Fish and Omega-3 Fatty Acids: Sex and Racial Differences in Cardiovascular Outcomes and Cognitive Function.

Both cardiovascular disease (CVD) and cognitive decline are common features of aging. One in 5 deaths is cardiac for both men and women in the United States, and an estimated 50 million are currently living with dementia worldwide. In this review, we summarize sex and racial differences in the role of fish and its very long chain omega-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in preventing CVD events and cognitive decline. In prospective studies, women with higher nonfried and fatty fish intake and women and Black individuals with higher plasma levels of EPA and DHA had a lower risk of CVD. In randomized controlled trials of EPA and DHA supplementation in primary CVD prevention, Black subjects benefited in a secondary outcome. In secondary CVD prevention, both men and women benefited, and Asians benefited as a prespecified subgroup. Fish and omega-3 polyunsaturated fatty acids are associated with prevention of cognitive decline in prospective studies. In randomized controlled trials of EPA and DHA supplementation, women have cognitive benefit. DHA seems more beneficial than EPA, and supplementation is more beneficial when started before cognitive decline. Although studies in women and racial groups are limited, life-long intake of nonfried and fatty fish lowers the risk of CVD and cognitive decline, and randomized controlled trials also show the benefit of EPA and DHA supplementation. These findings should be factored into recommendations for future research and clinical recommendations as dietary modalities could be cost-effective for disease prevention.

Eicosapentaenoic and docosahexaenoic acid supplementation and coronary artery calcium progression in patients with coronary artery disease: A secondary analysis of a randomized trial.

BACKGROUND AND AIMS: We previously reported that an omega-3 fatty acid index ≥4% with high-dose eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) prevented progression of noncalcified plaque. Higher coronary artery calcium (CAC) scores and progression of CAC are associated with increased cardiovascular events and mortality. We examined the effect of EPA + DHA on CAC score. METHODS: A total of 242 patients with coronary artery disease (CAD) on statin therapy were randomized to 1.86 g EPA and 1.5 g DHA daily or none (control) for 30 months. The CAC score was measured at baseline and 30-months with non-contrast, cardiac computed tomography. RESULTS: Both EPA + DHA and control groups had significant progression in CAC scores over 30 months (median change:183.5 vs 221.0, respectively, p < 0.001) despite a 13.6% reduction in triglyceride level with EPA + DHA. No significant difference was observed between groups for the total group, by baseline CAC scores of <100, 100-399, 400-999 and ≥1000 or quartiles of achieved levels of EPA, DHA and the omega-3 fatty acid index. Similar rates of CAC progression were noted in those on high-intensity statin compared to low- and moderate-intensity statin. CONCLUSIONS: EPA and DHA added to statin resulted in similar CAC progression over 30 months regardless of baseline CAC categories, statin intensity and achieved levels of EPA, DHA and the omega-3 fatty acid index.

Higher exercise capacity, but not omega-3 fatty acid consumption, predicts lower coronary artery calcium scores in women and men with coronary artery disease.

BACKGROUND AND AIMS: Higher coronary artery calcium (CAC) scores are associated with increased cardiovascular (CVD) events and mortality. Exercise capacity is predictive of CVD events. Our aim was to examine the relationship between exercise capacity and CAC in women and men. METHODS: CAC was measured in 203 men and 38 women with clinical coronary artery disease using multidetector coronary tomography. They were randomized to 3.36 g eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) daily or none for 30 months. Maximal exercise treadmill testing was performed at baseline with calculation of metabolic equivalents of task (METs) achieved as a measure of exercise capacity. RESULTS: Despite similar ages at baseline (64.0 ± 6.7 vs 62.7 ± 7.8 years, respectively, p = 0.225), women had lower CAC scores compared to men: 106.7 Agatston units [AU] vs 535.3, respectively, p < 0.001, and at every age (p < 0.001). Female CAC scores did not equal those of men until women were 20 years older. Higher levels of METs were associated with lower CAC scores in both women and men. After multivariate adjustment, METs was the most important predictor of CAC score in women at baseline and 30 months (p = 0.001 and 0.029, respectively) whereas only age predicted in men (p = 0.019 and 0.004, respectively). Annual CAC progression was significantly greater in men compared to women (94.8 AU/year vs 38.0, respectively, p = 0.014). No difference was observed in CAC progression in the EPA + DHA group compared to control in either men or women. CONCLUSIONS: The association of higher METs with lower CAC scores in both women and men supports recommending exercise to maximize cardiorespiratory fitness as this may minimize CAC scores and thus, potentially decrease risk for CVD events. This may be especially important for women since METs independently predicted baseline and 30 month CAC in women.

