Category: Omega-3

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Why and How To Lower Triglycerides in People at Risk of Heart Disease

Estimated reading time: 11 minutes

Triglycerides are important organic compounds. Most of the fat we consume in our diet is triglyceride and so is most of the fat we store in our body.

Fatty acids contained in triglycerides are an essential source of energy for human cells.

Triglyceride concentration can be measured in blood and may provide valuable information about metabolism and general health. High levels may reflect underlying metabolic disorders and evidence shows that high blood triglycerides are associated with increased risk of heart disease (1,2,3).

However, association only means that there is a correlation between two or more variables. In this case, the higher the blood triglycerides, the higher the risk of developing heart disease.

Hence, discovering an association between variables does not prove a causative relationship. Here, a correlation between triglyceride levels and the risk of heart disease does not prove that triglycerides cause heart disease. Nor does it prove that lowering them will prevent disease.

Interestingly, when it comes to assessing the risk of cardiovascular disease, triglycerides have always played second fiddle to cholesterol.

As a result, dietary advice for people with heart disease usually aims at lowering blood cholesterol, particularly LDL-cholesterol. Targeting LDL- cholesterol has become common practice.

Therefore, replacing saturated fat with polyunsaturated and monounsaturated fats, and increasing the intake of food products rich in fiber and complex carbohydrates such as whole grains, is usually recommended.

Interestingly, it may be tricky to address triglycerides at the same time as LDL cholesterol. The reason is that a diet that lowers LDL cholesterol may raise triglycerides and vice versa. For example, low-fat diets may lower LDL cholesterol but are less effective in lowering triglycerides compared to low-carbohydrate diets (4).

Another reason why main stream medicine has tended to ignore triglycerides is that the pharmaceutical industry has shown limited interest in developing drugs that influence triglycerides. However, this may have changed recently with the publication of the highly important REDUCE-IT trial (5).

Triglyceride-Rich Lipoproteins

High blood levels of triglycerides are most often associated with high levels of the two most important triglyceride-rich lipoproteins; chylomicrons and very low density lipoproten (VLDL).

The main role of these lipoproteins is to transport triglycerides and other types of lipids, such as cholesterol, in the circulation.

Triglycerides are composed of three molecules of fatty acids attached to a glycerol molecule.

Chylomicrons are formed in the intestine after a meal. They contain triglycerides and small amounts of cholesterol.

Chylomicrons are subsequently broken down by an enzyme called lipoprotein lipase into free fatty acids that are utilized for energy production by the heart and skeletal muscles or stored in fat (adipose) tissue.

The chylomicron remnants are then removed from the circulation by liver cells.

VLDL is produced by liver cells. It transports both triglycerides and cholesterol. Once in the circulation, VLDL is broken down by lipoprotein lipase in capillary beds, releasing triglycerides for energy utilization by cells or storage in adipose tissue.

The composition of VLDL changes when triglycerides have been released. VLDL then becomes becomes intermediate-density lipoprotein (IDL). Later, when the amount of cholesterol increases, IDL becomes low-density lipoprotein (LDL).

Triglyceride-Rich Lipoproteins Are Associated With Inflammation and Atherosclerosis

Triglyceride rich lipoproteins are associated with inflammation and increased atherosclerosis (6).

High levels of chylomicrons increase the risk of acute pancreatitis, an inflammation of the pancreas. Chylomicron and VLDL remnants increase inflammation of the endothelium (the innermost layer of the artery).

Chylomicron remnants and VLDL remnants have been shown to rapidly penetrate the arterial wall and promote atherosclerosis (7).

Recent data suggests that VLDL cholesterol or remnant cholesterol is a stronger promoter of atherosclerosis than LDL cholesterol (8).

Definition of Normal and High Levels of Triglycerides

Blood levels of triglycerides are stratified according to population data and their associated risk of coronary artery disease.

In the USA, triglycerides are measured in mg/dL but in Australia, Canada, and most European countries they are measured in mmol/L.

To convert from mg/dL to mmol/L, divide by 88.5

Here is how triglyceride levels are looked at in terms of cardiovascular risk:

Normal: <150 mg/dL (1.7 mmol/L)

Borderline high: 150 to 199 mg/dL (1.7 to 2.2 mmol/L)

High: 200 to 499 mg/dL (2.3 to 5.6 mmol/L)

Very high: ≥500 mg/dL (≥5.7 mmol/L)

The term hypertriglyceridemia is used to describe high blood levels of triglycerides.

Hypertriglyceridemia is a relatively common disorder. In the United States, 33 percent of adults have triglyceride levels above 150 mg/dl (1.7 mmol/L) and 18 percent have levels above 200 mg/dl (2.3 mmol/L)(9).

Fasting and Non-Fasting Levels of Triglycerides

Following a fatty meal, blood levels of triglycerides will rise. Hence, raised blood triglycerides following a meal (postprandial hypertriglyceridemia) are caused by chylomicrons produced in the intestine.

Chylomicrons disappear from the circulation soon after the triglycerides have been delivered to the tissues.

Moderate fasting hypertriglyceridemia is usually due to increased VLDL production by the liver. This is often a result of excessive carbohydrate intake.

Triglycerides may also become elevated with obesity, physical inactivity, smoking, diseases such as diabetes and renal failure, drugs such as estrogen, tamoxifen and corticosteroids, and genetic disorders (familial hypertriglyceridemia, familial combined hyperlipidemia, and familial dysbetalipoproteinemia).

There are several types of familial hypertriglyceridemia. These disorders are associated with increased risk of coronary artery disease (10) which appears independent of cholesterol levels (11).

Serum triglyceride values above 1000 mg/dL (11 mmol/L) are rare (less than 1/5000 individuals). The serum in these patients is opalescent due to an increase in VLDL or milky due to elevated chylomicrons.

Triglycerides and Cardiovascular Disease

Despite evidence that chylomicron and VLDL remnants promote atherosclerosis, the importance of lowering triglycerides has so far not been considered a priority for patients with coronary heart disease.

However, several conditions associated with high triglycerides, such as insulin resistance, a preponderance of small LDL particles, and low HDL- cholesterol, may play an important role in the development of atherosclerosis.

Reduced activity of lipoprotein lipase, which is common in insulin resistance, may slow the clearance of triglyceride-rich lipoproteins from the circulation.

