Atherosclerosis is hardening of a blood vessel from a buildup of plaque. Plaque is made of fatty deposits, cholesterol, and calcium. Plaque buildup causes the artery to narrow and harden.
Plaque buildup can slow and even stop blood flow. This means the tissue supplied by the artery is cut off from its blood supply. This often leads to pain or decreased function. This condition can cause a number of serious health problems. Depending on the location of the blockage, it can cause:
• Coronary heart disease —Loss of blood to areas of the heart
• Stroke —Loss of blood to areas of the brain
• Peripheral vascular disease —Loss of blood to the extremities
Atherosclerosis is a disease of the arterial vasculature that is characterised by the dysrupted balance and abnormal accumulation of lipids, inflammatory cells, matrix deposits and smooth muscle cell proliferation in the wall of medium- and large-calibre arteries. This accumulation is most commonly detected during the second decade of life and develops further with age. The implication of ageing and early development of atherosclerotic lesions makes a significant difference between chronic and acute plaque characteristics, which will be described in disease pathophysiology. The progression of
vascular lesions results in the reduction or cessation of blood flow through the vessel to the dependent tissues. Atherosclerotic lesions may occur anywhere within the arteries but are particularly prone to occur at vessel curves and bifurcations where the smooth flow of blood is disturbed by shear stress forces created by blood flow, which alter cell migration and proliferation in the vessel wall. The
vessels most likely to be affected by this flow-mediated effect include the coronary arteries, the carotid and cerebral arteries and the iliofemoral system, resulting in the respective clinical manifestations of myocardial ischaemia and infarction, stroke and peripheral vascular disease.
Atherosclerosis is particularly prevalent in the populations of developed countries, and is increasingly burdensome in developing countries. Statistics published by the American Heart Association show that over 17 million people died in 2013 due to cardiovascular disease, representing the first cause of death globally. In the United States, cardiovascular disease caused 800,937 deaths which accounted
for approximately 31% of all deaths in 2019. It is estimated that by 2030 the annual medical cost associated with cardiovascular diseases will rise to around $1,044 billion globally. In most cases, atherosclerosis is the root cause of these deaths. Improved medical care and risk factor modification, among other reasons, have declined the age-adjusted death rate for atherosclerosis-related diseases. Unfortunately, the long-term sequelae of atherosclerotic diseases have actually increased during that period. In fact, the number of deaths due to heart failure increased about 100%. This likely indicates that many individuals who would have otherwise succumbed to atherosclerosis now survive but are
debilitated by the long-term consequences of the disease. Unfortunately, the bad news continues – death rates for atherosclerosis-related diseases are actually increasing in developing countries due to the increased presence of disease risk factors associated with the Western lifestyle. As an important remark, the total number of deaths worldwide per year owing to ischaemic heart disease is expected to double between 1990 and 2020.
Atherosclerosis is a much-studied disease; however, physicians have few tools at their command to arrest its course where most efforts are mostly conducted towards disease prevention and amelioration. Reduction of the risk factors (in particular, reducing cigarette smoking and lowering cholesterol) has proved an effective means by which the incidence of diseases associated with
atherosclerosis can be altered. However, one of the most potent risk factors for developing atherosclerosis is a family history of early onset vascular disease, indicating a strong genetic component to disease pathogenesis. Unfortunately, the polygenetic basis for atherosclerosis
susceptibility has not been explained by vascular biologists (just as other diseases with many genetic modifiers, such as hypertension, remain poorly understood). One of the promises of the genomicera is that the means to determine the basis for diseases such as atherosclerosis will soon be at hand. A
generous portion of this article is devoted to presenting recent advancements towards understanding the genetic factors that modulate the pathogenesis of atherosclerosis and the shared resemblances with currently used atherosclerotic disease animal models.
The current framework for understanding how atherosclerotic lesions form and progress was initially provided by Russell Ross, PhD (1929–1999). Dr Ross proposed the ‘response to injury’ hypothesis, which argues that the initiating event in lesion formation is some form of ‘injury’ to the endothelium – the single cell layer that forms the luminal lining of all blood vessels. Modifications to this hypothesis have been made to incorporate subsequent observations, and it still provides a useful framework for understanding how lesions form, demonstrating his passion for atherosclerosis research.
