Atherosclerosis of the heart vessels is handled by cardiologists, brain vessels – neurologists ( angioneurologists ), atherosclerosis of the aorta, arteries of the lower extremities – vascular surgeons. In the diagnosis of atherosclerosis, a large role belongs to the instrumentalists who own methods of duplex scanning of vessels, electrocardiography, radiography (magnetic resonance imaging, angiography, contrast research methods, positron emission tomography).
Thus, there are no universal specialists on this issue. There are doctors who are well-versed in the issues of atherosclerosis of one or another vascular region, but in matters of biochemistry of lipids they often have amateurish knowledge. In connection with the above, it becomes clear that patients with atherosclerosis require amultidisciplinary approach and in most cases should be supervised collegially by physicians of different profiles.
To reveal the latent forms of IHD, the samples from the population were sampled on a treadmill and a bicycle ergometer with scrupulous study of ECG features.
The subsequent long-term work at the Institute of the Human Brain of the Russian Academy of Sciences forced to face patients with cerebrovascular disease (CEH).And at them on the first place as the reason of illness acted an atherosclerosis and an arterial hypertensia (AH). This meant the need to delve into the questions of duplex scanning of brachiocephalic arteries, analyze the results of magnetic resonance angiography of cerebral vessels, the data of positron emission tomography of the brain, not to mention the study of the lipid profile of blood in these patients.
In parallel, for many years, we had to be clinically examined for patients with familial hypercholesterolemia, along with geneticists from the Institute of Experimental Medicine
All this allowed us to gain experience that combined individual problems of cardiology, angioedema , lipidology , genetics, to study the clinical, genetic and clinical-biochemical features of patients with dyslipidemia and atherosclerosis.
The concept of lipids, the classification of dyslipidemia
Lipids – fat-like compounds – are part of the blood plasma; for normal functioning they are necessary for every cell of the body. The concept of ” dyslipidemia ” (DLP) appeared in medical literature in the last quarter of the 20th century. Until this time, when describing the lipid composition of the blood, they were most often referred to as ” hyperlipidemia ” (GLP), ie, that is, o high cholesterol (CH) or triglycerides (TG). About other deviations from the norm in the lipid composition of the blood at that time was little known.
In addition to cholesterol and TG, lipids include phospholipids (PL) and free (non-esterified) fatty acids (FFA).
ChS, TG, FL in the aqueous medium, which is the blood, are insoluble. To circulate in the plasma (and in these compounds almost all cells are constantly in need), the lipids must have acquired the ability to dissolve in the aquatic environment. This was possible after the combination of cholesterol, TG and PL into complexes with proteins, resulting in the formation of lipoprotein particles – lipoproteins or lipoproteins.
FFA is easier to transport, because they are easily combined with blood albumins and are transferred with them.
J. Gofman et al . (1949) proposed a classification of lipoproteins depending on their behavior in a solution of a certain density under ultracentrifugation . Since that time, lipoproteins (LP) have been divided into classes: chylomicra (CM) – the largest and least dense particles, very low density lipoprotein (VLDL), low density lipoprotein (LDL), high density lipoprotein (HDL). These physical properties of LPs reflect the features of their chemical structure.
The LP particle has a spherical shape, its core is formed by cholesterol- esters and TG, and its environment is made up of molecules of phospholipids and free cholesterol. One end of these molecules is apolarized and facing the nucleus, the other (outer) end of the molecule has a charge, so that it is immediately surrounded by polar water molecules, due to which the LP particles acquire solubility in the aqueous medium, transportability and the ability to be delivered to any cell.
We present a schematic representation of a low density lipoprotein particle – LDL
Apo B-100 is a protein particle, phospholipids, triglycerides, cholesterol esters and unesterified cholesterol are also shown .
Different density of LPs is explained by unequal relations between the content of cholesterol, TG and PL in LP particles, as well as by the quantitative and qualitative characteristics of the specialized proteins, apoproteins, that make up them .
The largest LPs are chylomicrons with a diameter of 80 to 1000 nanomycrons , 95% of which consist of TG and have the lowest density, they remain at the start with electrophoresis in a polyacrylamide gel.
VLDL have a diameter of 30-80 nanomecrons and 60 % consist of TG, contain up to 15 % XC- esters and the same amount of PL, their apoproteins ( apoB , apoS ,apoE ) are 5-7%, with the key protein being apoprotein B-100.
