Inflammation and Heart Disease

Two decades ago, many experts predicted that the modification of risk factors, in particular, the treatment of high blood pressure and lipid disorders, would eliminate coronary artery disease in 10 – 20 years. Unfortunately, this prediction was wrong.

Inflammation and heart diease

Although mortality from cardiovascular disease has decreased in many countries, coronary heart disease remains a significant cause of death and disability worldwide. Furthermore, the increased incidence of obesity and type 2 diabetes may ultimately reverse the declining mortality trend from heart disease.

Although there has been some improvement, one has to wonder why we haven’t had more success in reducing the prevalence and mortality from heart disease? Some will claim it’s because we haven’t succeeded in reducing the influence of traditional risk factors, such as high blood cholesterol. They will say that cholesterol lowering drugs (statins) are still underused among individuals at high risk and that many patients with heart disease are still not treated to target levels of low-density lipoprotein (LDL) cholesterol. And they could be right. There are ongoing trials, among them the FOURIER trial, testing the hypothesis that further lowering of LDL cholesterol with PCSK9 inhibitors on top of statin therapy will improve prognosis among patients with cardiovascular disease.

Another reason for the limited success is the possibility that there is a missing link. This link may be inflammation. It has been suggested that inflammation may play a major role in cardiovascular disease. If so, how can inflammation be modified?  To be able to answer this question we will have to start with the basics. What is inflammation? How is inflammation involved in heart disease? Will reducing inflammation lower the risk of heart disease?

When we talk about heart disease in adults, we usually mean atherosclerotic coronary artery disease. This disease was first described in the eighteenth century. However, its most serious clinical entity, acute myocardial infarction, generally known as acute heart attack was not recognized until the early twentieth century.

In the 1950’s acute myocardial infarction was recognized as one of the most common causes of death in the industrialized world. The symptoms were often dramatic and devastating. A previously healthy person was suddenly hit by severe chest pain, often associated with serious disturbances in heart rhythm, frequently resulting in sudden death. The survivors often had to deal with the consequences of damage to large parts of the heart muscle, sometimes resulting in heart failure, severely compromised quality of life and a shortened lifespan.

Acute myocardial infarction occurs when there is a sudden disruption of blood flow in a coronary artery.  The coronary arteries supply blood to the heart muscle. A sudden blockage is usually caused by a rupture of an atherosclerotic plaque within the vessel wall, with subsequent formation of a blood clot (thrombosis) at the rupture site. A sudden disruption of blood flow causes the death of heart muscle cells (infarction) and may impair the function of the heart muscle.

The hunt for conditions that predispose to acute myocardial infarction was well on its way by the mid-1950’s. In 1961 the Framingham team reported that high blood levels of cholesterol and high blood pressure were associated with increased risk of coronary artery disease. The term “coronary risk factors” was defined, and researchers were able to gradually uncover other conditions which predispose to this disease, such as cigarette smoking, the various fractions of cholesterol, insulin resistance, physical inactivity, mental stress, depression and dietary factors. However, although many risk factors have been identified and modified by preventive measures, coronary artery disease remains a common disorder. Despite extensive research, our understanding of the mechanisms behind coronary artery disease and acute clotting of diseased arteries is incomplete.

Today most scientists believe that inflammation plays a key role in atherosclerosis and acute myocardial infarction. As a matter of fact, signs of inflammation at the sites of atherosclerotic plaques have been observed for centuries.  In the nineteenth century, there was a fierce controversy between the prominent Austrian pathologist Carl von Rokitansky and his German counterpart, Rudolf Virchow. While the former attributed a secondary role to these inflammatory arterial changes, Virchow considered them to be of primary importance.

Today, almost two centuries later, important issues remain unresolved. How can vascular inflammation be measured and quantified? Which inflammatory mechanisms are most important when it comes to atherosclerosis and coronary artery disease. How can vascular inflammation be reduced or modified? Will measures that reduce inflammation affect the risk of atherosclerotic heart disease and its consequences?

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What Is Inflammation?

Inflammation is a protective tissue response to injury or destruction of tissues, which serves to destroy, dilute, or wall off both the injurious agent and the injured tissues. The classical signs of acute inflammation are pain (dolor), heat (calor), redness (rubor), swelling (tumor), and loss of function (functio laesa).

A good example of inflammation is when we get a splinter in our finger. The redness is caused by increased blood flow. The swelling is partly caused by white blood cells dispatched by the immune system to destroy the attacker and repair the injury. So, obviously, inflammation is one of the body’s most important defense mechanism. Without it, we would not be able to fight bacterial infections, injuries, and destruction of tissues. So, how can inflammation be harmful?

The body’s defenses are controlled by the immune system. The immune system is composed of biological structures and mechanisms that continuously protects us against diseases such as infections and cancer. Immune deficiency is associated with increased risk for these diseases. Autoimmune disorders such as rheumatoid arthritis, Hashimoto’s thyroiditis, systemic lupus erythematosus and type 1 diabetes are all associated with a dysfunction of the immune system.

Inflammation can be both acute and chronic. Acute inflammation is the initial response of the body to harmful stimuli.  Prolonged inflammation or chronic inflammation is characterized by simultaneous destruction and repair of the tissue from the inflammatory process.

When inflammation is appropriate, it protects us from disease. When inflammation is inappropriate or gets out of hand, it can cause disease. Autoimmune disorders are characterized by an inappropriate immune response against cells and tissues in our body. This commonly leads to inflammation of tissues and organs such as joints, endocrine organs like the pancreas and thyroid gland, visceral membranes and internal organs such as the lungs, kidneys and blood vessels. Vasculitis is a term that is commonly applied to autoimmune inflammation of arteries.

