Blood Vessels PDF

Pathology of BLOOD VESSELS Vascular disorders—and their downstream sequelae—are responsible for more morbidity and mortality than any other category of human disease. Although the most clinically significant lesions typically involve arteries, venous diseases also occur....

Pathology of BLOOD VESSELS Vascular disorders—and their downstream sequelae—are responsible for more morbidity and mortality than any other category of human disease. Although the most clinically significant lesions typically involve arteries, venous diseases also occur. 1  Principal Mechanisms of Vascular Diseases  1. narrowing/complete lumen obstruction  progressive (atherosclerosis)  precipitously ( thrombus or embolism)  2. weakening of the walls  dilation or rupture Vascular pathology results in disease via two principal mechanisms: (1) Narrowing (stenosis) or complete obstruction of vessel lumens, either progressively (e.g., by atherosclerosis) or precipitously (e.g., by thrombosis or embolism); and (2) weakening of vessel walls, leading to dilation or rupture. 2  Structure and Function of Blood Vessels Subendothelial connective tissue Vasa vasorum Basic components: endothelial cells, smooth muscle cells, and extracellular matrix We will first describe the important structural and functional characteristics of blood vessels to better appreciate how pathologic changes can result in disease states. General architecture and cellular composition are the same throughout the cardiovascular system. However, certain features of the vasculature vary with and reflect distinct functional requirements at different locations ( Fig. 11-1 ). To withstand the pulsatile flow and higher blood pressures in arteries, arterial walls are generally thicker than the walls of veins. Arterial wall thickness gradually diminishes as the vessels become smaller, but the ratio of wall thickness to lumen diameter becomes greater The basic constituents of the walls of blood vessels are endothelial cells and smooth muscle cells, and extracellular matrix (ECM), including elastin, collagen, and glycosoaminoglycans. The three concentric layers—intima, media, and adventitia—are most clearly defined in the larger vessels, particularly arteries. In normal arteries, the intima consists of a single layer of endothelial cells with minimal underlying subendothelial connective tissue. It is separated from the media by a dense elastic membrane called the internal elastic lamina. The smooth muscle cell layers of the media near the vessel lumen receive oxygen and nutrients by direct diffusion from the vessel lumen, facilitated by holes in the internal elastic membrane. However, diffusion from the lumen is inadequate for the outer portions of the media in large and medium-sized vessels, therefore these areas are nourished by small arterioles arising from outside the vessel (called vasa vasorum, literally “vessels of the vessels”) coursing into the outer one half to two thirds of the media. The outer limit of the media of most arteries is a well-defined external elastic lamina. External to the media is the adventitia, consisting of connective tissue with nerve fibers and the vasa vasorum. 3  Arteries  Large or elastic arteries  Medium sized or muscular arteries  Small arteries and arterioles  The relative amount and configuration of the basic constituents (media & ECM) differ along the arterial system owing to local adaptations to mechanical or metabolic needs. Based on their size and structural features, arteries are divided into three types: 1. Large or elastic arteries –aorta and its branches and pulmonary arteries 2. Medium sized or muscular arteries – other branches of the aorta, e.g., coronary and renal arteries 3. Small arteries (< 2mm) and arterioles (20 -100um) course within the substance of tissues and organs In the elastic arteries the media is rich in elastic fibers. This allows vessels such as the aorta to expand during systole and recoil during diastole, thus propelling blood through the peripheral vascular system. With aging, the aorta loses elasticity, and large vessels expand less readily, particularly when blood pressure is increased. Thus, the arteries of older individuals often become progressively tortuous and dilated (ectatic). In muscular arteries the media is composed predominantly of circularly or spirally arranged smooth muscle cells. In the muscular arteries and arterioles (see below), regional blood flow and blood pressure are regulated by changes in lumen size through smooth muscle cell contraction (vasoconstriction) or relaxation (vasodilation), controlled in part by the autonomic nervous system and in part by local metabolic factors and cellular interactions. Since the resistance of a tube to fluid flow is inversely proportional to the fourth power of the diameter (i.e., halving the diameter increases resistance 16-fold), small changes in the lumen size of small arteries caused by structural change or vasoconstriction can have a profound effect. Thus, arterioles are the principal points of physiologic resistance to blood flow. 4   Arterioles principal points of physiologic resistance to blood flow  Capillaries 7- 8 μ; with an endothelial lining but no media; rapid exchange of diffusible substance bet. blood and tissues  Post capillary venules where vascular leakage and leukocyte exudation occur Because of their poor support, veins are predisposed to irregular dilation, compression, and easy penetration by tumors and inflammatory processes 2/3 of all blood is in the veins, large capacity; Lymphatics – transport bacteria and tumor cells to distant sites Pathologic lesions involve vessels of characteristic size, range, and type; AS – large and elastic art; HPN – small arteries and arterioles; vasculitis – different vascular segments Capillaries, approximately the diameter of a red blood cell (7 to 8 μm), have an endothelial cell lining but no media. Collectively, capillaries have a very large total cross-sectional area; within the capillaries, the flow rate slows dramatically. With thin walls only and slow flow, capillaries are ideally suited to the rapid exchange of diffusible substances between blood and tissues. As normal tissue function depends on an adequate supply of oxygen through blood vessels, and since diffusion of oxygen in solid tissues is inefficient over distances of greater than approximately 100 μm, the capillary network of most tissues is very rich. Metabolically highly active tissues, such as the myocardium, have the highest density of capillaries. Blood from capillary beds flows initially into the postcapillary venules and then sequentially through collecting venules and small, medium, and large veins. In many types of inflammation, vascular leakage and leukocyte exudation occur preferentially in postcapillary venules ( Chapter 2 ). Relative to arteries, veins have larger diameters, larger lumens, and thinner and less well organized walls (see Fig. 11-1 ). Thus, because of their poor support, veins are predisposed to irregular dilation, compression, and easy penetration by tumors and inflammatory processes. The venous system collectively has a large capacity; approximately two thirds of all the blood is in veins. Reverse flow is prevented by venous valves in the extremities, where blood flows against gravity. Lymphatics are thin-walled, endothelium-lined channels that serve as a drainage system for returning interstitial tissue fluid and inflammatory cells to the blood. Lymphatics constitute an important pathway for disease dissemination through transport of bacteria and tumor cells to distant sites. As will be discussed in detail in this chapter, pathologic lesions involve vessels of a characteristic size, range, and/or type. Atherosclerosis, for example, affects elastic and muscular arteries, hypertension affects small muscular arteries and arterioles, and specific types of vasculitis involve different vascular segments. 5  Veins larger diameter, larger lumens, thinner , less organized walls irregular dilation, compression, & penetration  Lymphatics thin-walled, endothelial-lined channels; drainage system; pathway for disease dissemination 6  Vessel Development, Growth, and Remodeling  Vasculogenesis formation of blood vessels during embryogenesis  Angiogenesis or neovascularization, process of new vessel formation in mature organism  Arteriogenesis remodeling of existing arteries in response to chronic changes in pressure or flow results from interplay of endothelial cell- and smooth muscle- derived factors Three major processess characterize blood vessel formation and remodelling: vasculogenesis, angiogenesis, and arteriogenesis Vasculogenesis is the de novo formation of blood vessels during embryogenesis. Hemangioblast angiogenic precursors develop and migrate to the sites of vascularization. These differentiate into endothelial cells that associate to form a primitive vascular plexus; with time and the influence of local genetic, metabolic, and hemodynamic factors, this network of cells remodels (through pruning and/or vessel enlargement) into the definitive vascular system.[2,] The various isoforms of vascular endothelial growth factor (VEGF) are the primary growth factors involved in this process. Subsequent stabilization of the endothelial tubes during development (and induction of endothelial cell quiescence) also critically requires the recruitment of pericytes and smooth muscle cells, a process that involves angiopoietin 1 binding to endothelial cell Tie2 receptors. Angiogenesis (or neovascularization) constitutes the process of new vessel formation in the mature organism. Arteriogenesis refers to the remodeling of existing arteries in response to chronic changes in pressure or flow, and results from an interplay of endothelial cell–and smooth muscle cell–derived factors. 