Category: Atherosclerosis

It is often presented that people need to increase their iron intake by consuming more red meat or green vegetables to prevent anaemia and other diseases linked to low iron. Anaemia is a condition where the body does not make enough healthy red blood cells preventing the body’s tissues from getting sufficient oxygen. There is no doubt that iron is a vital element needed for various processes within our body; however, it is important to know that too much iron is toxic and can be equally as harmful, if not more. The purpose of this dissertation is to show the importance of iron levels in maintaining a healthy body, focussing on the function of the heart. It aims to show that it is crucial for iron levels to be tightly regulated and what problems can arise when iron levels drop below or exceed the normal level. Heart disease such as atherosclerosis, the narrowing of the arteries, will be discussed.

Scientific Abstract

Iron is one of the most essential elements in the body and is vital in many biological processes; however, when iron levels drop below or exceed the normal level, it can have detrimental effects on the organs in the human body, especially the heart which is the focus of this dissertation. Many studies have investigated the role of iron in different heart diseases, but the link is not yet fully understood. This dissertation aimed to show the importance of maintaining iron at the correct level in the body and the consequences which occur when they are not. Iron overload can lead to the oxidation of low-density lipoproteins which play a role in the development of atherosclerotic plaques. Additionally, high iron levels can affect the function of calcium channels in the heart, this is seen in cardiomyopathy. On the other hand, iron deficiency leads to ineffective erythropoiesis causing the heart to work harder resulting in physical changes in the heart as seen in heart failure.

This dissertation discusses the roles of iron, metabolism and looks at studies that have helped develop our understanding of the relationship between iron and heart diseases which arise when levels are not maintained.

Definition of What Is Iron

Iron is one of the most essential minerals in the body. It is a transition metal that can accept and donate electrons in oxidation-reduction reactions. These reactions are vital for numerous processes in the body. There are two main types of iron; ferrous iron and ferric iron. Ferric iron, Fe3+, is insoluble and is found in green vegetables, whereas ferrous iron, Fe2+, is soluble and is found in red meats and fish. Due to ferrous iron being soluble, it can be absorbed more efficiently than ferric iron.

Iron Absorption, Transport, and Storage

On average, a person will consume 10 to 20 mg of iron daily, however, only 5 to 35% will be absorbed depending on the individual’s requirements (Abbaspour et al., 2014). Normally, a male adult will have around 35 to 45 mg of iron per kilogram, whereas a premenopausal women’s iron levels will be lower due to menstruation. There is a steady loss of iron by desquamation of skin, sloughing of intestinal cells and blood loss which is balanced by steady absorption and recycling. Iron absorption takes place in the small intestine, in the duodenum and part of the upper jejunum. For iron to be absorbed, it needs to be converted from ferric iron into ferrous iron. This is done by a ferric reductase enzyme known as duodenal cytochrome B. The low pH in the duodenum aids this reduction. Ferrous iron is then transported from the lumen of the duodenum into the enterocyte by the divalent metal transporter (DMT-1). When the iron is in the enterocyte, it can either be stored as ferritin or transported across the basal membrane into the plasma through a transmembrane protein, ferroportin-1. For iron in the plasma to be transported around the body, iron is converted back into ferric iron by two copper-containing enzymes. Ceruloplasmin is an enzyme found in the plasma, and hephaestin is located on the basolateral membrane of the enterocyte (Ems, 2019). Ferric iron can then be transported around the body attached to transferrin. Due to the body having no mechanisms for iron loss, iron levels are maintained by tightly regulating absorption (Wallace, 2016). This is done by an important regulatory hormone called hepcidin which works by inhibiting efflux through ferroportin by binding to or degrading it (Nemeth and Ganz, 2006).

Plasma transferrin is an iron-binding glycoprotein that contains two sites which can bind ferric iron tightly but reversibly. Transferrin transports iron around the body to any cell which contains the transferrin receptor protein 1 (TfR1) (Gkouvatsos et al., 2012). Transferrin is endocytosed by cells containing the clathrin-dependant receptor, then once inside, the iron is released. There are four transferrin species that have different iron affinities and distribute iron to various parts of the body. Diferric transferrin is thought to be the most abundant form of transferrin as it has the highest affinity for TfR1 and it is believed that this form of transferrin delivers iron to the erythrocytes (Finberg, 2019).

Iron is distributed around the body for different purposes; approximately 70% of iron is found in haemoglobin (Hb) in red blood cells (RBCs) and in myoglobin which is found in muscle cells. 5% of iron is used in haem-containing enzymes and proteins (Johnson-Wimbley and Graham, 2011), and the remaining 25% of iron can be stored as ferritin or hemosiderin which is found in the liver, spleen, bone marrow and other areas (Saito, 2014). Ferritin is the major form of iron storage. It is a globular protein arranged into a hollow shell where up to 4500 iron atoms can be packed in. There are pores on its surface which allow the iron to enter and exit regulating iron levels (Hahn et al., 1943). However, when ferritin levels are exceeded, iron can be stored in hemosiderin. Hemosiderin has no fixed composition, consisting of ferritin particles, denatured proteins, and lipids. It is normally found in macrophages, glial cells and other cells of the reticuloendothelial system. When iron levels increase further, excess hemosiderin is deposited in the liver and heart (Fischbach et al., 1971).

Consequences of Iron Overload or Deficiency

Iron deficiency (ID) can lead to anaemia and according to the World Health Organisation, it affects around one-quarter of the world’s population. ID is most common in premenopausal women due to loss of iron through heavy menstruation or due to pregnancy. But, ID can be caused by other things too such as poor diet or mutations in genes for iron absorption such as the DMT-1 protein or the transferrin receptor (Dev and Babitt, 2017). Reduced iron levels can lead to minor symptoms such as fatigue and headache; however, it is also known to cause more severe problems such as impaired cognitive development and heart failure (Jáuregui-Lobera, 2014).

On the other hand, iron overload can cause just as many problems. Iron overload can be due to hereditary haemochromatosis (mutations in the hepcidin gene), thalassemia’s (abnormalities in globin synthesis), or transfusion overload (due to many blood transfusions). In iron overload, the transferrin levels are exceeded, and so non-transferrin bound iron (NTBI) is taken up by different organs. The excess iron leads to oxidative damage and increases the risk of liver failure, heart attack and heart failure along with other endocrine diseases. Iron overload has also been linked to neurodegenerative diseases such as Alzheimer’s and Parkinson’s (Dev and Babitt, 2017).

Roles of Iron

Iron has many different roles in the body. A major role of iron is in the transport of oxygen around the body (Wallace, 2016). Iron makes up a vital component in the erythrocytes called haemoglobin. Iron is the central atom in the haem group. It allows oxygen to bind reversibly and be transported around the body to active cells; therefore, it is essential that iron is incorporated into erythrocytes and so erythropoiesis has a high iron demand. The heart is a muscle that requires a large amount of energy and struggles when iron levels are low (Fitzsimons and Doughty, 2015). When iron levels drop below normal, it affects RBC production and so the heart needs to work harder to supply the body with oxygenated blood. This often leads to heart palpitations.

Additionally, iron is a redox element present in some enzymes in metabolic pathways where the enzymes act as electron carriers. For example, in oxidative metabolism, iron’s role is to transfer energy to the mitochondria. There are other iron-containing enzymes too which play a role in the synthesis of steroid hormones, bile acids and controlling some neurotransmitters in the brain.

Another area where iron is important is in DNA metabolism as many DNA repair enzymes, such as helicase and nucleases, use iron as a cofactor to function (Puig et al., 2017).

Over the last few decades, studies have found iron to have a role in the development of the immune system where iron is necessary for the proliferation and maturation of immune cells (Soyano and Gomez, 1999). More recently, it has been found that iron is also important in ferroptosis which is an iron-dependant and reactive oxygen species (ROS)-reliant form of cell death (Kobayashi et al., 2018) which plays an important regulatory role in the development of diseases (Li et al., 2020). Ferroptosis is biochemically different from other forms of cell death; it is initiated by the failure of antioxidant defences resulting in the oxidative degeneration of lipids leading to cell death.

Iron Overload

Iron overload can occur in patients who already have genetic and acquired blood disorders such as beta-thalassemia major and sickle cell disease. These diseases can cause ineffective erythropoiesis and so the patients depend upon regular RBC transfusions which can lead to iron overload. But overload can also be due to diet and iron accumulating over many years. Iron overload can cause iron to accumulate in the organs; however, iron accumulation in the heart can be particularly dangerous.

In 1981, it was proposed by Sullivan that increased iron stores were a risk factor for cardiovascular disease. He proposed that cardiovascular disease (CVD) cases in premenopausal women are lower in comparison to men due to women having lower iron stores (iron lost through menstruation). He believed that ID could protect against CVD and a way to prevent CVD was by regular venesection (Sullivan, 1981). Since Sullivan’s hypothesis, many studies have been conducted testing his theory. Currently, there are more studies that agree and support the iron hypothesis; nevertheless, there are also several experiments that either contradict Sullivan’s theory or did not find any evidence to linking iron to CVD.

Atherosclerosis

Atherosclerosis is a disease where a plaque builds up inside an artery. The plaque can be composed of fat, cholesterol, calcium or other components of the blood. Over time, these build up and harden leading to the narrowing of the artery. The lumen becomes narrower and so blood flow becomes restricted. If left untreated, the plaque can completely block blood flow and prevent the delivery of oxygen to respiring cells and tissues. This can lead to ischemia, if the blockage is in an artery in the heart, it can lead to a heart attack or if it blocks a vessel that supplies the brain, a stroke can occur (Rafieian-Kopaei et al., 2014).

The role of iron in the development of atherosclerosis is not yet fully understood and there are some studies that support the role of iron overload in atherosclerosis, but there are also studies which contradict these findings.

Studies linking iron overload to atherosclerosis believe iron takes part in the redox reactions. Iron changes from the ferrous state into the ferric state transferring an electron to form highly reactive oxygen species (ROS) such as the hydroxyl radical during mitochondrial electron transport. This redox reaction on iron is known as the Fenton reaction.

If there are large amounts of iron in the tissues, it can catalyse the formation of oxygen free radicals. These unstable radicals cause the oxidation of low-density lipoproteins. Oxidised low-density lipoproteins (oxLDL) promote the activation of endothelial cells which produce adhesion molecules and chemoattractants which attract monocytes and lymphocytes to the arterial wall (Linton et al., 2000). Macrophages endocytose oxLDLs resulting in the formation of foam cells which over time will develop into atherosclerosis. Foam cells are a type of macrophage that migrate to fatty deposits on arterial walls where they ingest more LDLs and become full of lipids giving then a foam-like appearance. Foam cells accumulate as the oxLDLs previously ingested increases macrophage’s uptake of oxLDLs by causing more scavenger receptors to be expressed on the cells surface (Sharkey-Toppen et al., 2014).

Experiments have been conducted to support this hypothesis. 26 rabbits were separated into four different groups; iron-overload/hypercholesterolemic (using intramuscular injections of iron), iron-overloaded, hypercholesterolemic (rabbit food enriched with 0.5% cholesterol) and an untreated group. Serum iron and ferritin levels were measured throughout the study and they found that in iron-overload/hypercholesterolemic and hypercholesterolemic groups, the aortas of these rabbits were narrowed but the iron-overload/hypercholesterolemic had the greatest narrowing of the aorta. The results they found agreed with there being a positive correlation between iron and atherosclerosis.