LDL are formed from VLDL under the influence of enzymes, their diameter is less – 20-25 nanomycrons , 40 % they consist of HS- esters , at 25 % – fromapoproteins , and their main apoprotein – apoprotein B-100 (is 95 %), in small amounts in LDL there are apoproteins apos and apoE . LDL also contain some free cholesterol and 6 % TG. LDL are the main transporter of cholesterol from the liver to the periphery.
Not so long ago, LDLs began to differentiate into separate subfractions (the most atherogenic are small, dense particles), the same applies to VLDL [R Krauss , 1995;Yu.I. Ragino , 2004].
HDL are characterized by the smallest diameter (13 nanomecrons ) and 45 % consist of proteins. The key protein of HDL is apoprotein A-I, it is 65 %, 20 % ofapoproteins represent A-II. The composition of HDL is 20 % Of HS- esters and PL. The main function of HDL is the delivery of cholesterol from the periphery (from the surface of somatic cells) to the liver. At present, several subfractions of HDL (depending on the degree of their maturity) are distinguished : HDL- 2a , HDL-2b and HDL-3, their functional differences are not fully understood.
The most important mission of HDL is not only the capture of cholesterol on the periphery and its transfer to the liver, but also the protection of LDL from peroxidation. It is known that LDL acquire atherogenicity only after its modification (peroxidation and other changes). These most important properties of HDL are proved by the work of AN Klimov and his colleagues and won universal recognition. Since that time, the definition of an antiatherogenic fraction of lipids has been fixed for HDL.
It is necessary to mention separately one more thing about the special fraction of LP-LP (a). It includes LDL, in which apo B-100 is connected by a disulfide bridge with a special protein – apo (a), homologous to plasmin [B. Nordesgaard et al ., 2011]. The elevated plasma content of lipoprotein (a) leads to its accumulation in the vascular wall and is complicated quite quickly by atherosclerosis.
It is necessary to distinguish primary and secondary GLP. As for secondary HLP, they are symptomatic and are caused by a certain initial disease. Most often it is diabetes mellitus, hypothyroidism, chronic nephrosis- nephritis or biliary cirrhosis. In most people, GLP can be induced artificially, if the daily diet includes excessive amounts of eggs and animal fats (alimentary GLP). We do not dwell on secondary GLP here.
Under primary GLP (DLP) implies genetically caused violations of the lipid composition of the blood, in the genesis of which a greater or lesser role can still play the features of nutrition, physical conditions, and certain concomitant diseases.
Classification of the GLF Frederickson [D. Fredrickson & R. Lees , 1965] distinguishes 6 types of GLP: I type – hyperhylomicronemia , at which the blood serum acquires a milky white color due to a large number of chylomicrons containing many TG (up to 800-1000 mg / dL and more). When the tube with blood is standing in the refrigerator, XM float up, so that the upper third of the tube forms a creamy layer. Type I GLP is rare, manifested from early childhood, accompanied by severe pancreatitis and hepatolenal syndrome.
IIa type – hypercholesterolemia (HCS) – characterized by a sharply increased content of LDL, while the content of TG remains normal; at IIb type (HCS in combination with moderate hypertriglyceridemia ) there is a high level of blood cholesterol, but at the same time the content of not only LDL cholesterol but also cholesterol is increased.
A distinctive feature of type III HLP is a very high level of both cholesterol and TG, as well as the presence of beta-fraction of VLDL. This fraction of lipoproteins behaves at electrophoresis as LDL, and with ultracentrifugation – like VLDL [A. N. Klimov, N.G. Nikulcheva , 1999]. This type of GLP leads to widespread atherosclerosis, affecting the aorta and most of its branches, so that it can be characterized by aortic aneurysm, intermittent claudication syndrome, ischemic heart and brain disease.
IIa and IIL types of HLP occur in 15-20 % of the adult population in Europe and the US, patients with type III HLP are very rare.
IV type of GLP is relatively widespread and is mainly manifested by hypertriglyceridemia (significantly increases the level of VLDL); this type of GLP can be complicated by cerebrovascular disease and / or coronary heart disease. Very often in these cases, a violation of tolerance to carbohydrates, and often diabetes mellitus type 2.
Occasionally you can face V type of GLP. On the composition of the blood, it resembles type I GLP, but the degree of CGM is less. This pathology is onlydeveloped to 35-40 years and is also characterized by hepatolienal syndrome (although less pronounced than in type I), pancreatitis, and impaired glucose tolerance or type II diabetes mellitus.
