Atherosclerosis - Research Paper Example

Atherosclerosis is a disease in which the integrity of the arteries are compromised through the fatty deposits that occur in the form of plaque in the walls of the artery, narrowing the lumen of the arteries and hindering or blocking the flow of blood in the arteries. The consequences of this blockage could be fatal leading to atherosclerosis being a major cause of mortality and morbidity around the world. World Health Organization estimates show that 17.5 million people died from the consequences of atherosclerosis around the world in 2005 and this figure is expected to rise to 20 million by the year 2015. The lesions of atherosclerosis start with fatty deposits and gradually develop into complicated lesions. The progressive development of atherosclerotic is classified into six types with increasing effect of compromising the function of the arteries. The first four types of the atherosclerotic lesions do not produce clinical symptoms, while the fourth and fifth type produces clinical symptoms. These clinical symptoms are dependent on the site of compromise of the integrity of the artery. The metabolism of lipids and their serum levels, body fat, obesity, infections and inflammations have a role to play in the development of atherosclerosis and are high risk factors for the development of atherosclerosis. In addition gender, heredity, diseases related to diet like metabolic syndrome, and life style are all factors that contribute to the development of atherosclerosis by themselves or in conjunction with the other factors. Two mechanisms are involved in the pathophysiology of atherosclerosis consisting of chronic endothelial injury and elevated lipid levels. Risk factors like infection, inflammation, and smoking can lead to epithelial injury and elevated lipid levels encourage formation of plaque loaded with lipids and initiate the formation of clot or thrombus. The formation of thrombus can lead to a total blocking of the lumen of the artery, which clinically manifests itself in different ways, depending on the location of the blockage, Occlusion in the arteries that supply blood to the heart manifest as myocardial infarction, while in the case of occlusion in the arteries supplying blood to the brain manifests as a stroke or a cerebrovascular event. Infarctions in the liver and kidneys through similar mechanisms impair their functions. The impaired blood flow as a result of the occlusion, if not reversed immediately can lead to ischemia of the involved tissues and death of the tissues, Pharmacological interventions in the treatment of atherosclerosis can be classified into five, based on the strategy of the intervention. Cholesterol lowering drugs target the reduction of low-density lipoprotein (LDL) component in the cholesterol profile. The cholesterol lowering drugs used are the statins and the fibrates. Anti-platelet drugs like aspirin attempt to prevent the clumping of platelets in narrowed arteries to form a clot. Anti-coagulants are used to thin the blood as a means of preventing the formation of clots. Drugs that target the reduction of blood pressure, like beta-blockers, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors have the beneficial effect of retarding the progress of atherosclerosis. The other drugs target various risk factor conditions like type-2 diabetes to manage the condition and thereby reduce the risk for atherosclerosis. Atherosclerosis 1. Introduction and Pathology Timby and Smith 2006, p.469, define atherosclerosis as “a condition in which the lumen of the arteries fill with fatty deposits (chiefly composed of cholesterol) called plaque”. (1). In spite of a better understanding of the disease processes involved in atherosclerosis and the advances of medical, atherosclerosis still remains a disease of considerable concern with it being a major cause of morbidity and mortality, with particular reference to the countries of the developed world including the United States of America (2). Atherosclerosis along with atheroma and arteriosclerosis are terms that apply to the lesions found that occur in the coronary and other arteries and compromise the lumen of the arteries. The hardening of the arteries can be differentiated into three different types of lesions namely Monckberg’s medial calcification that does not result in narrowing of the lumen of the arteries; arteriosclerosis a disease of the small blood vessels; and atherosclerosis, which