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Atherosclerosis: Difference between revisions
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''Ronak Delewi, MD; Hayang Yang, MsC; John Kastelein, MD, PhD''<br /> [[File:atherosclerosis_damage.svg|thumb|400px|right|]] | |||
''Ronak Delewi, MD; Hayang Yang, MsC; John Kastelein, MD, PhD''<br /> | |||
''A 53 years old man, without medical history or drug use, shows up in the family physician’s room and makes an anxious impression. His friend has recently suffered from myocardial infarction (MI) and he is worried that he might also face the same situation soon. As for family medical history, he has a father with hypertension and an uncle with diabetes mellitus. He doesn’t seem to have any symptoms or complaints at this moment, but he has been smoking for 25 years and is overweight. Due to these characteristics he is worried of having a high risk of getting a MI. During the physical examination, his BMI was 29, RR was 152/90 mmHg and heart rate was 75 bpm. The family physician orders a blood test for lipid profile and glucose. Both turn out to be in the normal range. ''<br /> | |||
''The family physician gives the patient several advices concerning primary prevention for atherosclerosis; quit smoking, try to achieve weight reduction, do regular physical activity, restrict alcohol consumption to <10-30g/day and follow a varied and balanced diet. Regarding the hypertension, the advice is to keep his RR under 140/90 mmHg. Antihypertensive medication is not indicated at this moment, because his 10-years risk of death due to cardiovascular diseases (Systematic COronary Risk Evaluation) is lower than 20%. He is advised for regular checkups of cardiovascular risk profile or report to the doctor’s office in case of chest pain.''<br /> | |||
== History == | == History == | ||
Since the 20th century, cardiovascular diseases (CVD’s) have grown to be the leading cause of death and disability in the world, illustrated by 17.3 million deaths per year in 2008. Out of all cardiovascular diseases, coronary heart disease (46% among males, 38% among females) and cerebrovascular disease (34% among males, 37% among females) are accountable for the largest proportion of CVDs. In 2008, heart attack and stroke were responsible for 7.3 million deaths and 6.2 million deaths subsequently. Obstructive coronary and cerebrovascular disease are caused in most instances by atherosclerosis. It is a life-time illness that over time can eventually lead to obstructive disease. Once atherosclerotic lesions become clinically significant, serious acute complications such as ischemic heart disease, MI and stroke may occur. This chapter concerns the complex pathological process of atherosclerosis, possible consequences of atherosclerosis and the most recent treatment for atherosclerosis in order to prevent CVD’s. <br /> | |||
== | == Arterial vessel in homeostasis == | ||
The core of the pathogenesis of atherosclerosis is dysfunction of arterial vessels. In order to understand the pathogenesis of atherosclerosis, it is thus necessary to know about the functions and state of non-pathological arterial vessels.<br /> | |||
=== Three layers of arterial vessel === | === Three layers of arterial vessel === | ||
The normal arterial vessel consists of 3 layers, namely intima, media and outer adventitia.<br /> | |||
The intima is located closest to the arterial lumen and is therefore most ‘intimate’ with the blood. This layer is composed of a single layer of endothelial cells (endothelium), connective tissue, and several smooth muscle cells. The endothelium functions as an active metabolic barrier as well as a carrier between blood and the arterial wall. It plays a crucial role in atherosclerosis. Connective tissue consists of a matrix of collagen, proteoglycans and elastin. Lymphocytes, macrophages and other types of inflammatory cells may occasionally reside in the intima. <br /> | |||
The media is the middle layer and is bounded by the internal and external elastic laminae. The media consists of layers of smooth muscle cells with contractile and synthetic function. As for the contractile function, smooth muscle cells enable vasoconstriction and vasodilatation. As for the synthetic function, they are responsible for the growth of the vascular extracellular matrix.<br /> | |||
The most external vessel wall layer is called the adventitia and contains fibroblasts, connective tissue, nerves, lymphatics and vasa vasorum. Inflammatory cells may occasionally reside in the adventitia. <br /> | |||
There is a constant dynamic interchange between the arterial wall and its cellular components and the surrounding extracellular matrix. By learning the physiology of this dynamic interchange and the functions of each cellular component, the dysfunction of these cellular components leading to atherogenesis can be understood. <br /> | |||
=== Cellular components involved in atherosclerosis === | === Cellular components involved in atherosclerosis === | ||
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In conclusion, the normal arterial endothelium consists of a dynamic interface with net anticoagulant properties, net relaxation of smooth muscle cells and anti-inflammatory characteristics. Endothelial cells may react to various changes in homeostasis and become ‘activated endothelial cells’.<br /> | In conclusion, the normal arterial endothelium consists of a dynamic interface with net anticoagulant properties, net relaxation of smooth muscle cells and anti-inflammatory characteristics. Endothelial cells may react to various changes in homeostasis and become ‘activated endothelial cells’.<br /> | ||
