J Leonard Dixon

One day I was taking a break from swimming in the pool when the fellow in the next lane struck up a conversation.  He told me how he had a heart attack eight months earlier.  He was now swimming to stay in shape. Before his heart attack his doctor had told him that his lipids were perfect!  Therefore, he did not watch what he ate and he would always go for that second slice of cheesecake!  Now everything was different.  Besides exercise he was now on a strict diet and watched everything he ate.  Then he turned to me and said, “But my doctor said my lipids were perfect and I still had a heart attack.  Can you believe it?”

Actually, I can.  If you understand lipid metabolism you can imagine how such a thing is possible.

The above story illustrates some of the criticisms of the lipid hypothesis concerning CHD.  But the Framingham Study showed us that the blood LDL cholesterol concentration was just the tip of one iceberg among many risk factor icebergs.  And the process of CHD development is extremely complex and occurs slowly over many years.  In fact, there are several biological avenues that can lead to increased atherosclerosis in the main coronary conduit arteries.

The experience of the Finns in East Finland after the realization that their diet was leading to increased CHD is probably the strongest data we have indicating that a high saturated fat diet, along with a diet low in plant materials, leads to high blood cholesterol levels and high CHD.  When the Finns changed their diet, treated high blood pressure, and decreased smoking, their CHD rates decreased to 50% of the rates originally observed in the late 1950-early 1960s.

But the CHD rate still remained high and it is difficult to reverse atherosclerosis after someone has been eating a poor diet for many years.  It is also the case that many other biological processes, besides high LDL cholesterol, are involved in the development of atherosclerosis.

Let’s review some of the biological mechanisms that are now being investigated for their effects on the development of plaques in the coronary arteries. The following figure shows that there are many biological factors that affect the health of the artery. On the left is a spanking clean artery, and on the right is an artery that has an atherosclerotic plaque. The surrounding arrows on the left show that there are many biological processes that influence and stimulate plaque development.

LDL-cholesterol is just one factor. Another factor is the health of smooth muscle cells.

Smooth Muscle Cell Growth & Migration

Smooth muscle cells surround the endothelial cells, the sub endothelial space, and the internal elastic lamina that line the artery lumen (central area). Just like regular muscle, smooth muscle cells can either contract or dilate in order to change the area of the opening. For reasons that we do not understand, smooth muscle cells can turn proliferative and begin to divide. Then with the help of an enzyme called MMP-9, a protease that can chew through matrix, smooth muscle cells undergo migration and can move into the subendothelial space or even into the lumen of the artery.

Jason Lee Johnson.  Emerging regulators of vascular smooth muscle cell function in the development and progression of atherosclerosis

Another factor involved in plaque development is the immune system and its powerful taskmaster, the inflammatory response, which is now considered a central mediator of atherosclerosis. As stated by one group of researchers, “Inflammation initiates, propagates, and complicates the course of atherosclerosis. A multitude of basic science work demonstrates this pathophysiological principle.”

D. Wolf; P. Stachon; C. Bode; A. Zirlik. Inflammatory mechanisms in Hämostaseologie 1/2014 63-71

An important aspect of the inflammatory response is the recruitment of immune cells to the location where the atherosclerotic plaque is growing. The reason for this is that the body wishes to repair the artery. But what really happens is that the immune cells will over react and damage the artery. The inflammatory response is thought to be behind the damaging effects of stress, infection, pollution and toxins.

Diabetes also has a very strong effect on coronary arteries. In fact, at each level of cholesterol concentration in the blood, diabetics have 4 times the rate of CHD compared to non-diabetics. This indicates that diabetes provides a very strong additional damaging effect on the artery above that provided by LDL-cholesterol.  How diabetes increases heart attacks is a major research area in medicine.

There have been reports that low levels of vitamin D metabolites are associated with increased rates of CHD. Low vitamin D action may cause cells in the artery to lay down calcium phosphate, thus leading to the calcium build up observed in advanced plaque regions.   Therefore, the extra levels of sunshine that people in the Mediterranean area receive the year round may increase vitamin D production in the skin. This would lead to greater activity of vitamin D dependent processes and cause the artery to be healthier, thus contributing to their lower rates of CHD. This is another reason why the intake of fish, which is high in vitamin D, may be protective against CHD.