However, there are limitations to this experiment as it was conducted on an animal model, a rabbit, and so cannot say with certainty that the same results will occur in humans. Additionally, the rabbits were artificially iron-overloaded, this is different from how iron-overload would occur in real life. Therefore, more studies are needed to prove the relationship between the overload of iron stores and atherosclerosis in humans (Araujo et al., 1995).

A study from 2012 also supports iron overload leading to atherosclerosis. In this experiment, increased iron storage was linked to increased oxidative stress, inflammation, and carotid intima-media thickness. The study was conducted on 72 healthy men and was able to clearly show an association between body iron stores with atherosclerosis. Even though this study showed a positive correlation, there are some limitations, one being that a relatively small sample size was used and so the results are not representative of a larger population and so further experiments need to be done (Syrovatka et al., 2011).

However, a study conducted in 2001 contradicts these findings. They reported that atherosclerotic lesions were reduced in apolipoprotein E-deficient (apoE-deficient) mice that were fed high-iron diets. Their results showed that in this group of mice, the aortic lesions were significantly reduced compared to mice who were fed the low-iron diet. Additionally, the results suggest that as iron levels increased, the rate of lesion development decreased. The reasoning behind these findings is unknown, but the researchers believe in several possible mechanisms. One theory is that iron controls gene expression for the scavenger proteins mentioned earlier, or even for adhesion molecules on the artery wall. Another idea, is that bioactive molecules, which are involved in the formation of atherosclerotic plaques, are destroyed by the iron meaning lesion formation is decreased (Kirk et al., 2001).

The findings from the 2001 study are the opposite of the findings from other studies. This may be due to different models being used, different environmental conditions, research methods and the pre-existing condition of the model being used. All these factors contribute to the different results seen in the studies.

Coclusion

Even though more studies are needed to support the role of iron in the pathogenesis of atherosclerotic plaques, it seems likely that iron does play an important role in their formation, alongside other risk factors such as hypertension, obesity, diabetes and more. It is suggested that iron regulates the oxidative modification of lipoproteins and impacts the initiation, progression and the destabilisation of the plaque (Kraml, 2017).

Atherosclerosis can be instigated by a variety of genetic and environmental factors. Individually environmental and genetic risk factors and how they affect atherosclerosis are understood. However, the understanding of how a genetic condition interacts with environmental factors is less understood. In this essay the interactions between Familial Hypercholesterolaemia (FH) and environmental factors interact and there consequences will be discussed.

FH is an autosomal codominant disease, it is inherited and affects the metabolism of lipoproteins (Ramaswami et al., 2019). FH is characterised by a mutation in the Low-density lipoprotein receptor (LDLR) gene, it affects up to 1 in 500 people worldwide (Wierzbicki, Humphries and Minhas, 2008). The disease is defined by very high plasma concentrations of low-density lipoproteins cholesterol (LDL) (Pimstone et al., 1998). The mutation of the LDLR gene is what causes the extremely high levels of LDL. This is because the defect can affect several vital steps in the receptor cycle, for example it inhibits the correct binding of LDL, the internalisation and the recycling of LDL also (Pimstone et al., 1998).

Understating the relationship between FH and environmental factors have been shown by using murine models, work by Ma. Y et al. shows two groups of homozygous LDLR knockout mice which were put on different diets. One group was fed a high fat diet (HF), and the other group were put on a regular chow diet (Ma et al., 2012). The total cholesterol and LDL levels of the mice on the HF diet increased dramatically over the first two weeks, this was then followed by a slower increase to the terminus after the twelve months (Ma et al., 2012). The HDL of the mice on the HF diet were elevated slightly and the triglyceride quantity did not increase drastically (Gomez et al., 2019). In comparison the mice that were on the regular chow diet plasma lipid levels were maintained for the whole 12 months. HF diet mice after 3 months had LDL levels of approximately 10 mmol/L, non-HF diet mice after 3 months had an LDL value of approximately 4mmol/L (Ma et al., 2012). This shows that even if you have FH eating a HF diet will further increase your risk of atherosclerotic lesions forming. This is because the main starting point of atherosclerosis is when the circulating LDL value is increased. There is however an argument for using mice, due to their inability to develop unstable plaques, and their reduced ability to develop plaques in the coronary arteries, but due to their notable work towards the understanding of atherosclerosis murine models are vital for research.

Further work undertaken by Frederick J. Raal et al, investigates whether lipid lowering drugs, predominately statins, reduce cardiovascular mortality in homozygous FH patients. To evaluate the efficiency fasting serum concentrations of total cholesterol, LDL, HDL and triglycerides were taken (Raal et al., 2011). The results of the research show that the patients who had received the new modern lipid lowering therapy showed a notable reduction in mortality (Raal et al., 2011). The data further suggested that even though LDL remained high, using statins delayed cardiovascular events for homozygous FH patients. This study did however have its faults, for example they only had 187 subjects, this is not enough and to improve validity an increased population size would is necessary. The research was also only undertaken in South Africa, so again to make the in research more valid they should do it in other countries to ensure results are not down to an ethnic predisposition (Martínez-Mesa et al., 2014).

In conclusion having FH and eating a HF diet leaves you at a greater risk of atherosclerosis. This indicates that there is a clear interaction between both genetic and environmental factors working together in atherosclerosis.

In ‘Stress: Portrait of a Killer’ a documentary by National Geographic goes in depth about how dangerous stress can be. For humans stress is always present. There is always a worry about work, finances, relationships, and other situations that poses a challenge. In most mammals stress is a few minutes of terror in a in a habitat full of predators. Biologist want to understand why humans, apes, and monkeys get more stress related diseases. They have concluded that humans and their primate cousins are highly intelligent with too much time to spare. It seems that humans and primates have evolved to be very intelligent to make themselves sick. Robert Sapolsky is a biological science professor who was spent more than 30 years studying the physiological effects of stress on health. During stress response all vertebrates release hormones which increase the animals heart rate and energy level. Stress is something that cannot be controlled. Constantly worrying about finances, work, or other situations trigger the release of adrenaline and other stress hormones. Over time stress can cause devastating consequences to health. In the video they also discussed some of the stress related diseases such as diabetes, high blood pressure, and a bunch of gastrointestinal disorders. Long term stress conquers the immune system making it vulnerable to infectious diseases. Being chronically stressed also affects brain function. Controlling stress is crucial to being healthy. Sapolsky advices tho try whatever to reduce stress to avoid any stress related disease. In class we briefly discussed atherosclerosis. A disease that can be caused by stress. High levels of cortisol receptors from long term stress can increase blood sugar, cholesterol, and blood pressure. This stress can build up plaque and deposit it in the arteries.

Description of the Disease

In the United States, heart disease is one of the leading causes of death. Millions of people suffer from this horrible disease. Heart attacks and strokes are caused by a common disorder known as atherosclerosis. Atherosclerosis takes place when plaque begins to build up in the artery walls. Fats, cholesterol, calcium, waste product from cells, and fibrin is what composes the plaque. If not treated this disease can be life threatening. Heart attacks and strokes can occur when the plaque begins to form and slowly blocking arteries causing the cut off of blood supply to the heart or the brain. Not only are strokes and heart attacks the most common condition, atherosclerosis is also in charge of other fatal diseases such as peripheral disease, and chronic kidney disease.

Etiology

The entire body contains many blood vessels called arteries. The arteries are very important because they are in charge of transferring blood from the heart to the entire body. The endothelium is the thin layer of cells that line the arteries. The endothelium keeps the inside of the arteries nice and smooth to keep good blood flow. The buildup of plaque begins when the endothelium is damaged by high blood pressure, high cholesterol and smoking. The entry of cholesterol in the wall of the artery happens when bad cholesterol goes through damaged endothelium, causing white blood cells to stream in digesting the bad cholesterol. The cholesterol and cells transform into plaque in the cell wall of the artery over time. Slowly the plaque begins to pile up creating bumps within the artery wall. If atherosclerosis is left untreated the bumps will continue the build up process creating a blockage. This may occur anywhere in the body. Atherosclerosis causes the heart to be at risk for potential attacks as well for strokes and many other health issues. When atherosclerosis begins, it usually does not present any symptoms until middle or older ages. When arteries begin to narrow down, it will cut off blood flow and create pain. Blockages can also burst causing the blood to clot inside an artery. The plaque that forms in the arteries can act in many different ways. Plaque can remain in the artery wall. It can reach a certain amount and stop its growth. This plaque does not block blood flow therefore there may be no symptoms. Plaque may also grow at a very slow rate. Over time it will cause blockage. Pain will surface in the chest or legs during exercise. The worst thing that can happen is rupturing a plaque. A ruptured plaque allows blood to clot and lead to a stroke or a heart attack. There are three main types of cardiovascular disease. The three main diseases are cerebrovascular disease, peripheral disease, and coronary artery disease. Cerebrovascular disease happens when ruptured plaques in the brain’s arteries cause strokes leaving permanent brain damage. Transient ischemic attacks are caused by temporary blockages in an artery. These are warnings of a stroke. In this case there is no brain injury. In peripheral disease, the arteries located at the legs are narrowed by plaque and can cause weak circulation. This will cause pain during walking and wounds do not heal very well. If the buildup of plaque is severe, amputation may be necessary. During coronary artery disease, the stable plaques in the heart may cause chest pains. If a plaque were to rupture it would clot and cause heart muscles to die, this is known as a heart attack.

Risk Factors of Atherosclerosis

There are many risk factors of atherosclerosis. Not exercising enough will cause someone to gain weight. As a person gains weight, they will have a higher chance of developing atherosclerosis. If they manage to lose the weight, their chances become smaller. Having high levels of LDL cholesterol, also known as bad cholesterol will also increase the risk of having atherosclerosis. Plaque is the mixture of LDL cholesterol, fats, calcium and white blood cells that will build up inside the walls of the arteries. In more severe cases, the blood flow can be completely blocked. (Atherosclerosis 2019). Old age is also a risk factor because plaque in the arteries have been gathered up longer and have had more time to do damage. A person’s lifestyle is one of the most important factors because it determines what type of diet they have. Genetics also play a role due to the fact that some people have a higher chance of having weaker arteries (Risk Factors 2019).

People are more likely to develop atherosclerosis if they have high blood pressure because high blood pressure adds force to the artery walls. With time, the added force will damage the arteries making them thinner and weaker.

Smoking can cause damage and constriction to blood vessels. It can raise cholesterol levels, and also raise blood pressure. It also affects oxygen levels by not allowing it to reach the body’s tissues. The toxins in tobacco smoke lower the high-density lipoprotein cholesterol (HDL). This is considered the good cholesterol. Toxins will also raise LDL levels which is the bad cholesterol. The nicotine and carbon monoxide will damage the vessel, more specifically the endothelium, making it much easier for plaque to settle (Smoking and your heart 2019).

There are also other new risk factors for atherosclerosis that scientists continue to study. Having a high level of a protein called C- reactive protein (CRP) has been found to have a significant relation to heart disease. Since CRP is present in atherosclerotic lesions, it may contribute to the progression of the progression and instability of the atherosclerotic plaque. Another emerging risk factor is having high levels of triglycerides in the blood. Researches suggest that targeting triglycerides may be an effective strategy. However, how triglycerides relate to the disease is still undetermined (New Study 2016).

