Atherosclerosis

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atherosclerosis is a syndrome characterized by the deposit and infiltration of lipid substances in the intima layer of the walls of medium- and large-caliber arteries. It is the most common form of arteriosclerosis.

It causes an inflammatory reaction and the multiplication and migration of the smooth muscle cells of the wall, which gradually narrow the arterial lumen. The specific thickenings are called atheromatous plaque.

Atherosclerosis is a common mechanism of various manifestations of cardiovascular disease, including coronary heart disease, heart failure, stroke, and hypertension.

Etymology and spelling

The term atherosclerosis comes from the Greek words ἀθήρα athéra ('paste') and σκληρός sklerós ('hard'). It does not come from ἀρτηρία arteria ('artery').

The Royal Spanish Academy, in its Pan-Hispanic Dictionary of Dudes, prefers atherosclerosis instead of atherosesclerosis > ("somewhat less frequent"). Instead, as an adjective he only proposes atheroandsclerotic. However, in the Spanish language there is a usual rule: when a prefix ending in a vowel is placed before a word that begins with a liquid s, an intermediate e is usually added.

Atheromatous plaques

Main article: Ateroma

Atheromatous plaques or atheromas are focal lesions that start in the intima of an artery.

Morphology

They present a soft, lumpy and yellowish central nucleus, formed by lipids (cholesterol and its esters), covered by a fibrous layer. Normally they only occur occupying a part of the circumference of the arterial wall, in the form of patches, variable throughout the vessel. Initially widespread, but increase in number as the disease progresses.

In advanced cases, a plaque calcification process is observed that increases the risk of acute plaque change:

the plaque rupture, its ulceration or erosion, which causes the exposure of thrombogenic agents and can generate the appearance of a thrombo and block a vessel located in front of the plaque area, which would result in a lack of blood input in the area irrigated by the corresponding artery (ischemia), which can be fatal if the block occurs in a coronary artery or in a brain artery;
a hemorrhage can occur inside the plate, for the rupture of the existing capillaries inside it, which can result in a hematoma and favor the rupture of the plate;
vasoconstriction of the affected area may also favor the breaking of the plate.

The key processes of atherosclerosis are thickening of the intima and accumulation of lipids.

Location

Atheromatous plaques have a clearly characteristic distribution, since they occur mainly in the large arteries, in areas of turbulent blood flow, especially:

Abdominal aorta, more often than chest aorta;
Especially in the origin orifice (ostium) of the major arterial branches;
In descending order (after the abdominal aorta), the most frequently affected vessels are:
- Coronary arteries;
- Internal carotids;
- Willis' polygon vessels, a set of arteries that supply blood to the brain;
Normally, the vessels of the upper extremities are not affected, as well as the mesenteric arteries (superior and lower) and the renal arteries (with the exception of their respective Ostia);
In the same individual several lesions often coexist in different stages of evolution.

Risk factors

This disease is the main cause of death in western or first world societies, such as North America, Europe or Australia, associated with an unhealthy lifestyle. Risk factors for the development of atherosclerosis can be grouped into two categories, depending on the possibility of acting on them.

Not modifiable

Age. Age has a dominant influence. Death rates from heart ischemic diseases (e.g. myocardial infarction) increase throughout life, even at an advanced age. Atherosclerosis is not normally evident up to half of life or later, when the artery lesions cause organ damage. Between 40 and 60 years the incidence of myocardial infarction is multiplied by five.
Sexual hormones. Male hormones are atherogenic, while estrogens protect from atherosclerosis, so in women the rate of atherosclerosis-related diseases increases after menopause.
Family history and genetic alterations. Family predisposition to atherosclerosis and heart ischemic diseases is well defined and is probably polygenic (i.e., several genes intervene). Normally, genetic propensity is associated with other risk factors, such as hypertension or diabetes, and less frequently to alterations in the metabolism of lipoproteins, which produce high levels of lipids in blood, such as in family hypercholesterolemia.

In a study published in 2021 in the journal Nature Communications, polymorphic variants were located in the PEAR1 and RGS18 genes highly related to the development of atheromatous plaques in cohorts of patients from Europe and America, thanks to the use of techniques that included the use of eQTL for the co-localization of the loci involved and RNA-Seq data of platelets. Once all the variants or SNPs were identified, their presence was verified in databases, thus finding that one of the polymorphisms corresponding to the minor allele of PEAR1 was related to an increase in the development of gastrointestinal bleeding up to 6 times above normal, due to a decrease in the phenomenon of platelet aggregation induced by lower gene expression.

