Correlation Between Oxysterol Consumption and Heart Disease

Fred A Kummerow

Disclosures

Clin Lipidology. 2013;8(3):289-294. 

Introduction

Fred A Kummerow speaks to Hannah Wilson, Assistant Commissioning Editor
Fred A Kummerow is a 98-year-old emeritus professor of comparative biosciences at the University of Illinois (USA). Kummerow has spent over six decades studying lipid biochemistry trying to explain the primary causes of heart disease. His research contradicts commonly held notions about the role of dietary cholesterol. Over his lengthy career, Kummerow has painstakingly collected and analyzed the findings that together reveal the underlying mechanisms linking oxidized fat to heart disease. He is a long-time advocate for a ban on trans fats in food and filed a petition with the US FDA to that regard in 2009.

The Majority of Your Work has Focused on the Role of Dietary Factors in Heart Disease; What First Attracted You to and Kept You Interested in a Career in This Field?

I had written an article for Science in 1957 titled 'Occurrence of Trans Fatty Acids in Human Tissue' with two of my graduate students.[1] This was the first result of my interest in studying how nutrition related to atherosclerosis. I had performed research on trans fatty acids and how they related to nutrition. Good nutrition is essential for keeping the blood flowing, so as to provide nutrition to all the cells. I realized that I could get funding from the National Heart, Lung and Blood Institute that was created by the US Congress in 1948 to undertake heart research and I stayed interested in this aspect because I wanted to find out the cause of heart disease. In 1979, I was asked by the editor of the American Journal of Clinical Nutrition to explain nutritional imbalance and angiotoxins as dietary risk factors.[2] I demonstrated that the nutritional imbalance was due to the increasing amount of vegetable oils in the diet and the consumption of excess oxysterols, which include those produced during the frying of foods and even include vitamin D. Swine fed a cholesterol-free diet developed the same type of atherosclerosis, at the electron microscope level, as a patient who had died of coronary heart disease. I therefore knew that dietary cholesterol was not necessary for the production of atherosclerosis in humans. This knowledge has kept me interested for the last 33 years in heart disease. I have continued to make important contributions to our understanding of heart disease throughout this time.

What Would You Consider to be the Biggest Achievement of Your Career to Date?

The biggest achievement of my career to date has been the publication of my article online in the January 2013 issue of The American Journal of Cardiovascular Disease.[3] In this publication, I described my findings; namely, that atherosclerosis in modern human beings is based on the biochemistry, composition and structure of three of the five phospholipids in the cell membrane of the coronary arteries. My findings indicate fried foods, powdered egg yolk, excess vegetable oils, partially hydrogenated vegetable oils and cigarette smoke as the greatest culprits in heart disease. Fried foods and powdered food substitutes are dietary sources of oxysterols, which alter the phospholipid membranes of our arteries in ways that increase the deposition of calcium, a key hallmark of atherosclerosis. Consumption of excess polyunsaturated fats stimulates the formation of oxysterols within the human body. Cigarette smoke and trans fats from partially hydrogenated vegetable oils interfere with fatty acid metabolism, leading to the interruption of blood flow, a major contributor to heart attacks and sudden death. In my opinion, many of these factors have been largely ignored by the medical establishment, which has focused instead on using drugs to lower cholesterol levels. I hope my recent publication in The American Journal of Cardiovascular Disease changes this and provides the answer for proper dietary advice.

Could You Tell us a Little About the Interactions of Oxysterols With Phospholipids in the Arteries and Their Contribution to the Development of Coronary Artery Disease?

Research by Shah and Schulman demonstrated that sphingomyelin undergoes hydrogenation in the presence of salt water, which is similar to human plasma, giving it an ionic charge that can interact with calcium.[4] In my laboratory, we demonstrated that liposomes are much more likely to precipitate in the presence of calcium when they are enriched with sphingomyelin. Altogether, this data demonstrates that oxysterols contribute to arterial calcification by increasing the sphingomyelin content of arterial cell membranes. Cells incubated with nonoxidized cholesterol did not affect sphingomyelin content.

