Section V. The Cardiovascular System

Atherosclerotic arterial disease (Chapter 20: The Blood Vessels), which is responsible for ischemic disease of the myocardium (Chapter 23: The Heart: III. Myocardium & Pericardium), brain, and other organs, is the major cause of death in developed countries, and accounts for over 40% of all deaths in the United States. The consequences of arterial narrowing and thrombosis have been considered in Chapter 9: Abnormalities of Blood Supply, a brief review of which may be beneficial at this stage. Hypertension (Chapter 20: The Blood Vessels) affects an estimated 25 million adult Americans.

Congenital heart diseases are considered in Chapter 21: The Heart: I. Structure & Function; Congenital Diseases. Although the incidence has declined with decreased prevalence of rubella as a result of immunization (Chapter 15: Disorders of Development), other teratogenic factors are continually being identified as placing the fetus at risk. Current incidence of significant congenital heart disease is about 25,000 per year in the United States. The incidence of rheumatic heart disease (Chapter 22: The Heart: II. Endocardium & Cardiac Valves) is also decreasing, in this case due to a general decline in streptococcal infections in developed countries. However, more than 1 million Americans suffer from chronic rheumatic valvular disease. Chronic valvular disease, the use of prosthetic valve replacements, and intravenous drug abuse are associated with infective endocarditis (Chapter 22: The Heart: II. Endocardium & Cardiac Valves), which is the most significant infectious disease of the heart. Primary neoplasms of the heart are rare, with the only common neoplasm the cardiac myxoma (Chapter 22: The Heart: II. Endocardium & Cardiac Valves).

Cardiac transplantation is still considered experimental, although there is an increasing tendency to use transplants for irreparable congenital diseases and primary myocardial diseases (cardiomyopathies, Chapter 23: The Heart: III. Myocardium & Pericardium). Transplantation is not discussed in this section, and the reader should refer instead to Chapter 8: Immunologic Injury.

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.

Structure of the Heart

The heart is composed of (1) the endocardium, which lines the internal surfaces of the cardiac chambers and valves; (2) the myocardium; (3) the pericardium, composed of an inner visceral layer covering the heart and an outer parietal layer completing the pericardial sac; and (4) a specialized conducting system consisting of the sinoatrial (SA) and atrioventricular (AV) nodes, the bundle of His, and the arborizing Purkinje fibers.

The muscular interatrial and interventricular septa divide the heart longitudinally into a right side, which accepts the deoxygenated systemic venous return and pumps it into the low-pressure pulmonary circulation; and a left side, which accepts the oxygenated pulmonary venous blood and pumps it into the aorta (Figure 21-1). The left side and the systemic arterial circulation are at much higher hydrostatic pressures than the right side and the pulmonary arterial circulation.

Each side of the heart is further divided by the atrioventricular valves into an atrium and a ventricle. The muscular atrial walls normally have a thickness not exceeding 2 mm. The right ventricle pumps blood into the relatively low-pressure pulmonary circulation (systolic pressure 15–30 mm Hg) and has a wall thickness of less than 0.5 cm. The left ventricle develops a systolic pressure of 100–140 mm Hg to maintain the high-pressure systemic circulation (Figure 21-2). The left ventricle normally has a wall thickness of up to 1.5 cm.

The pump mechanism of the heart is made possible by the presence of valves that isolate one part of the heart from another when they close (Figure 21-2). The cardiac valves are thin, translucent fibrous membranes that are attached circumferentially to the valve ring. Blood flow through normal open valves is nonturbulent and laminar and therefore not perceived by auscultation. When a valve closes, the free edges come firmly into apposition, effectively closing the orifice.

The atrioventricular valves are composed of two (mitral valve) or three (tricuspid valve) cusps. The free edges of the atrioventricular valves are attached to the papillary muscles of the ventricle by fibrous cords (chordae tendineae). Closure of the valves in systole prevents regurgitation of blood into the atrium.

The semilunar (aortic and pulmonary) valves remain closed during diastole, preventing regurgitation of blood from the great vessels into the ventricles.

Myocardial Function

The myocardium is composed of striated muscle fibers that contain myofibrils composed of serially repeating contractile units called sarcomeres. The myofibrils are invested by the sarcolemma. An individual sarcomere is limited by two adjacent Z bands and has a length that varies between 1.6 and 2.2 μm. It is composed of regularly overlapping actin and myosin filaments that are connected by cross-bridges in the overlapping zone (central A band of the sarcomere). In the relaxed state, these cross-bridges are maintained by troponin C, which acts as a regulatory protein that inhibits contraction. During contraction, troponin C inactivation permits alteration of the cross-bridges, permitting the actin and myosin filaments to slide between one another, leading to contraction. In cardiac muscle, all sarcomeres contract during every contraction.

At rest, the interior of the myofibril has (1) a negative charge with respect to the outside with a transmembrane potential of −80 to −100 mV; (2) a low intracellular Na+ and a high K+, maintained by the adenosine triphosphate (ATP)-driven sodium pump; and (3) a low Ca2+. During activation, there is an influx of Ca2+ into the cell through sarcolemmal channels, which causes a rapid Ca2+ release from the sarcoplasmic reticulum. The calcium combines with troponin C, producing the conformational changes in the actin–myosin cross-bridges that lead to contraction. After contraction, these events reverse, with reaccumulation of Ca2+ in the sarcoplasmic reticulum, reversal of Ca2+–troponin binding, and return of the actin and myosin filaments and cross-bridges to the resting state. The energy for most of these reactions is derived from ATP formed from substrate oxidation.

The cardiac (ventricular) output is the product of the heart rate and stroke volume and is normally 2.6–4.2 (L/min)/m2. The stroke volume is a function of the extent of shortening of fibers of the ventricular myocardium, which is dependent on the following three independent factors:

1. Ventricular preload (ventricular end-diastolic volume), which is the length of the muscle (which in turn is a function of the length of each sarcomere) at the onset of contraction. Most forceful contraction occurs at a sarcomere length of 2.2 μm, at which length the overlapping and cross-bridging of actin and myosin filaments is optimal. When sarcolemmal length increases, filament overlapping decreases; at 3.65 μm, there is no overlapping (the A band disappears), and no tension can develop. With decreasing sarcomere length, actin filament overlapping increases, and efficiency of interaction between actin and myosin decreases. The relation between length of sarcomere and force of contraction is the basis of Starling's law. (Within limits, an increase in the ventricular end-diastolic volume, which is a function of initial length of cardiac muscle, results in an increase in the force of ventricular contraction.)

2. Myocardial contractility (inotropic state) reflects the level of ventricular performance at a given end-diastolic volume. This is related to the velocity of shortening of the muscle fiber, which appears to be primarily related to the availability of Ca2+ in the vicinity of actin and myosin filaments in the cell. Positive inotropic agents such as Ca2+, norepinephrine, and digitalis exert their effect by increasing intracellular Ca2+ concentration.

3. Ventricular afterload is the amount of tension the muscle is called upon to develop during contraction. At a given preload and level of myocardial contractility, the extent of shortening of the myocardial fiber is inversely proportionate to the afterload. Afterload in the left ventricle is dependent on the mean pressure in the aorta, the volume of the ventricular cavity, and the thickness of the ventricular muscle wall. (Laplace's law: The tension of a myocardial fiber is a function of the product of the intracavitary pressure and ventricular radius divided by wall thickness.)

Physical Examination

Arterial Pulse

Palpation of the carotid and radial artery pulses permits recognition of the rate and rhythm of ventricular contraction as well as subtle changes in the pressure wave associated with certain cardiac diseases—exemplified by the sustained low-volume pulse in aortic valve stenosis or the bounding pulse in aortic valve incompetence.

Jugular Venous Pulse

The height of the internal jugular vein pulse wave provides a clinical estimate of central venous pressure. It is increased in right heart failure, volume overload, and pericardial tamponade or constriction. Alteration of the wave form of the jugular venous pulse also provides important information. For example, accentuation of the first, or a wave indicates that the pressure in the right side of the heart is increased; absence of the a wave is a sign of atrial fibrillation.

Cardiac Apex Beat

Localization of the cardiac apex beat by palpation permits rough evaluation of cardiac enlargement. A sustained heave at the apex is characteristic of left ventricular hypertrophy; a heave at the left parasternal border occurs with right ventricular hypertrophy.

Auscultation of the Heart

The normal heart usually has two sounds, the first due to closure of the atrioventricular valves and the second due to closure of the semilunar valves (usually perceived as slightly split because of asynchronous closure of pulmonary and aortic valves) (Figure 21-2). Various additional sounds may signify disease. A third heart sound (triple, or gallop, rhythm) may occur as a result of rapid ventricular filling in diastole and is seen in heart failure and mitral incompetence. An opening snap suggests mitral stenosis; a fourth heart sound, pulmonary or systemic hypertension; and a friction rub, pericarditis.

Cardiac murmurs result from turbulence of blood flow through the heart, usually across damaged valves and abnormal pressure gradients. Soft, innocent ejection systolic murmurs occur in high-output states such as fever or anemia and during vigorous exercise. Murmurs signifying congenital and valvular heart disease will be discussed later.

Electrocardiography

The electrocardiogram (ECG) is a graphic display of the electrical activity of the heart as recorded on the body surface by appropriately placed electrodes. The normal electrocardiographic tracing can be divided into (1) the P wave, due to atrial depolarization; (2) the PR interval, which is a rough measure of conduction time through the atrioventricular node; (3) the QRS complex, due to ventricular depolarization; and (4) the T wave, due to ventricular repolarization (Figure 21-2). The ST segment is isoelectric (ie, level with the baseline) in the normal physiologic state.

The ECG provides valuable information for assessment of (1) cardiac hypertrophy, (2) arrhythmias and conduction delays, (3) myocardial ischemia and infarction, (4) pericardial disease, and (5) electrolyte abnormalities (especially K+, Mg2+, Ca2+) and some drug effects (eg, digitalis).

