• Morphology. • Clinical Features. » OTHER SPECIFIC CAUSES OF MYOCARDIAL DISEASE • Adriamycin and Other Drugs. • Catecholamines. • Amyloidosis. • Morphology. • Iron Overload. • Morphology. • Hyperthyroidism and Hypothyroidism. • Morphology.– Pericardial Disease » PERICARDIAL EFFUSION AND HEMOPERICARDIUM » PERICARDITIS • Acute Pericarditis • Serous Pericarditis. • Morphology. • Fibrinous and Serofibrinous Pericarditis. • Morphology. • Purulent or Suppurative Pericarditis. • Morphology. • Hemorrhagic Pericarditis. • Caseous Pericarditis. • Chronic or Healed Pericarditis • Adhesive Mediastinopericarditis. • Constrictive Pericarditis. » RHEUMATOID HEART DISEASE– Tumors of the Heart » PRIMARY CARDIAC TUMORS • Myxoma • Morphology. • Lipoma • Papillary Fibroelastoma • Morphology. • Rhabdomyoma • Morphology. • Sarcoma » CARDIAC EFFECTS OF NONCARDIAC NEOPLASMS » Cardiac Transplantation 556
The human heart is a remarkably efficient, durable, and reliable pump that propels over6000 liters of blood through the body daily and beats more than 40 million times a yearduring an individuals lifetime, thereby providing the tissues with a steady supply of vitalnutrients and facilitating the excretion of waste products. As might be anticipated, cardiacdysfunction can be associated with devastating physiologic consequences. Heart diseaseis the predominant cause of disability and death in industrialized nations. In the UnitedStates, it accounts for about 40% of all postnatal deaths, totaling about 750,000individuals annually and nearly twice the number of deaths caused by all forms of cancercombined. The yearly economic burden of ischemic heart disease, the most prevalentsubgroup, is estimated to be in excess of $100 billion. The major categories of cardiacdiseases considered in this chapter include congenital heart abnormalities, ischemic heartdisease, heart disease caused by systemic hypertension, heart disease caused bypulmonary diseases (cor pulmonale), diseases of the cardiac valves, and primarymyocardial diseases. A few comments about pericardial diseases and cardiac neoplasmsas well as cardiac transplantation are also offered. Before considering details of specificconditions, we will review salient features of normal anatomy and function as well as theprinciples of cardiac hypertrophy and failure, the common end points of many differenttypes of heart disease.NormalThe normal heart weight varies with body height and weight; it averages approximately250 to 300 g in females and 300 to 350 g in males. The usual thickness of the free wall ofthe right ventricle is 0.3 to 0.5 cm and that of the left ventricle 1.3 to 1.5 cm. As will beseen, increases in cardiac size and weight accompany many forms of heart disease.Greater heart weight or ventricular thickness indicates hypertrophy, and an enlargedchamber size implies dilation. An increase in cardiac weight or size (owing tohypertrophy and/or dilation) is termed cardiomegaly.MyocardiumBasic to the hearts function is the near-inexhaustible cardiac muscle, the myocardium,composed primarily of a collection of specialized muscle cells called cardiac myocytes( Fig. 12-1 ). They are arranged largely in a circumferential and
Figure 12-1 Myocardium (cardiac muscle). A The histology of myocardium is shown, emphasizing thecentrally-placed nuclei of the cardiac myocytes (arrowhead), intercalated discs (representing specializedend-to-end junctions of adjoining cells; highlighted by a double arrow) and the sarcomeric structure visibleas cross-striations within myocytes. A capillary endothelial cell is indicated by an arrow.(Photomicrograph courtesy of Mark Flomenbaum, M.D., Ph.D., Office of the Chief Medical Examiner,New York City, NY.) B Electron microscopy of myocardium, showing myofibrillar (my) and mitochondrial(mi) architecture and the sarcolemmal membrane (s). Z bands are indicated by arrows. Bar = 1 µm.(Reproduced by permission from Vivaldi MT, et al. Triphenyltetrazolium staining of irreversible injuryfollowing coronary artery occlusion in rats. Am J Pathol 121:522, 1985. Copyright J.B. Lippincott, 1985.) 557spiral orientation around the left ventricle, the chamber that pumps blood to the systemiccirculation. Cardiac myocytes have five major components: (1) cell membrane(sarcolemma) and T-tubules, for impulse conduction; (2) sarcoplasmic reticulum, acalcium reservoir needed for contraction; (3) contractile elements; (4) mitochondria; and(5) nucleus. Cardiac muscle cells contain many more mitochondria between myofibrilsthan do skeletal muscle cells (approximately 23% of cell volume vs. 2%), reflecting the
almost complete dependence of cardiac muscle on aerobic metabolism. Cardiac musclecells each usually contain one spindle-shaped nucleus. Ventricular muscle contractsduring systole and relaxes during diastole.The functional intracellular contractile unit of cardiac muscle (like skeletal muscle) is thesarcomere, an orderly arrangement of thick filaments composed principally of myosin,and thin filaments containing actin. Sarcomeres also contain the regulatory proteinstroponin and tropomyosin. Cardiac muscle cells are composed of many parallelmyofilaments (arrays of sarcomeres in series), which are responsible for the striatedappearance of these cells. Contraction of cardiac muscle occurs by the cumulative effortof sliding of the actin filaments between the myosin filaments toward the center of eachsarcomere. The lengths of sarcomeres range from 1.6 to 2.2 µm, depending on the state ofcontraction. Shorter sarcomeres have considerable overlap of actin and myosin filaments,with consequent reduction in contractile force, whereas longer lengths enhancecontractility (Frank-Starling mechanism). Thus, moderate ventricular dilation duringdiastole increases the subsequent force of contraction during systole. With progressivedilation, however, there is a point at which effective overlap of the actin and myosinfilaments is reduced, and the force of contraction turns sharply downward, as occurs inheart failure.The myocytes comprise only approximately 25% of the total number of cells in the heart.However, because cardiac myocytes are so much larger than the intervening cells, theyaccount for more than 90% of the volume of the myocardium. The remainder areendothelial cells, mostly associated with the rich myocardial capillary network, andfibroblasts. Inflammatory cells are rare and collagen is sparse in normal myocardium.Reflecting their different functional requirements, atrial myocytes are generally smallerin diameter and less structured than their ventricular counterparts. Some atrial cells alsodiffer from ventricular cells in having distinctive electron-dense granules in thecytoplasm called specific atrial granules. They are the sites of storage of atrialnatriuretic peptide (ANP, or A-type natriuretic peptide), a polypeptide secreted into theblood under conditions of atrial distention. ANP can produce a variety of physiologiceffects, including vasodilation, natriuresis, and diuresis, actions beneficial in pathologicstates such as hypertension and congestive heart failure. Other natriuretic peptides are produced by the ventricles in response to elevations of ventricular pressure and volume(B-type, initially called brain natriuretic peptide) and by the vascular endothelium (C-type) in response to elevated shear stress.Functional integration of myocytes is mediated by structures unique to cardiac musclecalled intercalated disks, which join individual cells and within which specializedintercellular junctions permit both mechanical and electrical (ionic) coupling. One of thecomponents of intercalated disks are gap junctions, which facilitate synchronous myocytecontraction by providing electrical coupling with relatively unrestricted passage of ionsacross the membranes of adjoining cells. Gap junctions consist of clusters of plasmamembrane channels that directly link the cytoplasmic compartments of neighboring cells.Abnormalities in the spatial distribution of gap junctions and their respective proteins in
ischemic and myocardial heart disease may contribute to electromechanical dysfunction(arrhythmias).In addition, specialized excitatory and conducting myocytes within the cardiacconduction system are involved in regulating the rate and rhythm of the heart.Components include (1) the sinoatrial (SA) pacemaker of the heart, the SA node, locatednear the junction of the right atrial appendage with the superior vena cava; (2) theatrioventricular (AV) node, located in the right atrium along the atrial septum; (3) thebundle of His, which courses from the right atrium to the summit of the ventricularseptum; and its division into (4) right and left bundle branches that further arborize in therespective ventricles.Blood SupplyGenerating energy almost exclusively by the oxidation of substrates, the heart reliesheavily on an adequate flow of oxygenated blood through the coronary arteries. Withorigins from the aorta immediately distal to the aortic valve in the sinuses of Valsalva, thecoronary arteries consist of 5- to 10-cm long, 2- to 4-mm diameter conduits that run alongthe external surface of the heart (epicardial coronary arteries) and smaller vessels thatpenetrate the myocardium (intramural arteries). These small arteries yield arterioles and,ultimately, a rich network of capillaries in which there is nearly one vessel adjacent toeach cardiac muscle cell.The three major epicardial coronary arteries are (1) the left anterior descending (LAD)and (2) the left circumflex (LCX) arteries, both arising from bifurcation branches of theleft (main) coronary artery, and (3) the right coronary artery (RCA). Branches of theLAD are called diagonal and septal perforators, and those of the LCX are obtusemarginals. Most coronary arterial blood flow to the myocardium occurs duringventricular diastole, when the microcirculation is not compressed by the cardiaccontraction.Knowledge of the areas of supply (perfusion) of the three major coronary arteries helpscorrelate sites of vascular obstruction with regions of myocardial infarction (MI).Typically, the LAD supplies most of the apex of the heart (the rounded point at the distalparts of the ventricles as contrasted with the wide proximal part, the base), the anteriorwall of the left ventricle, and the anterior two-thirds of the ventricular septum. Byconvention, the coronary artery (either RCA or LCX) that gives rise to the posteriordescending branch and thereby perfuses the posterior third of the septum is called"dominant" (despite the fact that the LAD and LCX collectively perfuse the majority ofthe left ventricular myocardium—the LAD itself about 50%). In a right dominantcirculation, present in approximately four-fifths of individuals, the circumflex branch of
the left coronary artery generally perfuses only the lateral wall of the left ventricle, andthe RCA supplies the entire right ventricular free wall and the posterobasal 558wall of the left ventricle and the posterior third of the ventricular septum. Thus,occlusions of the right as well as the left coronary artery can cause left ventriculardamage.The right and left coronary arteries function as end arteries, although anatomically mosthearts have numerous intercoronary anastomoses (called the collateral circulation). Littleblood courses through these channels in the normal heart. However, when one artery isseverely narrowed, blood flows via collaterals from the high to the low pressure system,and causes the channels to enlarge. Progressive dilation of collaterals, stimulated byischemia, may play a role in providing blood flow to areas of the myocardium otherwisedeprived of adequate perfusion. However, when the principal blood flow is compromisedand collateral blood flow is inadequate, the subendocardium (myocardium adjacent to theventricular cavities) is the area most susceptible to ischemic damage.ValvesThe four cardiac valves (tricuspid, pulmonary, mitral, and aortic) maintain unidirectionalblood flow. The ability of the valves to permit unobstructed forward flow depends on themobility and pliability of their leaflets, which appear thin and translucent on grossinspection. The competency (ability to prevent reverse flow) of the semilunar valves(aortic and pulmonary) depends on the stretching and molding of their three leaflets(often called cusps) to fill the orifice in diastole (the closed phase), when there isbackpressure from the blood in the aorta or pulmonary artery. This requires the cusps tostretch to 40% to 50% larger than their area during systole (open phase), when they arerelaxed. During the closed phase, the cusps overlap along an area (the lunula) beneath thefree edge. Only the portion of the cusps below the closing edge separates aortic from leftventricular cavity blood; thus, defects or fenestrations of the cusp in the lunula usually donot compromise valve competence, but those below it will induce regurgitation. Thefunction of the semilunar valves also depends on the integrity and coordinatedmovements of the cuspal attachments. Thus, dilation of the aortic root can hindercoaptation of the aortic valve cusps during closure, yielding regurgitation. Each aorticcusp has a small nodule (nodule of Arantius) in the center of the free edge, whichfacilitates closure. The pulmonary valve has structure and function analogous to theaortic.The atrioventricular (AV) valves (mitral and tricuspid) have a different method ofmaintaining closure. Their free margins are tethered to the ventricular wall by manydelicate tendinous cords (chordae tendineae), attached to papillary muscles that arecontiguous with the underlying ventricular walls. Left ventricular papillary muscles arepositioned beneath the commissures and thereby receive cords from two adjacent leaflets.Thus, normal mitral valve competency depends on the coordinated actions of annulus
(the outer edge of the value orifice, where the leaflets attach), leaflets, cords, papillarymuscles, and associated left ventricular wall (collectively the mitral apparatus) acting tomaintain leaflet coaptation in the annulus. Left ventricular dilation or a ruptured cord orpapillary muscle can interfere with mitral closure, resulting in regurgitant flow. Tricuspidvalve function depends on analogous structures.The microstructure of the cardiac valves reflects their function ( Fig. 12-2 ). The cardiacvalves are lined with endothelium;Figure 12-2 Aortic valve histology, shown as a low-magnification photomicrograph of cuspal cross-sectionin the systolic (nondistended) state, emphasizing three major layers (ventricularis [v], spongiosa [s], andfibrosa [f]). Superficial endothelial cells (arrow) and diffusely distributed deep interstitial cells are noted.The strength of the valve is predominantly derived from the fibrosa, with its dense collagen (yellow). Thissection highlights the dense, laminated elastic tissue in the ventricularis (double arrow). The outflowsurface is at top. (Reproduced by permission from Schoen FJ: Aortic valve structure-function correlations:Role of elastic fibers no longer a stretch of the imagination. J Heart Valve Dis 6:1, 1997.)all have a similar, layered architecture consisting predominantly of a dense collagenouscore (fibrosa) close to the outflow surface and continuous with valvular supportingstructures, a central core of loose connective tissue (spongiosa), and a layer rich in elastin(ventricularis) below the inflow surface. The collagen of the fibrosa is responsible for the mechanical integrity of a valve, and the spongiosa functions as a shock absorber. Insystole, the elastin of the ventricularis contracts the cusps that were enlarged duringdiastole. The valve is populated throughout by interstitial cells, which produce and repairthe extracellular matrix (especially collagen) of the valve. In general, normal leaflets andcusps have scant blood vessels limited to the proximal portion because they are thinenough to be nourished by diffusion from the hearts blood. Pathological changes ofvalves are largely of three types: damage to the collagen with weakness of the leaflets inmyxomatous mitral valve disease, nodular calcification beginning in interstitial cells incalcific aortic stenosis, and fibrotic thickening in rheumatic heart disease (see later).
Effects of Aging on the HeartWith an increasing number of persons surviving into their eighth decade and beyond,knowledge of changes in the cardiovascular system that are expected to occur with agingis important. Indeed, the number of individuals aged 65 years and older willapproximately double from 2000 to 2050 (from 35 million to 79 million in the UnitedStates). Changes associated with aging occur in the pericardium, cardiac chambers,valves, epicardial coronary arteries, conduction system, myocardium, and aorta ( Table12-1 ).  559 TABLE 12-1 -- Changes in the Aging HeartChambersIncreased left atrial cavity sizeDecreased left ventricular cavity sizeSigmoid-shaped ventricular septumValvesAortic valve calcific depositsMitral valve annular calcific depositsFibrous thickening of leafletsBuckling of mitral leaflets toward the left atriumLambl excrescencesEpicardial Coronary ArteriesTortuosityIncreased cross-sectional luminal areaCalcific depositsAtherosclerotic plaqueMyocardiumIncreased massIncreased subepicardial fatBrown atrophy
Lipofuscin depositionBasophilic degenerationAmyloid depositsAortaDilated ascending aorta with rightward shiftElongated (tortuous) thoracic aortaSinotubular junction calcific depositsElastic fragmentation and collagen accumulationAtherosclerotic plaqueWith advancing age, the amount of epicardial fat increases, particularly over the anteriorsurface of the right ventricle and in the atrial septum. A reduction in the size of the leftventricular cavity, particularly in the base-to-apex dimension, is associated withincreasing age and accentuated by systemic hypertension. Accompanied by a rightwardshift and tortuosity of a dilated ascending aorta, this chamber alteration causes the basalventricular septum to bend leftward, bulging into the left ventricular outflow tract(termed sigmoid septum). Such reduction in the size of the left ventricular cavity cansimulate the obstruction to blood leaving the left ventricle that often occurs withhypertrophic cardiomyopathy, discussed later in this chapter.Several changes of the valves are noted with aging, including calcification of the mitralannulus and aortic valve, the latter frequently leading to aortic stenosis. In addition, thevalves can develop fibrous thickening, and the mitral leaflets tend to buckle back towardthe left atrium during ventricular systole, simulating a prolapsing (myxomatous) mitralvalve (see later). Moreover, many older persons develop small filiform processes (Lamblexcrescences) on the closure lines of aortic and mitral valves, probably arising from theorganization of small thrombi on the valve contact margins.Compared with younger myocardium, "elderly" myocardium also has fewer myocytes,increased collagenized connective tissue and, in some individuals, deposition of amyloid.In the muscle cells, lipofuscin deposits ( Chapter 1 ), and basophilic degeneration, anaccumulation within cardiac myocytes of a gray-blue byproduct of glycogen metabolism,may be present. Extensive lipofuscin deposition in a small, atrophied heart is calledbrown atrophy; this change often accompanies cachectic weight loss, as seen in terminalcancer.Although the morphologic changes described are common in elderly patients at necropsy,and they may mimic disease, in only a minority are they associated with clinical cardiacdysfunction.
PathologyAlthough many diseases can involve the heart and blood vessels, cardiovascular  dysfunction results from one or more of five principal mechanisms: • Failure of the pump. In the most common circumstance, the cardiac muscle contracts weakly or inadequately, and the chambers cannot empty properly. In some conditions, however, the muscle cannot relax sufficiently to permit ventricular filling. • An obstruction to flow, owing to a lesion preventing valve opening or otherwise causing increased ventricular chamber pressure (e.g., aortic valvular stenosis, systemic hypertension, or aortic coarctation). The increased pressure overworks the chamber that pumps against the obstruction. • Regurgitant flow causes some of the output from each contraction to flow backward, adding a volume workload to each of the chambers, which must pump the extra blood (e.g., left ventricle in aortic regurgitation; left atrium and left ventricle in mitral regurgitation). • Disorders of cardiac conduction. Heart block or arrhythmias owing to uncoordinated generation of impulses (e.g., atrial or ventricular fibrillation) lead to nonuniform and inefficient contractions of the muscular walls. • Disruption of the continuity of the circulatory system that permits blood to escape (e.g., gunshot wound through the thoracic aorta).Most cardiovascular disease arises from the interaction of environmental factors andgenetic susceptibility. The contemporary view holds that most clinical cardiovasculardiseases result from a complex interplay of genetics and environmental factors thatdisrupt networks controlling morphogenesis, myocyte survival, biomechanical stressresponses, contractility, and electrical conduction. For example, there is growing recognition that pathogenesis of congenital heart defects, in many cases, involves anunderlying genetic abnormality whose expression is strongly modified by external(environmental or maternal) factors. Moreover, since a diverse group of cytoskeletalprotein mutations have been linked with cardiac muscle cell dysfunction in thecardiomyopathies, perhaps subtle mutations or polymorphisms in these genes couldconfer an increased risk or more rapid onset of heart failure in response to acquiredcardiac injury. In these and other examples, the clinical expression of cardiac diseaserepresents the end result of multiple internal and external cues for growth, death, andsurvival of cardiac myocytes. These factors and pathways are shared with other normaltissues and pathological processes. 560Heart FailureThe abnormalities described above often culminate in heart failure, an extremelycommon result of many forms of heart disease. In heart failure, often called congestive
heart failure (CHF), the heart is unable to pump blood at a rate commensurate with therequirements of the metabolizing tissues or can do so only at an elevated filling pressure.Although usually caused by a slowly developing intrinsic deficit in myocardialcontraction, a similar clinical syndrome is present in some patients with heart failurecaused by conditions in which the normal heart is suddenly presented with a load thatexceeds its capacity (e.g., fluid overload, acute myocardial infarction, acute valvulardysfunction) or in which ventricular filling is impaired (see below). CHF is a commonand often recurrent condition with a poor prognosis. The magnitude of the problem isexemplified by the impact of CHF in the United States, where each year it affects nearly5 million individuals, is the underlying or contributing cause of death of an estimated300,000, and necessitates over 1 million hospitalizations. Moreover, CHF is the leading discharge diagnosis in hospitalized patients over age 65 and has an associated annual costof $18 billion. In many pathologic states, the onset of heart failure is preceded by cardiachypertrophy, the compensatory response of the myocardium to increased mechanicalwork (see below).The cardiovascular system maintains arterial pressure and perfusion of vital organs in thepresence of excessive hemodynamic burden or disturbance in myocardial contractility bya number of mechanisms. The most important are:  • The Frank-Starling mechanism, in which the increased preload of dilation (thereby increasing cross-bridges within the sarcomeres) helps to sustain cardiac performance by enhancing contractility • Myocardial structural changes, including augmented muscle mass (hypertrophy) with or without cardiac chamber dilation, in which the mass of contractile tissue is augmented • Activation of neurohumoral systems, especially (1) release of the neurotransmitter norepinephrine by adrenergic cardiac nerves (which increases heart rate and augments myocardial contractility and vascular resistance), (2) activation of the renin-angiotensin-aldosterone system, and (3) release of atrial natriuretic peptide.These adaptive mechanisms may be adequate to maintain the overall pumpingperformance of the heart at relatively normal levels, but their capacity to sustain cardiacperformance may ultimately be exceeded. Moreover, pathologic changes, such asapoptosis, cytoskeletal alterations, and extracellular matrix (particularly collagen)synthesis and remodeling, may also occur, causing structural and functional disturbances.Most instances of heart failure are the consequence of progressive deterioration ofmyocardial contractile function (systolic dysfunction), as often occurs with ischemicinjury, pressure or volume overload, or dilated cardiomyopathy. The most frequentspecific causes are ischemic heart disease and hypertension. Sometimes, however, failureresults from an inability of the heart chamber to relax, expand, and fill sufficiently duringdiastole to accommodate an adequate ventricular blood volume (diastolic dysfunction), ascan occur with massive left ventricular hypertrophy, myocardial fibrosis, deposition ofamyloid, or constrictive pericarditis. Whatever its basis, CHF is characterized by 
diminished cardiac output (sometimes called forward failure) or damming back of bloodin the venous system (so-called backward failure), or both.The molecular, cellular, and structural changes in the heart that occur as a response toinjury, and cause changes in size, shape, and function, are often called left ventricularremodeling. Our discussion focuses on structural changes and considers heart failure tobe a progressive disorder, which can culminate in a clinical syndrome characterized byimpaired cardiac function and circulatory congestion. Nevertheless, we recognize that themodern treatment of chronic heart failure emphasizes the neurohumoral hypothesis, inwhich neuroendocrine activation is important in the progression of heart failure. Thus,inhibition of neurohormones may have long-term beneficial effects on morbidity andmortality. In the future, patients with CHF may be helped by implanted mechanical cardiac assist devices, an area in which considerable progress has recently been made. CARDIAC HYPERTROPHY: PATHOPHYSIOLOGY AND PROGRESSION TO FAILUREThe cardiac myocyte is generally considered a terminally differentiated cell that has lostits ability to divide. Under normal circumstances, functionally useful augmentation ofmyocyte number (hyperplasia) cannot occur. Increased mechanical load causes anincrease in the content of subcellular components and a consequent increase in cell size(hypertrophy). Increased mechanical work owing to pressure or volume overload ortrophic signals (e.g., hyperthyroidism through stimulation of beta-adrenergic receptors)increases the rate of protein synthesis, the amount of protein in each cell, the number ofsarcomeres and mitochondria, the dimension and mass of myocytes and, consequently,the size of the heart. Nevertheless, the extent to which adult cardiac myocytes have somecapacity to synthesize DNA and whether this leads to some degree of cell division is anarea of considerable recent attention and debate. The extent of hypertrophy varies for different underlying causes. Heart weight usuallyranges from 350 to 600 gm (up to approximately two times normal) in pulmonaryhypertension and ischemic heart disease; from 400 to 800 gm (up to two to three timesnormal) in systemic hypertension, aortic stenosis, mitral regurgitation, or dilatedcardiomyopathy; from 600 to 1000 gm (three or more times normal) in aorticregurgitation or hypertrophic cardiomyopathy. Hearts weighing more than 1000 gm arerare.The pattern of hypertrophy reflects the nature of the stimulus ( Fig. 12-3 ). Pressure-overloaded ventricles (e.g., in hypertension or aortic stenosis) develop pressure-overload(also called concentric) hypertrophy of the left ventricle, with an increased wallthickness. In the left ventricle the augmented muscle may reduce the cavity diameter. Inpressure overload, the predominant deposition of sarcomeres is parallel to the long axesof cells; cross-sectional area of myocytes is expanded (but cell length is not). In contrast,volume overload stimulates deposition of new sarcomeres and cell length (as well as 561
width) is increased. Thus, volume-overload hypertrophy is characterized by dilation withincreased ventricular diameter. In volume overload, muscle mass and wall thickness areincreased approximately in proportion to chamber diameter. However, owing to dilation,wall thickness of a heart in which both hypertrophy and dilation have occurred is notnecessarily increased, and it may be normal or less than normal. Thus, wall thickness isby itself not an adequate measure of volume-overload hypertrophy.Cardiac hypertrophy is also accompanied by numerous transcriptional and morphologicchanges. With prolonged hemodynamic overload, gene expression is altered, leading tore-expression of a pattern of protein synthesis analogous to that seen in fetal cardiacdevelopment; other changes are analogous to events that occur during mitosis of normallyproliferating cells ( Chapter 1 ). Early mediators of hypertrophy include the immediate-early genes (e.g., c-fos, c-myc, c-jun and EGR1). Selective up-regulation or re-expressionof embryonic/fetal forms of contractile and other proteins also occurs, including β-myosin heavy chain, ANP, and collagen (see Chapter 1 ). The increased myocyte sizethat occurs in cardiac hypertrophy is usually accompanied by decreased capillary density,increased intercapillary distance, and deposition of fibrous tissue. Nevertheless, theenlarged muscle mass has increased metabolic requirements and increased wall tension,both major determinants of the oxygen consumption of the heart. The other major factorsin oxygen consumption are heart rate and contractility (inotropic state, or force ofcontraction), both of which are often increased in hypertrophic states.Thus, the geometry, structure, and composition (cells and extracellular matrix) of thehypertrophied heart are not normal. Cardiac hypertrophy constitutes a tenuous balancebetween adaptive characteristics (including new sarcomeres) and potentially deleteriousstructural and biochemical/molecular alterationsFigure 12-3 Left ventricular hypertrophy. A, Pressure hypertrophy due to left ventricular outflowobstruction. The left ventricle is on the lower right in this apical four-chamber view of the heart. B, Alteredcardiac configuration in left ventricular hypertrophy without and with dilation, viewed in transverse heartsections. Compared with a normal heart (center), the pressure-hypertrophied hearts (left and in A) haveincreased mass and a thick left ventricular wall, but the hypertrophied and dilated heart (right) hasincreased mass but a normal wall thickness. (Reproduced by permission from Edwards WD: Cardiacanatomy and examination of cardiac specimens. In Emmanouilides GC, Riemenschneider TA, Allen HD,Gutgesell HP (eds): Moss and Adams Heart Disease in Infants, Children, and Adolescents: Including the
Fetus and Young Adults, 5th ed. Philadelphia, Williams and Wilkins, 1995, p. 86.)(including decreased capillary-to-myocyte ratio, increased fibrous tissue, and synthesisof abnormal proteins). Thus, sustained cardiac hypertrophy often evolves to cardiacfailure. Ultimately, the primary cardiac disease and the superimposed compensatoryburdens further encroach on the myocardial reserve. Then begins the downward slide ofstroke volume and cardiac output that often ends in death. The proposed sequence ofinitially beneficial and later harmful events in the response to increased cardiac work issummarized in Figure 12-4 .The structural, biochemical, and molecular basis for myocardial contractile failure isobscure in many cases. Nevertheless, in some instances (e.g., myocardial infarction),there is obvious death of myocytes and loss of vital elements of the "pump";consequently, noninfarcted regions of cardiac muscle are overworked. In contrast, invalvular heart disease, increased pressure or volume work affects the myocardiumglobally. The molecular and cellular changes in hypertrophied hearts that initiallymediate enhanced function may contribute to the development of heart failure.   Proteins related to contractile elements, excitation-contraction coupling, and energyutilization may be significantly altered through production of different isoforms thateither may be less functional than normal or may be reduced or increased in amount.Alterations of intracellular handling of calcium ions may also contribute to impairedcontraction and relaxation. Loss of myocytes due to apoptosis may contribute to progressive myocardial dysfunction in cardiac disease with hypertrophy. Increased heart mass predicts excess cardiac mortality and morbidity. Indeed, besidespredisposing to CHF, left ventricular hypertrophy is an independent risk factor for suddendeath. Interestingly, and in contrast to the pathologic hypertrophy just discussed, hypertrophy that is induced by regular strenuous exercise (physiologic hypertrophy)seems to be an extension of normal growth and has minimal or no deleterious effect. Asuitable explanation for this discrepancy is yet lacking. 562
Figure 12-4 Schematic representation of the sequence of events in cardiac hypertrophy and its progressionto heart failure, emphasizing cellular and extracellular changes.The degree of structural abnormality of the heart in CHF does not always reflect the levelof dysfunction and, indeed, it may be impossible from morphologic examination of theheart to distinguish a damaged but compensated heart from one that has decompensated.At autopsy, the heart of patients having CHF is generally characterized by increasedweight, chamber dilation, thin walls, and microscopic changes of hypertrophy, but theextent of these changes varies from one patient to the next. Moreover, many of the
significant adaptations and morphologic changes noted in CHF are distant from theheart and are produced by the hypoxic and congestive effects of the failing circulation onother organs and tissues. Thus CHF represents a clinical syndrome characterizedprimarily by findings outside the cardiovascular system—in both "forward" (e.g., poororgan perfusion) and "backward" (dyspnea and peripheral edema) directions.To some extent, the right and left sides of the heart act as two distinct anatomic andfunctional units. Thus left-sided and right-sided failure can occur independently.Nevertheless, because the cardiovascular system is a closed circuit, failure of one side(particularly the left side) often produces excessive strain on the other, terminating inglobal heart failure. Despite this interdependency, the clearest understanding of thepathologic physiology and anatomy of heart failure is derived from a consideration ofeach side separately.LEFT-SIDED HEART FAILUREAs discussed, left-sided heart failure is most often caused by (1) ischemic heart disease,(2) hypertension, (3) aortic and mitral valvular diseases, and (4) nonischemic myocardialdiseases. The morphologic and clinical effects of left-sided CHF primarily result fromprogressive damming of blood within the pulmonary circulation and the consequences ofdiminished peripheral blood pressure and flow.Morphology.The findings in the heart vary depending on the cause of the disease process;abnormalities such as myocardial infarction or a valvular deformity may be present.Except with obstruction at the mitral valve or other processes that restrict the size of theleft ventricle, this chamber is usually hypertrophied and often dilated, sometimes quitemassively. There are usually nonspecific changes of hypertrophy and fibrosis in themyocardium. Secondary enlargement of the left atrium with resultant atrial fibrillation(i.e., uncoordinated, chaotic contraction of the atrium) may either compromise strokevolume or cause blood stasis and possible thrombus formation (particularly in the atrialappendage). A fibrillating left atrium carries a substantially increased risk of embolicstroke. The extracardiac effects of left-sided heart failure are manifested most prominently in the lungs, although the kidneys and brain may also be affected.Lungs.Pressure in the pulmonary veins mounts and is ultimately transmitted retrograde to thecapillaries and arteries. The result is pulmonary congestion and edema, with heavy, wetlungs as described in detail in Chapter 4 and Chapter 15 . It is sufficient to note here thatthe pulmonary changes include, in sequence, (1) a perivascular and interstitial transudate,particularly in the interlobular septa, responsible for Kerleys B lines on x-ray; (2)progressive edematous widening of alveolar septa; and (3) accumulation of edema fluidin the alveolar spaces. Moreover, iron-containing proteins in edema fluid and hemoglobinfrom erythrocytes, which leak from congested capillaries, are phagocytosed bymacrophages and converted to hemosiderin. Hemosiderin-containing macrophages in the
alveoli (called siderophages, or heart failure cells) denote previous episodes ofpulmonary edema.These anatomic changes are associated with striking clinical manifestations. Dyspnea(breathlessness), usually the earliest and the cardinal complaint of patients in left-sidedheart failure, is an exaggeration of the normal breathlessness that follows exertion. Withfurther impairment, there is orthopnea, which is dyspnea on lying down that is relievedby sitting or standing. Thus the orthopneic patient must sleep while sitting upright.Paroxysmal nocturnal dyspnea is an extension of orthopnea that consists of attacks ofextreme dyspnea bordering on suffocation, usually occurring at night. Cough is acommon accompaniment of left-sided failure.Kidneys.Decreased cardiac output causes a reduction in renal perfusion, which activates the renin-angiotensin-andosterone 563system, inducing retention of salt and water with consequent expansion of the interstitialfluid and blood volumes. This compensatory reaction can contribute to the pulmonaryedema in left-sided heart failure and is counteracted by the release of ANP through atrialdilation, which acts to decrease excessive blood volume. If the perfusion deficit of thekidney becomes sufficiently severe, impaired excretion of nitrogenous products maycause azotemia, in this instance prerenal azotemia ( Chapter 20 ).Brain.In far-advanced CHF, cerebral hypoxia may give rise to hypoxic encephalopathy (seeChapter 28 ), with irritability, loss of attention span, and restlessness, which may evenprogress to stupor and coma.RIGHT-SIDED HEART FAILUREIsolated right-sided heart failure occurs in only a few diseases. Usually it is a secondaryconsequence of left-sided heart failure because any increase in pressure in the pulmonarycirculation incidental to left-sided heart failure inevitably produces an increased burdenon the right side of the heart. The causes of right-sided heart failure must then include allthose that induce left-sided heart failure.Pure right-sided heart failure most often occurs with chronic severe pulmonaryhypertension and thus is called cor pulmonale. In this condition, the right ventricle isburdened by a pressure workload due to increased resistance within the pulmonarycirculation. Hypertrophy and dilation are generally confined to the right ventricle andatrium, although bulging of the ventricular septum to the left can cause dysfunction of theleft ventricle.
