Resolvins and maresins, members of the specialized proresolving mediator (SPM) family, are omega-3 fatty acid-derived lipid mediators that attenuate inflammation. We hypothesized that they play a role in the pathophysiology of coronary microvascular dysfunction (CMD) in women with ischemia and no obstructive coronary disease. In a pilot study, we measured the D-series resolvins (D1, D2, D3, and D5), resolvin E1, maresin 1, docosahexaenoic acid, eicosapentaenoic acid (precursor of resolvin E1), and 18-hydroxyeicosapentaenoic acid by mass spectrometry in the peripheral blood of 31 women enrolled in the Women’s Ischemia Trial to Reduce Events in Nonobstructive CAD (WARRIOR) trial who had confirmed CMD assessed by coronary flow reserve. We compared SPM levels with 12 gender and age-matched reference subjects. Compared with the reference subject group, those with CMD had significantly lower plasma concentrations of resolvin D1 and maresin 1 and significantly higher levels of docosahexaenoic acid and 18-hydroxyeicosapentaenoic acid. In conclusion, insufficient or ineffective SPM production may play a role in the pathophysiology of CMD. If our results are validated in a larger cohort, omega-3 fatty acid supplementation could be tested as a novel treatment for these patients.
Angina pectoris is a prevalent symptom of ischemic heart disease in both women and men. However, up to 2/3 of women and 1/3 of men who underwent coronary angiography did not have flow-limiting narrowing in their major epicardial arteries and were diagnosed with ischemia and no obstructive epicardial coronary artery disease (INOCA). Coronary microvascular dysfunction (CMD), defined as limited coronary flow reserve and/or endothelial dysfunction, is a key mechanism that contributes to myocardial ischemia and angina. Although the pathophysiology of CMD is multifactorial and not completely understood, emerging evidence supports chronic systemic inflammation and ineffective efferocytosis as crucial factors. Resolution of inflammation is an active process mediated, in part, by a family of mediators biosynthesized from omega-3 fatty acids, collectively referred to as specialized proresolving mediators (SPMs). These small, lipid cell-signaling molecules (resolvins, protectins, lipoxins, and maresins) are metabolites of omega-3 fatty acids. They resolve inflammation by inhibiting neutrophil functions and promoting macrophage anti-inflammatory actions. They have been linked to multiple processes in the microvasculature of other organs in murine models, including limiting angiogenesis, vascular permeability, smooth muscle migration and proliferation, and monocyte adhesion to endothelium. Importantly, the role of SPM in CMD has not been examined to date. We hypothesized that women with CMD are unable to effectively resolve inflammation in the heart because of insufficient production or ineffective activity of SPM.
The department of defense-funded Women’s Ischemia Trial to Reduce Events in Nonobstructive CAD (WARRIOR) trial ( ClinicalTrials.gov NCT 03417388) is a multicenter, randomized trial, enrolling women with INOCA to usual care or intensive medical therapy. We identified a subgroup of women currently enrolled in WARRIOR who previously had been participants in the observational Women’s Ischemia Syndrome Evaluation (WISE) Coronary Vascular Dysfunction cohort ( ClinicalTrials.gov NCT 00832702). As part of the WISE-Coronary Vascular Dysfunction study protocol, these women underwent assessment for CMD by coronary flow reserve and endothelial function testing, and each had concomitant peripheral blood sampling. After obtaining approval from the institutional review board at the University of Florida, we identified women who had previously documented CMD on the basis of limited coronary flow reserve and/or abnormal response to acetylcholine on coronary function testing done as part of the WISE project and who were presently enrolled in WARRIOR. We obtained frozen plasma samples corresponding to these subjects from the biorepository and from healthy age-matched reference subjects through the local blood bank. We extracted pertinent clinical characteristics from their baseline visit (at the time when coronary reactivity testing and peripheral blood sampling were performed) including medical co-morbidities, laboratory values, and medications.
We measured the D-series resolvins (D1, D2, D3, and D5), resolvin E1, maresin 1, docosahexaenoic acid (DHA) (precursor of the D-series resolvins and maresin), eicosapentaenoic acid (EPA) (precursor of resolvin E1), and 18-hydroxyeicosapentaenoic acid (18-HEPE) (an EPA metabolite released by macrophages), by liquid chromatography with tandem mass spectrometry according to established techniques. Quantitation was performed on a Thermo Fisher Scientific (Waltham, Massachusetts) TSQ Altis triple quadrupole mass spectrometer at the Southeast Center for Integrated Metabolomics, University of Florida. Plasma concentrations of the SPM between the groups were compared using a Wilcoxon-Mann-Whitney U test. A 2-sided p <0.05 was considered statistically significant.
A total of 31 women with INOCA and CMD currently enrolled in the WARRIOR trial were included in this pilot study ( Table 1 ). Compared with age-matched reference subjects, those with INOCA and CMD had significantly higher levels of 18-HEPE, EPA, and DHA ( Figure 1 ), but significantly lower blood concentrations of resolvin D1 and maresin 1 ( Figure 2 ). Maresin 1 levels in subjects with CMD were undetectable. Reference subjects had low substrate (DHA) and high product (resolvin D1 and maresin 1), whereas women with CMD had high substrate (DHA) and low product (resolvin D1 and maresin 1) ( Figure 3 ).
| Variable Age (years) White | 57 ± 10 29 (94%) |
| Diabetes mellitus Hypertension Hyperlipidemia Tobacco use | 5 (16%) 16 (52%) 24 (77%) 0 |
| Total cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglycerides (mg/dL) Hemoglobin A1c (%) | 152 [134-274] 80 [57-112] 61 [48-69] 97 [58-162] 5.4 [5.2-5.9] |
| Body mass index > 25 kg/m 2 Post-menopausal | 22 (71%) 28 (90%) |
| Medications Angiotensin-converting enzyme inhibitor Beta-blocker Aspirin Statin | 16 (52%) 8 (26%) 21 (68%) 24 (77%) |
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