Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Relative concentration(=multiples of upper reference limit) Hours after onset of chest pain Fig. 11.13 Acuteincreasesinmyocardium-derivedtroponinI,myocardialcreatinekinase(CK-MB),andmyoglobinfollowlingmyocardialinfarction.ThekineticsofenzymeelevationscanbeusedtoestimatethetimingoftheMI.Myoglobincanalsobemeasured,butissubstantiallylesssensitiveandspecificformyocardialinjury. specifically the myocardial isoform, CK-MB), and lactate dehydrogenase. Troponins (and to a lesser extent CK-MB) have high specificity and sensitivity for myocardial damage.


Pathology_Robbins

Pathology_Robbins. specifically the myocardial isoform, CK-MB), and lactate dehydrogenase. Troponins (and to a lesser extent CK-MB) have high specificity and sensitivity for myocardial damage. CK-MB has long been the biomarker of myocardial injury, but is now tested for less frequently in favor of the more sensitive cardiac-specific troponins. Total CK activity is not a reliable marker of cardiac injury since various isoforms of CK are found in non-cardiac tissues. However, the CK-MB isoform—principally derived from myocardium, but also present at low levels in skeletal muscle—is a more specific indicator of heart damage. CK-MB activity begins to rise within 2 to 4 hours of MI, peaks at 24 to 48 hours, and returns to normal within approximately 72 hours.


Pathology_Robbins

Pathology_Robbins. TnI and TnT normally are not found in the circulation; however, after acute MI, both are detectable within 2 to 4 hours, with levels peaking at 48 hours and remaining elevated for 7 to 10 days. Persistence of elevated troponin levels allows the diagnosis of an acute MI to be made long after CK-MB levels have returned to normal. With reperfusion, both troponin and CK-MB levels may peak earlier owing to more rapid washout of the enzyme from the necrotic tissue. Consequences and Complications of Myocardial Infarction


Pathology_Robbins

Pathology_Robbins. Consequences and Complications of Myocardial Infarction Extraordinary progress has been made in improving patient outcomes after acute MI; the overall in-hospital death rate for MI is approximately 7% to 8%, with MI associated with ST segment elevations (approximately 10% mortality) experiencing higher mortality rates than those without (approximately 6%). Unfortunately, out-ofhospital mortality is substantially poorer: one third of individuals with STEMIs die, usually of an arrhythmia within 1 hour of symptom onset, before they receive appropriate medical attention. Such statistics make the rising rate of coronary artery disease in developing countries with scarce hospital facilities all the more worrisome. Nearly three fourths of patients experience one or more of the following complications after an acute MI ( Fig. 11.14


Pathology_Robbins

Pathology_Robbins. Nearly three fourths of patients experience one or more of the following complications after an acute MI ( Fig. 11.14 Contractile dysfunction. In general, MIs affect left ventricular pump function in proportion to the volume of damage. In most cases, there is some degree of left ventricular failure manifested as hypotension, pulmonary congestion, and pulmonary edema. Severe “pump failure” (cardiogenic shock) occurs in roughly 10% of patients with transmural MIs and typically is associated with infarcts that damage 40% or more of the left ventricle. Papillary muscle dysfunction. Although papillary muscles rupture infrequently after MI, they often are dysfunctional and can be poorly contractile as a result of ischemia, leading to postinfarct mitral regurgitation. Much later, papillary muscle fibrosis and shortening or global ventricular dilation also can cause mitral valve insufficiency.


Pathology_Robbins

Pathology_Robbins. Right ventricular infarction. Although isolated right ventricular infarction occurs in only 1% to 3% of MIs, the right ventricle is affected by RCA occlusions leading to posterior septal or left ventricular infarction. In either case, right-sided heart failure is a common outcome, leading to pooling of blood in the venous circulation and systemic hypotension. Myocardial rupture. Rupture complicates only 1% to 5% of MIs but is frequently fatal when it occurs. Left ventricular free wall rupture is most common, usually resulting in rapidly fatal hemopericardium and cardiac tamponade ( Fig. 11.14A ). Ventricular septal rupture creates a VSD with left-to-right shunting ( Fig. 11.14B ), and papillary muscle rupture leads to severe mitral regurgitation (


Pathology_Robbins

Pathology_Robbins. Fig. 11.14A ). Ventricular septal rupture creates a VSD with left-to-right shunting ( Fig. 11.14B ), and papillary muscle rupture leads to severe mitral regurgitation ( Fig. 11.14C ). Rupture occurs most commonly within 3 to 7 days after infarction—the time in the healing process when lysis of necrotic myocardium is maximal and when much of the infarct has been converted to soft, friable granulation tissue. Risk factors for free wall rupture include age older than 60 years, anterior or lateral wall infarctions, female gender, lack of left ventricular hypertrophy, and first MI (since scarring associated with prior MIs tends to limit the risk for myocardial tearing).