Eva Kassi, Christos Adamopoulos, Efthimia K. Basdra, Athanasios G. Papavassiliou.  Role of Vitamin D in Atherosclerosis.  Circulation. 2013;128:2517-2531.

But why can’t I eat that second slice of cheesecake if my lipids are perfect?

The digestion and absorption of fat in the diet is extremely efficient, with greater than 90% of the fat consumed being rapidly absorbed and transported throughout the body for use or for storage in about 5-6 hours after a meal. This high efficiency and high capacity is evolutionary beneficial.   And it also explains why your cousin didn’t collapse and die on his way home after he went to an “all the steak you can eat” restaurant and ate three 21 ounce steaks. The body can handle this amount of fat occasionally. Large intakes of nutrients, including fat, occurred throughout history when hunter-gatherers made big kills of animals after times of relatively low food availability.

Over flow of fatty acids in the post-prandial state (after a meal) – the work of Dr. Elizabeth Parks

We now realize that very high amounts of saturated fatty acids can lead to fatty acid toxicity, which is often the result of damaged mitochondria, the power houses of the cell.   Repeated intakes of high fat diets may lead to sick or diminished mitochondria in both smooth muscle cells and in the cardiomyocytes, the main cell in heart muscle.

An example how this might occur has been put forth by Dr. Elizabeth Parks.  For the past 10 years Dr. Elizabeth Parks has carried out the most exciting and informative studies on fatty acid metabolism in humans. She showed how both dietary and stored fat contribute to the free fatty acids that permeate throughout our bodies at every second of the day. Most recently she has documented fatty acid spillover after meals containing fat. Fatty acid metabolism is explained more thoroughly in the next chapter, but I wish to cover fat absorption from the diet right now. The figure below shows how fat is absorbed from the small intestine into the blood and how it is then distributed throughout the body for storage or use.

Lambert JE, Parks EJ.  Postprandial metabolism of meal triglyceride in humans.   Biochim Biophys Acta. 2012 May;1821(5):721-6

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3588585/

Fat is digested in the small intestine and is taken up by intestinal cells and packaged into a special lipoprotein called a chylomicron (Chylo). Chylomicrons are transported in the lymph and are dumped into the blood at the thoracic duct.   Once the chylomicrons enter the blood they travel to peripheral tissues where an enzyme called Lipoprotein Lipase (LPL), which is on the surface of the vessels, traps the chylomicrons and cause hydrolysis of the triglycerides to free fatty acids. Through a mechanism that is not understood, these fatty acids enter the various tissues, where they are used for energy (bone marrow, muscle) or where they are stored (adipose tissue, aka fat cells). After permeating through the body what ever is left of a chylomicron particle is taken up by the liver. The most amazing thing about this process is its efficiency and speed; the half life of a chylomicron particle is five minutes.

In the second figure is a situation where there are much greater numbers of chylomicron particles in the blood and the tissues are not processing the fat fast enough. Therefore, there is fatty acid spillover into the blood and the fatty acids go to both the liver and the heart. The heart uses fatty acids for energy but it doesn’t have the ability to store them. Therefore, excess fatty acids cause damage to the mitochondria of the heart. The damage is probably not significant in the short time, but after many years of this abuse, there can be loss of active cardiomyocytes, the work horses of the heart.  There is also increased proliferation of smooth muscle cells that cause plaque growth.

Dietary fat that is adsorbed into the blood has to be efficiently stored in adipose or oxidized in peripheral tissues like muscle. If not, there will be spillover into the free fatty acid pool in blood and this could make its way to the heart. Conditions that exacerbate the spillover are lack of exercise, diabetes, and very large fat meals. So in addition to bringing in those extra kcal, that second piece of cheesecake may be damaging your heart mitochondria or causing plaque build up.

The blood lipids that your doctor measures are levels of lipids that are in your blood in the fasting state. But all of the above happens after you eat a meal. Therefore, your fasting blood lipids can be perfect, but you can be doing yourself harm by eating a consistent high, saturated fat diet.

