Lipoprotein Metabolism, PCSK9, Proteomics
Conditions
Keywords
LDL-C, Omega-3 Fatty Acid, PCSK9, HDL-C
Brief summary
Background: \- Metabolism is what the body does to turn food into energy. Omega-3 fatty acids are substances found in foods such as cold-water fish and shellfish that are essential for good health. Researchers want to see the effect of two fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on metabolism. They may be beneficial to cardiovascular health. Objective: \- To understand the effects of EPA and DHA on metabolism. Eligibility: \- Healthy people ages 18 years or above with plasma triglyceride (a type of fat in the blood) levels of 100 mg/dL or higher Design: * The study will last 20 to 24 weeks. * Participants will have 4 visits to the NIH Clinical Center. These will include: * Medical history * Physical Fasting blood and urine tests * CAVI tests: blood pressure is taken in the arms and legs, and the heart is monitored. * Participants will take an EPA/DHA dietary supplement. They will take 4 gel capsules, 3 times a day, for 6 or 7 weeks. Then they will not take the capsules for 8 to 10 weeks (a wash-out period). They will then take the capsules again for 6 or 7 weeks. * Participants will keep a food journal.
Detailed description
This is a novel randomized crossover, double-blinded pilot study that aims to investigate the effects of different omega-3 fatty acids, namely EPA and DHA, on lipoprotein metabolism. Subjects will be unblinded for performance of measurements after they complete the study. Subjects will receive EPA or DHA supplements for approximately 6 weeks with a wash out period of 8 weeks between the two arms of the study. The study consists of 4 outpatient visits when laboratory or research samples and CAVI tests will be performed. A 7-day food diary, pill count, and red cell membrane n-3 levels will be monitored to assess compliance. Serum cholesterol is transported by lipoproteins, such as VLDL, LDL and HDL, which vary in their relationship to cardiovascular risk. LDL is proatherogenic, whereas HDL is cardio-protective. Fish oil supplementation, such as EPA and DHA, has been shown to reduce triglycerides. EPA supplementation has also been shown to lower LDL-C, whereas DHA can raise both LDL-C and HDL-C. These differential effects on lipoproteins may alter the cardiovascular protection afforded by fish oil supplementation. This study will test the hypothesis that EPA and DHA may differ in their LDL-C lowering ability because of differences in how they modulate plasma PCSK9 levels, which is a major determinant of LDL-C levels. In addition, we will assess other parameters related to lipoprotein composition and function that may impact the cardioprotective effect of EPA and DHA. Other reported beneficial effects of omega-3 fatty acid supplementation, such as decreased platelet coagulability, markers of inflammation and changes in guy microbiota, will also be monitored.
Interventions
DRUGEPA-rich fish oil
4 gel capsules, 3 times/day for 6 weeks
4 gel capsules, 3 times/day for 6 weeks
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Male and female participants 18 years of age or above. * Subject must be healthy, with no known history of cardiovascular disease. * Subject understands protocol and provides written, informed consent in addition to a willingness to comply with specified follow-up evaluations.
