Atherosclerotic cardiovascular diseases (ASCVD) rank first in the structure of morbidity and mortality in various countries of the world. According to WHO definition, atherosclerosis (AS) is a variable combination of changes in artery inner lining (intima), comprising aggregations of lipids, complex carbohydrates, fibrous tissue, blood components, calcium salts depositions, and the underlying changes of the medium lining (media) in the arterial wall. AS has been thoroughly examined: its etiology, pathogenesis, development forms, and stages, and quite a lot of scientific literature has been published about it. However, neither diet nor strict control over risk factors, drugs, or physical activity can decisively change the global AS spreading. Therefore, it remains the leading death cause of the most active and productive population.

The reasons catering for ASCVD are split into modifiable and non-modifiable risk factors (RF). Non-modifiable RFs include age, gender, and burdened heredity for cardiovascular diseases. Modifiable RFs comprise dyslipidemia (DLP), arterial hypertension (AH), diabetes mellitus, factors contributing to thrombosis, enhanced values of homocysteine, uric acid, inflammation markers, unhealthy lifestyle features (obesity, inactivity, consumption of excessive saturated fats and refined carbohydrates, harmful addictions) [1].

The concept of early onset of the atherosclerotic process refers to the period of intrauterine development. Epidemiological studies have shown coronary thickening of the intima already in fetuses and infants; their prevalence and progression significantly increase in children and adolescents. The studies revealed that the coronary changes range from focal lesions with moderate thickening of the intima to diffuse mild thickening with the presence of mixed or non-stenotic plaques. The thickening of the intima is considered the initial stage of atherogenesis and the pathomorphological basis for the accumulation of lipids with the subsequent formation of an atherosclerotic plaque. Studies have confirmed that the initiation of the atherosclerotic process begins in the womb and progresses in infancy and childhood [2, 3]. All this allows us to talk about atherosclerosis as a significant pediatric problem.

The main AS RFs in children and adolescents are [4, 5, 6, 7, 8]:

• strong family history or cases of premature manifestation of cardiovascular diseases in the family,

• arterial hypertension,

• comorbid conditions related to early AS development: DM, obesity, hypothyroidism, HIV infection, systemic lupus erythematosus, radically cured neoplasms, organ transplantation, kidney diseases, hypersympathicotonia, hypodynamia, stressful situations, and harmful habits.

However, despite numerous studies on AS markers in children and adolescents, this problem is far from being resolved. Moreover, the data obtained are contradictory, since the climatic and geographical conditions, nutrition features, social environment, and child’s somatotype greatly influence AS risk factors, in particular, the level of atherogenic and anti-atherogenic lipid and LP fractions in blood, blood pressure (BP) enhancement, and body weight.

For a long time, AS can develop latently. Then, only many years later, clinical disease manifestations occur in the form of stenocardia, cerebrovascular diseases, atherosclerosis of the peripheral arteries, myocardial infarction manifestations, ischemic stroke, and sudden death.

Lipoproteins are an extensive group of compounds that differ significantly in their chemical structure and functions (Table1) [9].

No matter how much we may discuss causes and conditions of AS development and highlight the polyethological nature of AS as a disease, one thing remains unalterable: certain LP classes of are a primary substrate that, having penetrated the arterial wall, trigger the atherosclerotic plaque formation.

Blood lipids are: cholesterol (CH), triglycerides (TG), phospholipids (PL), free fatty acids (FFA).

Cholesterol is the main component of cell membranes. It is engaged in the synthesis of steroid hormones, sex hormones, and bile acid formation. The active cholesterol metabolites are its esters synthesized during free CH esterification with adding FFA radical and enzyme engagement of lecithin cholesterol acyltransferase. Hepatocytes secrete these metabolites into the blood flow as CH component of VLDL. CH is absorbed in the small intestine and participates in chylomicrons formation. Within the biochemistry process, 30% of the daily cholesterol demand is provided by food incoming from the body. Endogenous CH synthesis occurs in the smooth endoplasmic network of almost all vertebrate cells, and 70% of cholesterol is synthesized in hepatocytes from acetyl-CoA. At the first stage, acetyl-CoA is converted to 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) that under the influence of HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA reductase, HMGR) is converted to mevalonate [10]. Mevalonate, bypassing intermediate metabolites (mevalonate-5-pyrophosphate, isopentenyl-5-pyrophosphate, geranyl-pyrophosphate, farnesyl-pyrophosphate, squalene, lanosterol), is converted to CH. The products of CH catabolism are neutral sterols and bile. Bile acids play an important role in the digestive process. They are absorbed in the small intestine back into the blood and come into the liver, representing an additional material for CH resynthesis [11]. Hypercholesterolemia leads to many negative effects, including vascular and endothelial shifts that are the most significant in atherogenesis. Against the background of endothelium-dependent vascular dilatation, platelet adhesion increases, the production of a plasminogen activator inhibitor is stimulated, the plasminogen activator is inhibited, the tissue procoagulation factor is induced, and, ultimately, the function of heparin-sulfate-proteoglycans is disrupted. These shifts inhibit the endothelium anticoagulation properties and initiate blood clot formation. In parallel, pro-inflammatory changes occur in the endothelium, resulting in monocytes’ accumulation (macrophages, T lymphocytes) [12].