7  Congenital Anomalies  Developmental or Berry aneurysms. Intracerebral hemorrhage  Arteriovenous fistulas – intracerebral hge, Heart failure  Developmental defects  Rupture of an arterial aneurysm to adjacent vein  Penetrating injuries  Inflammatory necrosis of adjacent vessels  Intentionally created – chronic hemodialysis  Fibromuscular dysplasia focal irregular thickening of the walls of large and medium sized arteries renovascular HPN, aneurysm Developmental or Berry aneurysms – occur in cerebral vessels  rupture  fatal intracerebral hemorrhage A-V aneurysms – small, direct, connections between arteries and veins that bypass the intervening capillaries Though rarely symptomatic, variants of the usual anatomic pattern of vascular supply can become important during surgery when a vessel in an unexpected location is injured. Variations in the normal coronary artery anatomy are also extremely important to the cardiac surgeon or interventional cardiologist.[5,] Among the other congenital vascular anomalies, three are particularly significant, though not necessarily common: Developmental or berry aneurysms occur in cerebral vessels; when ruptured these can be causes of fatal intracerebral hemorrhage. They are discussed in Chapter 28. Arteriovenous fistulas are abnormal, typically small, direct connections between arteries and veins that bypass the intervening capillaries. They occur most commonly as developmental defects but can also result from rupture of an arterial aneurysm into an adjacent vein, from penetrating injuries that pierce arteries and veins, or from inflammatory necrosis of adjacent vessels; intentionally created arteriovenous fistulas are used to provide vascular access for chronic hemodialysis. Like berry aneurysms, ruptured arteriovenous fistulas can be an important cause of intracerebral hemorrhage. Large or extensive arteriovenous fistulas become clinically significant by shunting blood from the arterial to the venous circulations and forcing the heart to pump additional volume; high-output cardiac failure can ensue. Fibromuscular dysplasia is a focal irregular thickening of the walls of medium and large muscular arteries, including renal, carotid, splanchnic, and vertebral vessels. The cause is unknown but is probably developmental; first-degree relatives of affected individuals have an increased incidence. Segments of the vessel wall are focally thickened by a combination of irregular medial and intimal hyperplasia and fibrosis; this results in luminal stenosis, and in the renal arteries may be a cause of renovascular hypertension ( Chapter 20 ). Vascular outpouchings (aneurysms) may develop in the vessel segments with attenuated media and in some cases can rupture. Fibromuscular dysplasia can manifest at any age, although it is seen most frequently in young women; there is no association with use of oral contraceptives or abnormalities of sex hormone expression. 8 Developmental or Berry aneurysms  occur in cerebral vessels  rupture leads to fatal intracerebral hemorrhage 9 Arteriovenous fistulas  Direct connections (usually small) between arteries and veins that bypass the intervening capillary bed 10 Fibromuscular Dysplasia  Focal IRREGULAR thickening in medium & large muscular arteries, including renal, carotid, splanchnic & vertebral vessels 11  Vascular Wall cells and their Response to injury  Endothelial Cell properties and Functions IHS for endothelial cells – von Willebrand’s factor and CD31 (platelet-endothelial cell adhesion molecule-1, PECAM-1) Endothelium is critical for maintaining vessel wall homeostasis and circulatory function. Endothelial cells contain Weibel-Palade bodies, intracellular membrane-bound storage organelles for von Willebrand's factor ( Chapter 4 ). Antibodies to von Willebrand's factor and/or platelet-endothelial cell adhesion molecule-1 (PECAM-1 or CD31, a protein localized to interendothelial junctions) can be used to identify endothelial cells immunohistochemically. Vascular endothelium is a multifunctional tissue with a wealth of synthetic and metabolic properties; at baseline it has several constitutive activities critical for normal vessel homeostasis ( Table 11-1 ). Thus, endothelial cells maintain a nonthrombogenic blood-tissue interface (until clotting is necessitated by local injury, Chapter 4 ), modulate vascular resistance, metabolize hormones, regulate inflammation, and affect the growth of other cell types, particularly smooth muscle cells. In most regions the interendothelial junctions are substantially impermeable. However, tight endothelial cell junctions can loosen under the influence of hemodynamic factors (e.g., high blood pressure) and/or vasoactive agents (e.g., histamine in inflammation), resulting in the flooding of adjacent tissues by electrolytes and protein; in inflammatory states, even leukocytes can slip between adjacent endothelial cells ( Chapter 2 ). 12  Vascular Wall cells and their Response to injury Pathologic mediators or excessive stim’n by physiologic pathway  endothelial cell dysfunction  altered phenotype  impaired vasoreactivity or thrombogenic surface or abnormally adhesive to inflammatory cells Endothelial cell responses to environmental stimuli. Certain cues (e.g., laminar flow and constant growth factor levels) lead to stable endothelial cell activation that maintains a nonthrombotic interface with appropriate smooth muscle cell tone. Pathologic mediators or excessive stimulation by normal physiologic pathways (e.g., increased inflammatory cytokines) can result in endothelial cell dysfunction. VEGF, vascular endothelial growth factor. Endothelial activation – pathophysiologic stimuli ec adjust their usual (constitutive) functions and expresses newly acquired (inducible) properties Endothelial dysfunction – an altered phenotype that impairs vasoreactivity or induces a surface that is thrombogenic,or abnormally adhesive to inflammatory cells Structurally intact endothelial cells can respond to various pathophysiologic stimuli by adjusting their usual (constitutive) functions and by expressing newly acquired (inducible) properties—a process termed endothelial activation ( Fig. 11-2 ).[10,] Inducers of endothelial activation include cytokines and bacterial products, which cause inflammation and septic shock ( Chapter 2 ); hemodynamic stresses and lipid products, critical to the pathogenesis of atherosclerosis (see later); advanced glycosylation end products (important in diabetes, Chapter 24 ); as well as viruses, complement components, and hypoxia. Activated endothelial cells, in turn, express adhesion molecules ( Chapter 2 ), and produce cytokines and chemokines, growth factors, vasoactive molecules that result either in vasoconstriction or in vasodilation, major histocompatibility complex molecules, procoagulant and anticoagulant moieties, and a variety of other biologically active products. Endothelial cells influence the vasoreactivity of the underlying smooth muscle cells through the production of both relaxing factors (e.g., nitric oxide [NO]) and contracting factors (e.g., endothelin). Normal endothelial function is characterized by a balance of these responses. Endothelial dysfunction is defined as an altered phenotype that impairs vasoreactivity or induces a surface that is thrombogenic or abnormally adhesive to inflammatory cells. It is responsible, at least in part, for the initiation of thrombus formation, atherosclerosis, and the vascular lesions of hypertension and other disorders. Certain forms of endothelial cell dysfunction are rapid in onset (within minutes), reversible, and independent of new protein synthesis (e.g., endothelial cell contraction induced by histamine and other vasoactive mediators that cause gaps in venular endothelium, Chapter 2 ). Other changes involve alterations in gene expression and protein synthesis and may require hours or even days to develop. 13  Vascular Wall cells and their Response to injury  Vascular Smooth Muscle cells role in vascular repair & pathologic process capacity to proliferate when stimulated synthesize ECM collagen, elastin & proteoglycans, GF and cytokines Vasoconstriction and dilation Growth promoters – PDGF, endothelin-1, thrombin, FGF, IFN-γ and IL-1 Growth inhibitors- heparan sulfates, NO, and TGF-β Other regulators – RAS, catecholamines, estrogen receptor, and osteopontin As the predominant cellular element of the vascular media, smooth muscle cells play important roles in normal vascular repair and pathologic processes such as atherosclerosis. Smooth muscle cells have the capacity to proliferate when appropriately stimulated; they can also synthesize ECM collagen, elastin, and proteoglycans and elaborate growth factors and cytokines. Smooth muscle cells are also responsible for the vasoconstriction or dilation that occurs in response to physiologic or pharmacologic stimuli. The migratory and proliferative activities of smooth muscle cells are regulated by growth promoters and inhibitors. Promoters include PDGF, as well as endothelin-1, thrombin, fibroblast growth factor (FGF), interferon-γ (IFN-γ), and interleukin-1(IL-1). Inhibitors include heparan sulfates, nitric oxide, and TGF-β. Other regulators include the renin- angiotensin system (e.g., angiotensin II), catecholamines, the estrogen receptor, and osteopontin, a component of the ECM. 14  Hypertensive Vascular Disease Table 11-2 lists the major causes of hypertension. A small number of patients (approximately 5%) have underlying renal or adrenal disease (such as primary aldosteronism, Cushing syndrome, pheochromocytoma), narrowing of the renal artery, usually by an atheromatous plaque (renovascular hypertension) or other identifiable cause (secondary hypertension). However, about 95% of hypertension is idiopathic (called essential hypertension). This form of hypertension generally does not cause short-term problems. When controlled, it is compatible with long life and is asymptomatic, unless a myocardial infarction, cerebrovascular accident, or other complication supervenes. Like height and weight, blood pressure is a continuously distributed variable, and detrimental effects of blood pressure increase continuously as the pressure rises; no rigidly defined threshold level of blood pressure distinguishes risk from safety. Nevertheless, according to the National Heart, Lung, and Blood Institute of the U.S.A., a sustained diastolic pressure greater than 89 mm Hg, or a sustained systolic pressure in excess of 139 mm Hg, are associated with a measurably increased risk of atherosclerosis, and are therefore felt to represent clinically significant hypertension. Both the systolic and diastolic blood pressure are important in determining cardiovascular risk. By either criterion, some 25% of individuals in the general population are hypertensive. However, it must be emphasized that these cut-offs are somewhat arbitrary, and in patients with other risk factors for vascular disease such as diabetes, lower thresholds are applicable. Typically, for individuals with such “essential hypertension,” the best we can say is that the disorder is multifactorial, resulting from the combined effects of multiple genetic polymorphisms and interacting environmental factors. Hypertension is one of the major risk factors for atherosclerosis and underlies numerous other diseases. It can cause—among other things—cardiac hypertrophy and heart failure (hypertensive heart disease, Chapter 12 ), multi-infarct dementia ( Chapter 28 ), aortic dissection, and renal failure. Unfortunately, hypertension typically remains asymptomatic until late in its course and even severely elevated pressures can be clinically silent for years. Left untreated, roughly half of hypertensive patients die of ischemic heart disease (IHD) or congestive heart failure, and another third die of stroke. Prophylactic blood pressure reduction dramatically reduces the incidence and death rates from all forms of hypertension-related pathology A small percentage, perhaps 5%, of hypertensive persons show a rapidly rising blood pressure that, if untreated, leads to death within a year or two. Called accelerated or malignant hypertension, this clinical syndrome is characterized by severe hypertension (i.e., systolic pressure over 200 mm Hg, diastolic pressure over 120 mm Hg), renal failure, and retinal hemorrhages and exudates, with or without papilledema. It may develop in previously normotensive persons but more often is superimposed on pre-existing benign hypertension, either essential or secondary 15  Blood pressure regulation Blood Pressure = Cardiac output x Peripheral resistance Cardiac Output = Stroke volume X Heart rate Blood pressure is a function of cardiac output and peripheral vascular resistance ( Fig. 11-4A ), two hemodynamic variables that are influenced by multiple genetic, environmental, and demographic factors. The major factors that determine blood pressure variation within and between populations include age, gender, body mass index, and diet, particularly sodium intake. Cardiac output is highly dependent on blood volume, itself greatly influenced by the sodium homeostasis. Peripheral vascular resistance is determined mainly at the level of the arterioles and is affected by neural and hormonal factors. Normal vascular tone reflects the balance between humoral vasoconstricting influences (including angiotensin II, catecholamines, and endothelin) and vasodilators (including kinins, prostaglandins, and NO). Resistance vessels also exhibit autoregulation, whereby increased blood flow induces vasoconstriction to protect against tissue hyperperfusion. Other local factors such as pH and hypoxia, and the α- and β-adrenergic systems, which influence heart rate, cardiac contraction, and vascular tone, may also be important in regulating blood pressure. The integrated function of these systems ensures adequate perfusion of all tissues, despite regional differences in demand. 16  Hypertensive Vascular Disease  Regulation of Normal blood pressure  Cardiac output and peripheral vascular resistance  By the kidneys  Renin-angiotensin system activation with fall in BP  Production of antihypertensive subs, PGs and NO  reabsorption of sodium when blood volume is reduced causing expansion of volume  Natriuretic factors – volume expansion  Includes peptides secreted by atrial and ventricular myocardium; inhibits sodium reabsorption causing its excretion and diuresis  Induce vasodilation The kidneys play an important role in blood pressure regulation as follows ( Fig. 11-4B ): Through the renin- angiotensin system, the kidney influences both peripheral resistance and sodium homeostasis. Renin is secreted by the juxtaglomerular cells of the kidney in response to fall in blood pressure. It converts plasma angiotensinogen to angiotensin I, which is then converted to angiotensin II by angiotensinconverting enzyme. Angiotensin II raises blood pressure by increasing both peripheral resistance (direct action on vascular smooth muscle cells) and blood volume (stimulation of aldosterone secretion, and increase in distal tubular reabsorption of sodium). The kidney also produces a variety of vascular relaxing, or antihypertensive, substances (including prostaglandins and NO), which presumably counterbalance the vasopressor effects of angiotensin. When blood volume is reduced, the glomerular filtration rate falls, leading to increased reabsorption of sodium by proximal tubules, thereby conserving sodium and expanding blood volume. Natriuretic factors, including the natriuretic peptides secreted by atrial and ventricular myocardium in response to volume expansion, inhibit sodium reabsorption in distal tubules and thereby cause sodium excretion and diuresis. Natriuretic peptides also induce vasodilation and may be considered to represent endogenous inhibitors of the renin-angiotensin system 17  Mechanisms of Essential HPN  Genetic factors:  enzyme defects  inc aldosterone  eNaC protein mutation (Liddle syndrome)  Polymorphisms in genes encoding components of the renin-angiotensin system  Reduced renal Na+ excretion  Vasoconstrictive influence  Environmental factors- stress, obesity, smoking, physical inactivity, and heavy consumption of salt Single-gene disorders cause severe but rare forms of hypertension through several mechanisms. These include: Gene defects affecting enzymes involved in aldosterone metabolism (e.g., aldosterone synthase, 11β-hydroxylase, 17α- hydroxylase). These lead to an increase in secretion of aldosterone, increased salt and water resorption, plasma volume expansion and, ultimately, hypertension. Mutations affecting proteins that influence sodium reabsorption. For example, the moderately severe form of salt-sensitive hypertension, called Liddle syndrome, is caused by mutations in an epithelial Na+ channel protein that lead to increased distal tubular reabsorption of sodium induced by aldosterone. Inherited variations in blood pressure may also depend on the cumulative effects of polymorphisms in several genes that affect blood pressure. For example, predisposition to essential hypertension has been associated with variations in the genes encoding components of the renin-angiotensin system: there is an association of hypertension with polymorphisms in both the angiotensinogen locus and the angiotensin receptor locus. Genetic variants in the renin-angiotensin system may contribute to the known racial differences in blood pressure regulation. To summarize, essential hypertension is a complex, multifactorial disorder. Although single gene disorders can be responsible for hypertension in rare cases, it is unlikely that such mutations are a major cause of essential hypertension. It is more likely that essential hypertension results from interactions of mutations or polymorphisms at several loci that influence blood pressure, with a variety of environmental factors (e.g., stress, salt intake). Mendelian forms of hypertension and hypotension are rare but yield insights into pathways and mechanisms of blood pressure regulation, and they may help define rational targets for therapeutic intervention. Sustained hypertension requires participation of the kidney, which normally responds to hypertension by eliminating salt and water. Susceptibility genes for essential hypertension in the larger population are currently unknown but may well include genes that govern responses to an increased renal sodium load, levels of pressor substances, reactivity of vascular smooth muscle cells to vasoconstrictive agents, or smooth muscle cell growth. In established hypertension, both increased blood volume and increased peripheral resistance contribute to the increased pressure. 18  Vascular Pathology in Hypertension Onion-skin Hyaline Hyperplastic arteriolosclerosis arteriolosclerosis Hypertension not only accelerates atherogenesis (see below) but also causes degenerative changes in the walls of large and medium arteries that can lead to aortic dissection and cerebrovascular hemorrhage. Hyaline Arteriolosclerosis. Arterioles show homogeneous, pink hyaline thickening with associated luminal narrowing ( Fig. 11-5A ). These changes stem from plasma protein leakage across injured endothelial cells, and increased smooth muscle cell matrix synthesis in response to chronic hemodynamic stress. Although the vessels of elderly persons (either normo- or hypertensive) also frequently show hyaline arteriosclerosis, it is more generalized and severe in individuals with hypertension. The same lesions are also a common feature of diabetic microangiography; in that case the underlying etiology is hyperglycemia-induced endothelial cell dysfunction ( Chapter 24 ). In nephrosclerosis due to chronic hypertension, the arteriolar narrowing of hyaline arteriosclerosis causes diffuse impairment of renal blood supply and causes glomerular scarring ( Chapter 20 ). Hyperplastic Arteriolosclerosis. This lesion occurs in severe (malignant) hypertension; vessels exhibit “onion-skin lesions” characterized by concentric, laminated thickening of the walls and luminal narrowing ( Fig. 11-5B ). The laminations consist of smooth muscle cells with thickened, reduplicated basement membranes; in malignant hypertension they are accompanied by fibrinoid deposits and vessel wall necrosis (necrotizing arteriolitis), particularly in the kidney. 19  Arteriosclerosis  “Hardening of the arteries”  Arterial wall thickening  Loss of elasticity  Forms  Arteriolosclerosis – small arteries and arterioles  Monckeberg medial sclerosis – muscular arteries  Atherosclerosis – large elastic and muscular art Arteriosclerosis literally means “hardening of the arteries”; it is a generic term reflecting arterial wall thickening and loss of elasticity. There are three general patterns, with differing clinical and pathologic consequences: Arteriolosclerosis affects small arteries and arterioles, and may cause downstream ischemic injury. The anatomic variants, hyaline and hyperplastic, were discussed above in relation to hypertension. Mönckeberg medial sclerosis is characterized by calcific deposits in muscular arteries in persons typically older than age 50. The deposits may undergo metaplastic change into bone. Nevertheless, the lesions do not encroach on the vessel lumen and are usually not clinically significant. Atherosclerosis, from Greek root words for “gruel” and “hardening,” is the most frequent and clinically important pattern and will now be discussed in detail 20  Atherosclerosis Intimal lesions called atheromas Atherosclerosis is characterized by intimal lesions called atheromas (also called atheromatous or atherosclerotic plaques) that protrude into vessel lumens. An atheromatous plaque consists of a raised lesion with a soft, yellow, grumous core of lipid (mainly cholesterol and cholesterol esters) covered by a white fibrous cap ( Fig. 11-6 ). Besides mechanically obstructing blood flow, atherosclerotic plaques can rupture, leading to catastrophic vessel thrombosis; plaques also weaken the underlying media and thereby lead to aneurysm formation. Atherosclerosis causes far more morbidity and mortality (roughly half of all deaths) in the Western world than any other disorder. Because coronary artery disease is an important manifestation of the disease, epidemiologic data related to atherosclerosis mortality typically reflect deaths caused by heart disease ( Chapter 12 ); indeed, myocardial infarction is responsible for almost a quarter of all deaths in the United States. Significant morbidity and mortality are also caused by aortic and carotid atherosclerotic disease and stroke. 21  Atherosclerosis Major risk factors for Atherosclerosis  Non modifiable  Modifiable  Increasing age  Hyperlipidemia  Male gender  Hypertension  Family history  Genetic abnormalities  Cigarette smoking  Diabetes  C- reactive protein Additional risk factors inflammation hyperhomocysteinemia metabolic syndrome Factors affecting hemostasis Lipoprotein (a) Type “A” personality Obesity, lack of exercise Metabolic syndrome – char. By a number of abnormalities asst’d with insulin resistance, HPN and central obesity The prevalence and severity of atherosclerosis and IHD among individuals and groups are related to several risk factors, some constitutional (and therefore less controllable), others acquired or related to behaviors that are potentially amenable to intervention ( Table 11-3 ). Risk factors have been identified through several prospective studies in well-defined populations, most notably the Framingham Heart Study and Atherosclerosis Risk in Communities Study ( Fig. 11-7 ).[27,] Risk factors have a multiplicative effect; two risk factors increase the risk approximately fourfold. When three risk factors are present (e.g., hyperlipidemia, hypertension, and smoking), the rate of myocardial infarction is increased seven times. Constitutional risk factors in IHD. These include age, gender, and genetics. Age is a dominant influence. Although atherosclerosis is typically progressive, it usually does not become clinically manifest until middle age or later (see below). Between ages 40 and 60 the incidence of myocardial infarction increases fivefold. Death rates from IHD rise with each decade even into advanced age. Gender. Other factors being equal, premenopausal women are relatively protected against atherosclerosis and its consequences compared to age-matched men. Thus, myocardial infarction and other complications of atherosclerosis are uncommon in premenopausal women in the absence of risk factors such as diabetes, hyperlipidemia, or severe hypertension. After menopause, however, the incidence of atherosclerosis-related diseases increases and at older ages actually exceeds that of men. Although a favorable influence of estrogen has long been proposed to explain the protective effect, some clinical trials have failed to demonstrate any utility of hormonal therapy for vascular disease prevention. As discussed in greater detail in Chapter 9 , the atheroprotective effect of estrogens is related to the age at which the therapy is initiated. In younger postmenopausal women, there is a reduction in coronary atherosclerosis with estrogen therapy. The effect is unclear in older women. In addition to atherosclerosis, gender also affects a number of parameters that can influence outcomes of IHD; thus, women show differences in hemostasis, infarct healing, and myocardial remodeling. Genetics. Family history is the most significant independent risk factor for atherosclerosis. Many mendelian disorders associated with atherosclerosis, such as familial hypercholesterolemia ( Chapter 5 ), have been characterized. Nevertheless, these genetic diseases account for only a small percentage of cases. The well-established familial predisposition to atherosclerosis and IHD is usually multifactorial, relating to inheritance of various genetic polymorphisms, and familial clustering of other established risk factors, such as hypertension or diabetes. Modifiable risk factors in IHD. These include hyperlipidemia, hypertension, cigarette smoking, and diabetes. Hyperlipidemia—and more specifically hypercholesterolemia—is a major risk factor for atherosclerosis; even in the absence of other factors, hypercholesterolemia is sufficient to stimulate lesion development. The major component of serum cholesterol associated with increased risk is low-density lipoprotein (LDL) cholesterol (“bad cholesterol”); LDL cholesterol is the form of cholesterol that is delivered to peripheral tissues. In contrast, high-density lipoprotein (HDL, “good cholesterol”) mobilizes cholesterol from tissue and transports it to the liver for excretion in the bile. Consequently, higher levels of HDL correlate with reduced risk. Understandably, dietary and pharmacologic approaches that lower LDL or total serum cholesterol, and/or raise serum HDL, are of considerable interest. High dietary intake of cholesterol and saturated fats (present in egg yolks, animal fats, and butter, for example) raises plasma cholesterol levels. Conversely, diets low in cholesterol and/or with higher ratios of polyunsaturated fats lower plasma cholesterol levels. Omega-3 fatty acids (abundant in fish oils) are beneficial, whereas trans-unsaturated fats produced by artificial hydrogenation of polyunsaturated oils (used in baked goods and margarine) adversely affect cholesterol profiles. Exercise and moderate consumption of ethanol raise HDL levels, whereas obesity and smoking lower it. Statins are a class of drugs that lower circulating cholesterol levels by inhibiting hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in hepatic cholesterol biosynthesis. Hypertension (see above) is another major risk factor for atherosclerosis; both systolic and diastolic levels are important. On its own, hypertension increases the risk of IHD by approximately 60% (see Fig. 11-7 ). Hypertension is the most important cause of left ventricular hypertrophy and hence the latter is also related to IHD. Cigarette smoking is a well-established risk factor in men and probably accounts for the increasing incidence and severity of atherosclerosis in women. Prolonged (years) smoking of one pack of cigarettes or more daily doubles the death rate from IHD. Smoking cessation reduces the risk substantially. Diabetes mellitus induces hypercholesterolemia ( Chapter 24 ) and markedly increases the risk of atherosclerosis. Other factors being equal, the incidence of myocardial infarction is twice as high in diabetics as in nondiabetics. There is also an increased risk of strokes and a 100-fold increased risk of atherosclerosis-induced gangrene of the lower extremities 22  Pathogenesis of Atherosclerosis  Response to injury hypothesis  atherosclerosis as a chronic inflammatory and healing response of the arterial wall to endothelial injury. Lesion progression occurs through the interaction of modified lipoproteins, monocyte-derived macrophages and T-lymphocytes with the normal constituents of the arterial wall.  endothelial injury  accumulation of lipoproteins  monocyte adhesion to endothelium  platelet adhesion  factor release from platelets, macrophages & vascular wall cells  SMC proliferation and ECM production  lipid accumulation The clinical importance of atherosclerosis has stimulated enormous interest in understanding the mechanisms that underlie this disease and its complications. Historically, there have been two dominant hypotheses: one emphasizes intimal cellular proliferation, while the other focuses on the repetitive formation and organization of thrombi. The contemporary view of atherogenesis incorporates elements of both theories and also integrates the risk factors previously discussed.[40,] Called the response-to-injury hypothesis, the model views atherosclerosis as a chronic inflammatory and healing response of the arterial wall to endothelial injury. Lesion progression occurs through the interaction of modified lipoproteins, monocyte-derived macrophages, and T lymphocytes with the normal cellular constituents of the arterial wall ( Fig. 11-9 ). According to this model, atherosclerosis is produced by the following pathogenic events: Endothelial injury, which causes (among other things) increased vascular permeability, leukocyte adhesion, and thrombosis Accumulation of lipoproteins (mainly LDL and its oxidized forms) in the vessel wall Monocyte adhesion to the endothelium, followed by migration into the intima and transformation into macrophages and foam cells Platelet adhesion Factor release from activated platelets, macrophages, and vascular wall cells, inducing smooth muscle cell recruitment, either from the media or from circulating precursors Smooth muscle cell proliferation and ECM production Lipid accumulation both extracellularly and within cells (macrophages and smooth muscle cells) 23  Response to injury hypothesis FIGURE 11-9 Evolution of arterial wall changes in the response to injury hypothesis. 1, Normal. 2, Endothelial injury with adhesion of monocytes and platelets (the latter to sites where endothelium has been lost). 3, Migration of monocytes and smooth muscle cells into the intima. 4, Smooth muscle cell proliferation in the intima with ECM production. 5, Well-developed plaque. 24  Response to injury hypothesis 3, Migration of monocytes and smooth muscle cells into the intima. 4, Smooth muscle cell proliferation in the intima with ECM production. 5, Well-developed plaque. 25  HYPOTHETICAL SEQUENCE OF CELLULAR INTERACTIONS IN ATHEROSCLEROSIS Fig. 11-10 FIGURE 11-10 Hypothetical sequence of cellular interactions in atherosclerosis. Hyperlipidemia and other risk factors are thought to cause endothelial injury, resulting in adhesion of platelets and monocytes and release of growth factors, including platelet-derived growth factor (PDGF), which lead to smooth muscle cell migration and proliferation. Foam cells of atheromatous plaques are derived from both macrophages and smooth muscle cells—from macrophages via the very-low- density lipoprotein (VLDL) receptor and low-density lipoprotein (LDL) modifications recognized by scavenger receptors (e.g., oxidized LDL), and from smooth muscle cells by less certain mechanisms. Extracellular lipid is derived from insudation from the vessel lumen, particularly in the presence of hypercholesterolemia, and also from degenerating foam cells. Cholesterol accumulation in the plaque reflects an imbalance between influx and efflux, and high-density lipoprotein (HDL) probably helps clear cholesterol from these accumulations. Smooth muscle cells migrate to the intima, proliferate, and produce ECM, including collagen and proteoglycans. IL-1, interleukin-1; MCP-1, monocyte chemoattractant protein 1. Figure 11-10 highlights the concept of atherosclerosis as a chronic inflammatory response—and ultimately an attempt at vascular “healing”—driven by a variety of insults, including endothelial cell injury, lipid accumulation and oxidation, and thrombosis. Atheromas are dynamic lesions consisting of dysfunctional endothelial cells, recruited and proliferating smooth muscle cells, and admixed lymphocytes and macrophages. All four cell types are capable of liberating mediators that can influence atherogenesis. Thus, at early stages, intimal plaques are little more than smooth muscle cell and macrophage foam cell aggregates. With progression, the atheroma is modified by ECM synthesized by smooth muscle cells; connective tissue is particularly prominent in the intima, where it forms a fibrous cap, although lesions also typically retain a central core of lipid- laden cells and fatty debris that can become calcified. The intimal plaque may progressively encroach on the vessel lumen, or compress and cause degeneration of the underlying media; disruption of the fibrous cap can lead to thrombosis and acute vascular occlusion. 26  Morphology :Fatty streaks Fatty Streaks. Fatty streaks are the earliest lesions in atherosclerosis. They are composed of lipid-filled foamy macrophages. Beginning as multiple minute flat yellow spots, they eventually coalesce into elongated streaks 1 cm or more in length. These lesions are not significantly raised and do not cause any flow disturbance ( Fig. 11-11 ). Aortas of infants less than 1 year old can exhibit fatty streaks, and such lesions are seen in virtually all children older than 10 years, regardless of geography, race, sex, or environment. The relationship of fatty streaks to atherosclerotic plaques is uncertain; although they may evolve into precursors of plaques, not all fatty streaks are destined to become advanced lesions. Nevertheless, coronary fatty streaks begin to form in adolescence, at the same anatomic sites that later tend to develop plaques. 27  Morphology: Atherosclerotic plaques  Changes: -rupture, ulceration, erosion, thrombosis, hemorrhage, atheroembolism, aneurysm Atherosclerotic Plaque. The key processes in atherosclerosis are intimal thickening and lipid accumulation (see Fig. 11-10 ). Atheromatous plaques impinge on the lumen of the artery and grossly appear white to yellow; superimposed thrombus over ulcerated plaques is red- brown. Plaques vary from 0.3 to 1.5 cm in diameter but can coalesce to form larger masses ( Fig. 11-12 ). Atherosclerotic lesions are patchy, usually involving only a portion of any given arterial wall, and are rarely circumferential; on cross- section, the lesions therefore appear “eccentric” ( Fig. 11-13A ). The focality of atherosclerotic lesions—despite the uniform exposure of vessel walls to such factors as cigarette smoke toxins, elevated LDL, hyperglycemia, etc.—is attributable to the vagaries of vascular hemodynamics. Local flow disturbances (e.g., turbulence at branch points) leads to increased susceptibility of certain portions of a vessel wall to plaque formation. Though focal and sparsely distributed at first, atherosclerotic lesions can become more numerous and more diffuse with time. In humans, the abdominal aorta is typically involved to a much greater degree than the thoracic aorta. In descending order, the most extensively involved vessels are the lower abdominal aorta, the coronary arteries, the popliteal arteries, the internal carotid arteries, and the vessels of the circle of Willis. Vessels of the upper extremities are usually spared, as are the mesenteric and renal arteries, except at their ostia. Nevertheless, in an individual case, the severity of atherosclerosis in one artery does not predict its severity in another. Moreover, in any given vessel, lesions at various stages often coexist Atherosclerotic plaques are susceptible to the following clinically important changes (see also subsequent discussion): Rupture, ulceration, or erosion of the intimal surface of atheromatous plaques exposes the blood to highly thrombogenic substances and induces thrombosis. Such thrombosis can partially or completely occlude the lumen and lead to downstream ischemia ( Chapter 12 ) ( Fig. 11-14 ). If the patient survives the initial thrombotic occlusion, the clot may become organized and incorporated into the growing plaque. Hemorrhage into a plaque. Rupture of the overlying fibrous cap, or of the thin-walled vessels in the areas of neovascularization, can cause intra-plaque hemorrhage; a contained hematoma may expand the plaque or induce plaque rupture. Atheroembolism. Plaque rupture can discharge atherosclerotic debris into the bloodstream, producing microemboli. Aneurysm formation. Atherosclerosis-induced pressure or ischemic atrophy of the underlying media, with loss of elastic tissue, causes weakness resulting in aneurysmal dilation and potential rupture (see below). 28  Components: Morphology : Cells , ECM , Lipids FIGURE 11-13 Histologic features of atheromatous plaque in the coronary artery. A, Overall architecture demonstrating fibrous cap (F) and a central necrotic (largely lipid) core (C). The lumen (L) has been moderately compromised. Note that a segment of the wall is free of plaque (arrow); the lesion is therefore “eccentric”. In this section, collagen has been stained blue (Masson's trichrome stain). B, Higher power photograph of a section of the plaque shown in A, stained for elastin (black), demonstrating that the internal and external elastic membranes are attenuated and the media of the artery is thinned under the most advanced plaque (arrow). C, Higher magnification photomicrograph at the junction of the fibrous cap and core, showing scattered inflammatory cells, calcification (arrowhead) and neovascularization (small arrows). Atherosclerotic plaques have three principal components: (1) cells, including smooth muscle cells, macrophages, and T cells; (2) ECM, including collagen, elastic fibers, and proteoglycans; and (3) intracellular and extracellular lipid ( Fig. 11-13 ). These components occur in varying proportions and configurations in different lesions. Typically, there is a superficial fibrous cap composed of smooth muscle cells and relatively dense collagen. Beneath and to the side of the cap (the “shoulder”) is a more cellular area containing macrophages, T cells, and smooth muscle cells. Deep to the fibrous cap is a necrotic core, containing lipid (primarily cholesterol and cholesterol esters), debris from dead cells, foam cells (lipid-laden macrophages and smooth muscle cells), fibrin, variably organized thrombus, and other plasma proteins; the cholesterol is frequently present as crystalline aggregates that are washed out during routine tissue processing and leave behind only empty “clefts.” The periphery of the lesions show neovascularization (proliferating small blood vessels; Fig. 11-13C ). Typical atheromas contain abundant lipid, but some plaques (“fibrous plaques”) are composed almost exclusively of smooth muscle cells and fibrous tissue. 29  Consequences of Atherosclerotic Disease Principal outcomes  Smaller vessels can become occluded ischemia  Ruptured plaque can embolize distal vessel obstruction or to acute vascular thrombosis  Destruction of underlying vessel wall, which can lead to aneurysm secondary rupture and/or thrombosis Large elastic arteries (e.g., the aorta, carotid, and iliac arteries) and large and medium-sized muscular arteries (e.g., coronary and popliteal arteries) are the major targets of atherosclerosis. Symptomatic atherosclerotic disease most often involves the arteries supplying the heart, brain, kidneys, and lower extremities. Myocardial infarction (heart attack), cerebral infarction (stroke), aortic aneurysms, and peripheral vascular disease (gangrene of the legs) are the major consequences of atherosclerosis. The natural history, principal morphologic features, and main pathogenic events are schematized in Figure 11-15. The principal outcomes depend on the size of the involved vessels, the relative stability of the plaque itself, and the degree of degeneration of the underlying arterial wall: Smaller vessels can become occluded, compromising distal tissue perfusion. Ruptured plaque can embolize atherosclerotic debris and cause distal vessel obstruction, or can lead to acute (and frequently catastrophic) vascular thrombosis. Destruction of the underlying vessel wall can lead to aneurysm formation, with secondary rupture and/or thrombosis. 30  Consequences of atherosclerotic disease  Atherosclerotic stenosis  Effects of vascular occlusion depend on arterial supply and metabolic demand of the affected tissue  Acute plaque change  Plaque erosion or rupture is typically promptly followed by partial or complete vascular thrombosis resulting to acute tissue infarction  Rupture/fissuring  Erosion/ulceration  Hemorrhage into atheroma In small arteries, atherosclerotic plaques can gradually occlude vessel lumens, compromising blood flow and causing ischemic injury. At early stages of stenosis, outward remodeling of the vessel media tends to preserve luminal diameter as the total circumference expands. However, there are limits on this outward remodeling, and eventually the expanding atheroma impinges on blood flow. Critical stenosis is the Rubicon at which chronic occlusion significantly limits flow, and demand begins exceeding supply. In the coronary (and other) circulations, this typically occurs at approximately 70% fixed occlusion (i.e., loss of area through which blood can flow); at this degree of stenosis, patients classically develop chest pain (angina) on exertion (so- called stable angina; see Chapter 12 ). Although acute plaque rupture (below) is the most dangerous complication, atherosclerosis also takes a toll through chronically diminished arterial perfusion: mesenteric occlusion and bowel ischemia, chronic IHD, ischemic encephalopathy, and intermittent claudication (diminished extremity perfusion) are all consequences of flowlimiting stenoses. The effects of vascular occlusion ultimately depend on arterial supply and the metabolic demand of the affected tissue. Acute Plaque Change. Plaque erosion or rupture is typically promptly followed by partial or complete vascular thrombosis (see Fig. 11-14 ), resulting in acute tissue infarction (e.g., myocardial or cerebral infarction).[40,] Plaque changes fall into three general categories: Rupture/fissuring, exposing highly thrombogenic plaque constituents Erosion/ulceration, exposing the thrombogenic subendothelial basement membrane to blood Hemorrhage into the atheroma, expanding its volume It is now recognized that the precipitating lesion in patients who develop myocardial infarction and other acute coronary syndromes is not necessarily a severely stenotic and hemodynamically significant lesion before its acute change. Pathologic and clinical studies show that the majority of plaques that undergo abrupt disruption and coronary occlusion previously showed only mild to moderate luminal stenosis. The worrisome conclusion is that a rather large number of now asymptomatic adults may well have a real but unpredictable risk of a catastrophic coronary event. Regrettably, it is presently impossible to reliably detect individuals who will have plaque disruption or subsequent thrombosis. The events that trigger abrupt changes in plaque configuration and superimposed thrombosis are complex and include both intrinsic factors (e.g., plaque structure and composition) and extrinsic factors (e.g., blood pressure, platelet reactivity)[40,]; rupture of a plaque indicates that it was unable to withstand the mechanical stresses of vascular shear forces. We next discuss the intrinsic and extrinsic factors that influence the risk of plaque rupture. It is important to remember that the composition of plaques is dynamic and can materially contribute to risk of rupture. Thus, plaques that contain large areas of foam cells and extracellular lipid, and those in which the fibrous caps are thin or contain few smooth muscle cells or have clusters of inflammatory cells, are more likely to rupture, and are therefore called “vulnerable plaques 31  Consequences of Atherosclerotic Disease  Thrombosis  Can embolize (mural thrombus in artery)  Can contribute to the growth of atherosclerotic plaque  Vasoconstriction  Stimulated by  Circulating adrenergic agonists,  Locally released platelet contents  Impaired secretion of endothelial relaxing factors  Mediators released from perivascular inflammatory cells Thrombosis. As mentioned above, partial or total thrombosis associated with a disrupted plaque is critical to the pathogenesis of the acute coronary syndromes. In the most serious form, thrombus superimposed on a disrupted but previously only partially stenotic plaque converts it to a total occlusion. In contrast, in other coronary syndromes ( Chapter 12 ), luminal obstruction by thrombosis is usually incomplete, and can even wax and wane with time. Mural thrombus in a coronary artery can also embolize. Indeed, small fragments of thrombotic material in the distal intra-myocardial circulation or microinfarcts can be found at autopsy in patients after sudden death or in rapidly accelerating anginal syndromes. Finally, thrombus is a potent activator of multiple growth-related signals in smooth muscle cells, which can contribute to the growth of atherosclerotic lesions. Vasoconstriction. Vasoconstriction compromises lumen size, and, by increasing the local mechanical forces can potentiate plaque disruption. Vasoconstriction at sites of atheroma is stimulated by (1) circulating adrenergic agonists, (2) locally released platelet contents, (3) impaired secretion of endothelial cell relaxing factors (nitric oxide) relative to contracting factors (endothelin) as a result of endothelial cell dysfunction, and possibly (4) mediators released from perivascular inflammatory cells. 32 Consequences of Atherosclerotic Disease  Most commonly involved blood vessels  Lower abdominal aorta  Coronary arteries  Popliteal arteries  Internal carotid artery  Vessels of the circle of Willis  Major clinical consequences  Myocardial infarction (heart attack)  Cerebral infarction (stroke)  Aortic aneurysms  Peripheral vascular disease (gangrene of the LE) 33 34 35  Aneurysms and Dissection  Localized abnormal dilatation of a blood vessel or the heart  Congenital or acquired; fusiform or saccular  True aneurysm  Atherosclerotic  Syphilitic  Congenital vascular  Ventricular  False (pseudoaneurysm)  Extravascular hematoma that freely communicates with intravascular space An aneurysm is a localized abnormal dilation of a blood vessel or the heart ( Fig. 11-17 ); it can be congenital or acquired. When an aneurysm involves an intact attenuated arterial wall or thinned ventricular wall of the heart, it is called a true aneurysm. Atherosclerotic, syphilitic, and congenital vascular aneurysms, and ventricular aneurysms that follow transmural myocardial infarctions are of this type. In contrast, a false aneurysm (also called pseudo- aneurysm) is a defect in the vascular wall leading to an extravascular hematoma that freely communicates with the intravascular space (“pulsating hematoma”). Examples include a ventricular rupture after myocardial infarction that is contained by a pericardial adhesion, or a leak at the sutured junction of a vascular graft with a natural artery. An arterial dissection arises when blood enters the arterial wall itself, as a hematoma dissecting between its layers. Dissections are often but not always aneurysmal (see also below). Both true and false aneurysms as well as dissections can rupture, often with catastrophic consequences Aneurysms are generally classified by shape and size (see Fig. 11-17 ). Saccular aneurysms are spherical outpouchings (involving only a portion of the vessel wall); they vary from 5 to 20 cm in diameter and often contain thrombus. Fusiform aneurysms involve diffuse, circumferential dilation of a long vascular segment; they vary in diameter (up to 20 cm) and in length, and can involve extensive portions of the aortic arch, abdominal aorta, or even the iliac arteries. These types are not specific for any disease or clinical manifestations 36 37  Pathogenesis of Aneurysm  Weakening of vessels walls  Intrinsic quality of the vascular connective tissue is poor  Marfan syndrome - fibrillin  Loeys-Dietz syndrome –abn elastin, and col I & III  Ehlers Danlos syndrome – defect col III synthesis  Vit c def – defect in collagen cross-linking  Balance of collagen synthesis and degradation is altered by local inflammatory infiltrates and the destructive proteolytic enzymes they produce – inc MMT, dec TIMP  Vascular wall is weakened by loss of SMC or inappropriate synthesis of noncollagenous or nonelastic ECM  Stenosis of vasa vasorum Arteries are dynamically remodeling tissues that maintain their integrity by constantly synthesizing, degrading, and repairing damage to their ECM constituents. Aneurysms can occur when the structure or function of the connective tissue within the vascular wall is compromised. Although we cite here examples of inherited defects in connective tissues, weakening of vessel walls is important in the common, sporadic forms of aneurysms as well. The intrinsic quality of the vascular wall connective tissue is poor. In Marfan syndrome, for example ( Chapter 5 ), defective synthesis of the scaffolding protein fibrillin leads to aberrant TGF-β activity and progressive weakening of elastic tissue; in the aorta, the consequence is progressive dilation due to remodeling of the inelastic media. Loeys-Dietz syndrome is another recently recognized cause of aneurysms; in this disorder, mutations in TGF-β receptors lead to abnormalities in elastin and collagen I and III. Aneurysms in such individuals can rupture fairly easily (even at small size). Weak vessel walls due to defective type III collagen synthesis are also a hallmark of the vascular forms of Ehlers-Danlos syndrome ( Chapter 5 ), and altered collagen cross-linking associated with vitamin C (ascorbate) deficiency is an example of a nutritional basis for aneurysm formation. The balance of collagen degradation and synthesis is altered by local inflammatory infiltrates and the destructive proteolytic enzymes they produce. In particular, increased MMP production, especially by macrophages in atherosclerotic plaque or in vasculitis, probably contributes to aneurysm development; these enzymes have the capacity to degrade virtually all components of the ECM in the arterial wall (collagens, elastin, proteoglycans, laminin, fibronectin). Concurrently, decreased tissue inhibitor of metalloproteinase (TIMP) expression can also contribute to the overall ECM degradation. Genetic predisposition to aneurysm formation in the setting of inflammatory lesions (such as atherosclerosis) may be related to polymorphisms of MMP and/or TIMP genes, or to the nature of the local inflammatory response that results in increased production of MMP. The vascular wall is weakened through loss of smooth muscle cells or the inappropriate synthesis of noncollagenous or nonelastic ECM. Ischemia of the inner media occurs when there is atherosclerotic thickening of the intima, which increases the distance that oxygen and nutrients must diffuse. Systemic hypertension can also cause significant narrowing of arterioles of the vasa vasorum (e.g., in the aorta), which can cause outer medial ischemia. Ischemia is reflected in “degenerative changes” of the aorta, whereby smooth muscle cell loss—or change in synthetic phenotype—leads to scarring (and loss of elastic fibers), inadequate ECM synthesis, and production of increasing amounts of amorphous ground substance (glycosaminoglycan). Histologically these changes are collectively called cystic medial degeneration ( Fig. 11-18 ). These changes are nonspecific and can be seen in a variety of settings, including Marfan disease and scurvy. 38 39  Pathogenesis of Aneurysm  The most important disorders that predispose to aortic aneurysm are  Atherosclerosis – abdominal aa  Hypertension – ascending aorta Others trauma vasculitis infections (Mycotic aneurysm) congenital defects (“berry” aneurysm) The two most important disorders that predispose to aortic aneurysms are atherosclerosis and hypertension; atherosclerosis is a greater factor in abdominal aortic aneurysms, while hypertension is the most common condition associated with aneurysms of the ascending aorta. Other conditions that weaken vessel walls and lead to aneurysms include trauma, vasculitis (see below), congenital defects (e.g., berry aneurysms typically in the circle of Willis; Chapter 28 ), and infections (mycotic aneurysms). Mycotic aneurysms can originate (1) from embolization of a septic embolus, usually as a complication of infective endocarditis; (2) as an extension of an adjacent suppurative process; or (3) by circulating organisms directly infecting the arterial wall. Tertiary syphilis is now a rare cause of aortic aneurysms. The obliterative endarteritis characteristic of late-stage syphilis shows a predilection for small vessels, including those of the vasa vasorum of the thoracic aorta. This leads to ischemic injury of the aortic media and aneurysmal dilation, which sometimes involves the aortic valve annulus. 40 Aneurysm Mycotic aneurysm can originate 1. From embolization of septic embolus, usually as a complication of infective endocarditis 2. As an extension of an adjacent suppurative process 3. By circulating organisms directly infecting the arterial wall 41  Dissection  Arises when blood enters the arterial wall, as a hematoma dissect between its layers 42  ABDOMINAL AORTIC ANEURYSM  In men  Smokers, rarely develop before age 50  Atherosclerosis is the major cause Clinical consequences  rupture into peritoneal cavity or retroperitoneal tissue with fatal hemorrhage  Obstruction of a branch vessel  Embolism from atheroma or mural thrombus  Impingement on an adjacent structure  Presentation as an abdominal mass 43  ABDOMINAL AORTIC ANEURYSM Risk of rupture  Directly related to size of aneurysm; 6 cm, 25% peryear Treatment  Surgical bypass / Endoluminal stent grafts  Timely surgery is critical  Operative mortality is 5% in unruptured  Ruptured- >50% mortality 6 cm – 25% per year 5 cm and > - manage aggressively by surgical bypass using prosthetic graft but evolving towards the use of endoluminal stent grafts 44  AAAs Saccular or fusiform Below the renal arteries & above the bifurcation of aorta Variants: Inflammatory AAAs Mycotic AAAs Two AAA variants merit special mention: Inflammatory AAAs are characterized by dense periaortic fibrosis containing abundant lymphoplasmacytic inflammation with many macrophages and often giant cells. Their cause is uncertain. Mycotic AAAs are lesions that have become infected by the lodging of circulating microorganisms in the wall, particularly in bacteremia from a primary Salmonella gastroenteritis. In such cases suppuration further destroys the media, potentiating rapid dilation and rupture. 45  THORACIC AORTIC ANEURYSM  Most commonly associated with hypertension Signs and symptoms  encroachment on mediastinal structures  Respiratory difficulties due to encroachment on lungs/airways  Difficulty in swallowing due to esophageal compression  Persistent cough due to irritation of or pressure on the recurrent laryngeal nerves  Pain caused by erosion of bone  Cardiac disease due to aortic valve dilation or narrowing of coronary ostia  rupture Thoracic aortic aneurysms are most commonly associated with hypertension, although other causes such as Marfan and Loeys-Dietz syndromes are increasingly recognized. Regardless of etiology, these give rise to signs and symptoms referable to (1) encroachment on mediastinal structures, (2) respiratory difficulties due to encroachment on the lungs and airways, (3) difficulty in swallowing due to compression of the esophagus, (4) persistent cough due to irritation of or pressure on the recurrent laryngeal nerves, (5) pain caused by erosion of bone (i.e., ribs and vertebral bodies), (6) cardiac disease as the aortic aneurysm leads to aortic valve dilation with valvular insufficiency or narrowing of the coronary ostia causing myocardial ischemia, and (7) rupture. Most patients with syphilitic aneurysms die of heart failure induced by aortic valvular incompetence. 46 THORACIC AORTIC ANEURYSM 47  AORTIC DISSECTION  Occurs when blood splays apart the laminar planes of the media to form a blood-filled channel within the aortic wall  Two groups  Men aged 40 to 60 , with antecedent hypertension, >90%  Younger patients with systemic or localized abnormalities of CT affecting the aorta Aortic dissection occurs when blood splays apart the laminar planes of the media to form a blood-filled channel within the aortic wall ( Fig. 11-20 ); this can be catastrophic if the dissection then ruptures through the adventitia and hemorrhages into adjacent spaces. In contrast to atherosclerotic and syphilitic aneurysms, aortic dissection may or may not be associated with aortic dilation. Consequently, the older term “dissecting aneurysm” should be avoided. Aortic dissection occurs principally in two groups: (1) men aged 40 to 60, with antecedent hypertension (more than 90% of cases of dissection); and (2) younger patients with systemic or localized abnormalities of connective tissue affecting the aorta (e.g., Marfan syndrome). 48  AORTIC DISSECTION  Dissection can be iatrogenic  Dissection is unusual in the presence of substantial atherosclerosis or other cause of medial scarring such as syphilis, because the medial fibrosis inhibits propagation of the dissecting hematoma Dissections can also be iatrogenic (e.g., complicating arterial cannulations during diagnostic catheterization or cardiopulmonary bypass). Rarely, for unknown reasons, dissection of the aorta or other branches, including the coronary arteries, occurs during or after pregnancy. Dissection is unusual in the presence of substantial atherosclerosis or other cause of medial scarring such as syphilis, presumably because the medial fibrosis inhibits propagation of the dissecting hematoma. 49  AORTIC DISSECTION Cystic medial degeneration Inflammation is absent Usually initiates with intimal tear Intramural hematoma Dissecting hematoma spreads along laminar planes of aorta Hematoma may reenter the lumen of aorta through second distal intimal tear creating “double barreled aorta” FIGURE 11-20 Aortic dissection. A, An opened aorta with proximal dissection originating from a small, oblique intimal tear (identified by the probe), allowing blood to enter the media and creating an intramural hematoma (narrow arrows). Note that the intimal tear has occurred in a region largely free of atherosclerotic plaque and that propagation of the intramural hematoma is arrested at a site more distally where atherosclerosis begins (broad arrow). B, Histologic view of the dissection demonstrating an aortic intramural hematoma (asterisk). Aortic elastic layers are black and blood is red in this section, stained with the Movat stain. Pathogenesis. Hypertension is the major risk factor in aortic dissection. Aortas of hypertensive patients have medial hypertrophy of the vasa vasorum associated with degenerative changes in the aortic media and variable loss of medial smooth muscle cells, suggesting that pressure-related mechanical injury and/or ischemic injury (due to diminished flow through the vasa vasorum) is contributory. A considerably smaller number of dissections are related to inherited or acquired connective tissue disorders causing abnormal vascular ECM (e.g., Marfan syndrome, Ehlers-Danlos syndrome, vitamin C deficiency, copper metabolic defects). However, recognizable medial damage seems to be neither a prerequisite for dissection nor a guarantee that dissection is imminent. Regardless of the underlying etiology causing medial weakness, the trigger for the intimal tear and initial intramural aortic hemorrhage is not known in most cases. Nevertheless, once the tear has occurred, blood flow under systemic pressure dissects through the media, fostering progression of the medial hematoma. Accordingly, aggressive pressure-reducing therapy may be effective in limiting an evolving dissection. In some cases disruption of penetrating vessels of the vasa vasorum can give rise to an intramural hematoma without an intimal tear. Morphology. In most cases, no specific underlying causal pathology is identified in the aortic wall. The most frequent preexisting histologically detectable lesion is cystic medial degeneration (see Fig. 11-18 ); inflammation is characteristically absent. However, dissections can occur in the setting of rather trivial medial degeneration, and the relationship of the structural changes to the pathogenesis of dissection is uncertain. An aortic dissection usually initiates with an intimal tear. In the vast majority of spontaneous dissections, the tear is found in the ascending aorta, usually within 10 cm of the aortic valve ( Fig. 11-20A ). Such tears are typically transverse or oblique and 1 to 5 cm in length, with sharp, jagged edges. The dissection can extend along the aorta retrograde toward the heart as well as distally, sometimes into the iliac and femoral arteries. The dissecting hematoma spreads characteristically along the laminar planes of the aorta, usually between the middle and outer thirds ( Fig. 11-20B ). It often ruptures out through the adventitia causing massive hemorrhage (e.g., in the thoracic or abdominal cavities) or cardiac tamponade (hemorrhage into the pericardial sac). In some (lucky) instances, the dissecting hematoma reenters the lumen of the aorta through a second distal intimal tear, creating a new vascular channel and forming a “double-barreled aorta” with a false channel. This averts a fatal extra-aortic hemorrhage. In the course of time, false channels may be endothelialized and become chronic dissections. 50  AORTIC DISSECTION  The most common cause of death is rupture of the dissection outward into the pericardial, pleural or peritoneal cavities  Clinical manifestations  Cardiac tamponade  Aortic insufficiency  Myocardial infarction  Extension into great arteries of neck or other arteries  Compression of spinal arteries transverse myelitis The classic clinical symptoms of aortic dissection are the sudden onset of excruciating pain, usually beginning in the anterior chest, radiating to the back between the scapulae, and moving downward as the dissection progresses; the pain can be confused with that of myocardial infarction. The most common cause of death is rupture of the dissection outward into the pericardial, pleural, or peritoneal cavities. Retrograde dissection into the aortic root can cause disruption of the aortic valvular apparatus. Thus, common clinical manifestations include cardiac tamponade, aortic insufficiency, and myocardial infarction or extension of the dissection into the great arteries of the neck or into the coronary, renal, mesenteric, or iliac arteries, causing critical vascular obstruction and associated ischemic consequences; compression of spinal arteries may cause transverse myelitis. In the past aortic dissection was typically fatal, but the prognosis has markedly improved. Rapid diagnosis and institution of intensive antihypertensive therapy, coupled with surgical procedures involving plication of the aortic wall, permit 65% to 75% of stricken individuals to be saved. 51  DeBakey I DeBakey II DeBakey III De Bakey Classification of Dissection Type A (Proximal) – ascending portion only or both the ascending and descending aorta Type B (Distal) arise beyond take off of the great vessels Treatment: rapid dx + Intensive anti-HPN + Plication of aorta; 65 – 75% saved The risk and nature of complications of aorta dissection depend strongly on the region(s) affected; the most serious complications occur with dissections that involve the aorta from the aortic valve to the arch. Thus, aortic dissections are generally classified into two types ( Fig. 11-21 ). They are named after Dr. Michael DeBakey, a pioneer in vascular surgery. More common (and dangerous) proximal lesions (called type A dissections), involving either both the ascending and descending aorta or just the ascending aorta (types I and II of the DeBakey classification) Distal lesions not involving the ascending part and usually beginning distal to the subclavian artery (called type B dissections or DeBakey type III) 52  VASCULITIS  Vessel wall inflammation  Signs and symptoms:  fever, myalgia, arthralgia, malaise  Pathogenic mechanisms  Immune mediated inflammation  Direct invasion of vascular walls by infectious pathogens 53  NON INFECTIOUS VASCULITIS Immune complex-associated Vasculitis  Antibody and complement are detected  Antigen and antibody complexes may also be seen  Association with drug hypersensitivity  PENICILLINS  Secondary to viral infections  Antibody to viral proteins forming immune complexes  Hep B in patients with PAN 54 NON INFECTIOUS VASCULITIS Antineutrophil Cytoplasmic Antibodies  Circulating antibodies that react with neutrophil cytoplasmic antigens  Heterogenous autoantibodies directed against contituents of neutrophil primary granules, monocyte lysosomes, and endothelial cells  Anti myeloperoxidase (MPO-ANCA)- generate free radicals  -can be induced by therapeutic agents; p-ANCA  Anti proteinase -3 (PR3-ANCA)-  c-ANCA 55  NON INFECTIOUS VASCULITIS Mechanism for ANCA vasculitis  Drugs or cross reactive microbial antigens induce ANCAs  Subsequent infection, endotoxin exposure elicit cytokines that cause surface expression of PR3 and MPO on neutrophils and other cells  ANCAs react with these cytokine activated cells and cause injury (to the endothelium) or induce further activation (in neutrophils)  ANCA-activated neutrophils degranulate and cause injury by releasing reactive oxygen species, causing endothelial cell toxicity and other indirect tissue injury 56 NON INFECTIOUS VASCULITIS Anti Endothelial Cell Antibodies  Antibodies to endothelial cells (e.g. Kawasaki disease) 57 Vasculitis 58  GIANT-CELL (TEMPORAL) ARTERITIS  Most common form of vasculitis among elderly in US and Eu.  Chronic, typically granulomatous inflammation of large to small-sized arteries in the head  Temporal, vertebral, ophthalmic arteries  Ophthalmic artery involvement can lead to blindness  May also affect the aorta  Involves T-cell immune mediated response  Pro inflammatory cytokines like TNF and anti endothelial cell humoral response 59  GIANT-CELL (TEMPORAL) ARTERITIS  Rare before age 50  Constitutional symptoms  Fever fatigue weight loss  Facial pain  Headache  Diplopia to complete vision loss  Diagnosis: biopsy but negative biopsy does not exclude the diagnosis  Treatment: corticosteroid 60  GIANT-CELL (TEMPORAL) ARTERITIS  Degenerated internal elastic lamina  Nodular intimal thickening  Reduction of luminal diameter  Multinucleated giant cells  Nonspecific panarteritis  Healed staged- fibrosis 61  TAKAYASU ARTERITIS  Granulomatous vasculitis of medium and larger arteries ; Pulseless disease  Ocular disturbances  Weakening of the pulses in upper extremities  Transmural fibrous thickening of aorta (aortic arch and great vessels)  Luminal narrowing of major branch vessels  Aortic lesions similar with other giant cell aortitis  >50 yrs- giant cell aortitis  > neural involvement  Chronic ulceration of toes, feet, fingers followed by gangrene 82  INFECTIOUS VASCULITIS  Localized arteritis  Direct invasion of infectious agents  Aspergillus and Mucor  Hematogenous seeding of bacteria  Septicemia  Embolization from sepsis of infective endocarditis  Can weaken arterial walls and culminate in MYCOTIC ANEURYSMS or induce thrombosis and infarction. 83 84  RAYNAUD PHENOMENON  Result from exaggerated vasoconstriction of digital arteries and arterioles  Paroxysmal pallor of the hands and feet  Nose, earlobes, or lips maybe involved  Change color from red , white and blue from most proximal to distal 85  RAYNAUD PHENOMENON Primary Raynaud Phenomenon (Raynaud disease)  Exaggeration of central and local vasomotor re