Molecular Causes of the Disease
The primary cause of atherosclerotic vascular lesions is an alteration in the normal structure of low-density lipoproteins (LDLs) or defects in their corresponding LDL receptors. These modifications can affect both the protein and lipid components of the molecule.
Two main mechanisms drive the pathological modification of LDLs in the body:
- Lipid peroxidation — hyperactivation of this process damages 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
Atherosclerotic plaque formation occurs in several stages, with the immune system playing a key role in attempting to clear damaged lipids.
- Due to structural changes, modified LDLs are no longer recognized by normal receptors and become recognized as foreign entities by the body.
- This triggers phagocytosis: modified lipoproteins are actively engulfed by macrophages.
- By accumulating massive amounts of cholesterol internally, macrophages alter their morphology and transform into foam cells.
- These lipid-laden cells migrate across the endothelial barrier and penetrate the vascular intima (the innermost layer).
- Within the intima, foam cells inevitably rupture. The released cholesterol accumulates in the extracellular space, establishing the early 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). Levels of 4.8 mmol/L and 150 mg/dL are considered safe and within the normal range.
- Borderline high and high risk: Patients with levels of 240 mg/dL, 260 mg/dL, or 6.8 mmol/L require mandatory further medical evaluation, as these figures indicate a serious threat to the vascular system.
Familial Hypercholesterolemia and Statin Therapy
A severe clinical presentation of this pathology is familial hypercholesterolemia. It is characterized by a strong family history (e.g., early death of relatives from myocardial infarction) and extremely high total cholesterol levels (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), the rate-limiting enzyme in endogenous cholesterol synthesis.
- Reduction of the cholesterol pool: The level of intracellular (endogenous) cholesterol in hepatocytes (liver cells) drops precipitously.
- Activation of the SREBP pathway: Cholesterol depletion 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 surface of liver cells increases compensatorily.
- Blood clearance: The liver steps up its uptake of LDL particles from the bloodstream. As a result, the blood cholesterol concentration decreases therapeutically (e.g., dropping from 400 to 250 mg/dL).
Before treatment, a deficiency of receptors is observed on the cell surface while an excess of LDL circulates in the plasma. After successful statin therapy, membrane receptor density is restored, ensuring efficient lipid clearance from the blood.