In my laboratory, we have previously analyzed the plasma and arterial tissue of patients undergoing coronary artery bypass grafting (CABG) surgery to see how these tissues differed from those of controls with no stenosis, like the artery in the placenta. The CABG patients had greater levels of sphingomyelin in their arteries and greater concentrations of oxysterols in their plasma than their controls. We also observed similar results in aging swine, which developed atherosclerosis even without a source of cholesterol in their diets. To test whether the oxysterols in the plasma were responsible for the changes in the phospholipid membrane and whether these changes contribute to atherosclerosis, we incubated arterial cells with oxysterols. The oxysterols increased the synthesis and cell membrane content of sphingomyelin, as well as the uptake of calcium. The increase in sphingomyelin occurred before the increase in calcium uptake, suggesting that sphingomyelin itself may be the culprit in arterial calcification. Most remarkably, when we incubated cells with cholesterol that had not been oxidized, even at twelve times the concentration of the oxysterols we used, there was no effect on sphingomyelin content.[5] This demonstrates that cholesterol itself is not the culprit in heart disease and has to be oxidized in order to cause harm.

Throughout Your Career, Have You Noticed a Change in the Way Patients With Heart Disease Have Been Treated With Regard to Cholesterol and Lipid Levels: In What Ways has Our Knowledge Advanced and do You Think There Have Been Many Set-backs?

There have been no fundamental advances in coronary heart disease since the meeting that Dr Page had in Cleveland in 1955, where he invited 103 lipid chemists to a symposium focusing on the role of lipids in heart disease, as he related in his book, The Chemistry of Lipids as Related to Atherosclerosis. In this meeting, it was established that high levels of cholesterol in the plasma were responsible for the development of atherosclerosis. Testing for cholesterol levels such as LDL, HDL and other lipid levels was established in 1961 by the American Heart Association. Based on the misconception that cholesterol was the main cause of heart disease, pharmaceutical companies started developing drugs to lower the levels of cholesterol in patients with hyperglycemia. By the end of 1980s, doctors started prescribing statins and in my view, the biggest setback in heart disease treatment has been the overuse of statins for the treatment of high cholesterol. Statins work by reducing the 2 g of cholesterol per day produced by cells in the liver and can cause adverse effects in the body such as raised levels of liver enzymes and muscle issues such as rhabdomyolysis. Sales of statin medications nearly tripled when the National Cholesterol Education Program revised its guidelines to recommend statins as a prophylactic for many heart issues.[6] Although the Education Board cited randomized trials to back statin treatment for primary prevention of occlusive cardiovascular disease, a description in a paper from The Lancet states "not one of the studies provides such evidence".[6]

There have been many new, exciting areas of research in heart disease. The utilization of new genetic tests has allowed a triangle-shaped 'map' of causation for many diseases to be brought forth. This triangle of genetic susceptibility, environmental factors (such as diet) and infection by microorganisms seems to bring to light new research possibilities, not only in the implication of factors that cause disease, but also in new methods of detection and treatment. Clearly, my focus has been on the biochemistry in the veins and arteries, and dietary and environmental factors, which I think are very important for the prevention of heart disease. I think that the recent societal movement towards eating a balanced diet with plenty of fruits, vegetables, dairy products and meat, and minimal amounts of processed foods, to be a great advancement in the future of heart health.

In 2009, You Filed a Petition to the US FDA to Ban Partially Hydrogenated Fats (Trans Fats) From the American Diet. Could You Briefly Explain Your Reasons for Filing This Petition?

