Metabolite patterns associated with individual response to supervised exercise therapy in patients with intermittent claudication

Authors: BELLOMO, TIFFANY - University Of Pennsylvania; TSAO, NOAH - University Of Pennsylvania; JOHNSTON-COX, HILLARY - University Of Pennsylvania; BORKOWSKI, KAMIL - University Of California, Davis; SHAKT, GABRIELLE - University Of Pennsylvania; JUDY, RENAE - University Of Pennsylvania; MOORE, JONNI - University Of Pennsylvania; RATCLIFFE, SARAH - University Of Virginia; FIEHN, OLIVER - University Of California, Davis; FLOYD, THOMAS - University Of Texas Southwestern Medical Center; WEHRLI, FELIX - University Of Pennsylvania; MOHLER, EMILE - University Of Pennsylvania; Newman, John; DAMRAUER, SCOTT - University Of Pennsylvania

Submitted to: Journal of Vascular Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/5/2022
Publication Date: 10/25/2022
Citation: Bellomo, T.R., Tsao, N.L., Johnston-Cox, H., Borkowski, K., Shakt, G., Judy, R., Moore, J., Ratcliffe, S., Fiehn, O., Floyd, T.F., Wehrli, F.W., Mohler, E., Newman, J.W., Damrauer, S.M. 2022. Metabolite patterns associated with individual response to supervised exercise therapy in patients with intermittent claudication. Journal of Vascular Science. 3:379-388. https://doi.org/10.1016/j.jvssci.2022.10.002.
DOI: https://doi.org/10.1016/j.jvssci.2022.10.002

Interpretive Summary: Peripheral arterial disease (PAD) is associated with atherosclerosis of the lower extremities, and associated with significant pain after short episodes of walking. Supervised exercise therapy (SET) has some efficacy in pain reduction and increasing comfortable walking times, but the response to this therapy is variable. In this study, changes in the circulating profile of a braod range of metabolites, including inflammaotry mediators in response to SET in participants with PAD were assessed. Participants underwent a graded treadmill test before and after SET and blood was sampled before and after each treadmill test. Mathematical models were developed to identify metabolites or changes in metabolites at specific time points that associate with treadmill test performance or inter-individual variability in functional performance after SET. It was found that SET had a minimal effect on metabolite profiles and SET-associated improvement in treadmill test performance was modest. However, high levels of arachidonic acid (AA) and arachidonylethanolamide (AEA), an endogenous cannabinoid, or lower levels of the AA precursors dihomo-'-linolenic acid and diacylglycerol, before exercise interventions was associated with a shorter, or worse, walking time. Participants who were able to tolerate large increases in AA during acute exercise had longer, or better, walking times both before and after SET. Ultimately, by considered individual quantitative relationships between SET efficacy, certain lipids associated with inflammatory responses became relevant. These data suggest that AEA synthesis in working muscle may result in worse treadmill test performance and SET may help train patients withstand higher levels of AA and inflammatory signaling, resulting in longer walking times. These results improve our understanding of the mechanisms behind SET efficacy and may provide a means to assess an individuals response to this therapy.

Technical Abstract: Background: Although metabolomics have been used to better understand the etiology of peripheral arterial disease (PAD) progression, the metabolome’s response to supervised exercise therapy (SET) has not yet been investigated. Methods: Participants underwent the Gardner graded treadmill test before and after SET and blood was sampled before and after each treadmill test. We tested the average association of metabolite levels with the timing of blood draws. We then used five models to identify metabolites or changes in metabolites at specific time points that associate with treadmill test performance or inter-individual variability in functional performance after SET. Results: SET on average minimally effected the metabolome and the overall improvement in treadmill test performance after SET was modest. When analyzing individual time points, we found that high levels of anandamide (AEA) before any exercise interventions were associated with a shorter, or worse, walking time. We also found that increased arachidonic acid (AA) and decreased levels of AA precursors dihomo-'-linolenic acid and diacylglycerol before any exercise was associated with shorter walking times. Participants who were able to tolerate large increases in AA during acute exercise had longer, or better, walking times both before and after SET. Conclusion: Some metabolite associations only became relevant when we considered individual quantitative effects. We identified two pathways of relevance to individual response to SET: AEA synthesis may increase the activity at endocannabinoid receptors, resulting in worse treadmill test performance. SET may help train patients withstand higher levels of AA and inflammatory signaling, resulting in longer walking times.