Imaging

Echocardiography (M-mode, two-dimensional, Doppler, stress, and transesophageal) is a means of evaluation of cardiac structure with sound waves reflected from the heart. Chest radiography evaluates gross cardiac structure and size. Magnetic resonance imaging (MRI), radionuclide imaging, cine-computed tomography (CT), and positron emission tomography (PET) are newer modalities.

Cardiac Catheterization

Cardiac catheterization requires insertion of a catheter through a vein (to the right heart) or artery (to the left heart). This permits evaluation of pressures and oxygen saturation in the various chambers. Injection of radiopaque dye (angiography) permits visualization and photography of the contracting heart and the coronary arteries.

Endomyocardial Biopsy

Tissue can be taken from the inner surface of the heart with a biopsy forceps passed in a manner similar to a cardiac catheter. The main indications for endomyocardial biopsy are diagnosis of suspected myocarditis, cardiomyopathy, and organ rejection after heart transplantation.

Pain

Ischemic Pain

The most common cause of cardiac pain is myocardial ischemia. Pain is believed to be caused by stimulation of nerve endings by the lactic acid produced during anaerobic glycolysis. Ischemic pain classically is retrosternal and usually described as constricting in nature. It may radiate to the back, to either arm (especially the left), or up the neck into the jaw. Pain varies in severity from mild to excruciating. Angina pectoris is ischemic pain usually induced by exercise (sometimes by stress or cold) and relieved by rest.

Pericardial Pain

Inflammation of the parietal pericardium produces a sharp lower retrosternal pain that tends to vary with posture and respiration. It is often accompanied by signs of pericardial inflammation such as pericardial rub and effusion.

Cardiac Enlargement

Enlargement of the heart may result from dilation of the cardiac chambers (eg, in heart failure, myocarditis) or hypertrophy of the walls (eg, in hypertension, many valvular defects). Cardiac dilation and hypertrophy do not cause clinical symptoms but are useful indications of the presence of cardiac disease. Their presence may be recognized by clinical examination, radiography, or electrocardiography.

Documentation of cardiac hypertrophy at autopsy is usually done by measuring the thickness of the walls. Right ventricle thickness exceeding 0.5 cm or left ventricular thickness exceeding 1.5 cm constitutes hypertrophy.

Abnormal Cardiac Rhythm (Arrhythmia; Dysrhythmia)

Normal cardiac contraction is initiated in the sinoatrial (SA) node and conducted across the atrium to the atrioventricular (AV) node (His-Purkinje system). Ventricular contractions are coordinated by the branches of the AV node. Arrhythmias reflect (1) altered activity of the SA node, (2) the development of “new” ectopic foci that drive the heart at an accelerated or irregular rate, and (3) conduction defects (Table 21-1).

Patients are sometimes aware of arrhythmias, complaining of “missed beats” or palpitations. Some forms of arrhythmia produce characteristic alterations in the pulse. Electrocardiography is valuable in identifying cardiac arrhythmias.

Etiology

The principal cause of significant cardiac arrhythmia is ischemia. Other causes include infection (myocarditis), various inflammatory conditions (systemic lupus erythematosus, rheumatic fever, sarcoidosis), drugs (digitalis, quinine derivatives, antidepressants, catecholamines, beta-blockers, calcium channel blockers), electrolyte abnormalities (hyperkalemia), endocrine disease (thyrotoxicosis), and congenital abnormalities of the conduction system. Various tachycardias, usually benign, may be precipitated by anxiety or caffeine ingestion.

Clinical Effects

Cardiac output during arrhythmias depends on the stroke volume and heart rate. In bradyarrhythmias (slow heart rate), cardiac output falls when the reduction in heart rate cannot be compensated for by an increased stroke volume. In tachyarrhythmias (rapid rate), cardiac output may also fall because of decreased ventricular filling resulting from shortened diastole. In addition, ventricular oxygen consumption is increased and myocardial blood supply decreased because of inadequate coronary perfusion. Acute heart failure is therefore common in patients with ventricular tachycardia. The severity of cardiac arrhythmia is directly related to the decrease in cardiac output. Supraventricular tachycardias and incomplete heart block do not cause serious effects. Ventricular fibrillation results in cessation of effective ventricular ejection and causes rapid death. Ventricular tachycardia and complete heart block are serious arrhythmias associated with a variable decrease in cardiac output.

Cardiac Failure

Cardiac failure is inability to maintain a cardiac output that is adequate for tissue metabolic needs despite normal venous return. Cardiac output also falls below normal if venous return is reduced, as in the noncardiogenic types of shock (Chapter 9: Abnormalities of Blood Supply).

Etiology

Causes of cardiac failure are classified according to whether they produce predominantly left-sided or right-sided failure (Table 21-2) or low-output or high-output failure (Table 21-3).

Pathology & Clinical Effects

The effects of cardiac failure are classified as (1) forward failure, resulting from decreased cardiac output; or (2) backward failure, due to accumulation of venous return within the heart (cardiac dilation) or in the tissues draining to the heart (Figure 21-3). Although both occur together, one may dominate the clinical picture.

In addition, clinical changes associated with cardiac failure depend on (1) whether the left or right side is predominantly affected, (2) the magnitude of the decrease in cardiac output, and (3) whether failure is acute or chronic.

Left-Sided Heart Failure

Acute Cardiac Arrest

Cessation of effective left ventricular contraction (cardiac arrest) leads to sudden death. The causes include ventricular asystole (no contractions) or ventricular fibrillation (ineffective, uncoordinated contractions). Cerebral anoxia leads to loss of consciousness and death within a few minutes. When ventricular asystole is the cause, emergency cardiac resuscitation by external cardiac massage, if started immediately, may maintain an adequate circulation, allowing time for treatment of the cause.

Acute Severe Decrease in Output

An acute severe decrease in cardiac output may lead to cardiogenic shock. The decreased cardiac output evokes reflex sympathetic stimulation, which results in increased heart rate (tachycardia) and vasoconstriction in skin, muscle, intestine and kidney, diverting blood to the brain and heart (Chapter 9: Abnormalities of Blood Supply). The decreased glomerular filtration pressure resulting from vasoconstriction causes decreased urine output and an increased serum level of urea (prerenal uremia). Prolonged vasoconstriction diminishes tissue perfusion and renders shock irreversible. Death then follows rapidly.

In severe cardiogenic shock, the phase of compensation by reflex sympathetic activity may be very short.

Acute Backward Failure

The backward failure component of acute left heart failure is pulmonary edema. Failure of the left heart to pump the pulmonary venous return causes increased hydrostatic pressure in the pulmonary capillaries with transudation of fluid into the alveolar space (pulmonary edema).

Clinically, pulmonary edema is manifested as severe difficulty in breathing (dyspnea) accompanied by cough productive of pink, frothy sputum (the alveolar fluid transudate). The edema fluid produces wet sounds (rales or crepitations) on auscultation.

Chronic Backward Failure

Chronic left heart failure is dominated by the changes of chronic pulmonary venous congestion, which if prolonged induces fibrous thickening of the alveolar septa. The thickened alveolar septa represent increased resistance to lung expansion, causing dyspnea. The dyspnea is maximal when congestion of the lung is greatest, as in exercise (exertional dyspnea) and during sleep (recumbency), when peripheral edema fluid is mobilized, increasing venous return to the heart. Orthopnea (dyspnea in the recumbent position) and paroxysmal nocturnal dyspnea (dyspnea during sleep) are typical symptoms of chronic left heart failure.

Entry of small amounts of blood into the alveoli leads to the accumulation of hemosiderin-laden macrophages in the alveoli (Chapter 9: Abnormalities of Blood Supply), imparting a brown color to the fibrotic lung (brown induration of the lung).

Progressive fibrosis of the alveolar septa causes pulmonary hypertension, which leads to right ventricular hypertrophy and ultimately, right ventricular failure. The most common cause of right ventricular failure is left heart failure.

Right-Sided Heart Failure

Acute Severe Decrease in Output

Acute right heart failure occurs most commonly when a massive pulmonary embolus becomes impacted in and obstructs the outflow tract of the right ventricle and main pulmonary artery. This results in arrest of the circulation and sudden death.

Cardiac tamponade is another form of acute right heart failure. A sudden increase in pericardial cavity pressure due to fluid accumulation interferes with right ventricular diastolic filling, resulting in decreased right ventricular output.

Chronic Backward Failure

Chronic right heart failure is manifested clinically by systemic venous congestion. The jugular venous pulse is elevated. The liver is enlarged as a result of congestion and tender as a result of stretching of the liver capsule. Within the hepatic lobule, congestion occurs first around the central vein, which becomes darker than the periphery of the lobule, producing an appearance that resembles a cut nutmeg (nutmeg liver). Associated fatty change (due to anoxia) enhances this appearance. Cardiac cirrhosis may follow.

Peripheral edema is the most obvious feature of right heart failure, occurring in dependent areas—the ankles in ambulatory patients and the sacrum in recumbent ones.

Cardiac Edema

Edema occurs in both left and right heart failure. In left heart failure, edema fluid accumulates in the lungs, whereas in right heart failure the fluid gravitates to the dependent systemic veins. Chronic cardiac edema is primarily the result of sodium and water retention in the kidneys, which increases total body water as well as total plasma volume. Stimulation of the renin-angiotensin-aldosterone mechanism by the lowered cardiac output is the main factor (Chapter 2: Abnormalities of Interstitial Tissues).

Etiology

In most cases of congenital heart disease, there is no identifiable cause. Many cases probably result from the action of unknown teratogens in the first trimester of pregnancy, which is when fetal cardiac development takes place. Most congenital cardiac defects are not inherited.

In a few patients, a specific cause can be identified.

Rubella

Transplacental infection of the fetus by rubella virus in the first trimester of pregnancy is a cause of many cardiac anomalies, such as patent ductus arteriosus and pulmonary stenosis. Congenital rubella has decreased in frequency as a consequence of rubella immunization. Other viral infections, notably mumps and influenza, have been suggested as causes of congenital cardiac defects, but the evidence is not convincing.

