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The cardiovascular system in humans functions in delivering oxygenated blood to cells and tissues and returning venous blood to the lungs for gaseous exchange. Aside from the heart, this intricate system is composed of blood vessels namely the veins, arteries, and capillaries. The arteries, through its progressive branching, are the ones responsible for circulating oxygenated blood away from the heart. Arteries occur entirely in the human body except in the cornea, cartilages, epidermis, nails, and hair; the large-sized trunks typically located in highly protected areas of the body spanning in the extremities, alongside the flexor surface where exposure to injury is lessened. Significant variations exists in the manner in which the arteries are divided: in some instances, there is a subdivision in the short trunk into numerous branches at a point of origin such as the thyro-cervical trunk and celiac artery: the blood vessel may give rise to a number of branches successively, and continues to be the main trunk, as noted in the limbs; or the dichotomous division, for example aorta giving rise to two common iliacs. An arterial branch is smaller than the trunk where the artery gave rise; however, if the artery branches into two, the sectional area of these two blood vessels combined is higher than the trunk alone; and for all the branches of arteries, the combined sectional area is greater than the aorta; therefore a collection of arteries may form a cone, the apical region represents the aorta, located at the base of the system of capillaries (Gray 1918).
In each of these branching, the diameters of arterial lumen increasingly decrease until the formation of the smallest blood vessel, the capillary. Structurally, the typical arterial wall possesses three layers concentrically arranged known as tunics. Found at the innermost is the tunica intima lined with a simple squamous epithelium or the endothelium where underneath it is the subendothelial connective tissue. At the middle is the tunica media primarily composed of smooth muscle fibers; among these muscle cells are two classes of fibers occurring in varying amounts, the reticular and elastic fibers. Smooth muscle cells are primarily responsible for the production of the extra cellular matrix. The last layer which is outermost is referred to as tunica adventitia containing both elastic and collagen connective tissue fibers; in the adventitia, collagen is type 1. In some muscular arteries, the walls are notably wavy, consisting of two bands of elastic fibers. Sandwiched between the innermost and middle layers is the internal elastic lamina which is not observed in smaller arteries. The external elastic lamina is found surrounding the muscular tunica media which is noted in large-sized muscular arteries (Eroschenko, di Fiore, and Eroschenko 2008).
There is a gradual decrease and increase in expansion and contraction, respectively as the arteries convey blood away from the heart. At the same time, pressure and velocity of blood expulsion from the ventricles slowly diminishes in the arterial tree and maintenance of the arterial tree luminal velocity and pressure away from arterial heart contraction is necessary. This is where the role of density in smooth and elastic muscle fibers in the middle layer of the arterial tree distal to the heart comes into play. Away from the heart, the latter increases while the former decreases. The elastic fibers allows for arterial expansion while the smooth muscle fibers, for arterial contraction. Kumar (2001) demonstrated that the density of elastic muscle fibers is decreased gradually in the tunica media of coronary arteries while proceeding distal to the aortic-coronary junctions. This observation found support in Boucek et al. (1963), Spiro and Wiener (1963) Gross et al (1934), Parker (1958), Lukenheimer et al (1973).
The expansion of arteries is only possible during systole while contraction only in diastole. Haller (1760), Bichat (1803), Lister (1879) as cited in Kumar (2001) hypothesized that contraction of the arteries is during systole is incorrect since in this scenario, it leads to the closure of both pulmonary and aortic valves on one hand and on the other, contraction of ventricles will attempt at opening the valves, thus making it impossible to propel the blood column forward. In the diastolic phase, arterial tree contraction is possible because in this stage, both pulmonary and aortic valves is closed and the blood cannot revert to the left and right ventricles from the ascending aorta and pulmonary artery correspondingly due to arterial tree contraction which aids in the forward propulsion of blood. In the systolic phase, expansion of the arterial tree permits the accommodation of 60mL extra blood volume released by the left and right ventricles in systemic and pulmonary circulation where the arterial tree lumen always engorged in blood in a living individual. Contraction of the arteries which corresponds with diastole helps in closing both pulmonary and aortic valves.