VLDL remnants may enter the vessel wall or be converted to small LDL particles. Small LDL particles tend to circulate for a longer duration where they become susceptible to oxidation, glycation, and glyco-oxidation leading to increased risk of atherosclerosis.

Small dense LDL particles appear more strongly associated with the risk of cardiovascular events than larger particles (12,13). 

In the so-called SCRIP trial, high triglyceride levels were associated small, dense particles in 90 percent of subjects whereas lower triglyceride levels were associated with larger buoyant particles in 90 percent of subjects (14).

Recent genetic studies have addressed the relationship between triglyceride-rich lipoproteins and the risk of cardiovascular events. The results of one of these studies imply that the elevated cholesterol content of triglyceride-rich lipoprotein particles may cause coronary heart disease (15).

Another study found that a genetic mutation associated with low blood levels of triglycerides was associated with less risk of cardiovascular disease (16).

These studies strongly support the hypothesis that high blood levels of triglycerides may increase the risk of cardiovascular disease and that low levels may be protective.

The REDUCE-IT Trial – A Landmark Cardiovascular Study

The results of the REDUCE-IT trial were recently published in the New England Journal of Medicine and The Journal of the American College of Cardiology) (5,17).

The study randomized 8,179 statin-treated patients with triglycerides ≥135 and <500 mg/dL and LDL-cholesterol >40 and ≤100 mg/dL , and a history of atherosclerosis (71% patients) or diabetes (29% patients) to icosapent ethyl 4g/day or placebo.

Icosapent ethyl is a highly purified and stable EPA ethyl ester that has been shown to lower triglyceride levels.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the two most common long chain n-3 polyunsaturated fatty acids (PUFAs) in fish oil. Both are omega-3 fatty acids.

The primary cardiovascular outcome of cardiovascular death, nonfatal myocardial infarction, stroke, coronary revascularization, or unstable angina, for icosapent ethyl vs. placebo, was 17.2% vs. 22.0%. The absolute risk reduction of 4.8% is highly significant.

Triglyceride levels were lowered at one year by 39.0 mg/dl vs. 4.5 mg/dl on on icosapent ethyl vs. placebo. LDL cholesterol was lowered by 2 mg/dl vs. 7 mg/dl.

The rate of cardiovascular death was 9.6% vs 12.4 % on icosapent ethyl vs. placebo which is statistically significant. All-cause mortality was 6.7% vs. 7.6%, which is not statistically significant.

The risk of atrial fibrillation/flutter was 5.3% vs 3.9% and the risk of serious adverse bleeding was 2.7% vs. 2.1% on icosapent ethyl vs. placebo

Why Is the REDUCE-IT Trial so Important?

The large number of important ischemic events averted with icosapent ethyl, including a significant reduction in fatal and nonfatal stroke (28%), cardiac arrest (48%), sudden death (31%), and cardiovascular death (20%), is indicative of a very favorable risk- benefit profile

Although several mechanisms may explain the efficacy of the drug it has to be assumed that the lowering of blood triglycerides is the most important.

The study results are in stark contrast to cardiovascular outcome studies with other agents that lower triglyceride levels and with low-dose omega-3 fatty acid mixtures, where cardiovascular outcome benefit has not been consistently observed in statin-treated patients (17).

The distinction of the cardiovascular benefits observed in REDUCE-IT from the lack of cardiovascular benefits observed in statin-treated populations with add-on omega-3 fatty acid mixtures may likely be due to the high EPA levels.

EPA has unique lipid and lipoprotein, anti-inflammatory, anti-platelet, anti-thrombotic, and cellular modifying effects.

REDUCE-IT is the first trial to show that lowering triglycerides without affecting LDL-cholesterol significantly improves clinical outcome in high risk patients.

With the rapidly increasing prevalence of central obesity and metabolic syndrome , targeting triglycerides me even become more important in the near future.

Whether targeting triglycerides by dietary measures will improve cardiac outcome remains to be proven.

However, it would be naive to believe that dietary measures that tend to lower triglycerides are less important than those intended to lower LDL-cholesterol.

The Management of High Triglycerides

Non-Pharmacological Therapy

Lifestyle modification is the first-line therapy for people with elevated triglycerides.

Many individuals with high triglycerides have insulin resistance and metabolic syndrome. In these cases, hypertriglyceridemia is often associated with visceral obesity low levels of HDL cholesterol, high blood pressure and type 2 diabetes.

In mild to moderate hypertriglyceridemia, losing weight and reducing carbohydrate intake (especially high glycemic index foods and high fructose foods) can lower VLDL and triglycerides.

For these patients, weight loss, regular physical exercise, and avoidance of added sugars (18) are all important. Other risk factors such as smoking and high blood pressure should also be addressed (19).

Fatty acids used by the liver to produce VLDL are derived mainly from two sources.

Firstly, during conditions such as obesity, diabetes, and insulin resistance, there is increased fatty acid flux from adipose tissue to the liver. Secondly, there is an increased de novo synthesis of fatty acids in the liver mainly from carbohydrates.

For this reason, in mild to moderate hypertriglyceridemia, losing weight and reducing carbohydrate intake (especially high glycemic index foods and high fructose foods) can lower VLDL and triglycerides.

Dietary fat is not a significant source of liver triglyceride (20), and high fat diets usually don’t raise fasting triglycerides.

The situation may be different in more severe hypertriglyceridemia (above 500 to 1000 mg/dL (5.6 to 11.3 mmol/L)), where the clearance of chylomicrons becomes very slow. Under these circumstances, it is crucial to reduce dietary fat intake to lower triglycerides.

It is necessary for patients with severe hypertriglyceridemia to avoid alcohol abuse as it can cause substantial increases in triglyceride levels and cause acute pancreatitis.

Pharmacological Therapy

Several drugs are used for the management of hypertriglyceridemia.

Although statins are not very effective for lowering triglycerides per se, they are often used to reduce the risk of cardiovascular events in patients with hypertriglyceridemia.

One of the most commonly used drug to lower triglycerides is gemfibrozil (21).

Gemfibrozil belongs to a group of drugs called fibrates which lower triglycerides by increasing the synthesis of lipoprotein lipase which increases the clearance of triglycerides. 

Fibrate therapy with either fenofibrate or gemfibrozil can reduce triglyceride levels by 20 to 50 percent. In severe hypertriglyceridemia, gemfibrozil may lower triglycerides as much as 70 percent (22).

