Association Between Novel Circulating Biomarkers of Cytochromes P450-derived Eicosanoid Metabolism and Prognosis in Patients with Established Atherosclerotic Cardiovascular Disease
Creators: name: Robbins, Melody
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2019

description: Introduction: Atherosclerotic cardiovascular disease (ASCVD) is a major health problem that requires new therapeutic strategies. Cytochrome P450 (CYP) enzymes metabolize arachidonic acid to form epoxyeicosatrienoic acids (EETs), which exhibit cardioprotective effects in preclinical models. CYP-derived EETs are rapidly hydrolyzed by soluble epoxide hydrolase (sEH) into less active dihydroxyeicosatrienoic acids (DHETs). Inhibition of sEH has been proposed as a novel ASCVD treatment. However, the relationship between EET concentrations and ASCVD prognosis in humans has not been fully investigated. The purpose of this study was to evaluate the relationship between EETs and risk of future major adverse cardiovascular events (MACE).Methods: A secondary analysis was conducted on an existing cohort of 162 participants that underwent coronary angiography from 2012 to 2014. Plasma EET and DHET metabolite concentrations were quantified by liquid chromatography tandem mass spectrometry. The occurrence of MACE (defined as death, acute coronary syndromes ACS, ischemic stroke or a revascularization procedure) was retrospectively collected from the electronic health record. The time to MACE or last follow-up from the initial catheterization lab visit was calculated. In participants with available follow-up data and angiographic evidence of ASCVD at baseline (N equals 98), the relationship between baseline plasma EET concentrations (as well as sum EETs plus DHETs a biomarker of CYP function and 14,15-EET to DHET ratio a biomarker of sEH function), and risk of future MACE was evaluated using proportional hazards regression. These relationships were examined across low, medium, and high tertiles for each biomarker of interest. The analyses were adjusted for covariates that were associated with EET concentrations and/or ASCVD outcomes. Data are presented as percentages, median interquartile range, or adjusted hazard ratio (HR) 95 percent confidence interval (CI). A p- value of less than 0.05 was considered statistically significant.Results: The ASCVD study population, on average, was 65 years old, 42 percent female, 16 percent African-American, and 49 percent had a prior revascularization procedure. During a median follow-up of 3.8 years, 37 participants (38 percent) experienced a MACE. No significant difference was observed in baseline plasma EET concentrations across those with (0.61 ng/mL 0.52 to 0.71) versus without (0.66 ng/mL 0.54 to 0.83) a future MACE (p equals 0.406). Similarly, there were no significant differences in either baseline sum EETs plus DHETs (p equals 0.363) or 14,15-EET to DHET ratios (p equals 0.641). Compared to participants in the high EET concentration tertile group, those in the combined medium and low tertile group appeared to have a higher risk of future MACE (27 percent 9 of 33 versus 43 percent 28 of 65, respectively; adjusted HR 1.64 0.78 to 3.80, p equals 0.201). However, the observed trend was not statistically significant. A similar association with future MACE risk was observed with sum EETs plus DHETs (24 percent versus 45 percent; adjusted HR 1.98 0.90 to 4.87, p equals 0.094), but not 14,15-EET to DHET ratios (38 percent versus 36 percent; adjusted HR 0.94 0.44 to 1.91, p equals 0.866).Conclusions: No statistically significant associations were found between baseline plasma EET metabolite concentrations and the risk of future MACE. Compared to participants in the high tertile group, those in the low or medium EET and sum EETs plus DHETs tertiles may have a higher risk of future MACE; however, these findings were not statistically significant and should therefore be interpreted with caution. If a relationship between EET concentrations and occurrence of future MACE exists, the data suggests this may be attributed to lower CYP function rather than higher sEH function. Additional investigation in a larger population is warranted.