Inflammation and Heart Disease

The wall of most human arteries is composed of three layers. The innermost layer is the endothelium which overlies an intima of extracellular matrix and smooth muscle cells. The next layer, the media contains mainly smooth muscle cells and extracellular matrix. The outermost layer, the adventitia, consists of looser connective tissue, nerve endings, mast cells and the so-called vasa vasorum.

11968949_mAtherosclerotic lesions (atheromas) are focal thickenings of the innermost layer of the artery, the intima. They consist of cells, connective tissue, lipids, and debris. Bloodborne inflammatory and immune cells constitute an important part of an atheroma, the remainder being vascular endothelial and smooth muscle cells. Many of the immune cells exhibit signs of activation and produce inflammatory cytokines. Cytokines are important mediators of the inflammatory response.

Studies have indicated that the infiltration and retention of low-density lipoprotein (LDL) in the arterial intima initiate an inflammatory response in the artery wall. Modification of LDL, through oxidation or enzymatic attack in the intima, causes the release of phospholipids that can activate endothelial cells. Studies in animals and humans also indicate that high blood levels of cholesterol may cause focal activation of vascular endothelium.

Cholesterol crystals are needle like structures that are found in atherosclerotic plaques. The role of these crystals in the atherosclerotic process is unknown. It has been proposed that cholesterol crystals may play a central role in initiating inflammation in atherosclerosis.

Recruitment of white blood cells (leukocytes) to the arterial wall is an early event in the formation of an atherosclerotic plaque. What triggers leukocytes to adhere to the vascular wall is unknown. A widely accepted view suggests that prolonged high levels of LDL particles in the blood stream may promote an infiltration of these particles to the arterial intima. Indeed, experimental animals begin to recruit inflammatory leucocytes soon after starting a diet enriched in cholesterol and saturated fat.

When inside the vessel wall, some leucocytes (monocytes) change into so-called macrophages. These cells are prominent in the atherosclerotic plaque. Macrophages may ultimately be transformed into foam cells, the prototypical cell in atherosclerosis. The activated macrophages produce inflammatory cytokines and other substances. Many other types of leucocytes are found in atherosclerotic plaques which underline the important role of the immune system and inflammation in the formation of atherosclerosis.

The ultimate complication of atherosclerosis, the formation of the blood clot or thrombosis, also appears to depend on inflammation. A disruption or rupture of an atherosclerotic plaque is the process that most often triggers thrombosis. The most common form of plaque disruption, rupture of the plaque´s protective fibrous cap, relates closely to inflammatory processes. Plaques that tend to cause fatal coronary thrombi often contain large accumulations of inflammatory cells. They also typically have a thin protective fibrous cap that overlies the lipid core.

Interestingly, many thrombotic occlusions of a coronary artery, resulting in myocardial infarction, do not occur at the sites of critical narrowing of the artery. Rather, lesions that do not cause critical stenosis often underlie clots that cause acute myocardial infarction.

The balance between inflammatory and anti-inflammatory activity controls the progression of atherosclerosis and thrombosis. Metabolic factors also affect this process. Lipid deposition in the artery may initiate inflammation.The adipose tissue of patients with the metabolic syndrome and obesity produces inflammatory cytokines that may promote vascular inflammation.

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Inflammatory Biomarkers

A biomarker is a substance that can be measured, usually in blood,  and reflects a biological state. Biomarkers reflecting inflammation can help identifying and quantifying inflammation.

C-reactive protein (CRP) is a biomarker of low-grade inflammation.

Despite a lack of specificity for the cause of inflammation, data from a number of epidemiologic studies have shown a significant association between elevated serum plasma concentration of CRP and the prevalence of underlying atherosclerosis, the risk of recurrent cardiovascular events among patients with established disease, and the incidence of first cardiovascular events among individuals at risk for atherosclerosis.

Also, some drugs used in the treatment of heart disease, such as aspirin and statins, reduce serum levels of CRP. Reduced inflammation may contribute to the beneficial effects of these drugs.

CRP can be measured using various assays with different testing characteristics. The high sensitivity CRP assay (hs-CRP) is the most used assay to determine cardiovascular risk.

Lipoprotein-associated phospholipase A2 (LP-PLA2) is an emerging inflammatory marker. It is a lipoprotein-associated enzyme secreted by macrophages. Elevated Lp-PLA2 has been shown to predict the risk of myocardial infarction and stroke in population studies.

Other examples of inflammatory biomarkers are Interleukin-6 (IL-6) and fibrinogen.

Diet and Inflammation

The role of chronic inflammation in heart disease and other chronic diseases has stimulated research into the effects of diet, nutrition and other lifestyle measures on inflammatory markers. Although this research is still in its infancy, some knowledge is available on the relationship between dietary patterns and systemic inflammation.

11266323_mIn one study a relationship was found between glycemic index (GI) and hs-CRP, indicating that foods with high GI may be associated with inflammation.

Consumption of trans fats has been associated with markers of systemic inflammation.

Intake of omega-3 fatty acids has been associated with low levels of IL-6, suggesting an anti-inflammatory effect of omega-3.

Consumption of omega 6 fatty acids shows variable effects on inflammation. Both pro-inflammatory and anti-inflammatory effects have been described.

It has been suggested that high levels of dietary omega-6 may increase the amount of omega-3 needed to reduce inflammation. Consumption of carotenoids, flavonoids, and magnesium has been associated with lower levels of inflammatory markers.

Numerous studies have shown an association between fruit and vegetable consumption and low levels if inflammatory markers.