The major morphologic and clinical effects of pure right-sided heart failure differ fromthose of left-sided heart failure in that pulmonary congestion is minimal, whereasengorgement of the systemic and portal venous systems may be pronounced.Morphology.Liver and Portal System.The liver is usually increased in size and weight (congestive hepatomegaly), and a cutsection displays prominent passive congestion (see Chapter 18 ). Congested red centersof the liver lobules are surrounded by paler, sometimes fatty, peripheral regions. In someinstances, especially when left-sided heart failure is also present, the severe centralhypoxia produces centrilobular necrosis along with the sinusoidal congestion. Withlong-standing severe right-sided heart failure, the central areas can become fibrotic,creating so-called cardiac sclerosis or cardiac cirrhosis ( Chapter 18 ).Right-sided heart failure also leads to elevated pressure in the portal vein and itstributaries. Congestion produces a tense, enlarged spleen (congestive splenomegaly).Microscopically there may be marked sinusoidal dilation. With long-standing congestion,the enlarged spleen may achieve a weight of 300 to 500 gm (normal, approximately 150gm). Chronic edema of the bowel wall can also occur and in some patients may interferewith absorption of nutrients. In addition, accumulations of transudate in the peritonealcavity may give rise to ascites.Kidneys.Congestion of the kidneys is more marked with right-sided heart failure than with left-sided heart failure, leading to greater fluid retention, peripheral edema, and morepronounced azotemia.Brain.Symptoms essentially identical to those described in left-sided heart failure may occur,representing venous congestion and hypoxia of the central nervous system.Pleural and Pericardial Spaces.Accumulation of fluid in the pleural space (particularly right) and pericardial space(effusions) may appear. Thus, while pulmonary edema indicates left-sided heart failure,pleural effusions accompany right-sided heart failure. Pleural effusions can range from100 ml to well over 1 liter and can cause partial atelectasis of the corresponding lung.Subcutaneous Tissues.Peripheral edema of dependent portions of the body, especially ankle (pedal) andpretibial edema, is a hallmark of right-sided heart failure. In chronically bedriddenpatients, the edema may be primarily presacral. Generalized massive edema is calledanasarca.
The symptoms of pure left-sided heart failure are largely due to pulmonary congestionand edema. In contrast, in right-sided heart failure, respiratory symptoms may be absentor quite insignificant, and there is a systemic (and portal) venous congestive syndrome,with hepatic and splenic enlargement, peripheral edema, pleural effusion, and ascites. Inmany cases of chronic cardiac decompensation, however, the patient presents with thepicture of biventricular CHF, encompassing the clinical syndromes of both right-sidedand left-sided heart failure.Heart DiseaseWith the introduction to general principles of cardiac functional anatomy and heartfailure, we now turn to a discussion of the major forms of heart disease. Five categoriesof disease account for nearly all cardiac mortality: • Congenital heart disease • Ischemic heart disease • Hypertensive heart disease (systemic and pulmonary) • Valvular heart disease • Nonischemic (primary) myocardial disease.Although congenital heart disease is discussed first, it is important to keep in mind thatischemic heart disease is responsible for 80% to 90% of cardiovascular deaths and is theleading cause of all mortality in the developed world. 564Congenital Heart DiseaseCongenital heart disease is a general term used to describe abnormalities of the heart orgreat vessels that are present from birth. Most such disorders arise from faultyembryogenesis during gestational weeks 3 through 8, when major cardiovascularstructures develop. The most severe anomalies may be incompatible with intrauterinesurvival. Congenital heart defects compatible with embryologic maturation and birth aregenerally morphogenetic defects of individual chambers or regions of the heart, with theremainder of the heart developing relatively normally. Examples are infants born with adefect in septation ("hole in the heart"), such as an atrial septal defect (ASD) or aventricular septal defect (VSD), or a hypoplastic right or left ventricle, in which theunaffected ventricle is morphologically, electrically, and physiologically normal.Alternatively, the development of the muscular component of the heart may proceednormally, but vessels that arise from the heart may not have the appropriate connectionswith specific cardiac chambers. Some forms of congenital heart disease producemanifestations soon after birth, frequently accompanying the change from fetal topostnatal circulatory patterns (with reliance on the lungs, rather than placenta, foroxygenation). Others, however, do not necessarily become evident until adulthood (e.g.,aortic coarctation or ASD).
Owing largely to surgical advances in the correction of simple and complex structuralheart defects, the number of adults who have survived with congenital heart disease isincreasing rapidly. It is estimated that by 2020 there will be at least 750,000 adults withcongenital heart disease who require a very specialized form of care with novel medical,psychologic, and social dimensions. They include those who have never had cardiac surgery, those who have had reparative cardiac surgery and require no furtherintervention, and those who have had incomplete or palliative surgery. Although surgery may fully correct the hemodynamic abnormalities of congenital heartdisease, the heart following repair of a congenital defect may not be fully normal.Myocardial hypertrophy and other changes of cardiac remodeling brought about by thecongenital defect may be irreversible or even necessary for survival and growth.Although adaptive initially, such changes can elicit late-onset arrhythmias, ischemia, andmyocardial dysfunction, sometimes after many uneventful years subsequent to thesurgery. Associated prosthetic materials and devices, such as substitute valves ormyocardial patches, yield an additional risk of complications, most prominentlythromboembolism, infection, or dysfunction of the material or device. Moreover, theremay be specific difficulties resulting from hyperviscosity of the blood owing to increasedhematocrit, and maternal risks associated with childbearing in those with cyanoticcongenital disease.Incidence.Congenital heart disease is the most common type of heart disease among children.Although figures vary, a generally accepted incidence is approximately 1% of live births.The incidence is higher in premature infants and in stillborns. Twelve disorders accountfor about 85% of cases; their frequencies are presented in Table 12-2 .In the past few decades, the reported incidence of structural heart defects in newborns hasincreased owing to increased diagnostic sensitivity (especially cross-sectional andDoppler * TABLE 12-2 -- Frequencies of Congenital Cardiac Malformations Incidence per Million LiveMalformation Births %Ventricular septal defect 4482 42Atrial septal defect 1043 10Pulmonary stenosis 836 8 Patent ductus arteriosus 781 7 Tetralogy of Fallot 577 5 Coarctation of aorta 492 5
* TABLE 12-2 -- Frequencies of Congenital Cardiac Malformations Incidence per Million LiveMalformation Births %Atrioventricular septal defect 396 4 Aortic stenosis 388 4 Transposition of great arteries 388 4 Truncus arteriosus 136 1 Total anomalous pulmonary venous connection 120 1 Tricuspid atresia 118 1 TOTAL 9757Source: Hoffman JIE, Kaplan S: The incidence of congenital heart disease. J Am CollCardiol 39:1890, 2002.*Presented as upper quartile of 44 published studies. Percentages do not add to 100% owing to rounding.echocardiography and magnetic resonance imaging). The enhanced resolving power ofnoninvasive methods should prove particularly useful in the study of familial structuraldefects, because apparently unaffected relatives can be evaluated for subclinical evidenceof anomalies.Etiology and Pathogenesis.The etiology of congenital malformations in general was discussed in Chapter 10 . Wetherefore confine our remarks to factors of particular relevance to congenital cardiacmalformations.Congenital heart defects are caused by developmental abnormalities. However, the genesthat may be involved in these defects have been identified in only a minority ofconditions. In fact, well-defined genetic or environmental influences are identifiable inonly about 10% of cases of congenital heart disease, but the understanding of probablegenetic links is increasing. The obvious role of genetic factors in some cases isdemonstrated by the occurrence of familial forms of congenital heart disease and by anassociation of congenital cardiac malformations with certain chromosomal abnormalities(e.g., trisomies 13, 15, 18, and 21, and the Turner syndrome). Indeed, a congenital heartdefect in a parent or preceding sibling is the greatest risk factor for developing a cardiacmalformation. Trisomy 21 (associated with Down syndrome) is the most common knowngenetic cause of congenital heart disease. Environmental factors, such as congenital
rubella infection or teratogens, are responsible for some additional cases. Multifactorialgenetic, environmental, and maternal factors probably account for the remaining majorityof cases in which a cause is not apparent.The growing understanding of the genetics of congenital heart disease has also led to therecognition that powerful disease modifiers must exist. There is wide variation in the 565nature and severity of lesions in patients with identical genetic abnormalities. Thissuggests that altering key environmental or maternal factors could modify disease inhigh-risk individuals, whether or not the disease is caused by a distinct geneticabnormality. For instance, this type of strategy has resulted in marked reduction in neuraltube defects by increasing maternal dietary folate. Genetics of Cardiac Development and Congenital Heart Disease.Composed of diverse cell lineages, the heart is among the first organs to form andfunction in vertebrate embryos. Cardiac morphogenesis involves a myriad of genes and istightly regulated to ensure an effective embryonic circulation. Key steps involvespecification of cardiac cell fate, morphogenesis and looping of the heart tube,segmentation and growth of the cardiac chambers, cardiac valve formation, andconnection of the great vessels to the heart. The genetic regulation of heart formation has been widely studied in model organisms, including chick, frog, mouse, and zebrafish.In recent years, the zebrafish, an organism that is transparent and has externalfertilization, a brief generation time, and no requirement of a functional cardiovascularsystem for survival during embryogenesis, has permitted detailed genetic analysis of bothnormal development and cardiac defects. The molecular pathways controlling cardiac  development provide a foundation for understanding the basis of some congenital heartdefects and can be used to reveal pathways and interactions important in human disease. Several congenital heart diseases are associated with mutations in transcription factors.For example, mutation of the gene that encodes the transcription factor, TBX5, has beenshown to cause the ASD and VSD observed in the Holt-Oram syndrome, a rarehereditary condition associated with heart, arm, and hand defects. Another gene, encoding the transcription factor NKX2.5, causes nonsyndromic (isolated) ASD inhumans when one copy is missing. This gene is the human counterpart of the tinman geneof the fruit fly (so named because, like the Tin Man in The Wizard of Oz, fruit flyembryos lacking both copies of tinman have no hearts). Nevertheless, most ASDs do nothave an identifiable genetic etiology, and the mechanisms by which mutated transcriptionfactors cause clinically important heart defects are just beginning to be understood.Until recently, in most studies, defects were classified by their pathology; for example, allVSDs were considered as one group. A major advance has been to examine familialaggregation of defects based on presumed pathogenesis. Since some cardiac structuresshare developmental pathways, anatomically and clinically distinct lesions may be related
by a common genetic defect. Thus, the occurrence of distinct defects in the same familyremains consistent with a genetic model. Defects unrelated by pathogenesis wouldrequire a different interpretation.Developmental errors in mesenchymal tissue migration exemplify the concept thatdistinct syndromes share a common pathogenesis. Included in this category is a widerange of anomalies of the outflow tract, some due to failure of fusion and others due tofailure of septation. These lesions include isolated interruption of the aortic arch,persistent truncus arteriosus (failure of separation of aorta and pulmonary arteries), andtetralogy of Fallot (malalignment of aorta and pulmonary artery with the ventricles).Comprising 15% of congenital heart defects, outflow tract defects may be caused by theabnormal development of neural crest-derived cells, whose migration into the embryonicheart is required for formation of the outflow tracts of the heart ( Fig. 12-5 ).Considerable progress has been made during the past few years in identifying a region ofchromosome 22 that has a major role in development of the conotruncus, the branchialarches, and the face. Chromosome 22q11.2 deletions are seen in 15% to 50% of thesedisorders, rendering this abnormality a common genetic cause of congenital heart defects(see also Chapter 5 ). This condition includes developmental anomalies of the fourthbranchial arch and derivatives of the third and fourth pharyngeal pouches. Hypoplasia ofthe thymus and parathyroids causes immune deficiency (Di George syndrome, Chapter5 ) and hypocalcemia.Other common mechanisms of congenital heart disease include extracellular matrixabnormalities and situs and looping defects. The endocardial cushions have received themost attention as an area where defects in cell-cell and cell-extracellular matrixinteractions might produce malformations, as evidenced by a high frequency ofendocardial cushion defects and atrioventricular septal defects in Down syndrome. Situsand looping defects may arise from single genes that have a major effect on determininglaterality.Clinical Features.The varied structural anomalies in congenital heart disease fall primarily into three majorcategories: • Malformations causing a left-to-right shunt • Malformations causing a right-to-left shunt • Malformations causing an obstruction.A shunt is an abnormal communication between chambers or blood vessels. Abnormalchannels permit the flow of blood from left to right or the reverse, depending on pressurerelationships. When blood from the right side of the heart enters the left side (right-to-leftshunt), a dusky blueness of the skin and mucous membranes (cyanosis) results becausethere is diminished pulmonary blood flow, and poorly oxygenated blood enters thesystemic circulation (called cyanotic congenital heart disease). The most importantexamples of right-to-left shunts are tetralogy of Fallot, transposition of the great arteries,persistent truncus arteriosus, tricuspid atresia, and total anomalous pulmonary venous
connection. Moreover, with right-to-left shunts, bland or septic emboli arising inperipheral veins can bypass the normal filtration action of the lungs and thus directlyenter the systemic circulation (paradoxical embolism); brain infarction and abscess arepotential consequences. Clinical findings frequently associated with severe, long-standingcyanosis include clubbing of the tips of the fingers and toes (hypertrophicosteoarthropathy) and polycythemia.In contrast, left-to-right shunts (such as ASD, VSD, and patent ductus arteriosus [PDA])increase pulmonary blood flow and are not initially associated with cyanosis. However,they expose the postnatal, low-pressure, low-resistance pulmonary circulation toincreased pressure and/or volume, which can result in right ventricular hypertrophy and,potentially, failure. Shunts associated with increased pulmonary blood flow includeASDs; shunts associated with both increased pulmonary blood flow and pressure includeVSDs and PDA. The muscular pulmonary arteries (<1 mm diameter) first respond toincreased pressure by medial hypertrophy 566Figure 12-5 Cardiac defects related to neural crest abnormalities. A, Biologic pathways for cardiac neuralcrest-related defects. B, Disease phenotypes. DORV, double-outlet right ventricle; TGA, transposition of
the great arteries. (Reproduced by permission from Chien KR: Genomic circuits and the integrative biologyof cardiac diseases. Nature 407:227, 2000.)and vasoconstriction, which maintains relatively normal distal pulmonary capillary andvenous pressures, helping to prevent pulmonary edema. Prolonged pulmonary arterialvasoconstriction, however, stimulates the development of irreversible obstructive intimallesions. Eventually pulmonary vascular resistance increases toward systemic levels,thereby reversing the shunt to right-to-left with unoxygenated blood in the systemiccirculation (late cyanotic congenital heart disease, or Eisenmenger syndrome).Once significant irreversible pulmonary hypertension develops, the structural defects ofcongenital heart disease are considered irreparable. The secondary pulmonary vascularchanges can eventually lead to the patients death. This is the rationale for earlyintervention, either surgical or nonsurgical.Some developmental anomalies of the heart (e.g., coarctation of the aorta, aortic valvularstenosis, and pulmonary valvular stenosis) produce obstructions to flow because ofabnormal narrowing of chambers, valves, or blood vessels and therefore are calledobstructive congenital heart disease. A complete obstruction is called an atresia. In somedisorders (e.g., tetralogy of Fallot), an obstruction (pulmonary stenosis) is associated witha shunt (right-to-left through a VSD).In congenital heart disease, altered hemodynamics usually cause cardiac dilation orhypertrophy (or both). A decrease in the volume and muscle mass of a cardiac chamber iscalled hypoplasia if it occurs before birth and atrophy if it develops after birth.LEFT-TO-RIGHT SHUNTSThe diseases in this group cause cyanosis several months or years after birth. The mostcommonly encountered left-to-right shunts include atrial septal defects, ventricular septaldefects, patent (or persistent) ductus arteriosus, and AV septal defects, and are shown inFigure 12-6 . (For ease of recall, note that each is designated by an abbreviationcontaining the letter "D" as in ASD, VSD, PDA, and AVSD). 567
Figure 12-6 Schematic diagram of congenital left-to-right shunts. A, Atrial septal defect (ASD). B,Ventricular septal defect (VSD). With VSD the shunt is left-to-right, and the pressures are the same in bothventricles. Pressure hypertrophy of the right ventricle and volume hypertrophy of the left ventricle aregenerally present. C, Patent ductus arteriosus (PDA). D, Atrioventricular septal defect (AVSD). E, LargeVSD with irreversible pulmonary hypertension. The shunt is right-to-left (shunt reversal). Volumehypertrophy and pressure hypertrophy of the right ventricle are present. Arrow indicates the direction ofblood flow. The right ventricular pressure is now sufficient to yield a right-to-left shunt (Ao, aorta; LA, leftatrium; LV, left ventricle; PT, pulmonary trunk; RA, right atrium; RV, right ventricle.)Atrial Septal DefectAn ASD is an abnormal opening in the atrial septum that allows communication of bloodbetween the left and right atria (not to be confused with a patent foramen ovale, presentin up to one-third of normal individuals). ASD is the most common congenital cardiacanomaly and is usually asymptomatic until adulthood (see Fig. 12-6A ).Morphology.The three major types of ASDs, classified according to their location in the septum, aresecundum, primum, and sinus venosus. The secundum ASD, accounting for
approximately 90% of all ASDs, is a defect located at and resulting from a deficient orfenestrated oval fossa. ASDs are usually isolated (i.e., not associated with otheranomalies). When associated with another defect, such as tetralogy of Fallot, the otherdefect is usually hemodynamically dominant. The atrial aperture may be of any size andmay be single, multiple, or fenestrated. Primum anomalies (5% of ASDs) occur adjacentto the AV valves and are usually associated with a cleft anterior mitral leaflet. Thiscombination is known as a partial AV septal defect (see later). Sinus venosus defects(5%) are located near the entrance of the superior vena cava. They are commonlyaccompanied by anomalous connections of right pulmonary veins to the superior venacava or right atrium.ASDs result in a left-to-right shunt, largely because pulmonary vascular resistance isconsiderably less than systemic vascular resistance and because the compliance(distensibility) of the right ventricle is much greater than that of the left. Pulmonary bloodflow may be 2 to 4 times normal. Although some neonates may be in profound CHF,most isolated ASDs are well tolerated and usually do not become symptomatic before age30. A murmur is often present as a result of excessive flow through the pulmonary valve.Eventually, volume hypertrophy of the right atrium and right ventricle develops.Irreversible pulmonary hypertension develops in fewer than 10% of subjects with anisolated uncorrected ASD. The objectives of surgical closure of an ASD are the reversalof the hemodynamic abnormalities and the prevention of complications, including heartfailure, paradoxical embolization, and irreversible pulmonary vascular disease. Mortalityis low, and postoperative survival is comparable to that of a normal population. 568Figure 12-7 Gross photograph of a ventricular septal defect (membranous type); defect denoted by arrow.(Courtesy of William D. Edwards, M.D., Mayo Clinic, Rochester, MN.)
Ventricular Septal DefectIncomplete closure of the ventricular septum, allowing free communication and thus ashunt from left to right ventricles, is the most common congenital cardiac anomaly (seeFig. 12-6B ). Frequently, VSD is associated with other structural defects, such astetralogy of Fallot. About 30% occur as isolated anomalies. Depending on the size of thedefect, it may produce difficulties virtually from birth or, with smaller lesions, may notbe recognized until later or may even spontaneously close.Morphology.VSDs are classified according to size and location. Most are about the size of the aorticvalve orifice. About 90% involve the region of the membranous septum (membranousVSD) ( Fig. 12-7 ). The remainder lie below the pulmonary valve (infundibular VSD) orwithin the muscular septum. Although most often single, VSDs in the muscular septummay be multiple (so-called Swiss-cheese septum).The functional significance of a VSD depends on the size of the defect and the presenceof other anomalies. About 50% of small muscular VSDs close spontaneously, and theremainder are generally well tolerated for years. Large defects are usually membranousor infundibular, and they generally remain patent and permit a significant left-to-rightflow. Right ventricular hypertrophy and pulmonary hypertension are present from birth.Over time, irreversible pulmonary vascular disease develops in virtually all patients withlarge unoperated VSDs, leading to shunt reversal, cyanosis, and death.Large defects may become manifest virtually at birth with signs of cardiac failureaccompanying the murmur. Surgical closure of asymptomatic VSDs is generally notattempted during infancy, in hope of spontaneous closure. Correction, however, isindicated at age 1 year with large defects, before obstructive pulmonary vascular diseasebecomes irreversible.Patent Ductus ArteriosusPatent (also called persistent) ductus arteriosus (PDA) results when the ductus arteriosusremains open after birth (see Fig 12-6C ). About 90% of PDAs occur as an isolatedanomaly. The remainder are most often associated with VSD, coarctation of the aorta, orpulmonary or aortic stenosis. The length and diameter of the ductus vary widely.Most often PDA does not produce functional difficulties at birth. Indeed, a narrow ductusmay have no effect on growth and development during childhood. Its existence, however,can generally be detected by a continuous harsh murmur, described as "machinery-like."Because the shunt is at first left-to-right, there is no cyanosis. Obstructive pulmonaryvascular disease eventually ensues, however, with ultimate reversal of flow and itsassociated consequences.There is general agreement that an isolated PDA should be closed as early in life as isfeasible. Conversely, preservation of ductal patency (by administering prostaglandin E)
assumes great importance in the survival of infants with various forms of congenital heartdisease with obstructed pulmonary or systemic blood flow, such as aortic valve atresia.Ironically, therefore, the ductus may be either life-threatening or life-saving.Atrioventricular Septal Defect (AVSD)AVSD (also called complete atrioventricular canal defect) results from abnormaldevelopment of the embryologic AV canal, in which the superior and inferior endocardialcushions fail to fuse adequately, resulting in incomplete closure of the AV septum andinadequate formation of the tricuspid and mitral valves (see Fig. 12-6D ). The two mostcommon forms are partial AVSD (consisting of a primum ASD and a cleft anterior mitralleaflet, causing mitral insufficiency) and complete AVSD (consisting of a large combinedAV septal defect and a large common AV valve—essentially a hole in the center of theheart). In the complete form, all four cardiac chambers freely communicate, inducingvolume hypertrophy of each. More than one-third of all patients with the complete AVSDhave Down syndrome. Surgical repair is possible.RIGHT-TO-LEFT SHUNTSThe diseases in this group cause cyanosis early in postnatal life. Although a VSD is themost common congenital cardiac malformation, tetralogy of Fallot constitutes the mostcommon form of cyanotic congenital heart disease. Other relatively frequentlyencountered anomalies in this category include transposition of the great arteries,tricuspid atresia, total anomalous pulmonary venous connection, and truncus arteriosus(note that each entity begins with the letter "T"). Tetralogy of Fallot and transposition ofthe great arteries are illustrated schematically in Figure 12-8 .Tetralogy of FallotThe four features of the tetralogy of Fallot are (1) VSD, (2) obstruction to the rightventricular outflow tract (subpulmonary stenosis), (3) an aorta that overrides the VSD,and (4) right ventricular 569
Figure 12-8 Schematic diagram of the most important right-to-left shunts (cyanotic congenital heartdisease). A, Tetralogy of Fallot. Diagrammatic representation of anatomic variants, indicating that thedirection of shunting across the VSD depends on the severity of the subpulmonary stenosis. Arrowsindicate the direction of the blood flow. B, Transposition of the great vessels with and without VSD. (Ao,aorta; LA, left atrium; LV, left ventricle; PT, pulmonary trunk; RA, right atrium; RV, right ventricle.)(Courtesy of William D. Edwards, M.D., Mayo Clinic, Rochester, MN.)hypertrophy (see Fig. 12-8A ). All of the features result embryologically fromanterosuperior displacement of the infundibular septum. Even untreated, some patientswith tetralogy of Fallot often survive into adult life (in a large series of untreated patientswith this condition, 10% were alive at 20 years and 3% at 40 years). The clinicalconsequences of tetralogy of Fallot depend primarily on the severity of subpulmonarystenosis.