is responsible for almost ninety-nine percent of the ischemic heart disease, and therein lies the importance of atherosclerosis. The term atherosclerosis was provided by Marchand in 1904 to differentiate and emphasize the presence of lipids in some of the arteriosclerotic plaques. In human beings lesions in the epicardial coronary arteries generally contain lipids. (3). The traditional classification of atherosclerosis has been into three basic types of lesions consisting of the fatty streak, which is a flat or slightly elevated lesion that contains lipid-laden macrophages and smooth muscle cells; the fibrous plaque, which is an elevated lesion, wherein the lipid-laden cells are and extra-cellular lipids are covered with collagen, elastic fibers, and inflammatory cells, and are normally not associated with any significant clinical disease; and the complicated plaque, which is an altered fibrous plaque along with hemorrhage, hematoma, thrombosis, calcification, and cell necrosis. It is the complicated plaque that was traditionally associated with medial thinning and inflammation of all vascular layers of the walls of the artery, leading to narrowing of the lumen. (3). . A new classification for atherosclerosis was approved by the American Heart Association Scientific Council, which is based on the structure and composition of the lesions involved and is reflective of the natural history of the disease. In this new classification there are six types of lesions denoted as Type I to Type VI. Type I to Type III are considered as early precursor lesions, while Type IV to Type VI are advanced lesions in which there is distinct disruption of the intima as a result of an abundance in extra-cellular lipid that forms a lipid core. At the sites where atherosclerosis tends to develop the intima is found to be thickened from fibro-muscular tissue, elastic fibers, and proteoglycans. The Type IV lesion is of interest as though it may be small and non-occlusive, it has a tendency to rupture and lead to complete thrombotic arterial occlusion. The Type V lesion is typified by a significant increase in the quantum of collagen in the presence or absence of calcification. Type VI is the complicated lesion that is characterized by disruption of the surface, hematoma, hemorrhage, or thrombosis. (3). Irrespective of whether the occurrence takes place in Type IV or Type V lesions, there is general acceptance that erosions of plaque and fissures or tears with overlying microscopic mural thrombosis leads to complications in the stable long present coronary atherosclerotic plaques, resulting in acute ischemic events that could with the likelihood of death. Rupture of the plaque that develops into occlusive thrombosis has the most critical clinical significance, as it is responsible for most of the acute fatal coronary events, acute myocardial infarction, and sudden death. (2). Table – 1 Flow Chart of Pathways in the Evolution and Progression of Atherosclerotic Lesions Nomenclature and Main Histology Sequence in Progression Main Growth Mechanism Earliest Onset Clinical Correlation Type I lesion isolated macrophage foam cells I leading to II Growth mainly by lipid accumulation From first decade Clinically silent Type II fatty streak lesion II leading to III Growth mainly by lipid accumulation From first decade Clinically silent Type III intermediate lesion III leading to IV Growth mainly by lipid accumulation From third decade Clinically silent Type IV atheroma lesion !V leading to V and VI Growth mainly by lipid accumulation From third decade Clinically silent or overt Type V fibro atheroma lesion V leading to VI Accelerated smooth muscle and collagen increase From fourth decade Clinically silent or overt Type VI complicated lesion Thrombosis, hematoma From fourth decade Clinically silent or overt (3) 2. Etiology Research into the atherosclerosis has lead to the understanding that the metabolism of lipids and their serum levels, body fat, obesity, infections and inflammations have a role to play in the development of atherosclerosis and are high risk factors for the development of atherosclerosis. (1). Hyperlipidemia or high levels of fat in the blood are responsible for atherosclerotic changes associated with atherosclerosis. Gender, heredity, diseases related to diet like metabolic syndrome, and life style are all factors that contribute to the development of atherosclerosis by themselves or in conjunction with the other factors. There