Atherosclerosis – Etiological Factors and Pathogenesis

ATHEROSCLEROSIS


Atherosclerosis is a pathological process that leads to a change in the arterial wall as a result of the accumulation of lipids, the formation of fibrous tissue, and the formation of plaque, which narrows the lumen of the vessel. Atherosclerosis is not considered an independent disease, it is clinically manifested by general and/or local circulatory disorders, some of which are isolated into separate nosological forms.

Most often, the atherosclerotic process develops in the aorta, femoral, popliteal, tibial, coronary, internal, and external carotid arteries, and cerebral arteries. Atherosclerotic changes, as a rule, occur in the places of bifurcation of the aorta and arteries. Complications of atherosclerosis account for 1/2 of all deaths and 1/3 of deaths in people aged 35-65 years.

 

BLOOD LIPIDS IN ATHEROSCLEROSIS

In Atherosclerosis, In plasma, cholesterol and triglycerides are bound to proteins and are called lipoproteins (LP). The degree of their participation in atherogenesis depends on the size of the LA.

  • The smallest in size (5-12 nm) – high-density LP (HDL) – easily penetrate the arterial wall and just as easily leave it, thus not participating in atherogenesis.
  • Low-density LP (LDL, 18-25 nm), intermediate-density LP (IDL, 25-35 nm), and a small portion of very-low-density LP (VLDL, about 50 nm in size) are small enough to penetrate the arterial wall. After oxidation, these LPs are easily retained in the arterial wall.
  • Large LA – chylomicrons (75-1200 nm) and significant VLDL (80 nm) – are too large to penetrate the arteries, and therefore are not considered atherogenic.

There is a direct relationship between the content of LDL cholesterol and the risk of developing coronary heart disease (CHD) – the higher the content of LDL cholesterol, the higher the risk of developing CHD. There is an inverse relationship between the content of HDL cholesterol and the risk of developing coronary artery disease – the higher the level of HDL cholesterol in the blood, the lower the risk of developing coronary artery disease.

Triglycerides are found mainly in chylomicrons (80-95%), they are synthesized in the mucous membrane of the small intestine from fats from food, and in VLDL (55-80%). Severe hypertriglyceridemia is not considered atherogenic, since large chylomicrons and VLDL cannot penetrate the arterial wall, but pancreatitis can cause significant hypertriglyceridemia. LDL and HDL contain small amounts of triglycerides (5-15%).



ATHEROGENESIS IN ATHEROSCLEROSIS

In Atherosclerosis, The pathogenesis of atherosclerotic lesions of blood vessels (atherogenesis) is intended to explain three hypotheses. The very defeat of the vessel wall develops in stages.

STAGES OF ATHEROGENESIS

Atherosclerotic changes occur in the inner lining of the arteries. This process takes place in three stages (Fig. 1-1): fatty streak, fibrous plaque, and complex disorders.

Fig. 1-1. Atherosclerotic changes in the artery: a – fatty strip; b – fibrous plaque; c – complex violations. 1 – intercellular lipids; 2 – foam cells; 3 – fibrous capsule; 4 – smooth muscle cells; 5 – lipid core; 6 – thrombus; 7 – ulceration; 8 – calcification; 9 – hemorrhage

 

The fatty streak is an early morphological manifestation of atherosclerosis. From the moment a person is born, yellowish spots of 1-2 mm in size can be found in the vessels. These spots, which are lipid deposits, enlarge over time and merge. Smooth muscle cells and macrophages appear in the inner lining of the arteries, macrophages accumulate lipids and turn into foam cells. This is how a fatty strip appears, consisting of smooth muscle cells and macrophages containing lipids. But the deposition of lipids in the form of fatty strips in the wall of the arteries does not mean that the process must grow into the next stage (the formation of a fibrous plaque).

The fibrous plaque is located in the inner lining of the arteries and grows eccentrically, over time, reducing the lumen of the vessel. A fibrous plaque has a dense capsule consisting of endothelial cells, smooth muscle cells, T-lymphocytes, foam cells (macrophages), fibrous tissue, and a softcore containing esters and cholesterol crystals. Cholesterol is not formed by local synthesis but comes from the blood.

Complex violations consist of a decrease in the thickness of the fibrous plaque capsule less than 65 microns and is a violation of its integrity – the occurrence of cracks, ulcers, ruptures. This is facilitated by the following factors.

  • Increase in the zone of atheromatous by more than 30-40% of the total volume of fibrous plaque (due to the accumulation of cholesterol).
  • Infiltration of the fibrous plaque surface by macrophages (more than 15% of the plaque surface), leading to aseptic inflammation.
  • Exposure to metalloproteases produced by macrophages and destroying collagen, elastin, and glycoproteins.
  • The high content of oxidized LDL, which cause the production of inflammatory mediators and stimulate monocyte adhesion.

In Atherosclerosis, Violation of the integrity of the fibrous plaque leads to the attachment of platelets to it, their aggregation, thrombosis, and the development of a clinical picture corresponding to the location of the fibrous plaque (myocardial infarction, ischemic stroke, etc.), due to the partial or complete cessation of blood flow in the affected vessels.

 

PATHOGENESIS OF ATHEROSCLEROSIS

Three hypotheses are explaining the onset of atherosclerosis: lipid, chronic endothelial damage, and monoclonal.

Lipid hypothesis. It is assumed that the remnants of triglyceride-rich LP are captured by macrophages, which leads to the formation of early manifestations of the atherosclerotic process (the stage of lipid stripes). The prolonged stay of LP in the endothelium is accompanied by damage to these cells, which, in turn, leads to the deposition of lipids in the extracellular space. Endothelial damage and further progression of atherosclerotic changes contribute to the formation of fibrous plaque.

Endothelial damage. The hypothesis of chronic endothelial damage is based on the fact that several factors such as altered blood flow, an increase in the concentration of LDL cholesterol, toxic and infectious agents (viruses, bacteria, chlamydia), and a high content of homocysteine ​​can damage the surface of the inner lining of the artery. This leads to the development of chronic inflammation involving macrophages, T-lymphocytes, platelets, and smooth muscle cells.

The monoclonal hypothesis (neoplastic hypothesis) is based on the assumption that atherogenesis is based on a mutation of one of many genes that regulate the cell cycle, which leads to the proliferation of smooth muscle cells of the vascular wall. Altered smooth muscle cells trigger the atherosclerotic process.

 

TYPES OF HYPERLIPIDEMIA

There are five types of dyslipidemias (hyperlipidemias, Table 1-1).

  • Type I is characterized by a very high triglyceride content due to the increased concentration of chylomicrons.
  • Type Ia is high in LDL cholesterol.
  • Type IIb is characterized by a high concentration of triglycerides and cholesterol due to the increased content of LDL and VLDL.
  • Type III arises from the accumulation of fragments of chylomicrons and LDPP. Serum levels of cholesterol and triglycerides are increased.
  • Type IV is characterized by increased triglycerides, normal cholesterol levels, and increased VLDL levels.
  • Type V is characterized by a predominantly increased concentration of triglycerides and cholesterol.

Table 1-1. Types of hyperlipidemia according to Fredrickson (1967)

Type, the relative frequency

Lipidcausing hyperlipidemia

Laboratory data

Primary hyperlipidemia

Secondary hyperlipidemia

Type I, 1%

Mostly triglycerides

Hyper-chylomicronemia, lipoprotein lipase (LPLase) deficiency

Family insufficiency of LPLase

Systemic lupus erythematosus (SLE), pancreatitis, inadequately controlled diabetes mellitus

Type IIa, 10%

Cholesterol

Increased LDL content

Familial hypercholesterolemia

Hypothyroidism, nephrosis, dysglobulinemia, acute porphyria, idiopathic hypercalcemia

Type IIb, 40%

Cholesterol, triglycerides

Increased content of LDL and VLDL

Familial hypercholesterolemia, familial combined hyperlipidemia

Nephrotic syndrome, diabetes mellitus

Type III, 1%

Cholesterol, triglyceride

Increased content of DID

Familial dysbetalipoproteinemia

Diabetes mellitus, hypothyroidism, dysglobulinemia

Type IV, 45%

Triglycerides

Increased VLDL content

Familial hypertriglyceridemia, familial combined hyperlipidemia

Glycogenosis, hypothyroidism, SLE, diabetes mellitus, nephrotic syndrome, renal failure

Type V, 5%

Mostly triglycerides, cholesterol

Increased content of chylomicrons, VLDL

Familial hypertriglyceridemia, familial combined hyperlipidemia

Inadequately controlled diabetes mellitus, glycogenosis, hypothyroidism, nephrotic syndrome, dysglobulinemia, pregnancy, estrogen intake in familial hypertriglyceridemia

In Atherosclerosis, Distinguish between primary (hereditary, genetic) and secondary (for various diseases) dyslipidemia.

Primary hypercholesterolemia

  • Familial hypercholesterolemia (hyperlipidemia IIa according to Fredrickson) is an autosomal dominant disease. It is based on a defect in LDL receptors. Homozygotes occur with a frequency of 1 in 1 million. They are characterized by an increase in LDL cholesterol up to 15-31 mmol / l and the development of coronary artery disease up to 20 years of age. Heterozygotes (compared with homozygotes, the number of LDL receptors is reduced by 50%) occur with a frequency of 1 in 500. The content of LDL cholesterol reaches 6-15 mmol / l. IHD in such people develops between 30 and 40 years.
  • Polygenic hypercholesterolemia occurs against the background of a genetic predisposition under the influence of external factors (obesity, diet). The content of cholesterol in the blood is 6-8 mmol / l, ischemic heart disease develops up to 60 years.
  • Familial combined hyperlipidemia is observed in 1-2% of the population (hyperlipidemia IIa, IIb, IV according to Fredrickson).

Secondary hypercholesterolemia occurs in diabetes mellitus, kidney disease, liver, and biliary tract pathology, hypothyroidism, pancreatitis, obesity. Secondary hyperlipidemia develops much more often than primary.



CLINICAL PICTURE OF ATHEROSCLEROSIS

In Atherosclerosis, For a long time (several decades), the atherosclerotic process is latent, and only then do clinical signs appear. They depend on the predominant localization of the process and the degree of obstruction of the vascular bed.

Affected vessels. There are typical sites of predominant localization of the atherosclerotic process: the anterior interventricular branch of the left coronary artery, bifurcation of the carotid arteries, proximal parts of the renal arteries.

  • If the coronary arteries are affected, clinical signs of angina pectoris, myocardial infarction, or sudden cardiac death may occur.
  • When the arteries of the brain are damaged, transient ischemic attacks or stroke occur.
  • Damage to the arteries of the lower extremities by the atherosclerotic process leads to the appearance of intermittent claudication (including in Leriche’s syndrome) and gangrene.
  • The atherosclerotic process in the renal arteries leads to the development of persistent arterial hypertension (AH).
  • When the mesenteric arteries are affected, symptoms of intestinal ischemia appear.

Xanthomasxanthelasmassenile arch. External signs of an atherosclerotic process can be xanthomas (tuberous formations in the area of ​​the joints, calcaneal tendons, caused by the deposition of cholesterol), xanthelasma (various forms of spots on the skin of a yellowish-orange color, often towering, caused by the deposition of cholesterol and triglycerides in the skin) and the corneal arch (yellowish stripe along the edge of the cornea).

 

DIAGNOSTICS

In Atherosclerosis, Cholesterol To diagnose lipid metabolism disorders, the content of total cholesterol, HDL cholesterol, triglycerides is usually determined. If possible, direct determination of the concentration of LDL cholesterol is carried out (a more expensive and complex method). More often, the concentration of LDL cholesterol is calculated using the Friedwold formula:

LDL cholesterol (mmol / L) = Total cholesterol (mmol / L) – HDL cholesterol (mmol / L) – 0,45 X Triglycerides (mmol / l)

where all values ​​are given in mmol / L.

 

Or:

 

LDL cholesterol (mg%) = Total cholesterol (mg%) – HDL cholesterol (mg%) – 0.2 X Triglycerides (mg%)

where all values ​​are in mg%.

 

The recommended optimal concentration of total cholesterol is no more than mmol / L (190 mg%)and the concentration of LDL cholesterol is no more than mmol / L (115 mg%).

  • To assess the risk of CHD, the ratio of total cholesterol to HDL cholesterol is calculated. A ratio of more than 5 indicates a high risk of CHD.
  • Remember that plasma triglyceride concentration can vary significantly with food and alcohol intake. A triglyceride concentration of more than 2 mmol / l (180 mg%) is considered an indication for its re-determination.
  • In the acute stage of myocardial infarction and after heart surgery, the concentration of total cholesterol, HDL cholesterol, and LDL cholesterol may decrease, and the triglyceride content may increase.

Special diagnostic methods  – angiography (see Chapter 2 “Ischemic Heart Disease”) and ultrasound examination (US) of the vessels – allow visualizing fibrous plaques.

 

TREATMENT

In Atherosclerosis, Treatment of dyslipidemias begins with non-drug measures – lifestyle changes, diet (see Chapter 3 “Prevention of coronary heart disease”, Fig. 3-3). In the absence of the effect of non-drug measures, antihyperlipidemic agents are prescribed.

 

Antihyperlipidemic agents

There are four main classes of antihyperlipidemic drugs (MPs).

  • Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) – statins.
  • Bile acid sequestrants – anion exchange resins.
  • Derivatives of fabric acid – fibrates.
  • Preparations of nicotinic acid.

The characteristics of these antihyperlipidemic agents are given in the table. 1-2.

• The mechanism of the effect of statins (inhibitors of HMG-CoA reductase) is mediated by interference with the cholesterol cascade in the liver:

acetate → HMG-CoA → mevalonic acid → cholesterol → bile acids.

In Atherosclerosis, Competitive blocking of HMG-CoA reductase leads to a decrease in cholesterol synthesis. A decrease in cholesterol synthesis causes, by a feedback mechanism, an increase in the number of LDL receptors in hepatocytes, which leads to the capture of LDL cholesterol from the blood plasma and a decrease in its level.

  • The mechanism of action of bile acid sequestrants (anion exchange resins) is to bind bile acids in the intestinal lumen and excrete them with feces. This stimulates the synthesis of bile acids from cholesterol in the liver. A decrease in the content of endogenous cholesterol stimulates its synthesis, causes an increase in the number of LDL receptors in hepatocytes and a decrease in the concentration of LDL cholesterol in plasma. Thus, sequestrants are more indicated at high LDL cholesterol concentrations and normal triglyceride concentrations.
  • The mechanism of action of fibrates (derivatives of fabric acid) is to increase the activity of lipoprotein lipases (LPLases) and hydrolysis of triglycerides, decrease the synthesis of VLDL and increase the breakdown of LDL.
  • The main mechanism of action of niacin is to inhibit the liver secretion of triglyceride-rich LDL and VLDL (by reducing the mobilization of free fatty acids from fat stores). Nicotinic acid is especially indicated for high blood triglycerides.

Comparative characteristics of antihyperlipidemic agents. There are differences in the effect of antihyperlipidemic agents on the lipid spectrum. Statins, anion exchange resins, nicotinic acid effectively reduce the concentration of LDL cholesterol, while fibrates have little effect on it. HDL cholesterol increases slightly with the appointment of statins and resins, and with the appointment of nicotinic acid and fibrates, its increase is more significant. Triglyceride levels decrease moderately with statins and are more pronounced with fibrates and nicotinic acid.

In the absence of the effect of monotherapy, a combination of antihyperlipidemic agents is used. It is used for mixed hyperlipidemias, in this case, taking two or more drugs in lower doses has a good effect in case of intolerance to each in high doses.

The advantage in the treatment of dyslipidemia should give inhibitors of HMG-CoA reductase inhibitors (statins) as a class of lipid-lowering drugsreliably proven its effectiveness in reducing the mortality due to coronary artery diseasebut also to increase the duration of lifePossible therapy as a singleso- and several drugs.

 

Apheresis cholesterol LDL

Removal of cholesterol from the blood by filtration (apheresis of LDL cholesterol) is recommended in the presence of severe hyperlipidemia – as a rule, in patients with familial homozygous hypercholesterolemia, as well as in patients with hyperlipidemia refractory to drug treatment.

Table 1-2. Antihyperlipidemic agents

Class

Mechanism of action

Effect on LP

Namesdoses (days)

Contra-

indications

Side effects

Recommendations

Statins

Inhibit the activity of HMG-CoA reductase inhibitors, cholesterol synthesis is reduced, increasing the synthesis of apolipoprotein A 1

↓ LDL by 25-40%;

↓ VLDL

Lovastatin 10-80 mg (1); simvastatin 10-40 mg (1); pravastatin 10-40 mg (1); fluvastatin 20-40 mg (1); atorvastatin 10-80 mg (1)

Acute liver disease, pregnancy

Liver dysfunctions, myositis (rarely) with increased serum creatine phosphokinase (CPK) activity, insomnia, gastrointestinal (GI) tract disorders, allergies

Take in the evening with meals; the first 15 months, liver function tests every 3 months; prescribed with a caution against the background of alcohol, patients with liver disease, arterial hypotension, epilepsy, after traumatic brain injury (TBI)

Fibrates

Increase the activity of LPLases and hydrolysis of triglycerides, reduce the synthesis of VLDL and increase the catabolism of LDL

↓ triglycerides by 25-40%;

↓ VLDL; ↓ LDL;

-HDL by 10-15%

Gemfibrozil 600 mg (2); fenofibrate 100 mg (3); bezafibrate 200 mg (2-3); ciprofibrate 100 mg (1)

Pregnancy

Nausea, liver dysfunction, myositis, anemia

Take 30 minutes before meals

A nicotinic acid

Suppresses the synthesis of VLDL and LDL in the liver, increases the activity of LPLases

↓ triglycerides by 25-85%;

↓ VLDL by 25-35%; ↓ LDL

by 15-25%; may

-HDL

Nicotinic acid 50-100 mg (2) (up to 1-2 g / day)

Liver dysfunction, exacerbation of peptic ulcers, diabetes mellitus, gout

Erythema and itching of the skin, tachycardia, atrial arrhythmias, gastrointestinal disorders, hyperuricemia, hyperglycemia, liver dysfunctions

Recommend methionine-rich foods; start with 500 mg/day and gradually increase the dose to 3 g / day in

1-3 doses during or after meals