About the causes of atherosclerosis, the importance of cholesterol and the effect of drugs (statins)
Atherosclerosis — which in medical language is called atherosclerosis — is the most successful killer of our time. No other disease has killed and hurt as many people in the last 70 years. The dominant type of atherosclerosis is the one that affects the vessels of the heart and that is what we call coronary heart disease. People with coronary heart disease can be completely uneasy, or they can be troubled by angina (chest pain), or even have a heart attack. Atherosclerosis appears to have a penchant for the vessels of the heart, but it is also common to have atherosclerosis of the vessels of the brain (which can lead to stroke), the vessels of the kidneys (leading to stenosis of the renal arteries), and the vessels of the neck (which can lead to stroke). Atherosclerosis means that fat and certain types of cells accumulate inside the vessel wall itself (i.e. the wall of the vessel). A blood vessel can be seen as a tube and atherosclerosis means that it accumulates fat and cells in the wall of the tube.
In this chapter we will discuss what atherosclerosis is, how it arises, the importance of risk factors (especially the importance of cholesterol), as well as treatments (especially statins). This chapter is the first part of a five-part series. We hope that these chapters will highlight common questions and misunderstandings. We who write this text have no affiliation with any pharmaceutical company; we currently do not prescribe medicines; we have never received any remuneration from any company that sells or advocates any of the medicines or practices mentioned in these chapters; we do not sell books on this topic; and we do not sell any services on this topic. We are responsible for giving you the full sum of science, that is, both studies that speak for and against each cause.
In Sweden, this issue is sensitive
These three chapters are important because they make a further contribution to a debate that is quite inflamed in Sweden. Every day, cholesterol, statins and atherosclerosis are discussed on hundreds of Swedish pages and the discussion is about (1) the importance of cholesterol in atherosclerosis, coronary heart disease, heart attack, etc., and (2) the importance of lowering cholesterol, for example with statins. Our statistics show that today there are more blogs and discussions that question cholesterol and statins, and of course it is always good to question science. To illustrate what information you can meet if you are looking for information about statins today, I now do a search on Google. I search with the search term “are statins good?” and then get the following results:
As you immediately notice, the attitude towards statins and cholesterol is often skeptical. Among the results are blog posts and studies that report statins cause cancer, dementia, diabetes and much more. The question is: what is true about statins, cholesterol – what does science say? Here it is a matter of being sober because this field is extremely difficult to navigate and it is a matter of being objective and objective.
The elephant in the room: the absence of scientists
We humans have become blog-lovers. We read blogs all day, demonstrably. As for the topic of health and blogs, there is an elephant in the room. Because there are very few scientists on stage. On the other hand, there are hundreds of blogs that shaped hundreds of thousands of Swedes’s perception of cholesterol and statins, not to mention atherosclerosis.
The discussion on these blogs is necessary. The very best example is the discussion of LCHF, where two doctors (Dr Annika Dahlquist and Dr Andreas Eenfeldt) propagated for LCHF (low carb high fat) diet for many years but had to face strong criticism from the researchers. It turned out that Dr Dahlquist and Dr Eenfeldt were more right in the matter, and the scientists were more wrong. Dr Eenfeldt’s side (Kostdoc) continues to run a much-needed and scientific campaign for better health.
Unfortunately, the discussion of cholesterol and statins has been infected by two factors: (1) far too many confuse the fat content of the diet with blood lipids and (2) the absence of systematic review of the state of knowledge. As far as food fats and blood lipids are concerned, these two should not be mixed. Today we know that fatty foods are better for blood fats than foods rich in carbohydrates. However, the fact is that those who want to lower their blood fats will have difficulty doing this with the help of food: if a person with average intake of carbohydrates increases his intake of carbohydrates by 34%, then the good cholesterol decreases by 5%. When it comes to the absence of systematic reviews, it is usually the case that on blogs and forums detailed reviews of literature are rarely presented; usually one or a couple of studies are presented, which can never give an overall picture. Our task as a scientist is to try to give you the whole picture.