For the RGS18 gene loci, eQTL data were compared with epigenetic data, observing numerous polymorphisms for this region of the genome. To reaffirm these results, a line of knockout mice was created for the aforementioned gene, observing an abnormally increased platelet reaction in response to agonist substances such as ADP and epinephrine, as well as an increase in artery clogging due to loss of inhibition of G protein receptors on mouse platelets. Data were found for the minor allele of this gene that associated it with a higher risk of thrombosis in both European and African-American patients. In addition, another 2 variants were located that caused a decrease in the expression of RGS18 due to the interruption in the GATA1 and NFE2 binding sites. These results confirmed what was found in previous trials.

Modifiable

Hyperlipidemia or increased blood lipid level. It is the greatest risk factor for atherosclerosis. Most evidence refers to hypercholesterolemia, i.e. blood cholesterol levels. The main component of serum cholesterol associated with increased risk are low-density lipoproteins or LDL, which have a fundamental physiological role in the transport of cholesterol to peripheral tissues. However, high-density lipoproteins or HDL protect from atherosclerosis, as they remove cholesterol from tissues and atheromas to take it to the liver, where it is excreted with bile. That's why HDL is called "good cholesterol": the higher the level of HDL, the lower the risk, and vice versa for LDL. In particular, during the 1980s, the hypothesis of the oxidation of LDL was collated because it was observed that, in general, non-oxidized native LDLs do not cause the formation of foam cells; in that sense, LDL had to oxidize first to develop atherosclerosis; oxidation that begins with the oxidation of linoleic acid contained in LDL particles. The consumption of natural saturated fatty acids, exercise and moderate consumption of alcohol increase the level of HDL, while obesity and smoking decrease. A diet rich in cholesterol and saturated fatty acids (present in the egg yolk, animal fats and butter) increases the levels of LDL; however, the results of studies have been contradictory with respect to the relative importance of intake of saturated fats in the progression of atherosclerosis, some studies even observed an inverse association; also, there are contradictory studies Conversely, a low cholesterol and low cholesterol diet in the relationship between saturated and unsaturated fatty acids causes a reduction in LDL levels. Moreover, omega-3 fatty acids, abundant in fish oils, are probably beneficial, while transaturated fats produced by artificial hydrogenation of vegetable oils (used in baked products and margarines) can negatively affect cholesterol levels. On the other hand, there is quite convincing evidence that omega-6-type fatty acids promote heart disease. Drugs called statins reduce circulating cholesterol levels by inhibiting a key enzyme of cholesterol biosynthesis in the liver, HMG-CoA reductase.
Arterial hypertension (HTA), one of the main risk factors at any age, alone responsible for an increase of 60% risk of cardiovascular disease. HTA is the main cause of ventricular hypertrophy, related to heart failure. Men between 45 and 62 years of age whose blood pressure (Pa) is above 169/95 mmHg have five times more risk of cardiovascular accident than those with a Pa of 140/90 mmHg or less. Both increased systolic and diastolic pressures are important in increased risk. An increase in the Pa causes clutch forces that break the fragile endothelium that covers the interior surface of the arteries. Antihypertensive treatments reduce the incidence of atherosclerosis-related diseases such as strokes and cardiovascular accidents.
Tabaquism. Toxic substances containing tobacco such as nicotine have a direct toxic effect on the wall of the arteries, causing an inflammatory response. Smoking a pack of cigarettes or more a day doubles the death rate for cardiovascular disease. Quitting smoking decreases the risk significantly.
Diabetes mellitus. Diabetes induces hypercholesterolemia, and an increase in predisposition to atherosclerosis. The incidence of myocardial infarction is double in diabetics, and an increase of 100 times in the rate of gangrene of the lower extremities induced by atherosclerosis is observed.
Periodontitis. Periodontitis begins with an infection against microbial biofilm, followed by tissue destruction mediated by hyperactive or cebado leukocytes and the network of cytokines, eicosanoids, and matrix metaloproteins (MMPs) that cause clinically significant bone destruction and connective tissues. Bacterial accumulation in the teeth is decisive for the initiation and progression of periodontitis. Although bacteria are essential for the initiation of periodontitis, the severity of the disease and response to treatment is the result of modified factors (tabachism), taxpayers (diabetes) or predisponents (genetic charge). Multiple studies have shown that genetic factors are responsible for more than 50 percent of differences in the type and severity of periodontal diseases. The first association report with the specific gene variants involved was the group of interleukin genes (IL-1), but there are at least 12 other identified genetic factors that can also predispose the development of a periodontitis. Genomic and protein research has recently shown that susceptibility is due to multiple polymorphisms of a single nucleotide (SNPs) in the non-coding region of chromosome 9p21 for aggressive periodontitis, and that it can share a gene with coronary disease, suggesting that inflammatory pathogenic mechanisms when they are common, can contribute to the emergence and progression of both diseases.