is growing belief that prior infections due to Chlamdyia pneumonia is linked to the development of atherosclerosis. Such a hypothesis stems from studies into Chlamdyia pneumonia, which is a bacterium found to frequently cause respiratory tract infections that show the possibility of Chlamdyia pneumonia infecting smooth muscles and endothelial cells of the arterial walls accompanied by evidence that such infections promote the development of atherosclerosis. Inflammation is also implicated in the development of atherosclerosis, as evidence from studies suggest that there is an association between the level of body fat and the production of inflammation inflammatory and clot-facilitating proteins. Fatty tissues can cause the release of the pro-inflammatory proteins of interleukin 6, tumor necrosis factor-alpha, and plasminogen activator inhibitor-1. Life style factors that are associated with the development atherosclerosis include smoking and lack of physical activity, as these factors promote the hardening of the walls of the arteries. It is therefore safe to conclude that there are multiple factors involved in the etiology of atherosclerosis. An individual with elevated lipid levels in association with one or more of the other factors of smoking, or lack of physical activity, or stressful life, or obesity, or type 2 diabetes, hypertension, or a previous infection with micro-organisms like Chlamdyia pneumonia is at high risk for the development of atherosclerosis. (1). 3. Epidemiology The study of the epidemiology of atherosclerosis cannot be done in isolation of its consequences, as the presence of atherosclerosis is usually detected when its clinical manifestations appear in the form of its consequences. The consequences of atherosclerosis have been classified broadly as cardiovascular diseases and comprise of coronary heart disease, cerebrovascular disease and other circulatory disorders. (4). Cardiovascular disease is the most common cause of death in the modern world. Prior to the twentieth century infectious diseases and malnutrition were the responsible for the most number of deaths, and cardiovascular diseases contributed to less than ten percent of the global deaths. In the modern world cardiovascular disease has risen to cause nearly thirty percent of mortality in the world, with a bias to the developed world, where it accounts for almost forty percent of mortality, compared to twenty-eight percent in the developing world. (5). According to the World Health Organization (WHO) estimates nearly 17.5 million people died as a result of cardiovascular disease in 2005, of which 7.6 million were as a result of coronary heart disease and 5.7 million from stroke. Mortality as a result of cardiovascular disease is expected to rise to approximately twenty million by 2015, and the bias in favor of the developed world lessened due to the increasing trends of western lifestyles in the developing world. (6). In the United States of America it was estimated that eight million people had some from of cardiovascular disease in 2006. In 2005 cardiovascular disease claimed the lives 864, 480 people, making up 35.3 % of all mortality and proving to be the leading cause of death in the United States of America. (7). 4. Pathophysiology The pathophysiology of atherosclerosis is essentially associated with the formation of plaque that leads to reduction in the flow of blood in the arteries and initiates the formation of clot or thrombus. The formation of thrombus can lead to a total blocking of the lumen of the artery, which clinically manifests itself in different ways, depending on the location of the blockage, Occlusion in the arteries that supply blood to heart the manifest as myocardial infarction, while in the case of occlusion in the arteries supplying blood to the brain manifests as a stroke or a cerebrovascular event. Infarctions in the liver and kidneys through similar mechanisms impair their functions. The impaired blood flow as a result of the occlusion, if not reversed immediately can lead to ischemia of the involved tissues and death of the tissues, and quite resulting in damage to the organ beyond its ability to repair the damage. (8). Two mechanisms are believed to be involved in the pathophysiology of atherosclerosis consisting of chronic endothelial injury and elevated lipid levels. The epithelial lining of blood vessels can get damaged from a variety of causes like smoking, hypertension, microbial infection, abuse of drugs, and underlying disease. This loss of vascular endothelium in combination to the enhanced adhesion of platelets to the sub-endothelium brings about aggregation of platelets, along with chemotaxis of monocytes and T-lymphocytes at the site of the endothelial damage. Once this occurs platelet-derived and monocyte-derived growth factors are released that causes migration of the smooth muscle cells into the site of injury. This results in plaque formation that is loaded with lipids. Oxidative stress has been found to be a significant causative mechanism that is responsible for chronic endothelial injury, which then triggers several responses. Among these responses the oxidation of lipids is important, as it manifests in the form of atherosclerosis. (8). Pharmacological Interventions to Treat Atherosclerosis Pharmacological interventions in the treatment of atherosclerosis can be classified into five, based on the strategy of the intervention. Cholesterol lowering drugs target the reduction of low-density lipoprotein (LDL) component in the cholesterol profile and through that prevent or even reverse the accumulation of fatty deposits in the arteries. The cholesterol lowering drugs used are the statins and the fibrates. Anti-platelet drugs like aspirin attempt to prevent the clumping of platelets in narrowed arteries to form a clot and thereby increase the blockage of the artery. Anti-coagulants are used to thin the blood as a means of preventing the formation of clots. Drugs that target the reduction of blood pressure, like beta-blockers, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors have the beneficial effect of retarding the progress of atherosclerosis. The other drugs target various risk factor conditions like type-2 diabetes to manage the condition and thereby reduce the risk for atherosclerosis. (9). The pharmacokinetics of statins involves it being metabolized into active and inactive metabolites, which are excreted through the renal system. The pharmacological activity of statins is essentially based on the kinetic profile of the active metabolites. Almost all of the statins demonstrate very low bioavailability, because of the extensive first pass effect seen at the intestine or at the hepatic level. This kinetic aspect is suitable for the function of statins in atherosclerosis, as the liver is the principal target organ for the action of the statins. The several statins are essentially differentiated in the degree to which they are metabolized and the number of active and inactive metabolites. (10). A major portion of cholesterol that is present in the circulatory system does not enter by direct means from the digestive system. Instead they come from the smooth endoplasmic reticulum, where they are synthesized as a result of a set of chemical reactions catalyzed by HMG CoA reductase at one point in the chemical reaction. This suggests a way in which the amount of cholesterol circulating in the blood can be reduced, and that is the blocking of the synthesis of cholesterol through the interruption of the conversion of HMG CoA to mevalonate and the subsequent generation of cholesterol. Please see Figure – 1. For HMG CoA to be converted to mevalonate, the catalytic action of HMG CoA reductase is essential. The inhibition of HMG CoA reductase means that mevalonate cannot be produced and hence cholesterol cannot be synthesized. This is the principal mode of action or pharmacodynamics of the group of medicines the HMG CoA reductase inhibitors, which are also known as the statins. (11). Figure – 1 Putting HMG CoA Reductase Inhibitors Into Action (11). There are several oral anti-platelet agents available and they target one or more of the pathways in hemostatic cascade in their mode of action. Please see Figure – 2. Figure – 2 Anti platelet Agents Mode of Action (“Platelet interactions with agonists and antagonists of platelet aggregation, the vessel wall, other platelets, and adhesive macromolecules. Agents in parentheses prevent the formation or inhibit the function of the adjacent agonists of platelet aggregation. ADP = adenosine diphosphate, VWF = von Willebrand factor, cAMP = cyclic adenosine monophosphate, GP = glycoprotein”. (12). Aspirin is administered orally and it is quickly absorbed from the stomach and the proximal small intestine. The rate of its absorption is dependent on the stomach content, the disintegration rate of the ingested aspirin, and the gastric pH level. During absorption aspirin gets hydrolyzed into salicylic acid, which is carried to various parts of the body, with higher concentrations in the liver, heart, lungs, liver, renal cortex and plasma. Salicylate and the metabolites are quickly excreted through the renal pathway by both filtration and renal tubular secretion. (13). The pharmacodynamics of aspirin cab be briefly summed as aspirin acts through the irreversible acetylating of the enzyme cyclooxygenase (COX). There are two isoforms for COX, namely COX-1 and COX-2. Aspirin is selective in its inhibition of the COX isoforms in that it selectively inhibits COX-1. The anti-platelet activity of aspirin is the result of the selective inhibition of COX-1. (12). The pharmacodynamic effect of the anticoagulant heparin is through enhancing the inhibition of antithrombin on the activated clotting factors like thrombin. Of these clotting factors thrombin is the most responsive to the action of heparin. Pharmacokinetics of heparin essentially consists of it not being absorbed into the body through the gastrointestinal tract, and this makes it necessary for heparin to be administered intravenously or subcutaneously. Heparin acts very quickly, but its duration of action is short, thus it is administered either as a continuous intravenous infusion or multiple daily doses through the subcutaneous route. (14). Conclusion Atherosclerosis compromises the integrity of the lumen of the arteries, inhibiting the smooth circulation of blood. The pathophysiology of atherosclerosis is essentially associated with the formation of plaque that leads to reduction in the flow of blood in the arteries and initiates the formation of clot or thrombus. Depending on where the blockage and the resulting ischemia occurs tissues in the major organs of the body can be seriously damaged leading to fatal consequences. This makes atherosclerosis a major cause for mortality. The increased knowledge of the pathophysiology of atherosclerosis has led to the development of pharmacological interventions that have different approaches in the treatment of atherosclerosis. The essential pharmacological treatment strategies consist of cholesterol lowering agents, anti-platelet medications, and anticoagulants. Works Cited 1. Timby, K. Barbara & Smith, E. Nancy. Introductory medical-surgical nursing. Ninth Edition. Philadelphia: Lippincott Williams & Wilkins, 2006. 2. George, Jacob. “Mechanisms of Disease: The Evolving Role of Regulatory T Cells in Atherosclerosis”. Nature Clinical Practice Cardiovascular Medicine 5.9 (2008): 531-540. 3. Fishbein, C. Michael & Siegel, J. Robert. “Pathology of Coronary Atherosclerosis: Implications for Intravascular Ultrasound Imaging”. Intravascular ultrasound imaging in coronary artery disease. Ed. Robert, J. Siegel. New York: Informa Healthcare, 1997. 1-18. 4. Laharthe, A. Darwin. “Cardiovascular Diseases “. Handbook of epidemiology. Eds. Wolfgang Ahrens & Iris Pigeot. Basel: Birkhauser, 2005. 1363-1404. 5. Gaziano, A. Thomas & Gaziano, J. Mocahel. “Epidemiology of Cardiovascular Disease”. Harrisons Principles of Internal Medicine Eds. Anthony, S. Faucci, Harrison, R. Tinsley, Isselbacher, J. Kurt, Braunwald Eugene, & Petersdorf, G. Robert.. Seventeenth Edition. New York: McGraw Hill, 2008.1375-1378. 6. “Cardiovascular diseases”. 2007. World Health Organization. 19 April 2009. . 7. “Cardiovascular Disease Statistics”. American Heart Association. 19 April 2009. . 8. Morz, Jr. C. Richard. “Lipids”. Clinical chemistry. EDs. Shauna, C. Anderson & Cockayne Susan. New York: McGraw Hill Professional, 2003. 179-202. 9. “Arteriosclerosis / atherosclerosis: Treatments and drugs”. 2008. MayoClinic.com. 19 April 2009. . 10. Garcia, M. J. Reinoso, R. F., Navarro, S. A. & Prous, J. R. “Clinical Pharmacokinetics of Statins”. Methods & Findings in Experimental Clinical Pharmacology 25.6 (2003): 457-463. 11. Davidson, H. Michael & Jacobson, A. Terry. “How Statins Work: The Development of Cardiovascular Disease and Its Treatment With 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors”. 2001. Medscape CME. 19 April 2009. . 12. Nappi, Jean & Talbert Robert. “Dual Antiplatelet Therapy for Prevention of Recurrent Ischemic Events”. American Journal of Health-System Pharmacy 58.18 (2002) 19 April 2009. . 13. “Aspirin”. The Elephant Formulary. 19 April 2009. . 14. Frishman, H. William, Cheng-Lai, Angela & Nawarskas, James. Current Cardiovascular Drugs. Basel: Birkhauser, 2005. Read More