Morphology.The heart is often enlarged and may be "boot-shaped" owing to marked right ventricularhypertrophy, particularly of the apical region. The VSD is usually large and approximatesthe diameter of the aortic orifice. The aortic valve forms the superior border of the VSD,thereby overriding the defect and both ventricular chambers. The obstruction to rightventricular outflow is most often due to narrowing of the infundibulum (subpulmonicstenosis) but is often accompanied by pulmonary valvular stenosis. Sometimes there iscomplete atresia of the pulmonary valve and variable portions of the pulmonary arteries,such that blood flow through a patent ductus or dilated bronchial arteries, or throughboth, is necessary for survival. Aortic valve insufficiency or ASD may also be present,and a right aortic arch is present in about 25% of cases.The severity of obstruction to right ventricular outflow determines the direction of bloodflow. If the subpulmonary stenosis is mild, the abnormality resembles an isolated VSD,and the shunt may be left-to-right, without cyanosis (so-called pink tetralogy). As theobstruction increases in severity, there is commensurately greater resistance to rightventricular outflow. As it approaches the level of systemic vascular resistance, right-to-left shunting predominates and, along with it, cyanosis (classic tetralogy of Fallot). Withincreasing severity of subpulmonic stenosis, the pulmonary arteries are progressivelysmaller and thinner walled (hypoplastic), and the aorta is progressively larger in diameter.As the child grows and the heart increases in size, the pulmonic orifice does not expandproportionally, making the obstruction progressively worse. Thus most infants withtetralogy are cyanotic from birth or soon thereafter. The subpulmonary stenosis, however,protects the pulmonary vasculature from pressure overload, and right ventricular failure israre because the right ventricle is decompressed into the left ventricle and aorta.Complete surgical repair is possible for classic tetralogy of Fallot but is morecomplicated for patients with pulmonary atresia and dilated bronchial arteries.Transposition of the Great Arteries (TGA)Transposition of the great arteries implies ventriculoarterial discordance, such that theaorta arises from the right ventricle and the pulmonary artery emanates from the leftventricle (see Fig. 12-8B) . The AV connections are normal (concordant), with rightatrium joining right ventricle and left atrium emptying into left ventricle.The essential embryologic defect in complete TGA is abnormal formation of the truncaland aortopulmonary septa. The aorta arises from the right ventricle and lies anterior andto the right of the pulmonary artery ( Fig. 12-9 ); in contrast, in the normal heart, theaorta is posterior and to the left. The result is separation of the systemic and pulmonarycirculations, a condition incompatible with postnatal life unless a shunt exists foradequate mixing of blood. Patients with TGA and a VSD (about 35%) have a stableshunt. Those with only a patent foramen ovale or PDA (about 65%), however, haveunstable shunts that tend to close and therefore require immediate intervention to create ashunt (such as balloon atrial septostomy) within the first few days of life. Rightventricular hypertrophy becomes prominent because this chamber functions as the
systemic ventricle. Concurrently the left ventricle becomes thin-walled (atrophic) as itsupports the low-resistance pulmonary circulation.The outlook for infants with TGA depends on the degree of "mixing" of the blood, themagnitude of the tissue hypoxia, and the ability of the right ventricle to maintain thesystemic circulation. Without surgery, most patients die within the first months of life.Currently, most patients undergo a reparative operation (usually entailing transection and"switching" of the great arteries as well as of the coronary arteries) during the first severalweeks of life.Truncus ArteriosusThe persistent truncus arteriosus anomaly arises from a developmental failure ofseparation of the embryologic 570Figure 12-9 Transposition of the great arteries. (Courtesy of William D. Edwards, M.D., Mayo Clinic,Rochester, MN.)truncus arteriosus into the aorta and pulmonary artery. This results in a single great arterythat receives blood from both ventricles, accompanied by an underlying VSD, and thatgives rise to the systemic, pulmonary, and coronary circulations. Because blood from theright and left ventricles mixes, there is early systemic cyanosis as well as increasedpulmonary blood flow, with the danger of irreversible pulmonary hypertension.
Tricuspid AtresiaComplete occlusion of the tricuspid valve orifice is known as tricuspid atresia. It resultsembryologically from unequal division of the AV canal, and thus the mitral valve islarger than normal. This lesion is almost always associated with underdevelopment(hypoplasia) of the right ventricle. The circulation is maintained by a right-to-left shuntthrough an interatrial communication (ASD or patent foramen ovale). A VSD is alsopresent and affords communication between the left ventricle and the great artery thatarises from the hypoplastic right ventricle. Cyanosis is present virtually from birth, andthere is a high mortality in the first weeks or months of life.Total Anomalous Pulmonary Venous Connection (TAPVC)TAPVC, in which no pulmonary veins directly join the left atrium, resultsembryologically when the common pulmonary vein fails to develop or becomes atretic,causing primitive systemic venous channels from the lungs to remain patent. TAPVCusually drains into the left innominate vein or to the coronary sinus. Either a patentforamen ovale or an ASD is always present, allowing pulmonary venous blood to enterthe left atrium. Consequences of TAPVC include volume and pressure hypertrophy of theright atrium and right ventricle, and these chambers and the pulmonary trunk are dilated.The left atrium is hypoplastic, but the left ventricle is usually normal in size. Cyanosismay be present, owing to mixing of well-oxygenated and poorly oxygenated blood at thesite of anomalous pulmonary venous connection and a large right-to-left shunt at theASD.OBSTRUCTIVE CONGENITAL ANOMALIESCongenital obstruction to blood flow may occur at the level of the heart valves or withina great vessel. Relatively common examples include stenosis of the pulmonary valve,stenosis or atresia of the aortic valve, and coarctation of the aorta. Obstruction can alsooccur within a chamber, as with subpulmonary stenosis in tetralogy of Fallot.Coarctation of the AortaCoarctation (narrowing, constriction) of the aorta ranks high in frequency among thecommon structural anomalies. Males are affected twice as often as females, althoughfemales with Turner syndrome frequently have a coarctation (see Chapter 5 ). Twoclassic forms have been described: (1) an "infantile" form with tubular hypoplasia of theaortic arch proximal to a PDA that is often symptomatic in early childhood and (2) an"adult" form in which there is a discrete ridge-like infolding of the aorta, just opposite theclosed ductus arteriosus (ligamentum arteriosum) distal to the arch vessels ( Fig. 12-10 ).Encroachment on the aortic lumen is of variable severity, sometimes leaving only a smallchannel and at other times producing only minimal narrowing. Clinical manifestationsdepend almost entirely on the severity of the narrowing and the patency of the ductusarteriosus. Although coarctation of the aorta may occur as a solitary defect, it isaccompanied by a bicuspid aortic valve in 50% of cases and may also be associated withcongenital aortic stenosis, ASD, VSD, mitral regurgitation, and berry aneurysms of thecircle of Willis.
Coarctation of the aorta with a PDA usually leads to manifestations early in life; indeed,it may cause signs and symptomsFigure 12-10 Diagram showing coarctation of the aorta with and without PDA. (Ao, aorta; LA, left atrium;LV, left ventricle; PT, pulmonary trunk; RA, right atrium; RV, right ventricle; PDA, persistent ductusarteriosus.) (Courtesy of William D. Edwards, M.D., Mayo Clinic, Rochester, MN.) 571immediately after birth. Many infants with this anomaly do not survive the neonatalperiod without surgical or catheter-based intervention. In such cases, the delivery ofunsaturated blood through the ductus arteriosus produces cyanosis localized to the lowerhalf of the body.The outlook is different with coarctation of the aorta without a PDA, unless it is verysevere. Most of the children are asymptomatic, and the disease may go unrecognizeduntil well into adult life. Typically there is hypertension in the upper extremities, butthere are weak pulses and a lower blood pressure in the lower extremities, associated withmanifestations of arterial insufficiency (i.e., claudication and coldness). Particularlycharacteristic in adults is the development of collateral circulation between theprecoarctation arterial branches and the postcoarctation arteries through enlargedintercostal and internal mammary arteries and the radiographically visible erosions("notching") of the undersurfaces of the ribs.With all significant coarctations, murmurs are often present throughout systole.Sometimes a thrill may be present, and there is cardiomegaly owing to left ventricularhypertrophy. With uncomplicated coarctation of the aorta, surgical resection and end-to-
end anastomosis or replacement of the affected aortic segment by a prosthetic graft yieldsexcellent results.Pulmonary Stenosis and AtresiaThis relatively frequent malformation constitutes an obstruction at the pulmonary valve,which may be mild to severe. It may occur as an isolated defect, or as part of a morecomplex anomaly—either tetralogy of Fallot or TGA. Right ventricular hypertrophyoften develops, and there is sometimes poststenotic dilation of the pulmonary arteryowing to jetstream injury to the wall. With coexistent subpulmonary stenosis (as intetralogy of Fallot), the high ventricular pressure is not transmitted to the valve, and thepulmonary trunk is not dilated and may in fact be hypoplastic. When the valve is entirelyatretic, there is no communication between the right ventricle and lungs, and so theanomaly is commonly associated with a hypoplastic right ventricle and an ASD; flowenters the lungs through a PDA. Mild stenosis may be asymptomatic and compatible withlong life. The smaller the valvular orifice, the more severe is the cyanosis and the earlierits appearance.Aortic Stenosis and AtresiaHere we are concerned with the narrowings and obstructions of the aortic valve presentfrom birth. There are three major types of stenosis: valvular, subvalvular, andsupravalvular. With valvular aortic stenosis, the cusps may be hypoplastic (small),dysplastic (thickened, nodular), or abnormal in number (usually acommissural orunicommissural). In severe congenital aortic stenosis or atresia, obstruction of the leftventricular outflow tract leads to underdevelopment (hypoplasia) of the left ventricle andascending aorta. There may be dense, porcelain-like left ventricular endocardialfibroelastosis (see section on restrictive cardiomyopathy, later in this chapter). The ductusmust be open to allow blood flow to the aorta and coronary arteries. This constellation offindings, called the hypoplastic left heart syndrome, is nearly always fatal in the firstweek of life, when the ductus closes. Less severe degrees of congenital aortic stenosismay be compatible with long survival. Cogenital aortic stenosis is an isolated lesion in80% of cases.Subaortic stenosis represents either a thickened ring (discrete type) or collar (tunnel type)of dense endocardial fibrous tissue below the level of the cusps. Supravalvular aorticstenosis represents an inherited form of aortic dysplasia in which the ascending aorticwall is greatly thickened, causing luminal constriction. It may be related to adevelopmental disorder affecting multiple organ systems, including the vascular system,which includes hypercalcemia of infancy (Williams syndrome). Mutations in the elastingene cause supravalvular aortic stenosis, probably via disruption of an important elastin-smooth muscle cell interactions in arterial morphogenesis. A prominent systolic murmur is usually detectable and sometimes a thrill, which does notdistinguish the site of stenosis. Pressure hypertrophy of the left ventricle develops as aconsequence of the obstruction to blood flow. In general, congenital stenoses are welltolerated unless very severe. Mild stenoses can be managed conservatively with antibiotic
prophylaxis and avoidance of strenuous activity, but the threat of sudden death withexertion always looms.Ischemic Heart DiseaseIschemic heart disease (IHD) is the generic designation for a group of closely relatedsyndromes resulting from myocardial ischemia—an imbalance between the supply(perfusion) and demand of the heart for oxygenated blood. Ischemia comprises not onlyinsufficiency of oxygen, but also reduced availability of nutrient substrates andinadequate removal of metabolites (see Chapter 1 ). Isolated hypoxemia (i.e., diminishedtransport of oxygen by the blood) induced by cyanotic congenital heart disease, severeanemia, or advanced lung disease is less deleterious than ischemia because perfusion(including metabolic substrate delivery and waste removal) is maintained.In more than 90% of cases, the cause of myocardial ischemia is reduction in coronaryblood flow due to atherosclerotic coronary arterial obstruction. Thus, IHD is oftentermed coronary artery disease (CAD) or coronary heart disease. In most cases, there isa long period (decades) of silent, slowly progressive, coronary atherosclerosis beforethese disorders become manifest. Thus, the syndromes of IHD are only the latemanifestations of coronary atherosclerosis that probably began during childhood oradolescence (see Chapter 11 ).The clinical manifestations of IHD can be divided into four syndromes: • Myocardial infarction (MI), the most important form of IHD, in which the duration and severity of ischemia is sufficient to cause death of heart muscle. • Angina pectoris, in which the ischemia is less severe and does not cause death of cardiac muscle. Of the three variants—stable angina, Prinzmetal angina, and unstable angina—the latter is the most threatening as a frequent harbinger of MI. • Chronic IHD with heart failure. • Sudden cardiac death. 572As will be discussed in more detail later, acute myocardial infarction, unstable angina,and sudden cardiac death are sometimes referred to as acute coronary syndromes.Certain conditions aggravate ischemia through either an increase in cardiac energydemand (e.g., hypertrophy) or by diminished availability of blood or oxygen due tolowered systemic blood pressure (e.g., shock) or hypoxemia as discussed above.Moreover, increased heart rate not only increases demand through more contractions perunit time but also decreases supply (by decreasing the relative time spent in diastole—when coronary perfusion occurs).The risk of an individual developing detectable IHD depends in part on the number,distribution, and structure of atheromatous plaques, and the degree of narrowing theycause. However, the clinical manifestations of IHD are not entirely predicted by these
anatomic observations of disease burden. Moreover, there is an extraordinarily broadspectrum of the expression of disease from elderly individuals with extensive coronaryatherosclerosis who have never had a symptom, to the previously asymptomatic youngadult in whom modestly obstructive disease comes unexpectedly to medical attention as aresult of acute MI or sudden cardiac death. The reasons for clinical heterogeneity of thedisease are complex, but the often precipitous and variable onset and natural historylargely depend on the pathologic basis of the so-called acute coronary syndromes of IHD(comprising unstable angina, acute MI, and sudden death). The acute coronarysyndromes are frequently initiated by an unpredictable and abrupt conversion of a stableatherosclerotic plaque to an unstable and potentially life-threatening atherothromboticlesion through superficial erosion, ulceration, fissuring, rupture, or deep hemorrhage,usually with superimposed thrombosis. For purposes of simplicity, this spectrum ofalteration in atherosclerotic lesions will be termed either plaque disruption or acuteplaque change.Epidemiology.IHD in its various forms is the leading cause of death for both males and females in theUnited States and other industrialized nations. Each year, nearly 500,000 Americans dieof IHD. Awesome as these numbers may be, they represent an improvement over thosethat prevailed several decades ago. Since its peak in 1963, the overall death rate fromIHD has fallen in the United States by approximately 50%. This decline is a spectacularachievement that has resulted primarily from (1) prevention achieved by modification ofdeterminants of risk, such as smoking, elevated blood cholesterol, hypertension, and asedentary lifestyle, and (2) diagnostic and therapeutic advances, allowing earlier,  more effective, and safer treatments, including new medications, coronary care units,thrombolysis for MI, percutaneous transluminal coronary angioplasty (PTCA),endovascular stents, coronary artery bypass graft (CABG) surgery, and improved controlof arrhythmias. Additional risk reduction may potentially be associated with  maintenance of normal blood glucose levels in diabetic patients, control of obesity, andaspirin prophylaxis in middle-aged men. Nevertheless, continuing this progress in the 21st century will be particularly challenging, in view of a predicted increased longevityof "baby boomers" and others. The anticipated doubling of the population of individualsover age 65 by 2050 is expected to contribute to a dramatic increase in IHD andassociated deaths.Pathogenesis.The dominant influence in the causation of the IHD syndromes is diminished coronaryperfusion relative to myocardial demand, owing largely to a complex and dynamicinteraction among fixed atherosclerotic narrowing of the epicardial coronary arteries,intraluminal thrombosis overlying a disrupted atherosclerotic plaque, plateletaggregation, and vasospasm. The individual elements and their interactions are discussedbelow.More than 90% of patients with IHD have atherosclerosis of one or more of the coronaryarteries. The clinical manifestations of coronary atherosclerosis are generally due to
progressive encroachment of the lumen leading to stenosis (chronic, "fixed" obstructions)or to acute plaque disruption with thrombosis (generally both sudden and dynamic),which compromises blood flow. A fixed obstructive lesion of 75% or greater (i.e., only25% or less lumen remaining) generally causes symptomatic ischemia induced byexercise; with this degree of obstruction, the augmented coronary flow provided bycompensatory vasodilation is no longer sufficient to meet even moderate increases inmyocardial demand. A 90% stenosis can lead to inadequate coronary blood flow even atrest. Slowly developing occlusions may stimulate collateral vessels over time, whichprotect against distal myocardial ischemia and infarction even with an eventual high-grade stenosis.Although only a single major coronary epicardial trunk may be affected, two or all three—lateral anterior descending (LAD), left circumflex (LCX), and right coronary artery(RCA)—are often involved. Clinically significant stenosing plaques may be locatedanywhere within these vessels but tend to predominate within the first several centimetersof the LAD and LCX and along the entire length of the RCA. Sometimes the majorsecondary epicardial branches are also involved (i.e., diagonal branches of the LAD,obtuse marginal branches of the LCX, or posterior descending branch of the RCA), butatherosclerosis of the intramural branches is rare. However, as mentioned above, theonset of symptoms and prognosis of IHD depend not only on the extent and severity offixed, chronic anatomic disease, but also critically on dynamic changes in coronaryplaque morphology (discussed below).Role of Acute Plaque Change.In most patients the myocardial ischemia underlying unstable angina, acute MI, and (inmany cases) sudden cardiac death is precipitated by abrupt plaque change followed bythrombosis ( Fig. 12-11 and Fig. 12-12 ). Thus, these important manifestations are   termed the acute coronary syndromes. Most often, the initiating event is disruption ofpreviously only partially stenosing plaques with any of the following: • Rupture/fissuring, exposing the highly thrombogenic plaque constituents • Erosion/ulceration, exposing the thrombogenic subendothelial basement membrane to blood • Hemorrhage into the atheroma, expanding its volume.The events that trigger abrupt changes in plaque configuration and superimposedthrombosis are complex and poorly understood. Influences, both intrinsic (e.g., plaquestructure and composition) and extrinsic (e.g., blood pressure, platelet reactivity) areimportant. Acute alterations in plaque imply the inability of a plaque to withstand  mechanical stresses.The structure and composition of a plaque are dynamic and contribute to a propensity todisruption. Plaques that contain large areas of foam cells and extracellular lipid, and thosein which the fibrous caps are thin or contain few smooth muscle cells or have clusters ofinflammatory cells, are more likely to rupture, and are therefore called "vulnerableplaques." Fissures
573frequently occur at the junction of the fibrous cap and the adjacent normal plaque-freearterial segment, a location at which the blood flow-inducing mechanical stresses withinthe plaque are highest and the fibrous cap is thinnest. It is now recognized that the fibrouscap can undergo continuous remodeling. The balance of synthetic and degradativeactivity of collagen, the major structural component of the fibrous cap, accounts for itsmechanical strength and determines plaque stability and prognosis. Collagen is producedby smooth muscle cells and degraded by the action of metalloproteinases, enzymeselaborated by macrophages in atheroma. Thus, there is considerable evidence thatinflammation destabilizes the mechanical integrity of plaques (see below). Moreover,drugs such as statins (inhibitors of HMG Co-A reductase, a key enzyme in the synthesisof cholesterol) that reduce clinical events associated with IHD, are thought to stabilizeplaques by their lipid-lowering effect, as well as by reducing plaque inflammation. Influences extrinsic to plaque are also important. Adrenergic stimulation can elevatephysical stresses on the plaque through systemic hypertension or local vasospasm.Indeed, the adrenergic stimulation associated with awakening and arising induces apronounced circadian periodicity for the time of onset of acute MI, with a peak incidencebetween 6 a.m. and 12 noon, concurrent with a surge in blood pressure and immediatelyfollowing heightened platelet reactivity. Intense emotional stress can also contribute toplaque disruption; this is most dramatically illustrated by the marked increase in theincidence of sudden death that is associated with natural or other disasters such asearthquakes and the September 11, 2001 attacks in New York and Washington, DC. It is now recognized that the preexisting culprit lesion in patients who developmyocardial infarction and other acute coronary syndromes is not necessarily a severelystenotic and hemodynamically significant lesion prior to its acute change. Pathologic andclinical studies show that plaques that undergo abrupt disruption leading to coronaryocclusion often are those that previously produced only mild to moderate luminalstenosis. Approximately two thirds of plaques that rupture with subsequent occlusivethrombosis caused occlusion of only 50% or less before plaque rupture, and 85% hadinitial
Figure 12-11 Atherosclerotic plaque rupture. A, Plaque rupture without superimposed thrombus, in patientwho died suddenly. B, Acute coronary thrombosis superimposed on an atherosclerotic plaque with focaldisruption of the fibrous cap, triggering fatal myocardial infarction. C, Massive plaque rupture withsuperimposed thrombus, also triggering a fatal myocardial infarction (special stain highlighting fibrin inred). In both A and B, an arrow points to the site of plaque rupture. (B, reproduced from Schoen FJ:Interventional and Surgical Cardiovascular Pathology: Clinical Correlations and Basic Principles.Philadelphia, W.B. Saunders, 1989, p. 61.)stenosis less than 70%. Thus, the worrisome conclusion is that a rather large number of now asymptomatic adults in the industrial world have a real but unpredictable risk of acatastrophic coronary event. Regrettably, it is presently impossible to reliably predictplaque disruption or subsequent thrombosis in an individual patient.Accumulating evidence indicates that plaque disruption and the ensuing plateletaggregation and intraluminal thrombosis are common, repetitive, and often clinicallysilent complications of atheroma. Moreover, healing of subclinical plaque disruption andoverlying thrombosis is an important mechanism of growth of atherosclerotic lesions.Role of Inflammation.Inflammatory processes play important roles at all stages of atherosclerosis, from itsinception to the development of complications. The establishment of the initial lesion  requires the interaction between endothelial cells and circulating leukocytes, leading tothe accumulation of T cells and macrophages in the arterial wall. Entry of leukocytes intothe wall is a consequence of the release of chemokines by endothelial cells, and theincreased expression of adhesion proteins (ICAM-1, VCAM-1, E-selectin and P-selectin)in these cells. T cells located in the arterial wall produce cytokines such as TNF, IL-6 andIFN-γ that stimulate endothelial cells and activate macrophages, which become loadedwith oxidized LDL. At later stages of atherosclerosis, destabilization and rupture of theplaque may involve the secretion of metalloproteinases by macrophages. These enzymes weaken the plaque by digesting collagen at the fibrous cap or the shoulder of thelesion.Because of the important role of inflammation in the pathogenesis of atherosclerosis,several proteins involved in inflammation may serve as potential markers ofatherosclerosis. C-reactive protein (CRP), an acute phase reactant made in the liver, hasbeen suggested as a predictor of risk of coronary heart disease. In some, but not all,  studies CRP predicts risk independently from risk estimates provided by serum lipidlevels. It could be used to estimate the risk of myocardium infarct in patients with   [52A]angina, and the risk of new infarcts in patients who are infarct survivors.Role of Coronary Thrombus.As mentioned above, partial or total thrombosis associated with a disrupted plaque iscritical
574to the pathogenesis of the acute coronary syndromes. In the most serious form, acutetransmural MI (see later for distinction of transmural vs. subendocardial infarcts),thrombus superimposed on a disrupted but previously only partially stenotic plaqueconverts it to a total occlusion. In contrast, with unstable angina, acute subendocardialinfarction, or sudden cardiac death, the extent of luminal obstruction by thrombosis isusually incomplete (mural thrombus), and it may wax and wane with time.Mural thrombus in a coronary artery can also embolize. Indeed, small fragments ofthrombotic material in the distal intramyocardial circulation or microinfarcts may befound at autopsy of patients who have had unstable angina or sudden death. Finally,thrombus is a potent activator of multiple growth-related signals in smooth muscle cells,which can contribute to the growth of atherosclerotic lesions (see Chapter 11 ).Role of Vasoconstriction.Vasoconstriction compromises lumen size, and, by increasing the local mechanicalforces, can potentiate plaque disruption. Vasoconstriction at sites of atheroma isstimulated by: (1) circulating adrenergic agonists, (2) locally released platelet contents,(3) impaired secretion of endothelial cell relaxing factors relative to contracting factors(e.g., endothelin) due to atheroma-associated endothelial dysfunction
Figure 12-12 Schematic representation of sequential progression of coronary artery lesion morphology,beginning with stable chronic plaque responsible for typical angina and leading to the various acutecoronary syndromes. (Modified and redrawn from Schoen FJ: Interventional and Surgical CardiovascularPathology: Clinical Correlations and Basic Principles. Philadelphia, W.B. Saunders Co., 1989, p. 63.)(see Chapter 11 ), and possibly (4) mediators released from perivascular inflammatorycells.To summarize ( Fig. 12-12 and Table 12-3 ), the acute coronary syndromes—angina,acute MI, and sudden death—share a common pathophysiologic basis in coronary
atherosclerotic plaque disruption and associated intraluminal platelet-fibrin thrombusformation. The critical consequence is downstream myocardial ischemia. Stable anginaresults from increases in myocardial oxygen demand that outstrip the ability of markedlystenosed coronary arteries to increase oxygen delivery but is not usually associated withplaque disruption. Unstable angina derives from a sudden change in plaque morphology,which induces partially occlusive platelet aggregation or mural thrombus, andvasoconstriction leading to severe but transient reductions in coronary blood flow. Insome cases, distal microinfarcts occur secondary to thromboemboli. In MI, acute plaquechange induces total thrombotic occlusion. Finally, sudden cardiac death frequentlyinvolves a coronary lesion in which disrupted plaque and often partial thrombus andpossibly embolus have led to regional myocardial ischemia that induces a fatalventricular arrhythmia. Each of these important syndromes is discussed in detail first.Then we turn to the important consequences in the myocardium. 575 TABLE 12-3 -- Coronary Artery Pathology in Ischemic Heart Disease PlaqueSyndrome Stenoses Disruption Plaque-Associated ThrombusStable angina >75% No NoUnstable angina Variable Frequent Nonocclusive, often with thromboemboliTransmural Variable Frequent Occlusivemyocardial infarctionSubendocardial Variable Variable Widely variable, may be absent,myocardial infarction partial/complete, or lysedSudden death Usually Frequent Often small platelet aggregates or thrombi severe and/or thromboemboliANGINA PECTORISAngina pectoris is a symptom complex of IHD characterized by paroxysmal and usuallyrecurrent attacks of substernal or precordial chest discomfort (variously described asconstricting, squeezing, choking, or knifelike) caused by transient (15 seconds to 15minutes) myocardial ischemia that falls short of inducing the cellular necrosis thatdefines infarction. There are three overlapping patterns of angina pectoris: (1) stable ortypical angina, (2) Prinzmetal or variant angina, and (3) unstable or crescendo angina.They are caused by varying combinations of increased myocardial demand and decreasedmyocardial perfusion, owing to fixed stenosing plaques, disrupted plaques, vasospasm,thrombosis, platelet aggregation, and embolization. Moreover, it is being increasingly
recognized that not all ischemic events are perceived by patients, even though suchevents may have adverse prognostic implications (silent ischemia).Stable angina, the most common form and therefore called typical angina pectoris,appears to be caused by the reduction of coronary perfusion to a critical level by chronicstenosing coronary atherosclerosis; this renders the heart vulnerable to further ischemiawhenever there is increased demand, such as that produced by physical activity,emotional excitement, or any other cause of increased cardiac workload. Typical anginapectoris is usually relieved by rest (thereby decreasing demand) or nitroglycerin, a strongvasodilator. Although the coronary arteries are usually maximally dilated by intrinsicregulatory influences, nitroglycerin also decreases cardiac work by dilating the peripheralvasculature. In particular instances, local vasospasm may contribute to the imbalancebetween supply and demand.Prinzmetal variant angina is an uncommon pattern of episodic angina that occurs at restand is due to coronary artery spasm. Usually there is an elevated ST segment on theelectrocardiogram (ECG), indicative of transmural ischemia. Although individuals withthis form of angina may well have significant coronary atherosclerosis, the anginalattacks are unrelated to physical activity, heart rate, or blood pressure. Prinzmetal anginagenerally responds promptly to vasodilators, such as nitroglycerin and calcium channelblockers.Unstable or crescendo angina refers to a pattern of pain that occurs with progressivelyincreasing frequency, is precipitated with progressively less effort, often occurs at rest,and tends to be of more prolonged duration. As discussed above, in most patients,unstable angina is induced by disruption of an atherosclerotic plaque with superimposedpartial (mural) thrombosis and possibly embolization or vasospasm (or both). Althoughthe ischemia that occurs in unstable angina falls precariously close to inducing clinicallydetectable infarction, unstable angina is often the prodrome of subsequent acute MI. Thusthis syndrome is sometimes referred to as preinfarction angina, and in the spectrum ofIHD, unstable angina lies intermediate between stable angina on the one hand and MI onthe other.MYOCARDIAL INFARCTION (MI)MI, also known as "heart attack," is the death of cardiac muscle resulting from ischemia.It is by far the most important form of IHD and alone is the leading cause of death in theUnited States and industrialized nations. About 1.5 million individuals in the UnitedStates suffer an acute MI annually and approximately one third of them die. At least250,000 people a year die of a heart attack before they reach the hospital.Transmural versus Subendocardial Infarction.Most myocardial infarcts are transmural, in which the ischemic necrosis involves the fullor nearly full thickness of the ventricular wall in the distribution of a single coronaryartery. This pattern of infarction is usually associated with coronary atherosclerosis, acuteplaque change, and superimposed thrombosis (as discussed previously). In contrast, a
subendocardial (nontransmural) infarct constitutes an area of ischemic necrosis limitedto the inner one third or at most one half of the ventricular wall; under somecircumstances, it may extend laterally beyond the perfusion territory of a single coronaryartery. As previously pointed out, the subendocardial zone is normally the least well-perfused region of myocardium and therefore is most vulnerable to any reduction incoronary flow. A subendocardial infarct can occur as a result of a plaque disruptionfollowed by coronary thrombus that becomes lysed before myocardial necrosis extendsacross the major thickness of the wall; in this case the infarct will be limited to thedistribution of one coronary artery with plaque change. However, subendocardial infarctscan also result from sufficiently prolonged and severe reduction in systemic bloodpressure, as in shock, often superimposed on chronic, otherwise noncritical, coronarystenoses. In cases of global hypotension, resulting subendocardial infarcts are usuallycircumferential or nearly so, rather than limited to the distribution of a single majorcoronary artery.Incidence and Risk Factors.The risk factors for atherosclerosis, the major underlying cause of IHD in general, arediscussed in Chapter 11 and are not reiterated here. Suffice it to say that MI may occur atvirtually any age, but the frequency rises progressively with increasing age and whenpredispositions 576to atherosclerosis are present, such as hypertension, cigarette smoking, diabetes mellitus,genetic hypercholesterolemia, and other causes of hyperlipoproteinemia. Nearly 10% ofmyocardial infarcts occur in people under age 40, and 45% occur in people under age 65.Blacks and whites are equally affected. Throughout life, men are at significantly greaterrisk of MI than women; the differential progressively declines with advancing age.Except for those having some predisposing atherogenic condition, women areremarkably protected against MI during the reproductive years. Nevertheless, thedecrease of estrogen following menopause can permit rapid development of coronaryartery disease (CAD), and IHD is the overwhelming cause of death in elderly women.Moreover, recent epidemiologic evidence suggests that postmenopausal hormonereplacement therapy does not protect women against MI. Pathogenesis.We now consider the basis for and subsequent consequences of myocardial ischemia,particularly as they relate to the typical transmural myocardial infarct.Coronary Arterial Occlusion.As discussed above, transmural acute MI results from a dynamic interaction amongseveral or all of the following—coronary atherosclerosis, acute atheromatous plaquechange (such as rupture), superimposed platelet activation, thrombosis, and vasospasm—resulting in an occlusive intracoronary thrombus overlying a disrupted plaque. In
addition, either increased myocardial demand (as with hypertrophy or tachycardia) orhemodynamic compromise (as with a drop in blood pressure) can worsen the situation.Recall also that collateral circulation may provide perfusion to ischemic zones from arelatively unobstructed branch of the coronary tree, bypassing the point of obstructionand protecting against the effects of an acute coronary occlusion.In the typical case of MI, the following sequence of events can be proposed: • The initial event is a sudden change in the morphology of an atheromatous plaque, that is, disruption—manifest as intraplaque hemorrhage, erosion or ulceration, or rupture or fissuring. • Exposed to subendothelial collagen and necrotic plaque contents, platelets undergo adhesion, aggregation, activation, and release of potent aggregators including thromboxane A2 , serotonin, and platelet factors 3 and 4. • Vasospasm is stimulated by platelet aggregation and the release of mediators. • Other mediators activate the extrinsic pathway of coagulation, adding to the bulk of the thrombus. • Frequently within minutes, the thrombus evolves to completely occlude the lumen of the coronary vessel.The evidence for this sequence is compelling and derives from (1) autopsy studies ofpatients dying with acute MI, (2) angiographic studies demonstrating a high frequency ofthrombotic occlusion early after MI, (3) the high success rate of therapeutic thrombolysisand primary angioplasty, and (4) the demonstration of residual disrupted atheroscleroticlesions by angiography after thrombolysis. Although coronary angiography performedwithin 4 hours of the onset of apparent MI shows a thrombosed coronary artery in almost90% of cases, the observation of occlusion is seen in only about 60% when angiographyis delayed until 12 to 24 hours after onset. Thus with the passage of time, at least some occlusions appear to clear spontaneously owing to lysis of the thrombus or relaxation ofspasm or both.In approximately 10% of cases, transmural acute MI is not associated with atheroscleroticplaque thrombosis stimulated by disruption. In such situations, other mechanisms may beinvolved: • Vasospasm: isolated, intense, and relatively prolonged, with or without coronary atherosclerosis, perhaps in association with platelet aggregation (sometimes related to cocaine abuse). • Emboli: from the left atrium in association with atrial fibrillation, a left-sided mural thrombus or vegetative endocarditis; or paradoxical emboli from the right side of the heart or the peripheral veins which cross to the systemic circulation, through a patent foramen ovale, causing coronary occlusion. • Unexplained: cases without detectable coronary atherosclerosis and thrombosis may be caused by diseases of small intramural coronary vessels such as vasculitis, hematologic abnormalities such as hemoglobinopathies, amyloid deposition in
vascular walls, or other unusual disorders, such as vascular dissection and inadequate protection during cardiac surgery.Myocardial Response.The consequence of coronary arterial obstruction is the loss of critical blood supply tothe myocardium ( Fig. 12-13 ), which induces profound functional, biochemical, andmorphologic consequences. Occlusion of a major coronary artery results in ischemia and,potentially, cell death throughoutFigure 12-13 Postmortem angiogram showing the posterior aspect of the heart of a patient who died duringthe evolution of acute myocardial infarction, demonstrating total occlusion of the distal right coronaryartery by an acute thrombus (arrow) and a large zone of myocardial hypoperfusion involving the posteriorleft and right ventricles, as indicated by arrowheads, and having almost absent filling of capillaries, that is,less white. The heart has been fixed by coronary arterial perfusion with glutaraldehyde and cleared withmethyl salicylate, followed by intracoronary injection of silicone polymer. Photograph courtesy of Lewis L.Lainey. (Reproduced by permission from Schoen FJ: Interventional and Surgical CardiovascularPathology: Clinical Correlations and Basic Principles. Philadelphia, WB Saunders, 1989, p. 60.) 577the anatomic region supplied by that artery (called the area at risk), most pronounced inthe subendocardium. The outcome depends largely on the severity and duration of flowdeprivation.The principal early biochemical consequence of myocardial ischemia is the cessation ofaerobic glycolysis (and therefore initiating anaerobic glycolysis) within seconds, leadingto inadequate production of high-energy phosphates (e.g., creatine phosphate andadenosine triphosphate) and accumulation of potentially noxious breakdown products
(such as lactic acid). Myocardial function is exceedingly sensitive to severe ischemia;striking loss of contractility occurs within 60 seconds of onset of ischemia. This canprecipitate acute heart failure long before myocardial cell death. As detailed in Chapter1 , ultrastructural changes (including myofibrillar relaxation, glycogen depletion, cell andmitochondrial swelling) also develop within a few minutes after onset of ischemia.Nevertheless, these early changes are potentially reversible, and cell death is notimmediate. As demonstrated experimentally, only severe ischemia lasting at least 20 to40 minutes or longer leads to irreversible damage (necrosis) of some cardiac myocytes.Ultrastructural evidence of irreversible myocyte injury (primary structural defects in thesarcolemmal membrane) develops only after 20 to 40 minutes in severely ischemicmyocardium (with blood flow of 10% or less of normal). With prolonged ischemia, injury to the microvasculature then follows. This time frame is summarized in Table 12-4.Thus, myocardial necrosis begins at approximately 30 minutes after coronary occlusion.Classic acute MI with extensive damage occurs when the perfusion of the myocardium isreduced severely below its needs for an extended interval (usually at least 2 to 4 hours),causing profound, prolonged ischemia and resulting in permanent loss of function oflarge regions in which cell death has occurred. The predominant mechanism of celldeath is coagulation necrosis; apoptosis may also be important, but this is as yetuncertain. In contrast, if restoration of myocardial blood flow (known as reperfusion)follows briefer periods of flow deprivation (less than 20 minutes in the most severelyischemic myocardium), loss of cell viability can be prevented. This provides the rationalefor the very early clinical detection of acute MI—to permit early therapy such asthrombolysis, establish reperfusion of the area at risk, salvage as much ischemic but notyet dead myocardium as possible, and consequently minimize infarct size.Myocardial ischemia contributes to arrhythmias through complex and poorly understoodmechanisms, probably involving electrical instability (irritability). Sudden death, a  TABLE 12-4 -- Approximate Time of Onset of Key Events in Ischemic Cardiac MyocytesFeature TimeOnset of ATP depletion SecondsLoss of contractility <2 minATP reducedto 50% of normal 10 minto 10% of normal 40 minIrreversible cell injury 20–40 minMicrovascular injury >1 hrATP, adenosine triphosphate.