I filed a petition in the hope that the FDA would ban trans fats in processed foods. In 1957, I published an article in Science outlining the significant amounts of trans fatty acids that were found in the tissues of heart disease patients.[1] Feeding partially hydrogenated fats to rats caused deposition of trans fatty acids into their tissues. Therefore, it appears that there is a direct link between the trans fatty acids in dietary partially hydrogenated fat and the deposition of trans fatty acids into human and rat tissue. In the presence of trans fat, less linoleic acid is converted to arachidonic acid and less arachidonic acid is converted to prostacyclin. This leads to interrupted blood flow, which contributes to sudden death. I would like to point out the difference here between the trans fatty acids that occur naturally in small amounts in meat and dairy products. These trans fatty acids constitute only 2–5% of the total fat content and are harmless. The largest amount of trans fats in the modern diet originate from fried and processed foods. According to the Trans Fat Task Force, up to 45% of the total fat in those foods containing artificial trans fats is formed by partially hydrogenating soybean oil.[101] This is why we must work to remove all artificially created trans fats from the diet; consumers may be unaware of the amount of trans fat present in their food.

Could You Tell us Whether You Have had an Outcome From This Petition and if You Believe That Banning Trans Fats From the American Diet Will Truly be Achievable?

Yes, there has been an outcome. The FDA now requires labeling of all food products containing trans fatty acids. However, they have allowed foods with less than 0.5 g in a serving to be labeled 0% trans fat. This is misleading because one can often eat more than one serving size. A recent letter in The Journal of the American Medical Association contained a short article claiming that there are fewer trans fatty acids in the diet now than there were 10 years ago, but there is still trans fat present.[7] One of my former graduate students, Dr Robert Allen, was Director of Research at Anderson Clayton Corp. (AZ, USA), the largest hydrogenator in the world. He told me that he could make products free of trans fat but it would cost five cents more a pound and he would no longer be competitive [Allen R, Pers. Comm.]. I have another former student who is research director at Archer Daniels Midland (IL, USA). He told me that he is making trans-free fat for five cents more a pound, which keeps less of it from being sold [Tinney T, Pers. Comm.]. If the FDA would mandate the removal of all trans fats from the diet, then we could easily achieve greater levels of heart health.

Why do You Think Governments Around the World Have Been Slow to React to the Evidence Surrounding Trans Fats?

Governments around the world have been slow to react to trans fats because the companies that are making trans fats have plants in all corners of the world. The governments around the world do not own the plants. The companies are based in the USA and Great Britain. It is the companies that are slow to react because the governments do not pressure them to change. I have visited hydrogenation plants in China, Japan, India, Central and South America, Germany, Great Britain, Holland, Hungry, Bulgaria and Finland. I have also visited five plants in the USA. I have had a professor from Poland who worked with me for a year. He brought fats from Poland and Russia to learn about their trans fat content. He also worked for a year at the local plant that hydrogenates fat to learn more about hydrogenation of fats. On his return to Poland he became head of the Food Department at the University in Warsaw (Poland). Plants in South and Central America, Poland, Finland and Great Britain hydrogenate fish oil. If the companies had to make trans-free fat it would increase production time and the production cost would increase, thus reducing profit. The headquarters of these companies must consider cost, which occasionally occurs at the expense of consumer health.

What do You Think Would be the Next Steps if This Goal Were to be Achieved?

I believe we must model our future work on the progress demonstrated in Denmark. Denmark became the first country to introduce laws regulating the sale of foods containing trans fats in 2003. This legislation effectively banned trans fats from the Danish diet. Stender Dyerberg has hypothesized that that the Danish government's efforts to decrease trans fat intake from 6 to 1g per day over 20 years is related to a 50% decrease in deaths from ischemic heart disease.[8] This approach was employed in California in 2008, after Governor Arnold Schwarzenegger signed a bill to phase out the use of trans fats.[102] In 1985, I presented a paper titled 'Nutritional Aspects of Isomeric Fats' at a conference at the Nestlé Headquarters in Vevey, Switzerland.[9] The conference was led by the Research Director for Nestlé Corp., Marc Horisberger. Nestlé treats Europe as a single market. When Denmark decided to ban trans fats, Nestlé had to change the formulation of its food for Denmark and that benefited the whole of Europe, not only Denmark. I hope that more and more states, countries and major corporations will take notice of this movement, and begin to phase out trans fats.