Pathology_Robbins

Pathology_Robbins. Arrhythmias. MIs lead to myocardial irritability and conduction disturbances that can cause sudden death. Approximately 90% of patients develop some form of rhythm disturbance, with the incidence being higher in STEMIs versus NSTEMIs. MI-associated arrhythmias include heart block of variable degree (including asystole), bradycardia, supraventricular tachyarrhythmias, ventricular premature contractions or ventricular tachycardia, and ventricular fibrillation. The risk for serious arrhythmias (e.g., ventricular fibrillation) is greatest in the first hour and declines thereafter. Pericarditis. Transmural MIs can elicit a fibrinohemorrhagic pericarditis; this is an epicardial manifestation of the underlying myocardial inflammation ( Fig. 11.14D ). Heralded by anterior chest pain and a pericardial http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 11.14 Complicationsofmyocardialinfarction.(AtoC)Cardiacrupture.(A)Anteriorfreewallmyocardialrupture(arrow).(B)Ventricularseptalrupture(arrow).(C)Papillarymusclerupture.(D)Fibrinouspericarditis,withahemorrhagic,roughenedepicardialsurfaceoverlyinganacuteinfarct.(E)Recentexpan-sionofananteroapicalinfarctwithwallstretchingandthinning(arrow) andmuralthrombus.(F)Largeapicalleftventricularaneurysm(arrow).(A to E, Reproduced by permission from Schoen FJ: Interventionalandsurgicalcardiovascularpathology:clinicalcorrelationsandbasicprinciples,Philadelphia, 1989, Saunders; F, Courtesy of William D. Edwards, MD, Mayo Clinic, Rochester, Minnesota.) friction rub, pericarditis typically appears 2 to 3 days after infarction and then gradually resolves over the next few days. Extensive infarcts or severe pericardial inflammation occasionally can lead to large effusions or can organize to form dense adhesions that eventually manifest as a constrictive lesion.


Pathology_Robbins

Pathology_Robbins. Chamber dilation. Because of the weakening of necrotic muscle, there may be disproportionate stretching, thinning, and dilation of the infarcted region (especially with anteroseptal infarcts). Mural thrombus. With any infarct, the combination of attenuated myocardial contractility (causing stasis), chamber dilation, and endocardial damage (causing a thrombogenic surface) can foster mural thrombosis ( Fig. 11.14E ), eventually leading to left-sided thromboembolism. Ventricular aneurysm. A late complication, aneurysms of the ventricle most commonly result from a large trans-mural anteroseptal infarct that heals with the formation of a thinned wall of scar tissue ( Fig. 11.14F ). Although ventricular aneurysms frequently give rise to formation of mural thrombi, arrhythmias, and heart failure, they do not rupture. Progressive heart failure. This is discussed under “ ” next.


Pathology_Robbins

Pathology_Robbins. Progressive heart failure. This is discussed under “ ” next. The risk for complications and the overall prognosis depends on infarct size, site, and type (subendocardial versus transmural infarct). Thus, large transmural infarcts are associated with a higher probability of cardiogenic shock, arrhythmias, and late CHF, and patients with anterior transmural MIs are at greatest risk for free wall rupture, expansion, aneurysm formation, and formation of mural thrombi. By contrast, posterior transmural infarcts are more likely to be complicated by conduction blocks, right ventricular involvement, or both; when ventricular septal ruptures occur in this area, they are more difficult to manage. Overall, patients with anterior infarcts have a much more guarded prognosis than those with posterior infarcts. With subendocardial infarcts, thrombi may form on the endocardial surface, but pericarditis, rupture, and aneurysms rarely occur.