Triglycerides (TG) are compound esters of glycerol and fatty acids. They are synthesized in many organs and tissues, but the most significant are the liver, intestinal wall, adipose tissue, and the lactating mammary gland. The body of an adult receives 60–80 grams of TG with food daily [10].

Chylomicrons mainly perform diet TG transport function. During absorption, TG cleavage products first enter the epithelial cell membranes in the small intestine villi, and then they are transferred in the cytoplasm to the TG resynthesis site — the smooth endoplasmic reticulum. Commonly, TG is deposited in adipose tissue (visceral and subcutaneous). Under stress, significant physical exertion, TG undergoes lipolysis with the formation of free fatty acids absorbed by muscle cells as a substrate for mitochondrial oxidation and ATP synthesis. After a meal, TG concentration in blood increases, but after 10–12 hours, it returns to its original level.

Hypertriglyceridemia is one of the main ASCVD predictors [13]. Hypertriglyceridemia blocks not only the endothelium-dependent relaxation factor by suppressing the nitric oxide synthesis and L-arginine, but also promotes hypersecretion of endothelin 1 — a potent vasoconstrictor which is ten times higher than the effects of norepinephrine and angiotensin II [14, 15, 16].

Phospholipids are an integral part of cell membranes and LP. Phospholipids include polar lipids: phosphatidylcholine and sphingomyelin. Recently, the enzyme lipoprotein-associated phospholipase A2 (Lp-FLA2) has been studied intensively [17]. It is secreted by white blood cells and manifests its effect in circulating LP composition. Lp-FLA2 hydrolyzes the phospholipids of the surface monolayer of oxidized LDL with the formation of endogenous inflammatory mediators-lysophosphatidylcholine and oxidized non-esterified fatty acids, which play a crucial role in atherogenesis [18].

Lipid carriers are transport macromolecules in the form of lipid-protein complexes-lipoproteins. Lipoproteins differ in size, density, and the amount of CH and TG comprised by them. The structural LP elements are specific apoproteins. The main functions of apoproteins are LP interaction with the receptor apparatus of hepatocytes and other tissue cells and lipolysis rate regulation. In LP center, there are hydrophobic molecules of CH and TG esters, outside LP there is free (non-esterified) cholesterol, phospholipids and apoproteins.

In the sequence of hydrated density increase and size reduction, the main plasma lipoproteins, are: chylomicrons, very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDP) in two subfractions (HDL 2 and HDL 3), and lipoprotein(a) (Lp(a)) [11].

The main chylomicron apoproteins are apoB48, apoE, and apoCII. The first two are ligands binding the chylomicron remnants to hepatocyte scavenger receptors. ApoCII is a cofactor that activates plasma lipoprotein lipase, an enzyme that hydrolyzes LP with a high TG content.

In VLDL and IDL, the main apoproteins are apoB100 and apoE that function as ligands while binding to the liver receptor apparatus. VLDL, like chylomicrons, are hydrolyzed by lipoprotein lipase, and they comprise the cofactor apoCII. In LDL, the main and only apoprotein is apoB100, thanks to which they are captured and removed from the bloodstream by LDL-hepatocyte receptors [11, 19].

LDL Cholesterol (LDL-C) and VLDL cholesterol (VLDL-C) are the most atherogenic LP classes. They are complex protein-lipid supramolecular complexes that transport cholesterol and polyunsaturated fatty acids to cells respectively. The receptor uptake of LDL-C by cells is the most important factor determining the cholesterol level in blood [20]. These LP fractions are the leading atherogenesis originators, they change the endothelium properties, promote blood cell adhesion and activation of monocyte/macrophage chemotaxis with subsequent proliferation of smooth muscle cells. The mechanism of cholesterol transportation into the cell as a component of LDL-C by receptor-mediated endocytosis is known due to the brilliant paper by American scientists M. Brown and J. Goldstein who were awarded the Nobel Prize in 1985 [21]. The receptor-mediated capture of LDL-C ensures maintaining of LDL-C levels in the blood within the limits of normolipidemia, preventing AS development.