Exclusion criteria
* Pregnancy, planned pregnancy (within the study period) or women currently breastfeeding. * Subjects with weight changes greater than 20% over the past 3 months. * Subjects planning a significant change in diet or exercise levels. * Subjects already consuming more than 1.5 g per day of Eicosapentaenoic Acid (EPA) or Docosahexaenoic Acid (DHA) in any form. * Subjects taking supplements or medications that affect lipoproteins for at least the past six weeks including fish oil supplements, bile-acid sequestrants, plant sterol supplements, fibrates, statins or Niacin. * Subjects diagnosed with cancer or IBD, or that have taken diarrhea inhibitors, laxatives or prebiotics in the week before stool sampling (optional), or antibiotics within 3 months before sampling. * Subjects taking daily aspirin or other anti-platelet or anti-coagulants agents (Plavix). * History of prostate Cancer * Subjects with known bleeding disorders (for example, Hemophilia) * Known sensitivity or allergy to fish, shellfish or omega-3 fatty acids supplements * Subjects with chronic diarrhea, gastric bypass or lap-band procedures, ostomies, bowel motility problems, or other conditions that could affect intestinal fat absorption * Subjects with any acute and life-threatening condition, such as prior sudden cardiac arrest, acute myocardial infarction (last three months), stroke, embolism * Liver enzymes (aspartate aminotransferase (AST) or alanine transaminase (ALT)) levels above 3x upper limit of normal * Subjects initiating new medications or patients on multiple medications may also be excluded according to investigator discretion * Subjects previously diagnosed with cardiac dysrhythmia * Subjects with clinically diagnosed hepatic disease (including but not limited to auto immune disease, hepatitis and cirrhosis) * Anticipated surgery during the study period * Blood donation in the last 2 weeks or planned blood donation during the study * Subjects requiring regular transfusions for any reason * Subjects may also be excluded for any reason that may compromise their safety or the accuracy of research data. * Subjects being treated with tamoxifen, estrogens, or progestins that have not been stable for \>4 weeks. * Subjects that thyroid stimulating hormone (TSH) levels are greater than 1.5 x Upper Limit of Normal (ULN) or clinical evidence of hypothyroidism
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma PCSK9 Levels at Baseline and End of 6 Week Intervention | baseline to 6 weeks of intervention | Measure plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) level, at baseline, after 6 weeks of Eicosapentaenoic acid (EPA) or Docosahexaenoic acid (DHA) fish oil supplementation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | Baseline to 6 weeks of intervention | Measure plasma levels at baseline to 6 weeks of intervention for the following: triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), lipoprotein particle composition and size, and high-density lipoprotein (HDL) cholesterol efflux capacity. |
Countries
United States
Participant flow
Recruitment details
44 participants enrolled on protocol. 5 of these 44 participants were considered screen failures. 39 participants started the protocol.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: EPA-rich Fish Oil, Then DHA-rich Fish Oil Eicosapentaenoic acid (EPA)-rich fish oil 4 capsules 3 times per day after meal for a total of 3g per day for 6 weeks, followed by an 8-week washout period. Then docosahexaenoic acid (DHA)-rich fish oil 4 capsules 3 times per day after meal for a total of 3g per day for 6 weeks. | 19 |
| Arm 2: DHA-rich Fish Oil, Then EPA-rich Fish Oil Docosahexaenoic acid (DHA)-rich fish oil 4 capsules 3 times per day after meal for a total of 3g per day for 6 weeks, followed by an 8-week washout period. Then Eicosapentaenoic acid (EPA)-rich fish oil 4 capsules 3 times per day after meal for a total of 3g per day for 6 weeks. | 20 |
| Total | 39 |
Baseline characteristics
| Characteristic | Arm 2: DHA-rich Fish Oil, Then EPA-rich Fish Oil | Total | Arm 1: EPA-rich Fish Oil, Then DHA-rich Fish Oil |
|---|---|---|---|
| Age, Continuous | 34 years STANDARD_DEVIATION 11.2 | 32 years STANDARD_DEVIATION 10.9 | 31 years STANDARD_DEVIATION 10.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 38 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 16 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 16 Participants | 9 Participants |
| Sex: Female, Male Female | 15 Participants | 24 Participants | 9 Participants |
| Sex: Female, Male Male | 5 Participants | 15 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 35 | 0 / 37 | 0 / 33 |
| other Total, other adverse events | 0 / 35 | 0 / 37 | 0 / 33 |
| serious Total, serious adverse events | 0 / 35 | 0 / 37 | 0 / 33 |
Outcome results
Primary
Plasma PCSK9 Levels at Baseline and End of 6 Week Intervention
Measure plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) level, at baseline, after 6 weeks of Eicosapentaenoic acid (EPA) or Docosahexaenoic acid (DHA) fish oil supplementation.