Chromosomal Abnormalities

Down syndrome (trisomy 21) is associated with a 20% incidence of defects of the atrioventricular valves or the atrial and ventricular septa. Turner syndrome (45,XO) is associated with cardiac anomalies in about 20% of cases. Coarctation of the aorta is the most common anomaly. Trisomies 13 and 18 and cri-du-chat syndrome (5p−) are associated with ventricular septal defect.

Drugs

In the early 1960s, thalidomide caused severe structural abnormalities in the fetus, including cardiac anomalies. More recently, consumption of alcohol during early pregnancy has been shown to cause congenital cardiac defects (fetal alcohol syndrome).

Classification

Congenital heart defects (Table 21-4) can occur in either side of the heart at the atrial, ventricular, or aortopulmonary level. The common defects are classified according to (1) which side of the heart is involved; (2) whether there is a communication or shunt between the 2 sides; and (3) in those defects where there is a shunt, the presence or absence of cyanosis.

Cyanosis is bluish discoloration of the skin and mucous membranes caused by increased amounts of reduced hemoglobin in arterial blood. In congenital cyanotic heart disease, cyanosis is caused by right-to-left shunt, which allows unoxygenated venous blood to bypass the lungs and enter the systemic circulation (central cyanosis).

Atrial Septal Defect (ASD)

Ostium Secundum ASD

(Figure 21-4)

The most common type of ASD is a defect in the development of the septum secundum, which produces mild disease that is frequently not detected until adult life.

In most cases of ostium secundum ASD, the defect is large enough (> 2 cm) to cause near equalization of left and right atrial pressure, with flow of blood from left to right through the ASD. In the usual case, pulmonary flow is increased to about twice that of systemic output, and the right ventricle is dilated and hypertrophied owing to the volume overload. This is usually well tolerated, and right ventricular failure is uncommon.

Clinically, there is right ventricular hypertrophy and delayed pulmonary valve closure, causing a widely split second heart sound that does not vary with respiration (fixed split). Increased flow through the pulmonary valve produces an ejection systolic murmur and loud pulmonary valve closure. The diagnosis is confirmed by cardiac catheterization, echocardiography, or isotope studies.

The main complication of ostium secundum ASD is the development of pulmonary hypertension, increased right side pressure, and either right heart failure or reversal of the shunt and cyanosis. Paradoxic embolization to the systemic circulation and infective endocarditis may occur.

Ostium Primum ASD

Ostium primum defects are rare, constituting about 5% of all cases of ASD. They occur as large defects in the lower part of the atrial septum and are often associated with mitral valve lesions. Ostium primum defect is common in Down syndrome. Ostium primum ASD produces severe disease in early childhood, with features of mitral incompetence superimposed on the ASD.

Ventricular Septal Defect (VSD)

VSD is the most commonly encountered cardiac anomaly in children. Most defects occur in the membranous part of the interventricular septum just below the orifices of the semilunar valves (Figure 21-5). VSD is classified according to its size.

Small VSD (Maladie de Roger)

Small VSDs (< 0.5 cm in diameter) are common. They produce a low-volume shunt from the left to the right ventricle during systole. This shunt across a high pressure gradient produces a loud pansystolic murmur heard best at the left sternal edge. With a small defect, right ventricular pressure is increased only slightly. Cardiac catheterization shows entry of oxygenated blood into the right ventricle (Figure 21-6).

Patients with small VSDs have few symptoms. The defect tends to decrease in relative size as the heart grows and may even close spontaneously.

Large VSD

A large VSD is much more serious, with clinical manifestations appearing in early childhood. Initially, a large volume of blood is shunted from the left to the right ventricle during systole, producing volume overload of both ventricles, hypertrophy of both ventricles, and a pansystolic murmur.

Increased blood flow through the pulmonary circulation induces pulmonary hypertension and a loud pulmonary-valve closure sound. Progressive thickening and narrowing of the small pulmonary arteries leads to increase in right ventricular pressure, reduction in shunt volume and, finally, shunt reversal. This produces cyanosis (Eisenmenger's syndrome). Shunt reversal in VSD occurs some time after birth (tardive cyanosis) and is associated with decrease or disappearance of the pansystolic murmur. Patients with VSD are at risk for infective endocarditis (Chapter 22: The Heart: II. Endocardium & Cardiac Valves).

Patent Ductus Arteriosus (PDA)

The ductus arteriosus is a normal fetal vascular channel that connects the pulmonary artery and the aorta, permitting right ventricular output to bypass the inactive fetal lungs. At birth, when the lungs expand, pulmonary vascular resistance falls; flow across the ductus decreases, and it closes by muscle spasm. Permanent fibrotic occlusion is usually complete by 8 weeks. In premature infants, anatomic closure may be delayed several months. Indomethacin promotes the closure of a PDA.

A small PDA leads to a small left-to-right shunt, continuous throughout the cardiac cycle because there is a pressure gradient from the aorta to the pulmonary artery throughout the cycle. This causes the typical continuous (machinery) murmur of PDA. A small PDA causes only mild elevation of pulmonary artery pressure and minimal symptoms. Cardiac catheterization shows an increase in oxygen saturation of blood at the pulmonary artery level, the degree of this increase providing a measure of the shunted volume (Figure 21-7). The patent ductus may also be involved by a process analogous to infective endocarditis.

With a large PDA, the high aortic pressure is transmitted to the pulmonary artery, causing marked pulmonary hypertension and ultimately resulting in shunt reversal (Eisenmenger's syndrome).

Tetralogy of Fallot

Tetralogy of Fallot (Figure 21-8) is the most common cyanotic congenital cardiac anomaly. It is characterized by (1) a large ventricular septal defect; (2) stenosis of the pulmonary outflow tract; (3) dextroposition of the aorta, which overrides the right ventricle; and (4) hypertrophy of the right ventricle. The pulmonary stenosis raises right ventricular pressure so that the shunt across the VSD is right-to-left, with venous admixture of systemic arterial blood causing cyanosis.

Tetralogy of Fallot is a severe defect that presents at birth with central cyanosis (blue babies). The prognosis is very poor without treatment. With corrective surgery, which has become very successful in the past 2 decades, normal survival is the rule.

Incidence & Etiology

Acute rheumatic fever is a multisystem disease that occurs as a complication of streptococcal pharyngitis (Figure 22-1). It occurs mainly in children between 5 and 15 years of age, particularly those with low socioeconomic backgrounds who live in the overcrowded conditions that favor streptococcal pharyngitis. It is still prevalent in developing countries. Although its incidence has decreased in the United States, it occurs during sporadic epidemics of streptococcal pharyngitis. During such epidemics, approximately 3% of patients develop acute rheumatic fever.

Streptococcal pharyngitis caused by specific M serotypes of group A streptococci have a higher incidence of acute rheumatic fever than others. These are associated with the presence of high virulence factors such as (1) a high concentration of surface M protein—M types 5, 19, 24; and (2) large hyaluronate capsules (which produce mucoid colonies on culture)—M types 3 and 18. These serotypes are commonly responsible for epidemic streptococcal disease in the United States.

No genetic susceptibility factors have been identified.

Pathogenesis

The exact relationship between streptococcal infection and acute rheumatic fever is unknown. Cardiac injury is not the direct result of infection as shown by negative streptococcal cultures in affected heart tissue. The following facts suggest that the relationship is the result of an unproved immunologic hypersensitivity to streptococcal antigens: (1) Acute rheumatic fever occurs 2–3 weeks after streptococcal pharyngitis, often after the patient has recovered from the pharyngitis (Figure 22-1). (2) High levels of antistreptococcal antibodies (antistreptolysin O, anti-deoxyribonuclease (DNase), antihyaluronidase) are present in patients who develop acute rheumatic fever. (3) Early treatment of streptococcal pharyngitis with penicillin decreases the risk of acute rheumatic fever. (4) Immunoglobulin and complement are present on the surface membrane of affected myocardial cells.

While immunologic hypersensitivity is likely, the mechanism remains unknown. The presence of antibodies with activity against both streptococcal antigens and myocardial cells suggests the possibility of a type II hypersensitivity mediated by crossreacting antibodies. The presence in the serum of some patients of immune complexes formed against streptococcal antigens suggests type III hypersensitivity.

Clinical Features

(Table 22-1)

Acute rheumatic fever affects multiple organs. It has a sudden onset characterized by high fever and one or more of the following major features:

Carditis

Carditis is the most serious manifestation and occurs in about 35% of patients with a first attack of rheumatic fever.

Polyarthritis

Acute inflammation affecting multiple large joints is the presenting feature in 75% of patients. The joints are involved asymmetrically, and the inflammation tends to move from joint to joint (migratory polyarthritis). Affected joints are swollen, red, warm, and painful.

Chorea

Random involuntary movements (chorea) are caused by involvement of the basal ganglia of the brain. Chorea may develop up to 6 months after the streptococcal pharyngitis. It may persist for weeks but has an excellent prognosis.

Skin Lesions

Erythema marginatum (a circular ring of erythema surrounding central normal skin) is specific for rheumatic fever but occurs only in about 10% of cases. It is of short duration. Erythema nodosum (a nodular, red, tender rash typically seen over the anterior tibia) is less specific but occurs more commonly.

Subcutaneous Rheumatic Nodules

These occur mainly over bony prominences in the extremities. They are pea-sized, nontender, and last 6–10 weeks. Their presence usually indicates concurrent cardiac involvement. Pathologically, rheumatic nodules consist of foci of fibrinoid necrosis with a surrounding granulomatous reaction.

Pathology of Carditis

Cardiac involvement involves all layers of the heart (pancarditis). Endocarditis occurs in all patients with rheumatic carditis, whereas myocarditis and pericarditis are present only in severe cases.

The Aschoff body is the microscopic lesion that is diagnostic of rheumatic fever. It is characterized by an area of granular fibrinoid material surrounded by histiocytes, Aschoff giant cells, lymphocytes, plasma cells, fibroblasts, and collagen (Figure 22-2). Aschoff bodies occur in the connective tissue of the heart, most commonly in the subendocardial region and the myocardial interstitium.