Remember, humans needed to process huge amounts of fat after that successful hunt, so occasionally, it is OK to eat that first piece of cheesecake!

The Genius of Ancel Keys

If you read How to Eat Well and Stay Well the Mediterranean Way, published in 1975 and a New York Times Best Seller, you will recognize that Dr. Ancel Keys and Margaret Keys wrote an expansive review of diet and health that quite frankly cannot be surpassed by later books.   The vast amount of information in the book is staggering, and the recipes are real and every one of them was tested by the Keys family in their own kitchen.

The misinformation concerning Dr. Keys and his views on nutrition and health that are promulgated by some media personalities today is hard to explain. One wonders whether they have taken the time to read Dr. Keys’ books, including Seven Countries and the three cookbooks he and Margaret Keys wrote.

Dr. Keys spent most of his career studying nutrition and health.  And during a very long career, he made many discoveries, including these major accomplishments that had a great impact on the American people:

1. He formulated ready to eat meals (called K-rations) for the American armed forces during World War II.  These turned out to be a technical success and are immortalized in hundreds of movies and books about World War II.

2. He led a major study during World War II on starvation that provided important information on how to treat starved individuals

3. He conceived and implemented the Seven Countries study and identified important dietary factors that protected against coronary heart disease.

But in my opinion, the true genius of Dr. Keys was displayed when he and Margaret Keys wrote the 470 page cookbook, How to Eat Well and Stay Well the Mediterranean Way.   This book clearly explained the effects of diet on health and disease, and then they went on to show how to prepare healthy Mediterranean meals through the tested recipes in the book.  It was their attempt to disseminate their knowledge directly to the American public.

However, the problem in all this was that, although the book was on the New York Times Best Sellers list, the message did not get out to everyone.  And when the book went out of print, it was no longer available to provide guidance to Americans.

Quite honestly, I never heard of How to Eat Well and Stay Well the Mediterranean Way before I started to write about Ancel Keys. In fact, as I discussed earlier, it was difficult to find the book.  And when I read it, I was absolutely amazed at the vast amount of information that it conveyed. The most surprising observations in the entire book were that Dr. Keys stated conclusively that cholesterol intake and total fat intake were not important factors in the development of coronary heart disease.  On the contrary, it was clearly written that the type of dietary fat was the most important factor in the development of CHD.  This conclusion came from the observation that although the total fat kcal consumed on Crete was very high, there was very little coronary heart disease on the island. Dr. Keys scoured the island and could not find any patients with CHD in hospitals or being treated by doctors. This was especially important in convincing Dr. Keys that total fat was not the main culprit in CHD. How to Eat Well and Stay Well the Mediterranean Way was published in 1975 and Seven Countries was published in 1980, and, unfortunately, there was very little overlap in the background material that was presented in each book.

This may have been a mistake, because anyone who did not read How to Eat Well and Stay Well the Mediterranean Way because it was a cookbook, missed out on a wealth of information that it conveyed.  But some how the messages that Dr. Keys and Margaret wrote about were short lived, and because of this, some of the conclusions reached by Dr. Keys were needlessly debated by researchers in the cardiovascular field for many years afterward.

But the news about the Mediterranean diet is being spread by a whole new crop of researchers and physicians.  Even recently, a study on the Mediterranean diet that supported the observations of Dr. Keys was published in 2013.  This study on the protective effects of the Mediterranean diet on CHD was conducted by Dr. Ramon Estruch of the University of Barcelona, and was contributed to by other researchers from around Spain. It was a dietary intervention trial that was designed to have three groups, a control group that was instructed on how to eat a conventional low fat diet, and two groups that were instructed on how to eat a Mediterranean diet, with increased olive oil intake in one group and increased intake of a mixture of nuts in the the other group. When the study was published in the New England Journal of Medicine in April 2013, it was hailed by experts as a breakthrough and a successful study based on its experimental design.

The most important observation made in the study was that even when participants (with no cardiovascular disease at enrollment) were recruited quite late in life (men – 55 to 80 years of age; and women – 60 to 80 years of age), a traditional Mediterranean diet with either ample intake of olive oil or ample intake of nuts was protective (a relative risk reduction of approximately 30%) against acute myocardial infarction, stroke, or death from cardiovascular causes versus the conventional low fat diet was consumed by the control group.