leading cause of mortality in IHD patients, can be caused by massive cell injury withmechanical failure but is most often due to ventricular fibrillation caused by myocardialirritability induced by ischemia or infarction. Interestingly, studies of resuscitatedsurvivors of "sudden death" show that the majority do not develop acute MI; in suchcases, myocardial irritability induced by ischemia presumably led directly to the seriousarrhythmia.The progression of ischemic necrosis in the myocardium is summarized in Figure 12-14 .Irreversible injury of ischemic myocytes occurs first in the subendocardial zone. Withmore extended ischemia, a wavefront of cell death moves through the myocardium toinvolve progressively more of the transmural thickness of the ischemic zone. The preciselocation, size, and specific morphologic features of an acute myocardial infarct dependon: • The location, severity, and rate of development of coronary atherosclerotic obstructions • The size of the vascular bed perfused by the obstructed vessels • The duration of the occlusion • The metabolic/oxygen needs of the myocardium at risk • The extent of collateral blood vessels • The presence, site, and severity of coronary arterial spasm • Other factors, such as alterations in blood pressure, heart rate, and cardiac rhythm.The necrosis is largely complete within 6 hours in experimental models and humans,involving nearly all of the ischemic myocardial bed at risk supplied by the occludedcoronary artery. Progression of necrosis, however, may follow a more protracted coursein some patients (possibly over 6 to 12 hours or longer) in whom the coronary arterialcollateral system, stimulated by chronic ischemia, is better developed and thereby moreeffective.Morphology.The evolution of the morphologic changes in acute MI and its healing are summarized inTable 12-5 .Nearly all transmural infarcts involve at least a portion of the left ventricle (including theventricular septum). About 15% to 30% of those that affect the posterior free wall andposterior portion of the septum transmurally extend into the adjacent right ventricularwall. Isolated infarction of the right ventricle, however, occurs in only 1% to 3% of cases.Associated infarction of atrial tissue accompanies a large posterior left ventricular infarctin some cases. Transmural infarcts usually encompass nearly the entire perfusion zone ofthe occluded coronary artery. Almost always there is a narrow rim (approximately 0.1mm) of preserved subendocardial myocardium sustained by diffusion of oxygen andnutrients from the lumen.
The frequencies of critical narrowing (and thrombosis) of each of the three main arterialtrunks and the corresponding sites of myocardial lesions resulting in infarction (in thetypical right dominant heart) are as follows: • Left anterior descending coronary artery (40% to 50%): infarct involves anterior wall of left ventricle 578 near apex; anterior portion of ventricular septum; apex circumferentially • Right coronary artery (30% to 40%): infarct involves inferior/posterior wall of left ventricle; posterior portion of ventricular septum; inferior/posterior right ventricular free wall in some cases • Left circumflex coronary artery (15% to 20%): infarct involves lateral wall of left ventricle except at apexFigure 12-14 Schematic representation of the progression of myocardial necrosis after coronary arteryocclusion. Necrosis begins in a small zone of the myocardium beneath the endocardial surface in the centerof the ischemic zone. This entire region of myocardium (shaded) depends on the occluded vessel forperfusion and is the area at risk. Note that a very narrow zone of myocardium immediately beneath theendocardium is spared from necrosis because it can be oxygenated by diffusion from the ventricle. The endresult of the obstruction to blood flow is necrosis of the muscle that was dependent on perfusion from the
coronary artery obstructed. Nearly the entire area at risk loses viability. The process is called myocardialinfarction, and the region of necrotic muscle is a myocardial infarct.Other locations of critical coronary arterial lesions causing infarcts are sometimesencountered, such as the left main coronary artery or the secondary branches (e.g.,diagonal branches of the LAD artery or marginal branches of the LCX artery). Incontrast, stenosing atherosclerosis or thrombosis of a penetrating intramyocardial branchof the coronary arteries is almost never encountered. Occasionally the observation ofmultiple severe stenoses or thromboses in the absence of myocardial damage suggeststhat formation of collateral connections between coronary arteries was protective.The gross and microscopic appearance of an infarct at autopsy depends on the duration ofsurvival of the patient following the MI. Areas of damage undergo a progressivesequence of morphologic changes that consist of typical ischemic coagulative necrosis,followed by inflammation and repair that closely parallels that occurring after injury atother, noncardiac sites.Early recognition of acute myocardial infarcts by pathologists can be difficult,particularly when death has occurred within a few hours after the onset of symptoms. Myocardial infarcts less than 12 hours old are usually not apparent on gross examination.It is often possible, however, to highlight the area of necrosis that first becomes apparentafter 2 to 3 hours after the infarct, by immersion of tissue slices in a 579 TABLE 12-5 -- Evolution of Morphologic Changes in Myocardial InfarctionTime Gross Features Light Microscope Electron MicroscopeReversible Injury0–½ hr None None Relaxation of myofibrils; glycogen loss; mitochondrial swellingIrreversible Injury½–4 hr None Usually none; variable Sarcolemmal disruption; waviness of fibers at border mitochondrial amorphous densities4–12 hr Occasionally dark Beginning coagulation mottling necrosis; edema; hemorrhage12–24 Dark mottling Ongoing coagulationhr necrosis; pyknosis of nuclei;
TABLE 12-5 -- Evolution of Morphologic Changes in Myocardial InfarctionTime Gross Features Light Microscope Electron Microscope myocyte hypereosinophilia; marginal contraction band necrosis; beginning neutrophilic infiltrate1–3 Mottling with yellow- Coagulation necrosis, withdays tan infarct center loss of nuclei and striations; interstitial infiltrate of neutrophils3–7 Hyperemic border; Beginning disintegration ofdays central yellow-tan dead myofibers, with dying softening neutrophils; early phagocytosis of dead cells by macrophages at infarct border7–10 Maximally yellow- Well-developeddays tan and soft, with phagocytosis of dead cells; depressed red-tan early formation of margins fibrovascular granulation tissue at margins10–14 Red-gray depressed Well-establisheddays infarct borders granulation tissue with new blood vessels and collagen deposition2–8 wk Gray-white scar, Increased collagen progressive from deposition, with decreased border toward core of cellularity infarct>2 mo Scarring complete Dense collagenous scarsolution of triphenyltetrazolium chloride (TTC). This histochemical stain imparts a brick-red color to intact, noninfarcted myocardium where the dehydrogenase enzymes arepreserved. Because dehydrogenases are depleted in the area of ischemic necrosis (theyleak out through the damaged cell membranes), an infarcted area is revealed as anunstained pale zone (while old scarred infarcts appear white and glistening) ( Fig.12-15 ). Subsequently, by 12 to 24 hours, an infarct can be identified in routinely fixedgross slices owing to a red-blue hue caused by stagnated, trapped blood. Progressivelythereafter, the infarct becomes a more sharply defined, yellow-tan, somewhat softenedarea that by 10 days to 2 weeks is rimmed by a hyperemic zone of highly vascularizedgranulation tissue. Over the succeeding weeks, the injured region evolves to a fibrousscar.
The histopathologic changes also have a fairly predictable sequence (summarized inTable 12-5 and Figure 12-16 ). Using light microscopic examination of routinely stainedtissue sections, the typical changes of coagulative necrosis become detectable variably inthe first 4 to 12 hours. "Wavy fibers" may be present at the periphery of the infarct; thesechanges probably result from the forceful systolic tugs by the viable fibers immediatelyadjacent to the noncontractile dead fibers, thereby stretching and buckling them. Anadditional but sublethal ischemic change may be seen in the margins of infarcts: so-calledvacuolar degeneration or myocytolysis, involving large vacuolar spaces within cells,probably containing water. This potentially reversible alteration is particularly frequent inthe thin zone of viable subendocardial cells. SubendocardialFigure 12-15 Acute myocardial infarct, predominantly of the posterolateral left ventricle, demonstratedhistochemically by a lack of staining by the triphenyltetrazolium chloride (TTC) stain in areas of necrosis(arrow). The staining defect is due to the enzyme leakage that follows cell death. Note the myocardialhemorrhage at one edge of the infarct that was associated with cardiac rupture, and the anterior scar(arrowhead), indicative of old infarct. (Specimen the oriented with the posterior wall at the top.)myocyte vacuolization in other contexts may signify severe chronic ischemia.The necrotic muscle elicits acute inflammation (typically most prominent at 2 to 3 days).Thereafter macrophages remove the necrotic myocytes (most 580
Figure 12-16 Microscopic features of myocardial infarction and its repair. A, One-day-old infarct showingcoagulative necrosis along with wavy fibers (elongated and narrow), compared with adjacent normal fibers(at right). Widened spaces between the dead fibers contain edema fluid and scattered neutrophils. B, Densepolymorphonuclear leukocytic infiltrate in area of acute myocardial infarction of 3 to 4 days duration. C,Nearly complete removal of necrotic myocytes by phagocytosis (approximately 7 to 10 days). D,Granulation tissue characterized by loose collagen and abundant capillaries. E, Well-healed myocardialinfarct with replacement of the necrotic fibers by dense collagenous scar. A few residual cardiac musclecells are present.pronounced at 5 to 10 days), and the damaged zone is progressively replaced by theingrowth of highly vascularized granulation tissue (most prominent at 2 to 4 weeks),which progressively becomes less vascularized and more fibrous. In most instances,scarring is well advanced by the end of the sixth week, but the efficiency of repair
depends on the size of the original lesion. As healing requires the participation ofinflammatory cells that migrate to the region of damage through intact blood vessels,which often survive only at the infarct margins, the infarct heals from its borders towardthe center. Thus, a large infarct may not heal as readily nor as completely as a small one.A healing infarct may appear nonuniform, with the most advanced healing at theperiphery. Once a lesion is completely healed, it is impossible to distinguish its age (i.e.,the dense fibrous tissue scar of an 8-week-old and a 10-year-old lesion may look similar).Several infarcts of varying age are frequently found in the same heart. Repetitive necrosisof adjacent regions yields progressive extension of an individual infarct over a period ofdays to weeks. Examination of the heart in such cases often reveals a central zone ofrepairing infarct that is days to weeks older and whose healing is more advanced than thatof a peripheral margin of more recent ischemic necrosis. This contrasts 581with the appearance of a single-event infarct described above, in which the mostadvanced repair was peripheral. An initial infarct may extend because of retrogradepropagation of a thrombus, proximal vasospasm, progressively impaired cardiaccontractility that renders flow through moderate stenoses critically insufficient, thedevelopment of platelet-fibrin microemboli, the appearance of an arrhythmia that impairscardiac function, or poor perfusion owing to progressively impaired myocardial function.In general, the sequential morphology of evolving subendocardial and transmural infarctsis qualitatively similar, but subendocardial infarcts tend to be smaller.The temporal sequence of morphologic events in MI is summarized in Figure 12-17 ,emphasizing the possibility of interventions that might limit infarct size, sincemyocardium that is not yet necrotic is potentially salvageable.
Figure 12-17 Temporal sequence of early biochemical, ultrastructural, histochemical, and histologicfindings after onset of severe myocardial ischemia. For approximately 30 minutes after the onset of eventhe most severe ischemia, myocardial injury is potentially reversible. Thereafter, progressive loss ofviability occurs that is complete by 6 to 12 hours. The benefits of reperfusion are greatest when it isachieved early, with progressively smaller benefit occurring as reperfusion is delayed. (Modified withpermission from Antman E: Acute myocardial infarction. In Braunwald E, Zipes DP, Libby P (eds): HeartDisease: A Textbook of Cardiovascular Medicine, 6th ed. Philadelphia, WB Saunders, 2001, pp. 1114–1231.)Infarct Modification by Reperfusion.The most effective way to salvage ischemic myocardium threatened by infarction is torestore tissue perfusion as rapidly as possible. This is best accomplished by restoration ofcoronary flow (reperfusion) by thrombolysis, balloon angioplasty (also known aspercutaneous transluminal coronary angioplasty, or PTCA), or coronary arterial bypassgraft (CABG). Reperfusion-associated pathologies, including reperfusion-inducedarrhythmias, myocardial hemorrhage with contraction bands, irreversible cell damagedistinct from and additional to the injury associated with the original ischemic event(reperfusion injury), microvascular injury, and prolonged ischemic dysfunction
(myocardial stunning), are discussed below and summarized in Figure 12-18 .Thrombolytic therapy (dissolution of the offending thrombus by streptokinase or tissue-type plasminogen activator [t-PA] through activation of the fibrinolytic system) or PTCAis often used in an attempt to dissolve or mechanically disrupt the thrombus that initiatedacute MI. The 582Figure 12-18 Consequences of myocardial ischemia followed by reperfusion. A, Schematic illustration ofthe progression of myocardial ischemic injury and its modification by restoration of flow (reperfusion).Hearts suffering brief periods of ischemia of <20 minutes followed by reperfusion do not develop necrosis(reversible injury). Brief ischemia followed by reperfusion results in stunning. If coronary occlusion isextended beyond 20 minutes duration, a wavefront of necrosis progresses from subendocardium tosubepicardium over time. Reperfusion before 3 to 6 hours of ischemia salvages ischemic but viable tissue.
(This salvaged tissue may demonstrate stunning.) Reperfusion beyond 6 hours does not appreciably reducemyocardial infarct size. Late reperfusion may still have a beneficial effect on reducing or preventingmyocardial infarct expansion and left ventricular remodeling. B, Gross and C, microscopic appearance ofmyocardium modified by reperfusion. B, Large, densely hemorrhagic, anterior wall acute myocardialinfarction from patient with left anterior descending artery thrombus treated with streptokinaseintracoronary thrombolysis (triphenyl tetrazolium chloride-stained heart slice). (Specimen oriented withposterior wall at top.) C, Myocardial necrosis with hemorrhage and contraction bands, visible as dark bandsspanning some myofibers (arrow). This is the characteristic appearance of markedly ischemic myocardiumthat has been reperfused.purpose of these treatments is to restore blood flow to the area at risk for infarction andpossibly rescue the ischemic (but not yet necrotic) heart muscle. Removal of thrombus re-establishes flow through the occluded coronary artery in most cases; early reperfusioncan salvage myocardium and thereby limit infarct size, with consequent improvement inboth short- and long-term function and survival. As discussed above, loss of myocardial viability in infarction is progressive, occurring over a period of at least several hours.Thus, reperfusion of at risk myocardium offers an effective approach for restoring thebalance between myocardial perfusion and need. The potential benefit is clearly related tothe rapidity with which the coronary 583occlusion is alleviated; the first 3 to 4 hours following onset of symptoms are critical.Moreover, thrombolysis can at best remove a thrombus occluding a coronary artery; itdoes not significantly alter the underlying disrupted atherosclerotic plaque that initiatedit. In contrast, PTCA not only eliminates a thrombotic occlusion, but also can relievesome of the original obstruction caused by the underlying plaque. CABG provides flow around it.Recall that severe ischemia does not cause immediate cell death even in the most severelyaffected regions of myocardium, and not all regions of myocardium are equally ischemic.Therefore, the outcome distal to the occlusion following restoration of flow to previouslyischemic myocardium may vary from region to region. As indicated in Figure 12-18A ,reperfusion of myocardium sufficiently early (within 15 to 20 minutes) after onset ofischemia may prevent all necrosis. Reperfusion after a longer interval may not prevent allnecrosis but can salvage (i.e., prevent necrosis of) at least some myocytes that wouldhave died with more prolonged or permanent ischemia.The typical appearance of ischemic then reperfused myocardium is illustrated in Figure12-18B and C . A partially completed then reperfused infarct usually has hemorrhagebecause the vasculature injured during the period of ischemia becomes leaky onrestoration of flow. Moreover, disintegration of myocytes that were lethally damaged bythe preceding ischemia may be accentuated or accelerated by reperfusion. Microscopicexamination reveals that myocytes already irreversibly injured at the time of reflow oftenhave necrosis with contraction bands. Contraction bands are intensely eosinophilictransverse bands composed of closely packed hypercontracted sarcomeres. They are mostlikely produced by exaggerated contraction of myofibrils at the instant perfusion is
reestablished, at which time the internal portions of an already dead cell whosemembranes have been damaged by ischemia are exposed to a high concentration ofcalcium ions from the plasma. Thus reperfusion not only salvages reversibly injured cellsbut also alters the morphology of cells already lethally injured at the time of reflow.However, despite the potential for myocardial salvage by reperfusion of ischemicmyocardium, some small amount of new cellular damage may occur that blunts thebeneficial effect of reperfusion itself (reperfusion injury). The clinical significance of  myocardial reperfusion injury is uncertain. As discussed in Chapter 1 , reperfusion injuryis mediated, at least in part, by the generation of oxygen free radicals from infiltratingleukocytes during reperfusion. Recent advances in the understanding of cell death inischemia and reperfusion suggest that apoptosis may be prominent at reperfusion; thus,prevention of apoptosis may be a potential therapeutic target to limit reperfusion injury. Reperfusion-induced microvascular injury causes not only hemorrhage, but alsoendothelial swelling that occludes capillaries and may prevent local reperfusion to areasof critically injured myocardium (called no-reflow).Ischemic myocardium may have profound functional changes despite complete salvageof viability. Although most of the viable myocardium existing at the time of reflow ultimately recovers after alleviation of ischemia, critical abnormalities in cellularbiochemistry and function of myocytes salvaged by reperfusion may persist for as long asseveral days (prolonged postischemic ventricular dysfunction, or stunned myocardium).Stunning may induce a state of reversible cardiac failure that may benefit from temporarycardiac assist. Paradoxically, short-lived transient severe ischemia, as might occur inrepetitive angina pectoris or silent ischemia, may protect the myocardium against agreater subsequent ischemic insult (a phenomenon known as preconditioning) bymechanisms that are not well known. Myocardium that is subjected to persistently lowflow has chronically depressed function and is said to be hibernating. This portion of the myocardium may undergo profound restoration of function followingrevascularization by CABG surgery or balloon angioplasty.Clinical Features.MI is diagnosed classically by typical symptoms, biochemical evidence, and by the ECGpattern. Patients with MI have rapid, weak pulse and are often sweating profusely(diaphoretic). Dyspnea due to impaired contractility of the ischemic myocardium and theresultant pulmonary congestion and edema is common. In about 10% to 15% of MIpatients, the onset is entirely asymptomatic and the disease is discovered only later byECG changes, usually consisting of new Q waves. Such "silent" MIs are particularlycommon in patients with diabetes mellitus and in elderly patients.Laboratory evaluation is based on measuring the blood levels of intracellularmacromolecules that leak out of fatally injured myocardial cells through damaged cellmembranes; these molecules include myoglobin, cardiac troponins T and I (TnT, TnI),creatine kinase (CK), lactate dehydrogenase, and many others. Although these markershave become increasingly sensitive indicators of myocardial damage, they do not reflectits mechanism. From a biochemical perspective, the diagnosis of myocardial injury is 
established when blood levels of sensitive and specific biomarkers, such as cardiactroponin and the MB fraction of creatine kinase (CK-MB), are increased in the clinicalsetting of acute ischemia. The preferred biomarkers for myocardial damage are cardiac-specific proteins, particularly Troponin-I (TnI) and Troponin-T. Troponins are proteinsthat regulate calcium-mediated contraction of cardiac and skeletal muscle. These markershave nearly complete tissue specificity and high sensitivity. TnI and TnT are notnormally detectable in the circulation, but after acute MI, levels of both cardiac troponinsrise at 2 to 4 hours and peak at 48 hours. Troponin levels remain elevated for 7 to 10 daysafter the acute event.Formerly the "gold standard," cardiac creatine kinase (CK-MB) remains the bestalternative to troponin measurement. Creatine kinase is an enzyme that is highlyconcentrated in brain, myocardium, and skeletal muscle and is composed of two dimers,designated "M" and "B." The isoenzyme CK-MM is derived predominantly from skeletalmuscle and heart; CK-BB from brain, lung, and many other tissues; and CK-MBprincipally from myocardium, although variable amounts of the MB form are also presentin skeletal muscle. Total CK activity is sensitive but not specific, as CK is elevated inother conditions such as skeletal muscle injury. CK-MB activity begins to rise within 2 to4 hours of onset of MI, peaks at about 24 hours, and returns to normal withinapproximately 72 hours. Although the diagnostic sensitivities of cardiac troponin andCK-MB measurements are similar in the early stages of MI, persistence of elevatedtroponin levels for approximately 10 days allows the diagnosis of acute MI long afterCK-MB levels have returned to normal. The peak of either troponin or CK-MB isaccelerated in patients who have 584had reperfusion, owing to washing out of the enzyme from the necrotic tissue. Anabsence of a change in the levels of CK and CK-MB during the first 2 days of chest painand of troponin in the days following essentially excludes the diagnosis of MI.As discussed, C-reactive protein (CRP) may serve as a marker to predict the risk ofmyocardial infarct in patients with angina, and the risk of new infarcts in patients whorecover from infarcts. Using highly sensitive methods, serum CRP, levels of more  than 3 mg/L are associated with the highest risk of cardiovascular disease, while levels of1 to 3 mg/L are associated with moderate risk.  Other diagnostic modalities such as echocardiography (for visualization of abnormalitiesof regional wall motion), radioisotope studies such as radionuclide angiography (forchamber configuration), perfusion scintigraphy (for regional perfusion), and magneticresonance imaging (for structural characterization) sometimes provide additionalanatomic, biochemical, and functional data.Consequences and Complications of Myocardial Infarction.