Omega-3 fatty acids and cognitive function.

PURPOSE OF REVIEW: The aim is to provide an update on omega-3 polyunsaturated fatty acids (n-3 PUFA) in preventing cognitive decline and dementia. RECENT FINDINGS: Prospective studies and three new meta-analyses suggest that fish or n-3 PUFA intake are associated with a reduction in development of mild cognitive decline and Alzheimer's disease. Supplementation with docosahexaenoic acid (DHA) in randomized controlled trials (RCTs) in those with mild cognitive impairment showed benefit on cognitive decline, whereas there was no benefit in Alzheimer's disease. In cognitively healthy individuals with clinical coronary artery disease (CAD), 3.36 g EPA and DHA daily slowed cognitive ageing by 2.5 years. Of 15 RCTs in cognitively healthy individuals age more than 55 years, seven reported benefit, whereas eight did not. Potential mechanisms for differences in outcomes include dose, trial duration, apolipoproteinE genotype, sex, stage and rate of cognitive decline, cognitive testing employed and individual characteristics. The downstream product of DHA, neuroprotectin D1, may be involved in beneficial effects. SUMMARY: Patients with early memory complaints or a family history of dementia and those with CAD should be counselled on the potential benefits of fish intake and supplementation with n-3 PUFA. ApolipoproteinE4 carriers may especially benefit from DHA supplementation prior to development of cognitive decline.

Omega-3 fatty acids, subclinical atherosclerosis, and cardiovascular events: Implications for primary prevention.

BACKGROUND AND AIMS: High-dose eicosapentaenoic acid (EPA) therapy was beneficial in high-risk patients without clinical cardiovascular disease (CVD). Whether higher plasma levels of EPA and docosahexaenoic acid (DHA) have similar benefits in those without subclinical CVD is unclear. We aim to evaluate the interplay between plasma omega-3 fatty acids and coronary artery calcium (CAC) in relation to CVD events. METHODS: We examined 6568 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with plasma EPA and DHA levels and CAC measured at baseline. The primary outcome was incident CVD events (myocardial infarction, angina, cardiac arrest, stroke, CVD death). Hazard ratios for the primary outcome were adjusted for potential confounder using Cox regression. RESULTS: Mean ± SD age was 62.1 ± 10.2 years and 52.9% were females. The median follow-up time was 15.6 years. Higher loge(EPA) (adjusted hazard ratio, aHR = 0.83; 95% CI, 0.74-0.94) and loge(DHA) (aHR = 0.79; 95% CI, 0.66-0.96) were independently associated with fewer CVD events. The difference in absolute CVD event rates between lowest vs. highest EPA tertile increased at higher CAC levels. The adjusted HR for highest vs. lowest EPA tertile within CAC = 0 was 1.02 (95% CI, 0.72-1.46), CAC = 1-99 was 0.71 (95% CI, 0.51-0.99), and CAC≥100 was 0.67 (95% CI, 0.52-0.84). A similar association was seen in tertiles of DHA by CAC category. CONCLUSIONS: In an ethnically diverse population free of clinical CVD, higher plasma omega-3 fatty acid levels were associated with fewer long-term CVD events. The absolute decrease in CVD events with higher omega-3 fatty acid levels was more apparent at higher CAC scores.

Association Between Omega-3 Fatty Acid Levels and Risk for Incident Major Bleeding Events and Atrial Fibrillation: MESA.