Mechanism of the Disease

Even though we still don’t know the exact mechanism of atherosclerosis, some evidence has been found that in some people the condition can begins in childhood with the formation of tiny streaks of fat deposition in the arteries. For some people, it will progress rapidly in their 30’s. For other people, it doesn’t manifest until they reach age 50-60.

As the endothelium becomes more infiltrated by the fatty materials- primarily LDLs, macrophages, which are immune cells will travel to the site to look for the materials. The macrophages will be filled with lipids, they will be called foam cells which will die and gather up in the endothelial lining. Other materials such as: salts, calcium, smooth muscle cells will also gather up in the lining. This will take a toll on the lining and cause lesions. Atheromas, also known as atherosclerotic plaques will form. In addition, these plaques will make the vessel thinner, interfering with the flow of blood. If there is an injury to the endothelium because of the lipids damaging the vessels or as a result of another cause, there may be a formation of fibrous caps of scar tissue (Atherosclerosis 2019). The vessel walls will become less elastic in the areas of scar tissue. The flow of blood will decrease in the vascular beds due to the thick plaques that damage the arteries. In addition, the endothelium will be compromised and there may be a formation of a thrombus, or blood clot at the site of a plaque. It may then cause an obstruction in the channel or can even break free from the site and cause a block somewhere else (Atherosclerosis 2019).

Signs and Symptoms of Atherosclerosis

Atherosclerosis isn’t usually diagnosed until the person complains of chest pain. This is because there is no way to know until the artery is so narrowed or damaged that it can’t supply enough blood to the organs and tissues. A blood clot may also cause a block in blood flow, or even break apart and trigger a heart attack or stroke. The symptoms of moderate to severe atherosclerosis will depend on the area of the body where those arteries have been affected.

When atherosclerosis reached the heart arteries, people may have symptoms of chest pain or pressure. Another word for chest pain is angina. If there is atherosclerosis in the arteries in the brain, people will experience different signs and symptoms. These people could experience numbness or weakness in the arms or legs, as well as difficulty speaking or slurred speech. They may also temporarily lose vision in one eye. Another sign is drooping in the face muscles. These are signs of a transient ischemic attack (TIA). If a TIA is left untreated, it may turn into a stroke. Atherosclerosis in the arms or legs can also be signs of something called peripheral artery disease. Someone with peripheral artery disease leg pain when walking. Finally, when there is atherosclerosis in the arteries leading to the kidneys, it may lead to high blood pressure and even more serious, kidney failure (Arteriosclerosis/Atherosclerosis 2019).

Secondary Complications

One secondary complication that occurs when having atherosclerosis is high serum lipid levels. With the enhancement of LDL uptake by monocytes and macrophages, atherosclerotic lesions are initiated (Choy 2004). LDL stands for low density lipoprotein. LDL cholesterol can be bad and lead to clogged arteries (Choy 2004). If a person has an LDL level that is too high, plaque can form on the walls of the cardiovascular system, which then blocks the flow of blood to the heart and leads to a heart attack or stroke (Choy 2004). Another secondary complication a person may have if they experience atherosclerosis is aneurysms. When a person has an aneurysm, they experience a bulge in the wall of their artery. People do experience pain and throbbing when they have an aneurysm. If an aneurysm would burst, a person could face life threatening internal bleeding. Secondary complications like aneurysms, occur by destruction of mural architecture and concomitant loss of tensile strength attributable to bioengineering fatigue. Since atherosclerosis accelerates the breakdown of collagen and elastin, which is bad because they provide support to the wall of the aorta. As time passes, the walls of the aorta become fragile and damaged. The aortic wall then expands and forms a bulge due to elevated blood pressure through the aorta. This is the cause of how an aneurysm occurs. The last secondary complication is chronic kidney disease. Cardiovascular complications caused by an atherosclerosis disease correspond with patients with chronic kidney disease (Olechnowicz-Tietz 2013). These patients provide many atherosclerotic risk factors, some traditional, as well as some nontraditional risk factors such as inflammation and oxidative stress. Chronic kidney disease occurs when a person’s kidneys are damaged and prevent filtering of blood (Olechnowicz-Tietz 2013). When patients have an impaired renal function, they are at a higher risk for cardiovascular complications. Atherosclerosis disease impairs renal function, thus, leading to all these secondary complications.

Prognosis

Atherosclerosis is a disease that can be slowed down or destroyed, but if left untreated it progresses and the bump on the artery wall enlarges. If this bulge gets big enough, it creates a blockage. This makes not only a person’s heart at risk, but also puts them at risk for a stroke and other health complications. Also, when plaque builds up and ruptures this also causes threats for a heart attack and stroke.

Prevention/Treatment

A person can do a lot in or order to prevent the disease of atherosclerosis. Atherosclerosis is a disease that a person has a lot of control over. A person can prevent this from occurring by avoiding smoking, being overweight, having high cholesterol, and having high blood pressure (Holloway). When a person smokes, they damage the artery walls, which can ultimately lead to atherosclerosis (Holloway). When the artery walls are damaged, it is easier for plaque to build up. When a person has a high cholesterol, plaque can also build up on the lining of artery walls and narrow their arteries (Holloway). Exercise can help with lowering cholesterol and blood pressure. If lifestyle changes such as exercising and dieting doesn’t workout, a person can also take medication. Treatment for atherosclerosis include variety of medication that help lower your blood pressure and blood sugar levels, prevent blood clots, and prevent inflammation. Doctors can also prescribe statins that help people that have diabetes or high LDL cholesterol levels. If a person has severe atherosclerosis, they may even have to get surgery. For example, there is a procedure called coronary angioplasty, it is used to open blocked or narrowed coronary arteries. This procedure can also relieve chest pain by improving the blood flow to the heart. This disease will be hard to eliminate considering how many people that smoke a day and live an unhealthy lifestyle.

Works Cited

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4. Brumit, M. L. (2017, December 01). How to Lower Your Elevated LDL Cholesterol. Retrieved from https://thefhfoundation.org/lower-elevated-ldl-cholesterol
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Through which mechanisms might periodontal disease lead to an increased risk of atherosclerosis?

Introduction

Periodontal disease is the irreversible chronic inflammation of surrounding and supporting structures of teeth (periodontal ligament) and it affects around 20-25% of the global population (Nazir. MA, 2017), it’s caused due to the infection from various gram-negative anaerobic bacteria, mainly; Porphyromonas gingivalis and Treponema denticola. They create a biofilm layer which later develops into subgingival plaque, leading to alveolar bone resorption and ultimately exfoliation of teeth, these are characteristic features of periodontitis.

Atherosclerosis is also a chronic inflammatory condition which occurs as a result of hyperlipidemia, it is characterized by plaque deposits known as atheroma in major arteries. The process by which atherosclerotic plaque develops is demonstrated in figure 1, It’s a multifactorial process, with one of the debated risk factors being periodontal disease and thereby the mechanism of its involvement in the pathogenesis of atherosclerosis.

There have been several epidemiological studies which highlight an association between these two chronic inflammatory conditions, concluding that periodontal disease increases the risk and accelerates the progression of atherosclerosis (Miyaki et al. 2006, Ahn et al. 2016). In this review, I aim to explore the key mechanisms that studies have previously covered regarding this association. Many pathophysiological pathways have been proposed with regards to the link between periodontal disease and atherosclerosis, they can be divided into direct; bacteremia/endotoxemia as well as bacterial invasion and activation of endothelial cells and indirect mechanisms; molecular mimicry/autoimmunity and induction of inflammation.

Figure 1 (Xu. S, et al. 2016) – illustrates the process of atherogenesis; it involves adhesion of monocytes to the endothelial cell surface, migration of monocytes to the subendothelial space, ingestion of LDLs by macrophages leading to formation of foam cells which are characteristic of atherosclerosis, together with T cells form a fatty streak, smooth muscle cells migrate from the media to the intima and proliferate as the lesion progresses to form atherosclerotic plaques.

Figure 2 (Chistiakov et al. 2016) – This figure summarises the effects periodontal pathogens have on host cells with regards to the pathogenesis and progression of atherosclerosis

Direct mechanisms

Bacteremia/endotoxemia

Bacteraemia refers to the presence of bacteria in systemic circulation whilst endotoxemia is the presence of endotoxins (bacterial components) within systemic circulation. Given that the periodontal tissue is very well vascularized, which aids the entrance of periodontal pathogens into the bloodstream, this process occurs with such ease that it has been found that both bacteria and endotoxins from the oral cavity can enter systemic circulation during processes as simple as mastication and flossing (Geerts, SO. et al. 2002; Crasta, K. et al. 2009). Once within the bloodstream the bacteria and endotoxins either circulate the blood extracellularly or bound to a phagocytic cell before they are deposited to have their effects on various cells to promote atherogenesis, figure 2. Periodontal pathogens, including P.gingivalis, have been identified within atheroma using PCR (Haraszthy, V.I. et al. 2000), not only indicating the presence of periodontal pathogens within systemic circulation but also their involvement in atherogenesis.

Invasion and activation of endothelial cells

Once within the bloodstream, the periodontal pathogens must evade the host’s immune system in order to have their effect, one of the ways in which they do this is by the invasion of endothelial cells. A pioneering study by Deshpande et al. (1998) proved the ability of P.gingivalis to invade human umbilical vein endothelial cells (HUVEC) in a highly efficient process which requires the expression of major fimbriae (41 kDa) for both adherence and invasion of the endothelial cells. A two-step process for the interaction of P.gingivalis with host cells was been proposed; initial attachment mediated via 41 kDa major fimbriae, followed by a more intimate interaction mediated by minor fimbriae facilitating endocytosis of P.gingivalis. (Lamont and Jenkinson 1998. Njoroge et al. 1997. Takashaki et al. 2005). T.denticola has also shown the ability to invade endothelial cells via endocytosis, the pathogen was identified within endothelial cells using fluorescent in situ hybridization (FISH) of atherosclerotic plaque (Chukkapalli et al. 2014).

Once within the endothelial cells, the periodontal pathogens cause a series of events to initiate and promote atherogenesis. T.denticola causes a significant increase in known atherosclerotic risk factors, including VLDL, oxidized LDL serum levels, and pro-inflammatory mediators, leading to initiation of plaque formation following hyperlipidemia (Chukkapalli et al. 2014).

P.gingivalis causes increased monocyte chemoattractant protein-1 (MCP-1) secretion from endothelial cells (Kang and Kuramitsu, 2002), the role of MCP-1 is to cause the transmigration of monocytes through endothelial cells which ultimately leads to the formation of foam cells, these are characteristic of atheroma (figure 1). But for MCP-1 production to occur P.gingivalis must express major fimbriae (41kDa) as this only occurs once P.gingivalis is within the endothelial cell, and as mentioned, invasion of endothelial cells is fimbriae-mediated. This was confirmed when endothelial cells were cocultured with P.gingivalis whilst inhibiting endocytosis, the result was that no MCP-1 was produced (Takahashi et al. 2005). Other pro-inflammatory molecules are also produced during this interaction including; IL-1β, IL-8, ICAM-1, VCAM-1, and E-selectin (Takahashi et al. 2005). The mechanism by which these chemokines were produced is unclear, but the basis is due to cytoskeleton rearrangement. T.denticola was also found to induce the production of IL-8 and MCP-1 in endothelial cells by stimulating mRNA expression, transcription, and translation ultimately leading to the progression of atheroma formation (Okuda et al. 2007). The production of these chemokines is one of the first steps in developing an early atherosclerotic lesion.