Endocarditis (Valvulitis)

The valvular endocardium shows maximal involvement. The valves of the left side are affected more often and more severely than those of the right and the mitral valve more than the aortic. Involved valves show edema and denudation of the lining endocardium, particularly in areas of maximal trauma at the line of apposition of the free edge of the valve. Platelet-fibrin thrombi (rheumatic vegetations) form in areas of endocardial damage (Figure 22-3). Rheumatic vegetations do not become detached as emboli. Valve edema and vegetations may cause turbulence of blood and produce various transient murmurs (eg, Carey-Coombs diastolic murmur); murmurs occur in most patients with cardiac involvement.

Myocarditis

Acute myocardial involvement, characterized by the presence of numerous Aschoff bodies in the myocardium, causes tachycardia and dilation of the heart. Cardiac failure and arrhythmias occur in a small number of cases.

Pericarditis

Acute inflammation of the pericardium (fibrinous pericarditis) occurs only in severe cases, causing chest pain and a pericardial rub. Pericardial effusion is rarely of sufficient magnitude to cause problems.

Sequelae

Immediate

The great majority of patients with acute rheumatic fever recover completely from the acute attack, usually within 6 weeks. A very small number of patients (less than 1%) die in the acute phase of severe myocarditis (heart failure and arrhythmia).

Recurrences

A patient who has recovered from an attack of rheumatic fever is apt to develop recurrences. Recurrent attacks produce additional scarring and greatly increase the risk of later development of chronic rheumatic heart disease.

Chronic Rheumatic Heart Disease

Rheumatic endocarditis heals by fibrosis. Fibrosis may occur in the free endocardium, most commonly in the posterior wall of the left atrium (McCallum's patch) but is of greatest significance when it involves the valves, causing valve dysfunction (chronic rheumatic heart disease).

Chronic rheumatic heart disease tends to follow recurrent acute episodes of rheumatic fever by a variable interval (2–20 years). In some cases, chronic rheumatic heart disease occurs in patients with no history of an acute episode. In these cases, it is likely that the acute attack was subclinical. In others, severe valve destruction in the acute phase is permanent.

Fibrosis of the valve with fusion of the commissures leads to a rigid valve with a narrowed orifice (valve stenosis). Severe destruction of the valve apparatus may cause valve ring dilation, with thickening and shortening of chordae tendineae, resulting in regurgitation of blood through the valve when it is closed.

The mitral valve is the most commonly affected and is the only affected valve in 50% of cases. Combined mitral and aortic valve lesions are next most frequent (40%), with additional involvement of the tricuspid valve in a few cases. Pulmonary valve involvement is rare. The different valve lesions are discussed fully later in this chapter in the section on acquired valve lesions.

Prognosis & Treatment

The prognosis of rheumatic fever is determined by (1) the severity of the acute illness; (2) whether or not there is cardiac involvement because all other manifestations, including chorea, resolve completely; (3) the age of the patient—acute rheumatic fever in children under 5 years of age has the highest risk of carditis; and (4) whether or not there are recurrences—the greater the number of recurrences, the higher the incidence of subsequent chronic rheumatic heart disease. This is the rationale for prolonged prophylactic penicillin therapy in patients who have had an attack of acute rheumatic fever (to prevent streptococcal infection and subsequent recurrence of rheumatic fever).

Treatment of the acute attack of rheumatic fever with penicillin has no effect on the course of the disease. Salicylates and corticosteroids are useful for symptomatic treatment of rheumatic fever, but, again, have no effect on its course.

The heart is involved in 10–20% of cases of SLE. The immune complex-mediated injury may involve any layer of the heart. SLE is one of the most common causes of acute pericarditis in the United States. Pericarditis is fibrinous, with little effusion.

Libman-Sacks endocarditis is the most characteristic cardiac lesion of SLE. Multiple, small, flat vegetations occur on the mitral and tricuspid valves. Both the atrial and ventricular surfaces of the valve, the chordae tendineae, and the mural endocardium are involved. SLE valvulitis is rarely severe enough to cause valve dysfunction.

Infective endocarditis is an infection associated with formation of vegetations on the endocardial surface, usually on a valve. Most cases occur in adults. Patients developing disease in their native valves tend to be over 50 years old. Intravenous drug abusers tend to develop disease in the second and third decades. Endocarditis occurring in prosthetic valves is related to the age of the patient undergoing valve replacement surgery.

Classification

Infective endocarditis is classified according to three different characteristics, all of which are important in understanding and treating the disease (Table 22-2).

Infectious Agent

Identification of the infectious agent by blood culture is most important. The specific organisms involved occur in certain types of patients and produce different clinical courses (Table 22-2), but these are not constant. The agent reaches the heart via the bloodstream. Bacteremia may occur (1) following oral and dental procedures—viridans streptococci are the most common agents; (2) following urologic procedures such as prostatic biopsy and resection, cystoscopy, bladder catheterization, and gynecologic procedures—Enterococcus faecalis and gram-negative bacilli are common causes; (3) following skin infections associated with intravenous drug use—Staphylococcus aureus is a common cause; and (4) during surgery, particularly prosthetic valve replacement (Table 22-2).

Acute versus Subacute Endocarditis

1. Acute infective endocarditis is caused by virulent agents (S aureus, group A streptococci), which frequently infect previously normal valves. The course is fulminant, characterized by severe destruction of the valve, commonly causing acute valvular regurgitation; severe bacteremia associated with abscesses in the myocardium and throughout the body; and a high mortality rate.

2. Subacute infective endocarditis is commonly caused by less virulent agents such as viridans streptococci and Staphylococcus epidermidis and almost always occurs in a patient with a preexisting cardiac (usually valvular) abnormality. Subacute endocarditis has a more chronic course not characterized by severe valve destruction or abscess formation.

Patient Groups

Native Valve Endocarditis

Sixty to 80 percent of patients in this group have a previously damaged cardiac valve. The types of cardiac disease complicated by infective endocarditis are the following: (1) Chronic rheumatic valvular diseases—most commonly mitral regurgitation and aortic valve disease—are associated with 30% of all cases. (2) Congenital heart disease—most commonly ventricular septal defect, patent ductus arteriosus, Fallot's tetralogy, coarctation of the aorta, and bicuspid aortic valve—is the underlying condition in 15%. (3) Mitral valve prolapse is associated with 20%. (4) Calcific aortic stenosis is an important predisposing factor in the elderly. In 20–40% of cases, no underlying cardiac disease is identifiable. Viridans streptococci, E faecalis, and staphylococci are responsible for most of these cases. The mitral and aortic valves are the most commonly affected.

Intravenous Drug Abusers

This group consists mainly of young males, 80% of whom have no preexisting cardiac lesion. The endocarditis commonly complicates skin infection. S aureus is the infecting agent in over half of the cases. The tricuspid valve is affected in over 50% of cases.

Prosthetic Valve Endocarditis

Infection of prosthetic valves now accounts for 15–20% of cases of endocarditis. These fall into two groups.

1. Early-onset endocarditis, occurring within 2 months after surgery and usually related to perioperative bacteremia. About 50% of these cases are due to staphylococci and are associated with a fulminant course with valve failure.

2. Late-onset endocarditis, occurring over 2 months after surgery, resembles native valve endocarditis in etiology (viridans streptococci the most common agent) and course (usually subacute).

Pathogenesis

Two factors are essential in the pathogenesis of infective endocarditis: bacteremia (see above) and an abnormality in the endocardial surface that permits bacterial entry and multiplication. With a highly virulent agent such as S aureus, infection may occur with a minor, inapparent endocardial injury. With less virulent agents, a known preexisting endocardial abnormality exists, most commonly chronic rheumatic valve disease (see above).

The endocardial abnormality is apt to be the formation of sterile fibrin and platelet thrombi on the surface (nonbacterial thrombotic endocarditis). Such sterile thrombi occur in areas of endocardial trauma; over scarred valves; in areas of turbulent flow and high pressure jet effects, associated with valvular defects and congenital lesions; and in patients with debilitating chronic diseases, especially cancer. Bacteria that adhere to platelets and fibrin have an advantage, but the adhesion factors are not well understood. Entry of the organism into the thrombus permits multiplication and further deposition of fibrin and platelets, causing an enlarging thrombus (vegetation).

Pathology

Infected thrombi (vegetations) are the characteristic pathologic finding in infective endocarditis (Figures 22-4, 22-5, and 22-6; see also Chapter 9: Abnormalities of Blood Supply). The colonies of organisms within the vegetations are relatively protected from host defenses because the valves are avascular and the immune system cannot mount an adequate acute inflammatory response. In addition, the surface of the vegetation is covered by dense fibrin and platelets, which limit access of blood-borne leukocytes or antimicrobial substances such as antibiotics to the interior of the vegetation—where organisms are found.

The vegetations of infective endocarditis are multiple, large, and friable and commonly become detached from the valve as emboli. Vegetations tend to be larger and more friable in acute than in subacute endocarditis.

Vegetations occur principally on the valves of the left side of the heart, following the distribution of chronic rheumatic heart disease (mitral > aortic > tricuspid > pulmonary). Right-sided endocarditis is uncommon but may occur in (1) intravenous drug abusers, in whom the tricuspid valve is commonly affected; (2) patients with indwelling venous catheters extending into the right atrium; (3) patients with gonococcal endocarditis; and (4) patients with ventricular septal defect, the last because the jet of shunted blood causes endocardial injury in the right ventricle.

Clinical Features

(Figure 22-4)

Bacteremia (or Fungemia)

Blood culture is positive in more than 95% of cases and is the most important diagnostic test. Most patients have constant bacteremia; a few have intermittent bacteremia. For this reason, it is recommended that multiple blood cultures be drawn at intervals before the patient is given antibiotics.

Fever is the most common symptom. It is low-grade and persistent in subacute endocarditis and high with rigors in acute disease. Chronic bacteremia causes phagocytic and endothelial cell hyperplasia in the spleen, leading to splenomegaly. Bacteremia also causes petechial hemorrhages in the skin, retina (Roth spots), and nails (splinter hemorrhages). Weight loss and chronic anemia also occur in subacute disease. Finger clubbing is a common but late sign; its pathogenesis is unknown.

