Project Summary
Daily low-dose aspirin is routinely prescribed to prevent cardiovascular (CV) events, despite conflicting data on
its efficacy, especially with increasing body weight. While intended to inhibit platelet aggregation, aspirin has
other effects that may be important in reducing CV risk that are influenced by body weight.
Obesity and atherosclerosis are both characterized by chronic, low-grade inflammation and some
treatments aimed at reducing inflammation improve CV outcomes. The resolution of inflammation requires
specialized pro-resolving lipid mediators (SPMs). Several SPMs and their precursors are termed “aspirin-
triggered” (AT), as their production is stimulated in the presence of acetylated COX-2. We and others have
shown that AT-SPMs, including 15-epi-lipoxin A4 (15R-LXA4), are reduced in blood and tissues from obese
humans. Pre-clinical models have established that AT-SPMs inhibit atherosclerosis progression and have
plaque stabilizing effects. Small cross-sectional human cohorts have shown AT-SPMs inversely associated
with severity of atherosclerosis, but a potential association with prospective CV outcomes has not been tested.
The largest meta-analysis of aspirin trials showed that low-dose aspirin was effective at reducing major
adverse CV events (MACE) only in those weighing <70kg, whereas doses >300mg exhibited increasing
efficacy as body weight increased. While suggested to explain these findings, data on incomplete platelet
COX-1 inhibition from low-dose aspirin with increasing body weight are inconclusive. Thus, aspirin-mediated
factors extrinsic to platelet function in aggregation and thrombosis, such as deficient AT-SPMs, may mediate
obesity’s role in CVD and reduced benefit from low-dose aspirin with increasing body weight.
Our central hypothesis is that reduced levels of AT-SPMs contribute to excess CV risk and worse CV
outcomes with low-dose aspirin therapy. In our first Aim, we will test the effects of low- and regular-dose aspirin
regimens on AT-SPM levels and cellular function in humans across a wide range of body weights using a
randomized, placebo-controlled, crossover trial. We will measure lipid mediators, including thromboxanes,
leukotrienes, and SPMs, in serum and neutrophils before and after treatment with aspirin. We will also assess
measures of cellular inflammation including platelet activity, platelet-leukocyte aggregates, and leukocyte
surface expression of SPM receptors. In Aim 2, we will assess a predictive capacity of 15R-LXA4 for MACE in
persons with stable ischemic heart disease taking aspirin. Using a nested case-control design, we will assess
serum SPM profiles in 402 subjects in the ISCHEMIA randomized controlled trial and evaluate the capacity of
SPM profiles to predict CV outcomes in these subjects. We will also assess a mediating effect of body weight
on 15R-LXA4 levels.
This work will evaluate a novel mechanistic role for aspirin in CVD treatment, separate from thrombosis,
that may explain worse outcomes with increasing body weight.