The most important role in atherogenesis is played by peroxide-modified LDL-C that have strongly marked atherogenic properties. Peroxide-modified LDL-C is recognized by macrophages’ scavenger receptors, and it is quickly captured by them, resulting in accumulation of cholesterol esters and transformation of macrophages into foamy cells that contain products of oxidative degradation of fatty acids with high cytotoxicity, stimulating monocyte chemotaxis, delaying the migration of macrophages from the intima, stimulating the formation of leukotrienes. LP exhibit a “hormone-like effect” on cells. Pathophysiological effect of LDL-C is classified as damaging and having a causal relationship with the risk of ASCVD developing [22, 23]. All ApoB containing LP and their remnants are able to penetrate the endothelial barrier, especially under endothelial dysfunction. They initiate the deposition of lipids and formation of atherosclerotic plaques [24].

HDL Cholesterol (HDL-C) contains apoproteins ApoAI and AII. These apoproteins are ligands for binding HDL-C to peripheral tissue cells via specific ABCA1 cluster transporter receptors and scavenger B1 receptors in the liver. The main function of this LP class is the reverse CH transportation from peripheral tissues, the vascular wall, to hepatocytes. HDL cholesterol has a protective effect against AS, so they are called anti-atherogenic. HDL-C plays a key role in lipid metabolism and is an integrative indicator of the well-being of the lipid spectrum. HDL-C determines the amount of cholesterol in cells, stimulates utilization of TG-rich LP, and stabilizes LDL-C, protecting them from modification changes and atherogenic orientation [25, 26]. However, it should be noted that there is currently no evidence to support that an increase in HDL-C in plasma contributes to ASCVD risk reduction [19, 27] (Fig.1).

Fig. 1.

High density lipoprotein metabolism. HDL, high density lipoprotein; VLDL, very low density lipoprotein; TG, triglycerides; AI, AII, apolipoproteins; CE, cholesteryl esters; ABCA1, ATP-binding cassette transporter A1.

Factors associated with low HDL-C: male gender, progestogens, obesity, hypertriglyceridemia, diabetes Type 2, high carbohydrate intake, alcohol, smoking.

Factors associated with high levels of HDL-C: female gender, estrogens, increased physical activity, weight loss, moderate alcohol consumption.

Lipoprotein(a) (Lp(a)) is a conjugate of LDL-C with a specific apoprotein (a) that is similar in its structure to plasminogen and can affect the process of fibrinolysis by suppressing it. Besides, Lp(a) has pro-inflammatory properties due to oxidized phospholipids transfer [28, 29]. High Lp(a) concentrations in plasma are associated with an increased ASCVD risk, but for most patients this risk factor is less significant than LDL-C [30, 31].

Individuals with excessively elevated Lp(a) levels $>$180 mg/dL ($>$430 mmol/L) are currently found to be at an enhanced ASCVD risk, similar to patients with familial heterozygous hypercholesterolemia. Since ~90% of Lp(a) amount is hereditary, it is possible that an excessively high level of Lp(a) represents a new hereditary dyslipidemia related to an enhanced ASCVD risk during the lifetime, and its prevalence is twice as high as that of familial heterozygous hypercholesterolemia [32].

Currently, DLP prevalence varies significantly in the world, but there is a steady increase in these metabolic disorders. Of particular concern is the tendency to increase mortality from ASCVD between young people [50, 51].

In the analysis, DLP prevalence in the pediatric population in various countries of the world made: in Denmark – 6.4%, and in children and adolescents with obesity, DLP is four times more common – 28% [52]. The DLP prevalence in Chile makes 38%, in children and adolescents with obesity DLP prevalence makes 54% [53]. DLP structure in Iran is as follows: hypercholesterolemia occurs in 48%, hypertriglyceridemia – 50%, elevated hyper LDL-C – 20%, and decreased HDL-C – 88% [54]. In Thailand, hypercholesterolemia occurs in 1.2%, hypertriglyceridemia-10.6% [55]. In Turkey, in obese children and adolescents (2001–2013, Ankara), DLP was detected in 42.9% of cases. In DLP structure, hypercholesterolemia made 18.6%, hypertriglyceridemia – 21.7%, elevated LDL-C – 13.7%, and decreased HDL-C – 19.7%. With age and increase in body mass index, DLP prevalence also increased, while there were no significant differences in DLP frequency in girls and boys [56]. In Germany, a population sample from the LIFE Child Study was used to estimate the lipid spectrum. It was found that cholesterol and LDL-C concentrations reached their peak values in girls two years earlier than in boys. Hypercholesterolemia was detected in 7.8%, elevated LDL-C – 6.1%, and decreased HDL-C – 8.0%. Hypercholesterolemia in children aged 0 to 9 was found in 22.1%, and among children aged 10 to 16 this indicator is lower – 11.7% [57]. In the United States, from 1999 to 2012, there was a tendency to reduce DLP prevalence in children aged 8 to 17: hypercholesterolemia decreased from 10.6% to 7.8%; hypoalphacholesterolemia – from 17.9% to 12.8%; non-HDL-C – from 13.6% to 8.4% [58].

