Slowing HEART diSease With Lifestyle and Omega-3 Fatty Acids (HEARTS)

• The primary endpoint is change in coronary noncalcified plaque volume. [ Time Frame: Baseline and 30 months ] [ Designated as safety issue: No ]
  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. The hypothesis is that those on Lovaza will have less progression of coronary plaque compared to those in usual care.
  
  

• Coronary artery plaque assessment [ Time Frame: Baseline and 30 months ] [ Designated as safety issue: No ]
  1. Percent atheroma volume calculated as the proportion of the entire vessel wall occupied by atherosclerotic plaque and total atheroma volume, normalized to segment length.
  2. Maximum percent diameter stenosis and minimal luminal diameter.
  3. Number of subjects with categorical variables of maximal stenosis >50% and number with 3-vessel disease >20%.
  4. Number of subjects with stenosis of 0-29%, 30-49%, 50-69% and >70% stenosis at baseline compared to 30 months.
  5. Change in remodeling index - ratio of plaque volume at the most diseased site compared to the least diseased site.
  
  
• Metabolic syndrome parameters [ Time Frame: Baseline and 30 months ] [ Designated as safety issue: No ]
  Those on Lovaza will have improvement in parameters of the metabolic syndrome assessed by measures of systolic and diastolic blood pressure, lipid profiles (total cholesterol, triglycerides, HDL and LDL) and abdominal adiposity (quantitated by computerized tomography) and waist/hip ratio compared to those in usual care.
  
  
• Inflammatory markers [ Time Frame: Baseline and 30 months ] [ Designated as safety issue: No ]
  Compared to usual care, those on Lovaza will have 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. Additional inflammatory markers may be identified in the future and measured.
  
  
• Pericardial Fat [ Time Frame: Baseline and 30 months ] [ Designated as safety issue: No ]
  The amount of pericardial fat will be quantitated by CT at baseline and 30-month follow-up. The percent change between the two time-frames will be measured. Those on Lovaza and/or those who have lost weight will have a reduction (or lack of increase) in pericardial fat at 30-months compared to those in usual care.
  
  
• Insulin Resistance [ Time Frame: Baseline and 30 months ] [ Designated as safety issue: No ]
  Insulin resistance will be assessed by fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) at baseline and 30-months in the two study groups.
  
  
• Nonalcoholic steatohepatitis (NASH) [ Time Frame: Baseline and 30 months ] [ Designated as safety issue: No ]
  Reduction of inflammation in the liver associated with nonalcoholic steatohepatitis (NASH), a 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.
  
  
• Improvement in Medications [ Time Frame: Baseline and 30 months ] [ Designated as safety issue: No ]
  Comparison of rates of addition of anti-hypertensive, diabetic, or lipid lowering medications will be made between the two study arms at baseline and 30-months of follow-up.
  
  
• New onset diabetes [ Time Frame: Baseline and 30 months ] [ Designated as safety issue: No ]
  Comparison will be made of the numbers of persons who progress to diabetes between the two study groups at 30-months of follow-up.
  
  
• Change in Metabolic Syndrome [ Time Frame: Baseline and 30 months ] [ Designated as safety issue: No ]
  Comparison of numbers of persons who regress from ATPIII metabolic syndrome criteria (for those with metabolic syndrome) will be made between baseline and 30-month follow-up in the two study groups.
  
  
• Vitamin D and coronary plaque [ Time Frame: Baseline and 30 months ] [ Designated as safety issue: No ]
  Investigation of the relationship between vitamin D status and coronary plaque (both non-calcified and calcified), as well as with insulin resistance (HOMA-IR), beta-cell function (HOMA-%beta), and serum levels of inflammatory cytokines and adhesion molecules, known to be related to CVD risk will be made at baseline and 30-months in the two study groups.
  
  
• Vitamin D levels and plaque progression [ Time Frame: Baseline and 30 months ] [ Designated as safety issue: No ]
  Determination of whether baseline vitamin D levels predicts clinical response to omega-3 fatty acid supplementation and whether hypovitaminosis D is associated with plaque progression.
  
  
• Cognitive function [ Time Frame: Baseline, 1 year and 30-months ] [ Designated as safety issue: No ]
  To determine if those on Lovaza have less decline in cognitive function at 1 year and 30 months of follow-up compared to those in the usual care group.
  
  
• Exercise capacity and coronary plaque [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  To determine if exercise capacity correlates with coronary plaque measurements. The hypothesis is that those with better exercise capacity will have lower amounts of coronary plaque.
  
  
• Urinary microalbumin and coronary plaque [ Time Frame: Baseline and 30-months ] [ Designated as safety issue: No ]
  At baseline, subjects with lower urinary microalbumin will have lower amounts of coronary plaque. Those taking Lovaza will have less increase in urinary microalbmumin at 30-month follow-up compared to those in usual care.
  
  
• Visceral Fat [ Time Frame: Baseline and 30-months ] [ Designated as safety issue: No ]
  Those who lose weight will have a decrease in the amount of visceral fat (as measured by CT) and improvement in waist-hip ratio compared to those in usual 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 intensive lifestyle intervention (exercise and nutrition counselling geared toward weight loss with 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 active lifestyle 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 lifestyle will be associated with:

1. Change in total plaque volume per patient.
2. Improvement in the metabolic syndrome assessed by measures of waist/hip ratio, systolic and diastolic blood pressure, lipid profiles (total cholesterol, triglycerides, HDL and LDL), and abdominal adiposity quantitated by computerized tomography.
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. Comparison of rates of addition of anti-hypertensive, diabetic, or lipid lowering medication.
7. Comparison of numbers of persons with metabolic syndrome who progress to diabetes between groups.
8. Comparison of numbers of persons who regress from ATPIII metabolic syndrome criteria.
9. Investigation of the relationship between vitamin D status and coronary calcification, as well as with insulin resistance (HOMA-IR), beta-cell function (HOMA-%beta), and serum levels of inflammatory cytokines and adhesion molecules, known to be related to CVD risk.
10. Determination of whether baseline vitamin D levels predict clinical response to the lifestyle intervention, and whether hypovitaminosis D is associated with plaque progression.