Since the end of the 20th century, it became clear that the classification of Fredrickson does not exhaust the whole variety of violations of the lipid composition of the blood, based on the definition of XM, XC, TG, LDL, VLDL. Increasingly, they began to describe such forms of DLP, in which there is no increase in lipid levels, but a decrease in the content of HDL is detected (according to old terminology – alpha lipoproteins). As mentioned above, HDL is the only form of LP, aimed at capturing cholesterol from the surface of peripheral cells and transporting it to the liver for further “processing”. As it turned out, the deficit of HDL is conducive to the retention of cholesterol in the tissues, it leads to the development of atherosclerosis without HCS.
This form of DLP – a selectively low level of HDL in the absence of GLP – is quite common. This means that a more general definition of lipid lipid abnormalities – DLP – is more correct than GLP, since it covers all variants of these disorders. Thus, Fredrickson’s phenotypic classification should be supplemented by another type of lipid content disorder : selective lowering of the level of HDL ( hypoalphalipino-proteinemia ).
If we use the term ” Atherogenicity “ in relation to the types of DLP, that is, that is, the ability to be complicated by atherosclerosis, the third type of HLP should be considered the most atherogenic, then the Pa, IIL types of HLP (DLP) and the low level of HDL cholesterol (selective reduction of the alpha fraction of lipoproteins) occupy almost equal positions; Step IV is below the type of GLP, and the last place is occupied by the V type.
I type of GLP is not taken into account here, c. in mainly found in children and is associated not with heart lesions, but other internal organs (pancreas, liver, spleen).
It should be noted that although such large lipid particles as VLDL characteristic of IV and V types of GLP are not able to penetrate through the interendothelialspaces into the inner shell of the vessels, but after enzymatic cleavage they are transformed into smaller particles – remnants , which too can infiltrate into the intima vessels.
Standard guidelines for lipid composition of blood
It is necessary to distinguish between the norm of lipid parameters characteristic of a healthy person and the target level of the same indicators that should be sought in patients with clinical manifestations of atherosclerosis or with a complex of risk factors for IHD or CEH. In these latter cases, the approach to lipid standards should be more stringent, otherwise it will be difficult to stop the progression of the disease.
When talking about normal blood lipids in healthy people, you also need to take into account gender, age, blood pressure, the Quetelet index , the habit of smoking , hereditary complication of atherosclerosis and its complications. If there are several risk factors for atherosclerosis in an even healthy person, the approach to the lipid profile should also be more stringent. Thus, in healthy, but smoking men with hereditary burden of IHD, leading a sedentary lifestyle, with excessive body weight, blood lipid levels should be more stringent than in a healthy person without these risk factors.
Women, if they do not smoke and do not suffer from diabetes, are much less prone to atherosclerosis, so they will admit a higher level of blood lipids.
With this in mind, the normal limits of lipid blood counts can be defined as “sliding.”
Take, for example, a healthy non-smoker, a man of 40 years of age, of a regular physique (height 180 cm, body weight – 82 kg), leading an active lifestyle, without a hereditary burden of atherosclerosis. For him, the following parameters may be considered normal: total cholesterol – 5.2 mmol / l, TG – 1.3 mmol / l and HDL-C – 1.3mmol / l, LDL – 3.2 mmol / l, wherein the ratio of atherogenic will be 3 units. . In this series of indicators, only HDL cholesterol corresponds to the ideal norm for a middle-aged man. For patients with risk factors for IHD or CEH or with manifestations of these diseases, it is desirable to have a lower level of total cholesterol than indicated in the previous example, e. in the presence of signs of atherosclerosis and its complications, lower LDL cholesterol and the atherogeniccoefficient should be achieved .
In women, as indicated, the upper limit of the norm for total cholesterol and LDL cholesterol is higher than in men, but they should have a lower limit for the anti-atherogenic fraction of LP (HDL-C), which is defined as 53 mg / dl or 1.35 mmol / l (in men, this figure should be not less than 1.05 mmol / l or 41 mg / dL ).
In the last decade, lipid and other biochemical indices in millimoles / liter have been estimated , although in the English literature, the concentration of lipids in plasma is still often indicated in mg / dL. There are coefficients of transfer of some units to others. To translate the cholesterol values from mg / dl into mmol / l, their value should be divided by 39, for example, 250 mg / dl corresponds to 5.4 mmol / l (if reverse translation is required, then the cholesterol content in mmol / L should be multiplied by 39). When translating TG from one calculation to another, the coefficient “89” is used. Values of VLDL (Ch VLDL) and LDL (LDL-C) are derived by calculations after biochemical determination of total cholesterol, TG and HDL cholesterol.