Extraordinary progress has been made in improving the outcome of patients with acuteMI. Concurrent with the marked decrease in the overall mortality of IHD since the 1960s,the in-hospital death rate has declined from approximately 30% to an overall rate ofbetween 10% and 13% today (and to approximately 7% for patients receiving aggressivereperfusion therapy). Nevertheless, half of the deaths associated with acute MI occurwithin 1 hour of onset; these individuals never reach the hospital. In general, factorsassociated with a poor prognosis include advanced age, female gender, diabetes mellitusand, owing to a loss of functional myocardium, previous MI.Nearly three-fourths of patients have one or more complications following acute MI,which include the following (some of which are illustrated in Fig. 12-19 ): • Contractile dysfunction. Myocardial infarcts produce abnormalities in left ventricular function approximately proportional to their size. Most often, there is some degree of left ventricular failure with hypotension, pulmonary vascular congestion, and transudation into the interstitial pulmonary spaces, which may progress to pulmonary edema with respiratory impairment. Severe "pump failure" (cardiogenic shock) occurs in 10% to 15% of patients following acute MI, generally with a large infarct (often greater than 40% of the left ventricle). Cardiogenic shock has a nearly 70% mortality rate and accounts for two thirds of inhospital deaths. • Arrhythmias. Many patients have conduction disturbances and myocardial irritability following MI, which undoubtedly are responsible for many of the sudden deaths. MI-associated arrhythmias include sinus bradycardia, heart block (asystole), tachycardia, ventricular premature contractions or ventricular tachycardia, and ventricular fibrillation. Owing to the location of portions of the atrioventricular conduction system (bundle of His) in the inferoseptal myocardium, infarcts of this region may also be associated with heart block. Prompt intervention by mobile and hospital coronary care units can control potentially lethal arrhythmias in many patients. • Myocardial rupture. The cardiac rupture syndromes result from the mechanical weakening that occurs in necrotic and subsequently inflamed myocardium and include (1) rupture of the ventricular free wall (most commonly), with hemopericardium and cardiac tamponade, usually fatal (see Fig. 12-19A ); (2) rupture of the ventricular septum (less commonly), leading to a left-to-right shunt (see Fig. 12-19B ); and (3) papillary muscle rupture (least commonly), resulting in the acute onset of severe mitral regurgitation (see Fig. 12-19C ). Free-wall rupture may occur at almost any time after MI but is most frequent 3 to 7 days after onset, when coagulative necrosis, neutrophilic infiltration, and lysis of the myocardial connective tissue have appreciably weakened the infarcted myocardium (mean, 4 to 5 days; range, 1 to 10 days). However, as many as one quarter of cardiac ruptures occur within 24 hours. The lateral wall at the midventricular level is the most common site for postinfarction free-wall rupture. Risk factors for free-wall rupture include age older than 60, female gender, pre-existing hypertension, and lack of left ventricular hypertrophy. Moreover, this complication occurs more readily in patients without prior MI owing to an absence of fibrosis, which tends
to block myocardial tearing. Acute free-wall ruptures are usually rapidly fatal.However, a strategically located pericardial adhesion that aborts a rupture mayresult in the formation of a false aneurysm (that is, a contained rupture that resultsin a hematoma communicating with the ventricular cavity). The wall of a falseaneurysm consists only of epicardium and adherent parietal pericardium. Manyfalse aneurysms are filled with mural thrombus, and half ultimately rupture.Postinfarction rupture of septal myocardium causing an (acute) ventricular septaldefect complicates 1% to 2% of infarcts. • Pericarditis. A fibrinous or fibrohemorrhagic pericarditis usually develops aboutthe second or third day following a transmural infarct and usually resolves overtime (see Fig. 12-19D ). Pericarditis is the epicardial manifestation of theunderlying myocardial inflammation.• Right ventricular infarction. Although isolated infarction of the right ventricle isunusual, infarction of the right ventricular myocardium often accompaniesischemic injury of the adjacent posterior left ventricle and ventricular septum. Aright ventricular infarct of either type can yield serious functional impairment.• Infarct extension. New necrosis may occur adjacent to an existing infarct.• Infarct expansion. Owing to the weakening of necrotic muscle, there may bedisproportionate stretching, thinning, and dilation of the infarct region (especiallywith anteroseptal infarcts), which is often associated with mural thrombus (seeFig. 12-19E ).• Mural thrombus. With any infarct, the combination of a local myocardialabnormality in contractility (causing stasis) with endocardial damage (causing athrombogenic surface) can foster mural thrombosis ( Chapter 4 ) and, potentially,thromboembolism.• Ventricular aneurysm. In contrast to false aneurysms mentioned above, trueaneurysms of the ventricular wall are bounded by myocardium that has becomescarred. A late complication, aneurysms of the ventricular wall most commonlyresult from a large transmural anteroseptal infarct (often one that has undergoneexpansion) that heals 585into a large region of thin scar tissue, which paradoxically bulges during systole(see Fig. 12-19F ). Complications of ventricular aneurysms include muralthrombus, arrhythmias and heart failure, but rupture of the fibrotic wall does notoccur.• Papillary muscle dysfunction. As mentioned above, rarely, early dysfunction ofa papillary muscle following MI occurs due to its rupture. More frequently,postinfarct mitral regurgitation results from early ischemic dysfunction of apapillary muscle and underlying myocardium and later 586from papillary muscle fibrosis and shortening or ventricular dilation (see below).• Progressive late heart failure is discussed as chronic IHD below.
Figure 12-19 Complications of myocardial infarction. Cardiac rupture syndromes (A, B, and C). A,Anterior myocardial rupture in an acute infarct (arrow). B, Rupture of the ventricular septum (arrow). C,Complete rupture of a necrotic papillary muscle. D, Fibrinous pericarditis, showing a dark, roughenedepicardial surface overlying an acute infarct. E, Early expansion of anteroapical infarct with wall thinning(arrow) and mural thrombus. F, Large apical left ventricular aneurysm. The left ventricle is on the right inthis apical four-chamber view of the heart. (A–E, Reproduced by permission from Schoen FJ:Interventional and Surgical Cardiovascular Pathology: Clinical Correlations and Basic Principles,Philadelphia, WB Saunders, 1989.) (F, Courtesy of William D. Edwards, M.D., Mayo Clinic, Rochester,MN.)The propensity toward specific complications and the prognosis after MI dependprimarily on infarct size, site, and fractional thickness of the myocardial wall that isdamaged (subendocardial or transmural infarct). Large transmural infarcts yield a higherprobability of cardiogenic shock, arrhythmias, and late CHF. Patients with anterior
transmural infarcts are at greatest risk for free-wall rupture, expansion, mural thrombi,and aneurysm. In contrast, posterior transmural infarcts are more likely to be complicatedby serious conduction blocks, right ventricular involvement, or both, and when acuteventricular septal defects occur in this area, they are more difficult to manage. Overall,however, patients with anterior infarcts have a substantially worse clinical course thanthose with inferior (posterior) infarcts. With subendocardial infarcts, thrombi may formon the endocardial surface, but pericarditis, rupture, and aneurysms rarely occur.Multiple dynamic structural changes maintain cardiac output after acute MI. Both thenecrotic zone and the noninfarcted segments of the ventricle undergo progressive changesin size, shape and thickness comprising early wall thinning, healing, hypertrophy anddilation, and late aneurysm formation, collectively termed ventricular remodeling.   Clearly, the initial compensatory hypertrophy of noninfarcted myocardium ishemodynamically beneficial. However, the adaptive effect of remodeling may beoverwhelmed by expansion and ventricular aneurysm or late depression of regional andglobal contractile function owing to degenerative changes in viable myocardium. Thismay lead to late impairment of ventricular performance.Long-term prognosis after MI depends on many factors, the most important of which arethe quality of left ventricular function and the extent of vascular obstructions in vesselsthat perfuse viable myocardium. The overall total mortality within the first year is about30%, including those victims who die before reaching the hospital. Thereafter there is a3% to 4% mortality among survivors with each passing year. Infarct prevention throughcontrol of risk factors in individuals who have never experienced MI (primaryprevention) and prevention of reinfarction in those who have recovered from an acute MI(secondary prevention) are important strategies that have received much attention andhave achieved considerable success.CHRONIC ISCHEMIC HEART DISEASEThe designation chronic ischemic heart disease (CIHD) is used here to describe thecardiac findings in patients, often but not exclusively elderly, who develop progressiveheart failure as a consequence of ischemic myocardial damage. The term ischemiccardiomyopathy is often used by clinicians to describe CIHD. In most instances, there hasbeen prior MI and sometimes previous coronary arterial bypass graft surgery or otherinterventions. CIHD usually constitutes postinfarction cardiac decompensation owing toexhaustion of the compensatory hypertrophy of noninfarcted viable myocardium that isitself in jeopardy of ischemic injury (see earlier discussion of cardiac hypertrophy).However, in other cases severe obstructive CAD may be present without acute or healedinfarction but with diffuse myocardial dysfunction.Morphology.Hearts from patients with CIHD are usually enlarged and heavy, secondary to leftventricular hypertrophy and dilation. Invariably there is moderate to severe stenosingatherosclerosis of the coronary arteries and sometimes total occlusion. Discrete, gray-white scars of healed infarcts are usually present. The mural endocardium is generally
normal except for some superficial, patchy, fibrous thickenings, although mural thrombimay be present. The major microscopic findings include myocardial hypertrophy, diffusesubendocardial vacuolization, and scars of previously healed infarcts.The clinical diagnosis is made largely by the insidious onset of CHF in patients who havehad past episodes of MI or anginal attacks. In some individuals, however, progressivemyocardial damage is entirely silent, and heart failure is the first indication of CIHD. Thediagnosis rests largely on the exclusion of other forms of cardiac involvement. Suchpatients make up nearly half of cardiac transplant recipients.SUDDEN CARDIAC DEATHThis catastrophe strikes down about 300,000 to 400,000 individuals annually in theUnited States. Sudden cardiac death (SCD) is most commonly defined as unexpecteddeath from cardiac causes early after symptom onset (usually within 1 hour) or withoutthe onset of symptoms. In many adults, SCD is a complication and often the first clinicalmanifestation of IHD. With decreasing age of the victim, the followingnonatherosclerotic causes of SCD become increasingly probable:   • Congenital structural or coronary arterial abnormalities • Aortic valve stenosis • Mitral valve prolapse • Myocarditis • Dilated or hypertrophic cardiomyopathy • Pulmonary hypertension • Hereditary or acquired abnormalities of the cardiac conduction system • Isolated hypertrophy, hypertensive or unknown cause. Increased cardiac mass is an independent risk factor for cardiac death; thus, some young patients who die suddenly, including athletes, have hypertensive hypertrophy or unexplained increased cardiac mass as the only finding.The ultimate mechanism of SCD is most often a lethal arrhythmia (e.g., asystole,ventricular fibrillation). Although ischemic injury can impinge on the conduction systemand create electromechanical cardiac instability, in most cases the fatal arrhythmia istriggered by electrical irritability of myocardium that may be distant from the conductionsystem, induced by ischemia or other cellular abnormalities. The prognosis of patientsvulnerable to SCD, especially those with chronic IHD, is markedly improved byimplantation of an automatic cardioverter defibrillator, which senses and electricallycounteracts an episode of ventricular fibrillation.  587Morphology.Marked coronary atherosclerosis with critical (>75%) stenosis involving one or more ofthe three major vessels is present in 80% to 90% of SCD victims; only 10% to 20% of
cases are of nonatherosclerotic origin. Usually there are high-grade stenoses (>90%), andacute plaque disruption is common. A healed myocardial infarct is present in about 40%,but in those who were successfully resuscitated from sudden cardiac arrest, new MI isfound in only 25% or less. Subendocardial myocyte vacuolization indicative of severechronic ischemia is common.Arrhythmias that occur in the absence of structural cardiac pathology can also precipitatesudden death. The most important cause is the autosomal dominant long QT syndrome(Romano-Ward syndrome), which causes heightened cardiac excitability and episodicventricular arrhythmias. Mutations causing this disorder have been demonstrated in atleast five different genes that encode components of cardiac ion channels includingpotassium and sodium channels. Hypertensive Heart DiseaseHypertensive heart disease (HHD) is the response of the heart to the increased demandsinduced by systemic hypertension. Pulmonary hypertension also causes heart disease and is referred to as right-sided HHD, or cor pulmonale.SYSTEMIC (LEFT-SIDED) HYPERTENSIVE HEART DISEASEIn hypertension, hypertrophy of the heart is an adaptive response to pressure overloadthat can lead to myocardial dysfunction, cardiac dilation, CHF, and sudden death (seesection on cardiac hypertrophy, earlier in this chapter). The minimal criteria for thediagnosis of systemic HHD are the following: (1) left ventricular hypertrophy (usuallyconcentric) in the absence of other cardiovascular pathology that might have induced itand (2) a history or pathologic evidence of hypertension. Notwithstanding, theFramingham Study established unequivocally that even mild hypertension (levels onlyslightly above 140/90 mm Hg), if sufficiently prolonged, induces left ventricularhypertrophy. Approximately 25% of the population of the United States suffers fromhypertension of at least this degree. The pathogenesis of hypertension is discussed inChapter 11 .Morphology.Hypertension induces left ventricular pressure overload hypertrophy without dilation ofthe left ventricle. The thickening of the left ventricular wall increases the ratio of its wallthickness to radius, and increases the weight of the heart disproportionately to theincrease in overall cardiac size ( Fig. 12-20 ). The left ventricular wall thickness mayexceed 2.0 cm and the heart weight may exceed 500 gm. In time, the increased thicknessof the left ventricular wall imparts a stiffness that impairs diastolic filling. This ofteninduces left atrial enlargement.
Figure 12-20 Hypertensive heart disease with marked concentric thickening of the left ventricular wallcausing reduction in lumen size. The left ventricle is on the right in this apical four-chamber view of theheart. A pacemaker is incidentally present in the right ventricle (arrow).Microscopically, the earliest change of systemic HHD is an increase in the transversediameter of myocytes, which may be difficult to appreciate on routine microscopy. At amore advanced stage, the cellular and nuclear enlargement becomes somewhat moreirregular, with variation in cell size among adjacent cells, and interstitial fibrosis. Thebiochemical, molecular, and morphologic changes that occur in hypertensive hypertrophyare similar to those noted in other conditions of myocardial overload (see section oncardiac hypertrophy, earlier in this chapter).Compensated systemic HHD may be asymptomatic and suspected only in the appropriateclinical setting by ECG or echocardiographic indications of left ventricular enlargement.Other causes for such hypertrophy must be excluded. In many patients, systemic HHDcomes to attention by the onset of atrial fibrillation (owing to left atrial enlargement) orCHF with cardiac dilation, or both. Depending on the severity, duration, and underlyingbasis of the hypertension, and on the adequacy of therapeutic control, the patient may (1)enjoy normal longevity and die of unrelated causes, (2) develop progressive IHD owingto the effects of hypertension in potentiating coronary atherosclerosis, (3) sufferprogressive renal damage or cerebrovascular stroke, or (4) experience progressive heartfailure. The risk of sudden cardiac death is also increased. Effective control ofhypertension can prevent or lead to regression of cardiac hypertrophy and its associatedrisks. 588
PULMONARY (RIGHT-SIDED) HYPERTENSIVE HEART DISEASE (COR PULMONALE)Cor pulmonale, as pulmonary HHD is frequently called, consists of right ventricularhypertrophy, dilation, and potentially failure secondary to pulmonary hypertensioncaused by disorders of the lungs or pulmonary vasculature ( Table 12-6 ). PulmonaryHHD is the right-sided counterpart of left-sided (systemic) HHD. Although rightventricular dilation and thickening caused either by diseases of the left side of the heart orcongenital heart diseases are generally excluded by this definition of cor pulmonale,pulmonary venous hypertension that follows left-sided heart diseases of variousetiologies is quite common.Cor pulmonale may be acute or chronic, depending on the suddenness of development ofthe pulmonary hypertension. Acute cor pulmonale can follow massive pulmonaryembolism. Chronic cor pulmonale usually implies right ventricular hypertrophy (anddilation) secondary to prolonged pressure overload caused by obstruction of thepulmonary arteries or arterioles or compression or obliteration of septal capillaries (e.g.,owing to primary pulmonary hypertension or emphysema).Morphology.In acute cor pulmonale, there is marked dilation of the right ventricle withouthypertrophy. On cross-section, the normal crescent shape of the right ventricle istransformed to a dilated ovoid. In chronic cor pulmonale, the right ventricular wallthickens, sometimes up to 1.0 cm or more, and may even come to approximate that of theleft ventricle ( Fig. 12-21 ). More subtle stages of right ventricular hypertrophy may beobserved as thickening of the muscle bundles in the outflow tract, immediately TABLE 12-6 -- Disorders Predisposing to Cor PulmonaleDiseases of the Pulmonary ParenchymaChronic obstructive pulmonary diseaseDiffuse pulmonary interstitial fibrosisPneumoconiosesCystic fibrosisBronchiectasisDiseases of the Pulmonary VesselsRecurrent pulmonary thromboembolismPrimary pulmonary hypertensionExtensive pulmonary arteritis (e.g., Wegener granulomatosis)Drug-, toxin-, or radiation-induced vascular obstructionExtensive pulmonary tumor microembolism
Disorders Affecting Chest MovementKyphoscoliosisMarked obesity (pickwickian syndrome)Neuromuscular diseasesDisorders Inducing Pulmonary Arterial ConstrictionMetabolic acidosisHypoxemiaChronic altitude sicknessObstruction to major airwaysIdiopathic alveolar hypoventilationFigure 12-21 Chronic cor pulmonale, characterized by a markedly dilated and hypertrophied rightventricle, with thickened free wall and hypertrophied trabeculae (apical four-chamber view of heart, rightventricle on left). The shape of the left ventricle (to the right) has been distorted by the right ventricularenlargement. Compare with Figure 12-20 .below the pulmonary valve, or of the moderator band, the muscle bundle that connectsthe ventricular septum to the anterior right ventricular papillary muscle. Sometimes thereis secondary compression of the left ventricular chamber or tricuspid regurgitation withfibrous thickening of this valve.
Valvular Heart DiseaseValvular involvement by disease causes stenosis, insufficiency (regurgitation orincompetence), or both. Stenosis is the failure of a valve to open completely, therebyimpeding forward flow. Insufficiency, in contrast, results from failure of a valve to closecompletely, thereby allowing reversed flow. These abnormalities can be either pure, whenonly stenosis or regurgitation is present, or mixed, when both stenosis and regurgitationcoexist in the same valve, but one of these defects usually predominates. Isolated diseaserefers to disease affecting one valve, and combined disease implies that more than onevalve may be dysfunctional. Functional regurgitation results when a valve becomesincompetent owing to either (1) dilation of the ventricle, which causes the right or leftventricular papillary muscles to be pulled down and outward, thereby preventingcoaptation of otherwise intact mitral or tricuspid leaflets during systole, or (2) dilation ofthe aortic or pulmonary artery, pulling the valve commissures apart and preventing fullclosure of the aortic or pulmonary valve cusps. Abnormalities of flow often produceabnormal heart sounds known as murmurs.Valvular dysfunction can vary in degree from slight and physiologically unimportant tosevere and rapidly fatal. The clinical consequences depend on the valve involved, thedegree 589of impairment, the rate of its development, and the rate and quality of compensatorymechanisms. For example, sudden destruction of an aortic valve cusp by infection (as ininfective endocarditis; see later) may cause rapidly fatal cardiac failure owing to massiveregurgitation. In contrast, rheumatic mitral stenosis usually develops over years and itsclinical effects are remarkably well tolerated. Depending on degree, duration, andetiology, valvular stenosis or insufficiency often produces secondary changes in the heart,blood vessels, and other organs, both proximal and distal to the valvular lesion. Mostimportant are the myocardial hypertrophy and the pulmonary and systemic changesdiscussed earlier. Moreover, a patch of endocardial thickening often occurs at the pointwhere a jet lesion impinges, such as the focal endocardial fibrosis in the left atriumsecondary to a regurgitant jet of mitral insufficiency.Valvular abnormalities may be caused by congenital disorders (discussed earlier) or by avariety of acquired diseases. Most frequent are acquired stenoses of the aortic and mitralvalves, which account for approximately two-thirds of all valve disease. Valvular stenosisalmost always is due to a primary cuspal abnormality and is virtually always a chronicprocess. In contrast, valvular insufficiency may result from either intrinsic disease of thevalve cusps or damage to or distortion of the supporting structures (e.g., the aorta, mitralannulus, tendinous cords, papillary muscles, ventricular free wall) without primarychanges in the cusps. It may appear acutely, as with rupture of cords, or chronically withleaflet scarring and retraction.
The most important causes of acquired heart valve diseases are summarized in Table 12-7and are discussed in the following sections. In contrast to the many potential causes of  TABLE 12-7 -- Major Etiologies of Acquired Heart Valve DiseaseMitral Valve Disease Aortic Valve DiseaseMitral Stenosis Aortic StenosisPostinflammatory scarring (rheumatic heart Postinflammatory scarring (rheumaticdisease) heart disease) Senile calcific aortic stenosis Calcification of congenitally deformed valveMitral Regurgitation Aortic RegurgitationAbnormalities of Leaflets and Commissures Intrinsic Valvular DiseasePostinflammatory scarring Postinflammatory scarring (rheumatic heart disease)Infective endocarditis Infective endocarditisMitral valve prolapseFen-phen-induced valvular fibrosisAbnormalities of Tensor Apparatus Aortic DiseaseRupture of papillary muscle Degenerative aortic dilationPapillary muscle dysfunction (fibrosis) Syphilitic aortitisRupture of chordae tendineae Ankylosing spondylitis Rheumatoid arthritis Marfan syndromeAbnormalities of Left Ventricular Cavity and/or AnnulusLV enlargement (myocarditis, dilatedcardiomyopathy)Calcification of mitral ringLV, Left ventricular.Modified from Schoen, FJ: Surgical pathology of removed natural and prosthetic valves.Hum Pathol 18:558, 1987.
valvular insufficiency, only a relatively few mechanisms produce acquired valvularstenosis. The most frequent causes of the major functional valvular lesions are as follows: • Aortic stenosis: calcification of anatomically normal and congenitally bicuspid aortic valves • Aortic insufficiency: dilation of the ascending aorta, related to hypertension and aging. • Mitral stenosis: rheumatic heart disease • Mitral insufficiency: myxomatous degeneration (mitral valve prolapse)VALVULAR DEGENERATION CAUSED BY CALCIFICATIONThe heart valves are subjected to high repetitive mechanical stresses, particularly at thehinge points of the cusps and leaflets owing to (1) 40 million or more cardiac cycles peryear, (2) substantial tissue deformations at each cycle, and (3) transvalvular pressuregradients in the closed phase of approximately 120 mm for the mitral and 80 mm for theaortic valve. It is therefore not surprising that these normally delicate structures suffercumulative damage complicated by formation of calcific deposits (composed of calciumphosphate mineral), which may lead to clinically important disease (see Chapter 1 ). Themost frequent calcific valvular diseases, illustrated in Figure 12-22 , are calcific aorticstenosis, calcification of a congenitally bicuspid aortic valve, and mitral annularcalcification. Each comprises primarily dystrophic calcification without significant lipiddeposition or cellular proliferation, a process distinct from but with some features ofatherosclerosis. 590Figure 12-22 Calcific valvular degeneration. A, Calcific aortic stenosis of a previously normal valvehaving three cusps (viewed from aortic aspect). Nodular masses of calcium are heaped-up within thesinuses of Valsalva (arrow). Note that the commissures are not fused, as in postrheumatic aortic valvestenosis (see Fig. 12-24E ). B, Calcific aortic stenosis occurring on a congenitally bicuspid valve. One cusphas a partial fusion at its center, called a raphe (arrow). C and D, Mitral annular calcification, with calcificnodules at the base (attachment margin) of the anterior mitral leaflet (arrows). C, Left atrial view. D, Cutsection of myocardium.Calcific Aortic Stenosis
Aortic stenosis is the most common of all valvular abnormalities. Acquired aorticstenosis is usually the consequence of calcification owing to progressive and advancedage-associated "wear and tear" of either previously anatomically normal aortic valves orcongenitally bicuspid valves (with which approximately 1% of the population is born, seelater). The incidence of aortic stenosis is increasing with the rising average age of thepopulation. With the decline in the incidence of rheumatic fever in North America,rheumatic aortic stenosis now accounts for less than 10% of cases of acquired aorticstenosis. Aortic stenosis comes to clinical attention primarily in the sixth to seventhdecades of life with congenitally bicuspid valves but not until the eighth and ninthdecades with previously normal valves; hence the term senile calcific aortic stenosis isused to describe the latter condition.Morphology.The morphologic hallmark of non-rheumatic, calcific aortic stenosis (with either tricuspidor bicuspid valves) is heaped-up calcified masses within the aortic cusps that ultimatelyprotrude through the outflow surfaces into the sinuses of Valsalva, preventing theopening of the cusps. The calcific deposits distort the cuspal architecture, primarily at thebases; the free cuspal edges are usually not involved (see Fig. 12-22A ). The calcificprocess begins in the valvular fibrosa, at the points of maximal cusp flexion (the marginsof attachment), and the microscopic layered architecture is largely preserved. An earlier,hemodynamically inconsequential stage of the calcification process is called aortic valvesclerosis. In aortic stenosis, the functional valve area is decreased sufficiently to causemeasurable obstruction to outflow; this subjects the left ventricular myocardium toprogressively increasing pressure overload.Notably, in contrast to rheumatic (and congenital) aortic stenosis (see Fig. 12-24E ),commissural fusion is not a usual feature of degenerative aortic stenosis. By the timevalves with aortic stenosis are seen at surgical resection or postmortem examination,however, the cusps may be secondarily fibrosed and thickened. The mitral valve isgenerally normal in patients with calcific aortic stenosis, although some patients mayhave direct extension of aortic valve calcific deposits onto the mitral anterior leaflet orindependent calcification of the mitral annulus. In contrast, virtually all patients withrheumatic aortic stenosis have concomitant and characteristic structural abnormalities ofthe mitral valve (see later).Clinical Features.In calcific aortic stenosis (superimposed on a previously normal or bicuspid aortic valve),the obstruction to left ventricular outflow leads to a gradually increasing pressuregradient across the calcified valve, which may reach 75 to 100 mm Hg in severe cases.These pressures imply severe aortic stenosis with a valve area of approximately 0.5 to 1cm2 (normal, approximately 4 cm2 ). Left ventricular pressure must consequently rise to200 mm Hg or more in such instances, and cardiac output is maintained by thedevelopment of concentric left ventricular (pressure overload) hypertrophy. Thehypertrophied myocardium tends to be ischemic (owing to decreased coronary bloodflow reserve and impaired microcirculatory perfusion even in the presence of
unobstructed coronary arteries), and angina pectoris may appear. There may beimpairment of both systolic and diastolic myocardial function, with symptoms of CHF.Eventually, cardiac decompensation may ensue. The onset of symptoms (angina, CHF, orsyncope, for which the pathophysiologic basis is poorly understood) in aortic stenosisheralds the exhaustion of compensatory cardiac hyperfunction and carries a poorprognosis (approximately 50% with angina will die within 5 years and 50% with CHFwill die within 2 years) if not treated by surgery. Since medical therapy is ineffective in severe symptomatic aortic stenosis, such patients require prompt relief of the obstructionby surgical valve replacement. In contrast, most asymptomatic patients have an excellentprognosis. Thus, the presence or absence of symptoms is the crucial factor thatdetermines management of aortic stenosis.Calcific Stenosis of Congenitally Bicuspid Aortic ValveOccurring with an estimated frequency of approximately 1.4% of live births, bicuspid aortic valves are generally 591neither stenotic nor symptomatic at birth or throughout early life. However, they arepredisposed to progressive degenerative calcification, similar to that occurring in aorticvalves with initially normal anatomy (see Fig. 12-22B ). In a congenitally bicuspid aorticvalve, there are only two functional cusps. The two cusps are usually of unequal size,with the larger cusp having a midline raphe, resulting from incomplete separation duringdevelopment; less frequently the cusps are of the same size and the raphe is absent. The raphe that represents the incomplete commissure is frequently a major site of calcificdeposits. Once stenosis is present, the clinical course is similar to that described above forcalcific aortic stenosis. Valves that become bicuspid owing to an acquired deformity(e.g., postinflammatory commissural fusion in rheumatic valve disease) have a conjoinedcusp containing the fused commissure that is generally twice the size of the nonconjoinedcusp. The mitral valve is normal in patients with a congenitally bicuspid aortic valve.Bicuspid aortic valves may also become incompetent as a result of aortic dilation, cuspprolapse, or infective endocarditis.Mitral Annular CalcificationDegenerative calcific deposits can develop in the fibrous ring (annulus) of the mitralvalve, visualized on gross inspection as irregular, stony hard, and occasionally ulceratednodules (2–5 mm in thickness) that lie behind the leaflets (see Fig. 12-22C and D ). Theprocess generally does not affect valvular function. In unusual cases, however, it maylead either to regurgitation by interfering with systolic contraction of the mitral valvering, to stenosis by impairing opening of the mitral leaflets, or to arrhythmias andoccasionally sudden death by the calcium deposits penetrating sufficiently deeply toimpinge on the atrioventricular conduction system. Because calcific nodules may providea site for thrombi that can embolize, some patients with mitral annular calcification havean increased risk of stroke. The calcific nodules can also be the nidus for infective
endocarditis. Heavy calcific deposits are sometimes visualized on echocardiography orseen as a distinctive, ring-like opacity on chest radiographs. Mitral annular calcification ismost common in women over age 60 and individuals with myxomatous mitral valve (seebelow) or elevated left ventricular pressure (as in systemic hypertension, aortic stenosis,or hypertrophic cardiomyopathy).MYXOMATOUS DEGENERATION OF THE MITRAL VALVE (MITRAL VALVE PROLAPSE)In this valvular abnormality, one or both mitral leaflets are "floppy" and prolapse, orballoon back into the left atrium during systole. Mitral valve prolapse, as it is knownclinically, is estimated to affect 3% or more of adults in the United States, most oftenyoung women. Myxomatous degeneration of the mitral valve, as it is knownpathologically, is one of the most common forms of valvular heart disease in theindustrialized world. Usually an incidental finding on physical examination, mitral valveprolapse may lead to serious complications in a small minority of those who are affected.Morphology.The characteristic anatomic change in myxomatous degeneration is intercordalballooning (hooding) of the mitral leaflets or portions thereof ( Fig. 12-23 ). The affectedleaflets are often enlarged, redundant, thick, and rubbery. Frequently involved, thetendinous cords are elongated, thinned, and occasionally ruptured. Annular dilation ischaracteristic, a finding that is rare in other causes of mitral insufficiency. Concomitantinvolvement of the tricuspid valve is present in 20% to 40% of cases, and the aortic orpulmonic valve (or both) may also be affected. Commissural fusion that typifiesrheumatic heart disease is absent. Histologically, the essential change is attenuation of thefibrosa layer of the valve, on which the structural integrity of the leaflet depends,accompanied by focally marked thickening of the spongiosa layer with deposition ofmucoid (myxomatous) material. The collagenous structure of the cords is attenuated.Secondary changes reflect the stresses and injury incident to the billowing leaflets: (1)fibrous thickening of the valve leaflets, particularly where they rub against each other; (2)linear fibrous thickening of the left ventricular endocardial surface where abnormallylong cords snap against it; (3) thickening of the mural endocardium of the left ventricle oratrium as a consequence of friction-induced injury induced by the prolapsing leaflets; (4)thrombi on the atrial surfaces of the leaflets, particularly in the recesses behind theballooned cusps, and on the atrial walls these thrombi contact; and (5) focal calcificationsat the base of the posterior mitral leaflet.Secondary changes of myxomatous degeneration can also occur in mitral valves havingregurgitation of another etiology (e.g., ischemic dysfunction).Pathogenesis.The basis for the changes within the valve leaflets and associated structures is unknown.Favored is the proposition that there is an underlying developmental defect of connectivetissue, possibly systemic. In keeping with this, myxomatous is degeneration of the mitral
valve is a common feature of Marfan syndrome (caused by mutations in the geneencoding fibrillin-1; Chapter 5 ), and occasionally occurs in other hereditary disorders ofconnective tissues. Even in the absence of these well-defined conditions, in someindividuals with the floppy mitral valve syndrome, there are hints of systemic structuralabnormalities in connective tissue, such as scoliosis, straight back, and high-archedpalate. Subtle defects in structural proteins may predispose connective tissues rich inmicrofibrils and elastin (such as cardiac valves) to damage by long-standinghemodynamic stress. Alternatively, the prominent destruction and remodeling of thevalvular connective tissue evident in this disorder may be induced by a primaryhemodynamic, cellular, or metabolic abnormality. Clinical Features.Mitral valve prolapse is defined and revealed by echocardiography. Most patients withmitral valve prolapse are asymptomatic, and the condition is discovered only on routineexamination by the presence of a midsystolic click as an incidental finding on physicalexamination. In those cases where mitral regurgitation occurs, there is a late systolic orsometimes holosystolic murmur. A minority of patients have chest pain mimickingangina, dyspnea, and 592
Figure 12-23 Myxomatous degeneration of the mitral valve. A, Long axis of left ventricle demonstratinghooding with prolapse of the posterior mitral leaflet into the left atrium (arrow). The left ventricle is onright in this apical four-chamber view. (Courtesy of William D. Edwards, M.D., Mayo Clinic, Rochester,MN.) B, Opened valve, showing pronounced hooding of the posterior mitral leaflet with thrombotic plaquesat sites of leaflet-left atrium contact (arrows). C, Opened valve with pronounced hooding from patient whodied suddenly (double arrows). Note also mitral annular calcification (arrowhead).fatigue or, curiously, psychiatric manifestations, such as depression, anxiety reactions,and personality disorders. Although the great majority of patients with mitral valveprolapse have no untoward effects, approximately 3% develop one of four seriouscomplications: • Infective endocarditis, much more frequent in these patients than in the general population • Mitral insufficiency requiring surgery, either slow onset attributed to leaflet deformity, dilation of the mitral annulus, or cordal lengthening, or sudden onset owing to cordal rupture • Stroke or other systemic infarct, resulting from embolism of leaflet thrombi
• Arrhythmias, both ventricular and atrial. Sudden death occurs occasionally (see Fig. 12-23C ). The mechanism of ventricular arrhythmia is unknown in most cases.The risk of these complications is higher in men, older patients, and those with eitherarrhythmias or some mitral regurgitation, as evidenced by holosystolic murmurs and left-sided chamber enlargement. For patients with symptoms or at high risk for serious complications, surgical valve repair is often done.RHEUMATIC FEVER AND RHEUMATIC HEART DISEASERheumatic fever (RF) is an acute, immunologically mediated, multisystem inflammatorydisease that occurs a few weeks following an episode of group A streptococcalpharyngitis. Acute rheumatic carditis during the active phase of RF may progress tochronic rheumatic heart disease (RHD).The most important consequence of RF are chronic valvular deformities, characterizedprincipally by deforming fibrotic valvular disease (particularly mitral stenosis), whichproduces permanent dysfunction and severe, sometimes fatal, cardiac problems decadeslater. Rheumatic fever does not follow infections by streptococci at other sites, such asthe skin. The incidence and mortality rate of RF have declined remarkably in many partsof the world over the past 30 years, owing to improved socioeconomic conditions, rapiddiagnosis and treatment of streptococcal pharyngitis, and an unexplained decrease in thevirulence of group A streptococci. Nevertheless, in developing countries, and in many crowded, economically depressed urban areas in the Western world, RHD remains animportant public health problem. 593
Figure 12-24 Acute and chronic rheumatic heart disease. A, Acute rheumatic mitral valvulitissuperimposed on chronic rheumatic heart disease. Small vegetations (verrucae) are visible along the line ofclosure of the mitral valve leaflet (arrows). Previous episodes of rheumatic valvulitis have caused fibrousthickening and fusion of the chordae tendineae. B, Microscopic appearance of Aschoff body in a patientwith acute rheumatic carditis. The myocardial interstitium has a circumscribed collection of mononuclearinflammatory cells, including some large histiocytes with prominent nucleoli and a prominent binuclearhistiocyte, and central necrosis. C and D, Mitral stenosis with diffuse fibrous thickening and distortion ofthe valve leaflets, commissural fusion (arrows), and thickening and shortening of the chordae tendineae.Marked dilation of the left atrium is noted in the left atrial view (C). D, Opened valve. Noteneovascularization of anterior mitral leaflet (arrow). E, Surgically removed specimen of rheumatic aorticstenosis, demonstrating thickening and distortion of the cusps with commissural fusion (E, reproducedfrom Schoen FJ, St. John-Sutton M: Contemporary issues in the pathology of valvular heart disease.
