Basics of Atherosclerosis Pathogenesis
The atherosclerotic process does not occur spontaneously; it is triggered by a profound disturbance of lipid metabolism in the body. Under normal physiological conditions, there is a strict and well-calibrated balance between the volume of lipids delivered to cells to meet their needs and the volume transported back to the liver for subsequent utilization.
The foundation of the pathology's development is precisely this imbalance in the transport mechanism. The classical clinical and laboratory blood picture in progressive atherosclerosis demonstrates characteristic changes: there is a noticeable decrease in high-density lipoprotein (HDL) levels against the background of a simultaneous increase in low-density lipoprotein (LDL) concentration.
The direct result of this biochemical shift is hyperlipoproteinemia (HLP), an excess content of lipoproteins in the plasma. In modern medicine, there are five main types of HLP, which differ in the composition of lipid fractions. It is fundamentally important to understand that far from every one of these five types leads to the development of atherosclerosis.
Fredrickson Classification: High and Moderate Risk
For the convenience of clinically assessing the probability of vascular events and choosing treatment tactics, all types of hyperlipoproteinemias are traditionally divided according to the degree of atherogenic risk.
High Atherogenic Risk Group:
- Type IIa: Characterized by a sharp increase in cholesterol levels (CH ++) and the LDL fraction. This disorder is based on a genetic defect of the LDL receptor or the specific Apo B-100 protein. Statins, as well as bile acid sequestrants, are used as pharmacotherapy here.
- Type IIb: Two atherogenic fractions increase simultaneously in the blood plasma—LDL and VLDL. In addition, cholesterol (Ch ++) and triglyceride (TG ++) levels are significantly elevated. The precise molecular defect for this type is currently unknown. Pharmacotherapy is complex and includes fibrates, statins, and nicotinic acid preparations.
Moderate Atherogenic Risk Group:
- Type III: The blood concentration of IDLs increases (in literature, they may also be designated as $\beta$-VLDL or floating $\beta$-VLDL). Concurrently, an increase in Ch (++) and TG (++) is recorded. The reason lies in a defect of the Apo E protein, which leads to impaired normal utilization of remnants. The main drugs for treatment are fibrates.
- Type IV: An isolated increase in VLDL is observed with a moderate rise in cholesterol (Ch +) and a pronounced jump in triglycerides (TG ++). As with type IIb, the primary defect has not been established. The main group of prescribed drugs is fibrates.
Group Without Atherogenic Risk
There are specific lipid spectrum disorders that, despite pronounced changes in laboratory tests, do not lead to the formation of atherosclerotic plaques and belong to the group without atherogenic risk.
- Type I: Manifests as a colossal increase in triglyceride levels (TG +++) and the appearance of chylomicrons with a relatively small increase in cholesterol (Ch +). This pathology is directly related to a defect in the enzyme lipoprotein lipase or the Apo C-2 protein. Specific pharmacological drugs for the correction of this type are not indicated.
- Type V: According to the presented classification data, this type is accompanied by an increased HDL level. The molecular defect leading to this condition has not been identified. Specific drug pharmacotherapy in this case is not required or is not indicated in standard protocols.
Briefly: answers to topical questions
What is the mechanism of action of statins used in type IIa and IIb hyperlipoproteinemia?
The mechanism of action of statins consists in inhibiting HMG-CoA reductase, which is a key enzyme in cholesterol synthesis. This process occurs inside hepatocytes, leading to the inhibition of endogenous cholesterol formation in the liver. As a result of this action, the uptake of cholesterol from the blood by cells is enhanced, which ensures an effective decrease in its level in blood plasma.
What specific drugs belong to the group of bile acid sequestrants?
The following specific drugs, which are polymers, belong to the group of bile acid sequestrants:
- Cholestyramine is a typical representative of the sequestrant group.
- Cholestyramine binds bile acids in the intestinal lumen, which can impair the absorption of fat-soluble vitamins.
- Cholesterolamine adsorbs bile acids in the intestine and interrupts their enterohepatic circulation.
Through what mechanism do fibrates lower triglyceride levels in type III and IV hyperlipoproteinemias?
Fibrates lower triglyceride levels by activating nuclear receptors and stimulating lipoprotein lipase activity. The mechanism of action includes the following stages:
- Activation of PPAR$\alpha$ receptors (peroxisome proliferator-activated receptors).
- Increased synthesis and expression of endothelial lipoprotein lipase (LP lipase).
- Acceleration of the catabolism (breakdown) of triglyceride-rich particles: VLDL, IDL, and chylomicrons.
As a result of these processes, a pronounced decrease in blood plasma triglyceride levels occurs.
For quick memorization of high-risk type pharmacotherapy (IIa and IIb), use the abbreviation SSFN: Statins and Sequestrants (for IIa), plus Fibrates and Nicotinic acid (added for IIb).
Class and exam questions
What is the main cause of the development of atherosclerosis?
The core of the disorder lies in the imbalance between lipid delivery to peripheral tissues and their return to the liver. A typical picture includes decreased HDL and increased LDL.
Are all types of hyperlipoproteinemia equally dangerous and do they cause atherosclerosis?
No, the classification distinguishes 5 types that differ in the degree of risk. Types I and V belong to the group without atherogenic risk and do not provoke the development of the disease.
What molecular defect is characteristic of type III hyperlipoproteinemia?
In type III, an Apo E protein defect is observed. This leads to a severe disruption of lipoprotein remnant utilization processes in the body.
How does the pharmacotherapy of types IIa and IIb differ?
In type IIa, statins and bile acid sequestrants are prescribed. In type IIb, fibrates and nicotinic acid are added to statins, as VLDL and triglycerides are additionally elevated.
What else to study on this topic
- Pharmacodynamics of statins and bile acid sequestrants in the treatment of hyperlipoproteinemia.
- Mechanism of action of fibrates and nicotinic acid preparations.
- The role of LDL receptors and the Apo B-100 protein in cellular metabolism.
- Functions of the enzyme lipoprotein lipase and the Apo C-2 protein in chylomicron metabolism.
- Biochemical differences of floating $\beta$-VLDL (IDL) from other fractions.
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