The aforementioned factors are responsible for 80% of cardiovascular diseases. The rest is attributed to other minor factors:

Inflammation. The presence of inflammation is intimately linked to the development of atherosclerosis, being one of the main causal agents of pathogeny. Therefore, the determination of the presence of systemic inflammation has become an important element of risk stratification. One of the simplest and most sensitive methods is the determination of C-reactive protein levels (PCR). This is a protein of the acute phase synthesized primarily in the liver, produced at the end of the cascades of different inflammatory processes. In the case of atherosclerosis, it is synthesized by damaged endothelial cells, and the blood PCR levels accurately predict the risk of myocardial infarction, cerebral vascular event, peripheral arterial disease or sudden cardiac death, even in individuals in apparent good health. Although there is still no direct evidence that reducing PCR levels reduces cardiovascular risk, quitting smoking, weight loss and exercise reduce PCR levels, and treatment with statins also reduce PCR.
Homocysteinemia. Many clinical studies show a strong association between serum levels of homocysteine and cardiovascular disease, stroke and venous thrombosis. A decrease in folate intake and vitamin B12 can produce high levels of homocysteine in blood, although it is unclear whether the increase in folate intake and vitamin B12 decreases cardiovascular risk. Hocistinuria is a rare genetic disease that has high serum levels of homocysteine in newborns and premature vascular disease.
Metabolic syndrome, characterized by a set of abnormalities associated with insulin resistance. In addition to glucose intolerance, patients have hypertension and obesity. Together, hyperlipidemia is induced, which causes endothelial damage.
Lipoprotein (a), an altered form of LDL containing a fragment of LDL apolipoprotein B-100 together with apolipoprotein A. Lipoprotein (a) levels are associated with coronary and cerebrovascular risk, regardless of total cholesterol or LDL levels.
Factors that affect hemostasis. Some markers of the hemostatic or fibrinolytic function (such as a high level of plasminogen activator inhibitor) are predictive of major atherosclerotic events, such as myocardial infarction or stroke. The thrombin, both procoagulant and proinflammatory, and the factors derived from platelets, are fundamental contributors to vascular pathology.

Other factors, with a less pronounced effect or more difficult to quantify, include:

Sedentary life, with little physical exercise, as it modifies many risk factors, and ultimately decreases the inflammatory response on the wall of the arteries.
Stress, associated with a competitive lifestyle (personality "type A").
Obesity, often associated with hypertension, diabetes, hypertriglyceridemia and low HDL levels.
Infections by Chlamydia pneumoniae.

Alternatively, the following evidence implicates omega-6-rich vegetable oils as a causative factor in atherosclerosis and coronary heart disease:

Increased amounts of lynoleic acid oxidation products are found in LDL and plasma of patients with atherosclerosis.
Increased quantities of lynoleic acid oxidation products are found within atherosclerotic plates and the degree of oxidation determines the severity of atherosclerosis.
A high diet in oleic acid or low in linoleic acid decreases LDL susceptibility to oxidation.
Endothelial cells oxidize LDL by forming lynoleic acid hydrophoxides.
Lynoleic acid is the most abundant fatty acid in LDL and is extremely vulnerable to oxidation, being one of the first fatty acids in oxidation.
A meta-analysis of randomized controlled trials in humans found that when saturated fats plus trans fats are replaced with omega-6 fats (highs in linoleic acid), there is an increase in mortality for all causes.

In this regard, in the MARGARIN study (Mediterranean Alpha linolenic in Rich Groningen dietARy Intervention study), it was observed that the intake of 6 g of alpha-linolenic acid per day can be cardioprotective, while the intake of linoleic acid can increase the risk of cardiovascular disease. On the other hand, the Anti-Coronary Club trial found that more people died overall and from heart disease when saturated fat was replaced with polyunsaturated fat.

Pathogenesis

Atherosclerosis is a chronic inflammatory process in the wall of the large arteries that occurs in response to an attack on the endothelium. The development of this process takes place fundamentally in the arterial intima layer where atheromatous plaque develops. The aggressors can be one or several factors in the same individual: tobacco, arterial hypertension, diabetes mellitus, hyper-homocysteinemia, lipoproteins, free fatty acids or certain infections (Helicobacter pylori, Chlamydia pneumoniae).