Pathology_Robbins

Pathology_Robbins. In addition to the aforementioned scarring, the remaining viable myocardium attempts to compensate for the loss of contractile mass. Noninfarcted regions undergo hypertrophy and dilation; in combination with the scarring and thinning of the infarcted zones, the changes are collectively termed ventricular remodeling. The initial compensatory hypertrophy of noninfarcted myocardium is hemodynamically beneficial. The adaptive effect of remodeling can be overwhelmed, however, and ventricular function may decline in the setting of ventricular aneurysm formation. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net The long-term prognosis after MI depends on many factors, the most important of which are the quality of left ventricular function and the severity of atherosclerotic narrowing of vessels perfusing the remaining viable myocardium. The overall mortality rate within the first year is about 30%, including deaths occurring before the patient reaches the hospital. Thereafter, the annual mortality rate for patients who have suffered an MI is 3% to 4%. Chronic IHD, also called ischemic cardiomyopathy, is progressive heart failure secondary to ischemic myocardial damage. In most instances, there is a known clinical history of previous MI. After prior infarction(s), chronic IHD appears when the compensatory mechanisms (e.g., hypertrophy) of residual myocardium begin to fail. In other cases, severe CAD can cause diffuse myocardial dysfunction, and even micro-infarction and replacement fibrosis, without any clinically evident episode of frank infarction.


Pathology_Robbins

Pathology_Robbins. The heart failure of chronic IHD is typically severe and is occasionally punctuated by new episodes of angina or infarction. Arrhythmias, CHF, and intercurrent MI account for most of the associated morbidity and mortality. MORPHOLOGYPatientswithchronicIHDtypicallyexhibitleftventriculardilationandhypertrophy,oftenwithdiscreteareasofgray-whitescarringfromprevioushealedinfarcts.Invariably,thereismoderatetosevereatherosclerosisofthecoronaryarteries,sometimeswithtotalocclusion.Theendocardiumgenerallyshowspatchy,fibrousthickening,andmuralthrombimaybepresent.Microscopicfindingsincludemyocardialhypertrophy,diffusesubendocardialmyocytevacuolization,andfibrosisfrompreviousinfarction.


Pathology_Robbins

Pathology_Robbins. Because of the serious morbidity associated with IHD, there is much interest in exploring the possibility of using cardiac stem cells to replace damaged myocardium. Although cardiac regeneration in metazoans (such as newts and zebrafish) is well described, cardiac myocytes of higher-order animals are classically considered a post-mitotic cell population without replicative potential. Increasing evidence, however, points to the presence of bone marrow–derived precursors—as well as a small resident stem cell population within the myocardium—capable of repopulating the mammalian heart. These cells express a cluster of cell surface markers that allow their isolation and purification, and like all other tissue stem cells, they occur in very low frequency.


Pathology_Robbins

Pathology_Robbins. Besides self-renewal, these cardiac stem cells can generate all cell lineages seen within the myocardium. They have a slow intrinsic rate of proliferation, which is greatest in neonates and decreases with age. Of interest, stem cell numbers and progeny also increase after myocardial injury or hypertrophy, albeit to a limited extent, since hearts that suffer an MI clearly do not recover any significant function in the necrotic zone. Nevertheless, the potential for stimulating the proliferation of these cells in vivo is tantalizing because it could facilitate recovery of myocardial function after acute MI or chronic IHD. Ex vivo expansion and subsequent administration of such cells after an MI is another area of vigorous investigation. Unfortunately, results thus far have been less than exciting. Inthevastmajorityofcases,cardiacischemiaisduetocoronaryarteryatherosclerosis;vasospasm,vasculitis,andembolismarelesscommoncauses.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Aberrant rhythms can be initiated anywhere in the conduction system, from the sinoatrial (SA) node down to the level of an individual myocyte; they are typically designated as originating from the atrium (supraventricular) or within the ventricular myocardium. Abnormalities in myocardial conduction can be sustained or sporadic http://ebooksmedicine.net (paroxysmal). They can manifest as tachycardia (fast heart rate), bradycardia (slow heart rate), an irregular rhythm with normal ventricular contraction, chaotic depolarization without functional ventricular contraction (ventricular fibrillation), or no electrical activity at all (asystole). Patients may be unaware of a rhythm disorder, or may note a “racing heart” or palpitations (irregular rhythm); loss of adequate cardiac output due to sustained arrhythmia can produce lightheadedness (near syncope), loss of consciousness (syncope), or sudden cardiac death (see later).


Pathology_Robbins

Pathology_Robbins. Ischemic injury is the most common cause of rhythm disorders, either through direct damage or through the dilation of heart chambers that alters signal conduction. If the SA node is damaged (e.g., sick sinus syndrome), other fibers or even the atrioventricular (AV) node can take over pacemaker function, albeit at a much slower intrinsic rate (causing bradycardia). If the atrial myocytes become “irritable” and depolarize independently and sporadically (as occurs with atrial dilation), the signals are variably transmitted through the AV node leading to the random “irregularly irregular” heart rate of atrial fibrillation. If the AV node is dysfunctional, varying degrees of heart block occur, ranging from simple prolongation of the P-R interval on the ECG (first-degree heart block), to intermittent transmission of the signal (second-degree heart block), to complete failure (third-degree heart block).