Much of the research on dietary patterns and inflammation has looked at the Mediterranean diet or its components. Adherence to a traditional Mediterranean diet has been associated with a 9% reduction in total and cardiovascular mortality, 6% reduction in cancer, 13% reduction in Parkinson’s and Alzheimer’s disease incidence. All these diseases have been associated with low-grade systemic inflammation.

High intake of olive oil, vegetables. Legumes, fruits, and fish have been associated with low levels of hs-CRP, suggesting that these foods may reduce inflammation. In the ATTICA study adherence to the Mediterranean diet was associated with lower levels of hs-CRP.

Will Reducing Inflammation Help?

Whether inhibition of inflammation will prevent heart disease, or improve prognosis in those with known disease, is currently a major unresolved issue in clinical care. Much of the data evaluating the impact of atherosclerotic therapies on inflammatory biomarkers and clinical events has derived from aspirin or statins, agents that not only reduce inflammation but that either inhibit platelet function (aspirin) or significantly lower LDL cholesterol (statins)

The JUPITER trial demonstrated that potent statin therapy reduces the risk of heart attack and stroke among individuals with low levels of LDL-cholesterol who are at risk due to elevated levels of hs-CRP. It is not known whether the clinical benefits of treatment are due to LDL-reduction alone, to inflammation inhibition, or to a combination of both processes.

Two large clinical trials are underway to address the hypothesis that lowering inflammation will lower event rates and improve prognosis among patients with heart disease.

The CANTOS trial evaluated whether interleukin-1ß (IL-1ß) inhibition with the drug canakinumab can reduce the rates of myocardial infarction, stroke, and cardiovascular death among patients with a history of previous myocardial infarction and elevated levels of hsCRP (> 2 mg/L). It is a landmark study because it showed for the first time that blocking an important component of the inflammatory cascade involved in atherosclerotic heart disease is associated with an improved outcome.

The CIRT trial which is funded by the National Heart, Lung, and Blood Institute (NHLBI) will evaluate whether low dose treatment with methotrexate will reduce major vascular events among patients with a history of myocardial infarction and either diabetes or the metabolic syndrome. Methotrexate is commonly used in the treatment of autoimmune disorders such as rheumatoid arthritis and psoriasis arthritis.

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bhrdoc
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This is an excellent review Axel. I often wonder what role airpollution (which we know increases the risk of myocardial infarction) and all the man made chemicals we are exposed to play in causing inflammation.
Barbara Roberts, MD

Axel F Sigurdsson
Admin
Axel F Sigurdsson

Thanks Barbara. I just stumbled on this very recent article touching on the relationship between air pollution and atherosclerosis.

Raymund Edwards
Guest

Vitamin D appears important in controlling the extent to which this occurs

“When inside the vessel wall, some leucocytes (monocytes) change into so-called macrophages. These cells are prominent in the atherosclerotic plaque. Macrophages may ultimately be transformed into foam cells,”

https://www.plosone.org/article/info:doi/10.1371/journal.pone.0054625

Axel F Sigurdsson
Admin
Axel F Sigurdsson

Thanks Raymund. That´s interesting. Thus, vitamin D deficiency could be one of the factors contributing to inflammation.

David Brown
Guest

I think Dr. Bill Lands has a good grasp of inflammation. https://videocast.nih.gov/summary.asp?live=8108&bhcp=1 Dr. Lands begins speaking around minute 12. At about minute 19 Dr. Lands says, “Did you know that peanuts contain 4,000 milligrams of omega-6 per 28 gram, one ounce serving of peanuts… and one milligram of omega-3? Oops!” When I heard this, I realized my mistake. I’d been consuming a peanut butter sandwich for lunch almost daily for decades. Two months after I stopped consuming peanut butter my leg pains subsided. I watched that lecture in November 2009. I have since regained considerable strength and stamina. I have… Read more »

pronutritionist
Guest

Data is rapidly accumulating on diet and inflammation. See for example this open access review paper: https://goo.gl/HTuuQ

My toughts on fats and inflammation https://goo.gl/TlVtc

David Brown
Guest

Excerpt from thisAJCN article: https://ajcn.nutrition.org/content/83/6/S1505.full “Inflammation is an overt or covert component of numerous human conditions and diseases. Although the inflammation may afflict different body compartments, one common characteristic of these conditions and diseases is excessive or inappropriate production of inflammatory mediators, including eicosanoids and cytokines. The roles of n−6 and n−3 PUFAs in shaping and regulating inflammatory processes and responses suggest that the balance of these fatty acids might be important in determining the development and severity of inflammatory diseases. For example, a high intake of n−6 PUFAs, especially arachidonic acid, could contribute to inflammatory processes and so could… Read more »

Axel F Sigurdsson
Admin
Axel F Sigurdsson

Thanks for your comments David. I think there is a lot of evidence indicating that the omega-6:omega-3 issue is of importance when it comes to inflammation. Possibly, as suggested in your post, we should focus more on increasing omega-3 instead of reducing omega-6. There is lot of evidence indicating that increasing omega-3 has health benefits, but as pointed out in your post, there are no long term clinical trials that have tested whether reduced intake of omega-6 is beneficial.

By the way, I didn´t realize nuts contained so much omega-6.