In the review by A.M. Perak et al. [59], the lipid spectrum analysis in 26047 children and adolescents aged 6 to 19 for 1999–2016 was made. (the average age of subjects was 12.4 years, 51% were females). The study showed a decrease in cholesterol level from 164 mg/dL (1999–2000) to 155 mg/dL (2015–2016) and an increase in HDL-C concentration from 52.5 mg/dL (2007–2008) to 55.0 mg/dL (2015–2016).

Studies conducted in Brazil have evidenced a high DLP prevalence between adolescents, ranging from 24.2% to 71.4%. A characteristic feature in DLP structure was a widespread hypoalphacholesterolemia occurrence. DLP was more common in adolescents with obesity and unhealthy lifestyle components [60, 61, 62, 63, 64, 65].

In the Russian Federation, in the European North area (Arkhangelsk, 2002, 779 children and adolescents aged 7 to 16 years were examined) – DLP was detected in 48.98%. The study showed a widespread low HDL-C levels, and it did not correlate with DLP presence: it was recorded in subjects with both normolipidemia – 54% and DLP – 51%.

The wide prevalence of HDL-C is regarded as an adaptive mechanism under high body’s demand for cholesterol and its increased consumption to ensure energy processes in the environment of the European North [66].

Dyslipidemia is a congenital or acquired (secondary) disorder in the body lipid transport system manifested as a qualitative and/or quantitative change in blood plasma lipids and LP regarded as important ASCVD risk factors. J. W. Hoffman was the first who discovered the correlation of lipid and LP metabolism disorders with ASCVD in 1950. Some time later, D. S. Fredrickson and co-authors (1967) developed these ideas into a DLP classification. The first and very successful DLP classification was approved by WHO experts and subsequently became widely used throughout the world (Table2) [19].

This classification does not diagnose but establishes a DLP type, regardless of whether it is acquired or hereditary.

Hyperlipidemia by the nature of biochemical disorders, according to the classification by Fredrickson D. S., are split into types:

Type I – hyperchylomicronemia (induced by fats), characterized by severe hypertriglyceridemia and an increase in chylomicron concentration. In DLP structure, Type I makes less than 1%; it is usually caused by a hereditary defect in the gene encoding plasma lipoprotein lipase. DLP Type I is considered conditionally atherogenic. Prolonged circulation of chylomicron residuals in the blood may be accompanied by their accumulation in endothelium, provoking atherosclerotic plaque development. DLP Type I clinical markers are hepatosplenomegaly, pancreatitis attacks, and abdominal colic. It is manifested in children under 10 years of age.

Type IIa – hyper-$\beta$-lipoproteinemia, characterized by an isolated enhancement of LDL and cholesterol levels in blood. The frequency of DLP Type IIa makes 10%. This hyperlipidemia type is the most atherogenic. It is most often found in patients with coronary heart disease and in individuals with polygenic hypercholesterolemia. DLP Type IIa is also observed in patients with familial heterozygous hypercholesterolemia, when LDL-C concentrations can be 2–5 times higher than the reference.

Type IIb – hyper-$\beta$-lipoproteinemia,hypertriglyceridemia, characterized by an enhancement in the cholesterol and TG levels in plasma due to elevated LDL and VLDL-C concentrations. This DLP type occurs in 40% of individuals with hyperlipidemia. It is caused by apoB100 hyperproduction. In clinical practice, Type IIb is more often observed in patients with combined familial hyperlipidemia, metabolic syndrome, Type 2 diabetes mellitus (Type 2 diabetes). The clinical symptoms are manifested in children in the first 5 years of life—these are xanthomas, cardiopathies, and vegetative-vascular disorders.

Type III – dis-$\beta$-lipoproteinemia, a rare DLP form (less than 1%). It occurs in patients with the apoE2/E2 phenotype. In such patients, the capture of LDL-C by hepatocytes is disturbed to a much greater extent than in individuals with a different apoE phenotype. DLP is characterized by an expressed heterozygous hypercholesterolemia and hypertriglyceridemia. For clinical manifestations of this condition, concomitant metabolic disorders are needed: the metabolic syndrome, diabetes mellitus, fatty liver dystrophy, and hyperuricemia. The clinical markers of the disease are eruptive xanthomatosis, bright yellow staining of the palmar striae, and obesity. The probability of ASCVD development is very high.