Interestingly, Nassar et al. (2002) found that P.gingivalis can modulate the production of chemokines and adhesion molecules including; MCP-1 and IL-8, intracellular adhesion molecules (ICAM-1), and vascular cellular adhesion molecules (VCAM-1) in endothelial cells via fimbriae- and gingipain-mediated mechanisms, more specifically lysine-specific cysteine proteinase (gingipain K). Gingipains are a group of proteases secreted by P.gingivalis and their primary function is to degrade cytokines hence downregulating the host’s immune response. However, it was later discovered that endothelial cells treated with gingipains secreted by P.gingivalis exhibited a rapid loss of cell adhesion properties followed by apoptosis, hence causing detachment and death of these cells (Sheets et al. 2005). The stark difference between these two findings are likely due to the type of endothelial cells that were used; Nassar et al. used HUVEC whilst Sheets et al. used human arterial endothelial cells (HAEC), due to chemical differences between these two cells and given that atheroma develop within arteries rather than veins, it is reasonable to assume the findings of Sheets et al. to be more applicable to atherogenesis with regards the effects of gingipains on arterial endothelial cells. This would lead to vascular tissue destruction, which is indicated in atherosclerotic lesion progression, figure 1.

Indirect mechanisms

Molecular mimicry/autoimmunity

Molecular mimicry is the process by which an autoimmune response is initiated due to similarities in amino acid sequence between self-molecules and foreign antigens, this process involves the activation of T and B lymphocytes (Froude J et al, 1989). With regards to atherogenesis, molecular mimicry would involve the targeting of the host’s immune response against the host proteins expressed by endothelial cells in the vascular wall. Arterial endothelial cells express human heat shock protein 60 (hHSP60) on their cell surface in response to stress factors such as temperature or infection, the function of hHSP60 is to initiate an intracellular signaling cascade which mediates a range of inflammatory responses including the release of cytokines. Bacteria, including the periodontal pathogen P.gingivalis, express bacterial heat shock proteins known as GroEL, both these proteins are very well conserved meaning their sequences do not differ much between species. It has been proposed that cross-reactivity of the host’s immune response between hHSP60 and bacterial GroEL occurs (Ford P.J. et al. 2005; Ford P et al., 2004), meaning the host’s anti-P. gingivalis GroEL antibodies have been found to induce an immune response against stressed endothelial cells which ultimately leads to endothelial cell dysfunction hence atherosclerosis progression.

A study was undertaken to investigate the proposed cross-reactivity reaction. The results showed that anti-P.gingivalis antibodies levels were significantly higher in atherosclerosis patients with advanced periodontitis compared to those with periodontal health (Yamazaki et al. 2004). Clonal analysis of the T cells demonstrated the presence of both hHSP60- and GroEL-reactive T-cell populations within systemic circulation of the atherosclerosis patients who also suffer from periodontitis, they were also found within periodontal pockets and atherosclerotic plaque lesions. This indicates that both these T cells may have similar specificity to both hHSP60 and GroEL, and so anti-P. gingivalis GroEL antibodies can react with hHSP60 expressed on injured endothelial cells and therefore are both involved in the pathogenesis of atherosclerosis by means of endothelial cell dysfunction.

In addition, Th1 and Th2 cells specific to P.gingivalis GroEL were extracted from atherosclerotic lesions of periodontitis patients indicating that the immune response to this bacterium is involved in the pathogenesis of atherosclerosis (Choi J.I. et al. 2002)

Induction of inflammation

The presence of periodontal pathogens in systemic circulation has been shown to also influence the inflammatory stage of atherogenesis; more specifically in the development of an early atherosclerotic lesion (figure 1). The ways in which this inflammation is induced has been found to be as follows:

Toll-like receptors (TLRs) are involved in the innate immune system when activated they induce a signalling cascade which induces production of pro-inflammatory cytokines hence an immune response. P.gingivalis causes increased expression of TLR2, TLR3, TLR4, TLR6, and TLR9 on the surface of endothelial cells upon fimbriae-dependent invasion of endothelial cells (Yumoto H, et al 2005). It has also been found that more specifically TLR2 and TLR4 are heavily involved in inducing an inflammatory response characteristic of early atherosclerotic lesions specifically inflammatory activation of endothelial cells and macrophages (Edfeldt K. et al. 2002)

Release of TNF-α and IL-1β systemically occurs due to systemic exposure to gram-negative bacteria specifically LPS that these bacteria express which are involved in the pathogenesis of periodontal disease following bacteremia and endotoxemia (Hesse D.G. et al. 1988; Michie H.R. et al. 1988; Koopmans R. et al. 1994; Iacopino A.M., and Cutler C.W., 2000). These 2 cytokines are involved in the ‘cytokine cascade’ TNF-α being the first factor followed by IL-1β, these indirectly affect lipid production in the liver due to their effect on release of other cytokines hence increasing LDL and free fatty acid serum levels which leads to hyperlipidemia, an undisputed risk factor for atherosclerosis (Van der Poll T and Saurwein HP, 1993; Iacopino A.M., and Cutler C.W., 2000).

Finally, the cytokines released upon endothelial cell activation; IL-1β, IL-8, ICAM-1, VCAM-1, and E-selectin, cause localized inflammation which is one of the key steps in progression of early atherosclerotic lesions.

Conclusion

The mechanisms discussed show biological plausibility and appear to have the capacity to promote atherosclerosis both independently and collectively. The association found in epidemiological studies indicating an increased risk of atherosclerosis in subjects with periodontal disease now has many proposed mechanisms via both direct and indirect effects. These effects are initiated following bacteremia and endotoxemia of periodontal pathogens and their components. Then the bacteria, namely P.gingivalis and T.denticola, can either have direct effects on endothelial cells following their invasion, including; promoting the secretion of pro-inflammatory cytokines IL-8 and MCP-1, causing detachment and apoptosis of endothelial cells in a gingipain-mediated mechanism, both of which lead to progression of atherosclerosis. Or indirect effects which involve: molecular mimicry; induction of the immune system against self-molecules, namely the similar specificity between antibodies directed against hHSP60 and P.gingivalis GroEL, and induction of inflammation both locally and systemically to cause progression of early atherosclerotic lesions.

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Potential therapies for promoting plaque regression

Various targets have been proposed to induce plaque regression or slow down the atherosclerosis process. Some potential therapeutic targets are discussed in the following paragraphs within the idea of plaque regression (Table 2).

Evidence of plaque regression

The plaque regression concept was evidenced earlier from animal studies 101 and from patients undergoing medical therapy 102, 103. Murine apo E−/− or the LDL receptor−/− suggested that plaque regression occurs 104. Plaque regression is an important therapeutic target. However, no extensive investigational evidence shows that plaque regression can be accomplished for advanced lesions 101. Transplantation using a segment of the plaque-containing aorta from hyperlipidemic apo E−/− mouse helped to investigate features regressing plaque 65. In vivo data demonstrated a rapid loss of foam cells from premature lesions within 3 days post-transplantation 105, 106. Yet, a great challenge was the finding of an atherosclerosis model of spontaneous plaque rupture with humanized endpoints such as MI, stroke, and unexpected death. Recently, these features are proposed in apo E-/-Fbn1C1039G+/- mice 107, 108. This model could evaluate the potential plaque stabilizing therapies to better define systemic antiatherosclerosis factors and their mechanisms.

Lipid-lowering therapy

Administration of hypolipidemic and antioxidant drugs were proposed to prevent the progress of atherosclerosis. Numerous clinical trials highlighted the role of statins 109. Moderate-or intensive statins therapy reduces LDL cholesterol (LDL-C) 110, promote atheroma stabilization 111, and induces coronary plaque volume regression 12, 103, 109. Statin therapy also reduces fibro-fatty components and increases dense calcium volume in atheromatic plaque 112. Statin was also associated with reduced IP angiogenesis in the carotid arteries 113. SATURN trial showed that more than 60% of rosuvastatin or atorvastatin-treated patients showed plaque regression 112, 114. Therefore, statins may not affect the instability features of the plaque as reported by meta-analysis studies 12. Unfortunately, atherosclerosis continues to progress in up to one-third of patients despite high statin treatment 115. This reinforces the need to reduce “residual risk” of coronary events 115, 116.

Anacetrapib

The use of anacetrapib in a patient with atherosclerosis and under intense statin therapy resulted in a lower incidence of major coronary events than the use of placebo (ClinicalTrials.gov number, NCT01252953) (Table 2). Anacetrapib trials showed reduction in plaque progression (mostly by decreasing non-high-density lipoprotein cholesterol HDL-C) and improvement of plaque stability 117. Of importance imaging studies are expected to evaluate this finding 118.

Antibody technology against PCSK9

Recent therapeutic advances have been reported using ezetimibe and humanized monoclonal antibody technology against PCSK9 118. Ezetimibe favour cholesterol absorption inhibition ameliorates endothelial dysfunction and atherosclerosis regression in coronary arteries 119. Results from the ZIPANGU study in patients with stable cardiovascular disease (CVD) suggested that ezetimibe and atorvastatin are more effective on plaque regression than statin alone 120. The GLAGOV trial was the first to compare combination therapy with statin plus evolocumab (named also Repatha) to statin therapy alone 121. In this study, Evolocumab induces atheroma regression (Table 2). Furthermore, Alirocumab (named also Praluent) and Evolocumab, have recently been accepted for the treatment of familial and nonfamilial hypercholesterolemia 122, 123. However, more studies in demand to assess the effects of PCSK9 inhibition on clinical consequences.

Potential novel molecular targets and current perspectives

Activation of macrophage inflammasomes releases interleukin (IL)-1β and IL-18 and promotes atherosclerosis and its complications in vivo 124. Inflammasome stimulation may contribute to atherosclerotic plaque erosion and thrombosis, exclusively in subjects having CVD risk as type 2 diabetes or chronic kidney disease 125. This finding received a solid support by targeting inflammatory pathway with a monoclonal antibody inhibiting interleukin-1β (IL-1β) named also canakinumab (Table 2). Blocking IL-1β may directly affect vascular atherosclerotic disease evolution 126, 127. However, in phase II trial benefits of canakinumab on plaque inflammation were not detected 126. The outcomes of this Phase II trial are proposed to be addressed by the multinational Phase III trial (CANTOS). Unfortunately, in a recent press release, the FDA declined to approve canakinumab for cardiovascular risk reduction from the CANTOS trial 128. While the CANTOS suggests a favorable profile for inflammasome-derived IL-1β in CVD, the magnitude of the advantage was moderate, and there was an excess of infections associated with this therapy 129, perhaps due to decreased neutrophil levels 125. Recent progress in this field proposes that molecules upstream of IL-1β secretion, such as NLRP3, caspase-1/11, or CMPK2, may provide further therapeutic targets for preventing atherosclerotic vascular disease 125, 130. Another therapy for plaque stability is exploring vascular growth factor angiopoietin-2 (Ang-2) 31.Ang-2 activity might play a role in the progress of unstable plaque 131. Ang-2 blockage was associated with decrease in triglyceride levels in plasma and fatty streak formation in hypercholesterolemic mice 2, 132. These results suggest a favorable drugability and safety index for the clinical use of antibodies inhibiting Ang-2 activity (Table. 2). Furthermore, the anti-inflammatory drugs that impair efferocytosis 133 may present new weapons to slow down the progression and development of CVD, while the detailed mechanisms are unclear 9.

