Molecular causes of the disease
The root cause of atherosclerotic vascular lesions is an impairment in the normal structure of low-density lipoproteins (LDLs) or defects in their corresponding LDL receptors. These alterations can affect both the protein and lipid components of the molecule.
Two main mechanisms of pathological LDL modification occur in the body:
- Lipid peroxidation — hyperactivation of this process leads to damage of the lipoprotein lipid core.
- Protein glycosylation — non-enzymatic covalent attachment of glucose molecules to the protein moiety of the complex.
Cellular cascade of plaque formation
The process of atherosclerotic plaque formation occurs in several stages, with the immune system playing a key role as it attempts to clear damaged lipids.
- Due to structural alterations, modified LDLs are no longer recognized by normal receptors and become "foreign" entities to the body.
- In response, a phagocytosis reaction is triggered: the altered lipoproteins are actively engulfed by macrophages.
- Accumulating massive amounts of cholesterol intracellularly, macrophages alter their morphology and transform into so-called "foam cells".
- These lipid-overloaded cells migrate across the endothelial barrier and penetrate into the vascular intima (the innermost layer).
- Within the intima, foam cells inevitably rupture. The released cholesterol accumulates in the extracellular space, forming the initial stage of an atherosclerotic plaque.
Laboratory diagnostics and reference ranges
To assess the risk of cardiovascular events in patients with hypercholesterolemia, the atherogenic index (AI) is calculated.
Interpretation of total cholesterol levels:
- Normal values: less than 5.2 mmol/L (or less than 200 mg/dL). Values of 4.8 mmol/L and 150 mg/dL are considered safe and fall within the normal range.
- Borderline-high and high risk: patients with values of 240 mg/dL, 260 mg/dL, or 6.8 mmol/L require mandatory medical evaluation, as these figures indicate a serious threat to the vasculature.
Familial hypercholesterolemia and statin therapy
An example of a severe disease course is familial hypercholesterolemia. It is characterized by a burdened family history (e.g., early death of relatives from myocardial infarction) and an extremely high total cholesterol level (around 400 mg/dL).
Statins (e.g., lovastatin) are used to treat such conditions. Their mechanism of action involves a complex biochemical cascade:
- Competitive inhibition: Lovastatin acts as a structural substrate analog and blocks 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase), a critical enzyme in endogenous cholesterol synthesis.
- Reduction of the cholesterol pool: Intracellular (endogenous) cholesterol levels drop sharply in hepatocytes (liver cells).
- Activation of the SREBP pathway: Cholesterol deficiency serves as a signal to activate the SREBP transcription factor. It translocates to the cell nucleus and triggers the expression of the gene encoding the LDL receptor.
- Upregulation of receptor density: The number of LDL receptors (apoB-100/E) on the hepatic cell membrane compensatorily increases.
- Blood clearance: The liver steps up the uptake of LDL particles from the bloodstream. As a result, the blood cholesterol concentration is therapeutically reduced (e.g., from 400 to 250 mg/dL).
Before treatment, cell surfaces exhibit a receptor deficiency while excess LDL circulates in the plasma. Following successful statin therapy, membrane receptor density is restored, ensuring efficient lipid clearance from the blood.
Briefly: answers to topical questions
What is the formula for calculating the atherogenic index (AI)?
The atherogenic index (AI) is calculated using a mathematical formula reflecting the ratio of total cholesterol to its anti-atherogenic fraction.
The main calculation formula: $$AI = \frac{\text{Total Cholesterol} - \text{HDL}}{\text{HDL}}$$
A simplified calculation variant is also permitted, where the coefficient equals the ratio of low-density lipoprotein cholesterol (LDL) to high-density lipoprotein cholesterol (HDL). Normally, this indicator should not exceed 3.0–3.5; higher values indicate an increased risk of developing atherosclerosis.
Which classes of blood plasma lipoproteins are considered anti-atherogenic?
The anti-atherogenic classes of blood plasma lipoproteins consist exclusively of high-density lipoproteins (HDLs).
- High-density lipoproteins — inhibit the development of atherosclerosis by carrying out reverse cholesterol transport from peripheral tissues and vascular walls to the liver for subsequent disposal (conversion into bile acids or excretion via bile). Thereby, they reduce cholesterol accumulation in the vascular wall.
What other lipid profile parameters besides total cholesterol must be evaluated in familial hypercholesterolemia?
In addition to total cholesterol, the lipid profile should include the evaluation of:
- Low-density lipoproteins (LDLs);
- High-density lipoproteins (HDLs);
- Triglycerides.
Statin action cascade: HMG-CoA block → Endogenous pool drop → SREBP signal → Receptor synthesis → Decrease in blood LDL.
Class and exam questions
Which cells form the basis of an early atherosclerotic plaque?
The foundation is formed by "foam cells" — macrophages that have engulfed modified LDL, overloaded with cholesterol, penetrated the vascular intima, and ruptured there.
What is the molecular mechanism of action of lovastatin?
The drug is a competitive inhibitor of the enzyme HMG-CoA reductase. This reduces intracellular cholesterol synthesis and forces the cell to uptake more LDL from the blood.
At what cholesterol level does a patient require further medical evaluation?
When the normal limit of 5.2 mmol/L (200 mg/dL) is exceeded. Values such as 6.8 mmol/L or 240–260 mg/dL indicate high risk.
What else to study on this topic
- Calculation and clinical significance of the atherogenic index (AI)
- Biochemical mechanism of lipid peroxidation
- Genetics of familial hypercholesterolemia
- Functioning of the SREBP transcription factor
- Structure and function of apoB-100/E receptors
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