When infection is caused by virulent pyogenic organisms, miliary abscesses are produced in all organs of the body.

Immune Complexes

Antibodies and bacterial antigens combine to form circulating immune complexes. Deposition of immune complexes in the glomerular capillaries causes focal or diffuse proliferative glomerulonephritis (Chapter 48: The Kidney: II. Glomerular Diseases). Microscopic hematuria and proteinuria occur in over 50% of patients with infective endocarditis.

Cutaneous immune complex-mediated vasculitis is responsible for erythematous papules in the palms and soles (Janeway lesions) and characteristic tender red nodules in the fingers or toes (Osler's nodes). These occur in 25% of patients.

Valvular Dysfunction

Large vegetations on the valves impinge on the flow of blood, causing turbulence and cardiac murmurs. With changes in size of vegetations, the character of the murmurs changes, a feature that is typical of infective endocarditis.

Progressive destruction of the valve may produce valve perforation (Figure 22-6), currently the most common cause of acute mitral and aortic regurgitation.

Embolism

Emboli from the friable vegetations are common. With left-sided endocarditis, systemic embolism causes multifocal areas of infarction in the brain, kidney, heart, intestine, spleen, and extremities. With right-sided vegetations, embolism involves the pulmonary vessels.

In about 10% of cases of infective endocarditis, the organisms in the embolus produce a local infection in the artery at the site of lodgment, causing weakening of the arterial wall and formation of an aneurysm. These infective mycotic aneurysms may rupture and cause massive hemorrhage. (Note: The term “mycotic aneurysm” denotes an aneurysm resulting from any infection—not necessarily a fungal infection, as suggested by the adjective.)

Differential Diagnosis

(Table 22-3)

Infective endocarditis must be distinguished from other diseases causing fever of unknown origin and noninfective causes of endocarditis in which vegetations occur. These include acute rheumatic fever, collagen diseases such as systemic lupus erythematosus, and noninfective thrombotic endocarditis.

Noninfective endocarditis was at one time thought to be a clinically insignificant cause of valvular vegetations occurring in terminally ill patients—it was also called marantic (wasting) endocarditis for that reason. Recently it has been recognized that these vegetations may occur early in the course of many diseases, notably cancer. The vegetations occur mainly on the mitral and aortic valves and may be large and friable. Their detachment as systemic emboli is common and may result in significant abnormalities in these patients. Noninfective endocarditis may also be important in the pathogenesis of infective endocarditis.

Prevention & Treatment

When dental, oral, or urologic procedures are planned in patients with known cardiac valvular disease, antibiotic coverage during and immediately after the procedure is necessary to kill any organisms that enter the bloodstream before they reach the cardiac valves. Such antibiotic prophylaxis is effective in preventing infective endocarditis in these patients.

Antibiotic therapy, based on the antibiotic sensitivity of the organism cultured from the blood, is the mainstay of treatment of infective endocarditis. Even with appropriate antibiotic therapy, 10–20% of subacute cases and up to 50% of acute cases end in death. Therapy should be continued for 4–6 weeks to eradicate all organisms from the vegetations. Where there is severe valve damage and in prosthetic valve endocarditis, valve replacement is required.

Mitral Stenosis

Etiology

Mitral stenosis (Figure 22-7) is almost always the result of chronic rheumatic heart disease. Females are affected more than males in a ratio of 7:1.

Pathophysiology

(Figures 22-8 and 22-9)

Mitral stenosis causes resistance to blood flow through the open mitral valve during diastole. The resulting turbulence produces a murmur. In mild mitral stenosis, the pressure across the valve rapidly equalizes, and the murmur is restricted to the mid-diastolic part of the cycle. With increasing stenosis, the length of the diastolic murmur increases. The murmur is accentuated by atrial systole which precedes ventricular systole (presystolic accentuation). Closure of the abnormal mitral valve is often loud (loud first heart sound).

Normally, the mitral valve opens silently soon after aortic valve closure (S2) (Chapter 21: The Heart: I. Structure & Function; Congenital Diseases). However, an abnormal stenotic mitral valve opens with a clicking sound (opening snap, OS); the shorter the interval between S2 and OS, the higher the left atrial pressure and the more severe the stenosis. If the valve becomes rigid as a result of calcification, the opening snap disappears.

Obstruction to flow through the mitral orifice leads to left atrial dilation and hypertrophy (Figure 22-8). Blood tends to stagnate in the left atrium, predisposing to thrombus formation, especially if atrial fibrillation develops (a common complication of mitral stenosis). Left atrial thrombi may cause systemic embolism, or they may obstruct the narrowed mitral orifice, causing sudden death (ball valve thrombus).

Mitral stenosis leads to increased pulmonary venous pressure and features of left heart failure. If acute, pulmonary edema and pulmonary hemorrhage may occur; if chronic, the results are chronic venous congestion, pulmonary arterial hypertension, and right ventricular hypertrophy.

In mild mitral stenosis, left ventricular filling is normal and cardiac output is normal. With severe stenosis, left ventricular end-diastolic volume and cardiac output are decreased. The left ventricle, which pumps less blood than normal, may undergo mild atrophy.

Mitral Regurgitation (Mitral Insufficiency)

Etiology

Rheumatic heart disease accounts for about 40% of cases of mitral regurgitation, usually associated with mitral stenosis. Males and females are equally affected.

Mitral valve prolapse (floppy valve) syndrome is a degenerative change that is present in about 1% of the population (especially young women), the result of accumulation of mucopolysaccharides in the valve leaflet. Clinical mitral regurgitation occurs in only a small percentage of cases. A similar abnormality of the mitral valve is present in patients with Marfan's syndrome.

Chronic left ventricular failure with dilation of the mitral valve ring may cause functional mitral regurgitation. Acute mitral regurgitation may occur with rupture of chordae tendineae due to infective endocarditis or trauma or to rupture of papillary muscles due to myocardial infarction. Perforation of the valve leaflet may also occur in infective endocarditis.

Rarely, calcification of the valve ring in the elderly may lead to mitral regurgitation.

Pathophysiology

(Figures 22-10 and 22-11)

When the mitral valve is incompetent, regurgitation of blood from the left ventricle to the atrium occurs throughout systole, producing a typical pansystolic murmur. During diastole, regurgitant blood flows back across the mitral valve, producing a third heart sound and a diastolic flow murmur.

Left ventricular volume is greatly increased, because it is the sum of the cardiac output plus the regurgitant flow; the left ventricle is thus dilated and hypertrophied.

The left atrium, which accepts both the pulmonary venous return and regurgitant flow, is also dilated in chronic cases. Left atrial pressure and pulmonary venous pressure are increased. In chronic disease, there is pulmonary fibrosis, pulmonary arterial hypertension, and right ventricular hypertrophy followed by failure. Acute mitral valve regurgitation, as occurs with valve perforation or papillary muscle rupture, produces pulmonary edema and acute left heart failure with little left atrial dilation.

Aortic Stenosis

Etiology

Rheumatic aortic stenosis is commonly accompanied by mitral valve defects. Isolated aortic stenosis is uncommon in chronic rheumatic heart disease.

Congenital bicuspid aortic valves may undergo progressive fibrosis and calcification; this is now believed to be the cause of more than 50% of cases of aortic stenosis.

Calcification of the valve in the elderly may cause mild aortic stenosis.

Congenital narrowing of the left ventricular outflow tract above or below the aortic valve produces the same functional defect as aortic stenosis. Hypertrophic cardiomyopathy may also produce obstruction of the left ventricular outflow tract.

Pathophysiology

(Figure 22-12)

The flow through the stenotic aortic valve is turbulent, producing a rough ejection systolic murmur over the aortic valve.

Decreased flow of blood through the aortic valve causes decreased cardiac output, hypotension, and syncopal (fainting) attacks, myocardial ischemia, and angina (decreased coronary artery perfusion). Patients with severe stenosis may die suddenly. The systemic blood pressure is decreased, and this results in soft closure of the aortic valve (soft S2). The peripheral pulse is typically of low amplitude, with the pulse wave rising slowly and being sustained owing to the prolonged left ventricular ejection.

The left ventricle develops increased systolic pressure to overcome the resistance at the aortic orifice and undergoes hypertrophy. Increased oxygen demand by the myocardium aggravates the tendency to myocardial ischemia. Features of left ventricular failure are common.

Aortic Regurgitation (Aortic Insufficiency)

Etiology

Rheumatic heart disease accounts for about 50% of cases of aortic regurgitation. In most of these cases, there is associated mitral valve disease as well as aortic stenosis. Rheumatic heart disease rarely causes isolated aortic regurgitation.

Syphilis was once a common cause of isolated aortic regurgitation but now accounts for less than 10% of cases. Aortic regurgitation in syphilis is caused by dilation of the aortic root and valve ring due to aortitis. The valve itself is not directly affected.

Ankylosing spondylitis, which also involves the root of the aorta, is an important, although uncommon, cause (5% of cases) of isolated aortic regurgitation.

Rupture of the aortic valve may occur as a complication of blunt chest trauma and infective endocarditis. Infective endocarditis is the most common cause of acute aortic regurgitation.

Myxomatous degeneration of the aortic valve due to accumulation of mucopolysaccharides, similar to that seen in mitral valve prolapse syndrome, is being recognized as a possible cause of aortic regurgitation.

Pathophysiology

(Figure 22-13)

Regurgitation of blood across the incompetent aortic valve occurs in diastole. The pressure gradient across the valve is greatest in early diastole, and it is in this phase that the murmur is loudest (decrescendo murmur).

Regurgitation of blood from the aorta in diastole causes decreased diastolic blood pressure, sometimes to zero (which is the ventricular diastolic pressure). At the same time, the systolic pressure is elevated as a result of increased cardiac output (normal volume plus regurgitant volume). This causes a greatly increased pulse pressure, the typical bounding (water-hammer) pulse and capillary pulsations that are characteristic of aortic regurgitation. Massive dilation and hypertrophy of the left ventricle is typical. Left ventricular failure is common.