Background Randomized trials of pharmacologic strength omega-3 fatty acid (n3-FA)-based therapies suggest a dose-dependent cardiovascular benefit. Whether blood n3-FA levels also mediate safety signals observed in these trials, such as increased bleeding and atrial fibrillation (AF), remains uncertain. We hypothesized that higher baseline n3-FA levels would be associated with incident bleeding and AF events in MESA (Multi-Ethnic Study of Atherosclerosis), which included a population free of clinical cardiovascular disease at baseline. Methods and Results We examined the association between baseline plasma n3-FA levels (expressed as percent mass of total fatty acid) with incident bleeding and AF in MESA, an ongoing prospective cohort study. Bleeding events were identified from review of hospitalization International Classification of Diseases, Ninth Revision (ICD-9), and International Classification of Diseases, Tenth Revision (ICD-10), codes, and AF from participant report, discharge diagnoses, Medicare claims data, and study ECGs performed at MESA visit 5. Separate multivariable Cox proportional hazard modeling was used to estimate hazard ratios of the association of continuous n3-FA (log eicosapentaenoic acid [EPA], log docosahexaenoic acid [DHA], log [EPA+DHA]) and incident hospitalized bleeding events and AF. Among 6546 participants, the mean age was 62.1 years and 53% were women. For incident bleeding, consistent statistically significant associations with lower rates were seen with increasing levels of EPA and EPA+DHA in unadjusted and adjusted models including medications that modulate bleeding risk (aspirin, NSAIDS, corticosteroids, and proton pump inhibitors). For incident AF, a significant association with lower rates was seen with increasing levels of DHA, but not for EPA or EPA+DHA. Conclusions In MESA, higher plasma levels of n3-FA (EPA and EPA+DHA, but not DHA) were associated with significantly fewer hospitalized bleeding events, and higher DHA levels (but not EPA or EPA+DHA) with fewer incident AF events.

Regression of human coronary artery plaque is associated with a high ratio of (18-hydroxy-eicosapentaenoic acid + resolvin E1) to leukotriene B4.

Inflammation in arterial walls leads to coronary artery disease (CAD). We previously reported that a high omega-3 fatty index was associated with prevention of progression of coronary atherosclerosis, a disease of chronic inflammation in the arterial wall. However, the mechanism of such benefit is unclear. The two main omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are precursors of specialized pro-resolving lipid mediators (SPMs)-resolvins and maresins-which actively resolve chronic inflammation. To explore whether SPMs are associated with coronary plaque progression, levels of SPMs and proinflammatory mediators (leukotriene B4 [LTB4 ] and prostaglandins) were measured using liquid chromatography-tandem mass spectrometry in 31 statin-treated patients with stable CAD randomized to either EPA and DHA, 3.36 g daily, or no EPA/DHA (control). Coronary plaque volume was measured by coronary computed tomographic angiography at baseline and at 30-month follow-up. Higher plasma levels of EPA+DHA were associated with significantly increased levels of two SPMs-resolvin E1 and maresin 1-and 18-hydroxy-eicosapentaenoic acid (HEPE), the precursor of resolvin E1. Those with low plasma EPA+DHA levels had a low (18-HEPE+resolvin E1)/LTB4 ratio and significant plaque progression. Those with high plasma EPA+DHA levels had either low (18-HEPE+resolvin E1)/LTB4 ratios with significant plaque progression or high (18-HEPE+resolvin E1)/LTB4 ratios with significant plaque regression. These findings suggest that an imbalance between pro-resolving and proinflammatory lipid mediators is associated with plaque progression and potentially mediates the beneficial effects of EPA and DHA in CAD patients.

ω-3 Ethyl ester results in better cognitive function at 12 and 30 months than control in cognitively healthy subjects with coronary artery disease: a secondary analysis of a randomized clinical trial.

BACKGROUND: Omega-3 (n-3) fatty acids have shown benefit in cognitively impaired subjects, but the effect on cognitively healthy older subjects is unclear. OBJECTIVES: Our aim was to determine if long-term, high-dose ω-3 ethyl esters, EPA (20:5n-3) and DHA (22:6n-3), prevent deterioration of cognitive function in cognitively healthy older adults. METHODS: A total of 285 subjects with stable coronary artery disease (CAD) on statin treatment were randomly assigned to 3.36 g EPA and DHA or none (control) for 30 mo. Cognitive function was assessed in all 285 subjects at baseline and in 268 and 250 subjects who returned at 12- and 30-mo follow-up, respectively, with neuropsychological testing as a prespecified secondary outcome. A completer's analysis, along with a sensitivity analysis carrying forward the last observation, was performed. RESULTS: Over the 30-mo period, subjects randomly assigned to EPA and DHA had significantly better scores than control for verbal fluency, language, and memory (mean: 1.08; 95% CI: 0.25, 1.91; P = 0.011) and 2 tests of visual-motor coordination (mean: -2.95; 95% CI: -5.33, -0.57; P = 0.015 and mean: -9.44; 95% CI: -18.60, -0.30; P = 0.043, respectively). The better scores for EPA and DHA were due to an improvement at 12 mo compared with baseline in verbal fluency, language, and memory (P = 0.047) and 2 tests of visual-motor coordination (P = 0.033 and P < 0.001, respectively), whereas control had no change. Post hoc analyses indicated no difference by age, sex, or diabetes status. CONCLUSIONS: Cognitively healthy older adults with stable CAD randomly assigned to high-dose EPA and DHA had improved cognitive function over a 30-mo period compared with control. These findings may be especially important for CAD patients because CAD is a risk factor for cognitive decline.This trial was registered at clinicaltrials.gov as NCT01624727.

