Slowing HEART diSease With Lifestyle and Omega-3 Fatty Acids

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)