Human Pathol 18:568, 1967.)Morphology.Key pathologic features of acute RF and chronic RHD are shown in Figure 12-24 .During acute RF, focal inflammatory lesions are found in various tissues. They are mostdistinctive within the heart, where they are called Aschoff bodies. They consist of foci ofswollen eosinophilic collagen surrounded by lymphocytes (primarily T cells), occasionalplasma cells, and plump macrophages called Anitschkow cells (pathognomonic for RF).These distinctive cells have abundant cytoplasm and central round-to-ovoid nuclei inwhich the chromatin is disposed in a central, slender, wavy ribbon (hence the designation"caterpillar cells"). Some of the larger macrophages become multinucleated to formAschoff giant cells.During acute RF, diffuse inflammation and Aschoff bodies may be found in any of thethree layers of the heart—pericardium, myocardium, or endocardium—hence the lesion iscalled a pancarditis. In the pericardium, the inflammation is accompanied by a fibrinousor serofibrinous pericardial exudate, described as a "bread-and-butter" pericarditis, which 594generally resolves without sequelae. The myocardial involvement—myocarditis—takesthe form of scattered Aschoff bodies within the interstitial connective tissue, oftenperivascular.Concomitant involvement of the endocardium and the left-sided valves by inflammatoryfoci typically results in fibrinoid necrosis within the cusps or along the tendinous cordson which sit small (1- to 2-mm) vegetations—verrucae—along the lines of closure. Theseirregular, warty projections probably arise from the precipitation of fibrin at sites oferosion, related to underlying inflammation and collagen degeneration, and cause littledisturbance in cardiac function. Subendocardial lesions, perhaps exacerbated byregurgitant jets, may induce irregular thickenings called MacCallum plaques, usually inthe left atrium.Chronic RHD is characterized by organization of the acute inflammation and subsequentfibrosis. In particular, the valvular leaflets become thickened and retracted, causingpermanent deformity. The cardinal anatomic changes of the mitral (or tricuspid) valve areleaflet thickening, commissural fusion and shortening, and thickening and fusion ofthe tendinous cords (see Fig. 12-24 ). In chronic disease, the mitral valve is virtuallyalways abnormal, but involvement of another valve, such as the aortic, may be the mostclinically important in some cases. Microscopically there is diffuse fibrosis and oftenneovascularization that obliterate the originally layered and avascular leaflet architecture.Aschoff bodies are replaced by fibrous scar so that diagnostic forms of these lesions arerarely seen in surgical specimens or autopsy tissue from patients with chronic RHD.
Fibrosis resulting from healed inflammation outside the valves is usually of noconsequence.RHD is overwhelmingly the most frequent cause of mitral stenosis (99% of cases). Inpatients with RHD, the mitral valve alone is involved in 65% to 70% of cases, and mitraland aortic in about 25%; similar but generally less severe fibrous thickenings andstenoses can occur in the tricuspid valve and rarely in the pulmonic. Fibrous bridgingacross the valvular commissures and calcification create "fish mouth" or "buttonhole"stenoses. With tight mitral stenosis, the left atrium progressively dilates and may harbormural thrombus either in the appendage or along the wall. Long-standing congestivechanges in the lungs may induce pulmonary vascular and parenchymal changes and intime lead to right ventricular hypertrophy. The left ventricle is generally normal withisolated pure mitral stenosis.Pathogenesis.It is strongly suspected that acute rheumatic fever is a hypersensitivity reaction inducedby group A streptococci, but the exact pathogenesis remains uncertain despite many yearsof investigation. It is thought that antibodies directed against the M proteins of certain strains of streptococci cross-react with glycoprotein antigens in the heart, joints, and othertissues. The onset of symptoms 2 to 3 weeks after infection and the absence ofstreptococci from the lesions support the concept that RF results from an immuneresponse against the offending bacteria. Because the nature of cross-reacting antigens hasbeen difficult to define, it has also been suggested that the streptococcal infection evokesan autoimmune response against self-antigens. Only a minority of infected patientsdevelop RF, suggesting that genetic susceptibility influences the hypersensitivityreaction. The proposed pathogenetic sequence and time course of the disease aresummarized in Figure 12-25 . The chronic sequelae result from progressive fibrosis dueto both healing of the acute inflammatory lesions and the turbulence induced by ongoingvalvular deformities.Clinical Features.RF is characterized by a constellation of findings that includes as major manifestations(1) migratory polyarthritis of the large joints, (2) carditis, (3) subcutaneous nodules, (4)erythema marginatum of the skin, and (5) Sydenham chorea, a neurologic disorder withinvoluntary purposeless, rapid movements. The diagnosis is established by the so-calledJones criteria: evidence of a preceding group A streptococcal infection, with the presenceof two of the major manifestations listed above or one major and two minormanifestations (nonspecific signs and symptoms that include fever, arthralgia, or elevatedblood levels of acute phase reactants).Acute rheumatic fever typically occurs 10 days to 6 weeks after an episode of pharyngitiscaused by group A streptococci in about 3% of patients. Acute RF appears most often inchildren between ages 5 and 15, but about 20% of first attacks occur in middle to laterlife. Although pharyngeal cultures for streptococci are negative by the time the illnessbegins, antibodies to one or more streptococcal enzymes, such as streptolysin O and
DNAse B, are present and can be detected in the sera of most patients. The predominantclinical manifestations are those of arthritis and carditis. Arthritis is far more common inadults than in children. It typically begins with migratory polyarthritis accompanied byfever in which one large joint after another becomes painful and swollen for a period ofdays and then subsides spontaneously, leaving no residual disability. Clinical featuresrelated to acute carditis include pericardial friction rubs, weak heart sounds, tachycardia,and arrhythmias. The myocarditis may cause cardiac dilation that may evolve tofunctional mitral valve insufficiency or even heart failure. Overall the prognosis for theprimary attack is generally good, and only 1% of patients die from fulminant RF.After an initial attack, there is increased vulnerability to reactivation of the disease withsubsequent pharyngeal infections, and the same manifestations are likely to appear witheach recurrent attack. Carditis is likely to worsen with each recurrence, and damage iscumulative. Other hazards include embolization from mural thrombi, primarily within theatria or their appendages, and infective endocarditis superimposed on deformed valves.Chronic rheumatic carditis usually does not cause clinical manifestations for years oreven decades after the initial episode of RF. The signs and symptoms of valvular diseasedepend on which cardiac valve(s) are involved. In addition to various cardiac murmurs,cardiac hypertrophy and dilation, and heart failure, patients with chronic rheumatic heartdisease may suffer from arrhythmias (particularly atrial fibrillation in the setting of mitralstenosis), thromboembolic complications, and infective endocarditis. The long-termprognosis is highly variable. In some cases, there is a relentless cycle of valvulardeformity yielding hemodynamic abnormality, which begets further deforming fibrosis.Surgical repair of diseased valves by incising the fused mitral valve commissures andreplacement with prosthetic devices has greatly improved the outlook for patients withRHD. 595
Figure 12-25 The pathogenetic sequence and key morphologic features of acute rheumatic heart disease.INFECTIVE ENDOCARDITIS (IE)Infective endocarditis, one of the most serious of all infections, is characterized bycolonization or invasion of the heart valves or the mural endocardium by a microbe,leading to the formation of bulky, friable vegetations composed of thrombotic debris andorganisms, often associated with destruction of the underlying cardiac tissues. The aorta, aneurysmal sacs, other blood vessels, and prosthetic devices can also becomeinfected. Although fungi, rickettsiae (Q fever), and chlamydiae have at one time oranother been responsible for these infections, most cases are bacterial (bacterialendocarditis). Prompt diagnosis and effective treatment of IE can significantly alter theoutlook for the patient.
Traditionally, IE has been classified on clinical grounds into acute and subacute forms.This subdivision expresses the range of severity of the disease and its tempo, determinedin large part by the virulence of the infecting microorganism and whether underlyingcardiac disease is present. Acute endocarditis describes a destructive, tumultuousinfection, frequently of a previously normal heart valve, with a highly virulent organism,that leads to death within days to weeks of more than 50% of patients despite antibioticsand surgery. In contrast, organisms of low virulence can cause infection in a previouslyabnormal heart, particularly on deformed valves. In such cases, the disease may appearinsidiously and, even untreated, pursue a protracted course of weeks to months (subacuteendocarditis). Most patients with subacute IE recover after appropriate antibiotic therapy.The highly virulent organisms of acute endocarditis tend to produce necrotizing,ulcerative, invasive valvular infections that are difficult to cure by antibiotics and usuallyrequire surgery. In contrast, the lower-virulence organisms of subacute disease are lessdestructive than those of acute endocarditis, 596and the vegetations often show evidence of healing. Both the clinical and themorphologic patterns, however, are points along a spectrum, and a clear delineationbetween acute and subacute disease does not always exist.Etiology and Pathogenesis.As stated previously, IE may develop on previously normal valves, but a variety ofcardiac and vascular abnormalities predispose to this form of infection. In years past,RHD was the major antecedent disorder, but more common now are myxomatous mitralvalve, degenerative calcific valvular stenosis, bicuspid aortic valve (whether calcified ornot), and artificial (prosthetic) valves. Host factors such as neutropenia,immunodeficiency, malignancy, therapeutic immunosuppression, diabetes mellitus, andalcohol or intravenous drug abuse are predisposing influences. Sterile platelet-fibrindeposits that accumulate at sites of impingement of jet streams caused by pre-existingcardiac disease or indwelling vascular catheters may also be important in thedevelopment of endocarditis.The causative organisms differ somewhat in the major high-risk groups. Endocarditis ofnative but previously damaged or otherwise abnormal valves is caused most commonly(50% to 60% of cases) by Streptococcus viridans; this is not the organism responsible forrheumatic disease discussed earlier. In contrast, the more virulent S. aureus organismscommonly found on the skin can attack either healthy or deformed valves and areresponsible for 10% to 20% of cases overall; S. aureus is the major offender inintravenous drug abusers. The roster of the remaining bacteria includes enterococci
Figure 12-26 Infective (bacterial) endocarditis. A, Endocarditis of mitral valve (subacute, caused by Strep.viridans). The large, friable vegetations are denoted by arrows. B, Acute endocarditis of congenitallybicuspid aortic valve (caused by Staph. aureus) with extensive cuspal destruction and ring abscess (arrow).C, Histologic appearance of vegetation of endocarditis with extensive acute inflammatory cells and fibrin.Bacterial organisms were demonstrated by tissue Gram stain. (C, reproduced from Schoen FJ: Surgicalpathology of removed natural and prosthetic heart valves. Human Pathol 18:558, 1987.) D, Healedendocarditis, demonstrating mitral valvular destruction but no active vegetations.and the so-called HACEK group (Haemophilus, Actinobacillus, Cardiobacterium,Eikenella, and Kingella), all commensals in the oral cavity. Prosthetic valve endocarditisis caused most commonly by coagulase-negative staphylococci (e.g., S. epidermidis).Other agents causing endocarditis include gram-negative bacilli and fungi. In about 10%of all cases of endocarditis, no organism can be isolated from the blood ("culture-negative" endocarditis) because of prior antibiotic therapy, difficulties in isolating theoffending agent, or because deeply embedded organisms within the enlarging vegetationare not released into the blood.Foremost among the factors predisposing to the development of endocarditis is seeding ofthe blood with microbes. The portal of entry of the agent into the bloodstream may be anobvious infection elsewhere, a dental or surgical procedure that causes a transientbacteremia, injection of contaminated material directly into the bloodstream byintravenous drug users, or an occult source from the gut, oral cavity, or trivial injuries.Recognition of predisposing anatomic substrates and clinical conditions causingbacteremia facilitates prevention by appropriate antibiotic prophylaxis. Morphology.
In both the subacute and acute forms of the disease, friable, bulky, and potentiallydestructive vegetations containing fibrin, inflammatory cells, and bacteria or otherorganisms are present on the heart valves ( Fig. 12-26 ). The aortic and mitral valves 597are the most common sites of infection, although the valves of the right heart may also beinvolved, particularly in intravenous drug abusers. The vegetations may be single ormultiple and may involve more than one valve. Vegetations sometimes erode into theunderlying myocardium to produce an abscess cavity (ring abscess), one of severalimportant complications. The appearance of the vegetations is influenced by the type oforganism responsible, the degree of host reaction to the infection, and previous antibiotictherapy. Fungal endocarditis, for example, tends to cause large vegetations than doesbacterial infection. Systemic emboli may occur at any time because of the friable natureof the vegetations, and they may cause infarcts in the brain, kidneys, myocardium, andother tissues. Because the embolic fragments contain large numbers of virulentorganisms, abscesses often develop at the sites of such infarcts (septic infarcts).The vegetations of subacute endocarditis are associated with less valvular destructionthan those of acute endocarditis, although the distinction between the two forms may bedifficult. Microscopically, the vegetations of typical subacute IE often have granulationtissue at their bases (suggesting chronicity). With the passage of time, fibrosis,calcification, and a chronic inflammatory infiltrate may develop.Figure 12-27 compares the gross appearance of the vegetations of infective endocarditiswith those of the valve lesions characterized by non-infective thrombotic vegetations(NBTE), and with the endocarditis of systemic lupus erythematosus (SLE), calledLibman-Sacks endocarditis (see later).Figure 12-27 Diagrammatic comparison of the lesions in the four major forms of vegetative endocarditis.The rheumatic fever phase of RHD (rheumatic heart disease) is marked by a row of small, wartyvegetations along the lines of closure of the valve leaflets. IE (infective endocarditis) is characterized bylarge, irregular masses on the valve cusps that can extend onto the chordae (see Fig. 12-26 ). NBTE(nonbacterial thrombotic endocarditis) typically exhibits small, bland vegetations, usually attached at theline of closure. One or many may be present (see Fig. 12-28 ). LSE (Libman-Sacks endocarditis) has small
or medium-sized vegetations on either or both sides of the valve leaflets.Clinical Features.Fever is the most consistent sign of IE. However, with subacute disease, particularly inthe elderly, fever may be slight or absent, and the only manifestations are sometimesnonspecific fatigue, loss of weight, and a flulike syndrome. In contrast, acute endocarditishas a stormy onset with rapidly developing fever, chills, weakness, and lassitude.Complications generally begin within the first weeks of the onset of the disease. Theymay be immunologically mediated as exemplified by glomerulonephritis, owing totrapping of antigen-antibody complexes, which can cause hematuria, albuminuria, orrenal failure ( Chapter 20 ). Sometimes complications involving the heart or extracardiacsites call attention to endocarditis. Murmurs are present in 90% of patients with left-sidedlesions but may merely relate to the pre-existing cardiac abnormality predisposing to IE.The so-called Duke criteria ( Table 12-8 ) provide a standardized assessment of patientswith suspected IE that integrates factors predisposing patients to the development of IE,blood-culture evidence of infection, echocardiographic findings, and clinical andlaboratory information in assessing patients with potential IE. Previously important clinical findings secondary to microemboli are now uncommon. They include petechiae,red, linear, or flame-shaped streaks in the nail bed of the digits (splinter or subungualhemorrhages), erythematous or hemorrhagic nontender lesions on the palms or soles(Janeway lesions), subcutaneous nodules in the pulp of the digits (Osler nodes). Alsoincluded are retinal hemorrhages (Roth spots) in the eyes owing to the shortened clinicalcourse of the disease as a result of antibiotic therapy.Prevention of IE is important and is done by the prophylactic use of antibiotics in thepatient with some form of cardiac anomaly or artificial valve who is about to have adental, surgical, or other invasive procedure. 598 * TABLE 12-8 -- Diagnostic Criteria for Infective EndocarditisPathologic CriteriaMicroorganisms, demonstrated by culture or histologic examination, in a vegetation,embolus from a vegetation, or intracardiac abscessHistologic confirmation of active endocarditis in vegetation or intracardiac abscessClinical CriteriaMajorPositive blood culture(s) indicating characteristic organism or persistence of unusualorganism
Echocardiographic findings, including valve-related or implant-related mass or abscess, orpartial separation of artificial valveNew valvular regurgitationMinorPredisposing heart lesion or intravenous drug useFeverVascular lesions, including arterial petechiae, subungual/splinter hemorrhages, emboli,septic infarcts, mycotic aneurysm, intracranial hemorrhage, Janeway lesions †Immunologic phenomena, including glomerulonephritis, Osler nodes, Roth spots, ‡ §rheumatoid factorMicrobiologic evidence, including single culture showing uncharacteristic organismEchocardiographic findings consistent with but not diagnostic of endocarditis, includingnew valvular regurgitation, pericarditis*Diagnosis by these guidelines, often called the Duke Criteria, requires either pathologic or clinical criteria;if clinical criteria are used, 2 major, 1 major + 3 minor, or 5 minor criteria are required for diagnosis.Modified from Durack DT, et al: Am J Med, 96:200, 1994 and Karchmer AW, In Braunwald E, Zipes DP,Libby P (eds): Heart Disease. A Textbook of Cardiovascular Medicine, 6th ed. Philadelphia, WB SaundersCo., 2001, p. 1723.†Janeway lesions are small erythematous or hemorrhagic, macular, nontender lesions on the palms andsoles and are the consequence of septic embolic events.‡Osler nodes are small, tender subcutaneous nodules that develop in the pulp of the digits or occasionallymore proximally in the fingers and persist for hours to several days.§Roth spots are oval retinal hemorrhages with pale centers.NONINFECTED VEGETATIONSNonbacterial Thrombotic Endocarditis (NBTE)NBTE is characterized by the deposition of small masses of fibrin, platelets, and otherblood components on the leaflets of the cardiac valves. In contrast to the vegetations ofIE, discussed previously, the valvular lesions of NBTE are sterile and do not containmicroorganisms. NBTE is often encountered in debilitated patients, such as those withcancer or sepsis—hence the previously used term marantic endocarditis. Although thelocal effect on the valves is usually unimportant, NBTE may achieve clinical significanceby producing emboli and resultant infarcts in the brain, heart, or elsewhere.Morphology.In contrast to IE, the vegetations of NBTE are sterile, nondestructive, and small (1 to 5mm), and occur singly or multiply along the line of closure of the leaflets or cusps ( Fig.12-28 ). Histologically, they are composed of bland thrombus without accompanying
inflammatory reaction or induced valve damage. Should the patient survive theunderlying disease, organization may occur, leaving delicate strands of fibrous tissue.Pathogenesis.NBTE frequently occurs concomitantly with venous thromboses or pulmonary embolism,suggesting a common origin in a hypercoagulable state with systemic activation of bloodcoagulation such as disseminated intravascular coagulation ( Chapter 4 ). This may berelated to some underlying disease, such as a cancer, and, in particular, mucinousadenocarcinomas of the pancreas. The striking association with mucinousadenocarcinomas in general may relate to the procoagulant effect of circulating mucin,and thus NBTE can be a part of the Trousseau syndrome ( Chapter 7 ). Lesions of NBTE,however, are also seen occasionally in association with nonmucin-producing malignancy,such as acute promyelocytic leukemia, and in other debilitating diseases or conditions(e.g., hyperestrogenic states, extensive burns, or sepsis) promoting hypercoagulability.Endocardial trauma, as from an indwelling catheter, is also a well-recognizedpredisposing condition, and one frequently notes right-sided valvular and endocardialthrombotic lesions along the track of a Swan-Ganz pulmonary artery catheter.Endocarditis of Systemic Lupus Erythematosus (Libman-Sacks Disease)In SLE, mitral and tricuspid valvulitis with small, sterile vegetations, called Libman-Sacks endocarditis is occasionally encountered.Morphology.The lesions are small single or multiple, sterile, granular pink vegetations ranging from 1to 4 mm in diameter. The lesions may be located on the undersurfaces of theatrioventricular valves, on the valvular endocardium, on the cords, or on the muralendocardium of atria or ventricles. Histologically the verrucae consist of a finelygranular, fibrinous eosinophilic material that may contain hematoxylin bodies (the tissueequivalent of the lupus erythematosus cell of the blood and bone marrow, see Chapter 6 ).An intense valvulitis may be present, characterized by fibrinoid necrosis of the valvesubstance that is often contiguous with the vegetation. Leaflet vegetations can be difficultin some cases to distinguish from those of IE or NBTE (see Fig. 12-27 ). Subsequentfibrosis and serious deformity can result that resemble chronic RHD and require surgery.Thrombotic heart valve lesions with sterile vegetations or rarely fibrous thickeningcommonly occur with the antiphospholipid 599
Figure 12-28 Nonbacterial thrombotic endocarditis (NBTE). A, Nearly complete row of thromboticvegetations along the line of closure of the mitral valve leaflets (arrows). B, Photomicrograph of NBTE,showing bland thrombus, with virtually no inflammation in the valve cusp (c) or the thrombotic deposit (t).The thrombus is only loosely attached to the cusp (arrow).syndrome (discussed in Chapter 4 ). Circulating antiphospholipid antibodies are also  commonly associated with venous or arterial thrombosis, recurrent pregnancy loss, orthrombocytopenia. The mitral valve is more frequently involved than the aortic;regurgitation is the usual functional abnormality.CARCINOID HEART DISEASECarcinoid heart disease is the cardiac manifestation of the systemic syndrome caused bycarcinoid tumors. It involves the endocardium and valves of the right heart. Cardiaclesions are present in one half of patients with the carcinoid syndrome which ischaracterized by episodic flushing of the skin, cramps, nausea, vomiting, and diarrhea(see Chapter 17 ).Morphology.The cardiovascular lesions associated with the carcinoid syndrome are distinctive,consisting of fibrous intimal thickenings on the inside surfaces of the cardiac chambersand valvular leaflets. They
Figure 12-29 Carcinoid heart disease. A, Characteristic endocardial fibrotic lesion involving the rightventricle and tricuspid valve. B, Microscopic appearance of carcinoid heart disease with intimal thickening.Movat stain shows underlying myocardial elastic tissue black and acid mucopolysaccharides blue-green.are located mainly in the right ventricle, tricuspid and pulmonic valves, and occasionallyin the major blood vessels ( Fig. 12-29 ). The endocardial plaquelike thickenings are composed predominantly of smooth muscle cells and sparse collagen fibers embedded inan acid mucopolysaccharide-rich matrix material. Elastic fibers are not present.Underlying structures are intact, including the valve layers and the subendocardial elastictissue layer. Occasionally, left-sided lesions are also encountered.The clinical and pathologic findings relate to the elaboration by carcinoid tumors of avariety of bioactive products, such as serotonin (5-hydroxytryptamine), kallikrein,bradykinin, histamine, prostaglandins, and tachykinins. Which of the secretory productsinduces the syndrome or the cardiac pathology is still not clear. Nevertheless, plasmalevels of serotonin and urinary excretion of the serotonin metabolite 5-hydroxyindoleacetic acid correlate with the severity of the right heart lesions.  600The fact that the cardiac changes are largely right-sided is explained by inactivation ofboth serotonin and bradykinin in the blood during passage through the lungs by themonoamine oxidase present in the pulmonary vascular endothelium. In the absence ofhepatic metastases, gastrointestinal carcinoids (with venous drainage via the portalsystem) do not usually induce the carcinoid syndrome because there is rapid metabolismof serotonin during passage of blood through the liver. In contrast, primary carcinoidtumors in organs outside of the portal system of venous drainage (e.g., ovary and lung),may induce the syndrome without producing hepatic metastases. Left-sided lesions canoccur when blood containing the responsible mediator enters the left heart owing toincomplete inactivation because of very high blood levels. Left side lesions may also be aconsequence of a pulmonary carcinoid or patent foramen ovale with right to left flow.
Left-sided valve lesions with pathologic features similar to those seen in the carcinoidsyndrome have been reported to complicate the use of fenfluramine and phentermine(fenphen), appetite suppressants used for the treatment of obesity; these agents may affectsystemic serotonin metabolism. Occasionally, similar left-sided plaques are found in patients who receive methysergide or ergotamine therapy for migraine headaches; theseserotonin analogs are metabolized to serotonin as they pass through the pulmonaryvasculature.COMPLICATIONS OF ARTIFICIAL VALVESReplacement of damaged cardiac valves with prostheses has now become a common andoften life-saving mode of therapy. Artificial valves fall primarily into two categories:  (1) mechanical prostheses using different types of rigid, mobile occluders composed ofnonphysiologic biomaterials, such asFigure 12-30 Complications of artificial heart valves. A, Thrombosis of a mechanical prosthetic valve. B,Calcification with secondary tearing of a porcine bioprosthetic heart valve, viewed from the inflow aspect.caged balls, tilting disks, or hinged semicircular flaps, and (2) tissue valves, usuallybioprostheses consisting of chemically treated animal tissue, especially porcine aorticvalve tissue, which has been preserved in a dilute glutaraldehyde solution andsubsequently mounted on a prosthetic frame. Tissue valves are flexible and functionsomewhat like natural semilunar valves.Approximately 60% of substitute valve recipients develop a serious prosthesis-relatedproblem within 10 years postoperatively. Although the frequency of total prosthetic valve-related events is similar among valve types, the nature of these complicationsdiffers among types ( Table 12-9 and Fig. 12-30 ).