In recent decades there has been an extensive study of pathological vasa vasorum (VV) angiogenesis during atherogenesis, recognizing it as an integral component of the development of atherosclerotic plaques; For its part, metabolic resistance to insulin is strongly associated with microvascular resistance to insulin.

Endothelial dysfunction and increased permeability facilitate the entry of various inflammatory-triggering molecules and particles, such as low-density lipoproteins, into the arterial wall from the arterial lumen and VV.

Recognition of incoming particles by resident phagocytes in the vessel wall triggers a maladaptive inflammatory response that initiates the process of local plaque formation. The recruitment and accumulation of inflammatory cells and the subsequent release of various cytokines, especially from resident macrophages, stimulate the expansion of existing VVs and the formation of new, highly permeable microvessels. This, in turn, exacerbates the deposition of pro-inflammatory particles and results in the recruitment of even more inflammatory cells.

Progressive accumulation of leukocytes in the intima, which triggers proliferation of smooth muscle cells in the media, leads to vessel wall thickening and hypoxia, further stimulating VV neoangiogenesis (inducible transcription factors for VV). hypoxia (HIF)-1 and HIF-2 induce the transcription of proangiogenic genes such as vascular endothelial growth factor); that is, as the development of atherosclerosis progresses, the arterial wall thickens, particularly the intima, as a consequence of the proliferation and migration of fibroblasts and smooth muscle cells from the media to the intima; this vessel growth and wall thickening stimulates VV expansion (as in normal growth) to prevent tissue hypoxia.

Ultimately, this highly inflammatory environment damages the fragile plaque microvasculature, leading to intraplaque hemorrhage, plaque instability, and eventually acute cardiovascular events; plaque rupture or erosion followed by luminal thrombosis is the leading cause of clinical complications such as myocardial infarction, stroke, and sudden death.

Atherosclerotic plaque originates from lipid plaque that is already present in the large arteries at birth and transforms over time into atheromatous plaque, which initially causes no symptoms, but is usually manifested by diseases of the atherosclerotic syndrome when the risk factors of atherosclerosis are associated.

The risk factors cause tears in the lumen of the arteries of medium and large caliber, in which fatty substances are deposited, inflammation and finally narrowing of the lumen of the arteries and obstruction to blood flow. Cholesterol (LDL) is deposited within atheromatous plaques when the concentrations of low-density lipoproteins, or LDL, are high. The cells of the arterial wall interpret this deposit as an invasion and excite the immune system which causes inflammation. The excited immune cells are circulating monocytes that penetrate the artery wall, transform into macrophages, and begin to engulf LDL particles, becoming foam cells. The inflammation also forms a capsule of fibrous tissue between the plaque and the artery. As the atheromatous plaque advances, a narrowing or stenosis of the artery occurs, initially partial, until it evolves to a complete obstruction. In addition, atheromatous plaque is fragile and can rupture, bleed and form a thrombus or detach from the artery wall and cause a cholesterol embolism. The veins decrease in diameter due to the accumulation of fatty substances, increased fragility and hardening of the arteries. This causes an increase in blood pressure and if it occurs in the heart or brain it could cause death.

Schematically, the central elements of the pathogenesis of atherosclerosis are the following:

Chronic damage of the endothelium, which is usually produced in a subtle and progressive way, until the end of the dysfunction of the endothelium, which generates an increase in permeability, the adherence of the circulating leucocytes (initially monocytes) and the emergence of a thrombogenic potential.
Accumulation of lipoproteins, mainly LDL, with high cholesterol content, on the wall of the affected blood vessel (usually in the intimate layer of a large artery).
Modification of the accumulated lipoproteins in the oxidation lesion.
Accession of blood monocytes (and other leukocytes) to endothelio, followed by its migration to the intimate and its transformation into macrophages and in sparkling cells.
Accession of platelets.
Release factors by activated platelets, macrophages or vascular cells, which cause the migration of smooth muscle cells from the middle layer of the artery to the intimate layer.
Proliferation of smooth muscle cells in the intimate; these cells are modified and produced components of the extracellular matrix, such as collagen and proteoglycans, which accumulate in the intimate, generating the fibrous cover of the ateroma plate.
Increase in the accumulation of lipids, both intracellularly (in macrophages and in smooth muscle cells) and extracellularly.
Atheroma plates can remain stable, with a dense fibrous layer and an unimportant inflammatory and lipid component. These plates, although they can significantly reduce the light of the vessel, usually do not cause acute injury.
A plaque can become unstable (with a tendency to break) if it has a thin fibrous layer, a large lipid nucleus and an important inflammatory process. The breaking of the plate can generate a thrombo.

