Cholesterol Debate: Past, Present and Future (1)

Article by Jeanne Garbarino Cholesterol and Controversy: Past, Present and Future
published in Scientific American Blogging Network.
Translated by Evgenia Ryabtseva

Facts about cholesterol and the distance with obstacles that lies between it and the risk of developing cardiovascular diseases

According to experts, approximately 50% of the US population has cholesterol levels in the blood outside the normal range, which is reflected in the prevalence of diseases of the cardiovascular system. However, the theory that high cholesterol is the main risk factor for heart attacks and strokes has been the subject of scientific debate for several decades. Despite the fact that high cholesterol in the blood is currently considered an alarming symptom, some experts question the appropriateness of modern treatment standards involving statin therapy, since taking these cholesterol-lowering drugs in the blood may not be equally useful to all patients. Will history repeat itself? This article describes the history of cholesterol and its contradictory role in the past and present of scientific medicine.

In the early 1900s, a young Russian scientist Anichkov, by a lucky chance, conducted an experiment that later became one of the fundamental works on the study of diseases of the cardiovascular system. Instead of refuting the theory of aging put forward by his colleague, Anichkov confirmed it by revealing the relationship between this compound and vascular damage (atherosclerosis) as a result of feeding purified cholesterol to rabbits. However, despite the appearance of these data, the study of the role of cholesterol in the context of human health did not arouse enthusiasm among researchers, since most of the leading experts in this field did not consider herbivorous rabbits a model suitable for studying human diseases. Moreover, atherosclerosis was considered a natural and inevitable component of aging. Therefore, the study of the role of cholesterol in the development of cardiovascular diseases has been suspended for several decades.

About 40 years after Anichkov published the results of his experiments on rabbits, an American researcher Gofman began to show great interest in the concept of cholesterol as a determining factor in the development of diseases of the cardiovascular system. He was aware of the results obtained by Anichkov and, unlike most scientists of that time, took these data quite seriously. He was convinced of the existence of a clear relationship between cholesterol and atherosclerosis, which eventually led him to the need to find an answer to the question: how does cholesterol get into the bloodstream? Using the latest techniques at that time, he began to analyze the various chemical forms of cholesterol contained in the blood and identified the components of what we now call total cholesterol (such as high and low density cholesterol, which are discussed below). Unfortunately, the significance of the results of this study was recognized only many years later.

Over time, and as the number of supporters of the "lipid theory of aging" increased, the idea that a high concentration of cholesterol in the blood – a phenomenon known to doctors as hypercholesterolemia – is a causal factor in the development of myocardial infarction began to gain popularity. Gradually it became clear that the diet affects the level of cholesterol in the blood and, accordingly, promotes the formation of atherosclerotic plaques in the vessels and increases the risk of developing cardiovascular diseases. In 1955, the outstanding nutritionist of that time Ancel Keys from the University of Minnesota suggested that, despite the costs and the long period of time required to confirm the lipid theory, conducting large-scale clinical studies of the relationship between diet and health is of exceptional importance. (Article by Ancel Keys et al. Effects of Diet on Blood Lipids In Man. Partially Cholesterol and Lipoproteins was published in the journal Clinical Chemistry in February 1955.)

"There are good reasons for the current great interest in the effect of diet on the lipid content in the blood. In general, experts agreed that there is an important relationship between the concentration of certain lipid fractions in the blood and the development of atherosclerosis, as well as its consequence of coronary heart disease. The main characteristic of atherosclerosis is the presence of lipid deposits, mainly represented by cholesterol, in the walls of the arteries. At the same time, in both humans and animals, the most obvious factor affecting the composition of blood lipids is the diet."

The blood supply to the heart is carried out through two main vessels – the right and left coronary arteries, starting from the aorta immediately above the semilunar valves. Coronary diseases include angina pectoris (constricting chest pain), abnormal heart rhythms, heart failure due to weakening of the myocardium, heart attacks, cardiac arrest (sudden coronary death) - VM.

The result of this was an increase in the number of clinical studies conducted to study the effect of diet on the state of the cardiovascular system, one of which was the Seven Countries Study coordinated by Keyes, which began in 1958. As part of this first-of-its-kind study, the relationship between lifestyle, diet and the prevalence of cardiovascular diseases in men from different populations was analyzed. Despite the fact that the design of this study was found not to meet modern requirements, its main result, which linked the use of large amounts of cholesterol with heart disease, regardless of the peculiarities of culture, had quite a big impact on future events.