• Thromboembolic complications constituting local obstruction of the prosthesis by thrombus or distant thromboemboli are the major problem with mechanical valves ( Fig. 12-30A ). This necessitates long-term anticoagulation in patients with these devices. However, hemorrhagic 601 complications such as stroke or gastrointestinal bleeding may arise secondarily in patients who receive long-term anticoagulation. • Infective endocarditis is an infrequent but potentially serious complication. Endocarditis is located at the prosthesis-tissue interface, causing a ring abscess, which can eventually lead to a paravalvular regurgitant blood leak. In addition, vegetations may directly involve bioprosthetic valvular cusps. The major organisms causing such infections are staphylococcal skin contaminants (e.g., S. aureus, S. epidermidis), streptococci, and fungi. • Structural deterioration uncommonly causes failure of contemporary mechanical valves. However, it is a major failure mode of bioprostheses, with calcification and/or tearing causing secondary regurgitation (see Fig. 12-30B ). • Other complications include hemolysis induced by high blood shear, mechanical obstruction to flow inherent in all artificial valves, and inadequate or exuberant healing, causing a paravalvular leak or overgrowth of fibrous tissue, respectively. TABLE 12-9 -- Causes of Failure of Cardiac Valve ProsthesesThrombosis/thromboembolismAnticoagulant-related hemorrhageProsthetic valve endocarditisStructural deterioration (intrinsic)Wear, fracture, poppet failure in ball valves, cuspal tear, calcificationNonstructural dysfunctionGranulation tissue, suture, tissue entrapment, paravalvular leak, disproportion,hemolytic anemia, noiseCardiomyopathiesThe previous sections emphasize that myocardial dysfunction occurs commonly butsecondarily in a number of different conditions such as ischemic heart disease,hypertension, and valvular heart disease. Far less frequently observed is disease whosecause is intrinsic to the myocardium. Myocardial diseases are a diverse group thatincludes inflammatory disorders (myocarditis), immunologic diseases, systemic
metabolic disorders, muscular dystrophies, genetic abnormalities in cardiac muscle cells,and an additional group of diseases of unknown etiology.The term cardiomyopathy (literally, heart muscle disease) is used to describe heartdisease resulting from a primary abnormality in the myocardium. Although chronic myocardial dysfunction due to ischemia should be excluded from the cardiomyopathyrubric, the term ischemic cardiomyopathy has gained some popularity among clinicians todescribe CHF caused by CAD (as discussed in the section "Chronic Ischemic HeartDisease").In many cases cardiomyopathies are idiopathic (i.e., of unknown cause). However, amajor advance in our understanding of myocardial diseases, previously consideredidiopathic, has been the demonstration that specific genetic abnormalities in cardiacenergy metabolism or structural and contractile proteins underlie myocardial dysfunctionin many patients. Thus, etiologic distinctions have become somewhat blurred in   recent years. Moreover, myocardial disease of diverse and even unknown etiologies mayhave a similar morphologic appearance. Therefore, our discussion avoids thecontroversies associated with classification schemes and emphasizes clinicopathologic,etiologic, and mechanistic concepts.Without additional data, the clinician encountering a patient with myocardial disease isusually unaware of the etiology. Hence the clinical approach is largely determined by oneof the following three clinical, functional, and pathologic patterns ( Fig. 12-31 and Table12-10 ): • Dilated cardiomyopathy • Hypertrophic cardiomyopathy • Restrictive cardiomyopathyAmong these three categories, the dilated form is most common (90% of cases), and therestrictive is least prevalent. Within the hemodynamic patterns of myocardialdysfunction, there is a spectrum of clinical severity, and overlap of clinical features oftenoccurs between groups. Moreover, each of these patterns can be either idiopathic or dueto a specific identifiable cause ( Table 12-11 ) or secondary to primary extramyocardialdisease.Endomyocardial biopsies are used in the diagnosis and management of patients withmyocardial disease and in cardiac transplant recipients. Endomyocardial biopsy involvesinserting a device (called a bioptome) transvenously into the right side of the heart andsnipping a small piece of septal myocardium in its jaws, which is then analyzed by apathologist.DILATED CARDIOMYOPATHYThe term dilated cardiomyopathy (DCM) is applied to a form of cardiomyopathycharacterized by progressive cardiac dilation and contractile (systolic) dysfunction,usually with concomitant hypertrophy. It is sometimes called congestive cardiomyopathy.
Figure 12-31 Graphic representation of the three distinctive and predominant clinical-pathologic-functionalforms of myocardial disease. 602
TABLE 12-10 -- Cardiomyopathy and Indirect Myocardial Dysfunction: Functional Patterns and Causes Left Indirect Ventricular MyocardialFunctional Ejection Mechanisms of Dysfunction (NotPattern Fraction * Heart Failure Causes Cardiomyopathy)Dilated <40% Impairment of Idiopathic; alcohol; Ischemic heart contractility peripartum; genetic; disease; valvular (systolic myocarditis; heart disease; dysfunction) hemochromatosis; hypertensive heart chronic anemia; disease; congenital doxorubicin heart disease (Adriamycin); sarcoidosisHypertrophic 50–80% Impairment of Genetic; Friedreich Hypertensive heart compliance ataxia; storage disease; aortic (diastolic diseases; infants of stenosis dysfunction) diabetic mothersRestrictive 45–90% Impairment of Idiopathic; Pericardial compliance amyloidosis; constriction (diastolic radiation-induced dysfunction) fibrosis*Normal, approximately 50–65%. TABLE 12-11 -- Conditions Associated with Heart Muscle DiseasesCardiac InfectionsVirusesChlamydiaRickettsiaBacteriaFungiProtozoaToxinsAlcoholCobalt
CatecholaminesCarbon monoxideLithiumHydrocarbonsArsenicCyclophosphamideDoxorubicin (Adriamycin) and daunorubicinMetabolicHyperthroidismHypothyroidismHyperkalemiaHypokalemiaNutritional deficiency (protein, thiamine, other avitaminoses)HemochromatosisNeuromuscular DiseaseFriedreich ataxiaMuscular dystrophyCongenital atrophiesStorage Disorders and Other DepositionsHunter-Hurler syndromeGlycogen storage diseaseFabry diseaseAmyloidosisInfiltrativeLeukemiaCarcinomatosisSarcoidosisRadiation-induced fibrosisImmunologicMyocarditis (several forms)
Post-transplant rejectionAlthough it is recognized that approximately 25% to 35% of individuals with DCM havea familial (genetic) form, DCM can result from a number of acquired myocardial insultsthat ultimately yield a similar clinicopathologic pattern. These include toxicities(including chronic alcoholism, a history of which can be elicited in 10% to 20% ofpatients), myocarditis (an inflammatory disorder that precedes the development ofcardiomyopathy in at least some cases, as documented by endomyocardial biopsy), andpregnancy-associated nutritional deficiency or immunologic reaction. In some patients,the cause of DCM is unknown; such cases are appropriately designated as idiopathicdilated cardiomyopathy.Morphology.In DCM, the heart is usually heavy, often weighing two to three times normal, and largeand flabby, with dilation of all chambers ( Fig. 12-32 ). Nevertheless, because of the wallthinning that accompanies dilation, the ventricular thickness may be less than, equal to, orgreater than normal. Mural thrombi are common and may be a source of thromboemboli.There are no primary valvular alterations, and mitral or tricuspid regurgitation, whenpresent, results from left ventricular chamber dilation (functional regurgitation). Thecoronary arteries are usually free of significant narrowing, but any coronary arteryobstructions present are insufficient to explain the degree of cardiac dysfunction.The histologic abnormalities in idiopathic DCM also are nonspecific and usually donot reflect a specific etiologic agent. Moreover, their severity does not necessarilyreflect the degree of dysfunction or the patients prognosis. Most muscle cells arehypertrophied with enlarged nuclei, but many are attenuated, stretched, and irregular.Interstitial and endocardial fibrosis of variable degree is present, and smallsubendocardial scars may replace individual cells or groups of cells, probably reflectinghealing of previous secondary myocyte ischemic necrosis caused by hypertrophy-inducedimbalance between perfusion, supply and demand.Pathogenesis.Historically, the etiologic associations in dilated cardiomyopathy have includedmyocardial inflammatory 603
Figure 12-32 Dilated cardiomyopathy. A, Gross photograph. Four-chamber dilatation and hypertrophy areevident. There is granular mural thrombus at the apex of the left ventricle (on the right in this apical four-chamber view). The coronary arteries were unobstructed. B, Histology demonstrating variable myocytehypertrophy and interstitial fibrosis (collagen is highlighted as blue in this Masson trichrome stain).disease (myocarditis), toxicities (especially alcohol), and the peripartum state. Morerecently, the importance of genetic factors has been appreciated, and many cases that inpast years would have been called "idiopathic" can now be demonstrated to result fromspecific molecular defects related to cardiac muscle functions. Each of these subgroupswill be described below. • Myocarditis. Viral nucleic acids from coxsackievirus B and other enteroviruses have been detected in the myocardium of some patients, and sequential endomyocardial biopsies have demonstrated progression from myocarditis to DCM in others, suggesting that, in at least some cases, DCM was a consequence of myocarditis. Myocarditis is discussed in more detail below. • Alcohol or other toxicity. Alcohol abuse is also strongly associated with the development of dilated cardiomyopathy, raising the possibility that ethanol toxicity ( Chapter 9 ) or a secondary nutritional disturbance may be the cause of the myocardial injury. Alcohol or its metabolites (especially acetaldehyde) have a direct toxic effect on the myocardium. Nevertheless, the cause-and-effect relationship with alcohol alone remains uncertain, and no morphologic features serve to distinguish alcoholic cardiomyopathy from DCM of other etiology. Moreover, chronic alcoholism may be associated with thiamine deficiency, introducing an element of beriberi heart disease (also indistinguishable from DCM) (see Chapter 9 ). In yet other cases, a nonalcoholic toxic insult is the cause of the myocardial failure. Particularly important in this last group is myocardial injury caused by certain chemotherapeutic agents, including doxorubicin (Adriamycin), discussed later. In the past, cobalt has also caused CHF.
• Pregnancy-associated. A special form of dilated cardiomyopathy, termed peripartum cardiomyopathy, occurs late in pregnancy or several weeks to months postpartum. The cause of peripartum cardiomyopathy is poorly understood but is probably multifactorial. Pregnancy-associated hypertension, volume overload, nutritional deficiency, other metabolic derangement, or an as yet poorly characterized immunologic reaction may be involved. • Genetic influences. DCM has a familial occurrence in 25% to 35% of cases. In the genetic forms of DCM, autosomal dominant inheritance is the predominant pattern; X-linked, autosomal recessive, and mitochondrial inheritance are less common. The genetic abnormalities identified as causes of familial DCM in humans largely affect the cytoskeleton. In some families there are deletions in the mitochondrial genes resulting in abnormal oxidative phosphorylation, in others, there are mutations in genes encoding enzymes involved in beta-oxidation of fatty acids. The mitochendrial defects most frequently cause dilated cardiomyopathy in children. Although X-linked dilated cardiomyopathy is not the dominant form, it is the best understood. This disorder typically presents in the teenage years or in the early 20s and usually is rapidly progressive. X-linked cardiomyopathy has been linked to the gene for dystrophin, a cell membrane-based cytoskeletal protein that plays a critical role in linking the internal cytoskeleton with the external basement membrane. Recall that dystrophin is mutated in the most common skeletal myopathies (i.e., Duchenne and Becker muscular dystrophies, see Chapter 27 ). Interestingly, some patients and families with dystrophin gene mutations have DCM as the primary clinical feature. Myocarditis-associated enteroviral protease 2A has been shown to cleave dystrophin directly, suggesting a mechanism for the development of postmyocarditis DCM. Moreover,  disruption of dystrophin is a common finding in end-stage cardiomyopathy, dilated or ischemic. This disruption is reversible, correlating with 604 improvements in some patients, managed with a cardiac assist device. This  suggests that damage to the cytoskeleton may provide a final common (and potentially reversible) pathway for contractile dysfunction in heart failure of diverse causes. Other genes implicated in dilated cardiomyopathy include α- cardiac actin (which links the sarcomere with dystrophin), desmin, and the nuclear lamina proteins, lamin A and lamin C.Clinical Features.DCM may occur at any age, including in childhood, but it most commonly affectsindividuals between the ages of 20 and 50. It presents with slowly progressive signs andsymptoms of CHF such as shortness of breath, easy fatigability, and poor exertionalcapacity, but patients may slip precipitously from a compensated to a decompensatedfunctional state. In the end stage, patients often have ejection fractions of less than 25%(normal, approximately 50% to 65%). Fifty percent of patients die within 2 years, andonly 25% survive longer than 5 years, but some severely affected patients mayunexpectedly improve on therapy. Secondary mitral regurgitation and abnormal cardiac
rhythms are common. Death is usually attributable to progressive cardiac failure orarrhythmia and can occur suddenly. Embolism from dislodgment of an intracardiacthrombus may occur. Cardiac transplantation is frequently recommended.Arrhythmogenic Right Ventricular Cardiomyopathy (Arrhythmogenic Right Ventricular Dysplasia)Arrhythmogenic right ventricular cardiomyopathy, or arrhythmogenic right ventriculardysplasia, is a poorly understood condition with a distinct clinical presentation. It is mostcommonly associated with right-sided heart failure andFigure 12-33 Arrythmogenic right ventricular cardiomyopathy. A, Gross photograph, showing dilation ofthe right ventricle and near transmural replacement of the right ventricular free-wall myocardium by fat andfibrosis. The left ventricle has a virtually normal configuration. B, Histologic section of the right ventricularfree wall, demonstrating replacement of myocardium (red) by fibrosis (blue, arrow) and fat (collagen isblue in this Masson trichrome stain).various rhythm disturbances, particularly ventricular tachycardia. Left-sided involvementwith left-sided heart failure may also occur. In some cases it gives rise to sudden death.Morphologically, the right ventricular wall is severely thinned due to loss of myocytes,with extensive fatty infiltration and interstitial fibrosis ( Fig. 12-33 ). Most cases have nofamily history, but familial forms do occur. Although a gene defect was recentlylocalized on chromosome 14, the pathogenesis remains obscure. Pedigree analyses of  large kindreds indicate autosomal dominant inheritance with variable penetrance.Naxos syndrome appears to be a related disorder that has similar cardiac findings, inaddition to hyperkeratosis of plantar palmar skin surfaces. The abnormal gene in Naxosdisease codes for plakoglobin, also known as γ-catenin, an intracellular protein that links transmembrane adhesion molecules in desmosomes to desmin, the principalintermediate filament protein in cardiac myocytes.HYPERTROPHIC CARDIOMYOPATHYHypertrophic cardiomyopathy (HCM) is also known by such terms as idiopathichypertrophic subaortic stenosis and hypertrophic obstructive cardiomyopathy. It is
characterized by myocardial hypertrophy, abnormal diastolic filling and, in about onethird of cases, intermittent ventricular outflow obstruction. The heart is thick-walled,heavy, and hypercontracting, in striking contrast to the flabby, hypocontracting heart ofDCM. HCM causes primarily diastolic dysfunction; systolic function is usuallypreserved. The two most common diseases that must be distinguished clinically fromHCM are amyloidosis and hypertensive heart disease coupled with age-related subaorticseptal hypertrophy (see earlier section on hypertensive heart disease). Occasionally,valvular or congenital subvalvular aortic stenosis can also mimic HCM. 605Morphology.The essential feature of HCM is massive myocardial hypertrophy without ventriculardilation ( Fig. 12-34A, B ). The classic pattern is disproportionate thickening of theventricular septum as compared with the free wall of the left ventricle (with a ratiogreater than 1:3), frequently termed asymmetrical septal hypertrophy. In about 10% ofcases, however, the hypertrophy is symmetrical throughout
Figure 12-34 Hypertrophic cardiomyopathy with asymmetric septal hypertrophy. A, The septal musclebulges into the left ventricular outflow tract, and the left atrium is enlarged. The anterior mitral leaflet hasbeen moved away from the septum to reveal a fibrous endocardial plaque (arrow) (see text). B, Histologicappearance demonstrating disarray, extreme hypertrophy, and characteristic branching of myocytes as wellas the interstitial fibrosis characteristic of hypertrophic cardiomyopathy (collagen is blue in this Massontrichrome stain). C, Schematic structure of the sarcomere of cardiac muscle, highlighting proteins in whichmutations cause defective contraction, hypertrophy, and myocyte disarray in hypertrophic cardiomyopathy.The frequency of a particular gene mutation is indicated as a percentage of all cases of HCM; mostcommon are mutations in β-myosin heavy chain. Normal contraction of the sarcomere involves myosin-actin interaction initiated by calcium binding to troponin C, I, and T and α-tropomyosin. Actin stimulatesATPase activity in the myosin head and produces force along the actin filaments. Myocyte-binding proteinC modulates contraction. (A, reproduced by permission from Schoen FJ: Interventional and SurgicalCardiovascular Pathology: Clinical Correlations and Basic Principles. Philadelphia, W.B. Saunders,1989. C, from Spirito P, et al: The management of hypertrophic cardiomyopathy. N Engl J Med 336:775,1997.)
the heart. On cross-section, the ventricular cavity loses its usual round-to-ovoid shape andmay be compressed into a "banana-like" configuration by bulging of the ventricularseptum into the lumen (see Fig. 12-34A ). Although disproportionate hypertrophy caninvolve the entire septum, it is usually most prominent in the subaortic region. Oftenpresent are endocardial thickening or mural plaque formation in the 606left ventricular outflow tract and thickening of the anterior mitral leaflet. Both findingsare a result of contact of the anterior mitral leaflet with the septum during ventricularsystole, and they correlate with echocardiographically demonstrated functional leftventricular outflow tract obstruction during midsystole present in some cases.The most important histologic features of the myocardium in HCM are (1) extensivemyocyte hypertrophy to a degree unusual in other conditions, with transverse myocytediameters frequently greater than 40 µm (normal, approximately 15 µm); (2) haphazarddisarray of bundles of myocytes, individual myocytes, and contractile elements insarcomeres within cells (myofiber disarray); and (3) interstitial and replacement fibrosis(see Fig. 12-34B ).Pathogenesis.Hypertrophic cardiomyopathy is caused by a mutation in any one of several genes thatencode proteins that are part of the sarcomere, the contractile unit of cardiac and skeletalmuscle ( Fig. 12-34C ). Thus, HCM is a genetic disease of force generation within   the cardiac myocyte. Most cases are familial and the pattern of transmission is autosomaldominant with variable expression. Remaining cases appear to be sporadic. Mutationscausing HCM have been found in at least 12 sarcomeric genes, including β-myosin heavychain (β-MHC), cardiac troponinT, α-tropomyosin, and myosin-binding protein C(MYBP-C). Of these, mutations in the β-MHC (β-myosin heavy chain) gene are mostcommon; MYBP-C and troponinT are next in frequency. Mutations in these three genesaccount for 70% to 80% of all cases of HCM. The amino acid substitution 403 Arg→Gln(in β-MHC) is the most commonly reported mutation and has been described in multiplefamilies. This and the majority of the mutations causing HCM are single-point missensemutations. All told, more than 100 other mutations have been found in HCM, and hencethe disease is genetically quite heterogeneous.Although it is clear that these genetic defects are critical to the etiology of this entity, thesequence of events leading from mutations to disease are still poorly understood. Onecurrent hypothesis considers cardiac hypertrophy in HCM a compensatory phenomenonowing to impaired contraction of cardiac myocytes, which triggers the release of growthfactors that result in intense compensatory hypertrophy (leading to myofiber disarray)and fibroblast proliferation (causing interstitial fibrosis). As discussed above, HCM is a disease caused by mutations in proteins of the sarcomere,and DCM is mostly associated with abnormalities of the cytoskeleton. Despite theseetiologic differences, there are some common mechanistic and clinicopathologic threads
between the genetic forms of dilated and hypertrophic cardiomyopathy, as summarized inFigure 12-35 .Clinical Features.The basic physiologic abnormality in HCM is reduced chamber size and poor compliancewith reduced stroke volume that results from impaired diastolic filling of the massivelyhypertrophied left ventricle. In addition, approximately 25% of patients with HCM havedynamic obstruction to the left ventricular outflow. The limitation of cardiac output and asecondary increase in pulmonary venous pressure cause exertional dyspnea. Auscultationdiscloses a harsh systolic ejection murmur, caused by ventricular outflow obstruction asthe anterior mitral leaflet moves toward the ventricular septum during systole. Owing tothe massive hypertrophy, high left ventricular chamber pressure, and potentiallyabnormal intramural arteries, focal myocardial ischemia commonly results, even in theabsence of concomitant CAD, and thus anginal pain is frequent. The major clinicalproblems in HCM are atrial fibrillation with mural thrombus formation and possiblyembolization, infective endocarditis of the mitral valve, intractable cardiac failure,ventricular arrhythmias, and sudden death. Hypertrophic cardiomyopathy is one of themost common causes of sudden, otherwise unexplained, death in young athletes.Given the heterogeneous genetic defects of HCM, it should not be surprising that theclinical and morphologic features are markedly heterogeneous among affected patients.Many patients are stable over the many years of observation, and some improve. Mostpatients can be significantly helped by medical therapy that enhances ventricularrelaxation. Reduction of the mass of the septum by surgical excision of muscle is done insome cases to relieve outflow tract obstruction, if present. In a recently introducednonsurgical myocardial reduction, alcohol is infused through a catheter to induceinfarction of the myocardium.RESTRICTIVE CARDIOMYOPATHYRestrictive cardiomyopathy is a disorder characterized by a primary decrease inventricular compliance, resulting in impaired ventricular filling during diastole; thecontractile (systolic) function of the left ventricle is usually unaffected. Thus, the functional state can be confused with that of constrictive pericarditis or HCM. Restrictivecardiomyopathy can be idiopathic or associated with distinct diseases that affect themyocardium, principally radiation fibrosis, amyloidosis, sarcoidosis, metastatic tumor, orproducts of inborn errors of metabolism.Morphology.In idiopathic restrictive cardiomyopathy, the ventricles are of approximately normalsize or slightly enlarged, the cavities are not dilated, and the myocardium is firm. Biatrialdilation is commonly observed. Microscopically, there is often only patchy or diffuseinterstitial fibrosis, which can vary from minimal to extensive. Restrictivecardiomyopathy of disparate causes may have similar gross morphology. However,endomyocardial biopsy often reveals features that are disease-specific histologically.
Several other restrictive conditions require brief mention. Endomyocardial fibrosis isprincipally a disease of children and young adults in Africa and other tropical areas,characterized by fibrosis of the ventricular endocardium and subendocardium thatextends from the apex toward, and often involves the tricuspid and mitral valves. Thefibrous tissue markedly diminishes the volume and compliance of affected chambers andso induces a restrictive functional defect. Ventricular mural thrombi sometimes develop,and indeed there is a suggestion that the fibrous tissue results from the organization ofmural thrombi. The etiology is unknown.Loeffler endomyocarditis is also marked by endomyocardial fibrosis, typically with largemural thrombi similar to those 607Figure 12-35 Pathways of dilated and hypertrophic cardiomyopathy, emphasizing several importantconcepts. Some forms of dilated cardiomyopathy (others are caused by myocarditis, alcohol, and othertoxic injury or the peripartum state) and virtually all forms of hypertrophic cardiomyopathy are genetic inorigin. The genetic causes of dilated cardiomyopathy involve mutations in any of a wide variety ofproteins, predominantly of the cytoskeleton, but also the sarcomere, mitochondria, and nuclear envelope. In
contrast, the mutated genes that cause hypertrophic cardiomyopathy encode proteins of the sarcomere.Although these two forms of cardiomyopathy differ greatly in subcellular basis and morphologicphenotypes, they share a common pathway of clinical complications.seen in the tropical disease, but cases are not restricted to a specific geographic area. Inaddition to the cardiac changes, there is often an eosinophilic leukemia, which can resultin infiltration of other organs by eosinophils and a rapidly fatal downhill course. Thecirculating eosinophils are abnormal, and many are degranulated. The release of toxicproducts of eosinophils, especially major basic protein, is postulated to initiateendocardial damage, with subsequent foci of endomyocardial necrosis accompanied byan eosinophilic infiltrate. This is followed by scarring of the necrotic area, layering of theendocardium by thrombus, and finally organization of the thrombus. Eosinophilicendomyocardial disease has a poor prognosis, but benefits are reported from surgicalremoval of the fibrous/thrombotic layer of tissue (called endomyocardial stripping).Endocardial fibroelastosis is an uncommon heart disease of obscure etiologycharacterized by focal or diffuse fibroelastic thickening usually involving the mural leftventricular endocardium. Most common in the first 2 years of life, it is oftenaccompanied by some form of congenital cardiac anomaly, aortic valve obstruction inabout one third of all cases. Focal disease may have no functional importance, but diffuseinvolvement may be responsible for rapid and progressive cardiac decompensation anddeath.MYOCARDITISUnder this category are grouped inflammatory processes of the myocardium that result ininjury to cardiac myocytes. However, the presence of inflammation alone is not  diagnostic of myocarditis, because inflammatory infiltrates may also be seen as asecondary response in conditions such as ischemic injury. In myocarditis, by contrast, theinflammatory process is the cause of rather than a response to myocardial injury.Etiology and Pathogenesis.In the United States, infections and particularly viruses are the most common cause ofmyocarditis. Coxackieviruses A and B and other enteroviruses probably account for mostof the cases. Other less common etiologic agents include cytomegalovirus, humanimmunodeficiency 608virus (HIV), and a host of other agents listed in Table 12-12 . Although it is oftendifficult to isolate the offending virus from the tissues after the onset of clinicalsymptoms, serologic studies and, more recently, the identification of viral DNA or RNAsequences in the myocardium by polymerase chain reaction may identify the culprit insome cases. Whether the viruses are the direct cause of the myocardial injury or theyinitiate an immune response that cross-reacts with myocardial cells is unclear in most
cases. As with hepatitis viruses ( Chapter 18 ), T cells may damage virus-infected myocytes by reacting against viral antigens expressed on the cell membrane.Nonviral biologic agents are an important cause of myocarditis, particularly direct cardiacinfection caused by the protozoa Trypanosoma cruzi, the agent of Chagas disease.Although uncommon in the northern hemisphere, Chagas disease affects up to one half ofthe population in endemic areas of South America, and myocardial involvement is foundin approximately 80% of infected individuals. About 10% of patients die during an acute attack; others may enter a chronic immune-mediated phase and develop progressivesigns of cardiac insufficiency 10 to 20 years later. Trichinosis is the most commonhelminthic disease with associated cardiac involvement. Parasitic diseases, includingtoxoplasmosis, and bacterial infections, including Lyme disease and diphtheria, can alsocause myocarditis. In the case of diphtheritic myocarditis, toxins released byCorynebacterium diphtheriae appear to be responsible for the myocardial injury.Myocarditis occurs in approximately 5% of patients with Lyme disease, a systemicillness caused by the bacterial spirochete Borrelia burgdorferi, which has dermatologic,neurologic, and rheumatologic manifestations. Lyme carditis (myocarditis) manifestsprimarily as self-limited conduction system disease. Nevertheless, a temporary pacemaker is required for AV block in approximately 30% of patients.Myocarditis occurs in many patients with acquired immunodeficiency syndrome (AIDS). Two types have been identified: (1)  TABLE 12-12 -- Major Causes of MyocarditisInfectionsViruses (e.g., coxsackievirus, ECHO, influenza, HIV, cytomegalovirus)Chlamydiae (e.g., C. psittaci)Rickettsiae (e.g., R. typhi, typhus fever)Bacteria (e.g., Corynebacterium diphtheriae, Neisseria meningococcus, Borrelia (Lymedisease)Fungi (e.g., Candida)Protozoa (e.g., Trypanosoma Chagas disease, toxoplasmosis)Helminths (e.g., trichinosis)Immune-Mediated ReactionsPostviralPoststreptococcal (rheumatic fever)Systemic lupus erythematosusDrug hypersensitivity (e.g., methyldopa, sulfonamides)
Transplant rejectionUnknownSarcoidosisGiant cell myocarditisHIV, human immunodeficiency virus.inflammation and myocyte damage without a clear etiologic agent and (2) myocarditiscaused directly by HIV or by an opportunistic pathogen.There are also noninfectious causes of myocarditis. Myocarditis can be related to allergicreactions (hypersensitivity myocarditis), often to a particular drug such as antibiotics,diuretics, and antihypertensive agents. Myocarditis can also be associated with systemicdiseases of immune origin, such as RF, SLE, and polymyositis. Cardiac sarcoidosis andrejection of a transplanted heart are also considered forms of myocarditis.Against this background we can turn to the anatomic changes seen in the major forms ofmyocarditis.Morphology.During the active phase of myocarditis, the heart may appear normal or dilated; somehypertrophy may be present. The lesions may be diffuse or patchy. The ventricularmyocardium is typically flabby and often mottled by either pale foci or minutehemorrhagic lesions. Mural thrombi may be present in any chamber.During active disease, myocarditis is most frequently characterized by an interstitialinflammatory infiltrate and focal necrosis of myocytes adjacent to the inflammatory cells( Fig. 12-36 ). Myocarditis in which the infiltrate is mononuclear and predominantly lymphocytic is most common (see Fig. 12-36A ). Although endomyocardial biopsies arediagnostic in some cases, they can be spuriously negative because inflammatoryinvolvement may be focal or patchy. If the patient survives the acute phase ofmyocarditis, the inflammatory lesions either resolve, leaving no residual changes, or healby progressive fibrosis, as mentioned earlier.Hypersensitivity myocarditis has interstitial infiltrates, principally perivascular,composed of lymphocytes, macrophages, and a high proportion of eosinophils (see Fig.12-36B ).A morphologically distinctive form of myocarditis of uncertain cause, called giant cellmyocarditis, is characterized by a widespread inflammatory cellular infiltrate containingmultinucleate giant cells interspersed with lymphocytes, eosinophils, plasma cells, andmacrophages and having at least focal but frequently extensive necrosis ( Fig. 12-36C ).