Pulmonary Valve Lesions

Etiology

Congenital pulmonary valve stenosis is the most common cause of isolated pulmonary stenosis. Pulmonary stenosis also occurs as part of Fallot's tetralogy (Chapter 21: The Heart: I. Structure & Function; Congenital Diseases).

Carcinoid syndrome is associated with both pulmonary and tricuspid valve lesions, usually stenosis, in about 50% of cases. Carcinoid tumors (Chapter 41: The Intestines: III. Neoplasms) secrete serotonin (5-hydroxytryptamine), which promotes fibrosis in the endocardium, leading to plaque-like fibrotic lesions in the valves with fusion of commissures. The right-sided valves are chiefly affected in carcinoid syndrome because serotonin is rapidly metabolized in the lung and is present only in low concentration in pulmonary venous blood.

Pulmonary regurgitation is rare and most often functional in nature owing to valve ring dilation in pulmonary hypertension and right heart failure.

Pathophysiology

Pulmonary stenosis causes a rough ejection systolic murmur over the pulmonary valve, delayed closure of the pulmonary valve, and very soft valve closure owing to the low pressure in the pulmonary artery. Typically, the pulmonary component of the second heart sound is not heard. Right ventricular hypertrophy and failure occur.

Tricuspid Valve Lesions

Tricuspid regurgitation is usually due to right ventricular dilation in right heart failure. This causes a pulsatile jugular venous pulse and pulsatile enlargement of the liver owing to transmission of right ventricular systole to the venae cavae through the incompetent tricuspid valve.

Tricuspid stenosis rarely occurs in chronic rheumatic heart disease, and it is then almost always associated with mitral and aortic valve lesions. Tricuspid stenosis and regurgitation may also occur in carcinoid syndrome and as congenital defects.

Cardiac Myxoma

Myxoma is a benign neoplasm of the endocardium. Although it occurs rarely, it is by far the most common primary neoplasm of the heart. The majority occur sporadically. Five percent have an inherited basis with an autosomal dominant inheritance. Familial cases are associated with cutaneous nevi and neurofibromas. The neoplasm is derived from endocardial mesenchymal cells and usually forms a firm gelatinous polypoid mass that protrudes into the lumen of the heart (Figure 22-14). Myxoma occurs almost exclusively in the atria, particularly the left atrium. Histologically, it is composed of small stellate cells embedded in an abundant mucopolysaccharide stroma.

Clinical features of cardiac myxoma include systemic effects such as irregular, prolonged fever, weight loss, anemia, and increased plasma globulin levels. The reason for these systemic symptoms is unknown.

Additional features in left atrial myxoma include systemic embolism, resulting from detachment of fragments of the neoplasm; and mitral orifice obstruction. Turbulence of blood around the tumor produces a mid-diastolic murmur that resembles the murmur of mitral stenosis. Prolapse of the polypoid neoplasm into the mitral orifice may obstruct circulation and is a rare cause of sudden death.

Incidence

Ischemic heart disease is responsible for 500,000 deaths a year in the United States—or 25–30% of all deaths—and is the leading cause of death in most developed countries.

Etiology

Ischemic heart disease is caused by narrowing of one or more of the three major coronary artery branches (Figure 23-1). These are functional end-arteries, and sudden occlusion of any one leads to infarction in the area of supply. However, gradual narrowing may permit development of collaterals that are sufficient to prevent infarction.

Atherosclerosis accounts for 98% of cases of ischemic heart disease. The risk factors for ischemic heart disease are the same as those for atherosclerosis (Chapter 20: The Blood Vessels).

Other rare causes of coronary artery narrowing include coronary artery spasm (Prinzmetal angina); coronary artery embolism, most commonly in infective endocarditis; coronary ostial narrowing in syphilis and Takayasu's aortitis; coronary ostial occlusion in aortic dissection of the aorta; and various types of arteritis involving the coronary arteries, including polyarteritis nodosa, thromboangiitis obliterans, and giant cell arteritis.

Clinical Features

Ischemic heart disease may be manifested clinically in many ways (Figure 23-2). The more important ones—myocardial infarction, angina pectoris, sudden death, cardiac arrhythmias, and cardiac failure—are discussed below. An individual patient with ischemic heart disease may manifest more than one of these conditions.

Myocardial Infarction

Incidence

Approximately 1.5 million people in the United States suffer a myocardial infarction (heart attack) every year; of these, 25% die in the acute phase—half before they reach a hospital. Another 10% of patients die in the first year after surviving an infarct. Most patients are over 45 years of age, and men are affected three times more frequently than women, paralleling the incidence of atherosclerosis.

Etiology

Except in those rare causes of nonatherosclerotic coronary artery narrowing listed above, most patients who suffer myocardial infarction have severe atherosclerotic narrowing of one or more coronary arteries (Figure 23-3; see also Chapter 20: The Blood Vessels). A fresh thrombus overlying an atherosclerotic plaque is found in 40–90% of cases (Figure 23-4), the frequency varying greatly in different studies. Thrombosis may be precipitated by slowing and turbulence of blood flow in the region of a plaque or by ulceration of a plaque.

In cases where no thrombus is found, infarction may be precipitated by increased myocardial demand for oxygen, as occurs during exercise and excitement; reduction of coronary blood flow through a greatly narrowed artery due to cardiac slowing during sleep; or segmental muscular spasm of coronary arteries. In some cases, the thrombus may undergo lysis by the fibrinolytic system after infarction has occurred.

Distribution of Infarction

(Figure 23-1)

Myocardial infarction involves principally the left ventricle, interventricular septum, and conducting system. The atria and right ventricle are rarely involved, probably because their thin muscle walls derive a considerable part of their nutritional supply directly from the blood in the cardiac lumen. The distribution of infarction depends on which vessel is occluded. However, because collaterals develop in a chronically narrowed coronary circulation, the blood supply may traverse circuitous routes, leading to infarcts in unusual sites (paradoxic infarction).

Infarction may be transmural, involving the full thickness of the wall (Figure 23-5), or subendocardial. The subendocardial region has the most critical blood supply.

In acute infarction due to coronary occlusion, not all the muscle is necrotic in the early stages (ie, within the first 3 hours). The critically ischemic but not yet necrotic muscle in the affected region may be salvaged by immediate reperfusion by restoring coronary artery patency. The use of thrombolytic agents (streptokinase and tissue plasminogen activator) reduces the mortality rate by reducing infarct size and left ventricular failure if given within 3 hours after onset of occlusion. Mechanical reperfusion by angioplasty and coronary bypass surgery are usually reserved for cases not suitable for thrombolytic therapy.

Pathology

For 2 hours after the onset of myocardial infarction (as indicated by onset of pain or arrhythmias and shock), there are no morphologic changes in the necrotic myocardial fibers. At about 2 hours, electron microscopic changes appear (swelling of mitochondrial endoplasmic reticulum, fragmentation of myofibrils). Light microscopic changes may appear in 4–6 hours but are rarely detectable with certainty before 12–24 hours. Coagulative necrosis of the myocardial fibers is recognized by nuclear pyknosis and dark pink staining of the cytoplasm and loss of striations in the cytoplasm (Figure 23-6; Table 23-1; see also Chapter 9: Abnormalities of Blood Supply).

The tetrazolium test. Incubation of a slice of normal myocardium in tetrazolium produces a red-brown color resulting from reaction of tetrazolium with a dehydrogenase enzyme; infarcted myocardium remains pale because the enzyme is lost from the cells within hours after infarction. The value of this technique is limited.

Clinical Features

Ischemic pain is the dominant symptom of myocardial infarction—a tightening retrosternal pain that varies in severity from mild to excruciating. It resembles angina but is not relieved by rest or vasodilators. Twenty percent of cases of myocardial infarction occur without pain (silent infarction). The onset of ischemic pain is sudden and may occur during exercise, excitement, rest, or even sleep. Cardiac pain is often accompanied by signs of autonomic stimulation such as sweating, changes in heart rate, a lowered blood pressure (with or without shock), and additional heart sounds.

The diagnosis of myocardial infarction, when suspected clinically, is based on electrocardiographic and serum enzyme changes. Electrocardiography shows elevation of the ST segment above the isoelectric line within a few hours, representing an abnormal electrical potential associated with acute injury. The T wave becomes inverted, and in transmural infarction the dead muscle acts as an electrical window, producing an abnormal Q wave. As healing takes place, the ST segment returns to the isoelectric line, but T wave inversion and the Q wave persist.

Necrotic myocardial fibers release a variety of enzymes into the bloodstream (Figure 23-7). When both creatine kinase (CK)-MB isoenzyme and lactic acid dehydrogenase-isoenzyme 1 (LDH-1) serum levels are elevated, a specific diagnosis of acute myocardial infarction can be made. When a patient with chest pain shows no elevation of either of these enzymes on serial samples, myocardial infarction can be ruled out. Sequential creatine kinase-myocardial bound (CK-MB) levels are helpful in following the evolution of an infarct—eg, a secondary increase indicates new infarction or extension of the area of infarction.

Myocardial infarction is followed by elevation of temperature, increased neutrophil count in the peripheral blood, and changes in plasma proteins. Increases in acute phase reactants such as fibrinogen and haptoglobin cause elevation of the erythrocyte sedimentation rate. These changes are due to the release of chemical mediators in the area of infarction.

Complications

Arrhythmias

Abnormalities in cardiac rhythm occur in about 70% of cases of myocardial infarction, mainly during the first few hours. They represent a serious and preventable cause of death.

1. Ectopic electrical foci develop in the injured myocardium. Ventricular extrasystoles are common; ventricular tachycardia is less common but can lead to impaired ventricular filling and acute left ventricular failure. The most dangerous arrhythmia is ventricular fibrillation, which causes cardiac arrest.

   The occurrence of tachyarrhythmias bears no relationship to the size of the infarct. Successful management may therefore be followed by full recovery. Because most arrhythmias occur within the first 2 hours—often before the patient reaches a hospital—training of the lay community in cardiopulmonary resuscitation (CPR) is an important part of overall management. Community CPR training is recommended by the American Heart Association.

