List of abbreviations
- Cardiovascular disease (CVD)
- transient ischemic attack (TIA)
- low-density lipoprotein (LDL)
- very-low-density lipoprotein (VLDL),
- World Health Organization (WHO)
- World Heart Federation (WHF)
Why did I take this up for a detailed study?
First of all, atherosclerosis is one of my favourite topics in cardiovascular system that we learned. It is one of the topics that I am highly interested and this topic has been always the talk of people who have heart diseases. Moreover, it has a big impact on our daily lives as all of us are prone to it no matter what. To be able to understand it is a gift to myself as I embark on my medical journey. It is certainly going to be useful when I step into the medical profession.
Nowadays, atherosclerosis is a leading cause of vascular disease worldwide. It has many major clinical manifestations. This poses challenges to the world population as people’s diet and lifestyle nowadays have changed dramatically. These changes bring about side effects to those diseases. In some countries, heart diseases are the number one killer.
Cardiovascular disease (CVD) is also the number one cause of death in males and female and in all races and ethnicities throughout the world today. CVD is a big headache in developing countries. World Health Organization (WHO) and World Heart Federation (WHF) are always fighting this problem. Atherosclerosis and hypertensive heart disease which are the two-component of heart disease, develop as time goes by and in response to modifiable risk factors, presenting an opportunity to implement changes that may decrease the burden of CVD.
According to the World Health Organization (WHO), 30% of global deaths are due to CVD in 2008 which is around 17.3 million people. Of these deaths, an estimated 7.3 million were due to coronary heart disease (CHD) and 6.2 million were due to stroke. In fact, people who are under 59 years old has CHD as the second cause of death after HIV/AIDS, and it is the first for those 60 years old and above. By 2030, 23.3 million people will die from CVD as estimated. Despite this epidemic has receded in many developed countries in the past decades, low- and middle-income countries have experienced an increase in the prevalence of CVD and 80% of the global burden of CVD occurs there. (European Heart Journal Supplements, 2014)]
Another reason I chose this topic is because I might want to venture into the field of cardiology if I find myself gifted in that field. For now, I want to have a deep exposure to it and be able to grasp what I am learning so it will definitely help a lot if I take up this topic.
Review of Literature
Atherosclerosis is characterized by intimal atheromatous plaques lesions that impinge on the vascular lumen. The Greek word which means hardened gruel forms the word atherosclerosis. The name of the plaque (gruel hardening) reflects the main components of the lesion as the atheromatous plaques are raised lesions composed of soft friable (grumous) lipid cores (mainly cholesterol and cholesterol esters, with necrotic debris) covered by fibrous caps. (Robbin Basic Pathology)
Atherosclerosis is a chronic disease marked by chronic inflammation, endothelial dysfunction, and lipid accumulation in the vasculature.
Atherosclerosis is the most clinically important arterial disorder as it is the underlying cause of most cases of myocardial infarction, ischemic stroke, and peripheral arterial disease. (Gohan K.Hansson)
Atherosclerosis is highly prevalent in industrialized countries, with a growing frequency in all geographic regions of the world. (Michael A. Seidman) The prevalence and severity of atherosclerosis and IHD have been correlated with several risk factors in several prospective analyses.
Experimental and clinical research has shown that pathogenesis is complex and multifactorial and the relative importance of specific genetic and external factors vary among individuals.
Atherosclerotic plaque formation
As lipid accumulates in foam cells, macrophage-derived cytokines, such as tumor necrosis factor α (TNF- α), further trigger the recruitment and proliferation of smooth muscle cells and fibroblasts. Collagen and proteoglycans are secreted in large amounts by these cells. Initially, this extracellular lipid gets in between the intimal smooth muscle cells. As the lesion progresses, the extracellular lipid coalesces to form large pools which is the core of the atheroma.
Necrotic material from dead foam cells and macrophages which is contained in the core is called as the necrotic lipid core. Cholesterol will crystallize to form cholesterol clefts inside the lipid core.
Fibroblasts are recruited into the plaque and produce a huge amount of collagen forming fibrosis. As the plaque grows, the combined necrotic lipid core and the surrounding scar matrix form the characteristic fibroatheroma. Some plaques are necrotic cores covered by a thin fibrous cap, while others are primarily all fibrous tissue, known as fibrous plaques.