The giant cells are of either macrophage or myocyte origin. This variant carries a poorprognosis. The myocarditis of Chagas disease is rendered distinctive by parasitization of scatteredmyofibers by trypanosomes accompanied by an inflammatory infiltrate of neutrophils,lymphocytes, macrophages, and occasional eosinophils ( Fig. 12-36D ).Clinical Features.The clinical spectrum of myocarditis is broad; at one end the disease is entirelyasymptomatic, and such patients recover completely without sequelae. At the otherextreme is the precipitous onset of heart failure or arrhythmias, occasionally with suddendeath. A systolic murmur may appear, indicating functional mitral regurgitation related todilation of the left ventricle. Between these extremes are the many levels of involvementassociated with such symptoms as fatigue, dyspnea, palpitations, precordial discomfort,and fever. The clinical features of myocarditis can 609Figure 12-36 Myocarditis. A, Lymphocytic myocarditis, with mononuclear inflammatory cell infiltrate andassociated myocyte injury. B, Hypersensitivity myocarditis, characterized by interstitial inflammatoryinfiltrate composed largely of eosinophils and mononuclear inflammatory cells, predominantly localized toperivascular and large interstitial spaces. This form of myocarditis is associated with drug hypersensitivity.C, Giant cell myocarditis, with mononuclear inflammatory infiltrate containing lymphocytes and
macrophages, extensive loss of muscle, and multinucleated giant cells. D, The myocarditis of Chagasdisease. A myofiber is distended with trypanosomes (arrow). There is a surrounding inflammatory reactionand individual myofiber necrosis.mimic those of acute MI. Occasionally, years later, when an attack of myocarditis isforgotten, the patient may be diagnosed as having dilated cardiomyopathy. Indeed, manypatients have been observed to progress clinically from unequivocal myocarditis toDCM; endomyocardial biopsy findings of evolving disease have been documented insome.OTHER SPECIFIC CAUSES OF MYOCARDIAL DISEASEAdriamycin and Other Drugs.The anthracycline chemotherapeutic agents doxorubicin (Adriamycin) and daunorubicinare well-recognized causes of toxic myocardial injury that can cause DCM. The hazard is dose-dependent (cardiotoxicity becomes progressively more frequent above a totaldose of 500 mg/m2 ) and is attributed primarily to lipid peroxidation of myocytemembranes. Many other agents, such as lithium, phenothiazines, chloroquine, andcocaine have been implicated in myocardial injury and sometimes sudden death.Common morphologic threads running throughout the cardiotoxicity of many chemicalsand drugs (including diphtheria exotoxin) are myofiber swelling and vacuolization, fattychange, individual cell lysis (myocytolysis), and sometimes patchy foci of necrosis.Electron microscopy usually reveals cytoplasmic vacuolization and lysis of myofibrils,typified by Adriamycin cardiotoxicity. With discontinuance of the toxic agent, thesechanges may resolve completely, leaving no apparent sequelae. Sometimes, however,nonspecific hypertrophy with interstitial fibrosis or small focal replacement scars remain,and both the physiologic and morphologic patterns can be indistinguishable from those ofDCM.Another chemotherapeutic agent with cardiac toxicity is cyclophosphamide (Cytoxan),which, like Adriamycin, has dose-dependent cardiotoxic effects, but severecardiomyopathy may occur following single high-dose therapy. In contrast to the primarymyocyte injury with Adriamycin, the principal insult with cyclophosphamide appears tobe vascular, leading to myocardial hemorrhage.Catecholamines.Foci of myocardial necrosis with contraction bands, often associated with a sparsemononuclear inflammatory infiltrate consisting mostly of macrophages, are frequentlyobserved in patients who have a pheochromocytoma, with its elaboration ofcatecholamines ( Chapter 24 ). This is considered to be a manifestation of the generalproblem of "catecholamine effect", which is also seen in association with theadministration of large doses of vasopressor 610
agents such as dopamine. Cocaine also causes catecholamine-induced cell damage. The mechanism of catecholamine cardiotoxicity is uncertain, but it appears to relateeither to direct toxicity of catecholamines to cardiac myocytes via calcium overload or tovasoconstriction in the myocardial circulation in the face of an increased heart rate. Themononuclear cell infiltrate is likely a secondary reaction to the foci of myocyte cell death.Similar morphology may be encountered in patients who have recovered fromhypotensive episodes or have been resuscitated from a frank cardiac arrest; in such cases,the damage is a result of ischemia-reperfusion (see earlier) and inflammation follows.Curiously, some patients with intracranial lesions associated with elevated cerebrospinalfluid pressure and neurostimulation also develop focal myocardial necrosis withcontraction bands. Amyloidosis.Cardiac amyloidosis may appear along with systemic amyloidosis ( Chapter 6 ) or may beisolated to the heart, particularly in the aged. Cardiac amyloid deposits may occur in  the ventricles and atria (senile cardiac amyloidosis [SCA] or systemic senile amyloidosiswith cardiac involvement) or be limited to the atria (isolated atrial amyloidosis). In SCAthe protein deposits derive from transthyretin, a normal serum protein that transports boththyroxine and retinol-binding protein. The cardiac manifestations of isolated SCA may behistologically indistinguishable from those of primary amyloidosis ( Chapter 6 ), but SCAcan be identified by immunohistochemical staining of tissue with antisera totransthyretin. SCA has a far better prognosis than systemic amyloidosis. Although SCA is exclusively a disease of elderly people, mutant forms of transthyretin canaccelerate cardiac (and indeed systemic) amyloidosis. For example, the risk of isolatedcardiac amyloidosis is four times greater in African Americans than in Caucasians afterage 60; 4% of African Americans have a gene mutation in which isoleucine is substitutedfor valine at position 122 (Ile 122) that produces an amyloidogenic/fibrillogenic form oftransthyretin (autosomal dominant familial transthyretin amyloidosis). In isolated atrial amyloidosis, the deposits consist of atrial natriuretic peptide.Cardiac amyloidosis most frequently produces restrictive hemodynamics, but it can beasymptomatic or can be manifested by dilation, arrhythmias, or features mimicking thoseof ischemic or valvular disease owing to deposits in the interstitium, conduction system,vasculature, and valves, respectively.Morphology.Grossly, the heart in cardiac amyloidosis varies from normal to firm, rubbery, andnoncompliant with thickened walls. Usually the chambers are of normal size, but in somecases they are dilated. Numerous small, semitranslucent nodules resembling drips of waxmay be seen at the atrial endocardial surface, particularly on the left. Amyloid depositsoccur outside of the myocytes in the myocardial interstitium, conduction tissue, valves,endocardium, pericardium, and small intramural coronary arteries, and they arehighlighted by the classic apple-green birefringence demonstrated by polarization oftissue sections stained with Congo red or by the sulfated Alcian blue stain. In theinterstitium, amyloid deposits often form rings around cardiac myocytes and capillaries.
Intramural arteries and arterioles may have sufficient amyloid in their walls to compressand occlude their lumens, inducing myocardial ischemia ("small vessel disease").Iron Overload.Iron overload can occur in either hereditary hemochromatosis ( Chapter 18 ) orhemosiderosis owing to multiple blood transfusions. The heart in each is usually dilatedand the morphology does not belie the cause. Iron deposition is more prominent inventricles than atria and in the working myocardium than in the conduction system. It isthought that iron causes systolic dysfunction by interfering with metal-dependent enzymesystems.Morphology.Grossly, the myocardium of the iron-overloaded heart is rust-brown in color but isusually otherwise indistinguishable from that of idiopathic DCM. Microscopically, thereis marked accumulation of hemosiderin within cardiac myocytes (contrasted with theextracellular deposition of amyloid discussed previously), particularly in the perinuclearregion, demonstrable with a Prussian blue stain. This is associated with varying degreesof cellular degeneration and fibrosis. Ultrastructurally, the cardiac myocytes containabundant perinuclear siderosomes (iron-containing lysosomes).Hyperthyroidism and Hypothyroidism.Cardiac manifestations are among the earliest, most consistent features ofhyperthyroidism and hypothyroidism and reflect direct and indirect effects of thyroidhormones on the cells of the heart. In hyperthyroidism ( Chapter 24 ), tachycardia,palpitations, and cardiomegaly are common; supraventricular arrhythmias occasionallyappear. Cardiac failure occurs uncommonly, usually in the elderly superimposed on othercardiac diseases. In hypothyroidism ( Chapter 24 ), cardiac output is decreased, withreduced stroke volume and heart rate. Increased peripheral vascular resistance anddecreased blood volume result in narrowing of the pulse pressure, prolongation ofcirculation time, and decreased flow to peripheral tissues. Reduced circulation in the skinaccounts for the characteristic cold sensitivity.Morphology.In hyperthyroidism, the gross and histologic features are those of nonspecifichypertrophy. In well-advanced hypothyroidism (myxedema), the heart is flabby,enlarged, and dilated. Histologic features of hypothyroidism include myofiber swellingwith loss of striations and basophilic degeneration, accompanied by interstitialmucopolysaccharide-rich edema fluid. A similar fluid sometimes accumulates within thepericardial sac. The term myxedema heart has been applied to these changes.Pericardial Disease
Pericardial lesions are almost always associated with disease in other portions of the heartor surrounding structures, or are secondary to a systemic disorder; isolated pericardialdisease is unusual. 611PERICARDIAL EFFUSION AND HEMOPERICARDIUMNormally, there is about 30 to 50 mL of thin, clear, straw-colored fluid in the pericardialsac. Under various circumstances, the parietal pericardium undergoes distention by fluidof variable composition (pericardial effusion), blood (hemopericardium), or pus (purulentpericarditis). The consequences depend on the ability of the parietal pericardium tostretch, based on the speed of accumulation and the amount of fluid. Thus, with slowlyaccumulating effusions of less than 500 mL, the only clinical significance is acharacteristic globular enlargement of the heart shadow noted on chest x-ray. In contrast,rapidly developing fluid collections of as little as 200 to 300 mL—for example, in thehemopericardium caused by ruptured MI, traumatic perforation, infective endocarditis, orruptured aortic dissection—may produce compression of the thin-walled atria and venaecavae, or the ventricles themselves. As a consequence, cardiac filling is restricted,producing potentially fatal cardiac tamponade.PERICARDITISPericardial inflammation is usually secondary to a variety of cardiac diseases, thoracic orsystemic disorders, metastases from neoplasms arising in remote sites, or a surgicalprocedure on the heart. Primary pericarditis is unusual and almost always of viral origin.The major causes of pericarditis are listed in Table 12-13 . Most evoke an acutepericarditis, but a few, such as tuberculosis and fungi, produce chronic reactions. Since itis often impossible from pathologic examination to determine the etiologic basis for thereaction, a morphologic classification follows.Acute PericarditisSerous Pericarditis.Serous inflammatory exudates are characteristically produced by noninfectiousinflammations, such as RF, SLE, scleroderma, tumors, and uremia. An infection TABLE 12-13 -- Causes of PericarditisInfectious AgentsVirusesPyogenic bacteriaTuberculosisFungi
Other parasitesPresumably Immunologically MediatedRheumatic feverSystemic lupus erythematosusSclerodermaPostcardiotomyPostmyocardial infarction (Dressler) syndromeDrug hypersensitivity reactionMiscellaneousMyocardial infarctionUremiaFollowing cardiac surgeryNeoplasiaTraumaRadiationin the tissues contiguous to the pericardium, for example, a bacterial pleuritis, may causesufficient irritation of the parietal pericardial serosa to cause a sterile serous effusion thatmay progress to serofibrinous pericarditis and ultimately to a frank suppurative reaction.In some instances, a well-defined viral infection elsewhere—upper respiratory tractinfection, pneumonia, parotitis—antedates the pericarditis and serves as the primaryfocus of infection. Infrequently, usually in young adults, a viral pericarditis occurs as anapparent primary involvement that may accompany myocarditis (myopericarditis).Morphology.Whatever the cause, there is an inflammatory reaction in the epicardial and pericardialsurfaces with scant numbers of polymorphonuclear leukocytes, lymphocytes, andmacrophages. Usually the volume of fluid is not large (50 to 200 mL) and accumulatesslowly. Dilation and increased permeability of the vessels due to inflammation producesa fluid of high specific gravity and rich protein content. A mild inflammatory infiltrate inthe epipericardial fat consisting predominantly of lymphocytes is frequently termedchronic pericarditis. Organization into fibrous adhesions rarely occurs.Fibrinous and Serofibrinous Pericarditis.These two anatomic forms are the most frequent type of pericarditis and are composed ofserous fluid mixed with a fibrinous exudate. Common causes include acute MI (recall
Fig. 12-19D ), the postinfarction (Dressler) syndrome (likely an autoimmune conditionappearing several weeks after a MI), uremia, chest radiation, RF, SLE, and trauma. Afibrinous reaction also follows routine cardiac surgery.Morphology.In fibrinous pericarditis, the surface is dry, with a fine granular roughening. Inserofibrinous pericarditis, an increased inflammatory process induces more and thickerfluid, which is yellow and cloudy owing to leukocytes and erythrocytes (which may besufficient to give a visibly bloody appearance), and often fibrin. As with all inflammatoryexudates, fibrin may be digested with resolution of the exudate or it may becomeorganized (see Chapter 3 ).From the clinical standpoint, the development of a loud pericardial friction rub is themost striking characteristic of fibrinous pericarditis, and pain, systemic febrile reactions,and signs suggestive of cardiac failure may be present. However, a collection of serousfluid may obliterate the rub by separating the two layers of the pericardium.Purulent or Suppurative Pericarditis.This almost invariably denotes the invasion of the pericardial space by infectiveorganisms, which may reach the pericardial cavity by several routes: (1) direct extensionfrom neighboring inflammation, such as an empyema of the pleural cavity, lobarpneumonia, mediastinal infections, or extension of a ring abscess through themyocardium or aortic root in infective endocarditis; (2) seeding from the blood; (3)lymphatic extension; or (4) direct introduction during cardiotomy. Immunosuppressionpredisposes to infection by all of these pathways. 612Morphology.The exudate ranges from a thin to a creamy pus of up to 400 to 500 mL in volume. Theserosal surfaces are reddened, granular, and coated with the exudate ( Fig. 12-37 ).Microscopically there is an acute inflammatory reaction. Sometimes the inflammatoryprocess extends into surrounding structures to induce a so-called mediastinopericarditis.Organization is the usual outcome; resolution is infrequent. Because of the great intensityof the inflammatory response, the organization frequently produces constrictivepericarditis, a serious consequence (see later).The clinical findings in the active phase are essentially the same as those present infibrinous pericarditis, but signs of systemic infection are usually marked: for example,spiking temperatures, chills, and fever.Hemorrhagic Pericarditis.
An exudate composed of blood mixed with a fibrinous or suppurative effusion is mostcommonly caused by malignant neoplastic involvement of the pericardial space; in suchcases, cytologic examination of fluid removed through a pericardial tap may yieldneoplastic cells. Hemorrhagic pericarditis may also be found in bacterial infections, inpatients with an underlying bleeding diathesis, and in tuberculosis. Hemorrhagicpericarditis often follows cardiac surgery and sometimes is responsible for significantblood loss or even tamponade, requiring a "second-look" operation. The clinicalsignificance is similar to that of the spectrum of fibrinous or suppurative pericarditis.Caseous Pericarditis.Caseation within the pericardial sac is, until proved otherwise, tuberculous in origin;infrequently, fungal infections evoke a similar reaction. Pericardial involvementFigure 12-37 Acute suppurative pericarditis as an extension from a pneumonia. Extensive purulent exudateis evident in this in situ photograph.occurs by direct spread from tuberculous foci within the tracheobronchial nodes. Caseouspericarditis is rare but is the most frequent antecedent of disabling, fibrocalcific, chronicconstrictive pericarditis.Chronic or Healed PericarditisIn some cases, organization merely produces plaque-like fibrous thickenings of theserosal membranes ("soliders plaque") or thin, delicate adhesions of obscure origin thatare observed fairly frequently at autopsy and rarely cause impairment of cardiac function.In other cases, organization results in complete obliteration of the pericardial sac. This
fibrosis yields a delicate, stringy type of adhesion between parietal and visceralpericardium called adhesive pericarditis, which by itself rarely hampers or restrictscardiac action.Adhesive Mediastinopericarditis.This form of pericardial fibrosis may follow a suppurative or caseous pericarditis,previous cardiac surgery, or irradiation to the mediastinum. The pericardial sac isobliterated, and adherence of the external aspect of the parietal layer to surroundingstructures produces a great strain on cardiac function. With each systolic contraction, theheart is pulling not only against the parietal pericardium, but also against the attachedsurrounding structures. Systolic retraction of the rib cage and diaphragm, pulsusparadoxus, and a variety of other characteristic clinical findings may be observed. Theincreased workload causes cardiac hypertrophy and dilation, which may be quitemassive in more severe cases, mimicking DCM (see earlier).Constrictive Pericarditis.The heart may be encased in a dense, fibrous or fibrocalcific scar that limits diastolicexpansion and seriously restricts cardiac output, resembling restrictive cardiomyopathy.A well-defined history of previous pericarditis may or may not be present. In constrictivepericarditis, the pericardial space is obliterated, and the heart is surrounded by a dense,adherent layer of scar with or without calcification, often 0.5 to 1.0 cm thick, that canresemble a plaster mold in extreme cases (concretio cordis).Although the signs of cardiac failure may resemble those produced by adhesivemediastinopericarditis, cardiac hypertrophy and dilation cannot occur because of thedense enclosing scar, and the heart is consequently quiet with reduced output. The majortherapy is surgical removal of the shell of constricting fibrous tissue (pericardiectomy).RHEUMATOID HEART DISEASERheumatoid arthritis is mainly a disorder of the joints, but it is also associated with manynonarticular involvements (e.g., subcutaneous rheumatoid nodules, acute vasculitis, andFelty syndrome; see Chapter 26 ). The heart is also involved in 20% to 40% of cases ofsevere prolonged rheumatoid arthritis. The most common finding is a fibrinouspericarditis that may progress of fibrous thickening of the visceral and parietalpericardium with dense fibrous adhesions. Rheumatoid inflammatory granulomatousnodules resembling those that occur subcutaneously may also be identifiable in themyocardium. Much less frequently, rheumatoid nodules involve endocardium, valves ofthe heart, and root of the aorta. Rheumatoid valvulitis can lead to marked fibrousthickening and 613secondary calcification of the aortic valve cusps, producing changes resembling those ofchronic rheumatic valvular disease, but intercommissural adhesion is rarely present.
Tumors of the HeartPrimary tumors of the heart are rare; in contrast, metastatic tumors to the heart occur inabout 5% of patients dying of cancer. The most common primary tumors, in descendingorder of frequency (overall, including adults and children), are myxomas, fibromas,lipomas, papillary fibroelastomas, rhabdomyomas, angiosarcomas, and other sarcomas.The five most common tumors are all benign and collectively account for 80% to 90% ofprimary tumors of the heart.PRIMARY CARDIAC TUMORSMyxomaMyxomas are the most common primary tumor of the heart in adults ( Fig. 12-38 ). Although they may arise in any of the four chambers or, rarely, on the heart valves, about90% are located in the atria, with a left-to-right ratio of approximately 4:1 (atrialmyxomas).It has long been questioned whether cardiac myxomas are truly neoplastic lesions,hamartomas, or organized thrombi, but the weight of evidence is on the side of benignneoplasia. All the tumor cell types present are thought to derive from differentiation ofprimitive multipotential mesenchymal cells.Morphology.The tumors are almost always single, but rarely several occur simultaneously. The regionof the fossa ovalis in the atrial septum is the favored site of origin. Myxomas range fromsmall (less than 1 cm)
Figure 12-38 Left atrial myxoma. A, Gross photograph showing large pedunculated lesion arising from theregion of the fossa ovalis and extending into the mitral valve orifice. B, Microscopic appearance, withabundant amorphous extracellular matrix in which are scattered collections of myxoma cells in variousgroupings, including abnormal vascular formations (arrow).to large (up to 10 cm), sessile or pedunculated masses ( Fig. 12-38A ) that vary fromglobular hard masses mottled with hemorrhage to soft, translucent, papillary, or villouslesions having a gelatinous appearance. The pedunculated form is frequently sufficientlymobile to move into or sometimes through the AV valves during systole, causingintermittent and often position-dependent obstruction. Sometimes, such mobility exerts a"wrecking-ball" effect, causing damage to the valve leaflets.Histologically, myxomas are composed of stellate or globular myxoma ("lepidic") cells,endothelial cells, smooth muscle cells, and undifferentiated cells embedded within anabundant acid mucopolysaccharide ground substance and covered on the surface byendothelium ( Fig. 12-38B ). Peculiar structures that variably resemble poorly formedglands or vessels are characteristic. Hemorrhage and mononuclear inflammation areusually present.The major clinical manifestations are due to valvular "ball-valve" obstruction,embolization, or a syndrome of constitutional symptoms, such as fever and malaise.Sometimes fragmentation with systemic embolization calls attention to these lesions.Constitutional symptoms are likely due to the elaboration by some myxomas of thecytokine interleukin-6, a major mediator of the acute phase response. Echocardiographyprovides the opportunity to identify these masses noninvasively. Surgical removal isusually curative, although rarely, the neoplasm recurs months to years later.
Approximately 10% of patients with myxoma have a familial cardiac myxoma syndrome(known as Carney syndrome) characterized by autosomal dominant transmission,multiple cardiac and often extracardiac (e.g., skin) myxomas, spotty pigmentation, andendocrine overactivity. A careful history and physical examination in patients withcardiac myxoma is 614important to identify other signs of the Carney complex, as this diagnosis carriesimplications for family members of the patient. The gene PRKAR1 on chromosome 17(encoding a regulatory subunit of cAMP-dependent protein kinase A, possibly a tumorsuppressor gene) is mutated in about half of known Carney complex kindreds, while mostof the other kindreds have abnormalities in the locus 2p16. LipomaLipomas (excessive fat accumulations) may occur in the subendocardium or in thesubepicardium, or within the myocardium, as localized, poorly encapsulated masses,which may be asymptomatic, can create ball-valve obstructions as with myxomas, or mayproduce arrhythmias. Lipomas are most often located in the left ventricle, right atrium, oratrial septum and are not necessarily neoplastic. In the atrial septum, non-neoplasticdepositions of fat are called "lipomatous hypertrophy."Papillary FibroelastomaPapillary fibroelastomas are curious, usually incidental, lesions, most often identified atautopsy. They may embolize and become clinically important. Although these masses arecalled neoplasms, it is possible that at least some fibroelastomas represent organizedthrombi. Fibroelastomas resemble the much smaller, usually trivial, Lambl excrescencesthat are frequently found on the aortic valves of older individuals.Morphology.Papillary fibroelastomas are generally located on valves, particularly the ventricularsurfaces of semilunar valves and the atrial surfaces of AV valves. They constitute adistinctive cluster of hair-like projections up to 1 cm in diameter, covering up to severalcentimeters in diameter of the endocardial surface. Histologically, they are covered byendothelium, deep to which is myxoid connective tissue containing abundantmucopolysaccharide matrix and elastic fibers.RhabdomyomaRhabdomyomas are the most frequent primary tumor of the heart in infants and childrenand are frequently discovered in the first years of life because of obstruction of a valvularorifice or cardiac chamber. That rhabdomyomas are hamartomas or malformations ratherthan true neoplasms is supported by a high frequency of tuberous sclerosis (see Chapter28 ) in patients with cardiac rhabdomyomas. A recent study suggested that cardiac
rhabdomyomas may be due to a defect in apoptosis during developmental cardiacremodeling. Morphology.Rhabdomyomas are generally small, gray-white myocardial masses up to severalcentimeters in diameter located on either the left or the right side of the heart andprotruding into the ventricular chambers. Histologically they are composed of a mixedpopulation of cells, the most characteristic of which are large, rounded, or polygonal cellscontaining numerous glycogen-laden vacuoles separated by strands of cytoplasm runningfrom the plasma membrane to the more or less centrally located nucleus, the so-calledspider cells. These cells can be shown to have myofibrils.SarcomaCardiac angiosarcomas and other sarcomas are not clinically or morphologicallydistinctive from their counterparts in other locations ( Fig. 11-34 and Chapter 26 ) and sorequire no further comment here.CARDIAC EFFECTS OF NONCARDIAC NEOPLASMSWith enhanced patient survival due to diagnostic and therapeutic advances, significantcardiovascular effects of noncardiac neoplasms and their therapy are now commonlyencountered ( Table 12-14 ). Pathology derives from infiltration of tumor tissue,circulating mediators, or tumor therapy.The most frequent tumors involving the heart as metastases are carcinomas of the lungand breast, melanomas, leukemias, and lymphomas. Metastases can reach the heart andpericardium by retrograde lymphatic extension (most carcinomas), by hematogenousseeding (many tumors), by direct contiguous extension (primary carcinoma of the lung,breast, or esophagus), or by direct contiguous venous extension (tumors of the kidney orliver). Clinical symptoms are most often associated with pericardial spread, by either apericardial effusion that causes tamponade or by tumor bulk that is sufficient to directlyrestrict cardiac filling. Myocardial metastases are usually clinically silent or havenonspecific features, such as a generalized defect in ventricular contractility or TABLE 12-14 -- Cardiovascular Effects of Noncardiac NeoplasmsDirect Consequences of TumorPericardial and myocardial metastasesLarge vessel obstructionPulmonary tumor emboliIndirect Consequences of Tumor (Complications of Circulating Mediators)Nonbacterial thrombotic endocarditis (NBTE)
Carcinoid heart diseasePheochromocytoma-associated heart diseaseMyeloma-associated amyloidosisEffects of Tumor TherapyChemotherapyRadiation therapyModified from Schoen, FJ, et al: Cardiac effects of non-cardiac neoplasms. Cardiol Clin2:657, 1984. 615compliance. Bronchogenic carcinoma or malignant lymphoma may infiltrate themediastinum extensively, causing encasement, compression, or invasion of the superiorvena cava with resultant obstruction to blood coming from the head and upper extremities(superior vena cava syndrome). Renal cell carcinoma, because of its high propensity toinvade the renal vein, can grow in the lumen of the renal vein into and along the inferiorvena cava and can, occasionally, extend into the right atrium, blocking venous return tothe heart.Noncardiac tumors cause indirect cardiac effects, sometimes via circulating tumor-derived substances (e.g., NBTE [see earlier], carcinoid heart disease,pheochromocytoma-associated myocardial damage, multiple myeloma-derivedimmunoglobulin-causing amyloidosis). Complications of chemotherapy were discussedearlier in this chapter. Radiation used to treat breast, lung, or mediastinal neoplasms cancause pericarditis, pericardial effusion, myocardial fibrosis, and chronic pericardialdisorders. Other cardiac effects of radiotherapy include accelerated coronary arterydisease and mural and valvular endocardial fibrosis.Cardiac TransplantationTransplantation of cardiac allografts is now frequently performed (approximately 3000per year worldwide) for severe, intractable heart failure of diverse causes, the two mostcommon of which are DCM and IHD. Three major factors contribute to the widespreadsuccess of cardiac transplantation since the first successful human to human transplant in1967: (1) careful selection of candidates, (2) improved
Figure 12-39 Complications of heart transplantation. A, Cardiac allograft rejection typified by lymphocyticinfiltrate, with associated damage to cardiac myocytes. B, Graft coronary arteriosclerosis, demonstratingsevere diffuse concentric intimal thickening producing critical stenosis. The internal elastic lamina (arrow)and media are intact (Movat pentachrome stain, elastin black). (B, reproduced by permission from SalomonRN, et al: Human coronary transplantation-associated arteriosclerosis. Evidence for chronic immunereaction to activated graft endothelial cells. Am J Pathol 138:791, 1991.)maintenance (including the use of cyclosporin A, along with steroids and other drugs),and (3) early histopathologic diagnosis of acute allograft rejection by sequentialendomyocardial biopsy. Of the major complications (illustrated in Fig. 12-39 ), allograft rejection is the primaryproblem requiring surveillance; scheduled endomyocardial biopsy is the only reliablemeans of diagnosing acute cardiac rejection before substantial myocardial damage (andclinical recognition) has occurred and at a stage that is reversible in the majority ofinstances. Rejection is characterized by interstitial lymphocytic inflammation that, in itsmore advanced stages, damages adjacent myocytes (see Fig. 12-39A ). When myocardialinjury is not extensive, the "rejection episode" is usually either self-limited orsuccessfully reversed by increased immunosuppressive therapy. Advanced rejection maybe irreversible and fatal when not properly treated.The major current limitation to the long-term success of cardiac transplantation is late,progressive, diffuse stenosing intimal proliferation of the coronary arteries (graftarteriopathy) ( Fig. 12-39B ). This is a particularly vexing problem because it may lead tosilent MI (especially difficult to diagnose because these patients, with denervated hearts,do not experience chest pain); in this situation, CHF or sudden death is the usualoutcome. The mechanism of formation of these diffuse arterial lesions is uncertain.However, it is clear that low-level, chronic immunologic responses induce inflammatorycells and vascular wall cells to secrete growth factors that promote intimal smooth muscle
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