Person: Spite, Matthew
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Spite
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Matthew
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Spite, Matthew
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Publication Short-Term, High-Dose Fish Oil Supplementation Increases the Production of Omega-3 Fatty Acid–Derived Mediators in Patients With Peripheral Artery Disease (the OMEGA-PAD I Trial)(John Wiley & Sons, Ltd, 2015) Grenon, S Marlene; Owens, Christopher D; Nosova, Emily V; Hughes-Fulford, Millie; Alley, Hugh F; Chong, Karen; Perez, Sandra; Yen, Priscilla K; Boscardin, John; Hellmann, Jason; Spite, Matthew; Conte, Michael SBackground: Patients with peripheral artery disease (PAD) experience significant morbidity and mortality. The OMEGA-PAD I Trial, a randomized, double-blinded, placebo-controlled trial, addressed the hypothesis that short-duration, high-dose n-3 polyunsaturated fatty acids (n-3 PUFA) oral supplementation improves endothelial function and inflammation in PAD. Methods and Results: Eighty patients with stable claudication received 4.4 g of fish oil or placebo for 1 month. The primary end point was endothelial function as measured by brachial artery flow-mediated vasodilation. Secondary end points included biomarkers of inflammation, n-3 polyunsaturated fatty acids metabolome changes, lipid profile, and walking impairment questionnaires. Although there was a significant increase in FMD in the fish oil group following treatment (0.7±1.8% increase from baseline, P=0.04), this response was not different then the placebo group (0.6±2.5% increase from baseline, P=0.18; between-group P=0.86) leading to a negative finding for the primary endpoint. There was, however, a significant reduction in triglycerides (fish oil: −34±46 mg/dL, P<0.001; placebo −10±43 mg/dL, P=0.20; between-group differential P-value: 0.02), and an increase in the omega-3 index of 4±1% (P<0.001) in the fish oil group (placebo 0.1±0.9%, P=0.49; between-group P<0.0001). We observed a significant increase in the production of pathway markers of specialized pro-resolving mediators generated from n-3 polyunsaturated fatty acids in the fish oil group. Conclusions: High-dose, short-duration fish oil supplementation did not lead to a different response in the primary end point of endothelial function between the treatment and placebo group, but improved serum triglycerides and increased the production of downstream n-3 polyunsaturated fatty acids–derived products and mediators in patients with PAD. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01310270.Publication An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques(Nature Publishing Group, 2016) Fredman, Gabrielle; Hellmann, Jason; Proto, Jonathan D.; Kuriakose, George; Colas, Romain A.; Dorweiler, Bernhard; Connolly, E. Sander; Solomon, Robert; Jones, David M.; Heyer, Eric J.; Spite, Matthew; Tabas, IraChronic unresolved inflammation plays a causal role in the development of advanced atherosclerosis, but the mechanisms that prevent resolution in atherosclerosis remain unclear. Here, we use targeted mass spectrometry to identify specialized pro-resolving lipid mediators (SPM) in histologically-defined stable and vulnerable regions of human carotid atherosclerotic plaques. The levels of SPMs, particularly resolvin D1 (RvD1), and the ratio of SPMs to pro-inflammatory leukotriene B4 (LTB4), are significantly decreased in the vulnerable regions. SPMs are also decreased in advanced plaques of fat-fed Ldlr−/− mice. Administration of RvD1 to these mice during plaque progression restores the RvD1:LTB4 ratio to that of less advanced lesions and promotes plaque stability, including decreased lesional oxidative stress and necrosis, improved lesional efferocytosis, and thicker fibrous caps. These findings provide molecular support for the concept that defective inflammation resolution contributes to the formation of clinically dangerous plaques and offer a mechanistic rationale for SPM therapy to promote plaque stability.