In US and other developed countries, diseases affecting the cardiovascular system cause the death in 35 percent of cases; the main culprit is atherosclerosis. Libby (2002) regarded atherosclerosis as one of the most important diseases in industrialized western countries. Atherosclerosis is a cardiovascular condition caused by plaque build-up inside the artery. The disease presents itself clinically with its broad array of symptoms although some remain asymptomatic in their lifetime despite their harboring of plaques in their vascular system. Others may manifest in stroke and myocardial infarction which are ischemic symptoms. Stroke is associated with at least one "unstable plaque". Fuster et al. (1992) noted that the symptoms of atheroma clinically manifest in adulthood which typically involves a thrombosis. On the other hand, myocardial infarction produces "stable plaques" whose growth occurs at a slower rate. Risk for major thromboembolic and thrombotic atherosclerosis complications is more associated with atheroma instability rather than the disease's extent (Little et al. 1988). A stable angina is closely related with coronary artery plaques which are both fibrous and smooth while the unstable type of angina, sudden cardiac death, and acute myocardial infarction are nearly consistently linked with either ruptured or irregular plaques (Virmani et al. 2000). Among carotid artery disease patients, both rupture and irregularity of the plaque appeared to be connected with cerebral ischemic events. The risk for ischemic stroke is higher among patients having ulcerated or irregular plaques as evidenced by the carotid artery angiography regardless of the luminal stenosis of the blood vessel (Spagnoli et al. 2004). In all plaque types, a commonality is inflammation (Ross, 1999; Hansson, 2005).
The American Heart Association has recently reclassified atherosclerosis-related lesions into two, namely: nonatherosclerotic intimal and progressive atherosclerotic lesions. The third type known as healed atherosclerotic plaques are highly prevalent specifically in the carotid arteries. Another method of characterizing these lesions looks into the fibrous cap thickness and the inflammatory infiltrate grade. When a lesion develops from a streak of fat to an atheroma, the size of the lesion increases such that it undergoes the process known as adaptive positive remodelling characterized by the expansion of the external elastic lamina in order to contain the lesion while maintaining luminal size (Schwartz et al. 1999). When the external elastic lamina continues to expand, there is a 180 percent increase in the original area of the vessel which is caused by the lesion. Composing the lesion are T lymphocytes, smooth muscle cells, and monocyte-derived macrophages. The interplay of these cellular types along with the connective tissues is the determinant of plaque progression and development as well as complications like rupture and thrombosis.
In most adults, lesions come from preexisting intimal lesions which consist of fatty streaks and thickenings in the intimal layer. These fatty streaks are classified as intimal xanthomata according to Virmani et al. (2000) and possess fat-laden macrophages in its intimal layer. These lesions may have T lymphocytes and smooth muscle cells. On the other hand, intimal thickening mainly involves smooth muscle cells in a matrix rich in proteoglycan. In children, lesion distribution is highly correlated with adult atherosclerotic lesion distribution (Schwartz, deBlois, and O'Brien, 1995). Cellular replication was notably moderate in early lesions, while clonal among smooth muscle cells in adult lesions. Research on how early intimal lesions have evolved is very minimal and none has given clarification on the exact mechanisms that the pathologic condition is developed.
Progressive atherosclerotic lesions are grouped into two, namely: stable and unstable plaques. A stable plaque is one in which the diseased intimal thickening shows evidence of lipid deposition and no necrosis (Schwartz, deBlois, and O'Brien, 1995). Above the lipid is filled with smooth muscle cells, proteoglycans and may variably contain variable T lymphocyte and macrophage populations. Parts of a fibrous cap atheroma consist of the following: lipidic-necrotic core which contains extracellular lipid, cholesterol crystals, and necrotic debris enclosed by a thick fibrous cap. The cap contains smooth muscle cells in a collagen-proteoglycan matrix along with varying levels of macrophage and T lymphocyte infiltration. At the plaque shoulder are cells that elicit the inflammatory process specifically the macrophage foam cells and T lymphocytes proximal to the lipidic-necrotic core. This lesion may develop into a stable lesion that has undergone massive calcification or give rise to complications for instance mural hemorrhage.
Virmani et al. (2000) explained that in a fibrocalcific plague, it must have little or no lipid-rich necrotic core and a thick fibrous cap covers calcium depositions lying the tunica intima proximal to the tunica media. Studies have proven the regular occurrence of intimal tears in the calcified interface and neighboring arterial tissues that are noncalcified (Richardson, Davies, and Born, 1989), and a very likely observation is the active role that calcification has on the rupture of plaques. Schmermund and Erbel (2001) employed an electron-beam CT revealing that majority of AMI patients or those with unstable angina were found to record levels of coronary calcium. On the other hand, Hunt et al. (2002) concluded that carotid artery disease patients with calcified carotid artery plaques showed less symptoms of transient ischemic attack and stroke than those which are noncalcified. Arteries in the coronary and carotid areas present different types of atheromas, since calcification of those in the latter begins at the surface, erupting the calcified nodules.
Another type of plaque is termed a high-risk or vulnerable plaque since it is more likely to rupture in which thrombogenic material is released leading to thrombus formation. The diagnostic feature of this lesion is the presence of a large necrotic core with cholesterol-rich clefts. At its cap are a small amount of smooth muscle cells and copious T lymphocytes, macrophages, and inflammatory cells(Virmani et al. 2000; Naghavi et al. 2003). Burke et al. (1997) described that a plaque in the coronary arties is classified as vulnerable if the thickness of the cap is 65 Âµm at most. Mauriello (2007) determined that in the carotids, cap thickness in a vulnerable lesion is at most 165 Âµm.
Among fatal AMI patients, the proximal coronary artery show have thin fibrous cap atheromas. Blood vessels demonstrating thin fibrous cap atheromas usually do not show severe tightening but rather positive remodeling. The length of the necrotic core in thin fibrous cap atheromas is between 2-17 mm and 8 mm on the average, and a stenosis diameter of less than 50%. The necrotic core area in at least 75 percent of cases is lesser or equal to three millimeter squared (Virmani et al. 2006).
Occurrence of thrombi is the result of one of three significant events namely: plaque rupture, plaque erosion or, calcified nodule. Ulceration and plaque rupture have been given variable definitions and used interchangeably and are linked to the occurrence of vulnerable plaques. The observation that most of the ruptured plaques are enclosed by thrombus regardless of the presence or absence of a luminal occlusion is conclusive evidence that the plaques are casually associated with these clinical events. Carr et al. (1996) defined plaque rupture as the area where the fibrous cap is disrupted where the thrombus is continuous with the necrotic core. A typical characteristic of ruptured lesions is the large necrotic core and fibrous cap which is both disrupted and permeated by lymphocytes and macrophages. At the rupture site, there is a sparse concentration of smooth muscle cells in the fibrous cap. When the thrombosed arterial segment is serially sectioned and did not show any rupture in the fibrous cap, then the plaque is eroded (Carr et al. 1996). In the eroded site, the absence of endothelium is evident. The erosion has led to the exposure of the intima consisting largely of proteoglycans and smooth muscle cells but surprisingly, the erosion site is inflamed minimally (Farb et al. 1996). Rupture is different from erosion as the latter can occur in a region of pathologic intimal thickening. Current research proposed that erosion of the plaque is correlated to the mast cell presence at the cap and is attributed to the action of proteases produced by mast cells (Mayranpaa et al. 2006). Rarely, calcified nodules cause thrombotic lesion which is a type of lesion characterized with a disrupted fibrous cap and thrombi linked to nodules which are calcified, dense, and eruptive (Virami et al. 2000). It remains unclear as to the cause of wearing down of the fibrous cap which could be the physical forces applied by the nodules, proteolytic action of the cellular infiltrate surrounding it, or the combination of both.
Little is known with regard to the mechanisms governing the formation of thrombus on eroded, stenotic, or ruptured atherosclerotic plaques at both molecular and cellular levels. As suggested by the Virchow triad, arterial thrombosis is dependent on three salient factors namely: substrate of the arterial wall, local rheologic properties on the flow of blood, and systemic factors associated with circulated blood. Fuster et al. (2005) noted that the first two factors appeared to have been implicated in the formation of thrombus in the carotid arteries leaving the last to be the subject of further scientific investigation.
Present-day understanding regarding the mechanisms that explain the pathophysiology of atherothrombosis lays its foundation on clinical, experimental, and pathologic researches on acute coronary artery syndromes (ACS). When the thrombogenic substrate is exposed as represented by tissue factor -containing lipids is the determining factor on lesion thrombogenicity (Toschi et al., 1997). Extent of stenosis due to plaque rupture and mural thrombus likewise determine thrombogenicity, since flow rate is altered at the site of the lesion. Vessel geometry variations amplify shear forces which is directly and inversely proportional to flow velocity and diameter of the lumen raised to the third power, respectively. These result in increasing deposits of platelets at the stenotic apex. The process leads to a vicious cycle wherein mural thrombus formation results in vasoconstriction with the aid of factors produced by the platelets which are thromboxane A2 and serotonin which increases deposition of platelets dependent on shear force (Maseri et al 1977).
Spagnoli et al. (2005) observed that a number of plaques in the carotid arteries remain active thrombotically in the long term after the early clinical event which predisposes patients to continuous emboli release in the intracranial vascular bed. The pattern of the plaque has an organizing thrombus composed of fibrous tissue which is interspersed with the proteoglycan-rich matrix having a network of vascular channels with are thin-walled and large. Also present is the small region of acute thrombosis which contains platelets or fibrin in interaction with a variable population of T cells and macrophages. They were also able to detect plaques which are thrombotically active 30 mo post initial acute cerebrovascular event. Its presence can still be seen in 53.8% of plaques among patients who have undergone surgery 24 months after the onset of the symptoms.
Healed lesions show total occlusion of the lumen and dense collagen. Also shown is the absence of a necrotic core while a number of lesions whose ruptures have been healed manifest layers of necrotic core and lipid implying that thrombosis has occurred repeatedly. Studies on the morphology of the coronary arteries suggest that progression of the plaque beyond the 50% constriction of the cross-sectional-luminal area is usually due to multiple ruptures which are mostly silent clinically. There seemed to be also noted in carotid artery disease (Burke et al. 2001).
Macrophages have been implicated to effect atherosclerosis as well as the rupture of plaques (Libby, 2002). Hansson et al. (2002) defined macrophages as innate effects of immune responses since it does not need any antigenic specificity making them more vulnerable than the T-lymphocytes to indiscriminate damage of the tissues that help promote rupture of plaques. Numerous signals mediate recruitment and activation of macrophages and possess impressive molecular armamentarium that effect damage and repair of tissues as well as fibrinolysis and coagulation and communication with other members of the immune system.
The recruitment of macrophage by the abnormal endothelial layer over the developing atherosclerotic plaques is mediated by the expression of the inflammatory leukocyte adhesion molecules such as ELAM, VCAM, E-Selectin, P-Selectin, and ICAM in the endothelium. Upregulation of these molecules is exerted by a number of risk factors for instance, diabetes, hypertension, smoking or oxLDL. Particularly, hemodynamic, arterial pressure, and sheer stress modulate these substances; all of which are significant in the localization of atherosclerotic lesions (Davies, 2000). A high shear stress serves to protect areas from atherosclerosis, which presents preferentially in areas where the shear stress is low at the bends and branches (Davies, 2000). Marshall and Haskard (2002) detected a complicated upregulation of endothelial adhesion molecules by inflammatory cytokine action.
Varying inflammatory cytokines show differences in the time when it is expressed , varying adhesion molecules possess different affinity towards different subsets of leukocytes, and adhesion molecules may depend on either the redistribution or synthesis of proteins. Therefore, it is not rare when cytokine-specific activation patterns overlap with each other. This consequently leads to the model that leukocytes are home to sites which rely on adhesion molecule combinations rather they are the letters forming the home address (Springer, 1995). Evidence on its molecular significance is among knockout mice. Atherosclerosis resistance was apparent among mice knockout for ICAM-1 (Collins et al. 2000) while less VCAM-1 resulted in reduced atherosclerosis (Dansky et al. 2001) as true knockout mice for VCAM cannot be investigated because the deletion is lethal at the embryonic stage.
Using knockout mice has shown that chemoattractant cytokine or chemokine MCP-1 attracts recruitment of macrophage in atherosclerosis. Essentially, atherosclerosis is abolished in MCP-1-/- mice which indicates that MCP-1 is an absolute requirement in the development of atherosclerosis during its earliest phases (Gu et al. 1998). Gene therapy for anti-MCP-1 may possibly promote advanced plaque regression among mice indicative of the MCP-1's role in advanced plaques. MCP-1 acting alongside CCR-2 which is its receptor, and in the same way, CCR2-/- mice show resistance towards atherosclerosis as confirmed by Boring et al. (1998). Research on bone marrow transplantation provided evidence on the mediatory role of monocyte CCR-2 in the process (Guo et al. 2003). Because these CCRs are G-protein-linked receptors located at the 7-transmembrane segment, they form excellent targets in the development of small molecule antagonists (Fernandez and Lolis, 2002). Its effectiveness in the reduction of atherosclerosis is yet to be demonstrated. Rezaie-Majd et al. (2003) mentioned that in monocytes, MCP-1 serves as a chemoattractant, statins-reduced, and expressed in the atherosclerotic plaques. Conversely, the true nature of its role in atherosclerosis is not certain; thus it should be emphasized that in nature, in vivo recruitment of leukocyte is the intricate result of multifarious pleiotropic cytokines and endothelium- and leukocyte-active chemokines.
The exit of monocytes from circulation is followed by migration from the endothelium to the tissues altering phenotype and resulting in its becoming macrophages. This means that the macrophages have matured, differentiated or activated. In addition, there is considerable evidence on the presence of different types of macrophage differentiation which is dependent on various stimuli and corresponds to different phenotypes of macrophages. Some workers distinguish between the process differentiation which is defined as influences of activation and IFN-g, which are the outcomes of lipopolysaccharide in bacteria. In vitro macrophage differentiation is preceded with HLA-DR and CD16 (Fc-g-RIII) which is a surface marker (Boyle et al. 2001). CD16 serves as a receptor to the crosslinked type of antibody IgG which is noted in microorganisms or immune complexes. However, the presence of CD16 in macrophages of human plaques is still not clarified. Intriguingly microorganisms and immune complexes are considered to be risk factors of atherosclerosis. Boyle (2005) showed that a one-week in vitro culture resulted in the differentiation of macrophages which is closely linked to the acquisition of the pro-apoptotic effect on the co-cultured VSMCs. Apoptosis is defined as a programmed cell death and a number of scientists have shown higher rate of apoptosis in atherosclerotic plaques by employing several techniques. It was found that the apoptosis of VSMC which is macrophage-mediated seemed to require contact between cells and the action of Fas-L (Boyle et al, 2001). This implies that the process which was previously known to be cytotoxic T-lymphocytes (CTL)-specific also occurs in macrophages. It should be noted that there is a close association between CTL and human plaque apoptosis; however in CTL, apoptosis induction is securely constrained by self-MHC and antigen. Because macrophages could not identify MHCs or specific antigens, other mechanisms should control macrophage-induced apoptosis which necessitates nitric oxide (NO). This compound functions in upregulating VSMC Fas and Fas-L in macrophages (Boyle et al. 2001; Boyle, Weissberg, and Bennett, 2002).
The phenotypes of macrophages are interesting but a confused field of research. According to Riches (1995), there are three phenotypes namely: histotoxic, reparative and inflammatory. However, an overlap exists between histotoxic and pro-inflammatory phenotypes and some functions of macrophages like presentation of antigen is not covered by this scheme. An extension of this research by Rees demonstrated that programming of macrophages wherein activation and reduction of one cytokine to subsequent responses to the other cytokines indicate that there is commitment to the phenotype. One emergent specialized phenotype of the macrophage related to atherosclerosis is dendritic cells (DCs) (Boyle, 1997). These specialized cells are involved in the presentation of antigen to elicit an immune response (Soilleux et al. 2002).Immune response phenomena are noted in atherosclerosis (Libby, 2002) since atherosclerotic plaques in humans have CD4-positive T-helper lymphocytes which recognize LDL to be an antigen (Stemme et al. 1995).
CD80, an essential requirement in initiating a successful T lymphocyte reaction could be seen in human atherosclerotic plaques, and carotid plaques have cells which are immunoreactive towards DC markers which include DC-SIGN (Soilleux et al. 2002). Therefore, differentiation of macrophages to specialize in presenting antigen is promising to be important in understanding atherosclerosis. Mechanical and adhesion stimuli likewise control differentiation that when culture is subjected to both, massively affects the transcriptome profile of the macrophage, through the Jak/STAT and NF- k-B pathways (de Fougerolles et al. 2000). And this is also applicable to atherosclerosis. Mechanical strain causes alterations in the salient features of macrophages like the scavenger receptor expression for atherogenic OxLDL (Yang et al. 2000). This provides a partial explanation to the synergism between hypertension and hypercholesterolemia. Transendothelial migration modifies activation and encourages differentiation to the phenotype that is antigen-presenting (Randolph et al.1998).
Furthermore, activation is caused by several stimuli. Recently numerous stimuli have a link to atherosclerosis since it activates the macrophages. Included are OxLDL, in layman's term is known as bad cholesterol, diabetes advanced glycosylation end products, endothelin, and angiotensin II. It is a widely recognized fact that LDL though an atherosclerosis risk factor might not be the atherogenic form but instead oxidized by the plaque macrophages themselves (Witztum, 1994). Extensive research has given clarity to ox-LDL macrophage activation through macrophage scavenger receptors (MSRs) particularly CD36 and MSR-A.
Nonetheless, many other putative MSRs are defined by their binding ability towards other OxLDL configurations. These are LOX and CD68 and RAGEs, MSRs, and AGEs receptors share similarities. Basically, AGEs are diabetes proteins that have undergone over-glycosylation which are degenerate or modified forms of normal proteins which are identified and engulfed as "junk" (Schmidt et al. 2000). In fact, typical MSRs might perform the function of RAGEs particularly CD36 (Ohgami et al. 2001). RAGE catalyzes macrophage activation and located in area where inflammation is chronic as in atherosclerosis (Kislinger et al. 2001). Vasopressor peptides endothelin and AII have direct action on in vivo (Keidar et al. 2001) as well as in vitro (Wilson et al. 1999) macrophage activation. While this is largely unexplored, this provides a pathogenetic connection between high blood pressure and atherosclerosis.
Gordon (2003) described phenotypes of macrophages which are Th2 cytokines-induced. This is a contrast to the phenotype(s) which are triggered by microorganisms or Th1 cytokine IFN-g specifically as this other activation is related to twith macrophage mannose receptor upregulation (Gordon, 2003). Other phenotypic variances may be evident through a wider approach such as proteomic analysis. This other activation model corresponds roughly to the M1-M2 schema put forward by other workers and is connected to alterations in chemokine patterns (Mantovani et al. 2002).
Though IL-10-/- mice showed more atherosclerosis susceptibility (Mallat et al. 1999), IL-10 is a broad anti-inflammatory cytokine and Th2 cytokine role in atherosclerosis is not well studied (Gordon, 2003).
Expression of CD40 by macrophages is oxLDL-induced. CD40 constitutes the superfamily TNF-R whose activation is caused by CD154 (CD40L) action (Schonbeck and Libby, 2001). Antibodies anti- CD40 are responsible for the in vivo reduction of atherosclerosis (Mach et al. 1998). Several types of cells express CD40L but mainly by CD4+ T-helper cells. Therefore CD40L/CD40 is one pathway for the plaque T-lymphocyte -mediated activation of macrophages (Schonbeck and Libby, 2001). CD40 accelerates release of chemokine, induction of angiogenesis induction, and procoagulation activity by upregulated tissue factor (Schonbeck and Libby, 2001).
Antigen presenting of macrophages is described through the efforts of numerous researchers. Expression of a great number of effector molecules by macrophages is reviewed comprehensively by Hansson et al. (2002). In general, these enable macrophages to effect host tissue lysis which include atherosclerotic plaques expected to rupture plaques (Newby, Libby, and van der Wal, 1999). These will include death-inducing molecules such as Fas-L, reactive nitrogen species, inflammatory cytokines, eicosanoids, cysteine proteases, aspartate, serine proteases, and metalloproteinases.