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Atherosclerosis: Difference between revisions
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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 /> | 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 | 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. | ||
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| caption4 = Figure 4. Distribution of CVD death among females in 2008 | | caption4 = Figure 4. Distribution of CVD death among females in 2008 | ||
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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 | 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 diseases 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. | ||
== Arterial vessel in homeostasis == | == Arterial vessel in homeostasis == | ||
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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 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 | The media is the middle layer and is bounded by the internal and external elastic lamina. 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 /> | 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 /> | ||
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The normal artery wall contains endothelial cells that manage the homeostasis of the wall by structural, metabolic, and signaling functions. The endothelium plays a role as a barrier to elements contained in the blood, but is also an active biologic interface between the blood and other tissues, regulating cellular and nutrient trafficking. It has several important functions such as keeping certain elements in blood separated from the vessel and maintaining a balance between pro-coagulant and anticoagulant activity, pro- and anti-inflammatory response, and contracted and relaxed vasomotor tone.<br /> | The normal artery wall contains endothelial cells that manage the homeostasis of the wall by structural, metabolic, and signaling functions. The endothelium plays a role as a barrier to elements contained in the blood, but is also an active biologic interface between the blood and other tissues, regulating cellular and nutrient trafficking. It has several important functions such as keeping certain elements in blood separated from the vessel and maintaining a balance between pro-coagulant and anticoagulant activity, pro- and anti-inflammatory response, and contracted and relaxed vasomotor tone.<br /> | ||
The endothelium produces antithrombotic molecules in order to prevent blood from clotting. Certain molecules such as heparin sulfate, thrombomodulin, and plasminogen rest on the endothelial surface whereas molecules such as prostacyclin and | The endothelium produces antithrombotic molecules in order to prevent blood from clotting. Certain molecules such as heparin sulfate, thrombomodulin, and plasminogen rest on the endothelial surface whereas molecules such as prostacyclin and nitric oxide (NO) enter the blood. Endothelium can produce prothrombotic molecules when it encounters stressors; however, it normally maintains a balanced anticoagulant state, maintaining blood fluidity.<br /> | ||
Endothelial cells also have an important function as a regulator of the immune response. In a normal situation without pathologic stimuli, endothelial cells are not capable to halt and bind patrolling leukocytes, thus maintaining an anti-inflammatory state. When local injury or infection initiates pathologic stimulation, endothelial cells respond by secreting chemokines that attract white blood cells to the injured area. Additionally, endothelium produces cell surface adhesion molecules, which recruit mononuclear cells to the endothelium and therefore promote their migration to the injury site. This response is important to the development of atherosclerosis.<br /> | Endothelial cells also have an important function as a regulator of the immune response. In a normal situation without pathologic stimuli, endothelial cells are not capable to halt and bind patrolling leukocytes, thus maintaining an anti-inflammatory state. When local injury or infection initiates pathologic stimulation, endothelial cells respond by secreting chemokines that attract white blood cells to the injured area. Additionally, endothelium produces cell surface adhesion molecules, which recruit mononuclear cells to the endothelium and therefore promote their migration to the injury site. This response is important to the development of atherosclerosis.<br /> | ||
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Another function of endothelium is to modulate contraction of smooth muscle cells in the media by releasing substances such as vasodilators and vasoconstrictors. Vasodilators (e.g. NO, prostacyclin) and vasoconstrictors (e.g. endothelin) fine-tune the resistance of the vessel and subsequently alter the arterial blood flow. Endothelium normally maintains a state of net relaxed vasomotor tone with the predominance of vasodilators. Endothelium can also respond to various physical stimuli such as shear stress and can additionally dilate the blood vessel. The endothelium principally regulates such response through release of NO. This endothelial-dependent response is called flow-mediated vasodilation (FMD), which can be measured for clinical evaluation of endothelial function. For example, impairment of FMD is observed in the early stages of atherosclerosis. However, endothelial function tests are currently not recommended to be used for surrogate markers in clinical practice since the tests are technically challenging and the validation of clinical benefits in the evaluation of cardiovascular risk requires more evidence.