2. Heart block resulting from involvement of the conduction system occurs more commonly with posterior myocardial infarcts. It is usually due to involvement of the conduction fibers by edema around an infarct, in which case the heart block is temporary. Permanent heart block due to necrosis of the conducting fibers is less common. Complete heart block is characterized by severe bradycardia and reduced cardiac output. Death may occur.

3. Autonomic stimulation is a common occurrence in acute myocardial infarction, producing either tachycardia (sympathetic stimulation) or bradycardia (vagal stimulation).

Left Ventricular Failure

Acute left ventricular failure results from arrhythmia or massive necrosis of myocardium. The clinical effects are cardiogenic shock, acute pulmonary edema, and sudden death. The first two syndromes have a high mortality rate, even with treatment.

Progressive Infarction

Extension of the initial infarcted area to adjacent muscle occurs in 5–10% of patients in the first 10 days after the onset. The muscle around the infarcted area has a marginal blood supply that may become inadequate if there is an increased myocardial oxygen demand, eg, during exercise or under conditions of emotional stress. Vascular supply to the muscle is at risk also if there is a decrease in coronary perfusion, due either to extension of a thrombus or to decreased cardiac output. Progression of an infarct can be diagnosed by following the serum CK-MB levels. Progressive infarction is an indication for mechanical reperfusion by coronary angioplasty or coronary artery bypass surgery.

Pericarditis

Fibrinous or hemorrhagic pericarditis complicates myocardial infarction in about 30% of cases. It usually occurs within the first few days and may cause pericardial pain, pericardial rub, or pericardial effusion. Effusion sufficient to impair cardiac function is uncommon. Dressler's syndrome is a pericarditis that occurs 2–6 weeks after the onset of myocardial infarction. It is believed to be immunologically mediated.

Systemic Embolism from Mural Thrombi

Involvement of the endocardium by the infarct leads to the formation of mural thrombi over the area of infarction. Such thrombi may detach to become emboli that enter the systemic arteries.

Myocardial Rupture

The infarcted muscle represents an area of weakness that is maximal in the first week as the neutrophil enzymes cause liquefaction of the necrotic muscle fibers (Figure 23-8). Rupture may occur into the pericardial sac, producing hemopericardium and rapid death from cardiac tamponade; through the interventricular septum, producing an acute ventricular septal defect, with a left-to-right shunt and acute right ventricular failure; or within the papillary muscles, producing acute mitral regurgitation.

Ventricular Aneurysm

(Figure 23-9.) High intraventricular pressure may cause progressive outward bulging of the area of infarction during systole. This paradoxic motion of part of the ventricular wall during systole is called a ventricular aneurysm. Aneurysms may develop either in the first 2 weeks or after several months in the healed infarct and may cause left ventricular failure. Mural thrombi forming in an aneurysm may become detached as systemic emboli.

Angina Pectoris

Angina pectoris is characterized by episodic ischemic cardiac pain not associated with myocardial infarction. Two types of angina are recognized: angina of effort and variant (Prinzmetal's) angina.

Angina of Effort

Angina of effort is a common disorder usually caused by severe atherosclerotic narrowing of the coronary arterial system. The coronary arteries can provide the myocardium with adequate blood supply during rest but not during periods of exercise, stress, or excitement, which precipitate ischemic pain; the pain is relieved by resting or by administration of amyl nitrite or nitroglycerin (glyceryl trinitrate).

Pathologic changes associated with angina are variable and range from virtually no change in the myocardium to patchy areas of myocardial fibrosis and scars from previous infarcts. Infarction is not present; serum enzyme levels are not elevated; and the electrocardiogram (ECG) does not show changes of acute injury. Nonspecific changes in the ST segment such as ST depression and T wave inversion may reflect chronic ischemic damage. Electrocardiography during carefully graded exercise (treadmill test) is a sensitive method for detecting ischemic heart disease.

Patients with angina of effort have an increased risk of myocardial infarction, which may be preceded by an increase in the severity of anginal attacks (crescendo, or unstable angina).

Variant Angina

Variant (Prinzmetal's) angina is uncommon and occurs independently of atherosclerosis—which is, however, present in 75% of patients. Variant angina occurs at rest and is not related to myocardial work. It is believed to be caused by coronary artery muscle spasm of insufficient duration or degree to cause myocardial infarction. Spasm occurs near areas of stenosis in cases associated with atherosclerosis.

Sudden Death

Sudden death is a well-recognized occurrence in patients whose only abnormality at autopsy is severe coronary atherosclerosis. This has been attributed to ventricular fibrillation, leading to cardiac arrest. Studies of patients surviving such episodes (ie, in hospitalized patients) have shown that ventricular fibrillation often leads to death before myocardial infarction can develop. Many patients who die suddenly in this manner are heavy smokers.

Cardiac Arrhythmias

Ventricular arrhythmias (Chapter 20: The Blood Vessels) commonly occur in ischemic heart disease. Ventricular fibrillation, ventricular tachycardia, and complete heart block may lead to cardiac failure or sudden death.

Cardiac Failure

Ischemic heart disease may be manifested by chronic left ventricular failure with or without a history of infarction or angina. Clinical and electrocardiographic features are not specific for ischemic heart disease. T wave inversion on the ECG is a common finding.

Pathologic examination shows atherosclerotic narrowing of the coronary arteries and diffuse myocardial fibrosis. The total number of myocardial fibers is often diminished, and residual fibers may show compensatory hypertrophy. Cardiac failure occurs when hypertrophy of surviving muscle can no longer compensate for progressive loss of myocardial cells.

Myocarditis and cardiomyopathy are a group of diseases that chiefly involve the myocardium in the absence of hypertensive, congenital, ischemic, or valvular heart disease. The distinction between myocarditis and cardiomyopathy is somewhat arbitrary and not always made. Indeed, many authorities list myocarditis as a subset of cardiomyopathy. The term myocarditis is generally used to denote an acute myocardial disease characterized by inflammation. The cause may or may not be known. The term cardiomyopathy is then reserved for more chronic conditions in which inflammatory features are not conspicuous, including degenerative diseases and various diseases of unknown origin.

Myocarditis

Incidence

The incidence of myocarditis is difficult to establish, in part because of the rarity with which cardiac muscle biopsy is performed as a means of precise diagnosis. Even when the diagnosis of myocarditis is established, a definite cause is not usually recognized during life. Myocarditis is rarely (1% of cases) the cause of death in autopsy studies.

Etiology

Infectious Myocarditis

Viruses are believed to be the most common cause of myocarditis in developed countries (Figure 23-10). Coxsackie virus B is most frequently implicated; others include mumps, influenza, echo, polio, varicella, and measles viruses.

Clinical myocarditis may be seen in certain rickettsial diseases such as Q fever, typhus, and Rocky Mountain spotted fever. Ten percent of patients with Lyme disease (Lyme borreliosis) develop myocarditis and conduction abnormalities.

Myocardial inflammation in diphtheria is the result of an exotoxin. The diphtheria bacillus does not enter the bloodstream, but as it multiplies in the upper respiratory tract it produces exotoxin that does enter the bloodstream. Diphtheria exotoxin inhibits protein synthesis, leading to myocardial cell degeneration and necrosis. Diphtheria is now rare in countries with immunization programs.

American trypanosomiasis (Chagas' disease) is endemic in South America, where it is a common cause of myocarditis. In the acute phase, parasitization of myofibrils leads to focal necrosis and inflammation characterized by the presence of many eosinophils. The parasites are seen as pseudocysts in myocardial fibers (Figure 23-11). The chronic phase is characterized by interstitial fibrosis and lymphocytic infiltration. The conduction system is frequently involved. Parasites are scarce in the chronic phase.

The acute phase of trichinosis, in which numerous larvae of Trichinella spiralis enter the bloodstream, is characterized by myocarditis. The larvae enter myocardial fibers, causing necrosis and acute inflammation with numerous eosinophils.

The myocardium is involved rarely in the acute disseminated form of toxoplasmosis that occurs in immunocompromised patients. Toxoplasma gondii pseudocysts are present in myocardial fibers.

Autoimmune (Hypersensitivity) Myocarditis

Myocarditis occurs in various diseases believed to have an autoimmune pathogenesis. These disorders include rheumatic fever, rheumatoid arthritis, systemic lupus erythematosus, progressive systemic sclerosis, and polyarteritis nodosa. All are characterized by focal myocardial fiber necrosis, lymphocytic infiltration, and fibrosis; vasculitis may be present. Rheumatic fever may show Aschoff bodies.

Toxic Myocarditis

Many drugs may injure the myocardium. The more common ones are ethyl alcohol, doxorubicin, daunorubicin, cyclophosphamide, hydralazine, phenytoin, procainamide, and the tricyclic antidepressants. Inflammatory change is often minimal, and these myocardial diseases are sometimes regarded as cardiomyopathies (eg, alcoholic cardiomyopathy; see below).

Doxorubicin (Adriamycin), one of the most effective anticancer drugs in current use, has a dose-related toxic effect on the myocardium, producing cytoplasmic vacuolation followed by necrosis. The occurrence of cardiotoxicity limits the clinical use of the drug.

Sarcoid Myocarditis

Sarcoidosis may produce significant cardiac involvement with noncaseating granulomatous lesions identical to those found elsewhere. Myocardial cell necrosis and inflammation are rarely severe enough to cause heart failure.

Radiation Myocarditis

The myocardium is relatively resistant to the effects of radiation, but clinical myocarditis may develop from large doses of radiation to the mediastinum.

Idiopathic Myocarditis

Myocarditis may occur without known cause, characterized by diffuse inflammation, sometimes with giant cells (Fiedler's myocarditis) and eosinophils. Progressive acute heart failure or sudden death may occur.