Mie
Guest
Mie

Just like Reijo’s slides point out (and as he and I have earlier stated), there is no quality evidence whatsoever indicating that getting the amount of n-6 fatty acids that we currently get from our diet (that is, the average Western diet) is problematic. Inflammation seems to become a problem only when the intake is considerably larger. And n-6 fatty acids do have anti-inflammatory qualities, as well. About nuts: yes, many nuts (like peanuts, hazelnuts) have n-3/n-6 ratios in the range of about 1:10. However, that isn’t the case with all nuts: in walnuts the ratio is about 1:4. And… Read more »

David Brown
Guest

Mie says, “…there is no quality evidence whatsoever indicating that getting the amount of n-6 fatty acids that we currently get from our diet (that is, the average Western diet) is problematic.” I would say there is no quality evidence suggesting that intake of n-6 fatty acids above one or two percent of total calories is safe. Here’s the latest indication that n-6 is problematic. Excerpt: Metabolic syndrome is often accompanied by development of hepatic steatosis and less frequently by non-alcoholic fatty liver disease (NAFLD) leading to non-alcoholic steatohepatitis (NASH). Replacement of corn oil with medium chain triacylglycerols (MCT) in… Read more »

Mie
Guest
Mie

“I would say there is no quality evidence suggesting that intake of n-6 fatty acids above one or two percent of total calories is safe. Here’s the latest indication that n-6 is problematic. Excerpt:”

Dave, the day you a) stop flooding & quote mining and b) address the studies concerning n-6 & inflammation I’ve referred to earlier, I’ll consider replying to you in more details. In the meanwhile, I’ll simply ignore your posts.

Axel F Sigurdsson
Admin
Axel F Sigurdsson

Reijo. I looked at your slides. Interesting. Do you think the issue of omega-6/omega-3 ratio is overrated or irrelevant? Most of us generally think that increasing omega-3 is beneficial. But, what about reducing omega-6. Is it unnecessary? Can it be harmful? Would love to hear your thoughts.

pronutritionist
Guest

I think the ratio is overrated. The role of fats per se is overrated. The current intake of n-6 fats is near to optimal level in many countries like Finland (about 4,5 % of energy). Think, in Sydney Diet Heart intake of n-6 FAs was about 15 % of energy (supplement material table 6). If we used n-6 oils like in Sydney Diet Heart or in Rose Corn Oil studies, there would be need to reduce n-6 intake. But we do not. We use canola oil, olive oil and modern margarines instead. Blogosphere and many review papers cite falsely that… Read more »

Raymund Edwards
Guest

Bill lands seems to suggest that taking more omega 6 or more omega 3 will do very little because omega 6 is already too high. So the bad effects of adding extra Omega 6 and the beneficial effects of increasing omega 3 are already crowded out .

David Brown
Guest

Charles Serhan is one of the go to guys for information on inflammatory response. Google: Charles Serhan Nutrition, Trauma, and the Brain PDF Excerpt: “The prevailing theory on the actions of n-3 fatty acids (DHA, EPA) is that they compete for arachidonic acid in phospholipid stores, blocking the biosynthesis of eicosanoids that are proinflammatory such as leukotrienes and prostaglandins as well as vasoactive thromboxane. For an elegant review of this thesis, the readers are directed to Lands(2005). This competition between n-3 and n-6 pathways is evident with results from many studies and is demonstrable in vitro with isolated cells and… Read more »

Low-fat Richard
Guest
Low-fat Richard

Axel, I think Daniel Steinberg (2008) covered the inflammation issue pretty thoroughly. Why we are not having more success is because people are being treated too late in life. The mean age at the randomization in large statin trials is 63. Even though cholesterol is reduced and plaque build-up is somewhat regressed, the more stable plaques can still cause a rupture.on people with existing CHD or several decades cumulative burden of elevated cholesterol. Steinberg (2008) covers the very detailed mechanical models which indicates the inflammation is ceased once lipids are normalized. Moroever, he highlights the well established ecologic evidence: “Taken… Read more »

Mie
Guest
Mie

Now Richard, care to explain what relevance does this “SOS” that you keep copy/pasting everywhere have concerning the blog post at hand?

Low-fat Richard
Guest
Low-fat Richard

Mie, you should thank me, you cannot go wrong by much while copy/pasting Stamler and Steinberg. Axel, I come from a business background. We tend to study and scrutinize best-practise cases. I thought this was the natural frame-work and mind-set for all people. If you want to be good at something, you study the people who are already good at it. If you want to prevent CHD, look for the population who do not have CHD and study whether there is something to learn from them (Campbell et al 1998). Now, if you were as excited about potatoes, oatmeal, corn… Read more »

Axel F Sigurdsson
Admin
Axel F Sigurdsson

Richard, I don´t come from a business background. However, I have performed and participated in scientific work for many years. I don´t believe we can accept or reject a hypothesis until it is tested. That is definitively true for the inflammatory hypothesis. I don´t believe, as you seem to do, that atherosclerosis and coronary artery disease are only about cholesterol. Although there is a significant relative reduction in clinical events in many of the statin trials, there is a number of events among those on statins as well. Many patients who aret treated to target levels of LDL cholesterol have… Read more »

Low-fat Richard
Guest
Low-fat Richard

Dear Axel, I am certain that we are seeing success while treating inflammation also in terms of clinical end-points. And, certainly these issues must be raised also for the lay-people. However, I am still not sure whether the newly found focus on inflammation will be serving the big audience. I think Jeremiah Stamler had some good points in the interview. I agree that one must pay attention to issue beyond cholesterol. This is more crucial when treating high-risk patients at old age. However, If people understood the importance of LDL cholesterol (including its causal role in influencing CAD) and actually… Read more »

Mie
Guest
Mie

“I am certain that we are seeing success while treating inflammation also in terms of clinical end-points… However, I am still not sure whether the newly found focus on inflammation will be serving the big audience.”

