This paper tries to present new confirmation for the opinion about the infectious origin of atherosclerosis from the viewpoint of the current knowledge of hereditary immunity. The performed integrative investigation included the reinterpretation of known clinical and epidemiological observations, supported by immunological, molecular ecological, genetic, and genomic discoveries. The revealed body of firstly achieved information is compatible with the concept that infectious agents contribute the clue step to the development of atherosclerosis over its initial stage performed during the triggering of the arterial endothelial wall by the molecular agent of proposed infectious origin.
Atherosclerosis is a main disease that affects the cardiovascular system. It is accounted as the world’s biggest killer. Since 1990, more people have died early worldwide from only one clinical form of atherosclerosis—the coronary artery disease—than from any other awesome disease. Cardiovascular diseases now represent more than 30% of all causes of deaths worldwide [
Atherogenesis is a chronic process affecting arterial blood vessels and is characterized by the formation of multiple atheromatous plaques within the arterial wall. They develop as a result of the accumulation of calcium, collagen, elastin, and fatty materials such as cholesterol and triglyceride in an arterial wall. These components of atheromatous plaques are composed of macrophages and other leucocytes nearest the lumen of the artery.
The buildup of an atheromatous plaque is a slow process, developed over a period of several years through a complex series of cellular events occurring within the arterial wall. One recent hypothesis suggests that, for unknown reasons, leukocytes, such as monocytes or basophils, begin to attack the endothelium of the artery lumen. The formation of atheromatous plaques is performed in the arterial tunica intima, a region of the vessel wall located between the endothelium and the tunica media.
Despite considerable theoretical, epidemiological, immunological, genomic, and pharmacological efforts, the epidemic of atherosclerosis continues to increase its toll on human life. The current efficacy of the disease prevention and treatment is very low. Even the etiology of atherosclerosis remains uncertain. The closely connected issues of the origin, initial causes, pathogenesis, and epidemic spread of atherosclerosis are not yet satisfactorily understood. There are several theories about how and why atherosclerosis develops.
The response-to-injury theory suggests that atherosclerosis develops as a result of the influence of lengthy injuring on the inner lining of the artery. A number of such injuring factors are considered by the apologists of this theory. The list of these factors include, first of all, the biochemical influence on the metabolism of the artery wall caused by a high concentration of cholesterol and low concentration of high-density lipoprotein in the blood. Second is the oxidative damage to the artery lining caused by free radicals formed during reactions between oxygen and low-density lipoprotein (LDL) cholesterol. Finally, some authors suppose that atherosclerosis develops as a response to an infection within the artery wall [
The “response-to-endothelial injury” theory is the most widely accepted among researchers. However, nobody can confirm which ecological or physiological factor is responsible for the development of this “injury”. Besides, this theory is especially impotent to interpret the stochastically spotted and individually peculiar disposition of atherosclerotic affections around the body. The epidemic spread of atherosclerosis around the world is also out of the scope of the “response-to-endothelial injury” theory. There is a gap in the understanding of events leading to the devastation, and as such, there are opportunities for novel ideas and concepts to explain the status quo and elaborate approaches to reform the situation dramatically.
The role of infection in the initiation of atherogenesis was also the subject of various trials to evidence it by discoveries and discussions. Multiple investigations have demonstrated that infectious agents evoke cellular and molecular changes supportive of such a role. Although a definitive proof of a causal role of infection contributing to it is lacking, some researchers believe that atherosclerosis may be caused by an infection of the vascular smooth muscle cells.
Chickens, for example, develop atherosclerosis when infected with the Marek disease herpesvirus [
In addition, although the injury to arterial vessel wall and the associated inflammatory response to the injury are now generally recognized as the essential components of atherogenesis, as many as 50% of patients with atherosclerosis lack currently identified noninfectious triggering risk factors (such as hypertension, smoking, hypercholesterolemia, and diabetes), an observation indicating that leading factors predisposing to atherosclerosis are as yet undetected.
There is a gap in the understanding of initial events leading to atherosclerosis, and as such, there are opportunities for novel ideas and concepts to explain the status quo and elaborate approaches to reform the situation dramatically. This paper tries to present new confirmation for the opinion about the infectious origin of atherosclerosis from the viewpoint of the current knowledge of hereditary immunity.