<br /> | Another function of endothelium is to modulate contraction of smooth muscle cells in the media by releasing substances such as vasodilators and vasoconstrictors. Vasodilators (e.g. NO, prostacyclin) and vasoconstrictors (e.g. endothelin) fine-tune the resistance of the vessel and subsequently alter the arterial blood flow. Endothelium normally maintains a state of net relaxed vasomotor tone with the predominance of vasodilators. Endothelium can also respond to various physical stimuli such as shear stress and can additionally dilate the blood vessel. The endothelium principally regulates such response through release of NO. This endothelial-dependent response is called flow-mediated vasodilation (FMD), which can be measured for clinical evaluation of endothelial function. For example, impairment of FMD is observed in the early stages of atherosclerosis. However, endothelial function tests are currently not recommended to be used for surrogate markers in clinical practice since the tests are technically challenging and the validation of clinical benefits in the evaluation of cardiovascular risk requires more evidence.<br /> | ||
As mentioned earlier, endothelial cells can respond to or in other words get ‘activated’ due to changes in the local extracellular milieu. Examples of such changes are common stresses (e.g. shear stress and mild changes in temperature), transient infections and minor trauma. The term ‘endothelial cell activation’ (EC activation) refers to a change from the normal state, illustrated by loss of barrier function, pro-adhesive (leukocyte adhesion), | As mentioned earlier, endothelial cells can respond to or in other words get ‘activated’ due to changes in the local extracellular milieu. Examples of such changes are common stresses (e.g. shear stress and mild changes in temperature), transient infections and minor trauma. The term ‘endothelial cell activation’ (EC activation) refers to a change from the normal state, illustrated by loss of barrier function, pro-adhesive (leukocyte adhesion), vasoconstriction, and procoagulant properties. EC activation is not necessarily linked to disease and can be temporary and mild or permanent and severe.<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 /> | 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 /> | ||
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==== ''Smooth muscle cell migration'' ==== | ==== ''Smooth muscle cell migration'' ==== | ||
Smooth muscle cells play a central role at the phase of transition from fatty streak to plaque formation. During this phase, smooth muscle cells migrate from the media to the intima. After the migration, smooth muscle cells proliferate within the intima and secrete extracellular matrix macromolecules. Additionally, foam cells, activated platelets and endothelium stimulate substances that | Smooth muscle cells play a central role at the phase of transition from fatty streak to plaque formation. During this phase, smooth muscle cells migrate from the media to the intima. After the migration, smooth muscle cells proliferate within the intima and secrete extracellular matrix macromolecules. Additionally, foam cells, activated platelets and endothelium stimulate substances that induce the migration and accumulation of smooth muscle cells. For example, foam cells release platelet derived growth factor (PDGF), cytokines and growth factors that directly contribute to the migration and proliferation process, and they also activate smooth muscle cells and leukocytes to reinforce inflammation in the atherosclerotic lesion. Although plaque progression is traditionally known as a gradual and continuous process, recent evidence claims that this process can be strongly accentuated by bursts of smooth muscle replication. The observation of small ruptures within the plaque occurring without any clinical symptoms or signs supports this suggestion. These small ruptures expose tissue factor secreted by foam cells that stimulates coagulation and microthrombus formation in the lesion. Such microthrombus contains activated platelets that release additional factors such as PDGF and heparinase that can further stimulate local smooth muscle cell migration and proliferation. Heparinase stimulates smooth muscle cell migration and proliferation by degrading heparin sulfate, which normally counteracts this process.<br /> | ||
==== ''Extracellular matrix metabolism'' ==== | ==== ''Extracellular matrix metabolism'' ==== | ||
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* Diabetes Mellitus | * Diabetes Mellitus | ||
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Recent studies have shown that atherosclerosis is not just the inevitable process of aging, but also a process with many modifiable components. A worldwide INTERHEART study has established the importance of nine potentially modifiable risk factors for atherosclerosis, which account for over 90% of the population-attributable risk of a first MI (figure 12). A variety of non-modifiable risk factors such as advanced age, gender and hereditary coronary heart disease are important to recognize in patients with atherosclerosis. Recently the role of several biological markers associated with the development of cardiovascular events | Recent studies have shown that atherosclerosis is not just the inevitable process of aging, but also a process with many modifiable components. A worldwide INTERHEART study has established the importance of nine potentially modifiable risk factors for atherosclerosis, which account for over 90% of the population-attributable risk of a first MI (figure 12). A variety of non-modifiable risk factors such as advanced age, gender and hereditary coronary heart disease are important to recognize in patients with atherosclerosis. Recently, the role of several biological markers associated with the development of cardiovascular events is accentuated since one out of five cardiovascular events occurs in patients lacking the earlier mentioned risk factors. <br /> | ||
=== Common risk factors === | === Common risk factors === | ||
==== ''Dyslipidemia'' ==== | ==== ''Dyslipidemia'' ==== | ||