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Atherosclerotic vessels show cellular activation markers in the medial smooth muscle cells. By this stage, imaging techniques such as angiography and intravascular ultrasound can be used to see stenosis.
The decreased luminal size limit blood flow to the downstream tissue. By this stage, distant perfusion may not be of any help to supply the demands of the perfused tissue, leading to some symptoms, especially when there is hypoxia accompanying it, anemia, or hypotension.
Stable & Unstable Plaques
Due to the accumulation of lipids in foam cells, the slowly growing plaques will expand and smooth muscle cells migrate and then proliferate. This kind of plaques tends to stabilize and usually will not rupture. The so-called fibrin cap on the lesion matures. As a result of rapid lipid deposition, other plaques grow more rapidly. These have thin fibrin caps that are prone to rupture. Once a plaque ruptures, it can trigger an acute thrombosis.
Atherosclerosis is a chronic inflammatory and immune disease involving multiple cell types, including monocytes, macrophages, T-lymphocytes, endothelial cells, smooth muscle cells and mast cells g platelets, and the clotting cascade. Our innate immune responses including inflammatory cells of atherosclerosis involve monocytes and macrophages that respond to the over uptake of lipoproteins, while adaptive immune response involves antigen-specific T cells. Arterial endothelial cells initiate the innate immune response in atherosclerosis which respond to modified lipoproteins and lead to the generation of inflammatory cytokines and chemoattractant chemokines. Also, present together are CD4+ T inflammatory cells, regulatory T cells, and myeloid cells.
IL-10, IL-4, IL-13, and IL-37 inhibit the activation of macrophage and dendritic cells and therefore the over-expression of inflammatory cytokines. IL-38 binds to IL-36 receptors and exerts anti-inflammatory properties which is considered a protective effect in some autoimmune diseases. IL-38 is a member of the IL-1 cytokine family. Moreover, oxidized LDL-specific Tregs not only reduce the initiation, but also the progression of atherosclerosis and plaque formation. Statin drugs mediate this effect as it regulate TH1/TH2 imbalance. Tregs and their main subsets CD4+CD25+, Foxp3+, and T cells are crucial in mediating immune homeostasis and promoting the establishment and maintenance of peripheral tolerance.
TH17 cells contribute to the atherogenesis process and are involved in plaque formation. In addition, vascular arterial dendritic cells which are similar to Langerhans cells of the skin, are involved in atherosclerotic lesions. CD11b+ cells are myeloid cells in early differential stages that include dendritic cells, immature macrophages, and granulocytes. CD11b+ cells are important to atherogenesis but their inhibition does not reduce atherogenic plaque.
In atherosclerosis, intimal smooth muscle cell proliferation and luminal occlusion are the result of injury to the vessel wall. Low-density lipoprotein (LDL) remains the most important risk factor for this inflammatory disease process. Our aim is to reduce VSMC prostacyclin production, and also the down-regulation of cyclooxygenase expression. When circulating factors and inflammatory cells come into contact, endothelial cells will undergo apoptosis, leading to disruption of endothelial glycocalyx monolayer integrity. There are many pathological causes that may promote apoptosis in the endothelium, and these include oxidized LDL and certain cytokines such as IL-1 and TNF. OxLDL provokes a delayed but sustained increase in intracellular calcium in endothelial cells, which causes cell death, an effect that can be reversed by preventing the calcium increase. Via the scavenger receptor, oxLDL provokes depletion of cholesterol in endothelial cells causing impaired e-NOS targeting to cholesterol and an reduced capacity to activate the enzyme.
M1 macrophages generate high levels of IL-12, IL-23, IL-6, IL-1, and TNF; while activated M2 macrophages produce IL-4, IL-13, and IL-10 which can inactivate M1 macrophages, and this contributes to atherogenesis. An important pro-inflammatory cytokine which is TNF is capable of classical activation of macrophages to the M1 phenotype, which induces the production of other pro-inflammatory Th1 cytokines. IL-1 induces TNF and activates endothelial cell apoptosis along with growth factor deprivation. Platelet-derived growth factor (PDGF) is another cytokine which induces both smooth muscle migration and proliferation. In patients with inflammatory diseases such as atherosclerosis may have their symptoms reduced by a monoclonal antibody that targets inflammatory cytokines, such as IL-1 and TNF-α receptors. Expression and generation of IL-8 and IL-6 are also associated with plaque formation in human atherosclerosis. Lipids as we all know are a huge problem for the circulatory system, heart failure, and excessive cholesterol in macrophage foam cells of the arterial wall. This leads to the development of atherosclerotic plaque and accumulation of cholesteryl esters in the cytoplasm of macrophages, turning them into foam cells.