This is besides the point. The focus here is that of an ADDED benefit. No one’s arguing – well, no one who’s to be taken seriously – that well-known lifestyle factors should be ignored.

Next time, put more focus on the issue at hand and less on the ecological fallacies such as leaving out the majority of the findings of 7CS.

Low-fat Richard
Guest
Low-fat Richard

Mie,

you are absolutely right. Axel had a very informative article, and I enjoyed updating myself about the on-going trials. My only “beef” with the article was the overall tinge. I think the readers ought to be informed about overall context. Inflammation is not a crucial phenomenon in the etiology of coronary artery disease. There are plenty of people who indeed think we can neglect the well-established evidence about the traditional risk-factors and just focus on inflammation.

David Brown
Guest

“If you want to prevent CHD, look for the population who do not have CHD and study whether there is something to learn from them.” That’s a good idea. The Kitava study is about one such population. https://www.staffanlindeberg.com/TheKitavaStudy.html Interestingly, Kitivans consumed a low-fat/high-carbohydrate diet and about 77% of adults were daily smokers. Average cholesterol levels were higher in Kitiva than in Sweden. https://www.carbohydratescankill.com/2435/pearl-of-kitava-study-2-of-2 Comment: “Although Kitavans took in less fat than Swedish from their respective daily energy intake, according to the Kitava Study, nearly 81% of the fat, which Kitavans consumed, was saturated; and slightly over 47% of the saturated… Read more »

Raymund Edwards
Guest

Newish study on omega 3 , Showing benefit

https://www.ncbi.nlm.nih.gov/pubmed/23546563

And on the Kitavans , the most significant difference between them and the Swedes
were insulin levels that were 50% lower .

“For example, the mean insulin concentration in 50- to 74-year-old Kitavans was only 50% of that in Swedish subjects. Furthermore, serum insulin decreased with age in Kitava, while it increased in Sweden in subjects over 50 years of age. ”

https://www.ncbi.nlm.nih.gov/pubmed/10535381

also some more on Vitamin D. I would guess the Kitavans have much higher vitamin D levels and stable levels too )

https://www.thisisreallyinteresting.com/research-shows-why-low-vitamin-d-raises-heart-disease-risks-diabetics/

Mie
Guest
Mie

A new RCT on fish-oil

https://www.nejm.org/doi/full/10.1056/NEJMoa1205409

(more discussion here: https://www.forbes.com/sites/larryhusten/2013/05/08/another-disappointing-study-for-fish-oil-supplements/)

showed overall null results for fish-oil supplementation in terms of primary endpoints (CVD death, nonfatal stroke & MI: later, admission to the hospital for CV causes was added) and secondary endpoints. However, women benefited from fish-oil supplementation.

David Brown
Guest

Mie, Thanks for the info on fish oil. The data supports my contention that the absolute amount of polyunsaturated fatty acid intake becomes problematic in when it exceeds 2 to 3 percent of total caloric intake. Here’s further comment on the matter: “Previous studies of human populations that consume large amounts of omega-3 fatty acids as part of their normal diet suggest a protective effect against cardiac and inflammatory disease. But when researchers added the omega-3 rich fish oil to the diet of mice to see if it would reduce the inflammation caused by omega-6 rich vegetable oils, they were… Read more »

Mie
Guest
Mie

Dave:

“The data supports my contention that the absolute amount of polyunsaturated fatty acid intake becomes problematic in when it exceeds 2 to 3 percent of total caloric intake.”

I’ll give it a try…

No Dave, it doesn’t. If you had cared to read any of the meta-analyses provided by me or Reijo, you’d noticed that there’s no proof of this.

And what comes to your mouse study, what relevance does it have in the context of the abovementioned results from human RCTs? Nada.

Andrés
Guest

I don’t think that industrial fare (seed oils and margarine) sold to us as food has past the test of time. Anyone just looking for a reason to choose a prudent diet approach should at least read Chris Masterjhon take on the subject. I will keep avoiding them and not counting calories from anything, including omega-6 (mostly olive oil and nuts in my case).

Low-fat Richard
Guest
Low-fat Richard

Dave, The Kitava folk make up a nice example of healthy & trim starch-based cultures indeed. However, they consume way too much coconut fat and hence show elevated cholesterol levels, although they seem to be protected from CHD. Anyway, there’s too much data against SFAs which cannot be overlooked due to this seemingly anomalous example. I would be very cautious with the use of saturated fat laden tropical oils. The molecular basis for the effects of dietary saturated fat on plasma LDL cholesterol levels is well understood. Saturated fat influences the LDL receptor activity of liver cells as described by… Read more »

David Brown
Guest

So, in Singapore, coconut oil causes CHD but in Kitava it doesn’t? To me that make no sense. What does make sense is that tissue levels of omega-6 HUFA predict CHD mortality. https://wholehealthsource.blogspot.com/2009/05/eicosanoids-and-ischemic-heart-disease.html

Note also that when total cholesterol is graphed against mortality, the safest cholesterol levels fall in the 200 to 240 range.comment image

Low-fat Richard
Guest
Low-fat Richard

40% of the Japanese smokers in the both cohorts smoked 20 cigarettes per day, and CHD was nearly non-existent in Japan at the time, that is. Moreover, I did not mean that potatoes and corn should replace pharmacologic interventions. What I meant was that these naturally low-fat food groups do wonderful things to LDL cholesterol and hence the emphasis should be on these foods in order to prevent CHD. After all, CHD is a food-borne disease.

“Dubbing this disease inflammatory obfuscates the fact that atherosclerosis is a nutritional-metabolic disease”.