But there was something missing in the discussion section of the Estruch study, and this was the acknowledgment that the results largely supported the observations that Dr. Keys and his colleagues made in the Seven Countries study, and which Dr. Keys reported on in numerous scientific articles and in his two books, How to Eat Well and Stay Well the Mediterranean Way (1975) and Seven Countries (1980).

However, the editors of the New England Journal of Medicine asked Dr. Sarah Tracy to write an editorial to connect the current paper to earlier work by Dr. Keys and others.

Sarah W. Tracy, Ph.D. Something New under the Sun? The Mediterranean Diet and Cardiovascular Health N Engl J Med 368;14 p1274, April 4, 2013

Dr. Tracy wrote, “The first epidemiologic data supporting the Mediterranean diet came from the Seven Countries Study (SCS), a prospective investigation of diet and other cardiovascular-disease risk factors in 16 cohorts totaling nearly 13,000 men in the United States, Italy, Greece, Yugoslavia, Finland, the Netherlands, and Japan, which began in 1958…..The PREDIMED results would come as little surprise to the man behind the SCS, American physiologist and epidemiologist Ancel Keys, who advanced the low-fat diet and the low-saturated fat Mediterranean diet for the primary and secondary prevention of heart disease. Keys “discovered” the Mediterranean diet’s health benefits in the early 1950s, when visiting the region as a medical scientist concerned about the widely reported increase in heart attacks in the United States.”

In my mind, the Estruch study was an important study because it was carefully designed and strictly carried out under difficult, modern-day circumstances.  The most amazing outcome of the study was that the protective effects of the Mediterranean diet were observed in such an older population after only approximately five years of implementation. In fact, the study was stopped after a median follow-up of 4.8 years because the results were so persuasive, and the authors thought it was not ethical to continue the control population, which had higher rates of cardiovascular disease, on the conventional low fat diet.

Interestingly, there was one major difference between the results observed in Dr. Estruch’s study compared to the earlier results observed by Dr. Keys. This was that in the Estruch study, there were no differences in the rates of total deaths from all causes between the populations consuming the Mediterranean diet and the Control population that was consuming a standard low fat diet (Death from any cause 0.82 (0.64–1.07); 0.97 (0.74–1.26); 1.00 (control); p values were 0.15 and 0.82).  In contrast, at the time of Ancel Keys’ study, there were in fact lower total death rates (from all causes) in populations who consumed a Mediterranean diet compared to the participants in the U.S.A. and northern Europe, who consumed a classic “Western” style diet (See figures below). The differences in this important outcome were probably due to the fact that at the time of Keys’ investigations, the populations had been on the Mediterranean diet for most of their lives and they had received more comprehensive protective effects.  Also, the populations in other regions were consuming a higher fat diet.

In 2010 a meta analysis involving a total of more than 2 million subjects investigated the role of the Mediterranean diet in enhancing heath showed that that a 2-point increase in adherence to the Mediterranean diet was associated with a 8% reduction of death from all causes, a 10% reduction in incidence of cardio- and cerebrovascular diseases, a 6% reduction in the incidence of neoplastic diseases, and a 13% reduction in the incidence of neurodegenerative diseases. At first reading these reductions do not seem that significant, but one has to remember that people in many Mediterranean areas are subject to factors that promote a more “Western” lifestyle.

When discussing the utility of the Mediterranean diet today, the most important question would be the one that Dr. Ancel Keys would ask first, Is the Mediterranean diet that is being proposed today the same Mediterranean diet that he studied in the 1950s, when the coronary heart disease rates were extremely low to non-existent?  One problem with more modern studies of the health promoting effects of the Mediterranean diet are that the participants are greatly affected and influenced by the Western lifestyle.  However, the Estruch’s study and the 2010 meta analysis show that the positive effects of the Mediterranean diet can still be observed today.

Therefore, a general conclusion is that populations that consume a Mediterranean diet for their entire lives, not only exhibit lower rates of cardiovascular disease, but they also live a longer life, too, compared to populations eating a “Western” style diet.