When activated, mast cells release a broad spectrum of proinflammatory cytokines, growth factors, vasoactive substances, and proteolytic enzymes. A common myeloid progenitor produced human mast cells and have high affinity to IgE receptors (FcεRI). They are basically localized in mucosal and connective tissues and are distributed along blood vessels. The immediate surroundings in vessel wall can be affected by activation of mast cells, provoking matrix degradation, apoptosis, and enhancement as well as recruitment of inflammatory cells, which contributes mainly to atherosclerosis and plaque. Mast cells increase within the arterial wall during atherosclerosis, and they are found in the human arterial intima and adventitia during atherosclerotic plaque progression, as well as participating in plaque destabilization. Mast cells generate proteases such as tryptase and chymase. The activation of these enzymes can cause intra-plaque hemorrhage, macrophage and endothelial cell apoptosis, vascular leakage, and cytokine production, which lead to the recruitment of leukocytes to the plaque. Mast cells release angiogenic compounds, which induce not only cause the growth of microvessels but also result in leakiness and rupture of the fragile neo-vessels. This may result in intraplaque hemorrhage. Mast cells are present in human arterial intima where they can degranulate after stimulation and secrete chymase, which inhibits HDL apolipoprotein and may retard the output of cellular cholesterol.
MCs exhibit toll-like receptors (TLR) including TLR-9 and TLR-3, which can be activated by infections and lead to the generation of several cytokines and chemokines such as TNF, IFN-γ, IL-6, and IL-8. They accumulate in the stroma of a number of inflamed tissues in response to locally produced chemotactic factors for monocytes. IL-1 and TNF are macrophage products capable of inducing increased mast cell adhesion, along with macrophages, which also produce chemotactic factors such as LTB4. Chemokines and C5a for leukocytes, including T cells, participate in a process that may form an amplification mechanism for the recruitment of further immune cells into atheromatous plaque. Mast cells increase local inflammation with an augmentation of immune cells such as T lymphocytes and macrophages. Statins up-regulate eNOS, which can activate NF-κB and cause its translocation to the cell nucleus.
Comment by Administrator: Add the role of chronic inflammatory reaction in pathogenesis and also about Stable and unstable plaque
In this review of literature, I have read many things regarding atherosclerosis. I learned the causes, treatment, signs and symptoms, and its formation and also diagnosis by searching them up during free time. I have certainly made some useful readings and it no doubt helps in my understanding of atherosclerotic plaque formation, stable and unstable plaque, and also the chronic inflammation of atherosclerosis.
I learned that atherosclerosis is a disease in which plaque builds up inside your arteries. Plaque is a sticky substance made up of fat, cholesterol, calcium, and other substances found in the blood. Over time, plaque hardens and narrows your arteries. That limits the flow of oxygen-rich blood to your body.
List of References
- MSD Manual Professional Version Atherosclerotic plaque formation. Abstract at https://www.msdmanuals.com/professional/cardiovascular-disorders/arteriosclerosis/atherosclerosis
- European Heart Journal Supplements Perspectives: The burden of cardiovascular risk factors and coronary heart disease in Europe and worldwide. Abstract at https://academic.oup.com/eurheartjsupp/article/16/suppl_A/A7/358555
- Science direct. Abstract at https://www.sciencedirect.com/science/article/abs/pii/S0188440915001241
- Cardiovascular Innovations and Applications Global Burden of Cardiovascular Disease. Abstract at https://www.ingentaconnect.com/content/cscript/cvia/2016/00000001/00000004/art00002?crawler=true&mimetype=application/pdf
- Pathophysiology of Atherosclerosis Michael A. Seidman, Richard N. MitchellJames R. Stone, 225-226
- Atherosclerosis: a chronic inflammatory disease mediated by mast cells. Abstract at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655391/