Probucol

Probucol is a powerful anti-oxidant with anti-hyperlipidemic activity 134 (Table 2). This drug is thought to stabilize plaques at high risk, perhaps via various pleiotropic functions such as lipid-lowering, anti-inflammatory, and scavenger receptors suppression 135. In a recent study, in patients with CHD (n=300) probucol treatment reduce atherosclerotic plaque area as well as total cholesterol and soluble thrombomodulin levels 88. Despite of these findings, prospective studies are needed to determine whether the combination therapy of probucol with lipid-lowering agents improves vascular outcomes in subjects with CHD. However, probucol reduces HDL-C caused by the activation of CETP 136 and hepatic scavenger receptor class B type I (SR-BI) 137. Given that, probucol was left by western countries, although it is still used for a long time, especially in Japan.

Novel therapeutic targets for reducing atherosclerotic plaque

New targets in atherosclerosis research have been reported. Some studies suggested that semaphorin-3A (sema-3A) reduces atherosclerotic plaque progression by enhancing the motility and function of M2 macrophages and regulating foam cell formation in apoE-/- mouse 138, 139. Conversely, sema-3E another semaphorin is expressed in atherosclerotic plaques and regulated macrophage retention in plaques 140. Further investigations are in need to evaluate semaphorin roles atherosclerotic plaque formation. Another target to promote regression of atherosclerosis is through activation of the chemokine receptor CCR7-dependent emigration pathway in macrophages 25, 105. In deed, targeting CCR7 activation by statins was found to induce CD68+ release from plaques rather promoting atherosclerotic plaque regression 141. This indicates a new prospect in reducing atherosclerotic plaques 142. However, the role of CCR7 in atherosclerosis is more complex. Furthermore, genomic studies revealed novel targets of proteins as a novel target for anti-atherosclerotic therapy 133. Theses are asialoglycoprotein receptor 1, angiopoietin-related protein 4, and inflammatory pathways that damage efferocytosis (CD47) (Table 2). There is a need to validate the impact such targets on plaque regression.

Angiogenesis inhibitors

Angiogenesis is associated closely with plaque progression 143, 144 where its role in this process may take part in plaque destabilization and thromboembolic acute events 143. Various compounds emerge as alternatives to promote plaque stability by targeting IP angiogenesis. Earlier studies have reported that anti-angiogenic compounds; endostatin and TNP-470 to reduce atherosclerosis progression in apoE-/-mice 145. Another agent is Ghrelin, a 28-amino-acid acylated peptide 146 was found to inhibit IP angiogenesis in animal models 147. As reported recently, ghrelin may act by regulating expression of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) and reducing MCP-1 expression at late stage of atherosclerosis 143, 147. However, mechanism of action of Ghrelin on plaque stability have not yet been largely explored 147. Clinical trials with anti-angiogenic medications, mostly anti-VEGF/VEGFR, used in anticancer treatment, were associated with risk for cardiovascular adverse effects, and need further studies 144, 148. More recently, various compounds have been studied to inhibit IP angiogenesis with mechanism of action that interfere with angiogenesis 144, 147, 149 (Table 2). Studies based on a blocking antibody Bevacizumab against VEGF-A, Axitinib against VEGF receptor tyrosine kinase, and DC101 against VEGFR-2 showed potential ability for the treatment of IP angiogenesis and hemorrhage 149. Less studies targeting neovascularization were documented 108, possibly because of absence of relevant animal models. Previous works have showed that promotion of angiogenesis in myocardial ischemia is a potential strategy 2. However, angiogenesis promotes atherosclerosis growth in various animal models and probably causes plaque rupture 144, 148. Hence, more consideration should be paid to harmonize the regulation of angiogenesis in atherosclerotic CVD when using anti-angiogenic medications 148.

HDL biogenesis and plaque regression

Meta-analysis of clinical studies demonstrated that atherosclerosis regression as measured by (IVUS) after decreasing LDL levels was almost to be reached when HDL concentration was increased by 110. Despite this, sudden rupture of plaque remains the leading reason of acute coronary events 150-152. The role of HDL in plaque regression although still less well characterized 110. Infusion of reconstituted HDL into human subjects with acute coronary syndrome 116, 152 was found to promote regression of atherosclerosis lesion in 5 weeks of therapy 153. Other studies linked plaque regression to use of HDL mimetic peptides 116, 154 by targeting HDL biogenesis process through increasing apoA-I production or modulating ABCA1 155, 156. In vivo studies showed that macrophage cholesterol efflux (CE) mediated by ABCA1/ABCG1 may have an important role in suppressing apoptosis in advanced plaques 157. Defective HDL capacity in ABCA1 cholesterol efflux was observed in association with progressive atherosclerotic lesions 13. As established by us 71, 158, and others 159-161, an inverse association exists between HDL cholesterol efflux and carotid plaque instability and CVD, independently of the HDL-C levels. Although not yet determined, cholesterol efflux could be important biomarker in determining who will develop atherosclerosis. However, more recently, serum cholesterol efflux values do not correlate with plaque vulnerable markers in elderly subjects (~80 years, n=59) 162. One explanation is that cholesterol efflux may play a more protective role in the earlier steps of atherosclerosis 163. In support for this, cholesterol efflux association with cardiovascular events was found more evident in younger populations than others 162. More studies should be conducted to assess differences in HDL cholesterol according to atheromatous plaque severity or instability to better evaluate HDL biogenesis as therapeutic target for atherosclerosis (Table 2).

Locally applied therapy for vulnerable plaque

Other options exist for local therapy and plaque pacification. Photodynamic therapy broadly used in cancer patients, is explored in plaque regression therapies. This technology demonstrated ability to destroy mechanically macrophages and SMC without damaging structural integrity of the vessels with a photosensitizer 164. The application of photodynamic therapy is still limited 165 despite safety trails 164, 165. As recently reviewed, photodynamic therapy pertinence needs further evaluation and there is major challenges toward its translation into a clinical reality 166. Other options are with plaque sealing based on the concept that plaques may be intentionally ruptured with angioplasty balloon inflation after intervention 165. This technology is performed by placing a stent to prevent plaque acute events. However, this concept has fallen out of favor after the arrival of coronary stenting and the lack of clinical results 165. Nanoparticles approaches may provide possibilities of safe gene medication, with the goal of attenuating atherosclerosis 167 (Table 2). Of such, several important challenges persist regarding to nanoparticle drug delivery purposes where each particle arises from a unique set of design criteria and composite 168. Despite this, nanotechnology is exciting strategy for innovative effective medication as evidenced in vivo by reducing plaque at risk of rupture and changing in inflammatory markers. It would be important to know in a near future if these techniques would be associated with improvement in methods to detect “high-risk plaque” as well as improved stent technology and understanding of the so-called vulnerable plaques 62.

Conclusion

Our knowledge of plaque biology is increasingly expanding. The area of vulnerable plaque is receiving more awareness with the arrival of molecular imaging, letting better insight into plaque biology. Current advances in both atherosclerosis imaging and lipid-lowering treatment present additional questions for future consideration in the setting of reducing plaque at risk of rupture. Despite recent advances in primary prevention and therapeutic technology, treatment of atherosclerosis based on HDL biology remains in preclinical stages. Importantly, more effective effort should be directed toward developing more reliable models for an integrative approach to plaque assessment.

Introduction to atherosclerosis:

Atherosclerosis is the consequence of hyperlipidemia and lipid oxidation and has dependably been a noteworthy reason for mortality in created nations. It is an ailment of vascular intima, where all the vascular framework from aorta to coronary supply routes can be included and is described by intimal plaques.

The term atherosclerosis is of Greek starting point, which means thickening of the intimal layer of veins and collection of fat. Greasy material is situated in the focal center of the plaque, secured by stringy top. The term, atherosclerosis comprises of two sections; atherosis (gathering of fat joined by a few macrophages) and sclerosis (fibrosis layer involving smooth muscle cells [SMC], leukocytes, and connective tissue).

As of now, atherosclerosis is a typical illness wherein greasy stores called atheromatous plaques show up in the internal layers of supply routes. Arrangement of these plaques begins with the statement of little cholesterol gems in the intima and its basic smooth muscle. At that point, the plaques develop with the multiplication of sinewy tissues and the encompassing smooth muscle and lump inside the courses and subsequently diminish the bloodstream. Connective tissue generation by fibroblasts and testimony of calcium in the sore reason sclerosis or solidifying of the supply routes. At long last, the uneven surface of the supply routes results in clump arrangement and thrombosis, which prompts the unexpected deterrent of the bloodstream.

Hyperlipidemia and hyperglycemia are identified with expanded oxidative harm, which influences cell reinforcement status and lipoprotein levels. Studies have demonstrated that lipid bringing down therapeutic herbs can lessen the blood lipids, particularly after dinners notwithstanding their cell reinforcement impacts. In this manner, they can anticipate atherosclerosis and vascular endothelium harm.

Atherosclerosis:

Atherosclerosis is a narrowing of the conduits brought about by a development of plaque. Corridors are the veins that convey oxygen and supplements from your heart to the remainder of your body.

As you get more seasoned, fats, cholesterol, and calcium can gather in your supply routes and structure plaque. The development of plaque makes it hard for blood to course through your conduits. This development may happen in any course in your body, including your heart, legs, and kidneys.

It can result in a deficiency of blood and oxygen in different tissues of your body. Bits of plaque can likewise sever, causing a blood coagulation. Whenever left untreated, atherosclerosis can prompt heart assault, stroke, or heart disappointment.

Atherosclerosis is a genuinely basic issue related with maturing. This condition can be forestalled and numerous effective treatment alternatives exist.

Causes:

There are the following causes:

• High cholesterol:

1. Cholesterol is a waxy, yellow substance that is found normally in the body just as in specific sustenances you eat.
2. In the event that the dimensions of cholesterol in your blood are excessively high, it can stop up your conduits. It turns into a hard plaque that limits or squares blood flow to your heart and different organs.

• Diet:

1. it’s essential to eat a sound eating regimen. The American Heart Association (AHA) prescribes that you pursue a by and large solid dietary example that burdens:
2. a wide scope of products of the soil
3. entire grains
4. low-fat dairy items
5. poultry and fish, without skin
6. nuts and vegetables
7. non-tropical vegetable oils, for example, olive or sunflower oil

• Aging:

1. As you age, your heart and veins work more earnestly to siphon and get blood. Your courses may debilitate and turn out to be less flexible, making them progressively defenseless to plaque development
2. Other complitions:

• Atherosclerosis can cause:

1. heart disappointment
2. heart assault
3. unusual heart cadence
4. stroke
5. demise

It’s additionally connected with the accompanying maladies:

Coronary vein illness (CAD)

The coronary veins are veins that furnish your heart’s muscle tissue with oxygen and blood. Coronary supply route sickness (CAD) happens when the coronary corridors become hard.

Carotid vein illness

The carotid veins are found in your neck and supply blood to your cerebrum.

These supply routes might be undermined if plaque develops in their dividers. The absence of course may diminish how much blood and oxygen achieves your cerebrum’s tissue and cells. Get familiar with carotid supply route malady.

Fringe conduit ailment

Your legs, arms, and lower body rely upon your corridors to supply blood and oxygen to their tissues. Solidified corridors can cause course issues in these zones of the body.

Kidney ailment

The renal veins supply blood to your kidneys. Kidneys channel squander items and additional water from your blood.

