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“Fish oil is a whale of a story, that not surprisingly gets bigger with every telling.” J A Rogans, New England Journal of Medicine, 1996

“This isn’t just hype; we now have tremendous and compelling evidence from very large studies, some dating back 20 and 30 years, that demonstrate the protective benefits of omega-3 fish oil in multiple aspects of preventive cardiology.” Carl Lavie, MD, medical director of Cardiac Rehabilitation and Prevention, Ochsner Medical Center, New Orleans, LA, and lead author of a new review in the Journal of the American College of Cardiology (August 11, 2009)

 Evidence Piles Up: Fish Oil CV Benefits


(New Blood Test for Omega 3)

(Inflammatory Mechanisms Discovered)

Several years back, I wrote about a 2006 Harvard review which concluded that people who eat one or two weekly servings of fatty fish, such as wild salmon, may reduce their risk of death from heart attack by 36% and overall mortality by 17%. I also sketched the sequence of events that led us to appreciate the special benefits of fish oil. It started in 1970 with the discovery that Eskimos who eat mainly seal, whale, and fish have low cholesterol (except HDL) and a very low incidence of heart disease. The mystery fatty acids concentrated in their blood were identified as two forms of omega-3, which a decade or so later joined omega-6 as an essential fatty acid that must come in our food. As the years passed the connection between omega-3 fish oil and cardiovascular health grew stronger, bringing us to the 2006 report by the Harvard researchers. You’ll find more details in my earlier piece “Harvard Study Says: EAT FISH” http://www.cbass.com/EatFish.htm and in my book Great Expectations http://www.cbass.com/GreatExpectations.htm .

Now we have a “State-of-the-Art Paper” in the Journal of the American College of Cardiology (August 11, 2009) updating the status of “Omega-3 Polyunsaturated Fatty Acids and Cardiovascular Disease.”  Importantly, the report provides insight into potential mechanisms, along with recommended daily intake. It’s comprehensive--and a bit technical. Hang with me and you'll learn a lot of very interesting facts about omega-3s. I know I did. (Please consult your health care provider on how the information may apply to your situation.)

If you’re still on the fence about making fatty fish (or fish oil) a regular part of your diet, this may be the clincher.

Background Information

The new (2009) paper summarizes the current scientific data on the effects of omega-3 fatty acids in the primary and secondary prevention of cardiovascular (CV) disease. Primary prevention is directed at people with healthy hearts; secondary prevention applies to those with CV disease in the early stages or after symptoms arise.

Fatty fish that contain omega-3 fatty acids include salmon, sardines, herring, mackerel, albacore tuna, and others. Interestingly, fish don’t make fish oil. They accumulate it by eating marine microorganisms that are the original source of the omega-3 polyunsaturated fatty acids (PUFA). (Wild and farmed fish generally have about the same level of omega-3s, because farmed fish are fed fishmeal or fish oil from wild-caught fish.)

Many studies have shown that moderate fish consumption reduces the risk of cardiovascular disease. Most of the evidence indicates that the benefits come mainly from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the long-chain fatty acids in the omega-3 family. The American Heart Association (AHA) currently endorses a daily dose of 1,000 mg of combined DHA and EPA, either in the form of fatty fish or fish oil supplements; that dosage is for people diagnosed with coronary heart disease (CHD). (One gram or 1,000 mg of fish oil contains about 300 mg of combined EPA and DHA.) For those with healthy hearts, AHA recommends two oily fish meals per week, the equivalent of about 500 mg per day of combined EPA and DHA. (DHA and EPA are present in fatty fish, generally in a 2:1 ratio; fish oil, on the other hand, typically has a DHA/EPA ratio of 2:3 or lower.) 

Significantly, the new paper does not focus on alpha-linolenic acid (ALA), which is found in flaxseed and to a lesser extent in canola oil, olive oil, walnuts, and other nuts, as well as trace amounts in green leafy vegetables. ALA is omitted because "humans convert…less than 5% of ALA to EPA and even less to DHA.” While there is some evidence of benefit, the “overall evidence is much weaker for ALA than for EPA or DHA.”

We'll begin with the benefits of omega-3 fatty acids in various stages and forms of cardiovascular disease, along with the potential mechanisms involved.

Benefits and Mechanisms

Evidence continues to pile up that omega-3 from fish and fish oil prevent cardiovascular disease in healthy individuals, and also reduce heart problems and death in patients with existing heart disease. “Convincing evidence from extensive research over the past 3 decades points out the potential benefits of omega-3...in primary prevention, coronary heart disease and [after heart attack], sudden cardiac death, heart failure, atherosclerosis, and atrial fibrillation,” the researchers concluded.