Your Recent Work, Which Dismisses Dietary Cholesterol as One of the Major Risk Factors for the Development of Coronary Heart Disease, has Been Highlighted in Many Areas. Please Could You Tell us Some More About Your Findings and Why These Contradict What has Been Reported for a Number of Years?

Cholesterol was first implicated in progression of coronary heart disease in 1955[10] and the cholesterol hypothesis was reinforced by the Federal Trade Commission hearing on eggs in 1975.[103] I testified, as did Michael DeBakey, at this hearing in June 1975 that eggs were a good source of nutrition and that cholesterol was a necessary component for bodily function. I also testified that I did not know what caused heart disease in 1975. I did not realize until years later when the entire testimony was published that Dr Cooper, head of the NIH, had testified on 30 May, 1975, stating that eggs contained cholesterol, cholesterol caused heart disease and therefore people should not eat eggs.[103] Reading the final ruling of the Federal Trade Commission makes it evident that only two witnesses testified that cholesterol was not the answer to heart disease. All of the other witnesses (the head of the NIH and many prominent physicians, among others), testified that cholesterol was the cause of heart disease.[103]

The research conducted in my laboratory, as I described above, demonstrated that cholesterol is not a problem unless it is oxidized. Even Ancel Keys, who some consider the father of the cholesterol–heart disease hypothesis said in 1997: "There's no connection whatsoever between the cholesterol in food and cholesterol in the blood. And we've known all along. Cholesterol in the diet doesn't matter at all unless you happen to be a chicken or a rabbit".[11]

Please Could You Tell us Some More About the Studies That Have Led You to Your Current Hypothesis?

The reason for cholesterol being such a risk factor in heart disease is based on studies that used oxidized cholesterol.[12] Many studies used US Pharmacopeial Convention cholesterol, which Dr Imai has demonstrated to contain oxidized cholesterol.[12] Cholesterol can be easily oxidized as demonstrated in an article in an American Heart Association journal.[13] Diets enriched in oxidized fatty acids increase fatty streak lesions in the aorta of cholesterol-fed rabbits. Staprans et al. fed rabbits a chow diet to a control group, which received cholesterol that had been stored at -70°C under N2 to prevent oxidation.[13] A second group received the same diet, except approximately 0.5% of the total added cholesterol was oxidized. These rabbits received 25 mg oxidized cholesterol per day. Five oxysterols were found in the plasma of these rabbits: 7α-hydroxycholesterol, 7β-hydroxycholesterol, β-epoxycholesterol, α-epoxycholesterol, 7-ketocholesterol and 25β-hydroxycholesterol. The percentage of aortic area covered by fatty streaks was twice as great in the rabbits receiving oxidized cholesterol as in the controls. He demonstrated that oxidized cholesterol in the serum of rabbits is both synthesized endogenously and derived from food. Oxysterols are synthesized endogenously via enzymatic or radical-mediated oxidation. In my laboratory, seven oxysterols (two of them, cholestane-3β,5α,7β-triol and 27-hydroxycholesterol, were found in egg powder and frying fats, respectively) were found in elevated concentrations in the plasma of human patients who had undergone CABG surgery, suggesting that they are important in the development of atherosclerosis in both animals and humans.[14]

In addition, in 2000, plasma from 2000 cardiac catheterized patients who had different levels of stenosis: 0, 10–69 and 70–100%, were obtained from doctors at the local hospital in Urbana Champaign (IL, USA).[15] The plasma was analyzed and the results demonstrated that lipid oxidation products increased with the severity of stenosis and the total antioxidant capacity decreased with the severity of stenosis. The plasma cholesterol concentration, however, was not significantly different between these groups of patients. Therefore, the concentration of oxidation products, rather than the concentration of cholesterol in the plasma, increased with the severity of coronary heart disease.