Atherosclerosis of these courses may prompt kidney disappointment.

Risk factors:

There is a connection between the plasma fibrinogen level of PAI-1 as a fibrinolysis inhibitor and the danger of coronary corridor illnesses. Fibrinogen is a flowing glycoprotein which has movement in coagulation steps reacting to tissue and vascular damage.

Notwithstanding thrombotic job, fibrinogen causes cell proliferation, constriction of harmed cell dividers, incitement of platelet aggregation, and guideline of cell adhesion. Fibrinogen is an intense stage reactant like CRP and its blend can be expanded in light of aggravations or infections. Epidemiologic data bolsters the connection between’s fibrinogen levels and cardiovascular illnesses, localized necrosis, and ischemia. Fibrinogen takes an interest in irritation and thrombosis. Fibrinogen is most likely less influenced by fiery incitement contrasted and CRP and thusly is a particular marker. Fibrinogen increment in patients with atherosclerosis can be an auxiliary marvel, despite the fact that it takes an interest in injury arrangement and thrombosis.

Factor VII is additionally a coagulative protein, which has a significant job in thrombogenesis. A few examinations exhibit the connection between’s factor VII and provocative factors, for example, IL-6 and CRP in patients with hypercholesterolemia, which demonstrates their pathophysiologic relationship. There are additionally a few reports demonstrating the connection between’s coagulation framework constituents (fibrinogen and factor VII) or fibrinolytic factors (tissue plasminogen activator, PAI) and atherosclerosis

Family history :

In the event that atherosclerosis keeps running in your family, you might be in danger for solidifying of the conduits. This condition, just as other heart-related issues, might be acquired

High blood pressure:

Hypertension can harm your veins by making them powerless in certain zones. Cholesterol and different substances in your blood may decrease the adaptability of your courses after some time.

Lack of exercise:

Normal exercise is useful for your heart. It keeps your heart muscle solid and energizes oxygen and bloodstream all through your body.

Carrying on with an inactive way of life builds your hazard for a large group of ailments, including coronary illness.

• Smoking:

Smoking tobacco items can harm your veins and heart.

• Diabetes:

Individuals with diabetes have an a lot higher rate of coronary conduit illness (CAD).

• Diagnose:

During a physical test, your specialist may discover indications of limited, broadened or solidified conduits, including:

• A powerless or missing heartbeat beneath the limited territory of your course
• Diminished circulatory strain in an influenced appendage
• Whooshing sounds (bruits) over your conduits, heard utilizing a stethoscope

Contingent upon the consequences of the physical test, your specialist may recommend at least one analytic test, including:

• Blood tests. Lab tests can recognize expanded dimensions of cholesterol and glucose that may build the danger of atherosclerosis. You’ll have to abandon eating or drinking anything other than water for nine to 12 hours before your blood test.

Your specialist should let you know early if this test will be performed during your visit.

• Doppler ultrasound. Your specialist may utilize a unique ultrasound gadget (Doppler ultrasound) to gauge your pulse at different focuses along your arm or leg. These estimations can enable your specialist to check the level of any blockages, just as the speed of bloodstream in your corridors.

Lower leg brachial record. This test can tell on the off chance that you have atherosclerosis in the corridors in your legs and feet.

• Your specialist may analyze the circulatory strain in your lower leg with the pulse in your arm. This is known as the lower leg brachial list. An unusual contrast may demonstrate fringe vascular infection, which is normally brought about by atherosclerosis.
• Electrocardiogram (ECG). An electrocardiogram records electrical flag as they travel through your heart. An ECG can regularly uncover proof of a past heart assault. On the off chance that your signs and side effects happen regularly during activity, your specialist may request that you stroll on a treadmill or ride a stationary bicycle during an ECG.
• Stress test. A pressure test likewise called an activity stress test, is utilized to assemble data about how well your heart functions during physical activity.

Since exercise makes your heart siphon more earnestly and quicker than it does during most day-by-day exercises, an activity stress test can uncover issues inside your heart that probably won’t be detectable something else.

An activity stress test for the most part includes strolling on a treadmill or riding a stationary bicycle while your heart mood, circulatory strain, and breathing are checked.

In certain kinds of stress tests, pictures will be taken of your heart, for example, during a pressure echocardiogram (ultrasound) or atomic pressure test. In case you’re unfit to work out, you may get a drug that mirrors the impact of activity on your heart.

• Heart catheterization and angiogram. This test can appear if your coronary supply routes are limited or blocked.

A fluid color is infused into the corridors of your heart through a long, meager cylinder (catheter) that is encouraged through a supply route, as a rule in your leg, to the conduits in your heart. As the color fills your corridors, the supply routes become obvious on X-beam, uncovering regions of blockage.

• Other imaging tests. Your specialist may utilize ultrasound, an electronic tomography (CT) filter or attractive reverberation angiography (MRA) to examine your courses. These tests can regularly show solidifying and narrowing of enormous corridors, just as aneurysms and calcium stores in the vein dividers.

Your specialist will play out a physical test in the event that you have indications of atherosclerosis. They’ll check for:

• a debilitated heartbeat
• an aneurysm, an anomalous protruding or extending of a course because of shortcoming of the blood vessel divider
• moderate injury recuperating, which demonstrates a limited bloodstream

A cardiologist may tune in to your heart to check whether you have any unusual sounds. They’ll be tuning in for a whooshing commotion, which demonstrates that a vein is blocked. Your specialist will arrange more tests in the event that they figure you may have atherosclerosis.

Tests can include:

• a blood test to check your cholesterol levels
• a Doppler ultrasound, which uses sound waves to make an image of the supply route that shows if there’s a blockage
• a lower leg brachial file (ABI), which searches for a blockage in your arms or legs by looking at the circulatory strain in every appendage
• an attractive reverberation angiography (MRA) or a figured tomography angiography (CTA) to make photos of the huge corridors in your body
• a cardiovascular angiogram, which is a sort of chest X-beam that is taken after your heart corridors are infused with radioactive color
• an electrocardiogram (ECG or EKG), which estimates the electrical movement in your heart to search for any regions of diminished bloodstream
• a pressure test, or exercise resistance test, which screens your pulse and circulatory strain while you practice on a treadmill or stationary bike

Biochemistry:

atherogenic are viewed as the results of synthetic adjustment of LDL, instead of LDL themselves. The adjustment is made by methods for the free radicals or receptive oxidized nitrogen species (RONS). Their quick and wild age in the body may turn into an essential for the advancement of various sicknesses and neurotic procedures, for example, atherosclerosis, neurological, malignancies, maturing and irritation, and so forth… The article portrays the substance idea of free radicals, the component of their activity, and chain character of their age. The specific consideration is paid to nitric oxide, which is perceived in a wide exhibit of biologic frameworks, to be specific, activities on vascular endothelium and interceding macrophage action. The components of cell assurance from the harmful activity of RONS have been clarified. In view of the test information exhibited, very huge dosages of cancer prevention agents may prompt medical issues, instead of give benefits, since RONS are engaged with the systems which increment the survival of cells at horrible conditions. The total disability of their age advances the debilitating of cell resistance. The article depicts the way to give cell cholesterol homeostasis and the take-up of synthetically altered LDL by macrophage forager receptors. Macrophages devour overabundance changed lipoprotein getting to be froth cells. Froth cells aggregate, discharging development variables and cytokines that animate the movement of smooth muscle cells from the media to the intima, where they multiply, produce collagen and take up lipid, conceivably getting to be froth cells which are the principal guilty parties of atherosclerotic changes in the conduit dividers

Aortic atherosclerosis delivered in bunnies by sustaining them cholesterol was observed to be biochemically and morphologically unique in relation to raised injuries creating from white wall painting nonocclusive thrombus and was additionally not the same as level myointimal thickenings creating after catheter-actuated endothelial damage with transient platelet bond in both the normolipidemic and hypercholesterolemic state. The three kinds of injuries contrasted in regard to the season of beginning, power and time of decay of DNA union (cell expansion), collagen combination, collagen focus, lipid profile, take-up of Evans blue, and take-up of colloidal thorium dioxide. Injuries of Evans blue positive endothelial damage in the normolipidemic state at last formed into level myointimal thickenings with DNA, collagen, and lipid focuses fundamentally the same as the ordinary aortic divider. Sores from thrombus at last formed into raised thromboatherosclerotic sores with a lipid and collagen profile particularly higher and unique in relation to the typical aortic divider. The energy of DNA and collagen combination, collagen fixation, lipid profile, Evans blue and colloidal thorium dioxide take-up of the level myointimal thickenings from damage, and the raised thromboatherosclerotic injury from thrombus are not the same as the cholesterol atherosclerotic sore from cholesterol sustaining. Despite the fact that these three sorts of injuries have numerous highlights of cell damage and fix in like manner and with twisted recuperating when all is said in done, the organic chemistry and morphology of the three kinds of sores are unmistakably unique.

Signs and symptoms:

Most side effects of atherosclerosis don’t appear until a blockage happens. Basic side effects include:

• chest torment or angina
• torment in your leg, arm, and anyplace else that has a blocked supply route
• shortness of breath
• exhaustion
• disarray, which happens if the blockage influences flow to your mind
• muscle shortcoming in your legs from absence of dissemination

It’s likewise imperative to know the manifestations of heart assault and stroke. Both of these can be brought about by atherosclerosis and require quick restorative consideration.

The indications of a heart assault include:

• chest torment or inconvenience
• torment in the shoulders, back, neck, arms, and jaw
• stomach torment
• shortness of breath
• sweat
• dazedness
• sickness or spewing
• a feeling of looming fate

The side effects of stroke include:

• shortcoming or deadness in the face or appendages
• inconvenience talking
• inconvenience getting discourse
• vision issues
• loss of equalization
• abrupt, extreme cerebral pain

Heart assault and stroke are both medicinal crises. Call 911 or your nearby crisis benefits and get to a medical clinic’s crisis room as quickly as time permits on the off chance that you experience side effects of a heart assault or stroke.

Atherosclerosis in coronary conduits prompts chest torment with physical movement or stress (angina). Blockages in the corridors that feed blood to the mind can cause a stroke. Blockages in the conduits that supply the legs result in an excruciating condition called discontinuous claudication.

Treatment as a physiotherapist:

Exercise counteracts atherosclerosis in various ways. It keeps corridors sound by bringing down awful cholesterol and boosting great cholesterol. Also, it lessens other hazard factors for atherosclerosis and blood clusters, for example, hypertension, diabetes, corpulence, and stress.

Ordinary exercise additionally helps supply routes by boosting the generation of nitric oxide by the cells covering the veins, which helps flow. What’s more, new research in mice recommends that activity invigorates the bone marrow to deliver new cells for the blood vessel lining, which supplant maturing cells and fix harmed corridors.

Indeed, even in sound individuals who are free of atherosclerosis, age negatively affects supply routes. As you age, veins become stiffer, stickier, and smaller. Be that as it may, researchers in Italy found that in individuals who practiced normally, age had an a lot littler impact on supply routes.

‘You don’t need to be a marathon runner to enable your conduits to remain youthful. Only a few miles of lively strolling consistently will help,’ says Dr. Harvey Simon, manager in head of the Harvard Men’s Health Watch.