Endothelial injury may take the form of mechanical forces, such as high blood pressure or changes in shear stress and cyclic strain, which can occur at vessel bifurcations; metabolic conditions, such
as diabetes mellitus, hyperhomocysteinaemia or hyperlipidaemia, which produce substances that directly injure the endothelium; or environmental agents, such as the products of tobacco smoke or even infectious agents, which also impair endothelial cell function. It is important to note the close correlation between the factors that may cause endothelial injury and the known risk factors for atherosclerosis. Regardless of the cause, the injured endothelium becomes ‘dysfunctional’, and acquires properties that are proatherogenic and can drive atherosclerosis progression as happens with endothelial-to-mesenchymal transitional mechanisms. Normal adaptive vascular responses, such as the release of endothelium-derived nitric oxide, are impaired. Endothelial denudation or activation leads to adhesion of platelets and inflammatory cells that can release proatherogenic growth factors. These factors lead to proliferation and migration of vascular smooth muscle cells (VSMCs) and increased generation of extracellular matrix. Adherent monocytes and lymphocytes may also invade the vessel wall, where they participate in the inflammatory processes that contribute to lesion formation. Forms of low-density lipoprotein (LDL) cholesterol that accumulates in the vessel wall may be taken up by macrophages and other vascular cells, leading to foam cell formation.
Inflammation-induced cellular apoptosis and lipid accumulation result in lesions with necrotic cores of lipid and cellular debris. Intraplaque macrophages may be particularly destabilising in advanced plaques by releasingfactors suchas matrixmetalloproteinases that degrade the extracellular matrix and impair the integrity of the atherosclerotic lesion. Endothelial dysfunction and subsequent inflammatory response are thought to lie at the root of these processes, which together result in lesion formation with remodelling of the affected vascular wall.
Atherosclerotic lesions are classified according to several models primarily based on morphological considerations .Lesions develop over decades, beginning in the intima – the innermost layer of the arterial wall. The earliest identifiable lesion, the ‘intimal xanthoma’ or ‘fatty streak’, is a flat, non- obstructive accumulation of foam cells that can be found in most individuals in the second decade of life, and may regress. Several other types of atherosclerotic lesions, collectively called ‘progressive’ lesions, are common later in life. Whether these lesions inevitably arise from fatty streaks rather than appearing de novo has not been clearly identified. The different advanced lesions have a varied and complicated morphology and may be associated with serious complications. ‘Pathologic intimal thickening’ is largely a proliferative lesion of VSMCs in a proteoglycan-rich matrix containing extracellular lipid accumulations. ‘Fibrous cap atheromas’ also contain macrophage-derived foam cells and other inflammatory cells and have a necrotic core of apoptotic cellular debris and extracellular lipid situated below a fibrous cap rich in collagen. Some of these atheromas have a particularly ‘thin fibrous cap’ and abundant inflammatory cells, features associated with plaque instability. ‘Fibrocalcific plaques’ are larger, collagen-rich lesions with necrotic cores and significant calcification, but generally contain few inflammatory cells.