Functions of hereditary immunity in the genesis of atherosclerosis have been revealed by integrative interpretation of relevant clinical and epidemiological observations, supported by immunological, molecular ecological, genetic, and genomic discoveries. This classical methodological approach [
The development of atherosclerosis consists of two principally different events (
Atherosclerosis is an intra-arterial pathological process that induces inflammatory endothelial lesions with the appearance of lipid-containing foam cells. The earliest pathologic lesions of atherosclerosis are the fatty streaks that can be found in the arteries of many individuals by the age of 20 years. The fatty streaks are formed through the focal accumulation of serum lipoproteins within the intima of the vessel wall. The followed cholesterol metabolic pathways have a key role in atherosclerosis development [
However, there are many privileged individuals who are inherently resistant when challenged by triggering factors, thus preventing the secondary stage of atherogenesis. Knowledge of the resistant factors and their mechanisms of action would lead to a solution of the etiology [
Recent investigations of monogenetic diseases, candidate genes, genetic polymorphisms, and susceptibility loci associated with atherosclerotic diseases have been identified in recent years. It has become obvious that genetic ground significantly influences susceptibility to atherosclerotic vascular diseases. The development of any case of atherosclerosis is now considered as a result of multifactorial triggering involving interactions of multiple genetic factors [
However, the known risk factors’ features appear to be insufficient to explain the hereditary predilection to atherosclerosis. None of these risk factors, either alone or in couple, account for the entire contribution to the risk of atherosclerotic disease. In recent years, the interest in the identification of clue genetic risk factors to atherosclerosis continued to grow [
The clinical entity of atherosclerosis results from a particularly complex disease process, with scope for a large degree of heterogeneity among patients who have apparently similar clinical presentations and, as a corollary, extensive intraindividual genetic heterogeneity. This disease is characteristic of especially variable interindividual and individual manifestations.
Individual manifestations and courses of atherosclerosis are highly variable. Many people with structurally advanced atherogenesis may have no symptoms and experience no functional impairment. On the other hand, initially asymptomatic patients may be subjected to sudden cardiac or aortal death, whereas in many other people, the disease presents for a long time with clinically important symptoms and signs of relevant chronic diseases (coronary heart disease, high blood pressure, renal deficiency, or other local dysfunction of blood circulation), or they may suffer from various consequences of former myocardial infarction or stroke. Initially thought to be a chronic, slowly progressive, degenerative disease, it is now apparent that atherosclerosis is a disease with periods of activity and quiescence.
Although named a systemic disease, atherosclerosis manifests in a local manner and affects stochastically different organs and systems in different patients (
Plaques can be either single or multiple depending on the presence on the arterial endothelium of the quantity of places not immune to the relevant triggering agent. The nonimmune places are usually localized stochastically on the wall of either one or some of the arterial vessels. The cases of total affliction of large endothelial surfaces or many vessels many are extraordinarily seldom, which indicate the presence and heterozygosity of hereditary immunity to atherosclerosis among most of currently living people.
Coronary (heart) artery atherosclerosis leads to coronary artery disease, that is, to chest pain, heart attack, myocardial infarction, and sudden death. Thoracic aorta atherosclerosis leads to aortic aneurysm. Atheroma in arm or leg arteries may cause occlusive disease of relevant peripheral artery. In carotid arteries of the brain, the atherosclerosis leads to sudden dizziness, weakness, loss of hearing or speech, and blindness. Cerebral artery atherosclerosis may lead to a stroke on one side of the body. Hepatic artery atherosclerosis leads to insufficiency of the relevant lobe of the liver. Affection of the pancreatic artery leads to insufficiency of the pancreas.
Abdominal aorta atherosclerosis leads to abdominal aorta aneurysm. The location of plaques in a mesenteric artery can induce ischemic bowel disease. Atherosclerosis of a renal artery can lead to insufficiency of the relevant kidney, for instance, high blood pressure resistant to treatment. Peripheral artery atherosclerosis is caused by plaque buildup in the arteries that supply the extremities of the body (such as the hands and feet) with blood. In the femoral artery of the legs, the atherosclerosis leads to cramping and fatigue in the calves of the legs when walking and, finally, to the necrosis of the legs or fingers.