Pathology

In acute myocarditis, the heart is dilated, flabby, and pale. There may be small scattered petechial hemorrhages. Microscopically, there is edema, which separates myocardial fibers; hyperemia; and infiltration by lymphocytes, plasma cells, and eosinophils (Figure 23-10). Neutrophils may also be present if there is necrosis of individual muscle fibers. Recovery from acute myocarditis is associated with resolution. If myofibrillary necrosis has occurred, there may be irregular fibrosis.

Chronic myocarditis is a controversial entity characterized by cardiac failure, ventricular hypertrophy, and the presence of lymphocytes and plasma cells in the interstitium. This pathologic appearance may follow many of the causes listed above. Clinically, it appears as cardiomyopathy (see below).

Clinical Features

The onset is acute, with fever, chest pain, leukocytosis, and elevation of the erythrocyte sedimentation rate. Left ventricular failure may occur, manifested by a third heart sound (gallop rhythm) and mitral regurgitation caused by dilation of the mitral valve ring. Arrhythmias include extrasystoles, atrial and ventricular tachycardia, and atrial and ventricular fibrillation, and they may cause sudden death. Complete heart block is manifested by bradycardia and cardiac failure. Necrosis of myocardial fibers produces injury potentials in the ST segment and elevations of serum concentrations of creatine kinase, lactate dehydrogenase, and aspartate transaminase.

Cardiomyopathies

As defined above, cardiomyopathies are primary myocardial diseases characterized by a chronic course and minimal features of inflammation. Cardiomyopathy should be suspected in a young normotensive patient who develops cardiac failure in the absence of congenital, valvular, or ischemic heart disease. The term cardiomyopathy is also sometimes used to denote myocardial diseases associated with certain toxic, metabolic, and degenerative diseases, including alcoholism, amyloidosis, hemochromatosis, myxedema, thyrotoxicosis, beriberi (thiamin deficiency), certain glycogen storage diseases and mucopolysaccharidoses, Friedreich's ataxia, and the muscular dystrophies.

Incidence & Etiology

Cardiomyopathy is rare. It may be familial or sporadic. In most cases, no cause can be found (idiopathic), and the disorders listed above account for a relatively small proportion of cases.

Classification

Cardiomyopathies, both idiopathic and those secondary to known diseases, are classified according to type of functional abnormality. The following four types are recognized.

Dilated (Congestive) Cardiomyopathy

Dilated cardiomyopathy is characterized by failure of the ventricle to empty in systole. The ventricular end-systolic and diastolic volumes are increased, causing bilateral ventricular dilation and failure. Arrhythmias are common and sometimes cause sudden death. Most cases progress slowly to death from heart failure within 2 years from the onset of symptoms.

Histologic features are nonspecific. There is irregular atrophy and hypertrophy of myocardial fibers with progressive fibrosis.

Most cases are sporadic (10% are familial) and most have no detectable cause (idiopathic dilated cardiomyopathy). A few cases are associated with (1) metabolic diseases such as hypothyroidism, hyperthyroidism, hemochromatosis, and thiamin deficiency; (2) toxic diseases such as alcoholism and cobalt poisoning; (3) neuromuscular diseases such as Friedreich's ataxia; or (4) late pregnancy (peripartal cardiomyopathy).

Chronic alcoholism is the most common cause of secondary dilated cardiomyopathy. It differs from the idiopathic form only in that it may reverse if alcohol consumption stops.

Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy is characterized by marked hypertrophy of the ventricular muscle with resistance to diastolic filling. Both ventricles are diffusely involved in most cases.

Asymmetric septal hypertrophy (also called hypertrophic obstructive cardiomyopathy or HOCM; also called idiopathic hypertrophic subaortic stenosis, or IHSS) is a variant characterized by selective hypertrophy of the septum immediately below the aortic valve, obstructing the left ventricular outflow tract. Clinically, this condition mimics aortic stenosis.

About 50% of cases of hypertrophic cardiomyopathy are familial, and in some of these there is a suggestion of an autosomal dominant inheritance pattern. The suspect abnormal gene has been mapped to chromosome 14.

Restrictive Cardiomyopathy

Restrictive cardiomyopathy is characterized by decreased compliance of the ventricular muscle, increased resistance to diastolic filling, and cardiac failure. Many cases are now recognized as being due to amyloidosis. Other causes include hemochromatosis and myocardial sarcoidosis.

Cardiac amyloidosis occurs in several different situations (see also Chapter 2: Abnormalities of Interstitial Tissues): (1) senile amyloidosis, where the heart is frequently the only organ involved; (2) primary amyloidosis, where cardiac involvement is accompanied by deposition of amyloid in the tongue, intestine etc; and (3) secondary amyloidosis, in which the heart is affected infrequently. Amyloid deposition occurs in the myocardial interstitium and around small blood vessels. When involvement is diffuse, the myocardium is thickened and leathery-firm and has a waxy, pale gray color.

Obliterative Cardiomyopathy

Obliterative cardiomyopathy is characterized by marked subendocardial fibrosis resulting in encroachment of the lumen, decreased ventricular filling, and cardiac failure. Both left and right ventricles may be involved.

Two different diseases exist within this category. (1) In endocardial fibroelastosis, collagen and elastic tissue is laid down beneath the endocardium, with clinical features appearing during infancy. Some cases appear to be familial; others may be secondary to anoxia or fetal viral infection. (2) Endomyocardial fibrosis is an acquired disease in which there is fibrosis of the endocardium and inner myocardium. It is common in Africa and has been attributed to a diet rich in serotonin (eg, bananas), perhaps mimicking the carcinoid syndrome, in which elevated serotonin levels produce endocardial fibrosis.

Acute Pericarditis

Incidence

Acute pericarditis is relatively common in hospital practice.

Etiology

The common causes are infection, ischemic heart disease, uremia, and the connective tissue diseases.

Infectious Acute Pericarditis

Viral Pericarditis

Viruses known to cause pericarditis include coxsackievirus B, echovirus, and the agents of mumps, infectious mononucleosis (Epstein-Barr virus), and influenza. Viruses can be cultured from pericardial fluid.

Acute Idiopathic Pericarditis

This disorder is very similar clinically to viral pericarditis. It occurs in young adults and commonly follows a respiratory viral infection by 2–3 weeks, suggesting the possibility of hypersensitivity reaction. The disease is self-limited, with recovery in 1–2 weeks.

Tuberculous Pericarditis

Tuberculous pericarditis is due to direct spread of infection from a caseous mediastinal lymph node leading to acute followed by chronic pericarditis. It is now rare in developed countries.

Pyogenic Pericarditis

Infection of the pericardium by pyogenic organisms is caused by direct spread from a suppurative focus in the lung or pleura. Streptococcus pneumoniae, staphylococci, and gram-negative bacilli are the common causes. Effective antibiotic therapy of lung infections has reduced the frequency of this condition.

Noninfectious Acute Pericarditis

Acute pericarditis frequently complicates acute rheumatic fever, myocardial infarction, chronic renal failure (uremia), and connective tissue diseases such as systemic lupus erythematosus and rheumatoid arthritis. Malignant neoplasms may directly involve the pericardium and cause inflammation. Pericarditis may also occur after cardiac trauma and cardiac surgery. There is typically a delay of weeks after the trauma, suggesting that immunologic hypersensitivity may play a role. Delayed pericarditis occurring 2–3 weeks after myocardial infarction (Dressler's syndrome) probably has a similar hypersensitivity basis. Acute pericarditis may follow radiation therapy to the mediastinum in the treatment of cancer.

Pathology

The smooth pericardial surface is transformed into a reddened membrane roughened by adherent clumps of fibrin. Infiltration by neutrophils causes yellow discoloration. The visceral and parietal layers of pericardium are thus thickened and loosely adherent—said to peel apart like two slices of buttered bread (bread and butter appearance). Fluid exudation into the pericardial sac varies from minimal (dry, or fibrinous, pericarditis) to significant (pericarditis with effusion). The fluid is usually serous. Hemorrhagic effusions commonly occur in renal failure, malignant neoplasms, and tuberculosis.

Clinical Features

Pericarditis is an acute-onset illness characterized by fever, pericardial pain, and a pericardial rub. When there is significant effusion, the inflamed pericardial layers separate, and both the rub and the pain diminish. Pericardial effusion causes cardiac enlargement, dullness to percussion, and muffled heart sounds. With large effusions, raised intrapericardial pressure impairs diastolic filling of the right atrium, leading to acute right heart failure (cardiac tamponade). With rapidly developing effusions, cardiac tamponade may cause death very rapidly.

Diagnosis

Pericarditis can be diagnosed clinically by the presence of a pericardial rub or effusion, confirmed by chest x-ray, echocardiography, and examination of aspirated pericardial fluid (culture and cytologic examination).

Chronic Adhesive Pericarditis

Recovery from acute pericarditis frequently produces fibrous plaques (milk spots) in the visceral pericardium or adhesions between the two pericardial layers (chronic adhesive pericarditis). These are of no clinical significance.

Chronic Constrictive Pericarditis

Chronic constrictive pericarditis is uncommon, and in most cases the cause is not known. Tuberculosis and pyogenic infections were common causes in the past. Immunologic mechanisms may account for most noninfectious cases.

Chronic constrictive pericarditis is characterized by encasement of the heart in a greatly thickened fibrotic pericardium (Figure 23-12). Chronic inflammatory cells are frequently present, along with dystrophic calcification. The pericardial sac is obliterated.

The fibrous pericardium constricts the cardiac chambers, particularly reducing right atrial filling. Elevation of jugular venous pressure and decreased cardiac output result. Ascites and hepatic enlargement are common clinical features. Chest x-ray frequently shows pericardial calcification. Surgical removal of the thickened pericardial sac (pericardiectomy) is effective treatment.

The myocardium and pericardium are occasionally involved by metastatic tumor or by direct local invasion by lung carcinoma or malignant lymphoma.

Rhabdomyoma, which is composed of a disorganized mass of cardiac muscle, is a hamartoma that occurs in patients with tuberous sclerosis (see Chapter 62: The Central Nervous System: I. Structure & Function; Congenital Diseases). It is very rare.

Primary cardiac malignant neoplasms include pericardial malignant mesothelioma and angiosarcoma. They are very rare.