–Jeremiah Stamler

Someone
Guest
Someone

It is stunning that Richard keeps pasting always ecological evidence. I think it is generally accepted that prospective cohorts and randomized clinical trials should be the kind of evidence with most value. So why don’t we use them rather then the old ecological studies ? And what do they tell us ? Prospective cohort studies suggest that there is no strong relation with amount of saturated fat intake and CHD. What does RCT tell us, it suggests that at best substituting saturated fat to unsatured fat may give modest benefits if any. Both study types have their problems and weaknesses… Read more »

Low-fat Richard
Guest
Low-fat Richard

^The issue you were discussing, ecologic evidence vs. prospective cohorts were recently discussed in the the two editorial articles of Europe’s leading diet-heart experts (13 of them). They were not too welcoming to the idea’s expressed by Mozzafarian and Co. I personally think that the idea’s held Mozzafarian are ill founded, and they ignore several lines of evidence (see Stamler 2010). But I am not a scientist, I want to only expose people to the “second opinion” which I think receives fairly little attention. Mozzafarian is the hero to those who want to downplay the importance of SFA reduction. However,… Read more »

David Brown
Guest

This Medscape interview with Dr. Christopher Ramsden is outstanding: https://www.medscape.com/viewarticle/780949_3

Excerpt:

“For a little perspective, if you eat a diet from foods that are raised naturally — it doesn’t matter if it is predominantly vegetable-based or meat-based — as everybody would have done up until about 100 years ago, you are going to consume something like 2%-3% of calories from linoleic acid. So with that perspective, the burden of proof would seem to be on the group advocating changes from what you would get in a natural diet, rather than vice versa.”

Richard
Guest
Richard

Axel, did you see this, starting from around 7 min and onwards. From the recent AHA session: https://www.youtube.com/watch?v=DFMtoafT70c&feature=player_embedded “LDL is both necessary and sufficient for coronary disease.” Darren K. McGuire tells about the prevailing perceptions about cholesterol from the UT Soutwestern Medical Center (The place where Brown & Goldstein do their job) and predicts that in the future other lipid-markers besides LDL will loose their significance. The new antibodies allow such a dramatic lipid-lowering that smoking, diabetes and high blood-pressure cannot no longer affect your CHD risk once you are treated. Moreover, the HDL-C levels will not be important anymore… Read more »

Mie
Guest
Mie

“The new antibodies allow such a dramatic lipid-lowering that smoking, diabetes and high blood-pressure cannot no longer affect your CHD risk once you are treated. Moreover, the HDL-C levels will not be important anymore when the new injections enter the market. The quality of LDL will also be rendered largely insignificant when LDL is lowered drastically.” Could you pinpoint the exact time on the video when the abovementioned is mentioned? The point made around 16:30 was that in the context of lower and lower LDL levels, other risk factors become LESS RELEVANT. Do your understand the difference between “less relevant”… Read more »

Low-fat Richard
Guest
Low-fat Richard

At the end of the discussion the one who interviews McGuire says something about we having come to a point where people can continue smoking and having high blood-pressure and yet be unaffected (from CHD). McGuire says jokingly “it was you, who said it”. I don’t have the time review the videos, but that was the way I understood it with my imperfect English.

Mie
Guest
Mie

So you took a joke as a recommendation?

That’s what I thought.

Low-fat Richard
Guest
Low-fat Richard

It wasn’t a joke. McGuire merely conveyd that he agreed, but did not dare to put it that bluntly. What I’ve understood, in English language the phrase “it was you, who said it” has a certain, specific meaning. It implies that the responder generally agrees but would not dare to exactly express him/her self with the same terms.

Mie
Guest
Mie

And here come the semantics.

There simply isn’t any basis to state the smoking or blood pressure will have no role in CVD prevention in the case of low LDL. Have a look at the risk charts for once.

Low-fat Richard
Guest
Low-fat Richard

Well, cigarette smoking becomes just “less relevant” at the presence of low LDL-C levels. We have a large body of ecologic evidence, especially from the Pacific region where low-fats diet are consumed and cigarette smoking is practiced en masse. At the top of this, as McGuire concluded, not a single case of CHD among those with heterozygot PSCK9 knock-out mutation. Considering that the prevalence of this mutation is largely confined to the African-American minority, we can reckon that healthy-living patterns were probably even less prevalent among these individuals compared to the majority population. This assumption is of course not certain,… Read more »

David Brown
Guest

Further evidence that omega-6 is problematic. Excerpt: Another possible rationale for the differences in insulin resistance and inflammation across the diets may be the disparities in the linoleic content (C18:2),(11.4%, 9.4%, and 5.4% of total caloric intake for the 6%-SF, 12%-SF, and 24%-SF diets, respectively). Even when controlling for various ratios within an iso-caloric diet, the manipulation of one macronutrient, or sub-set of macronutrients, results in an uncontrollable alteration of another. As such, in the current study, alterations in the percentage of SF across diets also resulted in changes in the percentage of unsaturated fat. Thus, although the ratio of… Read more »

Low-fat Richard
Guest
Low-fat Richard

Doc,

did you notice this. Kaiser Permanente has an important message for physicians. I forward this for you because you are interested in preventative medicine.

Nutritional Update for Physicians: Plant-Based Diets
https://www.thepermanentejournal.org/files/Spring2013/Nutrition.pdf

Axel F Sigurdsson
Admin
Axel F Sigurdsson

Thanks Richard. I agree. Plant based diets are certainly effective for cardiovascular prevention. The problem as I see it is that people/patients have such a hard time sticking to it.

