• 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