The question is: what does the science say about blood lipids (cholesterol, LDL cholesterol, HDL cholesterol, etc.), the effect of statins, side effects of statins and risks of eating statins? Is cholesterol relevant or is everything a scam?
The importance of an objective and evidence-based debate
A nuanced and evidence-based debate is important. A debate in which every claim is strengthened by one, or preferably several, scientific studies. Sentence must not take part in the discussion, which must therefore be objective and evidence-based. There must be no room for conspiracy theories, but the evidence must be interpreted with sober eyes. If you read this, you will get a brief introduction to how your body works, especially the blood fats and how to interpret scientific studies.
Atherosclerosis, cholesterol and statins in three parts
In these three chapters we are now going to go through atherosclerosis, cholesterol, LDL cholesterol, blood lipids, statins and much more. We will discuss studies that speak both before and against the respective facts. The purpose of these three chapters is to educate You (individuals, patients) in these subjects and I repeat: none of us operating diabeteson.com has ever received compensation from any company or organization that sells or works with the medicines, substances or practices listed in these articles.
To understand atherosclerosis, blood lipids and LDL cholesterol, you have to understand a couple of terms that we are going through here.
Immune cell: An immune cell is a cell that is part of the body’s immune system. These cells fight bacteria, viruses, parasites and cancer cells. Unfortunately, it is common for these cells to make the mistake of attacking the body’s own cells instead. This is actually common; common forms of hypothyroidism, rheumatoid arthritis and type 1 diabetes are caused by just this.
Endothelial cell: Endothelium is cells lining the inner walls of blood vessels. Thus, blood vessels can be seen as tubes, and endothelial cells are cells that wallpaper the inside of the tube. That is, the endothelial cells are in direct contact with the blood flowing through the vessel. Endothelial cells have an important task, which is to signal to immune cells (which are in the blood) that they should stop, pass through the blood vessel and further out to the tissue around the vessel. This is needed, for example, if you fall and scrape up the skin. Then bacteria can get into the skin. Endothelial cells in the blood vessels around the injury begin to attract immune cells, so that the immune cells pass through the blood vessel and then out to the tissue where there are bacteria. See the following picture:
The three layers of the vessel wall: the vascular wall actually consists of three layers, as shown in the picture above. The thinnest and innermost layer is called intimate, and that layer consists of precisely the endothelial cells and supporting woven on which they rest. The layer middle is also the thickest layer and it is called media; this layer is populated with muscle cells (in English “smooth muscle”). The muscle cells allow the vessel to contract and expand as needed. The outer layer is external (sometimes called adventitia).
Lipoprotein: fat and cholesterol are vital for us humans. We use fat both as fuel and as building blocks in all cells in our body. However, fat cannot be transported freely in the blood — it must be transported in special complexes called lipoproteins. Lipoproteins are round structures consisting of fat (both in the shell and in the nucleus) and proteins. The proteins found on the lipoproteins are called apolipoproteins, and these are important. Here is an illustration on lipoprotein. The apolipoproteins are on the surface (apoE, apoB, etc.) and inside there are cholesterol (C) and triglycerides (T).
Rufolf Virchow (born in 1821, died in 1902) studied atherosclerosis as early as the 19th century and noted that atherosclerosis contained fat and the fat lump itself appeared to be inflamed. Ever since the days of Virchow, atherosclerosis has been studied extremely intensively, which is explained by the fact that this disease became the leading cause of death in about the 1950s. Since then, tens of thousands of studies have been conducted to map the causes and nature of atherosclerosis. These studies include animal studies, live and dead human studies, genetic studies (of all types), epidemiological studies (of all types) and randomised controlled clinical trials. The science behind atherosclerosis is extremely extensive. Despite this, much remains to be learned. Above all, it has not been possible, as desired, to translate several of the findings from animal studies into humans. 11
Despite some shortcomings, the main principles of atherosclerosis have been mapped out. It has also prompted the development of effective drugs that can significantly improve the prognosis. You’ve probably heard of statins (which lower LDL cholesterol), but there are many other methods and in 2017 the (perhaps) most anticipated study was published, namely the study that showed that attenuation of the body’s inflammation can reduce the risk of heart attack and stroke. 12. Inflammation has been considered the driving force behind atherosclerosis and therefore suppression of inflammation should reduce the risk of atherosclerosis (complications of atherosclerosis), as has now been proven in the first of two major studies on this.