Pathology_Robbins

Pathology_Robbins. Certain heritable conditions (fortunately rare) can also cause arrhythmias. They are important to recognize because they may alert physicians to the need for intervention to prevent sudden cardiac death (discussed later) in the proband and their family members. Some of these disorders are associated with recognizable anatomic abnormalities (e.g., congenital anomalies, hypertrophic cardiomyopathy, mitral valve prolapse). However, other heritable disorders precipitate arrythmias and sudden death in the absence of structural cardiac pathology (so-called “primary electrical disorders”). These syndromes can only be diagnosed by genetic testing, which is performed in those with a positive family history or an unexplained nonlethal arrhythmia. The most important of these are the channelopathies, which are caused by mutations in genes that are required for normal function of Na+, K+, and Ca+ channels. Since ion channels are responsible for conducting the electrical currents that mediate


Pathology_Robbins

Pathology_Robbins. which are caused by mutations in genes that are required for normal function of Na+, K+, and Ca+ channels. Since ion channels are responsible for conducting the electrical currents that mediate contraction of the heart, it is not surprising that defects in these channels may provoke arrythmias. The prototype is the long QT syndrome, characterized by prolongation of the QT segment in ECGs and susceptibility to malignant ventricular arrhythmias. Mutations in several different genes account for the cases of long QT syndrome, with KCNQ1 being the most common; it results in decreased potassium currents.


Pathology_Robbins

Pathology_Robbins. Sudden cardiac death (SCD) is defined as unexpected death due to a lethal arrhythmia such as asystole or sustained ventricular fibrillation. Roughly 400,000 individuals are victims of SCD each year in the United States. Coronary artery disease is the leading cause of SCD, being responsible for 80% to 90% of cases. Unfortunately, SCD may be the first manifestation of IHD. Of interest, autopsy typically shows severe atherosclerotic disease without evidence of acute plaque disruption. Thus, in the vast majority of cases, there is no associated myocardial infarction; 80% to 90% of patients who suffer SCD but are successfully resuscitated do not show any enzymatic or ECG evidence of myocardial necrosis—even if the cause is IHD! Healed remote MIs are present in about 40% of cases. In younger victims of SCD, nonatherosclerotic causes are more common, including the following: Hereditary (channelopathies) or acquired abnormalities of the cardiac conduction system


Pathology_Robbins

Pathology_Robbins. In younger victims of SCD, nonatherosclerotic causes are more common, including the following: Hereditary (channelopathies) or acquired abnormalities of the cardiac conduction system Myocardial hypertrophy. Increased cardiac mass is an independent risk factor for SCD; thus, in some young individuals who die suddenly, including athletes, hypertensive hypertrophy or unexplained increased cardiac mass is the only pathologic finding. Although ischemic injury (and other pathologic conditions) can directly affect the major components of the conduction system, most cases of fatal arrhythmia are triggered by electrical irritability of myocardium distant from the conduction system. The prognosis of many patients at risk for SCD, including those with chronic IHD, is markedly improved by implantation of a pacemaker or an automatic cardioverter defibrillator, which senses and electrically counteracts an episode of ventricular fibrillation.


Pathology_Robbins

Pathology_Robbins. The relationship of coronary artery disease to the various clinical end points discussed earlier is depicted in Fig. 11.15 Arrhythmiascanbecausedbyischemicorstructuralchangesintheconductionsystemorbymyocyteelectricalinstability.Instructurallynormalhearts,arrhythmiasmoreoftenareduetomutationsinionchannelsthatcauseaberrantrepolarizationordepolarization. SCDmostfrequentlyisduetocoronaryarterydiseaseleadingtoischemia.Myocardialirritabilitytypicallyresultsfromnonlethalischemiaorfrompreexistingfibrosisfrompreviousmyocardialinjury.SCDlessoftenisduetoacuteplaquerupturewiththrombosisthatinducesarapidlyfatalarrhythmia.