==== Vascular smooth muscle cells ==== | |||
As mentioned earlier, smooth muscle cells have two functions, namely contractile and synthetic. Vasoconstriction and vasodilatation are regulated by various vasoactive substances such as angiotensin II, acetylcholine, NO and endothelin, which are released by endothelium. Another element of contractile function is the elasticity of the vessel, which is regulated by the lamina elastica. They are situated between the smooth muscle cells and are responsible for the stretching of the vessel during systole and diastole. This function is crucial in the pathogenesis of atherosclerosis, because it prevents the weakening of the vessel wall that can prevail as a complication of atherosclerosis. For example, aneurysm due to weakening of the vessel wall is a serious complication of atherosclerosis.<br /> | As mentioned earlier, smooth muscle cells have two functions, namely contractile and synthetic. Vasoconstriction and vasodilatation are regulated by various vasoactive substances such as angiotensin II, acetylcholine, NO and endothelin, which are released by endothelium. Another element of contractile function is the elasticity of the vessel, which is regulated by the lamina elastica. They are situated between the smooth muscle cells and are responsible for the stretching of the vessel during systole and diastole. This function is crucial in the pathogenesis of atherosclerosis, because it prevents the weakening of the vessel wall that can prevail as a complication of atherosclerosis. For example, aneurysm due to weakening of the vessel wall is a serious complication of atherosclerosis.<br /> | ||
It is important to understand the synthetic function of smooth muscle cells since the dysfunction of it is thought to contribute to the pathogenesis of atherosclerosis. Normally the smooth muscle cells synthesize collagen, elastin and proteoglycans that form the connective tissue matrix of the vessel wall. Smooth muscle cells can also synthesize vasoactive and inflammatory mediators such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF- α). These mediators stimulate leukocyte migration and induce the endothelial cells to express leukocyte adhesion molecules as mentioned earlier. This synthetic function is found to be more dominant in case of an atherosclerotic plaque, which is illustrated in the next section (1.2). Although smooth muscle cells rarely divide in normal circumstances, it can proliferate in response to injury, which is an important sign of atherosclerotic plaque formation. <br /> | It is important to understand the synthetic function of smooth muscle cells since the dysfunction of it is thought to contribute to the pathogenesis of atherosclerosis. Normally the smooth muscle cells synthesize collagen, elastin and proteoglycans that form the connective tissue matrix of the vessel wall. Smooth muscle cells can also synthesize vasoactive and inflammatory mediators such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF- α). These mediators stimulate leukocyte migration and induce the endothelial cells to express leukocyte adhesion molecules as mentioned earlier. This synthetic function is found to be more dominant in case of an atherosclerotic plaque, which is illustrated in the next section (1.2). Although smooth muscle cells rarely divide in normal circumstances, it can proliferate in response to injury, which is an important sign of atherosclerotic plaque formation. <br /> | ||
==== Extracellular matrix ==== | |||
Vascular extracellular matrix in the media consists of elastin, proteoglycans and fibrillar collagen, which are principally synthesized by smooth muscle cells as mentioned earlier. With the provision of flexibility by elastin and biomechanical strength by fibrillar collagen, the arterial vessel is able to maintain the structural integrity despite high pressure within the lumen.<br /> | Vascular extracellular matrix in the media consists of elastin, proteoglycans and fibrillar collagen, which are principally synthesized by smooth muscle cells as mentioned earlier. With the provision of flexibility by elastin and biomechanical strength by fibrillar collagen, the arterial vessel is able to maintain the structural integrity despite high pressure within the lumen.<br /> | ||
== 1.2 Arterial vessel with atherosclerosis == | |||
=== Three pathologic stages of atherogenesis === | |||
Atherogenesis can be divided into five key steps, which are 1) endothelial dysfunction, 2) formation of lipid layer within the intima, 3) migration of leukocytes and smooth muscle cells to the vessel wall, 4) foam cells formation and 5) degradation of extracellular matrix. Via these consecutive steps, an atherosclerotic plaque is formed. The formation of the plaque can also be divided into three major stages namely 1) the fatty streak, which represents the initiation 2) plaque progression, which represents adaption and 3) plaque disruption, which represents clinical complications of atherosclerosis.<br /> | Atherogenesis can be divided into five key steps, which are 1) endothelial dysfunction, 2) formation of lipid layer within the intima, 3) migration of leukocytes and smooth muscle cells to the vessel wall, 4) foam cells formation and 5) degradation of extracellular matrix. Via these consecutive steps, an atherosclerotic plaque is formed. The formation of the plaque can also be divided into three major stages namely 1) the fatty streak, which represents the initiation 2) plaque progression, which represents adaption and 3) plaque disruption, which represents clinical complications of atherosclerosis.<br /> | ||