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Title:   Author  item
                                            HOLT, ROBERTA - University Of Californiaitem
                                            YIM, SUN - University Of Californiaitem
                                            SHEARER, GREGORY - Pennsylvania State Universityitem
                                            HACKMAN, ROBERT - University Of Californiaitem
                                            DJURICA, DRAGANA - University Of Californiaitem
                                            Newman, Johnitem
                                            SHINDEL, ALAN - University Of Californiaitem
                                            KEEN, CARL - University Of California
  Submitted to: Journal of Nutritional Biochemistry
                                    Publication Type: Review Article
                                    Publication Acceptance Date: 7/17/2015
                                    Publication  Date: 9/1/2015
                                    Citation: Holt, R.R., Yim, S., Shearer, G.C., Hackman, R.M., Djurica, D., Newman, J.W., Shindel, A.W., Keen, C.L. 2015. Effects of short-term walnut consumption on human microvascular function and its relationship to plasma epoxide content. Journal of Nutritional Biochemistry. 26(12):1458-1466. https://doi.org/10.1016/j.jnutbio.2015.07.012.DOI: https://doi.org/10.1016/j.jnutbio.2015.07.012                                                              
                                Interpretive Summary: While the adding walnuts into a standard or high fat diet have been reported to improve vascular function, the mechanisms underlying these effects are poorly defined.  This study is designed to evaluate the acute and short-term effects of walnut intake on microvascular function, platelet reactivity, and the relationship between changes in walnut intake-associated functional responses and changes in lipoprotein and plasma fatty acids and lipid mediators of vascular tone.  To this end, 36 hypercholesterolemic postmenopausal women were randomized to 4 weeks of either 5 or 40g of daily walnut intake.  Outcomes were measured after an overnight fast and 4 hours (h) after walnut intake, before and after the intervention.  Microvascular function was assessed by two predictors of future cardiovascular events, the reactive hyperemia index (RHI) that measures endothelial function, and the augmentation index corrected for a heart rate of 75 beats per min (AIx@75) that measures arterial stiffness.  Four weeks of walnut intake at 40g/d improved endothelial function.  During the first study visit, RHI increased and AIx@75 (i.e. arterial stiffness) decreased, 4 h after 40g of walnut intake.  These postprandial changes were not observed after 4wks of walnut intake.  No changes in vascular function were observed with 5g of walnut intake.  Four weeks of 40g/d of walnut intake reduced low density lipoprotein cholesterol levels, while lipoprotein alpha-linolenic acid (ALA) and linoleic acid (LA) concentrations were increased.  Changes in RHI were strongly correlated with changes in high density lipoproteins concentrations of the LA and ALA derived epoxides 12(13)-epoxyoctadecamonoenoic acid (r = 0.78; p=0.0002) and 15(16)- epoxyoctadecadienoic acid (r = 0.70; p=0.0016), respectively.  These results suggest that the consumption of walnuts can improve microvascular function in postmenopausal women with borderline high cholesterol levels.  The extent of this improvement was associated with changes in specific LA- and ALA-derived epoxides.  These data support the concept that intake of walnut-derived fatty acids can favorably influence microvascular function.
                                Technical Abstract: While improved vascular function after the incorporation of walnuts into controlled or high fat diets has been reported, the mechanisms underlying the effects of walnuts are poorly defined. 
Objective: To evaluate the acute and short-term effects of walnut intake on microvascular function and platelet reactivity, as well as, the relationship of changes in functional response after walnut intake to changes in lipoprotein and plasma fatty acids and oxylipins.
Design: Thirty-six hypercholesterolemic postmenopausal women were randomized to 4 weeks of 5 or 40g of daily walnut intake. Outcomes were measured after an overnight fast and 4 hours (h) after walnut intake, prior to and after the intervention. Microvascular function was assessed by the reactive hyperemia index (RHI) and the augmentation index corrected for a heart rate of 75 beats per min (AIx@75).
Results: Four weeks of 40g/d of walnut intake was associated with increased RHI. During the first study visit, RHI significantly increased, while AIx@75 decreased, 4 h after 40g of walnut intake. These changes were not observed after 4 weeks of walnut intake. No significant changes in vascular function were observed with 5g of walnut intake. Four weeks of 40g of walnut intake significantly reduced low density lipoprotein cholesterol levels, while lipoprotein alpha-linolenic acid (ALA) and linoleic acid (LA) concentrations were increased. Changes in RHI were correlated with changes in 12(13)-epoxyoctadecamonoenoic acid (r = 0.78; p=0.0002) and 15(16)- epoxyoctadecadienoic acid (r = 0.70; p=0.0016) epoxides of LA and ALA, respectively, within high density lipoproteins.  
Conclusion: Consumption of walnuts can improve microvascular function in postmenopausal women with borderline high cholesterol levels.  The extent of the improvement was associated with changes in specific LA and ALA epoxides.  These data support the concept that intake of walnut-derived fatty acids can favorably influence microvascular function.


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