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* Reduce the intake of refined sugars and replace them with complex sugars from fruits, vegetables, and grain products | * Reduce the intake of refined sugars and replace them with complex sugars from fruits, vegetables, and grain products | ||
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Incidence of atherosclerosis and coronary artery disease increases with higher levels of LDL particles. As mentioned earlier, LDL can accumulate in the intima of the artery in excess proportions and undergo chemical modifications that activate endothelial cells to proceed to atherosclerosis. When people generally refer to | Incidence of atherosclerosis and coronary artery disease increases with higher levels of LDL particles. As mentioned earlier, LDL can accumulate in the intima of the artery in excess proportions and undergo chemical modifications that activate endothelial cells to proceed to atherosclerosis. When people generally refer to ‘bad cholesterol’, they are referring to LDL particles. On the other hand, high level of high-density lipoprotein (HDL) is ‘good cholesterol’ since it protects against atherosclerosis by reversing the cholesterol transport from peripheral tissues to the liver for disposal and functions as an antioxidant. In order to give additional clearance to what is ‘bad cholesterol,’ all lipid and lipoprotein abnormalities that are associated with higher coronary risk will be named subsequently: increased total cholesterol, increased LDL-cholesterol, low HDL-cholesterol, elevated total-to-HDL-cholesterol ratio, hypertriglyceridemia, increased non-HDL-cholesterol, elevated lipoprotein A, elevated apolipoprotein B (apo B is primarily found in LDL), decreased apolipoprotein A-I (apo A-1 is found in HDL), small and dense LDL particles, and several genotypes of apolipoprotein E (apoE influences cholesterol and triglyceride levels as well as the risk of coronary heart disease).<br /> | ||
There are several causes to persistent elevated level of LDL, such as high fat consumption or genetic abnormalities (e.g. familial hypercholesterolemia). Familial hypercholesterolemia is a condition with genetically defected LDL receptors that cannot efficiently dispose LDL from the circulation. There are two types of this disease with different manifestations. Patients with the heterozygote type have only one defective gene for the receptor and suffer from high serum level of LDL, easily developing atherosclerosis. Homozygotes have a complete lack of normal LDL receptors and thus may experience cardiovascular events already in the first decade of life. In the absence of genetic abnormalities, the quantity of cholesterol in serum is strongly related to the high saturated fat consumption.<br /> | There are several causes to persistent elevated level of LDL, such as high fat consumption or genetic abnormalities (e.g. familial hypercholesterolemia). Familial hypercholesterolemia is a condition with genetically defected LDL receptors that cannot efficiently dispose LDL from the circulation. There are two types of this disease with different manifestations. Patients with the heterozygote type have only one defective gene for the receptor and suffer from high serum level of LDL, easily developing atherosclerosis. Homozygotes have a complete lack of normal LDL receptors and thus may experience cardiovascular events already in the first decade of life. In the absence of genetic abnormalities, the quantity of cholesterol in serum is strongly related to the high saturated fat consumption.<br /> | ||
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Inhibiting HMG-CoA reductase results into several mechanisms that explain the beneficial effect of using statins. One beneficial mechanism is via lowering LDL and raising HDL. This results into less lipid content in atherosclerotic plaques and improve their biologic activity. Furthermore, anti-thrombotic and anti-inflammatory condition is enhanced by other mechanisms such as increased NO synthesis and fibrinolytic activity, inhibition of smooth muscle proliferation and monocyte recruitment, and reduced production of matrix-degrading enzymes by macrophages. Several studies suggest that other mechanisms also contribute to anti-inflammatory condition. For example, statins reduce endothelial expression of leukocyte adhesion molecules and macrophage tissue factor production by inhibiting the macrophage cytokines or by activating PPAR-α. Another anti-inflammatory action of statins, supported by clinical trials is reducing the serum level of C-reactive protein, which is a marker of inflammation. <br /> | Inhibiting HMG-CoA reductase results into several mechanisms that explain the beneficial effect of using statins. One beneficial mechanism is via lowering LDL and raising HDL. This results into less lipid content in atherosclerotic plaques and improve their biologic activity. Furthermore, anti-thrombotic and anti-inflammatory condition is enhanced by other mechanisms such as increased NO synthesis and fibrinolytic activity, inhibition of smooth muscle proliferation and monocyte recruitment, and reduced production of matrix-degrading enzymes by macrophages. Several studies suggest that other mechanisms also contribute to anti-inflammatory condition. For example, statins reduce endothelial expression of leukocyte adhesion molecules and macrophage tissue factor production by inhibiting the macrophage cytokines or by activating PPAR-α. Another anti-inflammatory action of statins, supported by clinical trials is reducing the serum level of C-reactive protein, which is a marker of inflammation. <br /> | ||