In the Helsinki Heart Study, a clinical benefit of gemfibrozil therapy was found in the group with a triglyceride level >201 mg/dL (2.3 mmol/L) and an LDL-C/HDL-C ratio >5.0 (23).

The VA-HIT trial assessed the efficacy of gemfibrozil in patients with low HDL cholesterol, relatively low LDL cholesterol, and mild to moderate hypertriglyceridemia (24). Gemfibrozil raised HDL cholesterol by 6 percent, lowered triglycerides by 31 percent, but had no significant effect on LDL cholesterol. At five years, there was an absolute risk reduction of 4.4 percent with gemfibrozil.

In the ACCORD Lipid trial, fenofibrate improved outcomes in type 2 diabetes in a subset of patients with elevated triglyceride levels and low HDL cholesterol (25).

Nicotinic acid at doses of 1500 to 2000 mg daily can reduce triglyceride levels by 15 to 25 percent (26). However, studies supporting a clinical efficacy of nicotinic acid are lacking. There is data suggesting worsening of glycemic control when nicotinic acid is administered to patients with type 2 diabetes (27).

The AIM-HIGH trial studied the addition of nicotinic acid to statin therapy in patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of less than 70 mg/dL (1.81 mmol/L)(28). 

There was no incremental clinical benefit from the addition of nicotinic acid during a 36-month follow-up period, despite significant improvements in HDL cholesterol and triglyceride levels.

Intake of fish oil (29) can lower blood triglycerides by as much as 50 percent (30). Relatively high doses of omega-3 fatty acids (EPA + DHA) are needed to achieve this effect (up to 3-4 g/day).

Lovasa (Omecor) and icosapent ethyl (Vascepa) are commercial preparations of omega-3 fatty acids that can lower blood triglycerides by as much as 45 percent (31,32).

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VLDL – The Role of Triglyceride-Rich Lipoproteins and Remnant Cholesterol

Estimated reading time: 9 minutes

Knowing the role of VLDL (very low-density lipoprotein) and chylomicrons is a key factor in understanding how lipids (fats) and lipoproteins are involved in atherosclerotic cardiovascular disease (ASCVD).

In the current era of adiposity and metabolic disease, VLDL has gained a bigger role than before and may help explain many of the disorders associated with the obesity epidemic such as non-alcoholic fatty liver disease (NAFLD), type-2 diabetes, hypertension, and heart disease.

Lipoproteins are important biochemical substances whose main purpose is to carry lipids from one tissue to another. VLDL is produced by liver cells and is an important carrier of triglycerides (TGs) and to a lesser extent cholesterol. Once in the circulation, VLDL is broken down in capillary beds by an enzyme called lipoprotein lipase, releasing lipids, mainly TGs, for energy utilization by cells or storage in adipose tissue.

Lipids can not be transported in blood on their own because of their insolubility in water. The lipoproteins may be regarded as transportation vehicles for lipids, hence making them soluble in blood. TGs, cholesteryl esters, free cholesterol, and phospholipids are the major lipids carried by the lipoproteins

A lipoprotein particle usually consists of a single outer layer of phospholipid covering a central core of TGs and cholesteryl esters. The proteins on the surface of the lipoprotein particle are termed apolipoproteins. Apolipoproteins help stabilize the lipoprotein structure, and they play a key role in lipoprotein metabolism. Apolipoprotein A (apoA), apolipoprotein B (apoB), apolipoprotein C (apoC), an apolipoprotein E (ApoE) are the four major lipoproteins.

Lipoproteins are usually classified based on their density by ultracentrifugation into five classes; chylomicrons, VLDLs, intermediate-density lipoproteins (IDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs). Chylomicrons, IDL’s, and VLDLs are TG-rich lipoproteins, while LDLs and HDLs contain abundant cholesterol.

Another lipoprotein, Lipoprotein (a), not included in the traditional biochemical classification of lipoproteins, is of importance as well. However, measurements of Lipoprotein(a) are not widely available and seldom used in routine clinical practice, despite the fact that it is a strong risk marker for ASCVD.

Most of us learn about the lipoproteins because of their association with cholesterol. Measurements of blood cholesterol are frequently performed to assess cardiovascular risk. The amount of cholesterol carried by LDL, or LDL-cholesterol (LDL-C), is used worldwide to estimate the risk of ASCVD and lowering LDL-C has emerged as an important target to reduce risk.

However, recent research suggests that TG-rich lipoproteins, such as VLDL and IDL may also play a significant role in the development of ASCVD (1).

Triglyceride Absorption and Metabolism – The Role of Triglyceride-Rich Lipoproteins

Triglycerides consist of three molecules of fatty acids attached to a glycerol molecule.

Most of the fat we consume in our diet is TG. TGs consist of three molecules of fatty acids attached to a glycerol molecule.

When TGs enter the small intestine, they are emulsified and enzymatically digested to yield monoglyceride and fatty acids, both of which can enter cells found in the intestinal wall called enterocytes. From there, the lipids have to be transported into blood to be utilized by the body.

Once inside the enterocyte, fatty acid and monoglyceride are used to synthesize TGs again. The TGs are then combined with phospholipids, cholesterol, and apolipoproteins to form a chylomicron.

Chylomicrons are formed by enterocytes in the small intestine. They carry triglyceride, cholesterol, and phospholipids via the lymphatic system from where they enter the bloodstream.

Chylomicrons

The production of chylomicrons by the enterocytes takes place in an intracellular organ called the endoplasmic reticulum.

Phospholipids and apolipoproteins are used to construct a one layered membrane and the TGs and cholesterols are packaged inside this membrane. The spherical ball of outer phospholipid and protein with cholesterol and TG inside (away from the watery environment of the cell) is the chylomicron (2).

The chylomicrons enter lymphatic vessels from where they are transported to the bloodstream through the lymphatic system

Thus, the chylomicrons are the vehicles that enable the transport of lipids such as cholesterol, phospholipids, and TGs from the cells of the small intestine to the blood circulation.

A blood sample drawn after a fatty meal often looks milky due to the presence of chylomicrons. However, chylomicrons disappear from the circulation soon after the TGs are delivered to the tissues. The process may take few hours.

The liver is responsible for the removal of chylomicron remnants from the circulation.

