Slowing HEART diSease With Lifestyle and Omega-3 Fatty Acids

Conditions

Coronary Heart Disease, Metabolic Syndrome

Keywords

Coronary heart disease, metabolic syndrome, CT angiography

Brief summary

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.

Detailed description

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.

Francine K. Welty, Essa Hariri, Abdul Aziz Asbeutah, Ralph Daher, Maral Amangurbanova et al. (9 authors)

Journal of the American Heart Association2023-09-089 citations

10.1161/jaha.123.030071

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.

Malik A, Ramadan A, Vemuri B, Siddiq W, Amangurbanova M, Ali A, Welty FK.

2021-05-0116 citations

10.1093/ajcn/nqaa420

Exercise Capacity, Coronary Artery Fatty Plaque, Coronary Calcium Score, and Cardiovascular Events in Subjects With Stable Coronary Artery Disease.

Malik A, Kanduri JS, Asbeutah AAA, Khraishah H, Shen C, Welty FK.

2020-03-269 citations

10.1161/jaha.119.014919

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

Abdulhamied Alfaddagh, Tarec K. Elajami, Hasan Ashfaque, Mohamad Saleh, Bruce R. Bistrian et al. (6 authors)

Journal of the American Heart Association2017-12-0289 citations

10.1161/jaha.117.006981

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

Tarec K. Elajami, Abdulhamied Alfaddagh, Dharshan Lakshminarayan, Michael Soliman, Madhuri Chandnani et al. (6 authors)

Journal of the American Heart Association2017-07-0148 citations

10.1161/jaha.116.004740

Interventions

DIETARY_SUPPLEMENTOmega 3 acid ethyl esters

Lovaza 3.6 g daily

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

21 Years to 80 Years

Healthy volunteers

No

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) \-

Design outcomes

Primary

Measure	Time frame	Description
The primary endpoint is change in coronary noncalcified plaque volume.	Baseline and 30 months	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.

Secondary

Measure	Time frame	Description
Effect of Lovaza on Physical Function, Pain, Stiffness and Exercise	Baseline and 1 year	Those on Lovaza will have better physical function and less pain and stiffness as assessed by the WOMAC questionnaire and more minutes of exercise per week compared to control
Inflammatory markers	Baseline and 30 months	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	Baseline and 30 months	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	Baseline and 30 months	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.
Coronary artery plaque assessment	Baseline and 30 months	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.
Vitamin D Levels and coronary plaque progression	Baseline and 30 months	1. Investigation of the relationship between vitamin D status and coronary plaque progression, insulin resistance (HOMA-IR), beta-cell function (HOMA-%beta) and inflammatory cytokines 2. Do baseline vitamin D levels predict response to omega-3 fatty acid supplementation?
Cognitive function	Baseline, 1 year and 30-months	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	Baseline	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	Baseline and 30-months	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.
Nonalcoholic steatohepatitis (NASH)	Baseline and 30 months	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.

Countries

United States

Outcome results

None listed