Regardless of Keyes' research, the US National Institute of Heart Disease (now known as the National Institute of Heart, Lung and Blood Diseases) decided in 1948 to begin monitoring people aged 30-62 years living in Framingham, Massachusetts. One of the most well-known and cited clinical studies aimed at determining the general patterns of the development of cardiovascular diseases, the Framingham Heart Disease Study, which continues to this day, has revealed a number of factors associated with aspects of the health of the cardiovascular system, including smoking, high blood pressure and, naturally, high cholesterol in the blood blood. However, the latter parameter was not recognized as a risk factor for diseases of the cardiovascular system until 1961.

Despite the rejection of the lipid theory by some representatives of the "old school", many researchers and doctors have begun to recognize the existence of a relationship between cholesterol levels and human health. However, even more challenging was the idea that the consequences of the negative effects of high cholesterol levels can be eliminated or restored. In the early 1950s, studies conducted in the laboratories of Lawrence Kinsell (Institute for Metabolic Research, Highland General Practice Clinic) and Edward H. Ahrens (Rockefeller University) showed that eliminating saturated fats from the diet and replacing them with unsaturated fats significantly reduces the concentration of cholesterol in the blood. These data were confirmed by the results of three preclinical studies: a study by Paul Leren in Oslo (1966); a study conducted at the clinic of the Office for War Veterans in Vadsworth (1969) and a study conducted by Finnish psychiatric hospitals (1968).

However, the reaction of experts was still ambiguous. Some have recognized these new findings and a number of medical organizations, including the American Association of Cardiologists, have prepared carefully worded official press statements indicating the need to reduce saturated fat intake. However, some experts were more pessimistic about these data – perhaps because they did not believe that the US population would express a desire to make significant adjustments to the established lifestyle and diet. Or, perhaps, the lack of universal acceptance of the lipid theory was due to a lack of information about the biochemical processes involved in the detrimental effect of cholesterol on the human body. It was at this point that Hoffman's work became relevant.

During this period, a new actor appeared on the scene, Donald Fredrickson, who realized the potential of the data obtained by Hoffman concerning the transport of cholesterol in the bloodstream. He came to the conclusion that the study of the complex of cholesterol carriers – lipoproteins – is a promising approach to assessing the risk of developing diseases of the cardiovascular system. Based on Hoffman's data, Fredrickson and his colleagues transferred cholesterol studies to the clinic, which led to the rapid development of a new field of research on lipoprotein metabolism and its role in the development of atherosclerosis. However, there were still many questions concerning the regulation of the concentration of lipoproteins in the blood, especially those related to aspects of the interaction of natural factors and factors related to nutritional characteristics.

The assumption of the existence of a genetic component in the predisposition to high cholesterol levels and the risk of developing cardiovascular diseases formed the basis of a study by a young scientist who worked in the laboratory of Arno G. Motulsky from the University of Washington. In 1973, Joe Goldstein, now recognized as one of the founders of the modern trend in the study of cholesterol, for the first time compiled a genetic classification of the types of lipoproteins that carry cholesterol in the blood. However, the genetic nature of the regulation of cholesterol metabolism was determined only after Goldstein joined forces with Michael Brown, which led to the 1985 Nobel Prize in Physiology or Medicine. In a series of articles published in the 1970s and 1980s, Brown and Goldstein not only described the mechanisms of regulation of a key enzyme involved in the synthesis of cholesterol, but also elegantly demonstrated the existence of a genetic basis for the impossibility of removing from the blood a form of cholesterol that contributes to the development of heart disease, which was called low-density lipoproteins (LDL).

Thanks to Brown and Goldstein, the target of anticholesterol therapy was finally identified, but there were still no corresponding drugs on the market. At the same time, there was a need to obtain evidence that reducing the concentration of LDL cholesterol in the blood can reduce the risk of myocardial infarction and stroke. The final verdict on the path of cholesterol to recognition as the main risk factor for the development of cardiovascular diseases was made by the clinical study of primary prevention of coronary diseases (CPPT), launched in 1973 by the lipid research clinic, part of the National Institute of Heart, Lung and Blood Diseases. This randomized double–blind study showed that lowering the level of cholesterol in the blood (in this case with the help of cholestyramine, a compound that prevents the reabsorption of cholesterol in the intestine and stimulates its excretion through excretion with feces) leads to a reduction in the risk of myocardial infarction.

After the publication of these data in the early 1980s, [The Lipid Research Clinics Coronary Primary Prevention Trial Results. I. Reduction in incidence of coronary heart disease. JAMA 1984 Jan 20;251(3):351-64] many representatives of the medical community agreed with the correctness of the lipid theory. Moreover, the emergence of evidence in favor of the existence of a relationship between cholesterol levels and the risk of developing cardiovascular diseases has led to the launch of numerous projects and strategies dedicated not only to informing the public about the need to control cholesterol levels through diet, but also to the search for new therapies. This has led to the emergence of a new field of research and, accordingly, new aspects indicating the ambiguity of the role of cholesterol in the body.

The ending follows.

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31.01.2012