The purpose of the study is to target inflammation to reduce progression of noncalcified plaque in the coronary arteries using omega-3 fatty acid supplementation compared to standard of care.

Study Design: This is a randomized, parallel study design with a usual care control group. 278 subjects with coronary heart disease (CHD) are being randomized to omega-3 supplementation or standard of care (139 in each arm).

Multidetector computed tomographic angiography (MDCTA) is performed at baseline to quantitate the amount of noncalcified and calcified coronary plaque and again at 30 month follow-up to determine if there has been a change in the volume of noncalcified or total plaque. The primary endpoint is change in coronary noncalcified plaque volume during the 30 months of intervention between active and standard of care.

Hypothesis: Percent change in progression of coronary plaque volume will be less for the omega-3 fatty acid intervention compared to standard of care.

Secondary endpoints include plasma levels of inflammatory markers, lipids and measures of insulin sensitivity.

Secondary outcomes include testing the hypothesis that targeting inflammation with omega-3 fatty acids will be associated with:

1. Change in total plaque volume per patient.
2. improvement in physical function and exercise and reduction in pain and stiffness as measured by the WOMAC questionnaire
3. Reduction of mediators of inflammation in the circulation including CRP, PAI-1, serum amyloid A, MMP-9 and fibrinogen, pro-inflammatory cytokines including IL-6, TNF-a and IL-1b, the adhesion molecules VCAM-1 and ICAM-1, increase in adiponectin and reduction in serum nitrotyrosine as a marker of oxidative stress.
4. Reduction of insulin resistance assessed by fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR).
5. Reduction of inflammation in the liver associated with nonalcoholic steatohepatitis (NASH), a newly recognized component of the metabolic syndrome, and reduction of fatty liver quantitated by computerized tomography and levels of AST and ALT as markers of liver inflammation related to NASH.
6. Investigation of the relationship between vitamin D status and coronary plaque progression as well as with insulin resistance (HOMA-IR), beta-cell function (HOMA-%beta) and inflammatory cytokines.
7. Determination of whether baseline vitamin D levels predict clinical response to the omega-3 fatty acid intervention, and whether hypovitaminosis D is associated with plaque progression.

Inclusion Criteria:

1. coronary artery disease
2. previous myocardial infarction
3. angioplasty (> 6 months ago)
4. previous coronary bypass surgery (> 12 months ago)
5. stable angina
6. non-calcified plaque on prior CT
7. abnormal exercise tolerance test
8. aged 21- 80 years
9. BMI ≥ 27 kg/m2 and ≤ 35 kg/m2 if female and ≤ 40 kg/m2 if male (a BMI > 24.5 for subjects from Asian origin)
10. stable dose of statin for 1 month at screening or unable to tolerate a statin
11. normal renal function - estimated creatinine clearance calculated using Cockcroft-Gault (CG) equation ≥60 at screening [eCrCLCG (ml/min) = [(140 - age) x weight (kg)]/[SCr(mg/dl) x 72] x [0.85 if female] or serum Cr < 1.3
12. ALT, AST) < 3 times upper limits of normal)
13. normal thyroid function or on stable dose replacement therapy
14. an ETT performed within 12 months prior

Exclusion criteria

1. unstable angina (increase in frequency or severity of anginal episodes or development of chest pain at rest)
2. significant obstructive disease in left main coronary artery, ostial LAD or newly diagnosed three-vessel disease since prior cardiac catheterization by MDCTA
3. significant heart failure (NYHA class III and IV)
4. Current atrial fibrillation or Wolf-Parkinson-White (WPW) syndrome
5. allergy to beta-blocker in subjects with resting heart rate > 65 bpm
6. systolic blood pressure > 160 mm Hg
7. diastolic BP > 100 mm Hg
8. persons with allergies to iodinated contrast material or shellfish
9. allergy to nitroglycerin
10. history of asthma only if unable to tolerate beta-blockers
11. BMI > 35 kg/m2 if female and > 40 kg/m2 if male
12. body weight > 350 lbs
13. Use of drugs for weight loss [eg Xenical (orlistat), Meridia (sibutramine), Acutrim (phenylpropanolamine) or similar over-the-counter medications] within three months of screening
14. surgery within 30 days of screening
15. history of acquired immune deficiency syndrome or human immunodeficiency virus (HIV)
16. poor mental function or history of dementia/Alzheimer's Disease or on medications used for treatment of dementia [e.g. Tacrine (Cognex), Rivastigmine (Exelon), Galantamine (Razadyne, Reminyl), Donepezil (Aricept), Memantine (Namenda)] or any other reason to except patient difficulty in complying with the requirements of the study
17. medicine for erectile dysfunction within 72 hours prior to MDCTA
18. Prior stroke with residual cognitive deficit or functional deficit preventing any type of exercise
19. Current chemotherapy or radiation for malignancy
20. Current weekly alcohol consumption > 21 units/week (1 unit = 1 beer, 1 glass of wine, 1 mixed cocktail containing 1 ounce of alcohol)

Exclusions based on nuclear imaging:

1. Transient cavity dilation
2. More than one vascular territory involved with reversible defect (multiple defects)
3. Reversible defects involving the anterior wall, septum or apex (LAD territory)

Exclusions based on echocardiography imaging:

1. More than one vascular territory involved with inducible wall motion abnormalities (multiple defects) 2. Inducible wall motion abnormalities involving the anterior wall, septum or apex (LAD territory)

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