Although statin therapy can reduce the risk of atherosclerotic cardiovascular disease by about one third, there is still | Although statin therapy can reduce the risk of atherosclerotic cardiovascular disease by about one third, there is still a need for additional risk-reducing therapies. Thus, a new idea was developed to raise HDL cholesterol as a treatment for atherosclerosis. With the finding of the high-HDL phenotype of a human genetic deficiency of cholesteryl ester transfer protein (CETP), a new class of drugs was developed, which inhibits CETP. CETP functions as a mediator for transfer of cholesteryl ester from HDL to VLDL/LDL, which is then cleared by LDL receptors in liver. Thus when CETP is inhibited, this transfer process is inhibited and the direct hepatic HDL clearance pathway takes over. This leads to less fractional clearance of HDL from plasma, which is beneficial for atherosclerosis. Although the absolute clearance rate of HDL remains the same, the key step for atherosclerosis, which is the removal of cholesterol from macrophage foam cells in artery wall by HDL, is reduced. <br /> | ||
The most recently investigated CETP inhibitors are torcetrapib, anacetrapib, and dalcetrapib. In the Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events (ILLUMINATE) trial, involving 15,000 patients at high risk for coronary heart disease, torcetrapib was clinically investigated. Unfortunately this trial was prematurely stopped due to the finding of an increase in cardiovascular events associated with its use. Anacetrapib and dalcetrapib are still under active clinical investigation, since they differ in their mechanism of working from torcetrapib.<br /> | The most recently investigated CETP inhibitors are torcetrapib, anacetrapib, and dalcetrapib. In the Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events (ILLUMINATE) trial, involving 15,000 patients at high risk for coronary heart disease, torcetrapib was clinically investigated. Unfortunately this trial was prematurely stopped due to the finding of an increase in cardiovascular events associated with its use. Anacetrapib and dalcetrapib are still under active clinical investigation, since they differ in their mechanism of working from torcetrapib.<br /> | ||
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Tobacco smoking can lead to many mechanisms that contribute to atherosclerosis. Smoking is related with increased LDL level, decreased HDL level in blood and elevated insulin resistance. In addition it enhances oxidative modification of LDL by releasing free radicals and reduces generation of nitric oxide. This can promote endothelial dysfunction and thus lead to impairment of vasodilatation of coronary arteries and reduction of coronary flow reserve even in passive smokers. Tobacco smoking inappropriately stimulates sympathetic nervous system, increasing heart rate, blood pressure and perhaps coronary vasoconstriction. Smoking promotes prothrombotic environment through inhibition of endothelial release of tissue plasminogen activator, elevation of fibrinogen concentration in blood, enhancement of platelet activity (possibility related to sympathetic activation) and enhanced expression of tissue factor. Smoking can even damage the vessel wall and ultimately cause reduction of elasticity in vessel, enhancing the stiffness of vessel wall. Smoking has been associated with increased C-reactive protein and fibrinogen, suggesting correlation with inflammatory response, which is an important part of atherogenesis. There have also been findings that show higher expression of leukocyte adhesion molecules among smokers than nonsmokers. An elevation of homocysteine, an important biomarker of atherosclerosis has been associated with smoking. Smoking may additionally induce tissue hypoxia through displacement of oxygen with carbon monoxide in hemoglobin. <br /> | Tobacco smoking can lead to many mechanisms that contribute to atherosclerosis. Smoking is related with increased LDL level, decreased HDL level in blood and elevated insulin resistance. In addition it enhances oxidative modification of LDL by releasing free radicals and reduces generation of nitric oxide. This can promote endothelial dysfunction and thus lead to impairment of vasodilatation of coronary arteries and reduction of coronary flow reserve even in passive smokers. Tobacco smoking inappropriately stimulates sympathetic nervous system, increasing heart rate, blood pressure and perhaps coronary vasoconstriction. Smoking promotes prothrombotic environment through inhibition of endothelial release of tissue plasminogen activator, elevation of fibrinogen concentration in blood, enhancement of platelet activity (possibility related to sympathetic activation) and enhanced expression of tissue factor. Smoking can even damage the vessel wall and ultimately cause reduction of elasticity in vessel, enhancing the stiffness of vessel wall. Smoking has been associated with increased C-reactive protein and fibrinogen, suggesting correlation with inflammatory response, which is an important part of atherogenesis. There have also been findings that show higher expression of leukocyte adhesion molecules among smokers than nonsmokers. An elevation of homocysteine, an important biomarker of atherosclerosis has been associated with smoking. Smoking may additionally induce tissue hypoxia through displacement of oxygen with carbon monoxide in hemoglobin. <br /> | ||
Quitting smoking is known as one of the most effective preventive measures of CVD and their complications. Soon after the cessation cardiac | Quitting smoking is known as one of the most effective preventive measures of CVD and their complications. Soon after the cessation cardiac risks due to smoking decrease in a short period, and continue to diminish when cessation is permanently preserved. The risk for cardiovascular diseases among patients with coronary heart disease, cessation of smoking decreases the risk of cardiac events by 7-47%. Not only does cessation of smoking reduce risk of CVD, but also substantially reduce the risk of all-cause mortality.<br /> | ||
==== ''Lack of physical activity'' ==== | ==== ''Lack of physical activity'' ==== | ||