Dietary treatment to lower cholesterol and triglyceride and reduce cardiovascular risk.

PURPOSE OF REVIEW: To provide an update on dietary measures to lower levels of LDL-C and triglyceride and reduce cardiovascular (CVD) outcomes. RECENT FINDINGS: Fifty-year follow-up in the Seven Countries Study confirmed that cholesterol levels correlate with saturated fat intake and all-cause mortality and age at death. In the PURE study, refined carbohydrate increased CVD risk whereas saturated fat did not despite increasing LDL-C levels; limitations are discussed. Reports on CVD risk with eggs provide conflicting results. Plant-based diets with healthful complex carbohydrates reduced CVD. The REDUCE-IT trial lowered triglyceride 21.6% and reduced CVD events 26.1% with an omega-3 fatty acid, An omega-3 fatty acid index at least 4% with EPA and docosahexaenoic acid prevented coronary plaque progression. A clinician guide to counsel patients on nutrition and heart healthy diets was recently published. SUMMARY: Based on the evidence, individuals should continue to minimize saturated fats and refined carbohydrates, eliminate trans-fat and increase fruits, vegetables, whole grains, low-fat dairy, and fish or other omega-3 fatty acids. Adhering to a Mediterranean diet is strongly recommended because of lowering CVD and total mortality. High-dose omega-3 fatty acids lower triglyceride, reduce CVD and prevent coronary plaque progression.

Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association.

Hypertriglyceridemia (triglycerides 200-499 mg/dL) is relatively common in the United States, whereas more severe triglyceride elevations (very high triglycerides, ≥500 mg/dL) are far less frequently observed. Both are becoming increasingly prevalent in the United States and elsewhere, likely driven in large part by growing rates of obesity and diabetes mellitus. In a 2002 American Heart Association scientific statement, the omega-3 fatty acids (n-3 FAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were recommended (at a dose of 2-4 g/d) for reducing triglycerides in patients with elevated triglycerides. Since 2002, prescription agents containing EPA+DHA or EPA alone have been approved by the US Food and Drug Administration for treating very high triglycerides; these agents are also widely used for hypertriglyceridemia. The purpose of this advisory is to summarize the lipid and lipoprotein effects resulting from pharmacological doses of n-3 FAs (>3 g/d total EPA+DHA) on the basis of new scientific data and availability of n-3 FA agents. In treatment of very high triglycerides with 4 g/d, EPA+DHA agents reduce triglycerides by ≥30% with concurrent increases in low-density lipoprotein cholesterol, whereas EPA-only did not raise low-density lipoprotein cholesterol in very high triglycerides. When used to treat hypertriglyceridemia, n-3 FAs with EPA+DHA or with EPA-only appear roughly comparable for triglyceride lowering and do not increase low-density lipoprotein cholesterol when used as monotherapy or in combination with a statin. In the largest trials of 4 g/d prescription n-3 FA, non-high-density lipoprotein cholesterol and apolipoprotein B were modestly decreased, indicating reductions in total atherogenic lipoproteins. The use of n-3 FA (4 g/d) for improving atherosclerotic cardiovascular disease risk in patients with hypertriglyceridemia is supported by a 25% reduction in major adverse cardiovascular events in REDUCE-IT (Reduction of Cardiovascular Events With EPA Intervention Trial), a randomized placebo-controlled trial of EPA-only in high-risk patients treated with a statin. The results of a trial of 4 g/d prescription EPA+DHA in hypertriglyceridemia are anticipated in 2020. We conclude that prescription n-3 FAs (EPA+DHA or EPA-only) at a dose of 4 g/d (>3 g/d total EPA+DHA) are an effective and safe option for reducing triglycerides as monotherapy or as an adjunct to other lipid-lowering agents.

