Cholesterol Lipid Hypothesis Part IV - Endothelial Dysfunction
February 3, 2020
How does an artery clog?
Let us recap a little at this time.
1) Cholesterol and lipoproteins are significant and necessary for pathology to develop but not the only player in heart disease and atherosclerosis. I believe that inflammation is the root cause of the problem driving the lipid imbalance and plaque formation.
2) Lipoproteins are produced and recycled every day in order to deliver energy to tissues around the body via triglycerides and are a part of the ancient innate immune system.
They are primed and ready to fight all systemic pathogens that are trying to hurt us.
3) Your genetic makeup may dictate whether you produce and/or recycle more cholesterol/lipoproteins than are advantageous in our current environment.
This section is very tricky! There is a lot of science here. I apologize in advance. However, I could not find a reasonable way to tell this story without it.
Now we are going to continue to move well beyond just cholesterol and look at the plumbing.
The artery as discussed last week has an endothelial lining made up of layered thin cells that lay on top of a muscle layer which lays on top of a connective tissue layer making the tube complete. This area is where the dysfunction occurs that leads to a heart attack.
The process starts at the earliest ages. Teenagers have early signs of endothelial dysfunction long before the blood pressure is high or other markers are seen. This process is believed to start at birth and even possibly in utero. According to Dr. Houston, "the process is begun because of chemical stressors and epigenetic forces. Oxidative stress, inflammation and autoimmune dysfunction initiate and propagate hypertension and cardiovascular disease".
As we discussed last week, oxidative stress and inflammation begin in the body when we consume poor quality food and are exposed to toxins and infections initiating chemical reactions in the gut and blood stream that lead to damage.
During the 1960's, the authors of the Seven Countries Study epidemiologically analyzed the mortality risk of thousands of Europeans based on cholesterol levels. They found that the mortality risk was 5 times higher in those people that consumed the most saturated fat, smoked and had the lowest bioflavanoid levels or antioxidant foods consumed. A common feature of the traditional diet amongst populations in the Mediterranean region is a relatively high dietary intake of vegetables, fruits, legumes, whole grains, monounsaturated fats, and nuts, followed by moderate consumption of fish, dairy products (mainly cheese and yogurt), alcohol, and low consumption of red and processed meats. (Kromhout D. 1999). In their mind, the cholesterol level was dietarily driven and associated with heart disease. However, cigarette smoking and antioxidant loads are unrelated to pathways of cholesterol production yet are associated with heart disease. Therefore, there must be more to the story. Couple this with the that fact that we know that less than 50% of heart attack victims have abnormal cholesterol levels at the time of the first event leading us to assume that there are other significant causes of disease other than just abnormal cholesterol levels. This is my contention.
Adults with type 2 diabetes mellitus are 2 to 4 times more likely to die from a heart attack than non-diabetics and can be used as a study population for risk. Something about the disease diabetes has to play a role in the genesis or propagation of coronary artery narrowing and ultimately closure. The current thought is that whatever causes diabetes causes cholesterol and lipoprotein abnormalities which ultimately leads to heart disease.
Let us start with the foods that are known to be associated with obesity and diabetes development, saturated and trans fats, refined sugar and flour. People who consume large volumes of refined flour and sugar stimulate the hormones insulin and leptin to up-regulate genes related to lipid and glucose metabolism/storage. There is an increase in the liver produced enzyme HMG CoA reductase among others making more cholesterol and therefore lipoproteins to carry the energy produced in the lipoprotein cars.The increased insulin simultaneously pushes the excess glucose molecules into fat cells to be stored as triglycerides engorging them in the liver and the peripheral adipose tissue as a storage mechanism. These fat cells are metabolically active releasing pro inflammatory chemicals locally and systemically that increase cellular insulin receptor signaling dysfunction. This signaling defect over time worsens making insulin less active at the cell surface trapping glucose in the blood stream beginning the diabetic state. The fat cells continue to become enlarged unchecked making us appear overweight and fattening our livers. These engorged and inflamed fat cells become oxidized, glycated and targeted by the immune system for death because the immune system perceives them as damaged cells.
This is key point number one: Inflamed fat cells and damaged lipoproteins are now perceived by the immune system as bad guys and need to be dealt with! Now the question is where is this lipoprotein? If it is in the heart, we will have the genesis of coronary artery disease. A professional immune cell called a macrophage within the artery wall swallows small dense oxidized and inflamed LDL lipoproteins that have slipped into the endothelium. This macrophage/LDL cell is now called a foam cell. This foam cell continues to swallow more small LDL particles becoming engorged and dysfunctional releasing more inflammatory danger signals that start a local chemical reaction via the immune system that leads to further damage of the artery wall and then the development of a fibrous plaque to protect the area from further damage.
This is key point number two: If this process is transient, the immune system will do it's job and clear the dysfunctional inflamed dislocated foam cell and restore balance to the heart vessel. However, if the pressures that started the problem persist long term, you now have a chronic inflammatory problem in a critical place in the body. Not good. This is exactly what happens to humans that consume a standard American processed food calorie rich and nutrient poor diet while being sedentary, toxin exposed and mentally stressed.
Other than poor quality refined sugars, now let us now add in certain dietary fats that get incorporated into our cell membranes. The concerning ones are the chemically manufactured trans fats, saturated fats and vegetable-based poly unsaturated omega 6 fats (PUFA). Trans fats are now banned. Lets focus on the other two briefly.
The saturated fats that were noted to be a risk in the Seven Countries Study are known to increase inflammatory molecules in the blood stream. They are derived from animal products and are solid at room temperature. Examples include, milk, butter, corn fed beef, coconut oil among others. They also increase free fatty acids floating around in the blood stream which are directly related to dysfunctional insulin receptor signaling. (Glass et. al. 2012) The more saturated fat that you consume the more you will challenge your system from an inflammation perspective. This is not to say that saturated fats are all bad. It is a moderation decision only.
The PUFA omega 6 fatty acids are primarily derived from the oils of soybeans, corn and rapeseed/canola and are liquid at room temperature and when cooled. They are found in our fryers and junk foods and are unhealthy primarily because they have unstable chemical structures that at high heat or when exposed to pro oxidants become altered to an oxygen radicalized fat like lipid peroxides or oxidized LDL cholesterol.
These oxidized free fatty acids damage the cell membranes, mitochondrial energy production centers and cell signaling molecules leading to cell weakness and poor information transfer. This is not good on many levels.
Recap: In an obese person, we have a scenario where a fat cell has been stuffed by dietary sugar excess and the cell membrane is damaged by oxidized free fatty acids, FFA, making it an immune reactive adipocyte that is releasing pro-inflammtory chemicals systemically. As the lipoproteins increase in the blood stream to compensate for the excess FFA, a concentration gradient forms allowing a small dense LDL particle to slip into the heart vessel wall where it can be oxidized and engulfed by a professional macrophage forming a foam cell. If the foam cell is not appropriately cleared because of the chronic systemic inflammatory lipid onslaught, you have the nidus for an inflamed area that has invaded in the artery wall.
Thus, I believe that the inflammation is the major driver of persistent damage to the heart vessel not the cholesterol itself.
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