Robbins & Cotran Pathologic Basis of Disease PDF

See TARGETED THERAPY available online at www.studentconsult.com C H A P T E R Blood Vessels Richard N. Mitchell Marc K. Halushka...

See TARGETED THERAPY available online at www.studentconsult.com C H A P T E R Blood Vessels Richard N. Mitchell Marc K. Halushka 11 CHAPTER CONTENTS Vascular Structure and Function 485 Vasculitis 508 Veins and Lymphatics 517 Vascular Anomalies 487 Noninfectious Vasculitis 509 Varicose Veins 517 Vascular Wall Response to Immune Complex–Associated Vasculitis 509 Thrombophlebitis and Injury 487 Antineutrophil Cytoplasmic Antibodies 510 Phlebothrombosis 517 Intimal Thickening: A Stereotyped Anti–Endothelial Cell Antibodies 511 Superior and Inferior Vena Caval Response to Vascular Injury 488 Giant Cell (Temporal) Arteritis 511 Syndromes 517 Hypertensive Vascular Disease 489 Takayasu Arteritis 512 Lymphangitis and Lymphedema 518 Blood Pressure Regulation 490 Polyarteritis Nodosa (PAN) 513 Vascular Tumors 518 Vascular Pathology in Hypertension 492 Kawasaki Disease 513 Benign Tumors and Tumor-Like Arteriosclerosis 493 Microscopic Polyangiitis 513 Conditions 518 Atherosclerosis 493 Granulomatosis With Polyangiitis (GPA) 514 Intermediate-Grade (Borderline) Risk Factors 494 Churg-Strauss Syndrome 515 Tumors 520 Constitutional Risk Factors 494 Thromboangiitis Obliterans (Buerger Malignant Tumors 522 Modifiable Major Risk Factors 495 Disease) 515 Pathology of Vascular Additional Risk Factors 496 Vasculitis Associated With Other Noninfectious Intervention 523 Consequences of Atherosclerotic Disorders 515 Endovascular Stenting 523 Disease 502 Infectious Vasculitis 516 Vascular Replacement 523 Aneurysms and Dissection 504 Disorders of Blood Vessel Abdominal Aortic Aneurysm 506 Hyperreactivity 516 Thoracic Aortic Aneurysm 507 Raynaud Phenomenon 516 Aortic Dissection 507 Myocardial Vessel Vasospasm 517 Vascular pathology is responsible for more morbidity and veins at the same level of branching to accommodate pulsatile mortality than any other category of human disease. flow and higher blood pressures. Arterial wall thickness Although the most clinically significant lesions involve gradually diminishes as the vessels become smaller, but arteries, venous disorders are not inconsequential. Two the ratio of wall thickness to lumen diameter increases, principal mechanisms underlie vascular disease: allowing these muscular vessels to exert control over blood Narrowing (stenosis) or complete obstruction of vessel lumens, flow and pressure. Many disorders of the vasculature affect either progressively (e.g., by atherosclerosis) or precipi- only particular types of vessels and thus have characteristic tously (e.g., by thrombosis or embolism) anatomic distributions. Thus atherosclerosis affects mainly Weakening of vessel walls, leading to dilation or rupture elastic and muscular arteries, hypertension affects small muscular arteries and arterioles, and different varieties of To better appreciate the pathogenesis of vascular disor- vasculitis characteristically involve only vessels of a certain ders, it is important to first understand the normal vessel caliber. structure and function. The basic constituents of the walls of blood vessels are endothelial cells (ECs) and smooth muscle cells (SMCs), admixed with a variety of extracellular matrix (ECM) includ- VASCULAR STRUCTURE AND ing elastin, collagen, and glycosaminoglycans. The relative FUNCTION amount and configuration of the basic constituents differ along the vasculature owing to local adaptations to mechanical or The general architecture and cellular composition of blood metabolic needs. In arteries and veins, these constituents are vessels are comparable throughout the cardiovascular system. organized into three concentric layers—intima, media, and However, structural specializations that reflect distinct func- adventitia, which are anatomically more distinct in the arteries. tional roles characterize specific kinds of vessels (Fig. 11.1). The intima normally consists of a single layer of ECs For example, arterial walls are thicker than corresponding attached to a basement membrane with a thin underlying 485 486 C H A P T E R 11 Blood Vessels LOW PRESSURE HIGH PRESSURE Elastic artery Muscular artery Lumen Aorta Adventitia Large vein Intima Media Internal elastic lamina Intima Media Medium vein Muscular artery Lumen Adventitia Venule Arteriole Adventitia Pericytes BLOOD Media Intima PRESSURE CONTROL Post-capillary Capillary venule Endothelial cell Intima Media Adventitia GAS AND NUTRIENT EXCHANGE Figure 11.1 Regional specializations of the vasculature. Although the basic organization of the vasculature is constant, the thickness and composition of the various layers differs according to hemodynamic forces and tissue requirements. Thus, the aorta and other elastic arteries have substantial elastic tissue to accommodate high pulsatile forces, with the capacity to recoil and transmit energy into forward blood flow. These vessels have lamellar units that are comprised of repetitions of a layer of elastic fibers, a smooth muscle cell, and intervening extracellular matrix. Purely muscular arteries have elastic fibers only at the intersection of the intima and media or media and adventitia. In comparison, the venous system has relatively poorly developed thinner medial layers that permit greater capacitance, and the capillary wall permits ready diffusion of oxygen and nutrients because it is comprised only of an endothelial cell and sparse encircling pericytes. The different structure and functional attributes also influence the disorders that can affect the various parts of the vascular tree. Thus, loss of aortic elastic tissue will result in aneurysm, while stasis in a dilated venous bed can result in thrombosis. layer of ECM; the intima is demarcated from the media caused by structural changes or vasoconstriction can by the internal elastic lamina. have profound effects on blood pressure. The media of elastic arteries (e.g., the aorta) are arranged The adventitia lies external to the media and in many in layers of lamellar units of elastin fibers and SMCs arteries is separated from the media by a well-defined akin to tree rings. This high elastin content allows these external elastic lamina. The adventitia consists of loose vessels to expand during systole and recoil during connective tissue and can also contain nerve fibers. Dif- diastole—functionally propelling blood toward the tissues. fusion of oxygen and nutrients from the lumen is adequate With aging and the loss of elasticity, the aorta and larger to sustain thin-walled vessels and the innermost SMCs arteries become less compliant; besides transmitting higher of all vessels. In large- and medium-sized vessels, pressures into distal tissues, the arteries of older indi- however, small arterioles within the adventitia (called viduals often become progressively tortuous and dilated vasa vasorum—literally, “vessels of the vessels”) perfuse (ectatic). the outer half to two-thirds of the media. In muscular arteries, the media is composed predomi- nantly of circumferentially oriented SMCs. Arteriolar As already alluded to, arteries are divided into three SMC contraction (vasoconstriction) or relaxation types based on their size and structural features: (1) large (vasodilation) is regulated by inputs from the auto- or elastic arteries including the aorta, the major branches nomic nervous system and local metabolic factors. of the aorta (innominate, subclavian, common carotid, and Arterioles are the principal points of physiologic resistance iliac), and pulmonary arteries; (2) medium-sized or muscular to blood flow. Since the resistance to fluid flow is arteries comprising smaller branches of the aorta (e.g., inversely proportional to the fourth power of the coronary and renal arteries); and (3) small arteries (≤2 mm diameter (i.e., halving the diameter increases resistance in diameter) and arterioles (20 to 100 µm in diameter) within 16-fold), small decreases in the lumen size of arterioles tissues and organs.  Vascular wall response to injury 487 Capillaries are slightly smaller (5 µm) than the diameter Developmental or berry aneurysms occur in cerebral vessels; of a red blood cell (7 to 8 µm); they have an EC lining but when ruptured, these can cause fatal intracerebral hemor- no media, although variable numbers of pericytes, cells that rhage (Chapter 28). resemble SMCs, typically lie just deep to the endothelium. Arteriovenous fistulas are direct connections (usually small) Collectively, capillaries have a huge cross-sectional area and between arteries and veins that bypass capillaries. They also have a relatively low flow rate. The combination of occur most commonly as developmental defects but can thin walls and slow flow makes capillaries ideally suited also result from rupture of an arterial aneurysm into the for the exchange of diffusible substances between blood adjacent vein, from penetrating injuries that pierce arteries and tissues. Because functionally useful oxygen diffusion and veins, or from inflammatory necrosis of adjacent is limited to a distance of only approximately 100 µm, the vessels. Surgically generated arteriovenous fistulas capillary network of most tissues is very rich. Tissues with provide vascular access for chronic hemodialysis. Like high metabolic rates such as myocardium and brain have berry aneurysms, arteriovenous fistulas can rupture. Large the highest density of capillaries. or multiple arteriovenous fistulas become clinically Blood from capillary beds flows into postcapillary venules significant by shunting blood from the arterial to the and then sequentially through collecting venules and small, venous circulations, forcing the heart to pump additional medium, and large veins. In most forms of inflammation, volume and leading to high-output cardiac failure. vascular leakage and leukocyte exudation occur preferentially Fibromuscular dysplasia is a focal irregular thickening in from postcapillary venules (Chapter 3). medium and large muscular arteries including renal, Relative to arteries at the same level of branching, veins carotid, splanchnic, and vertebral vessels. The cause is have larger diameters, larger lumens, and thinner and less unknown. Segments of the vessel wall are focally thick- well-organized walls (see Fig. 11.1). These structural features ened by a combination of medial and intimal hyperplasia augment the capacitance of the venous side of the circulation, and fibrosis, resulting in luminal stenosis. In the renal which on average contains about two-thirds of total blood arteries, it can be a cause of renovascular hypertension volume. Reverse flow (due to gravity) is prevented in the (Chapter 20). Immediately adjacent vessel segments can extremities by venous valves. have markedly attenuated media (on angiography the Lymphatics are thin-walled, endothelium-lined channels vessels are said to have a “string of beads” appearance) that drain lymph (water, electrolytes, glucose, fat, proteins, leading to vascular outpouchings (aneurysms) that can and inflammatory cells) from the interstitium of tissues, even- rupture. tually reconnecting with the blood stream via the thoracic Anomalous coronary artery origin occurs from a develop- duct. Lymphatics transport interstitial fluid and inflammatory mental anomaly in which both coronary arteries arise cells from the periphery to lymph nodes, thereby facilitat- over the same coronary cusp of the aortic valve. Although ing antigen presentation and cell activation in the nodal many of these anomalies are benign, when a coronary tissues—and enabling continuous monitoring of peripheral vessel passes between the aorta and pulmonary artery tissues for infection. This can be a double-edged sword, it can be squeezed, for example, during exercise, limiting however, as these channels can also disseminate disease by blood flow and resulting in sudden death. transporting microbes or tumor cells to distant sites. VASCULAR WALL RESPONSE KEY CONCEPTS TO INJURY VASCULAR STRUCTURE AND FUNCTION The integrated functioning of ECs and SMCs impacts physi- All vessels except capillaries share a general three-layered ologic and pathophysiologic responses to hemodynamic architecture consisting of an endothelial-lined intima, surrounding and biochemical stimuli. Their function (and dysfunction) smooth muscle media, and supportive adventitia. are described briefly, followed by discussion of specific The SMCs and ECM of arteries, veins, and capillaries vary vascular disorders. according to hemodynamic demands (e.g., pressure, pulsatility) ECs form a specialized simple squamous epithelium lining and functional requirements. for blood vessels. Although ECs throughout the vascular The specific composition of the vessel wall at any given site tree share many attributes, populations that line different within the vascular tree influences the nature and consequences portions of the vascular tree (large vessels vs. capillaries, of pathologic injuries. arteries vs. veins) have distinct gene expression profiles, behaviors, and morphologic appearances. Thus ECs in liver sinusoids or in renal glomeruli are fenestrated (they have holes, presumably to facilitate filtration), while central VASCULAR ANOMALIES nervous system ECs (along with the associated perivascular cells) create an impermeable blood-brain barrier. Although rarely symptomatic, anatomic variants of the usual ECs are versatile multifunctional cells with a wealth of vascular supply are important to recognize, as the failure synthetic and metabolic properties. In the normal state they to do so may lead to surgical complications and impede have several constitutive activities that are critical for vessel attempted therapeutic interventions (e.g., placement of homeostasis and circulatory function (Table 11.1). Unless coronary artery stents). Among the other congenital vascular injured or otherwise activated, ECs have a nonthrombogenic anomalies, four are particularly significant, although not surface that maintains blood in a fluid state (Chapter 4). necessarily common. They also modulate medial SMC tone (thereby influencing 488 C H A P T E R 11 Blood Vessels Table 11.1 Endothelial Cell Properties and Functions formation, atherosclerosis, and the vascular lesions of Property/Function Mediators/Products hypertension and other disorders. Certain forms of endo- thelial dysfunction are rapid in onset (within minutes), Maintenance of permeability barrier reversible, and independent of new protein synthesis (e.g., EC contraction induced by histamine and other vasoactive Elaboration of anticoagulant, Prostacyclin antithrombotic, and Thrombomodulin mediators that cause gaps in venular endothelium (Chapter fibrinolytic regulators Heparin-like molecules 3). Other changes, such as the upregulation of adhesion Plasminogen activator molecules, involve alterations in gene expression and Elaboration of Von Willebrand factor protein synthesis and may require hours or even days prothrombotic molecules Tissue factor to develop. Plasminogen activator inhibitor Vascular SMCs are the predominant cellular element of Production of extracellular Collagen, proteoglycans the vascular media, playing important roles in normal matrix vascular repair and pathologic processes such as athero- Modulation of blood flow Vasoconstrictors: endothelin, ACE sclerosis. SMCs have the capacity to proliferate when and vascular reactivity Vasodilators: NO, prostacyclin appropriately stimulated; they can also synthesize collagen, Regulation of inflammation IL-1, IL-6, chemokines elastin, and proteoglycans and elaborate growth factors and and immunity Adhesion molecules: VCAM-1, cytokines. SMCs are also responsible for the vasoconstriction ICAM, E-selectin, P-selectin or dilation that occurs in response to physiologic or phar- Histocompatibility antigens macologic stimuli. Regulation of cell growth Growth stimulators: PDGF, CSF, FGF Growth inhibitors: heparin, TGF-β Intimal Thickening: A Stereotyped Response to ACE, Angiotensin-converting enzyme; CSF, colony-stimulating factor; FGF, fibroblast Vascular Injury growth factor; ICAM, intercellular adhesion molecule; IL, interleukin; LDL, low-density lipoprotein; NO, nitric oxide; PDGF, platelet-derived growth factor; Vascular injury associated with EC dysfunction or loss TGF-β, transforming growth factor-β; VCAM, vascular cell adhesion molecule. stimulates SMC recruit­ment and proliferation and associ- ated ECM synthesis; the result is intimal thickening that can compromise vascular flow. Healing of injured vessels vascular resistance); metabolize hormones such as angio- is analogous to the healing process that occurs in any other tensin; regulate inflammation; and affect the growth of other damaged tissue (Chapter 3) but has a somewhat unique cell types, particularly SMCs. Although interendothelial outcome because the process impacts downstream blood junctions are largely impermeable in normal vessels, vasoac- flow. ECs involved in repair can migrate from adjacent tive agents (e.g., histamine) cause contraction of ECs and uninjured areas into denuded areas or can derive from allow the rapid egress of fluids, electrolytes, and protein; in inflammation, even leukocytes can slip between adjacent ECs (Chapter 3). ECs can respond to various stimuli by adjusting their Basal state steady-state (constitutive) functions and by expressing newly Normotension acquired (inducible) properties—a process termed endothelial Laminar flow Non-adhesive, non- activation (Fig. 11.2). There are numerous inducers of Growth factors (e.g., VEGF) thrombogenic surface endothelial activation including cytokines and bacterial products, which elicit inflammation and, in severe cases, can promote septic shock (Chapter 4). Additional activators include hemodynamic stresses and lipid products that are Endothelium critical to the pathogenesis of atherosclerosis (see later) and advanced glycation end-products that are important in the Turbulent flow Hypertension pathogenic sequelae of diabetes (Chapter 24). Viruses, Cytokines complement components, and hypoxia also activate ECs. Increased expression of Complement procoagulants, adhesion Activated ECs, in turn, express adhesion molecules (Chapter Bacterial products molecules, and 3) and produce cytokines, chemokines, growth factors, Lipid products proinflammatory factors Advanced glycation vasoactive molecules that result either in vasoconstriction end-products Altered expression of or in vasodilation, induction of major histocompatibility chemokines, cytokines, Hypoxia, acidosis and growth factors complex molecules, procoagulant and anticoagulant factors, Viruses and a variety of other biologically active products. ECs Cigarette smoke “Activated” state influence the vasoreactivity of the underlying SMCs through the production of both vasodilating (relaxing) factors (e.g., Figure 11.2 Basal and activated endothelial cell states. Normal blood nitric oxide [NO]) and vasoconstrictive factors (e.g., endo- pressure, laminar flow, and stable growth factor levels promote a basal thelin). Normal EC function is characterized by a balance endothelial cell state that maintains a nonthrombotic, nonadhesive surface of these responses. with appropriate vascular wall smooth muscle tone. Injury or exposure to certain mediators results in endothelial activation, a state where Endothelial dysfunction refers to an alteration in endo- endothelial cells develop a procoagulant surface that can be adhesive for thelial phenotype—seen in many different conditions—that inflammatory cells and express factors that cause smooth muscle is often both proinflammatory and prothrombogenic. It is contraction and/or proliferation and matrix synthesis. VEGF, Vascular responsible, at least in part, for the initiation of thrombus endothelial growth factor.  Hypertensive vascular disease 489 1. Recruitment of smooth muscle 2. Smooth muscle 3. Elaboration of cells or smooth muscle precursor cell mitosis extracellular matrix Endothelium cells to the intima Intima Internal elastic lamina Smooth Media muscle cells Figure 11.3 Stereotypical response to vascular injury. Schematic diagram of intimal thickening, emphasizing intimal smooth muscle cell migration and proliferation associated with extracellular matrix synthesis. Intimal smooth muscle cells can derive from the underlying media or can be recruited from circulating precursors; the intimal cells are shown in a darker shade to emphasize that they have a proliferative, synthetic, and noncontractile phenotype distinct from medial smooth muscle cells. circulating precursors. Medial SMCs or circulating smooth muscle precursor cells also migrate into the intima, prolifer- HYPERTENSIVE VASCULAR DISEASE ate, and synthesize ECM in much the same way that fibroblasts fill in a wound (Fig. 11.3). The resulting neointima Systemic and local tissue blood pressures must be maintained is typically completely covered by ECs. This neointimal within a narrow range to prevent untoward consequences. response occurs with any form of vascular damage or Low pressures (hypotension) result in inadequate organ dysfunction, regardless of cause. Thus intimal thickening perfusion and can lead to dysfunction or tissue death. is the stereotypical response of the vessel wall to any insult. Conversely, high pressure (hypertension) can cause end- Neointimal SMCs have a phenotype that is distinct from organ damage and is one of the major risk factors for that of medial SMCs. Specifically, neointimal SMCs are more atherosclerosis (see later). proliferative, with increased biosynthetic capabilities and Like height and weight, blood pressure is a continuously reduced contractile function. This neointimal SMC behavior distributed variable. Detrimental effects of blood pressure is regulated by cytokines and growth factors derived from increase continuously as the pressure rises—no rigidly platelets, ECs, and macrophages, as well as thrombin and defined threshold level of blood pressure identifies those activated complement factors. With time and restoration who have an increased risk for cardiovascular disease. Both and/or normalization of the EC layer, the neointimal SMCs the systolic and the diastolic blood pressure are important can return to a nonproliferative state. in determining risk; specifically, according to the newest guidelines, individuals with diastolic pressures above 80 mm Hg or systolic pressures above 120 mm Hg are considered to have clinically significant hypertension. Approximately KEY CONCEPTS 46% of individuals in the general population are therefore RESPONSE OF VASCULAR WALL CELLS TO INJURY hypertensive based on these newer criteria. However, such cutoffs do not reliably assess risk in all patients; for example, All vessels are lined by endothelium; although all ECs share when other risk factors such as diabetes are present, lower certain homeostatic properties, ECs in specific vascular beds thresholds are applicable. have special features that allow for tissue-specific functions Table 11.2 lists the major causes of hypertension. Although (e.g., fenestrated ECs in renal glomeruli). the molecular pathways that regulate normal blood pressure EC function is tightly regulated in both the basal and activated are reasonably well understood, the causes of hypertension states. Various physiologic and pathophysiologic stimuli induce in most individuals remain largely unknown. A small number endothelial activation and dysfunction that alter the EC phe- of patients (approximately 10%) are said to have secondary notype (e.g., procoagulative vs. anticoagulative, proinflammatory hypertension resulting from an underlying renal or adrenal vs. antiinflammatory, and nonadhesive vs. adhesive). disease (e.g., primary aldosteronism, Cushing syndrome, Injury (of almost any type) to the vessel wall results in a ste- or pheochromocytoma), renal artery stenosis, or other reotyped healing response involving SMC proliferation, ECM identifiable cause. However, approximately 90% of hyperten- deposition, and intimal expansion. sion is idiopathic—so-called essential hypertension. It seems The recruitment and activation of the SMCs involves signals likely that hypertension is a multifactorial disorder resulting from cells (e.g., ECs, platelets, and macrophages) as well as from the cumulative effects of multiple genetic polymor- mediators derived from coagulation and complement cascades. phisms and interacting environmental factors. Excessive thickening of the intima can result in luminal stenosis The prevalence and vulnerability to complications of and vascular obstruction. hypertension increase with age and are higher among African 490 C H A P T E R 11 Blood Vessels Table 11.2 Types and Causes of Hypertension typically remains asymptomatic until late in its course, and (Systolic and Diastolic) even severely elevated pressures can be clinically silent for Essential Hypertension years. Left untreated, roughly half of hypertensive patients Accounts for 90%–95% of all cases die of ischemic heart disease or congestive heart failure, and another third die of stroke. Treatment with blood Secondary Hypertension pressure–lowering drugs dramatically reduces the incidence Renal and death rates attributable to all forms of hypertension- Acute glomerulonephritis related pathology. Chronic renal disease A small percentage of hypertensive persons (as much as Polycystic disease 5%) show a rapidly rising blood pressure that, if untreated, Renal artery stenosis leads to death within 1 to 2 years. This form of hypertension, Renal vasculitis Renin-producing tumors called malignant hypertension, is characterized by severe pressure elevations (i.e., systolic pressure more than 200 mm Endocrine Hg, diastolic pressure more than 120 mm Hg), renal failure, Adrenocortical hyperfunction (Cushing syndrome, primary and retinal hemorrhages and exudates, with or without aldosteronism, congenital adrenal hyperplasia, licorice ingestion) papilledema (swelling of the optic nerve that reflects Exogenous hormones (glucocorticoids, estrogen [including pregnancy- induced and oral contraceptives], sympathomimetics and tyramine- increased intracranial pressures). It can develop in previously containing foods, monoamine oxidase inhibitors) normotensive persons but more often is superimposed on Pheochromocytoma preexisting “benign” hypertension. Acromegaly In this section, we will first briefly outline normal blood Hyperthyroidism (thyrotoxicosis) pressure homeostasis, followed by a discussion of pathogenic Pregnancy-induced (preeclampsia) mechanisms that underlie hypertension and a description Cardiovascular of hypertension-associated pathologic changes in vessels. Coarctation of the aorta Polyarteritis nodosa Blood Pressure Regulation Increased intravascular volume Increased cardiac output Blood pressure is a function of cardiac output and periph- Rigidity of the aorta eral vascular resistance, both of which are influenced by Neurologic multiple genetic and environmental factors (Fig. 11.4). The Psychogenic integration of the various inputs ensures adequate systemic Increased intracranial pressure perfusion, despite regional demand differences. Sleep apnea Cardiac output is a function of stroke volume and heart Acute stress, including surgery rate. The most important determinant of stroke volume is the filling pressure, which is regulated through sodium homeostasis and its effect on blood volume. Heart rate and myocardial contractility (a second factor affecting Americans. Besides increasing risk of atherosclerosis, stroke volume) are both regulated by the α- and hypertension can cause cardiac hypertrophy and heart failure β-adrenergic systems, which also have important effects (hypertensive heart disease) (Chapter 12), multi-infarct dementia on vascular tone. (Chapter 28), aortic dissection (discussed later in this chapter), Peripheral resistance is regulated predominantly at the and renal failure (Chapter 20). Unfortunately, hypertension level of the arterioles by neural and hormonal inputs. BLOOD VOLUME HUMORAL FACTORS Sodium Constrictors Dilators Mineralocorticoids Angiotensin II Prostaglandins Atrial natriuretic peptide Catecholamines Kinins Thromboxane NO Leukotrienes Endothelin LOCAL FACTORS BLOOD CARDIAC PERIPHERAL Autoregulation PRESSURE OUTPUT RESISTANCE pH, hypoxia CARDIAC FACTORS Constrictors Dilators Heart rate α-adrenergic β-adrenergic Contractility NEURAL FACTORS Figure 11.4 Blood pressure regulation. Diverse influences on cardiac output (e.g., blood volume and myocardial contractility) and peripheral resistance (neural, humoral, and local effectors) impact the output blood pressure.  Hypertensive vascular disease 491 Vascular tone reflects a balance between vasoconstrictors blood pressure. Kidneys influence peripheral resistance and (including angiotensin II, catecholamines, and endothelin) sodium excretion/retention primarily through the renin- and vasodilators (including kinins, prostaglandins, and angiotensin-aldosterone system. NO). Resistance vessels also exhibit autoregulation, Renin is a proteolytic enzyme produced by renal juxta- whereby increased blood flow induces vasoconstriction glomerular cells, which are myoepithelial cells adjacent to protect tissues against hyperperfusion. Finally, blood to the glomerular afferent arterioles. Renin is released pressure is fine-tuned by tissue pH and hypoxia to in response to low blood pressure in afferent arterioles, accommodate local metabolic demands. elevated levels of circulating catecholamines, or low sodium levels in the distal convoluted renal tubules. The Factors released from the kidneys, adrenals, and myo- latter occurs when the glomerular filtration rate falls (e.g., cardium interact to influence vascular tone and to regulate when the cardiac output is low), leading to increased blood volume by adjusting sodium balance (Fig. 11.5). sodium resorption by the proximal tubules. The kidneys filter 170 liters of plasma containing 23 moles Renin cleaves plasma angiotensinogen to angiotensin I, which of salt daily. Thus with a typical diet containing 100 mEq in turn is converted to angiotensin II by angiotensin-converting of sodium, 99.5% of the filtered salt must be reabsorbed to enzyme (ACE), mainly a product of vascular endothelium. maintain total body sodium levels. About 98% of the filtered Angiotensin II raises blood pressure by (1) inducing sodium is reabsorbed by several constitutively active vascular contraction, (2) stimulating aldosterone secretion transporters. The small amount of remaining sodium is by the adrenal gland, and (3) increasing tubular sodium subject to resorption by the epithelial sodium channel (EnaC), resorption. Adrenal aldosterone increases blood pressure which is tightly regulated by the renin-angiotensin-aldo- by its effect on blood volume; aldosterone increases sterone system; it is this pathway that determines net sodium sodium resorption (and thus water) in the distal convo- balance. luted tubules, which increases blood volume. The kidneys and heart contain cells that sense changes The kidney also produces a variety of vascular relaxing sub- in blood pressure or volume. In response, these cells release stances (including prostaglandins and NO) that can circulating effectors that act in concert to maintain normal counterbalance the vasopressor effects of angiotensin. Atrial natriuretic peptide Volume overload Excretes Na+ and water Vasodilation Blood volume BLOOD PRESSURE Normotension BLOOD PRESSURE Blood Vaso- volume constriction Increased volume Excess dietary sodium (Low volume or low resistance; Inadequate excretion renal artery stenosis) (renal failure) Resorbs Na+ Hyperaldosteronism and water Increased sodium resorption (Gitelman, Bartter, and Liddle syndromes) Aldosterone Increased resistance Kidney Increased sympathetic tone (e.g., pheochromocytoma) Adrenal Increased renin-angiotensin- Liver aldosterone axis Renin Angiotensin II Angio- Angiotensin I tensinogen Angiotensin converting enzyme Endothelium in many tissues Figure 11.5 Interplay of renin-angiotensin-aldosterone and atrial natriuretic peptide in maintaining blood pressure homeostasis. 492 C H A P T E R 11 Blood Vessels Myocardial natriuretic peptides are released from atrial salt-sensitive hypertension, called Liddle syndrome, (dominant contributor) and ventricular (minor contributor) is caused by mutations in an epithelial Na+ channel myocardium in response to volume expansion; these inhibit protein that increase distal tubular reabsorption of sodium resorption in the distal renal tubules, thus leading sodium in response to aldosterone. to sodium excretion and diuresis. They also induce systemic vasodilation. Mechanisms of Essential Hypertension. As mentioned earlier, in the vast majority of cases hypertension results from complex interactions between multiple genetic and KEY CONCEPTS environmental influences. BLOOD PRESSURE REGULATION Genetic factors definitely contribute to blood pressure regulation, as shown by comparisons of monozygotic Blood pressure is determined by vascular resistance and cardiac and dizygotic twins and genetically related versus adopted output. children. Moreover, as noted earlier, several single-gene Vascular resistance is regulated at the level of the arterioles, disorders cause relatively rare forms of hypertension (and influenced by neural and hormonal inputs. hypotension) by altering net sodium reabsorption in the Cardiac output is determined by heart rate and stroke volume, kidney. Large genome-wide association studies point to which is strongly influenced by blood volume. Blood volume in more than 60 genetic loci in which variants individually turn is regulated mainly by renal sodium excretion or resorption. contribute minimally to blood pressure levels but in sum Renin, a major regulator of blood pressure, is secreted by the have larger effects. kidneys in response to decreased blood pressure in afferent Insufficient renal sodium excretion in the presence of normal arterioles. In turn, renin cleaves angiotensinogen to angiotensin arterial pressure may be a key initiating event in essential I; subsequent endothelial catabolism produces angiotensin II, hypertension and, indeed, a final common pathway for which regulates blood pressure by increasing vascular SMC the pathogenesis of hypertension. Insufficient sodium tone and by increasing adrenal aldosterone secretion, thereby excretion may lead sequentially to an increase in fluid increasing renal sodium resorption. volume, increased cardiac output, and peripheral vaso- constriction, thereby elevating blood pressure. At the higher blood pressure, enough additional sodium is Pathogenesis of Hypertension excreted by the kidneys to equal intake and prevent The vast majority (90% to 95%) of hypertension is idio- further fluid retention. Thus a new steady state of sodium pathic, the result of interacting genetic and environmental balance is achieved (“resetting of pressure natriuresis”), factors. Even without knowing the specific lesions, it is but at the expense of an increase in blood pressure. reasonable to suppose that small changes in renal sodium Vasoconstrictive influences, such as factors that induce vaso- homeostasis and/or vessel wall tone or structure act in constriction or stimuli that cause structural changes in the combination to cause essential hypertension (see Fig. 11.5). vessel wall, can lead to an increase in peripheral resistance Most other causes fall under the general rubric of renal and may also play a role in essential hypertension. disease, including renovascular hypertension (due to renal Environmental factors such as stress, obesity, smoking, artery occlusion). Infrequently, hypertension has an underly- physical inactivity, and heavy salt consumption all are ing endocrine basis. implicated in hypertension. Indeed, the evidence linking dietary sodium intake with the prevalence of hypertension Mechanisms of Secondary Hypertension. For many of in different populations is particularly impressive. the secondary forms of hypertension, the underlying pathways are reasonably well understood. Vascular Pathology in Hypertension In renovascular hypertension, renal artery stenosis causes decreased glomerular flow and pressure in the afferent Hypertension not only accelerates atherogenesis (see later) arteriole of the glomerulus. As already discussed, this but also causes degenerative changes in the walls of large induces renin secretion leading to increased blood volume and medium arteries that can lead to both aortic dissection and vascular tone via angiotensin and aldosterone and cerebrovascular hemorrhage. Three forms of small vessel pathways (see Fig. 11.5). disease are hypertension-related (Fig. 11.6). Primary hyperaldosteronism is one of the most common causes of secondary hypertension (Chapter 24). It may be idiopathic or less commonly caused by aldosterone- secreting adrenal adenomas. MORPHOLOGY Single-gene disorders cause severe but rare forms of Hyaline arteriolosclerosis. Arterioles show homogeneous, pink hypertension. hyaline thickening with associated luminal narrowing (Fig. 11.6A). Gene defects affecting enzymes involved in aldosterone These changes reflect both plasma protein leakage across injured metabolism (e.g., aldosterone synthase, 11β-hydroxylase, ECs and increased SMC matrix synthesis in response to the 17α-hydroxylase) can lead to increased aldosterone chronic hemodynamic pressures of hypertension. Although the secretion with downstream increases in salt and water vessels of older patients (either normotensive or hypertensive) resorption, plasma volume expansion, and, ultimately, also frequently exhibit hyaline arteriosclerosis, it is more generalized hypertension. and severe in patients with hypertension and diabetes (Chapter Mutations affecting proteins that influence sodium reabsorp- 24). In nephrosclerosis due to chronic hypertension, the arteriolar tion. For example, the moderately severe form of  Atherosclerosis 493 A B Figure 11.6 Vascular pathology in hypertension. (A) Hyaline arteriolosclerosis. The arteriolar wall is thickened with increased protein deposition (hyalinized), and the lumen is markedly narrowed. (B) Hyperplastic arteriolosclerosis (onion-skinning) causing luminal obliteration (arrow) (periodic acid-Schiff stain). (B, Courtesy Helmut Rennke, MD, Brigham and Women’s Hospital, Boston, Mass.) narrowing causes diffuse impairment of renal blood supply and ARTERIOSCLEROSIS glomerular scarring (Chapter 20). Hyperplastic arteriolosclerosis. This lesion occurs in severe Arteriosclerosis literally means “hardening of the arteries”; hypertension; vessels exhibit concentric, laminated (“onion- it is a generic term for arterial wall thickening and loss skin”) thickening of the walls with luminal narrowing (Fig. 11.6B). of elasticity. There are four general patterns, with different The laminations consist of SMCs with thickened, reduplicated clinical and pathologic consequences. basement membrane; in malignant hypertension, they are accom- Arteriolosclerosis affects small arteries and arterioles and panied by fibrinoid deposits and vessel wall necrosis (necrotizing may cause downstream ischemic injury. The two anatomic arteriolitis), particularly in the kidney (Chapter 20). variants, hyaline and hyperplastic, were discussed earlier Pulmonary hypertension can be caused by several entities in relation to hypertension. including left heart failure, congenital heart disease, valve disorders, Mönckeberg medial sclerosis is characterized by calcifications obstructive or interstitial lung disease, and recurrent thrombo- of the medial walls of muscular arteries, typically starting emboli.The arterioles in such affected lungs typically show histologic along the internal elastic membrane. Adults older than changes ranging from fibrotic intimal thickening to medial age 50 are most commonly affected. The calcifications hyperplasia. These are described in greater detail in Chapter 15. do not encroach on the vessel lumen and are usually not clinically significant. Fibromuscular intimal hyperplasia occurs in muscular arteries larger than arterioles. It is driven by inflammation (as in KEY CONCEPTS a healed arteritis or transplant-associated arteriopathy; HYPERTENSION see Chapter 12) or by mechanical injury (e.g., associated with stents or balloon angioplasty; see later) and can be Hypertension is a common disorder affecting roughly half of considered as a healing response. The affected vessels adults in the United States; it is a major risk factor for athero- can become quite stenotic; indeed, such intimal hyper- sclerosis, congestive heart failure, and renal failure. plasia underlies in-stent restenosis and is the major Essential hypertension represents 90% to 95% of cases and is long-term limitation of solid-organ transplants. a complex, multifactorial disorder involving both environmental Atherosclerosis, from Greek root words for “gruel” and influences and genetic polymorphisms that influence sodium “hardening,” is the most frequent and clinically important resorption, aldosterone pathways, and the renin-angiotensin- pattern and is discussed here. aldosterone system. Hypertension is occasionally caused by single-gene disorders or is secondary to diseases of the kidney, adrenal, or other endocrine organs. ATHEROSCLEROSIS Sustained hypertension requires participation of the kidney, Atherosclerosis underlies the pathogenesis of coronary, which normally responds to hypertension by eliminating salt cerebral, and peripheral vascular disease and causes more and water. In established hypertension, both increased blood morbidity and mortality (roughly half of all deaths) in volume and increased peripheral resistance contribute to the the Western world than any other disorder. Because coro- increased pressure. nary artery disease is an important manifestation of the Histologically, hypertension is associated with thickening of disease, epidemiologic data related to atherosclerosis arterial walls caused by hyaline deposits and, in severe cases, mortality typically reflect deaths caused by ischemic heart by proliferation of ECs or SMCs and replication of the basement disease (Chapter 12); indeed, myocardial infarction is membrane. responsible for almost a quarter of all deaths in the United 494 C H A P T E R 11 Blood Vessels FIBROUS CAP (smooth muscle cells, macrophages, foam cells, lymphocytes, collagen, elastin, proteoglycans, neovascularization) NECROTIC CENTER (cell debris, cholesterol crystals, foam cells, calcium) MEDIA Figure 11.7 Basic structure of an atherosclerotic plaque. Note that atherosclerosis is an intimal-based process with a complex interplay of cells and extracellular materials. Plaques can have secondary effects on the underlying media including a reduction in smooth muscle cells. States. Significant morbidity and mortality are also caused Constitutional Risk Factors by aortic and carotid atherosclerotic disease and stroke. Genetics. Family history is the most important independent The likelihood of atherosclerosis is determined by the risk factor for atherosclerosis. Certain Mendelian disorders combination of acquired (e.g., cholesterol levels, smoking, are strongly associated with atherosclerosis (e.g., familial hypertension), inherited (e.g., low-density lipoprotein [LDL] hypercholesterolemia; see Chapter 5), but they account receptor gene mutations), and gender- and age-associated for only a small percentage of cases. The well-established risk factors. Acting in concert, they cause intimal lesions familial predisposition to atherosclerosis and ischemic called atheromas (also called atheromatous or atherosclerotic heart disease is usually polygenic, relating to small plaques) that protrude into vessel lumens. An atheromatous effects of many shared alleles common to a family or plaque typically consists of a raised lesion with a soft population. grumous core of lipid (mainly cholesterol and cholesterol Age is a dominant influence. The development of athero- esters) covered by a fibrous cap (Fig. 11.7). Besides mechani- sclerotic plaque is a progressive process that usually cally obstructing blood flow, atherosclerotic plaques can becomes clinically manifest in middle age or later (see rupture leading to catastrophic obstructive vascular throm- later). Thus between ages 40 and 60, the incidence of bosis. Atherosclerotic plaques can also increase the diffusion myocardial infarction increases fivefold. Death rates from distance from the lumen to the media, leading to ischemic ischemic heart disease rise with each decade even into injury and weakening of the vessel wall, changes that can advanced age. Increasingly, however, this age association result in aneurysm formation. is being recognized as perhaps more than just the accu- mulated slings and arrows of vascular injury over the Epidemiology. Although atherosclerosis-associated ischemic years. Indeed, with aging, there is a tendency for the heart disease is ubiquitous among most developed nations, outgrowth of hematopoietic clones (so-called clonal risk reduction and improved therapies have combined to hematopoiesis of indeterminate potential [CHIP]) carrying moderate the associated mortality. At the same time, reduced mutations that confer a proliferative advantage. Many mortality from infectious diseases and the adoption of of these affect DNA modifications and transcriptional Western lifestyles has led to the increased prevalence of regulation (e.g., TET2 encoding an enzyme that converts ischemic heart disease in low income nations. As a result, methylcytosine to 5-hydroxymethylcytosine); as expected, the death rate for coronary artery disease in Africa, India, these can ultimately influence the risk of developing and Southeast Asia now exceeds that in the United States; hematologic malignancies. Perhaps more remarkable, eastern European countries have rates 3 to 5 times higher however, is that such clonal hematopoiesis is even more than the United States and 7 to 12 times higher than Japan. Table 11.3 Major Risk Factors for Atherosclerosis Risk Factors Nonmodifiable (Constitutional) The prevalence and severity of atherosclerosis and ischemic Genetic abnormalities heart disease among individuals and groups are related to Family history a number of risk factors identified through several prospec- Increasing age tive analyses (e.g., the Framingham Heart Study); some of Male gender these are constitutional (and therefore less controllable), Modifiable but others are acquired or related to specific behaviors and Hyperlipidemia potentially amenable to intervention (Table 11.3). These risk Hypertension factors typically have greater than additive effects, but Cigarette smoking treatment (even less than optimal) can mitigate some of the Diabetes Inflammation risk (Fig. 11.8).  Atherosclerosis 495 57.5 60 56.4 Men 50 Women 38 Estimated 10 yr rate (%) 36.8 40 28.8 27.7 30 23.4 16.5 17 20 13.7 11.3 8.7 9.2 10 5.5 A 0 BP systolic 120 160 160 160 160 160 160 Cholesterol 220 220 260 260 260 260 260 HDL-C 50 50 50 35 35 35 35 Diabetes – – – – + + + Cigarettes – – – – – + + LVH by ECG – – – – – – + 40 40 ≥2 Major risk factors ≥2 Major risk factors 1 Major risk factor 1 Major risk factor 30 All risk factors optimal 30 All risk factors optimal Lifetime Risk (%) Lifetime Risk (%) 20 20 10 10 0 0 0 55 60 65 70 75 80 85 90 0 55 60 65 70 75 80 85 90 B Attained Age (years) C Attained Age (years) Figure 11.8 Lifetime risk of death from cardiovascular disease. (A) Estimated 10-year risk of coronary artery disease in hypothetical 55-year-old men and women as a function of traditional risk factors (hyperlipidemia, hypertension, smoking, and diabetes). BP, Blood pressure; ECG, electrocardiogram; HDL-C, high-density lipoprotein cholesterol; LVH, left ventricular hypertrophy. In women (B) and men (C), one or more risk factors of blood pressure, cholesterol, diabetes, and cigarettes significantly increases the lifetime risk of a cardiovascular event. (A, From O’Donnell CJ, Kannel WB: Cardiovascular risks of hypertension: lessons from observational studies, J Hypertens Suppl 16(6):S3–S7, 1998, with permission from Lippincott Williams & Wilkins; B and C, Modified from Berry JD, Dyer A, Cai X, et al: Lifetime risks of cardiovascular disease, N Eng J Med 366:321–329, 2012.) significantly associated with increased all-cause cardio- of atherosclerosis-related diseases increases and at older vascular mortality. An explanation is beginning to emerge ages exceeds that of men. Although a favorable influence that the same CHIP mutations that affect cellular prolifera- of estrogen has been proposed to explain this effect, tion (e.g., TET2) can also impact the inflammatory clinical trials of estrogen replacement did not show any response of mononuclear cells and thereby influence benefit; indeed, postmenopausal estrogen therapy actually atherogenesis (see also later). increased cardiovascular risk in some older women. Gender. Premenopausal women are relatively protected against atherosclerosis and its consequences compared Modifiable Major Risk Factors with age-matched men. Thus myocardial infarction and Hyperlipidemia—and more specifically hypercholesterolemia— other complications of atherosclerosis are uncommon is a major risk factor for atherosclerosis; even in the absence in premenopausal women unless they are otherwise of other risk factors, hypercholesterolemia is sufficient to predisposed by diabetes, hyperlipidemia, or severe initiate lesion development. The major component of serum hypertension. After menopause, however, the incidence cholesterol associated with increased risk is LDL cholesterol 496 C H A P T E R 11 Blood Vessels (“bad cholesterol”). LDL is the lipid-cholesterol-protein complex that delivers cholesterol to peripheral tissues; in 25 contrast, high-density lipoprotein (HDL) is the complex C-Reactive protein (mg/L) that mobilizes cholesterol from the periphery (including 3.0 atheromas) and transports it to the liver for catabolism 20 and biliary excretion. Higher levels of HDL (“good cholesterol”) correlate with reduced risk. Relative risk 15 Understandably, dietary and pharmacologic interven- tions that lower LDL or total serum cholesterol are of considerable interest. Interestingly, approaches that 10 exclusively raise HDL are not effective. Although previ- ously considered important, the contribution of most dietary fats to atherosclerosis is now viewed as minimal. 5 Nevertheless, omega-3 fatty acids (abundant in fish oils) are considered beneficial, whereas trans unsaturated fats 0 produced by artificial hydrogenation of polyunsaturated 0–1 2–4 5–9 10–20 oils (used in baked goods and margarine) can adversely Framingham estimate of 10-year risk (%) affect cholesterol profiles. Statins are a class of drugs that lower circulating cholesterol levels by inhibiting hydroxy- Figure 11.9 C-reactive protein adds prognostic information at all levels methylglutaryl coenzyme A (HMG CoA) reductase, the of traditional risk identified from the Framingham Heart Study. Relative risk (y-axis) refers to the risk of a cardiovascular event (e.g., myocardial rate-limiting enzyme in hepatic cholesterol biosynthesis infarction). The x-axis is the 10-year risk of a cardiovascular event derived (Chapter 5). Statins are widely used to lower serum from the traditional risk factors identified in the Framingham study. In cholesterol levels, lowering rates of myocardial infarctions, each risk group, C-reactive protein values further stratify the patients. arguably one of the most significant success stories of (Data from Ridker PM, et al: Comparison of C-reactive protein and translational research. Interestingly, some of the benefit low-density lipoprotein cholesterol levels in the prediction of first of the statins may be due to “off-target” effects on reduc- cardiovascular events, N Engl J Med 347:1557, 2002.) ing inflammation (see also later). Hypertension can increase the risk of ischemic heart disease by approximately 60% versus normotensive populations. CRP is an acute phase reactant synthesized primarily Chronic hypertension is the most common cause of left by the liver. Although CRP does not appear to be causally ventricular hypertrophy, and hence the latter is also a related to the development of atherosclerosis or its surrogate marker for cardiovascular risk. sequelae, it is well established that plasma CRP is a strong, Cigarette smoking, and in particular prolonged (years) use, independent marker of risk for myocardial infarction, doubles the death rate from ischemic heart disease. stroke, peripheral arterial disease, and sudden cardiac Smoking cessation reduces that risk substantially. death, even among apparently healthy individuals Diabetes mellitus induces hypercholesterolemia (Chapter (Fig. 11.9). Accordingly, CRP levels are now incorporated 24) and markedly increases the risk of atherosclerosis. into risk stratification algorithms. Interestingly, CRP levels Other factors being equal, the incidence of myocardial are also typically lowered in concert with other risk infarction is twice as high in diabetics relative to normo- reduction measures including smoking cessation, weight glycemic individuals. There is also an increased risk of loss, exercise, and statin administration. strokes and a 100-fold increased risk of atherosclerosis- Hyperhomocysteinemia. Serum homocysteine levels correlate induced gangrene of the lower extremities. with coronary atherosclerosis, peripheral vascular disease, stroke, and venous thrombosis. Homocystinuria, due to Additional Risk Factors rare inborn errors of metabolism, results in elevated As many as 20% of all cardiovascular events occur in the circulating homocysteine (>100 µmol/L) and is associated absence of major risk factors (e.g., hypertension, hyperlip- with premature vascular disease. idemia, smoking, or diabetes). Indeed, more than 75% of Metabolic syndrome. Associated with central obesity cardiovascular events in previously healthy women occur (Chapter 9), this entity is characterized by insulin resistance, with LDL cholesterol levels below 160 mg/dL (levels gener- hypertension, dyslipidemia (elevated LDL and depressed ally considered to connote low risk). Clearly, other factors HDL), hypercoagulability, and a proinflammatory state. are contributory. Among those that are proven or suspected Dyslipidemia, hyperglycemia, and hypertension all are are the following: cardiac risk factors, while the systemic hypercoagulable Inflammation. Inflammation is present during all stages and proinflammatory state may contribute to endothelial of atherogenesis and is intimately linked with athero- dysfunction and/or thrombosis. sclerotic plaque formation and rupture (see later). With Lipoprotein a [Lp(a)] is an altered form of LDL that contains the increasing recognition that inflammation plays a the apolipoprotein B-100 portion of LDL linked to significant causal role in ischemic heart disease, assess- apolipoprotein A (apo A); Lp(a) levels are associated ment of systemic inflammation has become important with coronary and cerebrovascular disease risk, inde- in overall risk stratification. A number of circulating pendent of total cholesterol or LDL levels. markers of inflammation correlate with ischemic heart Factors affecting hemostasis. Several markers of hemostatic disease, and C-reactive protein (CRP) has emerged as one and/or fibrinolytic function (e.g., elevated plasminogen of the most stable and simplest to measure. activator inhibitor 1) are potent predictors of risk for  Atherosclerosis 497 Figure 11.10 Evolution of arterial wall changes in the response to injury Endothelium hypothesis. 1, Normal. 2, Endothelial injury with monocyte and platelet Intima adhesion. 3, Monocyte and smooth muscle cell migration into the intima, with macrophage activation. 4, Macrophage and smooth muscle cell uptake Media of modified lipids, with further activation. 5, Intimal smooth muscle cell Adventitia proliferation with extracellular matrix production, forming a well- 1. Chronic developed plaque. endothelial “injury”: Hyperlipidemia Hypertension Smoking Homocysteine Hemodynamic factors Toxins major atherosclerotic events including myocardial infarc- Viruses Response to injury tion and stroke. Platelet-derived factors as well as Immune reactions thrombin—through both procoagulant and proinflam- matory effects—are increasingly recognized as major contributors to local vascular pathology. Other factors. Factors associated with a less pronounced and/or difficult to quantitate risk include lack of exercise; competitive, stressful lifestyle (type A personality); and obesity (the last-mentioned also being complicated by hypertension, diabetes, hypertriglyceridemia, and 2. Endothelial dysfunction decreased HDL). (e.g., increased permeability, Platelet leukocyte adhesion), Monocyte Pathogenesis of Atherosclerosis monocyte adhesion and emigration The clinical importance of atherosclerosis has stimulated enormous interest in understanding the mechanisms that underlie its evolution and complications. The contemporary view of atherogenesis integrates the risk factors previously discussed and is called the “response to injury” hypothesis. This model views atherosclerosis as a chronic inflammatory and healing response of the arterial wall to endothelial injury. Lesion progression occurs through interaction of 3. Macrophage modified lipoproteins, macrophages, and T lymphocytes activation, with ECs and SMCs of the arterial wall (Fig. 11.10). Accord- smooth muscle recruitment Smooth ing to this schema, atherosclerosis progresses in the following muscle cell sequence: Endothelial injury and dysfunction, causing (among other Fatty streak things) increased vascular permeability, leukocyte adhe- sion, 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. 4. Macrophages and smooth muscle cells Platelet adhesion. engulf lipid Factor release from activated platelets, macrophages, and vascular wall cells, inducing SMC recruitment, either T lymphocyte from the media or from circulating precursors. SMC proliferation, ECM production, and recruitment of T cells. Fibrofatty atheroma Lipid accumulation both extracellularly and within cells (macrophages and SMCs). Calcification of ECM and necrotic debris late in the pathogenesis. We will now discuss the role of these factors in the pathogenesis of atherosclerosis in some detail, starting with 5. Smooth muscle proliferation, collagen endothelial injury. and other extracellular Lipid matrix deposition, debris Endothelial Injury. EC injury is the cornerstone of the extracellular lipid T lymphocyte Collagen response-to-injury hypothesis. Early lesions begin at sites of morphologically intact endothelium that exhibit 498 C H A P T E R 11 Blood Vessels features of endothelial dysfunction—increased perme- by increasing local reactive oxygen species production; ability, enhanced leukocyte adhesion, and altered gene besides causing membrane and mitochondrial damage, expression. Causes of EC dysfunction include toxins oxygen free radicals accelerate NO decay, dampening from cigarette smoke, homocysteine, and the local pro- its vasodilator activity. duction of inflammatory cytokines. However, the three Modified LDL. With chronic hyperlipidemia, lipoproteins most important causes of endothelial dysfunction are accumulate within the intima, where they may aggregate hemodynamic disturbances, hypercholesterolemia, and or become oxidized by free radicals produced by inflam- inflammation. matory cells. Such modified LDL is then accumulated by macrophages through a variety of scavenger receptors Hemodynamic Disturbances. The importance of hemo- (distinct from the LDL receptor). Because the modified dynamic turbulence in atherogenesis is illustrated by the lipoproteins cannot be completely degraded, chronic observation that plaques do not occur randomly, but rather ingestion leads to the formation of lipid-filled macro- tend to locate at the ostia of exiting vessels, branch points, phages called foam cells; SMCs can similarly transform and along the posterior abdominal aorta where flow patterns into lipid-laden foam cells by ingesting modified lipids are disturbed and nonlaminar. This is explained by the fact through LDL receptor–related proteins. Not only are the that laminar nonturbulent flow increases the production of modified lipoproteins toxic to ECs, SMCs, and macro- transcription factors and, in particular, Krüppel-like factor-2 phages, but their binding and uptake also stimulate the (KLF2) that turn on atheroprotective genes and turn off release of growth factors, cytokines, and chemokines that inflammatory gene transcription. Conversely, turbulent, create a vicious inflammatory cycle of monocyte recruit- nonlaminar flow drives a repertoire of genetic transcription ment and activation. The early lesions containing lipid- that makes those sites atheroprone. It is noteworthy that filled macrophages are called fatty streaks. some of the atheroprotective effects of statins also occur through KLF2 upregulation. Inflammation. Chronic inflammation contributes to the initiation and progression of atherosclerotic lesions. It is Hypercholesterolemia. Lipids are transported in the believed that inflammation is triggered by the accumulation bloodstream bound to specific