The lipid composition and calcium concentration in tissue samples obtained from cardiac catheterized CABG surgery patients were also obtained at the same hospital and were analyzed.[3] The total phospholipid concentration in the plaque of the carotid arteries of the CABG surgery patients did not differ from that in the nonplaque area from the same patient. However, the percentages of individual phospholipids changed. The percentage of sphingomyelin in the plaque was more than 20% higher than in the nonplaque tissues from carotid arteries. In coronary arteries, there was almost a 20% increase in sphingomyelin in the hard areas, which would form a plaque later on. In these areas, the calcium concentration also significantly increased to 23.6 ± 12.1 mg/g tissue, compared with 5.0 ± 1.02 mg/g tissue in the surrounding soft areas.

My hypothesis for the cause of heart disease and sudden coronary death is based on the composition, structure and biochemistry of the coronary arteries. The main generator of atherosclerosis and sudden death are oxysterols in excess. As demonstrated in the laboratory, normal levels of oxysterols in the plasma will not cause phosphatidylcholine to convert into sphingomyelin and therefore less calcium will bind to the arterial wall, resulting in fewer blockages in the arteries, which will then reduce the occurrence and risk of sudden cardiac death. Removing 27-hydroxycholesterol and cholestane-3β,5α,7β-triol from the diet should be considered as a therapeutic measure for heart disease. Trans fatty acids are, unfortunately, still being consumed at a high rate.

Do You Have Any/Know of Any Further Research That is Underway That Will Further Add to the Evidence That Dismisses Dietary Cholesterol as One of the Major Risk Factors for the Development of Coronary Heart Disease?

Research is currently underway to examine the connection between endothelial inflammation and dysfunction with the consumption of trans fatty acids. The consumption of these trans fatty acids has been positively associated with systemic markers of inflammation and endothelial dysfunction in studies.[16] Endothelial dysfunction is defined as a pathophysiological state, in which normal homeostatic properties of the vascular structure are impaired or lost entirely. Endothelial dysfunction has been positively linked to the incidence of atherosclerosis and is detectable early in the development of heart disease. Detection of inflammation and dysfunction are fundamental for early diagnosis and preventative intervention for cardiovascular diseases such as atherosclerosis, heart attack and stroke.

Do You Think That as Your Interpretation of the Supporting Literature Contradicts That Which has Been Widely Accepted, it is too Late for Change or That Change Will not be Taken Seriously?

I do not think it is too late, nor do I think that change will not be taken seriously; however, researchers need to be listened to. I feel like Galileo Galilei, during his attempts to prove that the earth was round. A statement in Science, a publication of the American Association for the Advancement of Science, said "he was declared suspect of heresy, which for some time led to a ban on the reprinting of his works". I believe that my discoveries will, in time, change the way cholesterol is viewed in the prevention and treatment of heart disease.

Based on Your 60-year Career in the Field and as a Nonagenarian Yourself, What Dietary Advice Would You Give to Aid the Avoidance of Coronary Artery Disease?

This is what I currently eat:

  • Breakfast: A scrambled egg, cooked whole grains and oatmeal served with several kinds of fruit, including banana and those with colored skin, topped with whole milk, a few walnuts, pecans or almonds, and plain yogurt. I drink a glass of whole milk with this. I eat an egg because it has all the amino acids that are required to synthesize the apoproteins, which carry lipids as lipoproteins in the blood;

  • Lunch: Meat or fish prepared under the broiler or baked, potatoes, some fresh or frozen vegetables, a lettuce salad with olive oil and lemon juice dressing, fruit and a glass of whole milk;

  • Dinner: Sometimes, vegetables or vegetable soup that uses up any vegetable leftovers, a piece of whole wheat bread with cheese, fruit and a glass of whole milk.

My best dietary advice is to eat a balanced diet with a differing protein source every day, avoid all trans fats and don't drink soda pop.

What Advances do You Anticipate in Your Field Over the Next Few Years?

I anticipate that coronary heart disease and cerebral stroke will no longer be the leading causes of death in the world.

Do You Believe That Coronary Heart Disease is an Issue That the USA and the Rest of the World, Will be Able to Conquer?

Yes, if you believe my research it has already been conquered. Other lipid laboratories will repeat my findings in the future.

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