Customary physical action utilizing enormous muscle gatherings, for example, strolling, running, or swimming produces cardiovascular adjustments that expansion practice limit, continuance, and skeletal muscle quality. Ongoing physical action likewise forestalls the improvement of coronary vein ailment (CAD) and diminishes indications in patients with set-up cardiovascular infection. There is likewise proof that activity lessens the danger of other ceaseless illnesses, including type 2 diabetes,1 osteoporosis,2 obesity,3 depression,4 and malignancy of the breast5 and colon.6 This American Heart Association (AHA) Scientific Statement for wellbeing experts condenses the proof for the advantages of physical action in the counteractive action and treatment of cardiovascular sickness, gives proposals to medicinal services experts to actualize physical action programs for their patients, and distinguishes territories for future examination. This announcement centers around high-impact physical movement and does not legitimately assess opposition works out, for example, weight lifting, in light of the fact that the majority of the examination connecting physical action and cardiovascular malady has assessed oxygen-consuming action. At whatever point conceivable, the composition gathering has referred to outline articles or meta-examinations to help ends and proposals. This proof backings the suggestion from the Centers for Disease Control and Prevention (CDC) and the American College of Sports Medicine (ACSM) that people ought to take part in 30 minutes or a greater amount of moderate-power physical action on most (ideally all) days of the week.

Introduction

Rheumatoid Arthritis (RA) is an autoimmune disorder that affects 0.5-1% of the population and is associated with significant morbidity, disability, and costs for society(1).

Atherosclerotic disease in both its subclinical and clinically established phases is widely prevalent throughout the world. Disease progression can eventually lead to the occurrence of acute cardiovascular events (CVE), such as myocardial infarction, unstable angina pectoris, and sudden cardiac death(2).

RA is associated with increased premature mortality mainly due to cardiovascular (CV) diseases (3). Atherosclerosis is emerging as an important complication of RA, with coronary artery disease being the major cause of mortality in these patients. Both men and women with RA are twice as likely to suffer from myocardial infarction when compared with the general population (4).

Subclinical atherosclerosis, mainly carotid artery plaques, may be observed in RA patients, which may be easily recognized by ultrasound, thus identifying those patients with higher CVE risk (5). Multiple lines of evidence reported that CV risk factors are probably underestimated in RA patients (6) , although the international recommendations clearly state about the assessment of this specific risk (7), the evidence of traditional CV risk factors and subclinical atherosclerosis does not fully explain the increased incidence of CVEs in these patients; suggesting that the CV risk may be independently associated with RA and in fact, this risk has been shown to be associated with additional features specific of RA, such as the systemic inflammatory process, disease duration and therapeutic strategies (3, 8-10).

Because heritability accounts for up to 60% of the risk in RA and 30%–60% of the risk in cardiovascular disease,(11) there has been increasing interest in attempting to identify genetic markers of atherosclerosis in RA. Multiple variants in multiple genes have been investigated regarding their association with clinical and subclinical cardiovascular (CV) disease, traditional CV risk factors, and CV mortality(12).

The human Osteoprotegerin (OPG) gene (also called TNFRSF11B) located on chromosome 8q24 is affected by genetic polymorphisms with functional consequences on CV disease and bone metabolism (13, 14). Several groups have reported that a single-nucleotide OPG polymorphism (SNP) located in the 59 UTR region (rs2073617), as well as one in exon 1 (rs2073618) and another in the promoter region (rs3134069), were associated with atherosclerosis and risk of cerebrovascular disease in nonrheumatic individuals (15, 16).

Osteoprotegerin (OPG) is a decoy receptor activator for nuclear factor κB ligand (RANKL) that acts as a regulator of bone resorption, immunity, and cardiovascular function. OPG expression has been detected in human atherosclerotic plaque as well as in osteoblasts (17, 18).

It is secreted by endothelial cells and smooth muscle cells in response to stimulation by proinflammatory cytokines, and it up-regulates the expression of endothelial adhesion molecules that facilitate the migration of monocytes and lymphocytes into the vascular intima during the process of atherogenesis (19).

OPG is also related to plaque rupture (20, 21). OPG is also expressed in synovial tissue obtained from the joints of RA patients suggesting a possible role in the pathogenesis of both atherosclerosis and RA (22).

Subsequently, we evaluated whether polymorphism rs2073618 in the exon I of the OPG gene affects plasma OPG levels and whether this polymorphism is associated with markers of subclinical carotid atherosclerosis in Egyptian Patients with Rheumatoid Arthritis

Patients and methods

Subjects

This cross-sectional study enrolled 80 patients with rheumatoid arthritis who were selected from the outpatient clinics and inpatient department of Rheumatology and Rehabilitation in Assiut University Hospitals.

In our study we had two groups of patients :

1. Group I: RA patients with atherosclerosis (no=38),
2. Group II: RA patients without atherosclerosis (no=42

Inclusion criteria:

• Participants are older than 18 years.
• All patients with RA were diagnosed and fulfilled American College of Rheumatology /European league against] rheumatism (ACR/EULAR) 2010 criteria for RA (23).

Exclusion criteria:

• Patients under the age of 18 years.
• Patients with definite diagnosis for any other systemic autoimmune disorders.
• Patients with a history of cardiovascular disease (previous stroke myocardial infarction or angina)

Clinical assessment

Every patient was subjected to the following:

• A) History taking including Age, sex, disease duration, history of the present illness, drug intake including steroids and calcium, past and family history of cardiovascular events, and risk factors for atherosclerosis (diabetes mellitus, smoking, hypertension, dyslipidemia).
• B) Physical examination including thorough clinical examination including:

1. Height and weight were measured and body mass index ( BMI) of the participants was calculated
2. Blood pressure was determined as the average of 2 measurements obtained 5 minutes apart after subjects had rested in the supine position for at least 10 minutes. Subjects were considered to have hypertension if they were taking antihypertensive agents or according to the latest version of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) recommendations(24).

• C)Activity of RA was defined by Disease Activity Score (DAS28 ) (25)
• D) Ability to perform activities of daily living was measured using the Modified Health Assessment Questionnaire (mHAQ)(26).

Laboratory assessment

including complete blood picture, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), High sensitive CRP(mg/L), plasma glucose, Liver function tests, Kidney function tests, rheumatoid factor titer, and anticyclic citrullinated peptide antibodies. A complete lipid profile was obtained with the measurement of total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides.

Human Osteoprotegerin (OPG) measurement

OPG ELISA (Enzyme-Linked-Immunosorbent Assay), SinoGeneClon Biotech Co Kit was used for the quantitative determination of OPG in serum samples, according to the manufacturer’s instructions.

The kit adopt purified OPG antibody to coat microtiter plate, make solid-phase antibody, was add OPG to wells, Combined OPG antibody with labeled HRP(horse radish peroxidase) to form antibody-antigen –enzyme antibody complex, after washing completely, add TMB(3,3,5,5 tetramethylbenzidin) substrate solution, TMB substrate becomes blue color at HRP enzyme-catalyzed, reaction is terminated by the addition of a stop solution and the color change is measured at a wavelength of 450 nm. The concentration of OPG by ng/L in the samples was determined by comparing the O.D.(optical density) of the samples to the standard curve.

Carotid artery ultrasonography:

The common carotid arteries were carefully examined for wall changes in all subjects, obtaining different longitudinal and transverse views with the high-resolution B-mode ultrasound equipment Logic P6 PRO GE healthcare. A region about 1.5 cm proximal to the carotid bifurcation was identified, and the intima-media thickness (IMT) of the far wall was evaluated as the distance between the luminal-intimal interface and the medial adventitial interface. One transverse and two longitudinal measurements of IMT were obtained from 4 contiguous sites at 2mm intervals, and the average of the 4 measurements were used for the analysis.

According to current sonographic criteria, we referred to ‘‘normal’’ IMT when complex intima-media is (0.9 mm). MIMT values> 0.9 mm were considered indicative of thickened intima (27).

Plaques were defined as focal widening relative to adjacent segments, with protrusion into the lumen of calcified or noncalcified material

All ultrasound measurements were performed by the same examiner who was unaware of the subject characteristics.

All these data were recorded for every patient in a separate sheet

Ethical consideration

The study was approved by the Institutional Ethics Committee Faculty of Medicine Assiut University. Also Informed consent was prepared by Arabic language prepared to be read by the participating patients or to read upon them if they were illiterate and then to be signed.

Statistical analyses

Data was collected and analyzed using SPSS (Statistical Package for the Social Science, version 20, IBM, and Armonk, New York). Continuous data was expressed in form of mean ± SD or median (range) while nominal data was expressed in form of frequency (percentage).

Chi²-test was used to compare the nominal data of different groups in the study while student t-test was used to compare mean of different two groups and ANOVA test for more than two groups in case of normally distributed data while Wilcoxon, Mann-Whitney, and Kruskal Wallis tests were used in case of not- normally distributed data. Person correlation was used to determine the correlation between OPG and other continuous variables.

Results

Demographic Data of Studied Groups:

As observed in Table1 Mean age of patients with rheumatoid arthritis (RA) and atherosclerosis was 56.64 ± 6.43 years, 89.5% of them were females, and 65.7% of them came from rural areas. The mean age of that patient with RA and without atherosclerosis was 51.78 ± 4.97 years, 90.5% of them were female and 64.3% of them came from rural areas.

Regarding smoking, four patients in each group were smokers. DM and HTN presented in 14 (36.8%) and 7 (18.4%) patients respectively of those with atherosclerosis, 16 (38.3%) and 10 (23.8%) patients respectively of those without atherosclerosis.

The mean body mass index in those patients with atherosclerosis was 26.01 ± 4.90 kg/m2 where 16 (42.1%) of them were normal weight and 14 (36.8%) were overweight respectively while mean body mass index in those patients without atherosclerosis was 28.50 ± 6.42 kg/m2 where 15 (35.7%) of them were normal weight and 10 (23.8%) overweight respectively. As regards the demographic data, all studied groups had no significant differences (P> 0.05).

Clinical Characteristics of Studied Patients:

Table 2 shows the clinical characteristic of studied patients. The mean duration of RA in those with patients with atherosclerosis was 14.08 ± 2.34 years and it was 11.10 ± 2.11 years in those patients without atherosclerosis. The onset of pain was chronic in majority of cases in both groups (in 65.8% of those with atherosclerosis and in 76.2% of those without atherosclerosis).

30 (78.9%) patients with atherosclerosis had morning stiffness with mean duration was 1.10 ± 0.66 hours while morning stiffness presented in 22 (52.4%) of patient without atherosclerosis with mean duration was 1.13 ± 0.58 hours. as regarding the swelling, patients with atherosclerosis had significantly higher feet swelling in comparison to those without atherosclerosis (19 (50%) vs. 10 (23.8%); P 0.03).

There were no significant differences between the studied patients as regarding the extra-articular manifestation.

As regarding systolic blood pressure and diastolic blood pressure, both groups had no significant differences. It was noticed that majority (39.5%) of studied group with atherosclerosis had stage II HTN while 76.2% of those without atherosclerosis had normal blood pressure.

Baseline Laboratory Data of Studied Groups:

All studied groups had no significant differences as regarding baseline laboratory data with exception of:

• Patients with atherosclerosis had significantly higher random blood sugar and higher CRP in comparison to those without atherosclerosis. ESR and HsCRP were significantly higher in both groups of RA.
• Patients with atherosclerosis had significantly higher LDL,, TG and cholesterol and lower HDL in comparison to those without atherosclerosis.
• Patients with atherosclerosis had significantly higher RF in comparison to those without atherosclerosis.(276.76 ± 45.67 vs. 217.91 ± 59.54; P= 0.03).
• It was noticed that level of Anti-CCP was higher in those patients with atherosclerosis in comparison to those without atherosclerosis but with no statistical significance (P= 0.06). Also, majority of studied patients either with or without atherosclerosis had positive Anti-CCP.