Pathology_Robbins

Pathology_Robbins. Hypertensive heart disease (HHD) is a consequence of the increased demands placed on the heart by hypertension, causing pressure overload and ventricular hypertrophy. As discussed in Chapter 10, hypertension is a common disorder associated with considerable morbidity and affecting many organs, including the heart, brain, and kidneys. The comments here will focus specifically on the major cardiac complications of hypertension, which result from pressure overload and ventricular hypertrophy. Myocyte hypertrophy is an adaptive response to pressure overload; there are limits to myocardial adaptive capacity, however, and persistent hypertension eventually can culminate in dysfunction, cardiac dilation, CHF, and even sudden death. Although hypertensive heart disease most commonly affects the left side of the heart secondary to systemic hypertension, pulmonary hypertension also can cause right-sided hypertensive changes—so-called “cor pulmonale.” http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 11.15 Pathwaysintheprogressionofischemicheartdiseaseshowingtherelationshipsamongcoronaryarterydiseaseanditsmajorsequelae.CORONARY ARTERY DISEASE Chronic ischemic heart disease Congestive heart failure Myocardial ischemia Acute plaque change; coronary artery thrombosis MYOCARDIAL INFARCTION with muscle loss and arrhythmias Ventricular remodeling Infarct healing Hypertrophy, dilation of viable muscle Myocardial ischemia of increased severity and duration SUDDEN CARDIAC DEATH The criteria for the diagnosis of systemic hypertensive heart disease are (1) left ventricular hypertrophy in the absence of other cardiovascular pathology (e.g., valvular stenosis), and (2) a history or pathologic evidence of hypertension. The Framingham Heart Study established unequivocally that even mild hypertension (above 140/90 mm Hg), if sufficiently prolonged, induces left ventricular hypertrophy. Roughly 25% of the U.S. population suffers from at least this degree of hypertension.


Pathology_Robbins

Pathology_Robbins. Compensated HHD typically is asymptomatic and is suspected only from discovery of elevated blood pressure on routine physical examination, or from ECG or echocardiographic findings of left ventricular hypertrophy. In some patients, the disease comes to attention with the onset of atrial fibrillation (secondary to left atrial enlargement) and/or CHF. The mechanisms by which hypertension leads to heart failure are incompletely understood; presumably the hypertrophic myocytes fail to contract efficiently, possibly due to structural abnormalities in newly assembled sarcomeres and because the vascular supply is inadequate to meet the demands of the increased muscle mass. Depending on the severity and duration of the condition, the underlying cause of hypertension, and the adequacy of therapeutic control, patients can (1) enjoy normal longevity and die of unrelated causes, (2) develop IHD owing to the effects of hypertension in potentiating coronary atherosclerosis, (3) suffer renal damage


Pathology_Robbins

Pathology_Robbins. control, patients can (1) enjoy normal longevity and die of unrelated causes, (2) develop IHD owing to the effects of hypertension in potentiating coronary atherosclerosis, (3) suffer renal damage or cerebrovascular stroke, or (4) experience congestive heart failure. The risk for SCD also is increased. Effective hypertension control can prevent or lead to the regression of cardiac hypertrophy and its attendant risks.


Pathology_Robbins

Pathology_Robbins. Cor pulmonale consists of right ventricular hypertrophy and dilation—frequently accompanied by right-sided heart failure—caused by pulmonary hypertension attributable to primary disorders of the lung parenchyma or pulmonary vasculature ( Table 11.3 ). Right ventricular dilation and hypertrophy caused by left ventricular failure (or by congenital heart disease) is substantially more common but is excluded by this definition. Cor pulmonale can be acute in onset, as with pulmonary embolism, or can have a slow and insidious onset when due to prolonged pressure overload in the setting of chronic lung and pulmonary vascular disease (see Table 11.3 MORPHOLOGYInacute cor pulmonale, therightventricleusuallyshowsonlydilation;ifanembolismcausessuddendeath,theheartmayevenbeofnormalsize.Chronic cor pulmonale ischaracterizedbyrightventricular(andoftenrightatrial)hypertrophy.Inextremecases,thethicknessoftherightventricularwallmaybecomparabletoorevenexceedthatoftheleftventricle(


Pathology_Robbins

Pathology_Robbins. Fig.11.16B ).Whenventricularfailuredevelops,therightventricleandatriumoftenaredilated.Becausechroniccorpulmonaleoccursinthesettingofpulmonaryhypertension,thepulmonaryarteriesoftencontainatheromatousplaquesandotherlesions,reflectinglongstandingpressureelevations. Valvular disease may result in stenosis, insufficiency (regurgitation or incompetence), or both. • Stenosis is the failure of a valve to open completely, obstructing forward flow. Valvular stenosis is almost Table 11.3 Disorders Predisposing to Cor Pulmonale Extensivepulmonaryarteritis(e.g.,Granulomatosiswithpolyangiitis) Drug-,toxin-,orradiation-inducedvascularobstruction Hypertensiveheartdiseasecanaffecteithertheleftventricleortherightventricle;inthelattercase,thedisorderismostoftenduetoprimarypulmonarydiseaseandiscalledcor pulmonale. Elevatedpressuresinducemyocytehypertrophyandinterstitialfibrosisthatincreaseswallthicknessandstiffness.