Mie
Guest
Mie

Andre: There’s nothing “industrial” in e.g. extra virgin olive oil – or if there is, then virtually everything we eat is “industrial”. And at any rate, “industrial” simply isn’t a synonym for “unhealthy” anymore than “natural” is a synonym for “healthy”. As for Masterjohn’s article, it’s the same ol’ PUFA/n-6 scare. Nothing statistically sound – and compared to the results from the aforementioned meta-analyses, it’s … well, just what you might expect from a blog post from an author who has decided his stance & to hell with the evidence. Masterjohn has nothing solid to back up the notion that… Read more »

David Brown
Guest

The so-called “n-6/PUFA scare” is not a scare. Here’s the latest review: Abstract Although early studies showed that saturated fat diets with very low levels of PUFAs increase serum cholesterol, whereas other studies showed high serum cholesterol increased the risk of coronary artery disease (CAD), the evidence of dietary saturated fats increasing CAD or causing premature death was weak. Over the years, data revealed that dietary saturated fatty acids (SFAs) are not associated with CAD and other adverse health effects or at worst are weakly associated in some analyses when other contributing factors may be overlooked. Several recent analyses indicate… Read more »

pronutritionist (@pronutritionist)
Guest

This review is behind the times and dismisses the meal studies on SFA totally.

Axel F Sigurdsson
Admin
Axel F Sigurdsson

Hi Reijo. Can you provide a reference so everybody understands what you mean by the meal studies on SFA.

Mie
Guest
Mie

Perhaps Reijo means the fact that SAFA is used when studying inflammation induced by fat content of food? It is the most pro-inflammatory of fats. See e.g. https://www.ncbi.nlm.nih.gov/pubmed/21430255 https://www.ncbi.nlm.nih.gov/pubmed/19625064 https://www.ncbi.nlm.nih.gov/pubmed/22059644 As for Lawrence’s work, it has numerous problems. 1) The part “Dietary fatty acids and serum cholesterol” fails to point out the detrimental effect that SAFA has on LDL receptor activity. Nor does Lawrence mention the multitude of metabolic ward studies that show very clearly that the effect of SAFA on blood lipids is simply nothing to be excited about. 2) When discussing Ramsden et al (2010), Lawrence fails to… Read more »

David Brown
Guest

Meal studies are generally too problematic to connect SAFA directly to inflammation. Interview with Ron Krauss: “Ron Krauss, there’s so much debate about saturated fat. Some studies say it’s perfectly fine to have it, and yet as a standard policy in most health clinics and with institutional recommendations, it’s, “keep the saturated fats low.” Meanwhile, your research has been a little frustrating. You don’t come out clearly saying one way or the other. Instead you say, it depends. It depends on what the saturated fat is eaten with.” Krauss responds: “I don’t know if I have to apologize for the… Read more »

Mie
Guest
Mie

“Meal studies are generally too problematic to connect SAFA directly to inflammation. Interview with Ron Krauss:” This interview doesn’t discuss meal studies nor metabolic ward studies. “Read that last sentence carefully. A very large percentage of people with a normal metabolic profile (Pattern A, larger particle LDL) shifted into a riskier, pattern B mode when saturated fat intake was reduced.” This may happen if fats, including saturated fat, is replaced with refined carbs. This has been shown multiple times. No such thing happens when SAFA is substituted by MUFA or PUFA nor carbs with low GI/high fiber content. In addition,… Read more »

Z.K.
Guest
Z.K.

I generally agree with David. The short term inflammation studies cited by Mie do not strongly support the conclusion that saturated fats are pro-inflammatory. In the first citation notice the weak conclusion and the last sentence – “In summary, our data indicate that exchanging SFA from butterfat for (n-6) PUFA in a mixed meal may decrease postprandial lipemia and affects several postprandial markers of inflammation and endothelial activation in overweight men. Postprandial glucose and insulin concentrations were not affected differently. The impact of these findings on long-term health remains to be elucidated.” In the second citation there was an increase… Read more »

Reijo Laatikainen (@pronutritionist)
Guest

IF you like to read what Ronald Krauss’s current view (2013) is on saturated fats, read this slide set named “setting the record straight the saturated fats” According to him good fats are “Good (fats):  Polyunsaturated fats (vegetable, nut, seed, fish oils)” https://www.ciaprochef.com/wohf2013/presentations/2013WOHF_RonaldKrauss.pdf And in this interview he recommends (conclusions and recommendations): “Use oils high in polyunsaturated fat (e.g., safflower, corn oil) and avoid foods with trans fats from partially hydrogenated oils (read the label). Unless you have a tendency for high cholesterol, you can *occasionally* eat cheese and butter.” Also see this “In addition”, says Dr.Krauss, “the results… Read more »

David Brown
Guest

Thanks for the information. I’m not seeking satisfaction. Rather, I’m just trying to sort things out. As I learn, I alter my opinions according to what makes sense. At present, the world-wide increase in n-6 consumption seems to correlate more strongly with the increased burdens of aggression, depression, and non-communicable disease than saturated fat. Excerpt: “…Crawford, Cordain, Simolopous, and others have advanced the concept of population-wide deficiencies of n-3 LCFAs in modern societies that rely on industrialized agriculture. Those authors cited, in part, that diets during the 4–5 million years of hominid evolution were likely abundant in seafood and other… Read more »

Mie
Guest
Mie

“As for those RCTs that showed no inflammatory effects in humans with increased intake of linoleic acid, it’s important to realize that it takes a long time for linoleic acid to noticeably alter anything measurable in terms of inflammation.”

Now Dave, once again: what is the experimental/physiological/etc. basis for this claim? How/why would LA be different from SAFA or trans fats?