Type IV – hyper-pre-$\beta$-lipopoproteinemia is manifested by hypertriglyceridemia and an elevated content of VLDL-C in blood. It is more often found in people who have been on a carbohydrate diet for a long time, abuse alcohol excessively, suffer from diabetes, obesity, chronic kidney diseases, take non-selective beta-blockers and/or thiazide diuretics for a long time. The prevalence of DLP Type IV in the general population is up to 45%. DLP Type IV can be a manifestation of hereditary hypertriglyceridemia based on a defect in the genes encoding the enzyme lipoprotein lipase, or its cofactor-apoCII. TG level for Phenotype IV ranges from 2.3–5.6 mmol/L, and HDL-C is often reduced. Clinical signs appear in children at different periods of life, more often at older ages: an enlarged liver of a solid elastic consistency with a blunt edge is palpated—a sign of fat hepatosis; xanthomas are rare, diabetes mellitus is often found. In addition, while examining the eye fundus, lipaemia retinalis can be detected.

Type V – hyperchylomicronemia, or hyper-pre-$\beta$lipoproteinemia. This DLP type is most often based on a hereditary defect of the apoCII gene manifested by high TG, VLDL-C and chylomicron levels. TG level can reach 20 mmol/L resulting in acute pancreatitis development. DLP Type V accounts for about 5% of all DLP cases.

Currently, it is important to differentiate between primary and secondary DLPs.

Primary DLP is characterized by stable changes in one or more lipid spectrum parameters in the absence of any other diseases. Primary DLP is characterized by specific disorders in the lipid and LP metabolism of a hereditary nature. In population studies of genetic relationships, more than 100 genes were identified that could affect the levels of cholesterol, TG, LDL-C, and HDL-C.

Familial hypercholesterolemia (FHCH) is one of the most common genetically determined diseases. Its cardinal signs are elevated blood levels of LDL-C, early development of ASCVD, as well as skin and tendon xanthomas [67, 68]. Heterozygous FHCH occurs in the general population with a frequency of 1:200–1:500, homozygous FHCH is a very rare pathology with a frequency of 1:160 000–1:320 000 [69]. The genetic basis of the disease is mutations of genes that encode the proteins of low-density lipoprotein receptors (LDLR/LDL), apoprotein B (apoB), proprotein converting subtilisin-kexin protein kinase type 9 (PCSK9). Homozygous FHCH has an extremely unfavorable prognosis due to an extremely early development of ASCVD [70]. So far, the genes are known with a proven FHCH association: LDLR, ApoB, PCSK9, and LDLRAP1 [71, 72, 73]. The phenotype determined by the LDLR, ApoB, and PCSK9 genes demonstrates autosomal and dominant transmission type, while the phenotype determined by mutations in LDLRAP1 gene has an autosomal recessive transfer.

In 20% of patients with FHCH, even with the use of modern molecular genetic research methods, no mutations are detected, but it does not exclude the diagnosis [74, 69].

Features of lipid metabolism under FHCH

As a result of LDL-C receptors’ deficiency, their connection with ApoB is disrupted. It leads to a decrease in LDL-C catabolism by the liver. Disorder of LDL cholesterol metabolism causes a sharp increase in the total cholesterol content in blood. The cholesterol enhances up to 600–1200 mg/dL (15–30 mmol/L) under homozygous FHCH, and up to 280–500 mg/dL (7–12.5 mmol/L) under heterozygous FHCH) [69, 72, 74, 75].

According to the classification by D. Frederikson, FHCH relates to hyperlipoproteinemia Type IIa. The level of HDL-C and apolipoproteins (Apo) A-I and A-II in homozygotes is reduced due to a combination of metabolic defects in the form of elevated catabolism and reduced apo A-I synthesis [72].

There are no clinical manifestations for heterozygous FHCH in children. This form, as a rule, is detected accidentally during a biochemical examination of child’s blood, against the background of other somatic or infectious diseases. In this case, an increased level of the total cholesterol and LDL cholesterol is revealed. Changes in these indicators in children can also be detected during a cascade screening examination [76, 77, 78].

Clinical manifestations in children with homozygous familial hypercholesterolemia, as a rule, occur as early as the first life decade. They are as follows:

Xanthomas (xanthomatous plaques, tuberous (tuberous) xanthomas, tendon xanthomas) are the earliest clinical manifestations and enable early diagnosis of the disease.