Pathology_Robbins

Pathology_Robbins. Thechronicpressureoverloadofsystemichypertensioncausesleftventricularconcentrichypertrophy,oftenassociatedwithleftatrialdilationduetoimpaireddiastolicfillingoftheventricle.Persistentlyelevatedpressureoverloadcancauseventricularfailurewithdilation. Corpulmonaleresultsfrompulmonaryhypertensionduetoprimarylungparenchymalorvasculardisorders.Hypertrophyofboththerightventricleandtherightatriumischaracteristic;dilationalsomaybeseenwhenfailuresupervenes. always due to a primary cuspal abnormality stemming from a chronic process (e.g., calcification or valve scarring).


Pathology_Robbins

Pathology_Robbins. always due to a primary cuspal abnormality stemming from a chronic process (e.g., calcification or valve scarring). • Insufficiency results from failure of a valve to close completely, thereby allowing regurgitation (backflow) of blood. Valvular insufficiency can result from either intrinsic disease of the valve cusps (e.g., endocarditis) or disruption of the supporting structures (e.g., the aorta, mitral annulus, tendinous cords, papillary muscles, or ventricular free wall) without primary cuspal injury. It can appear abruptly, as with chordal rupture, or insidiously as a consequence of leaflet scarring and retraction.


Pathology_Robbins

Pathology_Robbins. Stenosis or regurgitation may occur alone or together in the same valve. Valvular disease can involve only one valve (the mitral valve being the most common target), or more than one valve. Turbulent flow through diseased valves typically produces abnormal heart sounds called murmurs; severe lesions can even be externally palpated as thrills. Depending on the valve involved, murmurs are best heard at different locations on the chest wall; moreover, the nature (regurgitation versus stenosis) and severity of the valvular disease determines the quality and timing of the murmur (e.g., harsh systolic or soft diastolic murmurs). http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net The outcome of valvular disease depends on the valve involved, the degree of impairment, the tempo of its development, and the effectiveness of compensatory mechanisms. For example, rapid destruction of an aortic valve cusp by infection can cause massive regurgitation and the abrupt onset of cardiac failure. By contrast, rheumatic mitral stenosis usually progresses over years, and its clinical effects are well tolerated until late in the course. Valvular abnormalities can be congenital or acquired. By far the most common congenital valvular lesion is a bicuspid aortic valve, containing only two functional cusps instead of the normal three; this malformation occurs with a frequency of 1% to 2% of all live births, and has been associated with a number of mutations, including those affecting proteins of the Notch signaling pathway. The two cusps are of unequal size, with the larger cusp exhibiting a midline raphe resulting from incomplete cuspal separation (


Pathology_Robbins

Pathology_Robbins. Fig. 11.17B ). Bicuspid aortic valves are generally neither stenotic nor incompetent through early life; however, they are more prone to early and progressive degenerative calcification that gives rise to stenosis (see later). The most important causes of acquired valvular diseases are summarized in Table 11.4 ; acquired stenoses of the aortic and mitral valves account for approximately two thirds of all valve disease. Degenerative valve disease is a term used to describe changes that affect the integrity of valvular ECM. Degenerative changes include the following: Calcifications, which can be cuspal (typically in the aortic valve) ( Fig. 11.17A and B ) or annular (in the mitral valve) ( Fig. 11.17C and D ). Mitral annular calcification is usually asymptomatic unless it encroaches on the adjacent conduction system.