Time frame: baseline to 6 weeks of intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline | Plasma PCSK9 Levels at Baseline and End of 6 Week Intervention | 13.30 ng/mL | Standard Deviation 3.62 |
| EPA-rich Fish Oil | Plasma PCSK9 Levels at Baseline and End of 6 Week Intervention | 14.11 ng/mL | Standard Deviation 4.36 |
| DHA-rich Fish Oil Arm | Plasma PCSK9 Levels at Baseline and End of 6 Week Intervention | 12.44 ng/mL | Standard Deviation 3.48 |
Secondary
Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks
Measure plasma levels at baseline to 6 weeks of intervention for the following: triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), lipoprotein particle composition and size, and high-density lipoprotein (HDL) cholesterol efflux capacity.
Time frame: Baseline to 6 weeks of intervention
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Baseline | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | Triglyceride (TG) | 95.3 mg/dL | Standard Deviation 66.6 |
| Baseline | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | Total Cholesterol (TC) | 190.9 mg/dL | Standard Deviation 52.7 |
| Baseline | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | LDL-C | 110.1 mg/dL | Standard Deviation 49.6 |
| Baseline | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | Direct LDL-C | 115.7 mg/dL | Standard Deviation 48.6 |
| Baseline | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | Small Dense LDL | 36.1 mg/dL | Standard Deviation 19.9 |
| Baseline | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | LDL-TG | 13.1 mg/dL | Standard Deviation 4 |
| Baseline | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | HDL-C | 62 mg/dL | Standard Deviation 18.9 |
| Baseline | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | Direct HDL-C | 62.4 mg/dL | Standard Deviation 16.8 |
| Baseline | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | ApoE-HDL | 5.6 mg/dL | Standard Deviation 1.8 |
| EPA-rich Fish Oil | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | Small Dense LDL | 37.3 mg/dL | Standard Deviation 22.9 |
| EPA-rich Fish Oil | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | Triglyceride (TG) | 81.7 mg/dL | Standard Deviation 64.2 |
| EPA-rich Fish Oil | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | Direct LDL-C | 114.8 mg/dL | Standard Deviation 51.3 |
| EPA-rich Fish Oil | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | Direct HDL-C | 60 mg/dL | Standard Deviation 14.8 |
| EPA-rich Fish Oil | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | Total Cholesterol (TC) | 191.1 mg/dL | Standard Deviation 49.5 |
| EPA-rich Fish Oil | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | LDL-TG | 12.9 mg/dL | Standard Deviation 4.3 |
| EPA-rich Fish Oil | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | ApoE-HDL | 5.4 mg/dL | Standard Deviation 1.6 |
| EPA-rich Fish Oil | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | HDL-C | 63.4 mg/dL | Standard Deviation 20.2 |
| EPA-rich Fish Oil | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | LDL-C | 111.4 mg/dL | Standard Deviation 49.8 |
| DHA-rich Fish Oil Arm | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | LDL-TG | 12.8 mg/dL | Standard Deviation 4 |
| DHA-rich Fish Oil Arm | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | HDL-C | 63.4 mg/dL | Standard Deviation 20.4 |
| DHA-rich Fish Oil Arm | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | Direct LDL-C | 120.6 mg/dL | Standard Deviation 49.6 |
| DHA-rich Fish Oil Arm | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | ApoE-HDL | 5.9 mg/dL | Standard Deviation 1.9 |
| DHA-rich Fish Oil Arm | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | Small Dense LDL | 39.1 mg/dL | Standard Deviation 23.6 |
| DHA-rich Fish Oil Arm | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | LDL-C | 113.8 mg/dL | Standard Deviation 52.5 |
| DHA-rich Fish Oil Arm | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | Triglyceride (TG) | 82.1 mg/dL | Standard Deviation 57.9 |
| DHA-rich Fish Oil Arm | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | Direct HDL-C | 63.9 mg/dL | Standard Deviation 17.7 |
| DHA-rich Fish Oil Arm | Plasma Levels in Triglyceride, Cholesterol, and Lipoprotein From Baseline to 6 Weeks | Total Cholesterol (TC) | 193.5 mg/dL | Standard Deviation 54.4 |