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.

Background Aerobic exercise capacity is inversely associated with cardiovascular and all‐cause mortality in men and women without coronary artery disease ( CAD ); however, a higher amount of vigorous exercise is associated with a J‐shaped relationship in CAD patients. Therefore, the optimal type and amount of exercise for CAD patients is unclear. Coronary artery calcification ( CAC ) is associated with increased cardiovascular disease ( CVD ) events and mortality. Fatty plaque is more likely to rupture and cause coronary events than other types. We examined the association between exercise capacity, fatty plaque, CAC score and CVD events in CAD patients. Methods and Results A total of 270 subjects with stable CAD were divided into tertiles based on metabolic equivalents of task ( MET s) calculated from exercise treadmill testing. Self‐reported exercise was obtained. Coronary computed tomographic angiography measured coronary plaque volume and CAC score. After adjustment, fatty plaque volume was not different among the 3 MET groups. For each 1 MET increase, CAC was 66.2 units lower ( P =0.017). Those with CAC >400 and ≥8.2 MET s had fewer CVD events over 30 months compared to <8.2 MET s ( P =0.037). Of moderate intensity exercisers (median, 240 min/wk; 78% walking only), 62.4% achieved ≥8.2 MET s and lower CAC scores ( P =0.07). Intensity and duration of exercise had no adverse impact on coronary plaque or CVD events. Conclusions Achieving ≥8.2 MET s with moderate exercise intensity and volume as walking resulted in lower CAC scores and fewer CVD events. Therefore, vigorous exercise intensity and volume may not be needed for CAD patients to derive benefit. Registration URL : https://www.clinicaltrials.gov ; Unique Identifier: NCT 01624727.

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Background: The neutrophil/lymphocyte (N/L) ratio increases with the systemic inflammatory response due to an increase in neutrophils and decrease in lymphocytes with systemic inflammation. An elevated N/L ratio has been associated with an increased risk of cardiovascular disease (CVD), cancer and mortality. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) decrease levels of high sensitivity C-reactive protein (hs-CRP), the gold standard inflammatory marker, when levels of hs-CRP are elevated. Randomized trials have also reported a decrease in CVD events with EPA. The mechanism for this benefit is unclear. Objective: To examine the effect of high-dose EPA and DHA supplementation on inflammation as measured by the N/L ratio in the setting of low levels of hs-CRP. Methods: A total of 242 subjects with stable coronary artery disease on statin treatment were randomized to 3.36 g EPA+DHA daily or none. N/L ratio and the monocyte to lymphocyte (M/L) ratio were measured at baseline and 1 year. Results: Mean (SD) age was 63.1 years (7.7); mean (SD) LDL-C: 77.8 mg/dL (27.3); median [IQR] TG: 117.5 mg/dL [81.3,166.8] and median [IQR] hs-CRP: 0.75 mg/L [0.40,2.5]. Those on EPA+DHA had a 2.2% reduction in N/L ratio (P=0.014) at 1 year compared to those not on EPA+DHA who had a 12.2% increase (Figure) (between group P= 0.007). There was a trend toward benefit with the M/L ratio (P=0.078). Conclusion: High-dose EPA+DHA decreases systemic inflammation as reflected in the N/L ratio even with low hs-CRP levels. This is a new finding which suggests that under conditions of generally low levels of inflammation in terms of hs-CRP levels, the N/L ratio may be a more sensitive measure of underlying inflammation than hs-CRP and should be considered as an additional marker in future studies of omega-3 fatty acids. If a decrease in inflammation by N/L ratio were accompanied by a clinical decrease in CVD events, this would assist in determining a plausible mechanism of action.

Introduction: Higher amounts of noncalcified plaque and higher coronary artery calcium (CAC) scores are associated with increased cardiovascular events and mortality. The effect of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on noncalcified coronary plaque and more advanced calcified plaque as measured by the CAC score according to hypertensive (HTN) status is unknown. Methods: A total of 242 subjects with coronary artery disease (CAD) on statin were randomized to 3.36 g of EPA+DHA or none (control) for 30 months. Coronary plaque composition and CAC scores were measured with computed tomographic coronary angiography at baseline and 30-month follow-up. Results: Mean (SD) age was 63.1 years (7.7); mean (SD) LDL-C: 77.8 mg/dL (27.3) and median [IQR] triglyceride (TG): 117.5 mg/dL [81.3,166.8]. Despite a significantly higher CAC score at baseline in HTN subjects, both HTN and normotensive (NTN) subjects had similar CAC progression over 30 months with no difference between EPA+DHA and control groups (Figure B). NTN subjects on EPA+DHA had a 20.7% reduction in TG level and 36.6% lower neutrophil count, a marker of inflammation, and lack of progression of noncalcified plaque compared to control who had progression (median % change: -7.6 vs 13.2 mm 3 /mm, P=0.008) (Figure A). In contrast, HTN subjects on EPA+DHA and control had progression of noncalcified coronary plaque with no significant difference between the two groups (Figure A) Conclusions: EPA+DHA prevented progression of noncalcified plaque in NTN subjects but not HTN subjects with no effect on more advanced plaque which has calcified in the setting of low LDL-C and TG levels. The benefit of EPA+DHA in CAD patients on statin therapy appears limited to noncalcified coronary plaque in NTN subjects. Whether this benefit is related to more favorable effects on inflammation based on blood pressure status should be examined further.

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Introduction: Higher coronary artery calcium (CAC) scores have been associated with increased cardiovascular (CVD) events and mortality. Women develop coronary artery disease (CAD) on average 10-15 years older than men and have worse outcomes than men when CVD events occur. The effect of exercise capacity on CAC scores in women with CAD is unclear. Objective: To determine if exercise capacity is predictive of CAC scores in men and women with CAD. Methods: A total of 203 men and 38 women with known CAD had CAC scores measured using noncontrast multidetector coronary tomography. All subjects underwent maximal exercise treadmill testing with calculation of metabolic equivalents of task (METs) achieved as a measure of cardiorespiratory fitness. Results: Mean (SD) age was not different in men and women: 62.7 (7.9) and 64.4 (6.8) years, P=0.239, respectively. CAC scores were significantly lower in women compared to men: median [IQR]: 114.0 [27.5, 321.0] Agatston units vs 535.3 [182.9, 1367.4] respectively, (P<0.001) and were lower in women than men at any given age (Fig 1A). Female CAC scores did not equal those of men until women were 20 years older (Fig 1A). After adjustment for age, METs were associated with CAC scores in both men and women (Fig 1B). However, after multivariate adjustment for age, LDL-cholesterol, waist circumference, diabetes status and hypertension,, METs remained an independent predictor of CAC score in women (P=0.011) but not in men (P=0.223). Conclusions: Despite having known CAD, female CAC scores did not equal those of men until women were 20 years older. The independent association of METs with CAC score in women supports counseling women to exercise to maximize their cardiorespiratory fitness to minimize CAC scores. Since higher CAC scores predict adverse CVD events and mortality, lower CAC scores should protect women from development of CVD events and possibly lower their worse outcome.