Pathology_Robbins

Pathology_Robbins. Fig. 11.17A and B ) or annular (in the mitral valve) ( Fig. 11.17C and D ). Mitral annular calcification is usually asymptomatic unless it encroaches on the adjacent conduction system. Alterations in the ECM. In some cases, changes consist of increased proteoglycan and diminished fibrillar collagen and elastin (myxomatous degeneration); in other cases, the valve becomes fibrotic and scarred. Changes in the production of matrix metalloproteinases or their inhibitors Degenerative changes in the cardiac valves are probably an inevitable aspect of aging related to the repetitive mechanical stresses to which valves are subjected—40 million beats per year, with each normal opening and closing requiring substantial valve deformation. Calcific aortic degeneration is the most common cause of aortic stenosis. In most cases, calcific degeneration is asymptomatic and is discovered only incidentally by viewing


Pathology_Robbins

Pathology_Robbins. Calcific aortic degeneration is the most common cause of aortic stenosis. In most cases, calcific degeneration is asymptomatic and is discovered only incidentally by viewing Table 11.4 Etiology of Acquired Heart Valve Disease (myocarditis,dilatedcardiomyopathy)Calcificationofmitralring Fen-phen, Fenfluramine-phentermine.DatafromSchoenFJ:Surgicalpathologyofremovednaturalandprostheticvalves,Hum Pathol 18:558,1987. Fig. 11.17 Calcificvalvulardegeneration.(A)Calcificaorticstenosisofapreviouslynormalvalve(viewedfromabovethevalve).NodularmassesofcalciumareheapedupwithinthesinusesofValsalva(arrow).Notethatthecommissuresarenotfused,asinrheumaticaorticvalvestenosis(see Fig.


Pathology_Robbins

Pathology_Robbins. Fig. 11.19C ).(B)Calcificaorticstenosisoccurringonacongenitallybicuspidvalve.Onecusphasapartialfusionatitscenter,calledaraphe(arrow).(CandD)Mitralcalcification,withcalcificnoduleswithintheannulus(attachmentmargin)ofthemitralleaflets(arrows). (C)Leftatrialview.(D)Sectiondemonstratingtheextensionofcalcificationintotheunderlyingmyocardium.Suchinvolvementofadjacentstructuresneartheinterventricularseptumcanimpingeontheconductionsystem. http://ebooksmedicine.net calcifications on a routine chest radiograph or at autopsy. In other patients, valvular sclerosis and/or calcification can be severe enough to cause stenosis, necessitating surgical intervention. The incidence of calcific aortic stenosis is increasing in pace with longevity. In anatomically normal valves, it typically begins to manifest when patients reach their 70s and 80s; onset with bicuspid aortic valves is at a much earlier age (often 40 to 50 years of age).


Pathology_Robbins

Pathology_Robbins. Although simple progressive age-associated “wear and tear” is often invoked to explain the process, cuspal fibrosis and calcification also can be viewed as the valvular counterparts to age-related arteriosclerosis. Thus, chronic injury due to hyperlipidemia, hypertension, inflammation, and other factors implicated in atherosclerosis have been proposed as contributors to valvular degenerative changes, but firm evidence is lacking. opening(Fig. 11.17AandB );commissuralfusion(usuallyasignofpreviousinflammation)isnotatypicalfeatureofdegenerativeaorticstenosis,althoughthecuspsmaybecomesecondarilyfibrosedandthickened.Anearlier,hemodynamicallyinconsequentialstageofthecalcificationprocessiscalledaortic valve sclerosis.


Pathology_Robbins

Pathology_Robbins. In severe disease, valve orifices can be compromised by as much as 70% to 80% (from a normal area of approximately 4 cm2). Cardiac output is maintained only by virtue of concentric left ventricular hypertrophy; the chronic outflow obstruction can drive left ventricular pressures to 200 mm Hg or more. The hypertrophied myocardium is prone to ischemia, and angina may develop. Systolic and diastolic dysfunction collude to cause CHF, and cardiac decompensation eventually ensues. The development of angina, CHF, or syncope in aortic stenosis heralds the exhaustion of compensatory cardiac hyperfunction and carries a poor prognosis; without surgical intervention, 50% to 80% of patients die within 2 to 3 years.


Pathology_Robbins

Pathology_Robbins. In myxomatous degeneration of the mitral valve, one or both mitral leaflets are “floppy” and prolapse—they balloon back into the left atrium during systole. Primary mitral valve prolapse is a form of myxomatous mitral degeneration affecting some 0.5% to 2.4% of adults; thus, it is one of the most common forms of valvular heart disease, with women affected almost 7-fold more often than men. Conversely, secondary myxomatous mitral degeneration affects men and women equally, and can occur in any one of a number of settings in which mitral regurgitation is caused by some other underlying cause (e.g., IHD).