Mie
Guest
Mie

In addition, this point from the clip above

“In stark contrast, at the turn of the recent millennium, a single food source, soybean oil, appears to deliver 20% of all calories in the median US diet, with 9% of all calories from linoleic acid alone.”

seems … shall I say, “odd”. According to NHANES 2009-10, a regular American gets about 6,5% of total energy intake from n-6 fatty acids. Now, the intake of LA cannot possibly be HIGHER than the entire PUFA intake, can it?

pronutritionist
Guest

If linoleic acid would be toxic in long, it would show up in epidemiological studies. Linoleic acid intake is rather linked to decrease in inflammatory markers most cohorts. See Calder et al 2011 review paper I mentioned earlier. It’s free and has got nice table on this.

Nuts are very high in linoleic acid and they are either neutral or anti-inflammatory in RCTs. There is no solid human data to support your claims. Patient cases are interesting but not much of value when evaluating cause and effect.

Reijo Laatikainen (@pronutritionist)
Guest

Doc, some of the meal studies and longer RCT trials are referred in this slide deck of mine. https://www.slideshare.net/pronutritionist/fats-and-inflammation Mie mentioned also some more meal studies, but you may also look to a RCT by Bjermo et al. 2012. https://www.ncbi.nlm.nih.gov/pubmed/22492369 I guess it all began from Cerillo’s work: see open access paper below (Fig 1). They used cream as “high fat”. As many know, OGTT is glucose load. Cream causes long and strong inflammatory response. OGGT causes to inflammation byt the effect is shorter. https://circ.ahajournals.org/content/111/19/2518.full.pdf I also want to point out that a recent systematic review on human RCTs (not… Read more »

Low-fat Richard
Guest
Low-fat Richard

There’s not a single real diet-heart/lipid/atherosclerosis expert in the face of this planet who would promote the consumption of red meat, butter, high-fat cheese, whole milk & cream.

pronutritionist
Guest

See this recent randomized trial. Robust CRP reducing effects (-~60 %) on PUFA and increase on SAFA (+~30 %, NS).

“C-reactive protein significantly decreased (p<0.02) after the PUFA diet period (6.61±2.49 vs. 2.56±1.64 mmol/l, p<0.05), whereas its increase after the SAFA diet did not reach statistical significance (2.95±1.98 vs. 3.30±2.54 mmol/l, n.s.)"

https://www.biomed.cas.cz/physiolres/pdf/62/62_145.pdf

Intakes of PUFA and SAFA were extremely high.

David Brown
Guest

For me, it was frustrating to read this study due to lack of clarity. Quote: “The result of this study proved that proportion of PUFA and SAFA the dietary intake might affect the systemic inflammation and to influence CVD risk in addition to a change of concentration of atherogenic lipoproteins.” Then there’s this: “Although the direct effect of SAFA in vivo in men has not been proven by epidemiology and clinical data definitely, the molecular biology mechanism of the proinflammatory effect of SAFA has been described at the tissue cultures level (Suganami et al. 2009). Perhaps the reason for the… Read more »

R.E.
Guest
R.E.

In Dec 2013 it was shown that the inflammation is a product from Omega-6 and Fructose, Vegetable oils and Sugar. It is those two and LDL APOS B protein smaller than 25 nm that creates the plaque. Cholestrol have nothing to do with CVD. They are the medical care gang that are there to rebuild the damaged cells.

pronutritionist
Guest

Sorry that trial is not RCT but non-controlled

David Brown
Guest

RCTs are not the only legitimate science. Moreover, while RCTs may be helpful for determining whether a drug provides benefit or not, they may not be appropriate for determining whether nutrients such as saturated fats cause problems such as cancer or heart disease. More than 50 years of epidemiological studies and RCTs have done little to dispel the confusion over which fats cause harm at higher intakes and which are harmless or beneficial.

https://www.jclinepi.com/article/S0895-4356%2898%2900018-3/abstract
https://www.ncbi.nlm.nih.gov/pubmed/19364995

Raymund Edwards
Guest

Context matters

The lower the fasting Triglyceride.
The much lower the after meal excursions in Blood fats , Sugars and Inflammation

” All other metabolic responses were independent of the P/S ratio ingested.”

https://www.ncbi.nlm.nih.gov/pubmed/18829281

.

David Brown
Guest

Historically, Dietary Reference Values (DRV) for fats have been based on untested hypotheses as to how fats affect biochemistry. Recent research suggests that upper limits for total and saturated fat intake may be arbitrarily low. For example: OBJECTIVE—The recommendations for dietary fats in patients with type 2 diabetes are based largely on the impact of fatty acids on fasting serum lipid and glucose concentrations. How fatty acids affect postprandial insulin, glucose, and triglyceride concentrations, however, remains unclear. The objective of this study was to study the effect of fatty acids on postprandial insulin, glucose, and triglyceride responses. https://care.diabetesjournals.org/content/30/12/2993.full Another paper… Read more »

Kim
Guest
Kim

Hello!
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It up-regulate “survival genes,” those genes that enable cells to survive in the face of stress from free radicals and other oxidants, and down-regulates other genes that promote inflammation and fibrosis to help the body function at an optimal level. Please let me know if you would like more info. It is truly a class creating breakthrough product!! ([email protected])

Alfred O. Richardson
Guest

Chronic low-grade inflammation documented by high levels of inflammation-sensitive plasma proteins is associated with the fatality of future coronary events. Men who have been exposed to a low-grade inflammation many years earlier have a higher proportion of coronary heart disease deaths and less nonfatal myocardial infarction.

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