Ophthalmic changes are characterized by xanthelasmas. The most typical is the corneal lipidemic arch, i.e., a circular cornea opacity colored gray-white, 1 to 3 mm wide, with a smooth surface.

Cardiovascular system changes. The basis of cardiovascular lesion of atherosclerotic genesis is formed by a sharp increase in LDL-C level since the neonatal period. In patients with homozygous FHCH, the cardiovascular disease symptoms emerge before the age of 10. The process of atherosclerotic plaque formation is sharply accelerated. It results in stenosis of the vascular bed of the coronary, carotid, and renal arteries. The risk of early development of coronary heart disease is about 20 times higher than in the general population [69, 72, 74, 75].

In the histological study of the coronary arteries of children with homozygous FHCH, atherosclerotic changes correlate with final stages of the atherosclerotic process. There is a high frequency of sudden cardiac death against the background of acute myocardial infarction. The myocardial infarction development can occur as early as the first or second life decade [69, 75, 79, 80].

The aortic root, aortic valve, and elastic vessels are affected by the atherosclerotic process. Degenerative changes of the aortic valve flaps often occur. The cholesterol deposition on the aortic valve flaps can also lead to aortic insufficiency. The effort angina occurs due to both aortic stenosis and coronary atherosclerosis. In the case of renal vessel stenosis, the arterial hypertension is added [69, 81].

Family history data is very important for FHCH diagnosis. Early ASCVD initiation, myocardial infarction at a young age (under the age of 40), hypercholesterolemia and other clinical AS manifestations are very common.

Under heterozygous FHCH, the atherosclerotic process begins to manifest clinically after 17–20 years of life. Thus, in young men with heterozygous FHCH, the first cases of coronary heart disease are described since the age of 17, and in girls a little later, starting from the age of 25. According to examination of young patients aged 20 to 29 and diagnosed with heterozygous FHCH, the risk of fatal cardiovascular disease development increased 125-fold in women and 48-fold in men in the period before statin treatment, compared to those with normal CH levels [82].

Familial combined hyperlipidemia is currently defined as a common metabolic disorder characterized by an elevated serum cholesterol or TG levels in at least two members of the same family; variability in the hyperlipidemia type both in patient (individual variability) and in his sick relatives (variability within the family); an increased risk of early ASCVD [83]. In addition to the clinical and biochemical criteria listed above, familial combined hyperlipidemia is characterized by hyperapobetalipoproteinemia (apolipoprotein (apo) level) B $>$125 mg/dL) [84], elevated levels of non-esterified LC and C3-component of the complement [85].

Primary hypertriglyceridemia is the main risk factor for ASCVD. It is caused by a deficiency of hepatic lipoprotein lipase (elevated TG, normal cholesterol). The main genes associated with elevated TG levels (as the main phenotype) are APOA5, APOC2, APOE, GPD1, GPIHBP1, HNF1A, LMF1, LPL, and SLC25A40. According to studies’ findings, carriers of APOA5 gene have a 3-fold higher risk of ASCVD development [86]. Clinically, primary hypertriglyceridemia is manifested by an abdominal pain from childhood (pancreatitis), hepatosplenomegaly, retinal vascular damage, peripheral neuropathy, and xanthomas. Weak or moderate hypertriglyceridemia can increase dramatically when exposed to provoking factors: uncompensated diabetes mellitus, hypothyroidism, alcohol abuse, and administration of combined oral contraceptives. In each case, TG level in plasma may exceed 10 g/L. Within exacerbation periods, patients develop mixed hyperlipidemia, i.e., the concentration of both VLDL and chylomicrons increases. High chylomicrons levels predispose to formation of eruptive xanthomas and pancreatitis development [87].

Sitosterolemia is a disease caused by an enhanced cholesterol absorption and accumulation of sterols, especially of plant origin. Clinical markers of the disease are the presence of xanthus, premature AS, hemolytic anemia, and liver pathology. The disease is associated with mutations in ABCG5 and ABCG8 genes.

Hypoalphalipoproteinemia is a disease related to a group of diseases with a low level of HDL-C and a high prevalence of early AS development. The genes associated with low HDL-C of monogenic etiology are ApoA1, ABCA1, LCAT, SAR1B, and ABCG1. ApoA1 gene is responsible for the phenotype of familial hypoalphalipoproteinemia with autosomal dominant inheritance. ABCA1 gene is associated with Tangier disease inherited on an autosomal recessive basis. Clinical markers of the disease are enlarged tonsils colored bright yellow-orange, splenomegaly, lymphodenopathy, muscle weakness in extremities, reflex weakening, loss of sensitivity. In the bone marrow punctate, “frothy” cells are found. LCAT gene mutation in Chromosome 16 is associated with “fish-eye” disease (partial insufficiency of lecithin cholesterol-acyltransferase – LCAT) is an autosomal recessive disease characterized by DLP and eye damage.