Very Low-Density Lipoprotein (VLDL)

The primary role of chylomicrons is to transport digested lipids to the tissues of the body following a meal. Hence, chylomicrons are not needed in the fasting state, and they usually disappear within a few hours following a fatty meal.

However, TGs will still have to be transported between tissues in the absence of chylomicrons. TGs from the liver and adipose tissue need to be mobilized for fatty acids to be available as fuel for the cells of the body. VLDL is the leading carrier of TG within the circulation.

VLDL is produced by the liver. It carries both cholesterol and triglycerides. The ratio of the mass of TG to that of cholesterol in VLDL is about 5:1. The main lipoproteins in VLDL are ApoB-100, ApoC and ApoE.

VLDL is produced by the liver. It carries both cholesterol and TGs. The ratio of the mass of TG to that of cholesterol in VLDL is about 5:1. The main apolipoproteins in VLDL are ApoB-100, ApoC and ApoE.

The fatty acids used by the liver to produce VLDL are derived mainly from two sources. Firstly, during conditions such as obesity, diabetes, and insulin resistance, there is increased fatty acid flux from adipose tissue to the liver. Secondly, there is an increased de novo synthesis of fatty acids in the liver mainly from carbohydrates.

Hence, high blood levels of VLDL are associated with metabolic syndrome and insulin resistance (3). Furthermore, high consumption of added sugar and refined carbohydrates will promote VLDL production by the liver, a phenomenon, known as carbohydrate-induced hypertriglyceridemia. Feeding a high carbohydrate diet increases the production rate and reduces the clearance rate of VLDL particles.

High consumption of added sugar and refined carbohydrates will promote VLDL production by the liver, a phenomenon, known as carbohydrate-induced hypertriglyceridemia.

Carbohydrate-induced hypertriglyceridemia may seem paradoxical because the increase in dietary carbohydrate usually comes at the expense of dietary fat. Thus, when the content of the carbohydrate in the diet increases, fat in the diet decreases, but the TG content in the blood still rises (4).

Dietary fat, on the other hand, is not is not a significant source of liver TG (5), and high-fat diets usually don’t raise fasting TGs.

After the release of triglycerides from VLDL, its composition changes and it becomes IDL. IDL is also defined as a TG-rich lipoprotein. Later, when the amount of cholesterol increases, IDL becomes LDL.

High concentration of TG-rich lipoproteins is associated with low levels of HDL-cholesterol (HDL-C). This is partly a result of an exchange of lipids between TG-rich lipoproteins and HDL, leading to TG-enriched HDL particles low in cholesterol. There is an association between low levels of HDL-C and increased risk of ASCVD (6).

TG-Rich Lipoproteins, Remnant Cholesterol, and Atherosclerotic Cardiovascular Disease

TG-rich remnant lipoproteins can penetrate the arterial wall and are easily retained. The entrapment of lipoproteins within the vascular wall may be a key factor in promoting atherosclerosis (7).

It has been suggested that the risk associated with TG-rich lipoproteins is mainly due to their cholesterol content, often called remnant cholesterol (8). Because of their larger size, TG-rich lipoproteins carry 5 to 20 times as much cholesterol per particle as LDL.

One study found that a nonfasting remnant cholesterol increase of 1 mmol/l (39 mg/dl) is associated with a 2.8-fold causal risk for coronary heart disease (9).

Patients at increased risk of ASCVD often have a lipoprotein profile characterized by elevated plasma TG-rich lipoproteins, a predominance of small LDL particles, and low HDL-C. This lipid pattern is typical for patients with insulin resistance and metabolic syndrome.

Apolipoprotein C-III (Apo C-III) is found on the surface of TG lipoproteins. There is an association between high levels of apo-C-III and high TG levels and increased risk of ASCVD. Apo-C-III may contribute to the development of atherosclerosis by several mechanisms. The gene most strongly associated with plasma triglyceride levels is the gene encoding for apo-C-III, called APOC3 (10).

There is overwhelming evidence for VLDL and especially for VLDL remnants being an important contributor to ASCVD (11). It has been suggested that reducing plasma remnant lipoproteins rather than LDL should be the target for patients with metabolic syndrome.

How To Reduce VLDL

Measurements VLDL or VLDL-cholesterol (VLDL-C) are seldom performed in clinical practice. However, it is possible to estimate VLDL-C from the TG levels. As the ratio between TG and cholesterol in VLDL is usually 5:1, it can be assumed that VLDL-C is 1:5 of the TG value.

As VLDL is the main carrier of TG’s in the circulation, high VLDL is associated with high TG’s. So. the best way to reduce VLDL is to lower TG’s.

Following a fatty meal, blood levels of TG’s will rise.However, raised blood TG’s following a meal (postprandial hypertriglyceridemia)are caused by chylomicrons,whereas elevated fasting TG’s are due to VLDL produced from TG’s in the liver. The latter may often be a result of excessive carbohydrate intake.

Lifestyle modification is the first-line therapy for people with elevated TG’s and VLDL.

Many individuals with high TG’s have insulin resistance (3), often associated with visceral obesity, low levels of HDL-C, high blood pressure and type 2 diabetes. For these patients, weight loss, regular physical exercise, and avoidance of added sugars, high glycemic index foods, and high fructose foods are important measures (12). Other risk factors such as smoking and high blood pressure also have to be addressed (13).

The situation may be different in more severe hypertriglyceridemia (above 500 to 1000mg/dL (5.6 to 11.3 mmol/L)), where the clearance of chylomicrons becomes very slow. Under these circumstances, it may be crucial to reduce dietary fat intake to lower triglycerides.

It is necessary for patients with severe hypertriglyceridemia to avoid alcohol abuse as it can cause substantial increases in triglyceride levels and lead to acute inflammation of the pancreas (pancreatitis).

Intake of fish oil can lower blood TG’s by as much as 50 percent (14). Relatively high doses of omega-3 fatty acids (EPA + DHA) are needed to achieve this effect (up to 3-4 g/day).




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The Omega-3 Index

Estimated reading time: 8 minutes

Although regular intake of omega-3 fatty acids is believed to have several health benefits, some questions remain unanswered.

Do we all need more omega-3 or just some of us? Is eating fish sufficient or do we need to take supplements? Is there a way to tell if the cells in our body are getting enough omega-3 or if we are deficient? The Omega-3 Index may provide answers to some of these questions.

The Omega-3 Index reflects the relative amount of omega-3 fatty acids within red blood cell membranes. The index can be measured by specific analytical methods using a simple blood sample.

Studies show that a low Omega-3 Index is associated with increased risk of cardiovascular disease, and it has been proposed that raising the index may help to reduce risk.

The fats we consume in our diet are mainly triglycerides. Triglycerides are composed of three molecules of fatty acids attached to a glycerol molecule. The type of fatty acids in triglycerides determines the characteristics of fatty foods, such as whether it is solid or liquid at room temperature.

Triglycerides are composed of three molecules of fatty acids attached to a glycerol molecule.

Chemically, fatty acids are chains of carbon atoms with an organic acid (carboxyl) group (-COOH) at one end and a methyl group (-CH3) at the other end.

Fatty acids differ in chain length. Foods contain fatty acids with a chain length of 4 to 24 carbons, and most have an even number of carbons. Shorter fatty acids are more water soluble and more likely to be liquid.

Measurements of fatty acids in red blood cell membranes can provide important information about fatty acid intake. Recently, the relative amount of omega-3 fatty acids in red blood cells has attracted interest as it may provide information about the future risk of heart disease.

Red Blood Cell Fatty Acids and Omega-3 Index

Five main categories of fatty acids can be found in red blood cells; saturated fatty acids, monounsaturated fatty acids, omega-3 polyunsaturated fatty acids (n-3), omega-6 polyunsaturated fatty acids (n-6), and trans fats.

The omega-3 and omega-6 fatty acids can not be produced by the human body. These fatty acids must come from food and are therefore called essential fatty acids.

The omega-6 fatty acids have more than one double bond in their chain, the first one positioned at the sixth carbon atom from the acid end of the carbon chain. Examples are linoleic acid and arachidonic acid. All of the omega-6 fatty acids can be synthesized from linoleic acid, but linoleic acid itself can not be synthesized by the body and has to be provided in our diet.

Linoleic acid is typically found in vegetable oils (corn, safflower, soybean) and small amounts are found in canola, olive and flaxseed oils.

Omega-3 fatty acids are polyunsaturated fatty acids with a first double bond at the third carbon atom from the acid end of the chain. There are three main types; alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). ALA is found in many vegetable oils (rapeseed, flaxseed, and soybean), canola and olive oils, seeds, and nuts. EPA and DHA are typically found in fatty fish and fish oils.

The fatty acid status of red blood cells can be assessed from a blood sample using highly standardized analytical laboratory methodology. The test result reflects the amount of different fatty acids within the red blood cell membranes. Thus, we can tell how much of the fats is trans fat, saturated fat, omega 6, and omega-3 respectively.

The Omega-3 Index reflects the relative amount of EPA + DHA in red blood cells. It is expressed as the percentage of the total amount of fatty acids present. In fact it’s quite simple; if 8% of all the fatty acids present in red cell membranes is EPA+DHA, the Omega-3 Index is 8%.

From a methodological point of view, determining the Omega-3 Index has distinct advantages over determining levels of EPA+DHA in blood or plasma.

The Omega-3 Index and Cardiovascular Risk

It has been hypothesized that the Omega-3 Index may predict the risk of future cardiovascular events such as coronary heart disease and cardiac arrest. If that’s correct, a low Omega-3 Index may be regarded as a risk factor, similar to smoking, high blood pressure and high blood levels of LDL cholesterol.

The average Omega-3 Index in the United States is believed to be between 4-5 %. In Japan, where coronary artery disease is less common and life span longer, the average Omega-3 Index is 9-10% (1). In general, the Omega-3 Index is higher in countries that consume more omega-3 fatty acids.

The Seattle PCA study published in 1995 showed that compared with an Omega-3 Index of 3.3%  (the mean of the lowest quartile), an index of 5.0% (the mean of the third quartile) was associated with a 70% reduction in the risk of primary cardiac arrest (2). Similar results were found in the Physicians Health Study published 2002 (3).

In a 2004 publication, Harris and Von Schacky presented data from epidemiological studies and randomized controlled trials showing that the Omega-3 Index was inversely associated with the risk for mortality from coronary heart disease (4). An Omega-3 Index of ≥8% was associated with the greatest protection, whereas an index of ≤4% was associated with the least.

Another study, published 2008 showed that the Omega-3 Index as independently associated with the risk of developing acute coronary syndrome (5). The risk of acute coronary syndrome was 70% lower in individuals with Omega-3 Index > 8 compared with those with an index <4.

Results from The Heart and Soul Study published in Circulation 2010 showed that in patients with stable coronary heart disease, an Omega-3 Index below median was associated with significantly higher mortality than among patients with an index above median (6).

One study found that a higher omega-3 index is associated with increased insulin sensitivity and a more favourable metabolic profile in middle-aged overweight men (7).

All the above data suggest that the Omega-3 Index is inversely associated with the risk of cardiovascular disease. However, these studies don’t prove that there is a causative relationship between the Omega-3 Index and cardiovascular disease nor that improving the index will reduce risk.

What Is the Optimal Omega-3 Index and How Can It Be Improved?

An Omega-3 Index >8% is optimal while an index of <4% may be regarded as deficient.

The simplest way to improve the Omega-3 Index is to increase the intake of EPA and DHA by eating marine products rich in omega-3 fatty acids.

Studies show that the Omega-3 Index is influenced by intake of EPA and DHA: every 4 g of EPA and DHA ingested per month increased the Omega-3 Index by 0.24 % (8). The Omega-3 Index is also influenced by age, diabetes, body mass index, gender, physical activity, and some other factors, like social status and alcohol intake (9, 10).

Increased intake of EPA and DHA may have several health benefits (11).

A meta-analysis of 36 randomized trials (12) indicated that fish oils may reduce both systolic and diastolic blood pressure, especially among elderly people with hypertension. Studies also suggest that intake of fish oil lowers heart rate (13).

Several randomized studies have suggested that fish oil improves the function of the endothelium, the innermost layer of our arteries (14).

EPA and DHA are precursors to substances called eicosanoids. Eicosanoids are important regulators of inflammation. Therefore, many experts believe that fish oils may help to reduce chronic low-grade inflammation.

Although some studies have not been able to show that fish oil consumption reduces blood markers of inflammation, other studies (15) have suggested that they may do so when relatively high doses are given (> 2 g/day).

Intake of fish oil lowers blood levels of triglycerides by 25-30 percent (16). Relatively high doses are needed to achieve this effect (up to 3-4 g/day).

What Types of Fish Contains Most Omega-3 Fatty Acids?

Examples of fish that contains most amounts of omega-3 (EPA + DHA) are salmon, herring pickled, tuna Bluefin, mackerel, sardines (canned in oil) and oysters (steamed).

Examples of fish which contains intermediate amounts of omega 3 (EPA + DHA) are swordfish, rainbow trout, sea bass, crab king, walleye, tuna (canned in water) and flatfish.

Examples of fish that contains lower amounts of omega-3 (EPA + DHA) are Halibut, Northern lobster, clams, scallop, haddock, cod, mahi-mahi, shrimp, and catfish.

Recommendations For the Intake of Omega-3 Fatty Acids

For people without cardiovascular disease, most experts recommend eating a variety of fish (preferably oily) at least twice a week to maintain a mean intake of 4-500 mg of EPA+DHA daily.

For those with documented coronary heart disease, a daily dose of EPA+DHA of 1.000 mg per day is recommended, preferably from fish. This can be achieved by eating oily fish 4-5 times a week. Fish oil supplements may also be used.

Many fish oils supplements are available. Important questions have been asked regarding these supplements such as if they are contaminated or if they contain as much EPA+DHA as they say they do?

The International Fish Oil Standards Program may be helpful to check out the quality of different types of fish oils and omega-3 supplements.




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Fish Oil – Health Benefits of Omega-3 Explained

Estimated reading time: 10 minutes

Fish oil is one of the most commonly used dietary supplement.

It has been recommended by some major societies and public health authorities for cardiovascular risk modification, to treat high blood triglycerides and as a treatment following acute myocardial infarction (heart attack).

However, many questions remain unanswered. How does fish oil improve health? Is the evidence strong enough to recommend its use? Should it be recommended to everyone or only those at increased risk of heart disease? Are there any side effects? What’s the optimal daily dose? Is consuming oily fish enough or do we need additional fish oil supplement?

History

More than forty years ago, Danish scientists found that the total amount of fat in the diet of Americans, Danes and Greenland Eskimos was similar (1).

At the same time they reported that the death rate from coronary artery was much lower among the Greenland Eskimos, compared with the Americans and Danes.

While visiting Greenland and studying the diet of the native Eskimos, the Danish researchers found that their diet was indeed quite different from that in the US and Denmark.

The fat content of the native diet was largely from whale blubber, seal fat, and fish fat, all very high in omega-3 fatty acids.

The scientists attributed the low death rate from heart disease among the Eskimos to the high consumption of marine-derived omega-3 fatty acids.

Recently, a Canadian paper (2) claimed that the Danish researchers may have underestimated the incidence of coronary artery disease among the Inuits, and therefore their conclusions may not be valid. However, these early studies sparked a great amount of interest among scientists in the possible cardiovascular benefits of omega-3 fatty acids.

Since then, scientific studies have have identified two types of long chain omega-3 polyunsaturated fatty acids in fish oils as the most likely active constituents behind the positive health effects of seafood. These are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

Omega-3 Fatty Acids

The body can synthesize most fatty acids as it needs them. Therefore, it is not necessary to get them in the diet.

Some fatty acids cannot be produced by the human body. This is true for the omega-6 and omega-3 fatty acids. These fatty acids must come from food and are therefore called essential fatty acids.

Omega-3 fatty acids are polyunsaturated fatty acids with a double bond at the third carbon atom from the end of the carbon chain. There are three main types; alpha-linolenic acid (ALA), EPA and DHA. ALA is found in many vegetable oils (rapeseed, flaxseed, and soybean), seeds and nuts. EPA and DHA are typically found in fatty fish and fish oils.

Docosahexaenoic acid (DHA) is a chain of 22 carbon atoms with six double bonds (22:6)

ALA is an 18-carbon fatty acid with three double bonds (18:3). It can be elongated and desaturated in the body to EPA with 20 carbon atoms and five double bonds (20:5) and DHA with 22 carbons and six double bonds (22:6).

However, for these reactions to occur it must compete with omega-6, so only a fraction of ALA is converted to EPA and DHA.

Like other dietary fatty acids, EPA and DHA are transported in the circulation mainly as triglycerides in lipoprotein particles. These two fatty acids are incorporated into phospholipids in cell membranes throughout the body, particularly in the heart and brain. They are also stored in fat tissue as triglycerides.

The Effects of Fish Oil on Health and Cardiovascular Disease Mechanisms

The intake of marine omega-3 fatty acids may have several health benefits. For example, some studies suggest positive effects on rheumatoid arthritis (3), inflammatory bowel disease (4) and Alzheimer’s disease (5). There is also evidence suggesting that fish oil may promote hair growth (6).

Most of the research on the possible health benefits of omega-3 fatty acids has been within the field of cardiovascular medicine. Several studies have addressed the effects on cardiovascular risk factors, endothelial function, blood clotting and inflammation.

Fish Oil and Blood Lipids

High blood levels of triglycerides, LDL cholesterol (the bad cholesterol) and low levels of HDL cholesterol (the good cholesterol) are associated with increased risk of heart disease.

Intake of fish oil can lower blood levels of triglycerides by as much as 50 percent (7). Relatively high doses are needed to achieve this effect (up to 3-4 g/day).

Fish oil consumption modestly elevates blood levels of LDL cholesterol and HDL cholesterol.

Intake of omega-3 may lower the preponderance of small dense LDL-particles (8). This may account for the slightly raised LDL cholesterol. Large particles can carry more cholesterol. However, small LDL-particles have a stronger association with cardiovascular risk than large particles (9).

Fish Oil, Blood Pressure and Heart Rate

High blood pressure is a risk factor for coronary artery disease, heart failure and stroke.

Many studies have addressed the effects of fish oil on blood pressure. A meta-analysis of 36 randomized trials (10) indicated that fish oils may reduce both systolic and diastolic blood pressure, especially among elderly people with hypertension. Relatively high doses were used in most of these studies (median dose 3.7 g/d).

 

It is believed that the blood pressure lowering effects of fish oil is due to reduced vascular resistance in small arteries, probably mediated by increased production of nitric oxide. Nitric oxide is a powerful vasodilator (dilates arteries).

Studies also suggest that intake of fish oil lowers heart rate (11).

Fish Oil and Endothelial Function

The endothelium is a thin cellular layer lining the innermost part of the arteries. Endothelial cells are in direct contact with circulating blood. The endothelium plays an important role for the regulation of blood flow.

Abnormal endothelial function is often found among people with high blood pressure, diabetes and heart disease. Improving endothelial function may be important for individuals suffering from these disorders.

Several randomized studies have suggested that fish oil improves endothelial function (12).

This effect may explain some of the proposed beneficial effects of omega-3 fatty acids on cardiovascular function.

Fish Oil and Blood Clotting

During the early studies of the dietary habits and health of the Inuits it became apparent that they often suffered from nose bleeds. This is probably due to the increased bleeding time caused by ingestion of high doses of omega-3 fatty acids.

Despite the increased bleeding time, clinical studies have not shown that high doses of omega-3 fatty acids increase the rates of clinical bleeding problems (13).

Whether fish oils can reduce the risk of thrombosis (blood clotting inside blood vessels) remains to be proven.

Fish Oil and Inflammation

EPA and DHA are precursors to substances called eicosanoids. Eicosanoids are important regulators of inflammation.

Therefore, many experts believe that fish oils may help to reduce chronic low-grade inflammation.

Although some studies have not been able to show that fish oil consumption reduces blood markers of inflammation, other studies (14) have suggested that they may do so when relatively high doses are given (> 2 g/day).

Clinical Efficacy of Fish Oil

The clinical efficacy of fish oil has been intensively studied, particularly in the field of cardiovascular disease. A number of trials haves assessed the effects on coronary heart disease, arrhythmia (heart rhythm disorders) and sudden death.

Many experts believe that the positive effects of fish oil consumption on blood lipids, blood pressure, endothelial function, blood clotting and inflammation may be translated into improved clinical outcome.

There are three important questions that have to be asked about the efficacy of fish oils when it comes to cardiovascular disease. Firstly, does intake of fish oils lower the risk of healthy individuals. Secondly, does fish oil reduce risk among people at increased risk. And finally, does fish oil consumption improve outcome among these already affected by heart disease?

So, what do the studies say?

Fish Oil and Coronary Artery Disease

Observational studies on the consumption of fish and fish oils among western populations have shown conflicting results.While some studies have indicated less risk of cardiovascular disease among individuals with high consumption of fish and fish oils, others have not (15, 16).

In a large Japanese cohort, where the intake of omega-3 fatty acids was high, consumption of fish and fish oils was associated with reduced risk of coronary heart disease (17).

One systematic review and meta-analysis pooled data from 19 large prospective cohort studies and randomized trials in participants consuming either fish or fish oil supplements. The study found that consumption of marine omega-3 fatty acids was associated with lower risk of death from heart disease and sudden cardiac death (18).  The authors concluded that the benefits of fish consumption exceed the potential risks.

 

Randomized clinical trials have studied whether fish oil intake may reduce the risk of cardiovascular events. Some of these studies have indicated a positive effect while others have not.

One of the first randomized trials addressing the issue was published in 1989 (19). Two groups of more than 1000 men each who had just had a myocardial infarction (heart attack) were studied. One group was advised to ingest oily fish two times a week. The other group was not given this advice. After two years, there was a 29% reduction in life-threatening arrhythmias in the men advised to eat oily fish compared with the other group.

These initial results were later supported by the GIZZI-Prevenzione Trial (20), a large prospective randomized trial of more than 11.000 patients who had a recent myocardial infarction. Compared with placebo, 850 mg EPA+DHA significantly lowered the risk of death due to cardiovascular causes as well as death from all causes. There was a 45 % reduction in the risk of sudden death.

However, these highly positive results were not replicated in subsequently published large trials (21, 22, 23).

A meta-analysis of available randomized clinical trials published 2012 indicated that omega-3 fatty acid supplementation was not associated with a lower risk of heart attack or stroke or death from any cause, death from heart disease or sudden death (24).

The large Risk and Prevention Study, a double-blind placebo controlled trial published 2013 enrolled 13.513 patients with multiple cardiovascular risk factors or known cardiovascular disease (24). Patients were assigned 1 g/day of omega-3 fatty acids or placebo (olive oil). After a median follow–up of five years, the number of cardiovascular deaths, heart attacks and stroke was similar in both groups.

In this study, the participants received maximal medical therapy including aspirin, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers and cholesterol-lowering drugs. It has been suggested that the beneficial effects of omega-3 fatty acids may be diminished in patients already receiving aggressive risk management.

Administration and Dosing

EPA and DHA are found in cold-water fish such as salmon, mackerel, halibut, sardines, tuna, and herring.

Many over-the-counter preparations of fish oil are available. There is also a prescription formula (Lovaza, Omacor) in the US.

Different fish oil formulations contain variable amounts of EPA and DHA. Thus, a 1 g capsule may contain between 200 and 950 mg of EPA and DHA. A common amount in fish oil capsules is 180 mg of EPA and 120 mg of DHA, a total of 300 mg (EPA + DHA).

It is believed that a reasonable target intake to affect cardiovascular risk is 250 to 500 mg/day of EPA + DHA. This can be achieved by 1 g/day of fish oil supplement (between 200 to 800 mg of EPA+DHA, depending on the formulation) or 1-2 servings per week of fatty fish.

Although it appears that higher doses are safe, the US FDA does not recommend ordinary daily intakes of more than 2 g EPA+DHA. However, doses of 4 g/day have been approved for the treatment of high blood triglycerides (hypertriglyceridemia).

Fish Oils and Cardiovascular Disease – The Bottom Line

Treatment with marine-derived omega-3 fatty acid for the prevention of major cardiovascular adverse outcomes is supported by a number of randomized clinical trials and refuted by others.

Therefore, it is hard to give general advice on fish oil as a tool to reduce the risk of cardiovascular events among healthy people or to improve prognosis among those already affected by cardiovascular disease.

We will have to await results from ongoing clinical trials to further clarify this issue.

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Dietary Fat and Heart Disease – The Changing Landscape

Most of us know that the risk of heart disease can be modified by lifestyle. For more than fifty years, that’s what we’ve been taught by the people we trust, scientists, medical professionals and public health officials.