Chronic endothelial damage

The specific causes of endothelial dysfunction in early atherosclerosis are not fully understood. Possible culprits include hypertension, hyperlipidemia, tobacco smoke toxins, homocysteine, and infectious agents. However, the two main causes of endothelial dysfunction are hypercholesterolemia and hemodynamic disturbances.

Regarding hemodynamic disturbances, a frequent observation is that atheromatous plaques accumulate in the entrance orifices of the vessels (ostia), in the branching areas and on the posterior wall of the abdominal aorta, sites where turbulent blood flow is observed. In vitro studies have shown that the presence of laminar flow induces the expression of protective genes against atherosclerosis (for example, the antioxidant enzyme superoxide dismutase).

The lipids are transported in the blood associated with specific apoproteins, forming lipoprotein complexes. Dyslipoproteinemia can be caused either by a mutation that modifies a lipoprotein or its receptor, or by other diseases that affect circulating lipid levels (such as nephrotic syndrome, alcoholism, hypothyroidism, or diabetes). Common alterations in lipoproteins are: increase in LDL-cholesterol levels, decrease in HDL-cholesterol levels or increase in lipoprotein (a) levels.

Mechanisms by which hyperlipidemia contributes to atherogenesis include:

Chronic hyperlipidemia (especially hypercholesterolemia), can directly induce endothelial dysfunction, by increasing local production of reactive oxygen species (ERO); oxygen-free radicals can damage tissues and accelerate the disappearance of nitric oxide (NO), reducing its vasodilating activity;
in chronic hyperlipidemia, liproteins accumulate within the intimate. These lipids are oxidized by ERO effect generated by macrophages or endothelial cells. The oxidized LDLs are detected by the "scavenger" receptors (verbatim translation: "carroñero"), different from the LDL receptors, are ingested by these and accumulated in the phagocytes, which are called "spicuous cells". Oxidized LDLs also stimulate the release of growth factors, cytokines and chemokines by endothelial cells, which recruit more monocytes to the lesion. Finally, oxidized LDLs are toxic to endothelial cells and smooth muscle cells, and may induce their abnormal functioning.

On the other hand, although there is evidence that infections can trigger the underlying inflammatory process in atherosclerosis, this hypothesis has yet to be conclusively proven. Herpesvirus, cytomegalovirus, or Chlamydia pneumoniae can be detected in atherosclerotic plaques (but not in normal arteries), and epidemiological studies have detected higher levels of chlamydial antibodies in patients with severe atherosclerosis. However, it may be due to the fact that Chlamydia pneumoniae bronchitis is common in smokers, a population at risk for cardiovascular disease.

Proliferation of smooth muscle cells

Proliferation of smooth muscle cells and deposition of an extracellular matrix by them converts a line of fat (the initial lesion) into a mature atheroma, contributing to disease progression. Smooth muscle cells can come from the medial layer of the artery, but also from circulating precursors, with a different capacity for proliferation and synthesis. Growth factors involved in smooth muscle cell proliferation and extracellular matrix synthesis include PDGF (released by endothelial cells, macrophages, and smooth muscle cells), FGF, and TGF-α. The recruited smooth muscle cells secrete primarily collagen, which stabilizes the plaque. However, the activated inflammatory cells of atheromas can induce apoptosis of smooth muscle cells (thus releasing the calcium accumulated inside, favoring plaque calcification) and increase catabolism of the extracellular matrix, which would increase instability. of the plate.

Atherosclerotic diseases

The diseases that form the atherosclerosis syndrome and that are characterized by affectation of the arteries by atheromatous plaques and consequently obstruction to blood flow or ischemia are, depending on the artery of the affected organ:

Ischemic cardiopathy, with its highest representative, acute myocardial infarction, in the heart.
Cerebral vascular accident, in the form of stroke or brain thrombosis or brain hemorrhage, in the central nervous system.
Intermittent Classification, with its highest severity of acute arterial ischemia of lower limbs.
Erectile dysfunction: It is the main cause of impotence in people over 40 years of age.
Ischemic colitis is an area of inflammation (irritation and swelling) caused by interference with blood flow to the colon (large instino), in the arteries of the intestines.
Aneurysm of aorta, with its utmost gravity in the dissection of aorta.

Treatment

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