The metabolic syndrome (MetS) is comprised of a cluster of closely related risk factors, including visceral adiposity, insulin resistance, hypertension, high triglyceride, and low high-density lipoprotein cholesterol; all of which increase the risk for the development of type 2 diabetes and cardiovascular disease. A chronic state of inflammation appears to be a central mechanism underlying the pathophysiology of insulin resistance and MetS. In this review, we summarize recent research which has provided insight into the mechanisms by which inflammation underlies the pathophysiology of the individual components of MetS including visceral adiposity, hyperglycemia and insulin resistance, dyslipidemia, and hypertension. On the basis of these mechanisms, we summarize therapeutic modalities to target inflammation in the MetS and its individual components. Current therapeutic modalities can modulate the individual components of MetS and have a direct anti-inflammatory effect. Lifestyle modifications including exercise, weight loss, and diets high in fruits, vegetables, fiber, whole grains, and low-fat dairy and low in saturated fat and glucose are recommended as a first line therapy. The Mediterranean and dietary approaches to stop hypertension diets are especially beneficial and have been shown to prevent development of MetS. Moreover, the Mediterranean diet has been associated with reductions in total and cardiovascular mortality. Omega-3 fatty acids and peroxisome proliferator-activated receptor α agonists lower high levels of triglyceride; their role in targeting inflammation is reviewed. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone blockers comprise pharmacologic therapies for hypertension but also target other aspects of MetS including inflammation. Statin drugs target many of the underlying inflammatory pathways involved in MetS.

Inflammation in arterial walls leads to coronary artery disease (CAD). Because specialized proresolving lipid mediators (SPMs; lipoxins, resolvins, and protectins) stimulate resolution of inflammation in animal models, we tested whether n-3 fatty acids impact SPM profiles in patients with CAD and promote clot remodeling. Six patients with stable CAD were randomly assigned to either treatment with daily 3.36 g Lovaza for 1 yr or without. Targeted lipid mediator-metabololipidomics showed that both groups had absence of resolvin D1 (RvD1), RvD2, RvD3, RvD5 and resolvin E1-all of which are present in healthy patients. Those not taking Lovaza had an absence of aspirin-triggered resolvin D3 (AT-RvD3) and aspirin-triggered lipoxin B4 (AT-LXB4). Lovaza treatment restored AT-RvD3 and AT-LXB4 and gave levels of RvD6 and aspirin-triggered protectin D1 (AT-PD1) twice as high (resolvin E2 ∼5 fold) as well as lower prostaglandins. Principal component analysis indicated positive relationships for patients with CAD who were receiving Lovaza with increased AT-RvD3, RvD6, AT-PD1, and AT-LXB4 SPMs identified in Lovaza-treated patients with CAD enhanced ∼50% at 1 nM macrophage uptake of blood clots. These results indicate that patients with CAD have lower levels and/or absence of specific SPMs that were restored with Lovaza; these SPMs promote macrophage phagocytosis of blood clots. Together, they suggest that low vascular SPMs may enable progression of chronic vascular inflammation predisposing to coronary atherosclerosis and to thrombosis.-Elajami, T. K., Colas, R. A., Dalli, J., Chiang, N., Serhan, C. N., Welty, F. K. Specialized proresolving lipid mediators in patients with coronary artery disease and their potential for clot remodeling.

BackgroundAlthough statins reduce cardiovascular events, residual risk remains. Therefore, additional modalities are needed to reduce risk. We evaluated the effect of eicosapentaenoic acid and docosahexaenoic acid in pharmacologic doses added to statin treatment on coronary artery plaque volume.Methods and ResultsA total of 285 subjects with stable coronary artery disease on statins were randomized to omega‐3 ethyl‐ester (1.86 g of eicosapentaenoic acid and 1.5 g of docosahexaenoic acid daily) or no omega‐3 (control) for 30 months. Coronary plaque volume was assessed by coronary computed tomographic angiography. Mean (SD) age was 63.0 (7.7) years; mean low‐density lipoprotein cholesterol ≤80 mg/dL. In the intention‐to‐treat analysis, our primary endpoint, noncalcified plaque volume, was not different between groups (P=0.14) but approached significance in the per protocol analysis (P=0.07). When stratified by age in the intention‐to‐treat analysis, younger omega‐3 subjects had significantly less progression of the primary endpoint, noncalcified plaque (P=0.013), and fibrous, calcified and total plaque. In plaque subtype analysis, controls had significant progression of fibrous plaque compared to no change in the omega‐3 ethyl‐ester group (median % change [interquartile range], 5.0% [−5.7, 20.0] versus −0.1% [−12.3, 14.5], respectively; P=0.018). Among those on low‐intensity statins, omega‐3 ethyl‐ester subjects had attenuation of fibrous plaque progression compared to controls (median % change [interquartile range], 0.3% [−12.8, 9.0] versus 4.8% [−5.1, 19.0], respectively; P=0.032). In contrast, those on high‐intensity statins had no difference in plaque change in either treatment arm.ConclusionsHigh‐dose eicosapentaenoic acid and docosahexaenoic acid provided additional benefit to statins in preventing progression of fibrous coronary plaque in subjects adherent to therapy with well‐controlled low‐density lipoprotein cholesterol levels. The benefit on low‐intensity statin, but not high‐intensity statin, suggests that statin intensity affects plaque volume.Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01624727.