Pathology_Robbins

Pathology_Robbins. The basis for primary myxomatous degeneration of the mitral valve is unknown. Nevertheless, an underlying (possibly systemic) intrinsic defect of connective tissue synthesis or remodeling is likely. Thus, myxomatous degeneration of the mitral valve is a common feature of Marfan syndrome (due to fibrillin-1 mutations, Chapter 7) and occasionally occurs in other connective tissue disorders. In some patients with primary disease, additional hints of systemic structural abnormalities in connective tissue, including scoliosis and high-arched palate, may be found. Subtle defects in structural proteins (or the cells that make them) may cause hemodynamically stressed connective tissues rich in microfibrils and elastin (e.g., cardiac valves) to elaborate defective ECM. Secondary myxomatous change presumably results from injury to the valve myofibroblasts, imposed by chronically aberrant hemodynamic forces.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Fig. 11.18 Myxomatousdegenerationofthemitralvalve.Thereisprominenthoodingwithprolapseoftheposteriormitralleaflet(arrow) intotheleftatrium;theatriumalsoisdilated,reflectinglong-standingvalvularinsufficiencyandvolumeoverload.Theleftventricleisshownontheright inthisfour-chamberview.(Courtesy of William D. Edwards, MD, Mayo Clinic, Rochester, Minnesota.) http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Most patients are asymptomatic, and the valvular abnormality is discovered incidentally. In a minority of cases, patients complain of palpitations, dyspnea, or atypical chest pain. Auscultation discloses a midsystolic click, caused by abrupt tension on the redundant valve leaflets and chordae tendineae as the valve attempts to close; there is sometimes an associated regurgitant murmur. Although in most instances the natural history and clinical course are benign, approximately 3% of patients develop complications such as hemodynamically significant mitral regurgitation and CHF, particularly if the chordae or valve leaflets rupture. Patients with primary myxomatous degeneration also are at increased risk for the development of infective endocarditis (see later), as well as SCD due to ventricular arrhythmias. Stroke or other systemic infarctions may rarely occur from embolism of thrombi formed in the left atrium.


Pathology_Robbins

Pathology_Robbins. Rheumatic fever is an acute, immunologically mediated, multisystem inflammatory disease that occurs after group A β-hemolytic streptococcal infections (usually pharyngitis, but also occasionally infections at other sites, such as skin). Rheumatic heart disease is the cardiac manifestation of rheumatic fever. It is associated with inflammation of all parts of the heart, but valvular inflammation and scarring produce the most important clinical features.


Pathology_Robbins

Pathology_Robbins. The valvular disease principally takes the form of deforming fibrotic mitral stenosis; indeed rheumatic heart disease is essentially the only cause of acquired mitral stenosis. The incidence of rheumatic fever (and thus rheumatic heart disease) has declined remarkably in many parts of the Western world over the past several decades due to a combination of improved socioeconomic conditions, rapid diagnosis and treatment of streptococcal pharyngitis, and a fortuitous (and unexplained) decline in the virulence of many strains of group A streptococci. Nevertheless, in developing countries and economically depressed urban areas in the United States, rheumatic fever and rheumatic heart disease remain important public health problems.


Pathology_Robbins

Pathology_Robbins. Acute rheumatic fever is a hypersensitivity reaction classically attributed to antibodies directed against group A streptococcal molecules that cross-react with host myocardial antigens (see also Chapter 5). In particular, antibodies against M proteins of certain streptococcal strains bind to proteins in the myocardium and cardiac valves and cause injury through the activation of complement and Fc receptor–bearing cells (including macrophages). CD4+ T cells that recognize streptococcal peptides can cross-react with host antigens and elicit cytokine-mediated inflammatory responses. The characteristic 2-to 3-week delay in symptom onset after infection is explained by the time needed to generate an immune response; streptococci are completely absent from the lesions. Since only a small minority of infected patients develop rheumatic fever (estimated at 3%), genetic susceptibility to the development of the cross-reactive immune responses is likely in those affected. The deforming fibrotic


Pathology_Robbins

Pathology_Robbins. of infected patients develop rheumatic fever (estimated at 3%), genetic susceptibility to the development of the cross-reactive immune responses is likely in those affected. The deforming fibrotic lesions are the predictable consequence of healing and scarring associated with the resolution of the acute inflammation.


Pathology_Robbins

Pathology_Robbins. Thepericardiummayexhibitafibrinousexudate,whichgenerallyresolveswithoutsequelae. Themyocardialinvolvement—myocarditis—takestheformofscatteredAschoffbodieswithintheinterstitialconnectivetissue. