Atheroma or Atherosclerotic plaque - How and why it is formed

Generality

What is an atheroma?

The atheroma, better known as atherosclerotic plaque, can be defined as a degeneration of the arterial walls due to the deposition of plaques formed essentially by fat and scar tissue.

Complications

An artery infused with lipid material and fibrotic tissue loses elasticity and resistance, is more susceptible to rupture and reduces its internal lumen, hindering blood flow. Furthermore, in case of atheroma rupture, reparative and coagulative processes are established which can lead to rapid occlusion of the vessel (thrombosis), or generate more or less severe embolisms if a fragment of the atheroma detaches and is pushed - like a wandering mine - in the suburbs, with the risk - if the fibrinolytic phenomena do not intervene in time - of obstructing an arterial vessel downstream.

In light of this description it is easy to understand how atherosclerotic plaques - although asymptomatic even for decades - often give rise to complications, typically starting from late adulthood, such as: angina pectoris, myocardial infarction, stroke, gangrene.

Atheroma is the typical expression of a chronic inflammatory disease called atherosclerosis, the main cause of cardiovascular diseases that in turn - at least in industrialized countries - represent the leading cause of death among the population.

Structure of arterial vessels

It is known to most as a diet rich in animal fats (saturated) and cholesterol - together with overweight and obesity, smoking and physical inactivity - represents one of the main risk factors for atherosclerotic disease.

To understand how an atheroma is formed it is first necessary to briefly brush up the histology of the arterial walls, which are formed by three layers:

• the intimate, with its 150-200 micrometers in diameter, is the innermost or deepest layer of the vessel, the one in close contact with the blood; it consists mainly of endothelial cells, which delimit the lumen of the vessel constituting the element of contact between blood and arterial wall
• the average habit, of 150-350 micrometers in diameter, is composed of smooth muscle cells, but also of elastin (which gives elasticity to the vessel) and collagen (structural component)
• the adventitia represents the outermost layer of the artery; of 300-500 micrometers in diameter, it contains fibrous tissue and is surrounded by perivascular connective tissue and epicardial fat.

Atherosclerotic lesions mainly affect the large and medium arteries, where the elastic tissue prevails (especially in the large arteries) and muscle (especially in the medium and small arteries). Moreover, they tend to develop in predisposed regions, such as the branching points of the arteries characterized by a turbulent blood flow, sparing the adjacent segments. The atherosclerotic process begins very early, from adolescence (a problem of childhood obesity) or from early adulthood.

Atheroma biology

The atherosclerotic process starts from the endothelial cells, therefore from the innermost layer of the arterial vessel.

Considering the endothelial tissue as a simple coating of the vessels is very reductive, so that today the endothelium is considered a real organ, capable of processing many active substances capable of modulating the activity, not only of the various structures of the vessel wall, but also blood cells and coagulation system proteins that come into contact with the endothelium surface. These active substances are partly released in the immediate vicinity (paracrine secretion), exerting their effects on the vessel wall, and in part released into the bloodstream (endocrine secretion), to carry out their action at a distance (eg nitric oxide and endothelin) ; others still adhere to the surface of endothelial cells expressing their action by direct contact, as happens for the adhesion molecules for leukocytes or for those that influence coagulation.

• we must not think of the artery as a simple conduit that guarantees the transport of blood where needed. Rather, we must imagine it as a dynamic and complex organ, made up of different cellular and molecular actors

In summary, the endothelium represents the metabolic fulcrum of the vascular wall, to the point of regulating cell proliferation, inflammatory phenomena and thrombotic processes. For this reason, endothelial tissue plays a critical role in regulating the entry, exit and metabolism of lipoproteins and other agents that can participate in the formation of atherosclerotic lesions.

Formation stages and atheroma growth

The process of formation and growth of the atheroma, which as we have seen develops over the course of years or even decades, consists of various stages, which we describe below:

• Adhesion, infiltration and deposition of LDL lipoprotein particles in the intimacy of the artery; this deposit is called lipid streak ("fatty streak") and is mainly related to the excess of lipoprotein LDL (hypercholesterolemia) and / or the defect of HDL lipoprotein. Oxidation of LDL proteins plays a major role in the initial processes of atheroma formation
  • We recall that the oxidation of LDL can be favored by free radicals formed following cigarette smoking (reduced activity of glutathione peroxidase), hypertension (due to increased production of angiotensin II), Diabetes Mellitus (advanced glycosylation products present) in diabetics), genetic alterations and hyperhomocysteinemia; vice versa, reactive oxygen species are inactivated by dietary antioxidants, such as vitamins C and E, and cellular enzymes such as glutathione peroxidase
• The inflammatory process triggered by the entrapment and oxidation of LDL lipids, with consequent endothelial damage, leads to the expression of adhesion molecules on the cell membrane, and to the secretion of biologically active and chemotactic substances (cytokines, growth factors, radicals) free), which together favor the recall and subsequent infiltration of leukocytes (white blood cells), with transformation of monocytes into macrophages;
  • we recall that nitric oxide (NO) produced by endothelial cells, in addition to the well-known vasodilatory properties, also exhibits local anti-inflammatory properties, limiting the expression of adhesion molecules; for this reason it is currently considered a protective factor against atherosclerosis. Well, physical activity has been shown to increase the synthesis of nitric oxide. In other studies, on the other hand, in response to acute exercise, a reduction in the endothelial adhesion of leukocytes has been demonstrated, while it has been known for some time that regular exercise is associated with a lower concentration of C-reactive protein (thermometer). of inflammation) at rest. More generally, physical exercise prevents and corrects certain conditions that constitute a risk for atherosclerosis, such as hypertension, hyperglycemia and insulin resistance. Furthermore, it increases HDL levels and strengthens endogenous antioxidant systems, thus preventing the oxidation of LDL and their deposition in the arteries.
• Macrophages engulf the oxidized LDLs by accumulating lipids in their cytoplasm and transforming themselves into foamy cells (foam cells), rich in cholesterol. Up to this point - although it represents a (purely inflammatory) precursor of atherosclerotic plaques - the lipid streak can dissolve. In fact, only the accumulation of lipids, free or in the form of foam cells, has occurred. In the later stages, the accumulation of fibrotic tissue leads to the irreversible growth of the true atheroma.

• If the inflammatory response is not able to effectively neutralize or remove harmful agents, it can continue indefinitely and stimulate the migration and proliferation of smooth muscle cells, which migrate from the middle tunic to the inner producing extracellular matrix that acts as a structural scaffold of the atherosclerotic plaque (atheroma). If these responses continue further, they can cause thickening of the arterial wall: the fibrolipid lesion replaces the simple lipid accumulation of the initial phases and becomes irreversible. The vessel, for its part, responds with a process called compensatory remodeling, trying to remedy the stenosis (shrinkage induced by plaque), gradually expanding so as to keep the lumen of the vessels unaltered.

• The synthesis of inflammatory cytokines by endothelial cells acts as a booster for immunocompetent cells such as T lymphocytes, monocytes and plasma cells, which migrate from the blood and multiply inside the lesion. At this point it is believed that as the lesion grows, due to the lack of nutrients and hypoxia, smooth muscle cells and macrophages may undergo apoptosis (cell death), with calcium deposits on dead cell residues and on extracellular lipids. Thus complicated atherosclerotic lesions are born.

• The final result is the formation of a more or less large lesion, consisting of a central lipid core (lipid core) wrapped in a connective fibrous cap (fibrous cap), infiltrated with immunocompetent cells and calcium nodules. It is important to underline that in the lesions there can be a great variability in the histology of the formed tissue: some atherosclerotic lesions appear predominantly dense and fibrous, others may contain large quantities of lipids and necrotic residues, while most present combinations and variations of each of these features. The distribution of lipids and connective tissue within the lesions determines their stability, ease of rupture and thrombosis, with the consequent clinical effects.

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Causes

The pathogenesis of the atherosclerotic plaques described above demonstrates how atherosclerosis is a complex pathology, in which various components of the vascular, metabolic and immune systems participate.

Therefore, it is not a simple passive accumulation of lipids within the vascular wall. However, as anticipated, atherosclerotic plaques can occlude the vessel lumen even by 90% without showing clinically evident signs. The rather serious problems begin in the event of a rapid growth of a blood clot (thrombus) following the breakage of the fibrous capsule or the endothelial surface, or the hemorrhage of the microvessels inside the lesion. Thrombi, formed on the surface or inside the lesion, can cause acute events in two ways:

1) can enlarge in situ until completely occluding the vessel blocking the blood flow from the point where the plaque develops;

2) they can detach themselves from the site of the lesion and follow the blood flow until they get stuck in a small-caliber vascular branch, preventing the flow of blood from that point onwards.

Both these events prevent the correct oxygenation of the tissues, inducing necrosis. The occlusion of the vessel can also be favored by the vasospasm induced by the endothelium release by the endothelial cells.

Furthermore, the weakening of the vessel wall can lead to a generalized dilation of the artery, which over the years can lead to the formation of an aneurysm.

To summarize, by simplifying the concept as much as possible, the formation of atheromas is the consequence of three processes:

1. the accumulation of lipids, mainly free cholesterol and cholesterol esters, in the sub-endothelial space of the arteries;
2. the onset of an inflammatory state with infiltration of lymphocytes and macrophages which, engulfing the accumulated lipids, become foam cells (foam cell);
3. migration and proliferation of smooth muscle cells