Thus, research results have been translated into clinically effective drugs. Today’s drugs can slow down or even stop atherosclerosis (more dramatic effects have also been noted, which we will discuss later). Such drugs lead to a reduced risk of stroke, heart attack and even death.
Research shows that atherosclerosis begins with the fact that the endothelial cells make a mistake. Endothelial cells are like wallpaper covering the inside of the vessel wall. Thus, it is these cells that are in direct contact with the blood that flows past, at high speed and with high pressure. However, endothelial cells are not just a wallpaper lining a tube. These cells are extremely sophisticated and can record blood flow and pressure in the vessel, thereby adjusting the vessel. If the pressure is high, endothelial cells can release neurotransmitters that allow muscle cells in the vascular wall to relax and thus expand the blood vessel so that the pressure can decrease again.
Endothelial cells have more important functions. One of the most important functions is to attract immune cells, but only when necessary. Imagine that you scraped up the skin so that bacteria managed to get into the skin. Bacteria are not good and to fight them, our immune cells (our immune system) need to get to the place where the bacteria are, so that they can kill the bacteria. However, the immune cells are in the blood and must move from the blood to the tissue. They can do this because endothelial cells are smart — endothelial cells detect (via neurotransmitters) bacteria in the tissue and therefore begin to express proteins on their cell surface. These proteins attract immune cells that flow past so that the cells can hook up in the endothelial cell, enter the vascular wall and then out to the tissue and bacteria.
A long, long, series of studies suggest that atherosclerosis begins with the endothelial cells suddenly begin to express proteins that attract immune cells, even though there is no damage to the tissue around the vessel. Thus, atherosclerosis begins with endothelial cells attracting immune cells. At the same time, the vessel becomes more permeable so that other particles in the blood (in addition to immune cells) can enter the vessel wall. 13
Lipoproteins that are rich in cholesterol and have apolipoprotein B on the surface appear to play a central role in this. LDL (low density lipoprotein) has just these characteristics. LDL (and other lipoproteins) 70 nm in diameter can easily enter the vascular wall. The fact is that at levels of LDL cholesterol about 0.5 to 1.0 mmol/L (which newborns have) this does not happen; i.e. at low levels of LDL cholesterol LDL does not enter the vascular wall, and the risk of atherosclerosis is very low 14 As the LDL level rises above this level, storage increases of LDL in the intima layer of the vascular wall and it also notes that the atherosclerosis becomes more pronounced, as well as the risk of complications. In animal studies, it is clear that after increasing the concentration of LDL in the blood, atherosclerosis also increases. 15
This means that endothelial cells function is disrupted in the presence of high blood lipids and high levels of LDL cholesterol have been shown to be consistently the strongest driving force behind this. In addition to LDL cholesterol, high blood sugar, smoking and high blood pressure are factors that can disrupt endothelial cell function with the same end result. Later it appears that inflammation in the body, i.e. a general inflammation, also appears to be a driving force behind this. People with cardiovascular diseases (diabetes, coronary heart disease, hypertension, obesity, etc.) often have an inflammation in the body and this can be detected by measuring the level of “high-sensitivity CRP” in the blood. So, the atherosclerosis begins with the fact that slightly irritates the endothelial cells so that they invite immune cells into the vascular wall. 16
Atherosclerosis is characterized by having much of the following two things: (1) immune cells, especially macrophages and (2) LDL cholesterol. LDL cholesterol is small particles, as well as HDL cholesterol, and therefore they can easily enter the vascular wall. Immune cells and LDL cholesterol do not agree inside the vascular wall, but immune cells begin to react to LDL cholesterol. This means that the immune cells begin to attack the LDL cholesterol particles, thereby triggers inflammation inside the vascular wall.