An omega-3 fatty acid plasma index ≥4% prevents progression of coronary artery plaque in patients with coronary artery disease on statin treatment.

BACKGROUND AND AIMS: Higher blood levels of the omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been associated with fewer cardiovascular events and lower mortality in prospective studies. Our aim was to determine a target level of EPA and DHA to prevent progression of coronary artery plaque. METHODS: 218 subjects with stable coronary artery disease on statins were randomized to high-dose EPA and DHA (3.36 g daily) or no omega-3 for 30 months. Coronary plaque volume was measured by coronary computed tomographic angiography. Plasma phospholipid levels of EPA, DHA and total fatty acids were measured by gas chromatography mass spectrometry. The omega-3 fatty acid index was calculated as EPA+DHA/total fatty acid. RESULTS: Mean (SD) age was 62.9 (7.8) years; mean (SD) LDL-C level 78.6 (27.3) mg/dL and median triglyceride level 122 mg/dL. Subjects assigned to EPA and DHA had increased plasma EPA and DHA levels variably from 1.85% to 13.02%. Plasma omega-3 fatty acid index ≥4% prevented progression of fibrous, noncalcified, calcified and total plaque in nondiabetic subjects whereas those in the lowest quartile (<3.43%) had significant progression of fibrous, calcified and total plaque. No difference was observed in diabetic subjects. CONCLUSIONS: EPA and DHA added to statins prevented coronary plaque progression in nondiabetic subjects with mean LDL-C <80 mg/dL, when an omega-3 index ≥4% was achieved. Low omega-3 index <3.43% identified nondiabetic subjects at risk of coronary plaque progression despite statin therapy. These findings highlight the importance of measuring plasma levels of omega-3 fatty acids early and at trial conclusion. Targeting an omega-3 index ≥4% maximizes cardiovascular benefit.

New Areas of Interest: Is There a Role for Omega-3 Fatty Acid Supplementation in Patients With Diabetes and Cardiovascular Disease?

PURPOSE OF REVIEW: Summarize studies on omega-3 fatty acids in prevention of albuminuria in subjects with diabetes. RECENT FINDINGS: Several small, short-term trials suggested benefit on albuminuria in subjects with diabetes; however, results were not definitive. Welty et al. showed that eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for 1 year slowed progression of early-stage albuminuria in subjects with diabetes with clinical coronary artery disease on an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, the majority of whom had an albumin/creatinine ratio (ACR) < 30 µg/mg. Moreover, significantly more (3-fold) subjects on EPA and DHA had a decrease in ACR compared to control, and three on EPA and DHA had a change in category from > 30 µg/mg to < 30 µg/mg, whereas no controls did. Potential mechanisms for benefit are discussed. These results suggest that there is benefit and perhaps even reversal of albuminuria with EPA and DHA at an early stage of disease in those with ACR < 30 µg/mg and those with microalbuminuria (ACR > 30).

The effect of eicosapentaenoic and docosahexaenoic acids on physical function, exercise, and joint replacement in patients with coronary artery disease: A secondary analysis of a randomized clinical trial.

BACKGROUND: Poor physical function impairs fitness and exercise and is associated with worse cardiovascular outcomes and all-cause mortality. Joint pain and stiffness limit physical function. OBJECTIVE: To determine if eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation improves physical function and exercise in coronary artery disease (CAD) patients. METHODS: A total of 291 subjects with stable CAD were randomized to either Lovaza (1.86 g of EPA and 1.5 g of DHA daily) or no Lovaza (control) for 1 year. Change in pain, stiffness, and physical function was assessed by the Western Ontario and McMaster Universities Arthritis Index. Minutes of exercise per week were recorded, and musculoskeletal events were reported. RESULTS: Mean age (standard deviation) was 63.3 (7.6) years. In the intention-to-treat analysis, compared with controls, those on Lovaza had better physical function (mean difference, -11.0%, 95% confidence interval [CI] -18.5% to -3.5%, P = .004), better total Western Ontario and McMaster Universities Arthritis Index scores (mean difference, -9.8%, 95% CI -16.6% to -3.0%, P = .005), more exercise per week (135 minutes vs 197 minutes, respectively, P = .028), and less joint replacement (11 vs 1, respectively, P = .002). Pain and stiffness showed a trend toward significance (P = .06). The per-protocol analysis also showed less stiffness compared with controls (mean difference, -11.5%, 95% CI -22.9% to -0.1%, P = .048). CONCLUSION: High-dose EPA and DHA may benefit CAD patients by preserving physical function, increasing amount of exercise, and reducing joint replacement. EPA and DHA may be a safe preventative strategy against musculoskeletal symptoms in CAD patients.