If the TG value is given in mg / dl , one-fifth of the TG is taken to obtain the VLDL value: for example, at TG = 250 mg / dL value of VLDL = 50 mg / dl. If the TG determination was carried out in mmol / l, then the fission factor is “2.2,” ie, ie at TG = 2.8 mmol / l – VLDL content = 1.3 mmol / l.
To calculate the content of LDL (more precisely, LDL cholesterol), it is necessary to subtract the sum of HDL cholesterol and cholesterol LP from the value of total cholesterol. Thus, for a general XC = 250 mg / dL , HDL cholesterol = 40 mg / dL and VLDL cholesterol = 50 mg / dL Calculation of LDL cholesterol is as follows: 250 – (40 + 50) = 160 mg / dl. In calculations in mmol / l, if the total cholesterol content is 6.4 mmol / L, HDL cholesterol = 1.03 mmol / L, and VLDLP cholesterol 1.3 mmol / L, then LDL cholesterol is 6.4 – (1.03 + 1.3) = 4.1 mmol / l.
To assess the atherogenicity of the lipid spectrum of blood, it is convenient to use an additional criterion – the coefficient of atherogenicity . Calculation of this coefficient according to AN Klimov is very simple: we need to take the difference between the values of total cholesterol and cholesterol and cholesterol and divide it by the HDL cholesterol. For example, with a total cholesterol level of 6.4 mmol / L and a cholesterol ratio of 1.03 mmol / L, the atherogenicity coefficient is calculated as a fraction with a difference (6.4-1.03) in the numerator and 1.03 in the denominator, which will be expressed as 5.2 units. Normally, this figure should not exceed 2.5 units.
Mechanisms of development of primary GLP or DLP
Modern ideas about the mechanism of the development of hyperlipidemia would have been impossible without the brilliant works of J. Goldstein & M. Brown (1974-1977), for which they were awarded the Nobel Prize 1985 in
The authors discovered the main pathway for the cellular uptake of LDL: they described specialized LDL receptors that can be incorporated into the membranes of liver and other somatic cells and actively capture LDL from their blood washing. These receptors are synthesized in cellular organelles, transported to the surface of the cell membrane, where, by capturing LDL, they form the “LDL-LDL receptor” complex. With the help of a special transport protein, the newly formed complex moves from the cell membrane inwards, to its organoids, and undergoes processing and utilization therein.
The synthesis of LDL receptors is a self-regulating process. If the cell is in need of cholesterol, the synthesis of LDL receptors is stimulated, and if there is no need for cholesterol in a given time period in the cell, the synthesis of LDL receptors is inhibited or terminated. In other words, the number of LDL receptors on the surface of cells is not constant and depends on the saturation of the CS cell. This is how the physiological process of cholesterol metabolism proceeds with the normal functioning of LDL receptors, intracellular transport proteins that move the LDL receptors to the cell membrane, and the “LDL + LDL” receptor complexes, transported from the membrane to the interior of the cell.
If the synthesis of LDL receptors or the proteins that transport them is disrupted, problems will arise with the capture of LDL from the peripheral blood, which will result in the accumulation of LDL in the blood plasma, ie , will cause HCS.
It should be noted that the normal uptake of LDL by their receptors is only ensured if the structure of the LDL itself is correct. If the LDL structure turns out to be wrong (nonstandard), then the connection with normal receptors is extremely difficult, which will also lead to HCS.
It is necessary to touch here and antiatherogenic fraction of lipids – HDL, which are synthesized in the liver and in the wall of the small intestine. The newly synthesized ( nascent ) HDL are disc-shaped and contain only unesterified or free cholesterol. Under the action of the enzyme lecithin-cholesterol acyltransferase (LHAT), free cholesterol in these particles is converted to esterified . As the cholesterol is esterified, the HDL particles mature and assume a spherical shape, after which they are designated as HDL-2 and HDL-3. Only at this stage, the HDL acquire the ability to take the cholesterol from the peripheral cells and transport it to the liver.
With a sufficient number of normally functioning HDL particles and a physiological process of entrapping these particles with the liver (in harmony with properly functioning LDL receptors) , a normal cholesterol exchange is provided between the liver, blood plasma and peripheral tissues.