Immune cells attack LDL cholesterol and a particular type of immune cells called macrophages begins to take up (“eat up”) LDL cholesterol. This causes the LDL cholesterol to accumulate inside the macrophages. The macrophages react by releasing neurotransmitters that whip up the inflammation further and attract even more immune cells from the blood. This leads to the accumulation of LDL cholesterol and immune cells inside the wall of blood vessels and together they cause inflammation of the vascular wall. This inflammation maintains itself by attracting even more immune cells and even more LDL cholesterol because the andothelium becomes easier to penetrate when inflammation occurs.17
Macrophages are especially harmful. Numerous studies have tried to determine the exact functioning of these cells in atherosclerosis. This is of course a delicate challenge, but so far it has been possible to see that the macrophages in atherosclerosis occur in several variants. Some are pro-inflammatory, which means they take up LDL cholesterol and start inflammation by secreting inflammatory substances. Other macrophages appear to function as dendrite cells, which means that they pick up lipoproteins (LDL cholesterol) and present them to other immune cells which then also begin to react to the lipoproteins. What are the other immune cells? All of them! In atherosclerosis, all types of immune cells are actually found, although macrophages and T-cells appear to predominate. This means that atherosclerosis is an inflammatory focus. 18
But the vessel also contains muscle cells (they are in the layer called media). These muscle cells give the artery stability and strength. They are also they regulate the circumference of the vessel. When smooth muscle cells contract, the vessel circumference decreases and when they relax, the circumference increases. These muscle cells are fundamental to atherosclerosis, namely they begin to migrate towards the inflammatory area. The muscle cells thus move towards the inflammation, and there they begin to release proteins that encapsulate the inflammation. This means that muscle cells produce a shell of protein (similar to fibers) that packs the atherosclerosis. Inside, macrophages and other immune cells work to attack lipoproteins, while more and more lipoproteins (especially LDL cholesterol) enter the inflamed area. Many macrophages die on the coup, and their content of cholesterol leaks out, giving the atherosclerosis the characteristic yellow tint. 19
This process continues and becomes chronic. More and more cholesterol and more immune cells accumulate in the vessel. This is ansamely called a plaque, or more presist an atherosclerotic plaque.
Why is this a problem?
- A large plaque may begin to bulge into the vessel and can thus cause a constriction that causes blood flow to deteriorate. If the constriction becomes very pronounced, the blood flow may be so impaired that oxygen starvation occurs in the organ supplied by that vessel. People who have angina simply have large plaques in the coronary vessels.
- Atherosclerotic plaques are unstable. The envelope around the plaque can burst, which leads to the fact that the contents of the plaque come into contact with proteins and cells in the blood. Several of these proteins and cells then believe that the blood vessel is broken and that the most appropriate is to create a blood clot (the blood clots). Such clots can be so large that all blood flow in the vessel is shut down and then severe oxygen starvation occurs in the organ supplied by that vessel. Such clots are the cause of acute heart attack and 80% of all strokes.
What plaques are bursting?
Studies, both in humans and animals, show that plaque size is not decisive. The plaques that burst are characterized by (1) intense inflammation of the plaque, (2) fewer smooth muscle cells, compared to stable plaques, and (3) in addition, the plaque sheath is weaker (which often means that there is less collagen protein in the envelope).
So what do risk factors (high blood pressure, high cholesterol, diabetes, etc.) have to do with this?
High blood lipids (especially LDL cholesterol), high blood pressure, high blood sugar, general inflammation in the body and smoking irritate the endothelial cells so that this atherosclerosis starts. LDL is particularly effective, but other risk factors should not be neglected. In the next part of this series of articles, we’ll look at how science connects LDL to atherosclerosis (atherosclerosis). The question is whether LDL is a causal factor, i.e. whether LDL actually causes atherosclerosis. Recently, it has been questioned whether cholesterol, and in particular LDL cholesterol, is a cause of atherosclerosis.20.
We have not yet answered this question. In the next chapter, we will review studies that include more than 2 million participants, which together have been followed for over 20 million years. We will discuss studies that speak for and against the respective positions.