The progressive atherosclerotic lesions may lead to clinical manifestations of the disease that correlate with the lesion type (morphology) and location. Certain lesion types are associated with nonlethal disease manifestations, whereas others are associated with lethal consequences. Due to the variation in the subclinical progression of such manifestations, there is high significance to identifying common characteristics between animal models of disease that replicate in humans. Plaque ulceration, calcification, intraplaque haemorrhage and thrombosis complications in diverse and more advanced plaques very much determine plaque vulnerability for rupture and possible severe complications. The morphology of pathologic intimal thickening and fibrocalcific plaques differs greatly. However, both are stable lesions and are rarely, if ever, associated with thrombosis and, therefore, heart attack or stroke. Fibrocalcific plaques, however, may protrude eccentrically into the lumen, which results in reduced blood flow and symptoms such as recurrent angina pectoris and claudication. Pathologic intimal thickening and fibrous cap lesions are somewhat less stable, but not to the extent of thin fibrous cap atheroma lesions. The intimal surface of these lesions may suffer, aneurysms, disruptions (‘fissures’) or gross denudation (the ‘ulcerative plaque’), which can serve directly as a nidus for acute thrombosis, but it is usually. nonocclusive. Fibrous plaques may also protrude eccentrically into the lumen and reduce blood flow to dependent tissues, leading to stable angina or claudication. In contrast, thin fibrous cap atheromas are considered ‘unstable’ or ‘at risk’ of rupture. Such plaques are subject to major surface disruption, leading to plaque rupture with extrusion of lipid core components, activation of the coagulation cascade and usually occlusive thrombosis. Thromboembolic morphological characteristics are difficult to exert from experimental models, which will be described later. Rupture is believed to be most commonly caused by degradation of the fibrous cap by released inflammatory cell proteases or intraplaque haemorrhage due to plaque neovascularization. Intra- plaque haemorrhage without rupture can also lead to rapid progression of obstructive symptoms such as angina. These lesions, by virtue of their tendency to rupture and cause occlusive thrombi, can cause acute occlusion of coronary and cerebral vessels, which results in myocardial infarction and stroke – the most deadly consequences of atherosclerotic disease.
Atherosclerosis is a complex multifactorial disease resulting from both genetic and environmental factors. Generally accepted risk factors significant for the development of atherosclerosis include increasing age, hypertension, hypercholesterolaemia, diabetes mellitus and smoking. Being male is also a strong risk factor for the development of atherosclerosis, although this gap may be decreasing with the increase in smoking and obesity rates in females. Increased serum LDL and decreased serum high-density lipoprotein (HDL) concentrations are strong risk factors for the development of atherosclerosis. Dietary factors and obesity are associated with the development of atherosclerosis, in part, through the development of insulin resistance and type II diabetes. Therapeutic interventions to correct these risk factors (hypertension, diabetes, tobacco use and lipid abnormalities) are effective in reducing the risk of atherosclerotic complications. Other risk factors have been proposed, but are of uncertain magnitude or significance. Several of these risk factors (hypertension, diabetes and dyslipidaemia) themselves have a genetic component, anda familyhistoryofpremature atherosclerosis is a strong risk factor for atherosclerotic disease. Both genetic and environmental factors, such as nutrition and physical exercise, affect the manifestation of atherosclerotic lesions either directly by modification of traditional risk factors or indirectly through mechanisms not yet identified. The genetic contribution to disease likely affects its pathophysiology at different stages of disease development.
Most people are diagnosed after they develop symptoms. However, people can be screened and treated for risk factors.
Tests that evaluate the atherosclerotic arteries are:
• Cardiac catheterization
• Electrocardiogram (ECG)
An important part of treatment is reducing risk factors.
Treatment may include:
• Interfere with the forming of blood clots
• Control blood pressure if elevated
• Lower cholesterol if elevated
• Improve the flow of blood through narrowed arteries
These procedures involve a thin tube called a catheter. It is inserted into an artery. They are most often done for arteries in the heart. They may be used to treat atherosclerosis elsewhere in the body as well. These procedures include:
• Balloon angioplasty —A balloon-tipped catheter is used to press plaque against the wall of the artery. This increases the amount of space for the blood to flow.
• Stenting—Usually done after angioplasty. A wire mesh tube is placed in a damaged artery. It will support the wall of the artery and keep it open.
• Atherectomy —Instruments are inserted via catheter. They are used to cut away and remove plaque so that blood can flow more easily. This procedure is not used as often.
Surgical options include:
• Endarterectomy —Removal of the lining of an artery obstructed with large plaques. This is often done in carotid arteries of the neck. These arteries bring blood to the brain.
• Arterioplasty— Repair of an aneurysm. It is usually done with synthetic tissue.
• Bypass —Creation of an alternate route for blood flow. The procedure uses a separate vessel for blood to flow.