Thus, primary DLPs can be classified genotypically or phenotypically by biochemical analysis. In the genotypic classification, DLPs are split into monogenic (caused by mutations in a single gene) and polygenic (caused by associations of multiple mutations).

Congenital DLPs are disorders of lipid metabolism detected in a child on the first days of life; these disorders are not hereditary or familial but caused by adverse factors that affected the fetus in the intrauterine period (chronic fetal hypoxia, maternal diabetes, obesity, toxicosis, nephropathies [88, 89, 90].

Hypolipidemia in newborns. LP content in blood plasma in healthy newborns is significantly lower than in adults. Especially remarkable are chylomicrons’ absence and a significant decrease in VLDL-C value. The main blood class in newborns is HDL-C. In total, LDL-C and VLDL-C are 170 mg% in newborns, which is 5 times less than in maternal blood. The distribution of LP classes is as follows: HDL-C 49.7–56%; LDL-C 35.6–41%; VLDL-C 3–14.7%. LDL-C was found to contain higher TG levels (more than 50% of all TG in umbilical blood), protein, and cholesterol. The composition of HDL-C in newborns’ blood compared to maternal blood is characterized by a higher content of phospholipids, cholesterol, and lower esterified cholesterol and TG values. With age, HDL-C level decreases, and LDL-C level increases [91].

Secondary DLPs. Today, several diseases are known to result in secondary DLP development (Table3) [92]. There is a large number of pathological conditions associated with secondary hypercholesterolemia that require a differential diagnosis:

(1) endocrine system pathologies (hypothyroidism, hypopituitarism, polycystic ovarian syndrome, lipodystrophy, porphyria);

(2) kidney pathologies (chronic kidney diseases, hemolytic-uremic syndrome, nephrotic syndrome);

(3) liver diseases (obstructive liver diseases, cholestasis, biliary cirrhosis, Alagille syndrome);

(4) systemic connective tissue diseases (juvenile rheumatoid arthritis, systemic lupus erythematosus);

(5) accumulation diseases (glycogenosis, Gaucher disease, Niemann-Pick disease, Tay-Sachs disease);

(6) kawasaki disease;

(7) anorexia nervosa, idiopathic hypercalcemia;

(8) klinefelter syndrome, Turner syndrome;

(9) medications (glucocorticoids, beta-blockers, antiretroviral drugs);

(10) exogenous causes (alcohol).

Secondary DLPs (mostly hyperlipidemia) is a frequent metabolic syndrome in children and adolescents, and it is confirmed under many diseases. It is no exaggeration to say that every disease, especially in young children, is accompanied to a greater or lesser extent by lipid metabolism disorders. Enhanced lipid peroxidation, functional and structural disorders of the phospholipid spectrum of cell membranes are regarded as the main pathochemical mechanism of many pathological processes in childhood. Secondary DLPs are more often combined, when changes in several lipid and LP fractions are detected, and isolated DLPs, as a rule, are found to be primary.

Today, there is no doubt that lipid metabolism disorders are at the heart of atherogenesis; it has been proven by the National Cholesterol Education Program (NCEP) designed to normalize and reduce the level of cholesterol in blood and resulted in progress in ASCVD prevention.

DLP is a molecular disease associated with lipid and LP metabolism disorders in human body. The more narrow is the term “hyperlipidemia” which reflects an increase in the amount of various classes of lipids and LP. It is of the greatest interest from a practical point of view, since it is the major ASCVD risk factor.

2001 NCEP ATP III recommendations are widely used as criteria for normolipidemia in clinical practice (Table4) [93].

The classification proposed by Koletzko et al. [94] deems to be more up-to-date (see Table5).

The content of LDL-C is determined by the calculation method according to W. T. Friedewald’s formula: LDL-C = Cholesterol total – (HDL-C + TG/2.2) (when determining the indicators in mmol/L);

LDL-C = Cholesterol – (HDL-C + TG/5) (when determining the indicators in mg/dL).

The level of non-HDL-related cholesterol (Cholesterol-HDL-C) is recommended to be determined in individuals with TG level $\ge$2.3 mmol/L. Under hypertriglyceridemia, the number of TG-rich particles (chylomicrons, VLDL-C, and IDL cholesterol) increases, and therefore, the amount of cholesterol comprised in these particles increases as well. The W. T. Friedewald formula in such cases does not reflect the actual amount of atherogenic cholesterol.