Effect of Eicosapentaenoic and Docosahexaenoic Acids Added to Statin Therapy on Coronary Artery Plaque in Patients With Coronary Artery Disease: A Randomized Clinical Trial.

BACKGROUND: Although 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 RESULTS: A 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. CONCLUSIONS: High-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.

Eicosapentaenoic and Docosahexaenoic Acids Attenuate Progression of Albuminuria in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease.

BACKGROUND: Albuminuria is a marker of inflammation and an independent predictor of cardiovascular morbidity and mortality. The current study evaluated whether eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation attenuates progression of albuminuria in subjects with coronary artery disease. METHODS AND RESULTS: Two-hundred sixty-two subjects with stable coronary artery disease were randomized to either Lovaza (1.86 g of EPA and 1.5 g of DHA daily) or no Lovaza (control) for 1 year. Percent change in urine albumin-to-creatinine ratio (ACR) was compared. Mean (SD) age was 63.3 (7.6) years; 17% were women and 30% had type 2 diabetes mellitus. In nondiabetic subjects, no change in urine ACR occurred in either the Lovaza or control groups. In contrast, ACR increased 72.3% (P<0.001) in diabetic subjects not receiving Lovaza, whereas those receiving Lovaza had no change. In diabetic subjects on an angiotensin-converting enzyme-inhibitor or angiotensin-receptor blocker, those receiving Lovaza had no change in urine ACR, whereas those not receiving Lovaza had a 64.2% increase (P<0.001). Change in ACR was directly correlated with change in systolic blood pressure (r=0.394, P=0.01). CONCLUSIONS: EPA and DHA supplementation attenuated progression of albuminuria in subjects with type 2 diabetes mellitus and coronary artery disease, most of whom were on an angiotensin-converting enzyme-inhibitor or angiotensin-receptor blocker. Thus, EPA and DHA supplementation should be considered as additional therapy to an angiotensin-converting enzyme-inhibitor or angiotensin-receptor blocker in subjects with type 2 diabetes mellitus and coronary artery disease. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01624727.

Specialized proresolving lipid mediators in patients with coronary artery disease and their potential for clot remodeling.

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.

Targeting inflammation in metabolic syndrome.

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.

Effects of Therapeutic Lifestyle Change diets high and low in dietary fish-derived FAs on lipoprotein metabolism in middle-aged and elderly subjects.

The effects of Therapeutic Lifestyle Change (TLC) diets, low and high in dietary fish, on apolipoprotein metabolism were examined. Subjects were provided with a Western diet for 6 weeks, followed by 24 weeks of either of two TLC diets (10/group). Apolipoprotein kinetics were determined in the fed state using stable isotope methods and compartmental modeling at the end of each phase. Only the high-fish diet decreased median triglyceride-rich lipoprotein (TRL) apoB-100 concentration (-23%), production rate (PR, -9%), and direct catabolism (-53%), and increased TRL-to-LDL apoB-100 conversion (+39%) as compared with the baseline diet (all P < 0.05). This diet also decreased TRL apoB-48 concentration (-24%), fractional catabolic rate (FCR, -20%), and PR (-50%) as compared with the baseline diet (all P < 0.05). The high-fish and low-fish diets decreased LDL apoB-100 concentration (-9%, -23%), increased LDL apoB-100 FCR (+44%, +48%), and decreased HDL apoA-I concentration (-15%, -14%) and PR (-11%, -12%) as compared with the baseline diet (all P < 0.05). On the high-fish diet, changes in TRL apoB-100 PR were negatively correlated with changes in plasma eicosapentaenoic and docosahexaenoic acids. In conclusion, the high-fish diet decreased TRL apoB-100 and TRL apoB-48 concentrations chiefly by decreasing their PR. Both diets decreased LDL apoB-100 concentration by increasing LDL apoB-100 FCR and decreased HDL apoA-I concentration by decreasing HDL apoA-I PR.