Chapter 20. The Blood Vessels

The Systemic Circulation

The systemic circulation supplies arterial blood to the tissues; it begins at the aortic valve and ends with the openings of the venae cavae into the right atrium. Its component vessels and their function may be described as follows:

Elastic arteries—the aorta and its major branches—convert the spasmodic left ventricular output into a more continuous distal flow.

Muscular arteries—the internal carotid, coronary, brachial, femoral, renal and mesenteric arteries—distribute blood to the tissues.

Arterioles—by definition, arteries less than 2 mm in diameter—have muscular walls and a rich sympathetic nerve supply that permits adjustment of luminal size. Arterioles regulate the pressure decrease from aortic to capillary levels (Figure 20-1). Adjustment of resistance within the arterioles is a major factor determining systemic blood pressure and distribution of flow.

The microcirculation consists of capillaries, precapillary sphincters, and postcapillary venules. It is the site of exchange with tissue fluids.

Veins are low pressure capacitance vessels that return blood to the heart. Forward flow in the veins is facilitated by endothelial valves.

The Pulmonary Circulation

The main function of the pulmonary circulation is to effect respiratory gas exchange in the pulmonary capillary bed; it begins at the pulmonary valve and ends in the left atrial openings.

The pulmonary circulation is at low pressure (25/10 mm Hg). Because this is lower than the plasma osmotic pressure, there is normally no fluid movement out of the alveolar capillaries, permitting the alveoli to remain dry for effective gas exchange.

The Portal Circulations

Portal circulations within the systemic circulation interpose a second capillary bed, which enables a specific function by the involved tissues. The hepatic portal circulation delivers intestinal and splenic blood to the liver so that organ has first access to substances absorbed from the intestine. A minor portal circulation in the pituitary stalk transports releasing hormones from the hypothalamus directly to the anterior pituitary gland.

The Lymphatic Circulation

Lymphatic vessels originate in the interstitial compartment of tissues and end in the opening of the thoracic duct into the jugular vein. Their main function is to transport large molecules and excess fluid from the interstitium back into the blood. Lymphatic vessels have thin walls with endothelial valves spaced at intervals that promote central flow; the lymphatic system operates under very low pressure.

Interspersed in the lymphatic system are the lymph nodes, which represent organs of the immune system (Chapter 4: The Immune Response).

Vascular Endothelium

The endothelium is a simple, flat layer of cells that lines the internal surface of the entire vascular system. The vascular endothelium synthesizes a large number of different substances, the most important of which are prostaglandins (mainly prostacyclin, PGI2, and thromboxane A2), heparan sulfate, and coagulation factor VIII. Factor VIII is a useful marker for endothelial cells and can be demonstrated in tissue sections by immunohistologic techniques. Pulmonary endothelial cells synthesize angiotensin-converting enzyme.

Coarctation of the Aorta

Coarctation of the aorta is a congenital malformation characterized by narrowing of the vessel's lumen. Two distinct types are recognized.

Infantile (Preductal) Coarctation

Infantile coarctation of the aorta is a rare defect characterized by extreme narrowing of a segment of aorta proximal to the ductus arteriosus. The upper half of the body is supplied by the aorta proximal to the coarctation; the lower half is supplied from the pulmonary artery through a patent ductus arteriosus, producing cyanosis restricted to the lower part of the body. The defect is often fatal early in life unless corrected.

Adult Coarctation

(Figure 20-2)

Adult coarctation of the aorta is a more common defect, seen oftener in males than in females. It is characterized by localized narrowing of the aorta immediately distal to the closed ductus arteriosus. It may be asymptomatic if the lower half of the body receives an adequate blood supply through the narrowed aorta or well developed collaterals. Coarctation of the aorta is common in patients with Turner's syndrome.

With severe adult coarctation, ischemia in the lower half of the body results in pain in the leg muscles during exercise (intermittent claudication). Hypertension is due mainly to a decrease in renal blood flow, which stimulates the renin-angiotensin-aldosterone mechanism. Mechanical obstruction to aortic flow plays only a minor role in causing hypertension. Development of collateral arteries, mainly around the shoulder girdle, may be seen clinically or on x-rays as notching of ribs. The circuitous passage of blood to the lower aorta through these collaterals causes the femoral pulse to be delayed and the blood pressure in the legs to be lower than that in the arms.

Coarctation of the aorta is associated with (1) bicuspid aortic valve, which may be complicated by infective endocarditis (Chapter 22: The Heart: II. Endocardium & Cardiac Valves); and (2) berry aneurysms in the cerebral vessels, rupture of which causes subarachnoid hemorrhage.

Marfan's Syndrome

Marfan's syndrome is an inherited disease transmitted as an autosomal dominant trait. The abnormal gene on chromosome 15q codes for a fibrillin protein. Fibrillin is part of the connective tissue scaffolding necessary for deposition of elastic fibers. Abnormal elastic tissue, seen as fragmented fibers in affected tissues, is the typical morphologic abnormality in Marfan's syndrome. The aorta, cardiac valves, eyes, and skeletal system are most affected. Elastic degeneration of the aortic media is associated with myxomatous change and leads to (1) medial weakness with aortic root dilation, which causes aortic valve regurgitation; (2) aortic dissection (see below); and (3) spontaneous rupture of the aorta. Similar changes in the mitral valve produce mitral prolapse syndrome, which may cause mitral incompetence.

Skeletal abnormalities such as increased height, arachnodactyly (thin, long, “spider-like” fingers), and a high-arched palate are characteristic. Ligamentous abnormalities cause dislocation of the lens and hypermobile joints. Abraham Lincoln is believed by many scientists to have had Marfan's syndrome. Clinically, most patients are asymptomatic. Athletes with Marfan's syndrome who undergo severe physical stress are prone to develop aortic dissection and rupture, which may cause sudden death.

Other Inherited Disorders of Connective Tissue

Other rare inherited diseases in which there is defective connective tissue formation include Ehlers-Danlos syndrome, pseudoxanthoma elasticum, osteogenesis imperfecta, and the mucopolysaccharidoses—all associated with aortic medial degeneration and weakening, predisposing to aortic root dilation and aortic rupture.

Congenital (Berry) Aneurysms

“Congenital” aneurysms occur in small muscular arteries, most commonly in the circle of Willis (Figure 20-3), where their rupture causes subarachnoid hemorrhage (Chapter 64: The Central Nervous System: III. Traumatic, Vascular, Degenerative, & Metabolic Diseases). Berry aneurysms are not truly congenital because they are not present at birth, but there is a congenital defect in the arterial media that permits development of the aneurysm in adult life. Rupture of such aneurysms is particularly apt to occur in hypertensive patients.

Atherosclerosis*

Atherosclerosis is thickening of the artery resulting from deposition of specific atheromatous lesions. “arteriosclerosis” is a nonspecific term that denotes thickening and loss of elasticity (“hardening”) of the Arteries from Any Cause. Changes Associated with Aging and Hypertension Often Lead to Arteriosclerosis.

Incidence

Atherosclerosis is the main cause of ischemic heart disease and cerebrovascular disease, and it is the major primary cause of death in most developed countries. The incidence of deaths due to atherosclerotic arterial disease increased in the United States until the mid 1960s, when it leveled off and began to decline. By 1986, death rates from atherosclerotic coronary and cerebral arterial disease had decreased over 50% when compared with death rates in 1968. The cause of this highly desirable trend is uncertain, although it is probably related to changes in diet and exercise habits and better control of hypertension. In North America and Europe, some degree of atherosclerosis is almost invariably present in the aorta and muscular arteries after age 30 years. The incidence and severity are generally less in South America, Africa, and Asia.

Etiology

The basic abnormality in atherosclerosis is the deposition of complex lipids in the intima. The cause is uncertain. Numerous risk factors have been identified (Table 20-1). The major controllable risk factors are discussed here.

Hypertension

Hypertension is the most important risk factor in people over 45 years of age. Ischemic heart disease is five times more common in an individual whose blood pressure is > 160/95 mm Hg than in one who is normotensive (blood pressure < 140/90 mm Hg). The risk is diminished when high blood pressure is controlled with drugs.

Cigarette Smoking

People who smoke more than 10 cigarettes per day have a threefold increase in risk. The risk declines to normal 1 year after cessation of smoking. The association of smoking with atherosclerosis is thought to be related to the presence of factors such as carbon monoxide that may cause endothelial cell injury.

Diabetes Mellitus

All diabetics who have had the disease for more than 10 years are likely to have significant atherosclerosis. Part of the risk in diabetes is due to the coexistence of other risk factors such as obesity, hypertension, and hyperlipidemia. Other suggested reasons for increased risk are (1) increased glycosylation of collagen, which increases LDL binding to collagen in atheromatous lesions; and (2) the fact that glycosylated high-density lipoprotein (HDL) is more easily degraded than is normal HDL. Because the latter two mechanisms are dependent on glycosylation, which is dependent on elevated blood glucose, it may explain how rigid control of diabetes can reduce the risk of atherosclerosis.

Hyperlipidemia

(Table 20-2.) The presence of hyperlipidemia is the strongest risk factor for atherosclerosis in patients under age 45. Both primary and secondary hyperlipidemias increase the risk. Lipoproteins associated with endogenous lipid metabolism such as low-density lipoprotein (LDL) and intermediate-density lipoprotein (IDL) are much greater risk factors than chylomicrons associated with exogenous lipid metabolism (Figure 20-4). Increased levels of the following components of plasma lipids have been identified as associated with increased risk:

Total Serum Cholesterol

A level of > 240 mg/dL (> 6 mmol/L) imposes a high risk; 200–239 mg/dL (5.2–6.0 mmol/dL) is borderline; < 200 mg/dL (< 5.2 mmol/L) is desirable.

Low Density Lipoprotein Cholesterol (LDL-C)

A level of > 160 mg/dL (> 4.2 mmol/L) imposes a high risk; 130–159 mg/dL (3.4–4.1 mmol/L) is borderline; < 130 mg/dL (< 3.4 mmol/L) is desirable. The LDL-C serum level is determined by the following formula after direct measurement of plasma levels of total cholesterol (C), cholesterol associated with high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG):

LDL-C levels are greatly elevated in familial hypercholesterolemia, which is caused by a mutation in the gene coding for the LDL receptor on the cell surface. Lack (in homozygotes) or decrease (in heterozygotes) of LDL-C receptor leads to failure of clearing of plasma LDL-C by cells and a subsequent increase in plasma LDL-C. There is also an increased production of LDL in these patients, due to failure of metabolism of intermediate density lipoproteins (IDL) by the liver. (IDL also uses the LDL receptor for uptake into the liver cell, and when this fails, IDL is converted to LDL [Figure 20-4].) As LDL accumulates in the plasma, it is taken up by tissues that do not depend on the presence of LDL receptors—macrophages (resulting in xanthomas in the skin and connective tissues) and probably the arterial intima. Homozygotes have extremely high LDL-C levels and develop severe atherosclerotic disease in their teens. Heterozygotes are common (1:500 people in the population), have a twofold to threefold elevation of plasma cholesterol, and develop premature atherosclerosis. Heterozygous familial hypercholesterolemia is found in 3–6% of survivors of myocardial infarction.

Total Plasma Triglyceride

A level > 250 mg/dL (> 2.8 mmol/L) imposes a high risk. Accurate risk evaluation for triglycerides has been difficult because of the associated changes in the more significant cholesterol levels.

Patients who have high-risk lipid levels should be treated to reduce these levels because reduction has a protective effect and may even cause some regression of atherosclerosis. Patients with borderline levels should be treated if they have two or more of the highly significant risk factors other than hyperlipidemia listed in Table 20-1.

Low HDL-Cholesterol

The risk of athero-sclerosis bears an inverse relationship to plasma level of cholesterol associated with high-density lipoprotein (HDL-C). An HDL-C level < 35 mg/dL (< 0.9 mmol/L) imposes a high risk. Low HDL-C levels occur more commonly in (1) males, (2) cigarette smokers, (3) diabetics, (4) inactive people who do not exercise regularly, and (5) patients with high triglyceride levels. Regular exercise and a small daily intake of alcohol have been shown to increase plasma HDL-C levels.

High-density lipoproteins are believed to remove cholesterol liberated from cell turnover. It is possible that HDL also removes cholesterol from atheromatous plaques as part of this function, explaining its protective effect in atherosclerosis.

Abnormal Apoproteins

Apoproteins are proteins that are associated with lipid to form lipoproteins and are genetically determined. Different apoprotein types are associated with different lipoproteins (Table 20-3; Figure 20-4). In addition to being structural components of the lipoprotein molecule, apoproteins function (1) as ligands that interact with cell receptors which bind lipoproteins, and (2) as cofactors of enzymes of lipid metabolism. The following abnormalities of apoproteins, which are inherited, are associated with an increased risk of atherosclerosis:

Familial Type III Hyperlipoproteinemia,

which is associated with an increased plasma level of intermediate-density lipoproteins (IDL) and accelerated atherosclerosis. IDL is normally derived from very-low-density lipoproteins (VLDL), which cleaves off triglyceride and leaves the cholesteryl ester-rich IDL (Figure 20-4). IDL is associated with apoproteins B100 and E and is either taken up by the liver cell for recycling into VLDL or metabolized into LDL. Hepatic uptake of IDL is dependent on recognition of IDL by the same receptor that recognizes LDL. The binding of IDL to the receptor is dependent on the presence of apoprotein E. Patients with familial type III hyperlipoproteinemia inherit an abnormal apoprotein E, resulting in failure of IDL uptake by the liver, increased IDL in the plasma, and atherosclerosis.

Abnormal HDL-Associated Apoproteins

High-density lipoproteins are believed to remove excess cholesterol from cells and tissues (probably including atheromatous lesions, explaining their protective effect). HDL is associated with several apoproteins, three of which (A1, C3, and A4) are encoded by genes clustered on chromosome 11. Inherited abnormalities of these apoproteins lead to a defect in HDL function and have been associated with atherosclerosis. The best-understood component is defective Apo-AI. Normally, Apo-AI serves as a cofactor for the enzyme lecithin-cholesterol acyltransferase (LCAT), which is necessary for the metabolism and removal of cholesterol taken up by HDL. With defective Apo-AI, this reaction fails, interfering with the normal protective function of HDL.

Increased Lipoprotein (a)

Lipoprotein (a) [Lp(a)] is associated with an increased risk. Lp(a) is a variant of LDL in which the normal LDL apoprotein (B100) is linked by disulfide bridges to a distinct apoprotein (a) which is encoded by a single gene. Plasma levels of Lp(a) are determined by the amount of apoprotein(a) that is produced. Apo(a) has structural similarity to plasminogen (it contains 37 copies of kringle 4, which is part of the plasminogen molecule that normally binds to fibrin during fibrinolysis). It is known that microthrombi are frequently formed in relation to atherosclerotic lesions. If these are normally removed by plasminogen, the presence of Apo(a) in the lesions can inhibit this process by competing with plasminogen for kringle 4 receptors on the fibrin molecule.

Pathogenesis

The mechanism responsible for lipid deposition in the intima and formation of the atheromatous lesion is unknown. The following hypotheses of the pathogenesis of atherosclerosis are not mutually exclusive.

Reaction to Endothelial Injury

The primary event of atherosclerosis according to this hypothesis is endothelial injury. Nondenuding endothelial injury is believed to lead to adherence of blood monocytes, which are activated, imbibe LDL and actively enter the intima, and become macrophages. Active macrophages release free radicals that oxidize LDL. Oxidized LDL is toxic to endothelium, causing endothelial loss and exposure of subendothelial connective tissue to blood components. This leads to platelet adhesion and aggregation and to fibrin deposition, forming microthrombi. Platelets release various factors—one of which has been identified as being mitogenic—causing migration of smooth muscle into the intima and proliferation therein. The activated macrophages and smooth muscle cells secrete numerous cytokines that can be found in the early lesion. These include platelet-derived growth factor (PDGF), tumor necrosis factor (TNF), fibroblast growth factor (FGF), and interleukin-1, some of which may also have mitogenic capability.

The smooth muscle cells, macrophages, and matrix accumulate LDL from the plasma, a process that is enhanced by the presence of increased LDL in the blood. Smooth muscle cells and endothelial cells have LDL receptors on their surfaces, and macrophages are capable of taking up LDL—facts that would explain the high association of LDL with lesions. This sets up a cycle of changes that involves macrophage activation, LDL oxidation, and endothelial damage that cause progression of the atheromatous lesion.

The nature of the initial endothelial injury is unknown. Physical shear injuries are maximal at sites of arterial branching, which are the sites most involved in atherosclerosis, and hypertension would aggravate these injuries. There may be a toxic effect of hypercholesterolemia itself, and exogenous toxins such as carbon monoxide are present in the serum of cigarette smokers. Homocysteine-induced endothelial injury is believed to be responsible for the premature atherosclerosis seen in patients with homocystinuria.

Thrombus Encrustation

According to this hypothesis, the primary event is thrombosis. The thrombus becomes incorporated into the intima and then undergoes lipid degeneration to initiate the lesion. Thrombosis is now thought not to be the initial event, but it probably plays a role in the development and enlargement of the lesion. Lipoprotein(a) promotes development of atherosclerosis by virtue of its inhibition of plasminogen activity, which suggests that removal of fibrin is important in preventing progression of the atheromatous lesion.

Monoclonal Hypothesis

The smooth muscle cell proliferation in the lesion was shown, at least in some cases, to be monoclonal. This suggested that mitogen-induced smooth muscle proliferation was the primary event. This is unlikely, as it has been shown that monoclonality of the smooth muscle cells is not a constant feature. However, mitogen-induced smooth muscle proliferation is still thought to be important in the development of the atheromatous lesion.

Pathology

The lesions associated with atherosclerosis are the fatty streak, the fibrous atheromatous plaque, and the complicated lesion. The latter two are definitely pathologic and are responsible for clinically significant disease.

The Fatty Streak

Fatty streaks are thin, flat, yellow streaks in the intima. They consist of macrophages and smooth muscle cells the cytoplasm of which has become distended with lipid (to form foam cells). Fatty streaks occur maximally around the aortic valve ring and thoracic aorta. They are present very early in life, often in the first year, and are seen all over the world irrespective of sex, race, or environment. They increase in number until about age 20 years and then remain static or decrease. There is controversy about whether some fatty streaks progress into fibrous atheromatous plaques or whether they are independent of atherosclerosis.

The Fibrous Atheromatous Plaque

This is the basic lesion of clinical atherosclerosis. It consists of three zones: (1) A fibrous cap under the endothelium, consisting of dense collagen and scattered smooth muscle cells and macrophages; (2) the lipid zone, which consists of foam cells (lipid-laden macrophages and smooth muscle cells) and extracellular lipid and debris; and (3) the basal zone, composed of proliferated smooth muscle cells and connective tissue. Different plaques contain varying amounts of these three layers; some are mainly fibrous, and others are predominantly fatty.

The fibrous atheromatous plaque appears grossly as a yellow-white elevation on the intimal surface of the artery (Figure 20-5). In cut section, the center of the plaque consists of semisolid yellow material (Gk ather- = porridge). Microscopically, the three zones are recognizable and are of varying thickness in different plaques (Figure 20-6). Needle-shaped cholesterol crystals are commonly present in the lipid zone.

Fibrous atheromatous plaques are present in the aorta in most cases, with maximal change most commonly in the abdominal aorta (Figure 20-5). Involvement of muscular arteries such as the coronary, carotid, vertebrobasilar, mesenteric, renal, and iliofemoral arteries is associated with luminal stenosis. This is common and is responsible for many of the clinical manifestations of atherosclerosis (Table 20-4). Plaques tend to be most prominent at points of branching of the major arteries. In severe disease, plaques become confluent, involving much of the intimal surface (Figure 20-5).

The Complicated Plaque

(Figure 20-7.) Thrombosis is the most important complication of atherosclerosis because it may cause complete occlusion of the artery. Thrombosis is caused by (1) slowing and turbulence of blood in the artery in the region of the plaque and (2) ulceration of the plaque.

Dystrophic calcification is very common and occurs in the lipid zone of the plaque. Severely affected vessels (including the aorta) may become converted into calcific tubes. Ulceration of the endothelium overlying the plaque may cause the lipid contents of the plaque to be discharged into the circulation as cholesterol emboli (Chapter 9: Abnormalities of Blood Supply). Ulceration of the plaque may also precipitate arterial thrombosis at the site. Vascularization of the plaque occurs by ingrowth of poorly supported vessels from the medial aspect. These may rupture, leading to hemorrhage into the plaque, which may then expand sufficiently to occlude the lumen of the artery. Hemorrhage may also cause ulceration and thrombosis. Aneurysms may develop in arteries weakened by extensive plaque formation; the abdominal aorta is the favored site of atherosclerotic aneurysms.

Clinical Features

(Table 20-4)

Narrowing of Affected Arteries

Ischemia from arterial narrowing is responsible for most of the clinical effects of atherosclerosis (Figure 20-8). A decrease in blood flow usually occurs only with severe (> 70%) narrowing of the vessel. Aortic narrowing is almost never sufficient to cause symptoms. However, narrowing of coronary, cerebral, renal, mesenteric, and iliofemoral vessels often causes ischemic changes in the organs and tissues supplied. Superimposed thrombotic occlusion of these arteries may cause infarction.

Embolism

Ulceration of the atheromatous plaque may result in embolization of the lipid contents of the plaque (Figure 20-7). This is important in the cerebral circulation, where small emboli produce transient ischemic attacks. Emboli can sometimes be visualized in the retinal arteries on funduscopic examination.

Aneurysm

(Figure 20-9.) In severe athero-sclerotic involvement of the aorta, the wall may be weakened to an extent that leads to dilation or aneurysm formation. Atherosclerotic aneurysms occur mainly in the lower abdominal aorta and may appear as a fusiform dilation of the whole vessel circumference or a saccular bulge on one side of it.

Systemic Hypertension

Hypertension is defined as sustained elevation of systemic arterial blood pressure. While the concept is clear, the exact pressure that constitutes hypertension is an arbitrary determination based on pressures associated with a statistical risk of developing diseases associated with hypertension. In adults, a diastolic pressure below 85 mm Hg is normal; 85–89 mm Hg is high normal; 90–99 mm Hg is mild hypertension; 100–109 mm Hg is moderate hypertension; 110–119 mm Hg is severe hypertension; and >120 mm Hg is very severe hypertension. In a person with a diastolic pressure of < 90 mm Hg, a systolic pressure < 140 mm Hg is normal; 140–159 mm Hg is borderline isolated systolic hypertension; and >160 mm Hg is isolated systolic hypertension. Both diastolic and isolated systolic hypertension are associated with increased risk of cardiovascular complications.

Incidence

About 15–20% of adults in the United States have blood pressures over 160/95 mm Hg, and nearly 50% have pressures over 140/90 mm Hg. The incidence is higher in African-Americans than in whites, Asians, and Hispanic-Americans. Hypertensive individuals have increased mortality rates related to associated atherosclerotic arterial disease in direct proportion to the severity of the hypertension. Control of blood pressure decreases the risk of cardiovascular morbidity.

Etiology & Pathogenesis

(Figure 20-10)

Essential Hypertension

Essential hypertension occurs as a primary phenomenon without known cause. It is the most common type of hypertension, usually occurring after age 40 years, with a familial incidence suggestive of polygenic inheritance upon which environmental factors are superimposed.

The pathogenesis is uncertain. No constant changes have been identified in plasma levels of angiotensin, renin, aldosterone, or catecholamines—or in the activity of the sympathetic nervous system or baroreceptors—that could account for the elevated blood pressure. Some hypertensive individuals have elevated levels of plasma angiotensin, which has been related to the finding of a variant angiotensin gene. Inhibitors of angiotensin-converting enzyme are effective antihypertensive drugs.

The currently favored hypothesis is that essential hypertension is due to high dietary intake of sodium in a genetically predisposed individual. There may be associated failure of excretion by the kidney in the face of a prolonged high sodium load. Sodium retention results in an increase in circulating natriutretic factors. One of these inhibits membrane Na+–K+ ATPase, thereby leading to intracellular accumulation of Ca2+. Cytosol Ca2+ is increased in essential hypertension; in vascular smooth muscle, increased cytosol Ca2+ enhances reactivity and tends to cause vasoconstriction. This effect of Ca2+ is inhibited by calcium channel-blocking drugs, which are effective antihypertensive agents.

Endothelium derived factors such as nitrous oxide are produced in response to shear forces, intraluminal pressure, circulating hormones, and platelet factors. Nitrous oxide acts on the underlying smooth muscle cells, causing vasodilation. An abnormality in the nitrous oxide system has been suggested as causing hypertension. Nitrous oxide donors such as nitroprusside are effective antihypertensive agents.

Secondary Hypertension

Secondary hypertension is that due to a preceding defined disease process (Table 20-5). Even though an underlying cause can be identified in less than 10% of cases of hypertension, this group of patients is important because many of their diseases can be treated. Secondary hypertension must be strongly suspected in a patient under 40 years of age who develops hypertension.

Secondary hypertension results from accentuation of one of the many factors (renin, aldosterone, renal sodium reabsorption, catecholamines, sympathetic stimulation) that may increase cardiac output or peripheral resistance (Figure 20-10 and Table 20-5).

Pathology

Benign Hypertension

In the earliest phase of hypertension, vasoconstriction is produced by smooth muscle contraction and there are no microscopic changes in blood vessels. Following sustained vasoconstriction, there is thickening of the media due to muscle hypertrophy, progressing to hyaline degeneration and intimal fibrosis. These changes are known as hyaline arteriolosclerosis and are found with longstanding hypertension of mild to moderate degree (benign hypertension). The tissues supplied by affected vessels may show changes of chronic ischemia.

Malignant Hypertension

Malignant hypertension is characterized by papilledema (which defines the entity), retinal hemorrhages and exudates, and blood pressures usually > 200/140 mm Hg. It is characterized pathologically by the occurrence of fibrinoid necrosis of the media with marked intimal fibrosis and extreme narrowing of the arteriole (Figure 20-11). The tissues supplied by affected vessels show acute ischemia with microinfarcts and hemorrhages. Malignant hypertension is frequently associated with elevated serum renin levels, establishing a vicious cycle that tends toward further elevation of the blood pressure.

Clinical Features

(Table 20-6)

Early Hypertension

The early phase of hypertension is asymptomatic, and the diagnosis can be made only by detecting the elevation of blood pressure.

Hypertensive Heart Disease

Systemic hypertension results in increased work for the left ventricular muscle, which undergoes hypertrophy, thereby maintaining cardiac output. With severe hypertension, particularly in the malignant phase, left ventricular failure occurs.

Hypertension is a major risk factor for coronary atherosclerosis and ischemic heart disease. Ischemia is aggravated by the increased oxygen demand of the hypertrophied myocardium.

Hypertensive Renal Disease

Changes in renal arterioles occur in most cases of hypertension, resulting in decreased glomerular filtration rate, progressive fibrosis, and loss of nephrons in the kidneys. Renal ischemia resulting from these changes sets up a vicious cycle (falling glomerular filtration rate, renin release, angiotensin production, salt retention) that aggravates the hypertension.

Renal failure with elevation of serum creatinine usually occurs only in patients with malignant hypertension. Fibrinoid necrosis is present in renal arterioles (Figure 20-11). Hematuria occurs, and marked reduction in glomerular filtration rate may progress to acute renal failure.

Hypertensive Cerebral Disease

Hypertensive patients have a greatly increased incidence of cerebrovascular disease, both thrombosis and hemorrhage (strokes). Cerebral thrombosis is the result of atherosclerosis; cerebral hemorrhages result from rupture of microaneurysms in small intracerebral perforating arteries.

Hypertensive encephalopathy is due to spasm of small arteries in the brain induced by very high blood pressures. The temporary spasm, though insufficient to cause infarction, leads to cerebral edema, which produces headache and transient cerebral dysfunction.

Hypertensive Retinal Disease

The retinal arterioles show all the changes of hypertension on funduscopic examination (hypertensive retinopathy). Narrow, irregular arteries with thickened walls characterize mild to moderate hypertension. Malignant hypertension leads to papilledema, retinal hemorrhages, and fluffy exudates (cotton wool spots)—ill-defined areas of edema and repair resulting from ischemia (Figure 20-12).

Diagnosis, Treatment, & Prognosis

The blood pressure should be measured several times over a period of several weeks to make certain that hypertension is sustained. It is important to look for clinical effects due to hypertension and for treatable causes, especially in patients under 40 years, because essential hypertension is uncommon in this age group.

When a treatable cause of hypertension such as renal artery stenosis or an adrenal neoplasm is present, surgery is curative. Patients with essential hypertension must receive lifelong treatment with antihypertensive drugs. The prognosis for patients with essential hypertension depends on how well the blood pressure is controlled. With modern effective drugs, the prognosis is good. Without control of blood pressure, even patients with mild hypertension develop significant complications after 7–10 years. Untreated hypertension shortens life by 10–20 years, usually by increasing the rate of atherosclerosis.

Medial Calcification (Monckeberg's Sclerosis)

Medial calcification is a clinically unimportant but very common degenerative change affecting muscular arteries such as the femoral, radial, and uterine arteries. The tunica media shows extensive calcification. There is no luminal narrowing or endothelial damage. Medial calcification does not produce any clinical abnormality—it is seen in elderly persons and is regarded as an aging change.

Aortic Dissection (Dissecting Aneurysm of the Aorta)

Incidence & Etiology

(Figure 20-13)

In aortic dissection, there is disruption of the media of the aorta by entry of blood under high pressure through an intimal tear. Hypertension is present in 70% of patients and is the most important factor, causing tearing of the endothelium and intima and permitting entry of blood at high pressure into the weakened media. Myxomatous degeneration of the media (Erdheim's cystic medial degeneration) is present in 20% of cases.

Pathology

Aortic dissection is associated with an intimal tear, usually just above the aortic valve or immediately distal to the ligamentum arteriosum. Blood enters the media at this intimal tear and dissects between the layers of smooth muscle in the media. Cystic medial degeneration, when present, facilitates dissection (Figures 20-13 and 20-14).

Cystic medial degeneration appears microscopically as ill-defined mucoid lakes with associated patchy loss of elastin fibers and smooth muscle. Cystic medial degeneration and aortic dissection are more common in patients with Marfan's syndrome.

Lathyrism is a similar condition induced experimentally in animals by feeding a diet of sweet peas. The high content of β-aminopropionitriles in sweet peas interferes with collagen synthesis, causing myxomatous degeneration of the media.

Clinical Features

The clinical effects of aortic dissection depend upon its site and extent. Dissection of the media produces sudden severe pain, which is usually retrosternal and mimics the pain of myocardial infarction. Arteries taking origin from the aorta may become occluded, or rupture may occur leading to massive hemorrhage (Figure 20-13). Thirty percent of patients die within 24 hours. In those who survive, treatment with antihypertensive drugs and surgery has greatly improved survival.

Varicose Veins

Abnormally dilated and tortuous veins occur in several sites—in the legs, rectum (hemorrhoids), esophagus (varices in portal hypertension), or spermatic cord (varicocele). They are associated with increased pressure in the affected vessels, obstruction to adequate venous drainage, or increased blood flow in the affected vessels.

Etiology

In the legs, varicose veins involve the superficial saphenous venous system and result (1) from obstruction to the deep veins of the leg, with the superficial varicose veins representing the collateral venous drainage; or (2) from incompetence of the valves in the saphenous veins and in the perforating veins that normally prevent flow of blood from the deep to the superficial veins. The latter mechanism involving valve incompetence is responsible for most cases of varicose veins. The cause of valve incompetence is unknown but is probably a degenerative phenomenon.

Clinical Features

Varicose veins are visible in the leg as markedly dilated tortuous veins (Figure 20-15) whose distribution depends upon which valves are incompetent. They are associated with obesity and pregnancy, and there may be a familial predisposition.

Varicose veins produce adverse cosmetic effects and chronic aching and swelling, and they serve as sites for recurrent thrombophlebitis, stasis dermatitis, and skin ulceration. Stasis ulcers typically occur in the region of the ankle.

Treatment

Treatment consists of surgical removal of the varicose superficial leg veins or, for small varices, local injection of sclerosing agents. Before such treatment is undertaken, deep venous occlusion must be excluded; otherwise, the venous drainage of the entire leg may be compromised.

Inflammation of blood vessels (vasculitis) is a feature of many diseases (Table 20-7).

Syphilitic Aortitis

Syphilitic aortitis occurs in the tertiary stage of syphilis, often many decades after the primary infection. The spirochete cannot usually be demonstrated in the lesions, and it has been suggested that immunologic hypersensitivity plays a part in pathogenesis.

Although syphilis remains a common disease, syphilitic aortitis has become rare today because of successful treatment of early syphilis.

Pathology

The ascending thoracic aorta is maximally affected. The vasa vasorum, which normally provide blood supply to the adventitia and outer media of the aorta, are primarily involved by inflammation and luminal narrowing due to intimal fibrosis (endarteritis obliterans). Ischemia leads to degeneration and fibrosis of the outer two thirds of the aortic media, which is supplied by the vasa vasorum. There is compensatory irregular fibrous thickening of the intima (tree-bark appearance).

Clinical Features

Weakening of the aortic wall causes (1) dilation of the aortic root and aortic-valve incompetence; (2) aneurysmal dilation of the aorta; (3) narrowing of the openings of the coronary arteries (ostial stenosis), causing myocardial ischemia; and (4) rupture, which is rapidly fatal.

Takayasu's Disease

Takayasu's disease (also called occlusive thromboaortopathy, aortic arch syndrome, and pulseless disease) is a disease of unknown cause that is uncommon in the United States but has a relatively high incidence in Japan. Females are affected more often than males in a 9:1 ratio. About 90% of cases occur in persons under 30 years of age. There is an increased association with human leukocyte antigen (HLA)-DR4.

Pathology

The disease process usually is restricted to the aortic arch, although in 30% of cases the whole aorta is involved and in 10% only the descending aorta.

Marked fibrosis involves all layers of the wall, causing narrowing and occlusion of arteries taking origin from the aorta. Microscopic examination shows infiltration of the media and adventitia by neutrophils and chronic inflammatory cells, particularly around the vasa vasorum. In a few cases, granulomas with giant cells are seen.

Clinical Features

Occlusion of the origin of the aortic arch vessels leads to loss of radial pulses and ischemic neurologic lesions. Ocular ischemia with visual impairment is typical. In cases that involve the descending aorta, involvement of renal arteries may lead to hypertension.

The course is variable and may end in death either in the acute phase or after several years of slowly progressive disease.

Giant Cell Arteritis (Temporal Arteritis)

Giant cell arteritis is an uncommon disease, virtually confined to individuals over 50 years of age. The cause is uncertain. Type IV hypersensitivity against arterial wall antigens has been demonstrated in a few cases.

Pathology

Giant cell arteritis is so named because its microscopic features are dominated by granulomatous inflammation and the presence of numerous giant cells. Fragmentation of the internal elastic lamina is followed by fibrosis. Thrombosis may occur in the acute phase.

The inflammation affects medium-sized muscular arteries, with a predilection for the superficial temporal artery and intracranial arteries, including those supplying the retina. About 50% of patients have pain and stiffness in the shoulder and hip (polymyalgia rheumatica).

Clinical Features

The most common clinical presentation is with severe headache associated with thickening and tenderness of the inflamed superficial temporal artery. Diagnosis is by biopsy of the artery; because involvement may be focal, it is important to attempt biopsy of tender inflamed segments. Elevation of the erythrocyte sedimentation rate, although not specific, is a useful diagnostic test.

Diagnosis followed by treatment with corticosteroids is important because involvement of the retinal artery may cause permanent blindness. Cranial nerve paralyses may also occur.

Polyarteritis Nodosa

Polyarteritis nodosa is an uncommon disease that occurs most frequently in young adults. Males are more frequently affected than females. The disorder is believed to be a type III immunologic hypersensitivity (immune complex) reaction. Hepatitis B surface antigen is present in the complexes in 30–40% of patients; the antigen involved in other cases is unknown. Antineutrophil cytoplasmic autoantibodies are present in the serum in a minority of patients.

Pathology

Medium-sized and small arteries throughout the body show characteristic segmental lesions consisting of nodular reddish swellings and multiple microaneurysms. Arterial rupture with tissue hemorrhages and thrombosis with tissue ischemia may occur in the acute phase. In the chronic phase, the involved artery is thickened and narrowed by fibrosis.

Microscopic examination shows fibrinoid necrosis of the media and acute inflammation involving all layers (Figure 20-16). In the chronic phase, the artery shows less specific concentric fibrosis of the wall. A typical feature of polyarteritis is the coexistence of acute and chronic lesions at different sites.

Clinical Features

The usual course is progressive, with exacerbations and remissions. Without treatment, the 5-year survival rate is less than 20%; with steroid therapy, 50% of patients are alive after 5 years.

In the acute phase, patients develop fever, with variable signs and symptoms according to the pattern of organ involvement (Table 20-8).

Diagnosis of polyarteritis is clinical. Biopsy of acutely affected tissue such as muscle or kidney may provide histologic confirmation.

Wegener's Granulomatosis

Wegener's granulomatosis is characterized by necrotizing vasculitis, similar to that seen in polyarteritis nodosa but with extensive extravascular necrosis and granulomatous reaction; and, in most cases, involvement of the lungs, nasopharynx, and kidney (glomerulonephritis). Antineutrophil cytoplasmic autoantibodies are present in the serum in 95% of cases. The course is rapidly progressive. The disease responds partially to immunosuppressive therapy, but the overall prognosis is poor. Wegener's granulomatosis is discussed in greater detail in Chapter 35: The Lung: II. Toxic, Immunologic, & Vascular Diseases.

Allergic Angiitis & Granulomatosis of Churg & Strauss

This is an uncommon immunologically mediated disease occurring in both sexes and at all ages that has features which overlap with those of polyarteritis nodosa and Wegener's granulomatosis. It affects multiple organs, but pulmonary involvement is dominant. Severe asthma and peripheral blood eosinophilia are usually present. The vasculitis resembles polyarteritis nodosa except that it affects small vessels, including venules in addition to muscular arteries, and is associated with granuloma formation. The 5-year survival rate is 25%.

Mucocutaneous Lymph Node Syndrome (Kawasaki Disease)

Kawasaki disease is a rare disease that occurs in children. The cause is unknown, but it is believed to be an immunologic hypersensitivity triggered by an infectious agent. The disease is characterized clinically by an acute onset of fever, with conjunctival and oral edema and hemorrhage and cervical lymphadenopathy that is usually self-limited. Coronary artery vasculitis, characterized by inflammation, intimal thickening, narrowing, and aneurysm formation occurs in severe cases. Myocardial infarction and coronary aneurysmal rupture cause death in 3% of cases.

Thromboangiitis Obliterans (Buerger's Disease)

Thromboangiitis obliterans is rare in the United States and Europe but is a common cause of peripheral vascular disease in Israel, Japan, and India. The disease occurs most often in young men in the age group from 20 to 30 years and is largely restricted to heavy cigarette smokers. Exacerbations and remissions of the disease are closely related to changes in smoking habits. The mechanism by which smoking provokes the disease is unknown.

Pathology

Thromboangiitis obliterans is characterized by segmental involvement of small and medium-sized arteries, mainly in the lower extremities. The lesion frequently involves adjacent veins and nerves.

In the acute phase, there is marked swelling and neutrophilic infiltration of the entire neurovascular bundle. Thrombosis is common. Healing by fibrosis and organization of thrombi produces thick cord-like vessels with occluded lumens.

Clinical Features

Progressive ischemia of the lower limbs produces intermittent claudication, with pain in the calf muscles precipitated by exercise and relieved by rest. As the disease progresses, the amount of exercise necessary to produce pain (called the claudication distance) decreases, leading to progressively greater disability.

With severe disease, pain is present at rest along with trophic changes in the skin, culminating in dry gangrene.

The disease is progressive. Abstinence from smoking frequently results in remissions, but it is not uncommon for these patients to continue smoking cigarettes even as disease progresses to extreme disability and amputation of their limbs.

Small Vessel Vasculitis

Necrotizing vasculitis affecting small vessels occurs in a large number of different diseases, most of which are mediated by type III immune complex hypersensitivity (Table 20-9). Noninflammatory small vessel disease occurs in diabetes mellitus. (See Diabetic Microangiopathy, Chapter 46: The Endocrine Pancreas (Islets of Langerhans).)

Raynaud's disease is a distinct process of unknown cause characterized by small vessel spasm without anatomic abnormalities. Raynaud's phenomenon, which has similar clinical consequences, occurs as a secondary manifestation of many diseases in which small vessel vasculitis occurs. Both disorders are characterized by numbness and pallor or cyanosis of hands and feet in response to cold.

Pathology

The changes are similar to those seen in polyarteritis nodosa except that smaller arterioles are involved. Fibrinoid necrosis of the arteriolar walls is accompanied by intense neutrophil infiltration of the vessels. Degeneration of neutrophils in the lesions causes lysis and fragmentation of nuclei (leukocytoclasia) and deposition of nuclear fragments (nuclear dust) in and around the affected vessel. Thrombosis and hemorrhage are common. Immunoglobulin and complement can be demonstrated by immunologic techniques in these lesions.

Clinical Features

These diseases are characterized by involvement of multiple organs. Skin involvement leads to raised purpuric patches (palpable purpura). Renal involvement is associated with glomerulonephritis. Individual diseases are considered elsewhere (Table 20-9).

Thrombophlebitis

Thrombophlebitis and phlebothrombosis have been discussed in Chapter 9: Abnormalities of Blood Supply. Two specific types of thrombophlebitis will be discussed briefly here.

Phlegmasia Alba Dolens (Painful White Leg)

This is a rare but specific type of deep-leg-vein thrombophlebitis that occurs during the later months of pregnancy. There is extreme swelling of the leg associated with severe pain, tenderness, and increased temperature. The cause is not known.

Migratory Thrombophlebitis

Episodic inflammation of superficial veins at multiple sites occurs in association with thromboangiitis obliterans or with carcinomas of internal organs such as the pancreas, stomach, lung, or colon. (This is called Trousseau's syndrome after the French physician who described it in himself. He died of pancreatic cancer.) The mechanism by which the neoplasm produces thrombophlebitis is unknown.

Lymphangitis

Bacterial Lymphangitis

Lymphangitis commonly complicates bacterial infections of the skin, with Streptococcus pyogenes the most common cause. The inflamed lymphatics appear as painful, red streaks, frequently associated with acute lymphadenitis.

Filarial Lymphangitis

Filarial lymphangitis is extremely common in the tropics and is caused by Wuchereria bancrofti and Brugia malayi transmitted by mosquitoes of the Aedes and Culex species. Microfilariae reaching the lymphatics mature into adult worms, and death of the worms causes acute lymphangitis. This is followed by fibrotic occlusion of the lymph channels, resulting in obstruction and chronic lymphedema (elephantiasis).

Benign Neoplasms

Hemangioma

Hemangiomas are common. About 70% are present at birth, which suggests that they may be hamartomas rather than true neoplasms. The skin, liver, and brain are common sites, but any organ may be involved. Hemangiomas are composed of well-formed vascular spaces lined by endothelial cells that show no cytologic atypia. They are classified as capillary hemangiomas, composed of vessels of capillary size; or cavernous hemangiomas, composed of large thin-walled vascular spaces.

Capillary hemangiomas are usually found in the skin and mucous membranes as small (< 1 cm), red to blue plaques or nodules. Most grow slowly with the growth of the individual. One specific type (strawberry hemangioma) grows rapidly during the first few months of life and then regresses (80% regress completely by 5 years).

Cavernous hemangiomas occur in skin as well as in the viscera, forming a soft spongy mass that may reach 2–3 cm in size. They grow slowly.

Hemangiomas in deep subcutaneous tissues and skeletal muscle (intramuscular hemangiomas) tend to be ill-defined and require wide excision to prevent local recurrence. They do not metastasize.

Glomus Tumor (Glomangioma)

A glomus is a small temperature-receptor organ situated in small arterioles. Benign neoplasms of glomi may occur anywhere in the skin but are most common under the fingernails and toenails. They occur in adults, forming small, firm, red-blue lesions that are extremely painful. They vary in size from 1 mm to 1 cm.

Microscopically, glomangiomas are composed of vascular spaces separated by nests of small, regular round cells with scant cytoplasm.

Lymphangioma

Cavernous lymphangioma (also called cystic hygroma) is a benign tumor that occurs mainly in the neck in infancy, causing considerable enlargement of the neck. It is common in Turner syndrome. The larger tumors may obstruct delivery through the birth canal. Lymphangiomas also occur in the mediastinum and retroperitoneum in adults. Lymphangiomas can grow to large size, making complete surgical removal difficult. They do not metastasize.

Malignant Neoplasms

Angiosarcoma (Hemangiosarcoma)

Angiosarcoma is a rare neoplasm of adults. It may occur anywhere in the body, but the skin, soft tissue, bone, liver, and breast are the common sites. Hepatic angiosarcomas have been etiologically associated with thorium dioxide (Thorotrast), a radiologic dye that was used in 1930–1950, and vinyl chloride, used in the plastics industry.

Angiosarcoma is a malignant neoplasm of endothelial cells. It typically forms interdigitating vascular spaces; less-differentiated angiosarcoma may be solid and composed of anaplastic cells. Angiosarcomas are destructive, infiltrative neoplasms that metastasize early via the bloodstream.

Angiosarcoma usually presents as a large, hemorrhagic, rapidly growing mass. The prognosis is poor, mainly because of early and widespread metastasis.

Kaposi's Sarcoma

Kaposi's sarcoma was a rare neoplasm in the United States until 1979. It occurred mainly in elderly Jewish men of European origin, involving the lower extremities as a slowly growing, ulcerative skin lesion with a protracted course (classic type). A more aggressive type of Kaposi's sarcoma is endemic in South Africa among the Bantu tribe, mainly affecting children and young adult males (endemic type).

In 1979, Kaposi's sarcoma occurred in epidemic proportions in patients with acquired immune deficiency syndrome (AIDS). These patients have a much more aggressive variant of Kaposi's sarcoma that involves viscera such as intestine, lung, lymph nodes, and liver, as well as the skin. Cases of disseminated Kaposi's sarcoma occur also in other immunocompromised patients, particularly after renal transplantation.

The cause of Kaposi's sarcoma and how it is related to immune deficiency are unknown. The genome of cytomegalovirus is found in many neoplastic cells, but whether this is incidental or has an etiologic relationship is uncertain.

Kaposi's sarcoma is an infiltrative lesion composed of spindle-shaped endothelial cells that form poorly developed vascular slits. Erythrocyte extravasation and hemosiderin deposition occur commonly. The neoplastic cells are poorly differentiated and have an increased mitotic rate. Disseminated Kaposi's sarcoma is believed to be due to the occurrence of multiple neoplasms all over the body rather than to metastasis.

Lesions of Kaposi's sarcoma appear as purple patches, plaques, or nodules in the skin, which may ulcerate (Chapter 7: Deficiencies of the Host Response). In the viscera, they appear as hemorrhagic masses. In the immunodeficient individual, Kaposi's sarcoma is rapidly progressive; death occurs within 3 years in most patients with AIDS.

Lymphangiosarcoma

Lymphangiosarcoma is a malignant neoplasm of lymphatic endothelium. It is rare, occurring with greatest frequency in patients who develop lymphedema in the upper extremity after radical mastectomy followed by radiation therapy for breast carcinoma (Stuart-Treves syndrome). Removal of axillary lymphatics causes lymphedema, and the use of radiation may contribute to malignant transformation. The neoplasm grows rapidly and metastasizes early. The prognosis is poor.