Early lesions of the endothelium appear as fatty streaks. These later develop into atherosclerotic plaques (
Plaque buildup in the vessels that supply an organ with blood may cause dysfunctions of the relevant organ. Symptoms of any atherosclerotic affection depend on the size of the affection’s location as well as on the danger of the focal bloodstream blockage (
The symptoms of atherosclerosis differ at first depending on the location of plaques (
feature of clinical manifestations in this kind of pathology.
The progression of the plaques leads to the narrowing of the affected arteries and relevant local limitation of blood flow. Atherosclerosis usually does not cause symptoms until it severely narrows an artery or totally blocks an artery. Usually, symptoms begin when there is at least a 75% blockage in the locality of the affected artery. As a plaque encroaches on the luminal area, blood flow becomes limited, and flow cannot increase on demand.
Any artery in the body as well as any part of the artery can be involved, but only in severe local narrowing or obstruction of some arteries, those that supply more critically important organs—first of all, heart, brain, and kidney—is atherosclerosis revealed in its life-threatening form (
Although the identification of susceptibility genes for these common, complex diseases is a vital goal, the real progress in unearthing novel genes has been slow. The optimistic predictions of the impact of genetics on the diagnosis and prevention of atherosclerosis [
Hereditary immunity is a result of natural selection performed in the population by infectious epidemic processes. Most members of the population become inherently immune, whereas some heterozygotes possess both immune and susceptible loci in their bodies (
Thus, it becomes obvious that humans, that is, different parts of their individual aortic circulatory systems, reveal extraordinary genetic diversity in their predisposition to atherosclerosis. Affected people have many differences in the manifestations of their atherosclerosis, especially in its location, size, and the grade of expression. Individuals of an observed human population can be conveniently divided into at least four principal categories, as follows:
1) The totally unaffected (homozygous) organisms that have no atherosclerotic plaques. Those people formed substantial quotes of some modern populations.
2) Mildly affected (heterozygous) organisms in which few plaques have appeared, whereas other areas of the body arterial vessels are left unaffected.
3) Mostly serious form of the disease with intermediate grade of atherosclerosis formed by location of solitary plaques in the artery of especially important organs.
4) Extraordinarily rare but exceptionally dangerous disease with dissemination of multiple atherosclerotic lesions in many parts of the arterial basin.
In Finland, 835 people of every 100,000 of the population die of heart disease. China, with 81 per 100,000 people affected, has one of the lowest. Among women, the highest rate in the world is seen in Scotland, with the lowest in Catalonia in Spain [
This kind of pathology is more characteristic of the mixed populations. Recently, its prevalence in developing countries has rapidly increased as well. The epidemic of cardiovascular diseases has taken on a global dimension. Women are more likely to die than men—55% of the people who died from cardiovascular disease are women.
The future identification of specific susceptibility genes will add to our knowledge of the molecular pathophysiology of atherosclerosis [
Studies of atherogenic vascular pathology have shown substantial racial differences in the predilection to atherosclerosis. Among Caucasians, the pathology is likely to be in a proximal location such as the bifurcation of the carotid arteries in the neck. This type of lesion is accessible to surgical correction. Among the Orientals, the vascular degeneration is more likely to occur within the brain. The Orientals are also more likely to develop small vessel diseases that may cause different types of stroke, including the hemorrhagic one [
In addition, some observations indicate allelic heterogeneity for genetic susceptibility to atherosclerosis [
Atherosclerosis is the most common cause of death not everywhere in the world but among some populations of “industrialized” countries, especially in the United States, England, Scotland, Finland, Scandinavia, and Russia. As health improvements and industrialization come to developing countries, they also start to adopt what are considered “Western habits,” such as smoking, less physical activity, and a diet rich in fatty fast foods. Atherosclerosis is becoming more prevalent in the Western world and is beginning to become prevalent in countries where the populations are adopting Western lifestyles including xenogamous admixture [
During the last two decades of XX century, researchers have proposed bacterial and viral triggers for some diseases that have been accounted as noninfectious before [