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Rounding the corner on residual risk: Implications of REDUCE-IT for omega-3 polyunsaturated fatty acids treatment in secondary prevention of atherosclerotic cardiovascular disease.

ABSTRACT: Patients with established atherosclerotic cardiovascular (CV) disease remain at increased risk of major adverse cardiovascular events even during optimal lipid-lowering therapy. Recent studies using the methods of Mendelian randomization, as well as analyses of data from large statin trials, have concluded that elevated triglyceride (TG) levels contribute to that increased risk. Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) from fish and shellfish (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) reduce TG levels when added to the diet in sufficient amounts, and they have favorable effects on several other markers of CV risk. However, trials of omega-3 PUFAs have had inconsistent findings regarding CV risk reduction. Recently, the REDUCE-IT (Reduction of Cardiovascular Events with EPA-Intervention Trial) trial reported that treatment of such high-risk patients with icosapent ethyl, a purified and stabilized ethyl ester of EPA, reduced the risk of the trial's primary CV endpoint by 25% (95% confidence intervals [CI], 32%-17%; P

SUBMITTER: Baum SJ

PROVIDER: S-EPMC6727875 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Rounding the corner on residual risk: Implications of REDUCE-IT for omega-3 polyunsaturated fatty acids treatment in secondary prevention of atherosclerotic cardiovascular disease.

Baum Seth J SJ Baum Seth J SJ Scholz Kenneth P KP

Clinical cardiology 20190629 9

Patients with established atherosclerotic cardiovascular (CV) disease remain at increased risk of major adverse cardiovascular events even during optimal lipid-lowering therapy. Recent studies using the methods of Mendelian randomization, as well as analyses of data from large statin trials, have concluded that elevated triglyceride (TG) levels contribute to that increased risk. Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) from fish and shellfish (eicosapentaenoic acid [EPA] and docosahex ...[more]

PMID: 31254481

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Project description:BackgroundDespite the advances in the treatment of multiple myeloma (MM), complete remission is usually challenging. The interactions between tumor and host cells, in which exosomes (EXs) play critical roles, have been shown to be among the major deteriorative tumor-promoting factors herein. Therefore, any endeavor to beneficially target these EX-mediated interactions could be of high importance.Objectivesa) To investigate the effects of myeloma EXs on natural killer (NK) cell functions. b) To check whether treatment of myeloma cells with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), two polyunsaturated omega-3 fatty acids with known anti-cancer effects, can modify myeloma EXs in terms of their effects on natural killer functions.MethodsL363 cells were treated with either EPA or DHA or left untreated and the released EXs (designated as E-EX, D-EX and C-EX, respectively) were used to treat NK cells for functional studies.ResultsMyeloma EXs (C-EXs) significantly reduced NK cytotoxicity against K562 cells (P ≤ 0.05), while the cytotoxicity suppression was significantly lower (P ≤ 0.05) in the (E-EX)- and (D-EX)-treated NK cells compared to the (C-EX)-treated cells. The expression of the activating NK receptor NKG2D and NK degranulation, after treatment with the EXs, were both altered following the same pattern. However, C-EXs could increase IFN-γ production in NK cells (P < 0.01), which was not significantly affected by EPA/DHA treatment. This indicates a dual effect of myeloma EXs on NK cells functions.ConclusionOur observations showed that myeloma EXs have both suppressive and stimulatory effects on different NK functions. Treatment of myeloma cells with EPA/DHA can reduce the suppressive effects of myeloma EXs while maintaining their stimulatory effects. These findings, together with the previous findings on the anti-cancer effects of EPA/DHA, provide stronger evidence for the repositioning of the currently existing EPA/DHA supplements to be used in the treatment of MM as an adjuvant treatment. EXs released from L363 (myeloma) cells in their steady state increase IFN-γ production of NK cells, while reduce their cytotoxicity against the K562 cell line (right blue trace). EXs from L363 cells pre-treated with either EPA or DHA are weaker stimulators of IFN-γ production. These EXs also increase NK cytotoxicity and NKG2D expression (left brown trace) compared to the EXs obtained from untreated L363 cells. Based on these findings, myeloma EXs have both suppressive and stimulatory effects on different NK functions depending on the properties of their cells of origin, which can be exploited in the treatment of myeloma.

Dataset Information

Rounding the corner on residual risk: Implications of REDUCE-IT for omega-3 polyunsaturated fatty acids treatment in secondary prevention of atherosclerotic cardiovascular disease.

Publications

Rounding the corner on residual risk: Implications of REDUCE-IT for omega-3 polyunsaturated fatty acids treatment in secondary prevention of atherosclerotic cardiovascular disease.

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