Therapeutic History in both Studied Patients:

The therapeutic history of studied patients was summarized at Table 6. Both groups had no significant differences as regarding types of drugs, duration of use and daily dose with exception duration of steroids and Salazopyrin were significantly higher in those with atherosclerosis.

Disease Activity in Studied Patients:

It was noticed that majority (52.6%) of patients with atherosclerosis had high disease activity while 10 (26.3%) and 8 (21.1%) of them had moderate and low disease activity. 5 (11.9%), 17 (40.5%) and 15 (35.7%) of patients without atherosclerosis had low, moderate and high disease activity respectively and 5 (11.9%) were on remission.

As regarding VAS (patients and doctor), and DAS (28ESR and 28CRP), both groups had no significant differences but patients without atherosclerosis had significantly lower MHAQ- DI in comparison to those with atherosclerosis (1.76 ± 0.43 vs. 1.92 ± 0.26; P= 0.04).

OPG titer and OPG (TNFRSF11B) genotypes in Studied Patients:

As regards OPG titer, RA patients with atherosclerosis had higher OPG levels in comparison to those without atherosclerosis (664.34 ± 74.56 vs. 633.34 ± 55.89; P= 0.03).

As regarding types of OPG genotypes, 15 (39.5%), 19 (50%), and 4 (10.5%) of patients with atherosclerosis had CC, CG, and GG genotypes respectively while 18 (42.9%), 20 (47.6%), and 4 (9.5%) of those without atherosclerosis had CC, CG, and GG mutations respectively. It was noticed that the two studied groups had no significant differences as regarding type of OPG genotypes. Also, the C allele was the most frequent allele in all groups.

Types of OPG genotypes and its Titre based on Carotid Atheroma:

It was noticed that OPG’s titre was significantly higher in patients with rheumatoid arthritis who had carotid atheroma in comparison to those without atheroma (684.45 ± 81.53 vs. 641.96 ± 106.65).

Demographic, Clinical, and Laboratory Data of Patients Based on Types of OPG’s Polymorphism:

Table 13 shows the demographic, clinical and laboratory data of studied patients base on OPG’s polymorphism. It was noticed that CC, CG and GG genotypes had no significant differences as regarding demographic, clinical and laboratory data with exception of:

• Patients with GG mutation had significant lower frequency of deformity
• ·RBS and CRP were significantly higher in those patients with CC mutation

Disease Activity, Anti-CCP, RF and OPG’s Titre in Studied Patients Based on OPG’s Polymorphism:

It was noticed that all genotypes of OPG in the current study had no significant differences as regarding disease activity, Anti- CCP, RF, OPG’s titre and sonographic findings with exception of patients with CC and CG mutations had significantly higher Anti- CCP in comparison t those with GG mutation.

Correlation between OPG’sTitre with Different Parameters in the Study:

It was noticed that OPG had insignificant correlation with different parameters in the current study with exception of positive significant correlation with intimal thickness (r=0.37; P= 0.01), RF (r=0.30; P= 0.03) and ACCP (r=0.33; P= 0.03).

Discussion

In our study we had two groups of patients

1. Group I: RA patients with atherosclerosis (no=38).
2. Group II: RA patients without atherosclerosis (no=42),.

All patients with RA were diagnosed and fulfilled American College of Rheumatology /European league against rheumatism (ACR/EULAR) 2010 criteria for RA

To the best of our knowledge, this is the first study to investigate the osteoprotegerin gene polymorphism rs2073618 as a potential marker of subclinical carotid atherosclerosis and RA in Egyptian population.

There were no statistically significant differences between rs2073618 GG, GC, CC genotypes nor G, C alleles among RA patients with atherosclerosis and those without atherosclerosis.

Serum OPG levels were significantly higher in rheumatoid arthritis patients with atherosclerosis (664.34 ± 74.56 ng/L) than patients without atherosclerosis (633.34 ± 55.89 ng/L) (P = 0.03). Also, serum OPG levels were significantly higher in patients with rheumatoid arthritis who had carotid atheroma in comparison to those who didn’t have an atheroma (684.45 ± 81.53 ng/L vs. 641.96 ng/L ± 106.65, P = 0.01).

However, no statistically significant difference could be detected upon comparing median values of serum OPG levels among studied genotype groups (neither genotype nor alleles). The GG genotype had a median level of serum OPG 646.37 ± 85 ng/L, the GC genotype had a median level of serum OPG 668.19 ± 93.02 ng/L, and the CC genotype had a median level of serum OPG 661.09 ± 54.89 ng/L. C allele had a median level of serum OPG 661.11 ± 54.11 ng/L, and the G allele had a median level of serum OPG 665.19 ± 76.89.

Serum OPG levels showed significant positive correlation with RF (r = 0.30, p = 0.03), ACPA (r = 0.33, p = 0.03) and CIMT (r = 0.37, p = 0.01).

Lopez-Mejias et al., 2015 enrolled 151 white Spanish patients who met the 1987 American College of Rheumatology and the 2010 American College of Rheumatology/European League against Rheumatism criteria for RA diagnosis. The aforementioned patients included 54 consecutive patients with established CVD and 97 age-matched and sex-matched cases without CVD. OPG concentrations were also determined in 62 control subjects without CVD.

In agreement with our results; their study showed that RA severity markers, including RF and anti-CCP positivity and erosive disease, were associated with high OPG concentrations. In patients with RA, age, body mass index (BMI), rheumatoid factor (RF) positivity status were significantly correlated with OPG concentrations [partial R (p) = 0.175 (0.03), –0.277 (0.0009), 0.323 (< 0.0001), 0.217 (0.008), and 0.159 (0.05), respectively].

OPG concentrations increased from 6.38 (3.46–9.31) to 7.07 (5.04–10.65) and 8.64 (6.00–11.52) ng/ml {Median (interquartile range)} in controls and RA patients without CVD and those who had CVD, respectively (p = 0.0002). Upon adjustment for age, sex, traditional risk factors, and BMI in mixed regression models, OPG concentrations remained lower in controls compared to patients with RA without CVD (p = 0.05) and in the latter compared to those with CVD (p = 0.03); the association of OPG concentrations with CVD among patients with RA also persisted after additional adjustment for RF and anti-CCP antibody positivity, and erosion status (p = 0.04) (28).

Morisawa et al., 2015 investigated 114 CAD patients (89 men, 25 women; with mean age of 68.7± 10.3 years) and measured the Gensini score (a marker of the extent of coronary atherosclerosis), the mean CIMT, and the plasma levels of OPG and asymmetric dimethylarginine (ADMA; as a marker of endothelial function).

In concordance with our results, Patients with early carotid atherosclerosis had higher OPG levels than those without. The OPG levels were found to be significantly associated with ADMA (r = 0.191, P = 0.046) and the mean CIMT (r = 0.319, P = 0.001), but not with the Gensini score(29).

Pleskovič et al., 2017 investigated whether polymorphism rs2073618 of the OPG gene is associated with subclinical markers of carotid atherosclerosis in subjects with type 2 diabetes mellitus; no statistically significant difference could be detected (p = 0.68) upon comparing median values of serum OPG levels among studied genotype groups when only subjects with type 2 DM were included in the analysis. The GG genotype had a median level of 73.26 (47.03–96) pg/ml, the GC genotype had a median level of 67.56 (44.26–90.43), and the CC genotype had a median level of 61.6 (47.63 -137.89) pg/ml which agrees with our results.

Also in the previous forementioned study; there was no significant difference among CC, CG, and GG genotypes nor C and G allele as regards assessment of CIMT and presence or absence of plaque.(30).

In a study by Soufi et al., 2004 a total of seven different OPG gene polymorphisms were identified in cohort of 468 male patients with or without CAD. Although none of these polymorphisms was associated with the presence of CAD separately which agree with our results, linkage of the 950 and 1181 polymorphisms exhibited a significantly different distribution in patients with CAD compared with patients without CAD. Genotypes 950 TC/1181 GC and 950 CC/1181 CC were overrepresented in men with CAD and were associated with an increased risk of CAD, suggesting that these genotypes may contribute to an increased susceptibility of atherosclerosis (13).

Chung et al., 2015 examined the association between selected genetic polymorphisms and coronary atherosclerosis in patients with RA. Genotypes for single-nucleotide polymorphisms (SNPs) in 152 candidate genes linked with autoimmune or cardiovascular risk were measured in 140 patients with RA. The association between the presence of coronary artery calcium (CAC) and SNP allele frequency was assessed by logistic regression with adjustment for age, sex, and race. 139 patients in whom rs2073618 genotypes were available, 37 (26.6%) had the CC, 62 (44.6%) the CG, and 40 (28.8%) the GG genotypes. Among RA patients with CC genotype, 75.7% had coronary calcium; as compared with 43.6% in those with CG genotype and with 37.5% in those with GG genotype (p = 0.001).

However, in a posthoc analysis examining the association of (rs2073618) genotypes and serum osteoprotegerin concentrations, differences were non-significant (18). Median (interquartile range, IQR) concentrations were 1548 (1042–2509), 1497 (1100–1698), and 1657 (1132–2105) pg/mL, respectively, (p = 0.38).

Genre et al., 2014 examined the role of three functional polymorphisms (rs3134063, rs2073618, and rs3134069) located in the gene encoding osteoprotegerin. The study showed a protective effect of the osteoprotegerin (OPG) CGA haplotype on the risk of cardiovascular disease in patients who were anti-CCP negative. Further examination of the role of individual SNPs suggested that the GG genotype in rs2073618 was associated with a significant reduction of cerebrovascular, but not cardiovascular events (31).

One study showed that the same polymorphism in the gene encoding osteoprotegerin, rs2073618, was associated with atherosclerosis in diabetic patients. The same CC genotype was associated with a three-fold increased risk of stroke in patients with diabetes (15) and the frequency was two-fold higher in patients who underwent carotid endarterectomy compared to control subjects. This last association was even stronger when the results were adjusted for age, sex, hypertension, hypercholesterolemia, diabetes, coronary artery disease, peripheral artery disease, and smoking (32).

Conclusion:

Limitations:

As our study sample size was relatively small, it could produce false-negative results, or it might underestimate the magnitude of the association. Our findings need to be evaluated in larger groups of different ethnicities. In an attempt to clarify the potential role of the OPG/RANKL/ RANK system in atherogenesis, it would have been beneficial to measure not only OPG but also RANKL and RANK serum levels. Interactions between genes of the OPG/RANKL/RANK axis and the development of carotid atherosclerosis remain to be investigated.

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)

Background

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

Introduction

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.

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.

Chronic Inflammation

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

Summary

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

1. MSD Manual Professional Version Atherosclerotic plaque formation. Abstract at https://www.msdmanuals.com/professional/cardiovascular-disorders/arteriosclerosis/atherosclerosis
2. 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
3. Science direct. Abstract at https://www.sciencedirect.com/science/article/abs/pii/S0188440915001241
4. 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
5. Pathophysiology of Atherosclerosis Michael A. Seidman, Richard N. MitchellJames R. Stone, 225-226
6. Atherosclerosis: a chronic inflammatory disease mediated by mast cells. Abstract at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655391/