“This isn’t just hype; we now have tremendous and compelling evidence from very large studies, some dating back 20 and 30 years, that demonstrate the protective benefits of omega-3 fish oil in multiple aspects of preventive cardiology,” said Carl Lavie, MD, lead author of the article. “The strongest evidence of a cardioprotective effect of omega-3 appears in patients with established cardiovascular disease and following a heart attack, with up to a 30 percent reduction in CV-related death.” (Study details below)

“It is also well established that omega-3 PUFA [polyunsaturated fatty acids] lower plasma triglyceride concentrations,” the researchers reported. Omega-3s are most effective in people with very high triglycerides. High doses of Omega-3 are also required, however. “The triglyceride-lowering doses of DHA and EPA is 3 to 4 g/day,” says the report. “This dose typically reduces triglyceride levels by 30% to 40% and has been shown to reduce severely elevated triglycerides (>500 mg/dl) by 45%.” It also works in combination with statins. “When added to baseline statin therapy in patients with triglyceride levels between 200 and 499 mg/dl, this dosage of omega-3 PUFA lowers triglyceride levels by close to 30%.”

The effect of fish oil therapy on LDL “bad” cholesterol is more troublesome. According to the report, there is generally no significant improvement in LDL cholesterol. Moreover, the researchers say patients often notice increases in LDL “between 5% and 50%.” That may not be so bad, however. The report explains why: “Omega-3 PUFA-enriched LDL has been reported to be larger and fluffier, which is potentially less [artery clogging] than the smaller, dense LDL particles.” (See Update below)   

The known mechanisms involved are growing in number and becoming clearer.

Here’s the general hypothesis: “It appears that omega-3 PUFA confer CV benefits largely through DHA and EPA enrichment of membrane phospholipids [components].” See my earlier discussion of “the pacemaker or leaky membrane hypothesis:” http://www.cbass.com/EatFish.htm .

Moving beyond the general to the specific, the report lists the following potential EPA and DHA effects: Vasodilation, Decreased blood pressure, Improvement in arterial and endothelial function, Decreased platelet aggregation, Anti-inflammation effects, Antiarrhythmic effects, Improvements in autonomic function [heart rate, breathing, etc], Plaque stabilization, Reduced atherosclerosis, Reduced triglycerides, Up-regulate adiponectin production [<heart attack risk], Reduced collagen deposition [<stiffening].

I don’t pretend to understand particulars of these mechanisms, but it’s clearly an impressive list. (See Update below.)

Recommended Intake

As noted above, the American Heart Association (AHA) currently recommends a daily dose of 1,000 mg of combined DHA and EPA for people with coronary heart disease (CHD). For those with healthy hearts, AHA recommends 2 oily fish meals per week The report says these recommendations are consistent with the latest research.

The dosage for people with CHD is based on a large ongoing Italian study (GISSI-Prevenzione), where 11,323 post-heart attack patients were given a daily capsule containing 850 mg of combined EPA and DHA or “usual care.” After one year, patients taking the fish oil capsule showed a “highly significant” 45% reduction in sudden cardiac death, and 21% and 30% reduction in overall and cardiovascular mortality. Long-term follow-up has continued to show significant reductions in major clinical events after 3.5 years.

The other large studies referred to by Dr. Lavie above are the Diet and Reinfarction Trial (DART) two decades ago, where omega-3 PUFA (oily fish or fish oil) were found to “reduce 2-year all-cause mortality by 29%, and more recently (2007) the Japan EPA Lipid Intervention Study (JELIS), where 18,645 patients were given a statin, or a statin and 1,800 mg/day of purified EPA. “At the end of the 5-year study, those randomized to EPA had a 19% reduction in major CV events.”

“In combination,” the report stated, “the DART, GISSI-Prevenzione, and JELIS trails indicated that omega-3 PUFA lower CV risk in both primary and secondary prevention settings.” Many studies were reviewed, but these three—along with another showing a “very impressive” 9% reduction in death rate of patients gravely ill with congestive heart failure—appear to be the major ones. Nearly 40,000 participants were involved in the four trials.   

The recommended dosage for healthy adults is “the intake associated with the lowest risk for CHD death in several U.S. studies.”

Importantly, major health organizations from around the world have guidelines for increasing consumption of fish.

Dr. Lavie and his colleagues say further studies are needed to gauge the benefits of measuring blood levels of omega-3 PUFA. (See Update below.) More study is also needed to determine the best mixture of DHA relative to EPA for those at risk for various CV diseases. As noted earlier, the DHA/EPA ratio in fish and in fish oil are not the same. Perhaps it would be a wise to consume a combination of fish and fish oil, at least until the optimum ratio is known. (My thought, not the researchers)

Unfortunately, all trends have not been positive.

 Cross-Cultural Effects

As noted earlier, the Eskimo experience played a major role in discovery of the CV benefits of eating fatty fish. The experience of the Japanese and other Asian populations has confirmed the CV benefits of fish consumption. Unfortunately, the reverse experience of Europeans and Americans (little fish, more heart disease) may have diluted the benefits enjoyed by other cultures. In their report, Dr. Lavie and his colleagues relate a 2008 study which appears to reveal negative cross-cultural effects.

The study compared 281 Japanese men born and living in Japan, 282 Japanese men living in the U.S., and 360 Caucasian men born and living in the U.S. The Japanese men living in Japan had higher levels of omega-3 PUFA in their blood, along with less thickening in their carotid arteries and less coronary artery calcification, both independent predictors of atherosclerosis. Unfortunately, the Japanese men living in the U.S. had roughly the same levels of atherosclerosis as the Caucasian men born and living in the U.S.

Western dietary practices have apparently undermined the CV benefits enjoyed by Asian and Eskimo cultures, by reducing fish intake and increasing consumption of saturated and trans fats. Perhaps the new report will help to spread the “Eskimo factor” worldwide.

I promised to discuss the possible adverse effects of omega-3s. Can we get too much of a good thing?

Adverse Effects

I have wondered whether fish-oil capsules could increase my risk of bleeding to death or having a stroke. Dr. Lavie’s report eases my concern.

We have a famous test case. Greenland Eskimos were found to have prolonged bleeding times, but apparently not long enough to cause problems. Normal volunteers given “hyper-Eskimo” doses of omega-3 PUFA—over 20 grams a day—remain in the “high end of the normal range.” Some concerns about “hemorrhagic complications” remained, however.

A comprehensive review in 2007 found “no increased risk of clinically significant bleeding” with daily doses of up to 7 grams of combined DHA and EPA—“even when combined with antiplatelet therapy or warfarin.” Be that as it may, it would still be wise to consult your doctor before consuming more omega-3s than the AHA endorses.

The most commonly observed adverse effects are: “nausea, gastrointestinal upset, and ‘fishy’ burp.”

The one major concern that we hear most about is the consumption of contaminants, namely mercury. The FDA has advised children and pregnant or nursing women to avoid fish with a high content of mercury.

As we wrote earlier, most indications are that omega-3 benefits exceed the dangers by a wide margin; see http://www.cbass.com/EatFish.htm

Dr. Lavie and his colleagues seem to concur. They cite a study of 12,000 British women who ate more fish than the U.S. FDA recommendation during their pregnancy—and had offspring with “better cognitive and behavioral development than offspring of women who consumed less fish during pregnancy.”

They also point out that the most commonly consumed sources of omega-3s, salmon, sardines, trout, oysters, and herring, “are quite low in mercury.”

They add, however, that fish oil is likely to contain less mercury than the fish itself—because mercury “is water soluble and protein bound.” Water and protein, of course, are “present in the muscle of the fish but not in the oil.”

Credibility Grows

The researcher leave us with this catchy stamp of approval: “Based on the growing evidence for the benefits of fish oils, we agree that this story represents a fish tale with growing credibility.” We also agree with Rogans’ comment from over 20 years ago that fish oil is a whale of a story, that not surprisingly gets bigger with every telling.”

That tells the tale, doesn't it?.


New Blood Test for Omega 3

I've learned many things at the Cooper Clinic, something new virtually every visit. My 11th exam, just completed, was no exception. They have begun testing for omega 3, using a blood test developed by William Harris, PhD, an international expert on omega-3 fatty acids, and Clemens von Schacky, MD, a cardiologist in Munich, Germany. Named after Harris and Schacky, the test is called the HS-Omega-3 Index.

Dr. Harris, Director of Cardiovascular Health Research at Sanford Research/USD in Sioux Falls, SD, sums up the need for the test in one sentence. "Based on what we currently know there is no nutrient more important for decreasing the risk of cardiovascular death--and more lacking--than omega 3," says Harris.

Most health-conscious people these days know their cholesterol numbers. Before long, your personal omega-3 index may become another "must-know" number. (I now know mine.) Lynn McFarlin, my doctor at the Cooper Clinic, has been testing patients for about three months. The results are troubling. The target HS-Omega-3 Index is 8% and above, a level associated with the lowest risk of death from coronary heart disease (CHD). On the other hand, an Index of 4% or less (common in the US) indicates the highest risk. Between 4% and 8% is the intermediate zone, indicating moderate risk.

In line with the comment by Dr. Harris, only 11 or 12 of the roughly 170 patients McFarlin has tested so far are in the "low risk" category. "Americans are very deficient in omega 3," he told me.

The HS-Omega-3 Index measures the EPA+DHA in the membranes of red blood cells and is expressed as a percent of total fatty acids. The Index is a proven surrogate for omega-3 levels in the heart and other tissues.

"Risk" assessment refers only to that associated with omega-3 level. Risk associated with other factors such as cholesterol, blood pressure, diabetes, family history, smoking, etc. are independent. All risk factors should be considered in assessing overall risk.

My Index level is 8.6%, in the low risk zone. The highest reading Dr. McFarlin has seen so far is 10. As noted, the vast majority of his patients have been below the 8% target level. I gather that quite a few have been below 4%.

Interestingly, my lipid profile has changed. As explained in the main article (above), people consuming fatty fish or fish oil often notice increases in LDL "bad" cholesterol of 5% to 50%. My LDL went up about 12%, from 80 to 90. (Below 100 is the target number.) Hopefully, my LDL is  the larger and fluffier variety mentioned. My triglycerides also increased, but remain in the desirable range.

Happily, my HDL "good" cholesterol sky-rocketed to 78, my highest reading by far. As would be expected, my total cholesterol also went up--but remains in the target zone, under 200. My Chol/HDL ratio improved slightly, from 2.5 to 2.4. A ratio under 4.5 is considered good. Dr. McFarlin calls my overall lipid panel "still very healthy."

Now, let's look at a new study revealing how omega 3 works its magic.

Inflammatory Mechanisms Uncovered

As noted earlier, the general hypothesis is that omega-3 fatty acids enrich the components of membranes in the body. A key target is the endothelial cells that line blood vessels. We now have a breakthrough at the University of Birmingham demonstrating how this works. The discovery is especially noteworthy because it's so easy to visualize. It reveals how omega 3 blocks inflammation, a key factor in cardiovascular and other diseases.

Dr. Ed Rainger, lead researcher in the UK study, explained: "We've all heard about the health benefits of eating fish and its beneficial effects on cardiovascular disease, possibly due to their anti-inflammatory properties, yet little is known about the normal cellular mechanisms by which omega-3 fatty acids produce their protective effects." He and his colleagues hoped to fill the vacuum. Their study was published in the online journal PLoS Biology on August 25, 2009.

Normally, inflammation occurs when white blood cells migrated from the blood, through the blood-vessel wall and into surrounding tissue. This process is regulated by endothelial cells lining the blood vessels. To observe how this works, the researchers created a model of a blood vessel using a glass tube.

They coated the glass tube with endothelial cells, and added omega 3s. They then pumped white blood cells into the tube. What they saw watching through a microscope was a revelation. The white blood cells were unable to cross the endothelial barrier. The omega 3s were blocking them, the researchers reported.

The icing on the cake came when they repeated the experiment without the omega 3s--and the white blood cells easily passed through the endothelial barrier.

Importantly, they also observed that omega 6, the other essential fatty acid, triggers the passage of white blood cells through the endothelial barrier. This finding, Dr. Rainger said, supports "the idea that omega-6 fatty acids are...required to sustain a normal inflammatory response without which we would be prone to serious infection and tissue damage."

In short, inflammation can both help and hurt. Omega 6 has a pro-inflammatory effect, balanced by an omega-3 driven anti-inflammatory effect.

The problem, it seems, is that modern Western diets contain too much omega 6 and not enough omega 3. A press release from the University of Birmingham says the imbalance may explain the rise of diseases such as asthma, coronary heart disease, cancers, autoimmunity and neurodegenerative diseases, all of which are believed to stem from an excess of inflammation in the body.

Bottom line: Eat fatty fish or take fish oil. I do both.

For more about the competition between omega 3 and omega 6, see "Harvard Study Says: Eat Fish" http://www.cbass.com/EatFish.htm

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