But the doubters have always been out there, and they ask questions. How do these people know what’s good and bad for us? Well, of course, we’re aware that their evidence is based on scientific data. But, is the data reliable and has it been interpreted correctly?

For decades we’ve been told that saturated fat, the type found in meat, butter, and cheese, raises the risk of heart disease. Health officials have urged the public to avoid saturated fat as much as possible, saying it should be replaced with unsaturated fats like that found in nuts, fish, seeds and vegetable oils. In fact, many consider this to be conventional wisdom, which basically means that it’s undebatable. However, recent research has challenged this view and the debate on the risk associated with consuming saturated fat has grown louder by the years.

One of the main reason saturated fat has historically had a bad reputation is that it increases LDL-cholesterol, the type of cholesterol that is supposed to raise the risk for heart attacks. But the effects of saturated fat on blood cholesterol are probably more complex than that. For example saturated fat also increases HDL-cholesterol, the so-called good cholesterol. However, the effect of polyunsaturated fat (PUFA) on blood cholesterol and traditional lipid profile is generally considered more favorable than the effect of saturated fat.

A few days ago, a scientific study published in the Annals of Internal Medicine caught the headlines of news media around the world. The main reason for the attention is the fact that the study did not find that people who ate more saturated fat had more heart disease than those who ate less. Furthermore, the study did not find less heart disease in those eating higher amounts of omega-6 PUFA or those eating more monounsaturated fat.

The study deserves our attention, not only because it challenges current wisdom and modern dietary guidelines, but because it summarizes a very large amount of data from three different types of studies. However, because it’s not an open access paper, and because it’s a landmark study, I thought it would be proper to summarize the main findings as I see them.

The Study Design

The study was performed by researchers from the UK, USA, and the Netherlands and was led by a team at the University of Cambridge in the UK. It was a systematic a review and meta-analysis of available scientific data addressing the association between dietary fatty acid intake, fatty acid biomarkers (measured in blood or adipose tissue), or fatty acid supplementation and the risk of coronary heart disease (CHD).

The investigators performed a systematic review of the scientific literature in order to find studies that fitted for their meta-analysis. The studies selected were both observational studies as well as randomized controlled clinical trials. To be eligible, the studies had to fulfill certain criteria. For example, observational studies were eligible if they were prospective in design with at least one-year follow-up and involved participants from a general population (not people with known heart disease). Intervention studies were eligible if they were randomized and recorded CHD outcomes. A total 72 studies of more than 600 thousand individuals were selected for the final meta-analysis.

In order to grasp the results of the paper, it is important to understand that the meta-analysis consisted of three parts. Firstly, the association between the intake of different dietary fats with CHD was studied. Secondly, the association of measurements of fatty acid biomarkers with CHD was addressed. Thirdly the association between fatty acid supplements and CHD was studied.

Saturated fat, Omega-6 and Monounsaturated Fat Don’t Affect Risk

There was no statistically significant association between dietary saturated fatty acid intake and the risk of CHD. Furthermore, intake of omega-6 PUFA was not associated with the risk of CHD. The authors of the paper, therefore, conclude: “Our findings do not clearly support cardiovascular guidelines that promote high consumption of omega-6 polyunsaturated fatty acids and suggest reduced consumption of total saturated fatty acids”.

When studying measurements of biomarkers, it is important to keep in mind that there are many types of saturated fatty acids and many types of PUFA’s. Palmitic and stearic acids are saturated fats that were not significantly associated with the risk of CHD. However, margaric acid was significantly associated with lower risk of CHD. Margaric acid is an odd-chain saturated fatty acid. It’s levels are moderately correlated with milk and dairy consumption. The findings support the possibility that odd-chain saturated fats reflecting milk and dairy consumption, may be less harmful in terms of risk for CHD. Arachidonic acid was the only omega-6 fatty acid that correlated with lower risk of CHD.

Studies of dietary intake and biomarker studies did not find any significant association between monounsaturated fat and the risk of CHD.

Dietary Long-Chain Omega-3 PUFA’s Are Protective

Dietary long-chain omega-3 PUFA was associated with lower risk of CHD. These findings were supported by the blood biomarker studies which showed some evidence that circulating levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid  (DHA) (the two main types of omega-3 PUFA) are associated with lower risk of CHD. Alfa-linolenic acid was neutral in terms of risk.

On the other hand, meta-analysis of omega-3 and omega-6 PUFA supplements suggests that supplementation with these nutrients does not significantly affect the risk of CHD. However, the authors point out that more data is needed because the available data is limited. There is a large ongoing trial on the effects of omega-3 PUFA in primary prevention (VITAL). This study will also address the efficacy of vitamin D.

Trans-Fats Increase the Risk of Heart Disease

Not surprisingly, dietary trans-fats were associated with increased risk of heart disease. However, only five published prospective cohort studies contributed to this analysis.

The Changing Landscape

For the last five years, a number of reports (1, 2, 3, 4, 5) have concluded that there is a weak association between the consumption of saturated fat or major foods that contain saturated fatty acids (meat and milk) and the risk of CHD. The above study certainly adds strength to these conclusions. It appears that the advice to encourage high consumption of polyunsaturated fatty acids and low consumption of saturated fats is not based on solid scientific evidence, and needs to be reconsidered. In fact, the study suggests that dietary fat composition me play a much smaller role for cardiovascular risk than previously thought.

Finally, a few questions need to be asked. Firstly, is this the final verdict? Well, I guess not. But certainly, these new results have to be taken seriously. Secondly, how did public health authorities manage to get it wrong for fifty years? Was it because the available scientific data was unreliable, or was it because the data was wrongly interpreted? Was it because the pieces of the puzzle had to fit into a preconceived notion? And thirdly, how will we get it right? How will the new landscape on dietary fats and heart disease be introduced to the public, and how will this landscape affect the food industry?

I know for sure that many experts will cover their ass by suggesting that the macro-nutrient approach is outdated, and they’re probably right. Dietary recommendations focusing on how much to eat of different types of fats and how much of our daily energy intake should be carbohydrates, protein or fat, are both misleading and impractical. So maybe we will soon see a paradigm shift in the way medical professionals and public health officials educate people about the effect of diet and nutrition on health and disease.

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