseases, exact mechanisms to these effects are still being explored but known to have a relationship with bioactive lipids. We found that part of the bioactive lipids associated with physical activity also presented a relationship with cardiovascular diseases, but in the opposite way. This means that bioactive lipids that are increased with more exercise are likely to reduce the risk of cardiovascular diseases (myocardial infarction, stroke, coronary revascularization, or cardiovascular death) and vice-versa. Better understanding the behavior of these bioactive lipids can potentially enhance the knowledge about the benefits of exercising and how the body uses these effects towards a favorable environment for good cardiometabolic health. We also verified that even though the body mass index is important for lipid metabolism, some bioactive lipids do not depend on this factor.

Scientific Abstract

Background: To better understand the cardioprotective mechanisms of regular physical activity (PA), we examined its association with plasma bioactive lipids (BAL) and prospective cardiovascular disease (CVD) events and evaluated the extent to which BMI might mediate this association.

Methods: Self-reported PA was examined with BAL assayed by an untargeted metabolomics platform in VITAL (N=1032) with validation in JUPITER (N=589). We evaluated both BMI-mediated and non-mediated PA-BAL associations with incident CVD using adjusted conditional logistic regression in two nested CVD case-control studies: VITAL-CVD (770 pairs, followed by mediation analysis) and JUPITER-CVD (415 case-control pairs – validation).

Results: Twenty-two BAL associated with PA and BMI-mediated also presented a relationship with incident CVD, of which 20 were BMI-mediated and 2 non-BMI-mediated. No relationship with CVD was found from the set of PA-BAL associations not mediated by BMI (indirect effect p≥.05). Notably, BALs related to decreased risk of CVD were positively associated with PA and vice-versa.

Conclusion: We identified a signature of 22 PA-related BAL, which were also associated with incident CVD in two independent case-control studies. Although BMI-mediated associations were predominant, non-mediated effects were also detected, implying that more than one pathway may play a role in the PA-CVD relationship.

Clinical Implications
Better understanding the behavior of molecules fundamental in internal body control, namely bioactive lipids, can enhance the knowledge about mechanisms involved on the benefits of exercising and how the body favorably uses these effects towards a good cardiometabolic health.

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