Currently, the non-HDL-related cholesterol (non-HDL-C) indicator is recommended to be used as a target level in patients with diabetes mellitus and metabolic syndrome, since they are more likely to have hypertriglyceridemia and low HDL-C levels. The target value of non-HDL-C for the corresponding risk categories is calculated by adding 0.8 mmol/L to the target level of LDL-C.

• Non-drug therapy: dietary cure, physical inactivity prevention, overweight and obesity prevention activities, refusal of bad habits.

• Hypolipidemic therapy.

• Extracorporeal treatment methods.

Today, AS is not only the area that children’s doctors are in charge of, but also, first and foremost, it is the problem of pediatrics in view of the need for early diagnostic, preventive and therapeutic effects. It determines the relevance and significance of purposeful DLP identification as the leading RF of atherogenesis in children, teenagers and adolescents. DLP plays a significant role in ASCVD development, while ASCVD dominates the structure of morbidity and mortality in the world.

The conducted epidemiological studies have shown a wide spread of DLP in children and adolescents – more than 70% in the population. It justifies the need for further additional examination of this contingent in order to verify the diagnosis and timely resolve the issue of management tactics.

FHCH prevalence in the general population is quite high – 1:200. At the same time, unfortunately, the diagnosis of the disease remains extremely low. No more than 1% of patients are diagnosed before the developed clinical manifestations. FHCH is an extremely severe disease with an unfavorable prognosis. Severe complications of the atherosclerotic process in the form of acute myocardial infarction are possible already in the first decade of life. The first clinical manifestation of the disease is skin xanthomas, lesions of the cardiovascular system, and the eyes. However, to date, pediatricians are not sufficiently informed about the clinical course and modern approaches to FHCH treatment. It results in late diagnosis and incorrect patient management tactics.

Children with FHCH should be monitored by pediatricians, pediatric cardiologists who have received additional training in lipidology. Normalization of lifestyle is a mandatory component in the first stage of child management. It includes normalization of the physical activity level, the elimination of additional risk factors for the development of cardiovascular diseases, and a hypocholesterolemic diet.

An important area of management of pediatric patients is the adjustment of other risk factors for the development of cardiovascular diseases. Among them, it is mandatory to stop smoking, including passive smoking, to normalize blood pressure and to eliminate excess body weight. The determination of lipoprotein(a) helps to identify an increased risk of developing cardiovascular diseases. An increase in this indicator of more than 50 mg/dL increases the risk of early development of coronary heart disease by 1.5 times. It is extremely important to treat concomitant diseases that increase the risk of developing cardiovascular diseases: Type 1 and Type 2 diabetes, chronic kidney diseases, connective tissue diseases, etc. Diet is of crucial importance in the correction of familial hypercholesterolemia in childhood. The restriction in nutrition does not apply only to children of the first year of life. In children over one year of age, the total caloric content of food is reduced by 30% due to strict restrictions on the amount of saturated fat and trans fats containing the highest amount of cholesterol. Cholesterol intake should not exceed 300 mg/day.

Timely hypolipidemic therapy can reduce the total cholesterol and LDL-C levels. Statins should be prescribed for FHCH as early as the first decade of life, to prevent the development of cardiovascular catastrophes. With insufficient effectiveness of statins, another class of drugs that prevent the absorption of cholesterol in the intestine (ezetimibe) is connected. Currently, to enhance the hypolipidemic effect, a third class of drugs for combined hypolipidemic therapy with subtilisin/kexin type 9 proprotein kinase inhibitors is proposed. In severe cases, the addition of LDL-C apheresis is possible. If hypercholesterolemia persists, liver transplantation is executed.

Today, more and more young people suffer from AS, and it has become the greatest epidemic of our era, threatening to affect the entire Earth population in the near future unless its prevention activities have been revealed by studying the pre-disease and the onset disease periods. Today, it is of no doubt that an intense AS prevention shall be started at an early age. AS is not just one of pediatric problems, but a primary pediatric problem in terms of prevention and treatment efficiency. Revealing children predisposed to AS development can be of great practical importance due to exceptional possibilities of adjusting functional disorders of organs, systems, and metabolism in childhood and adolescence.

AVB, VET, LVP, VMP conceived and designed the content; AVB, VET wrote the manuscript; LVP, VMP supervised and prepared the final version for submission.

Not applicable.

Authors express the gratitude to all the peer reviewers for their opinions and constructive suggestions.

This research received no external funding.

The authors declare no conflict of interest.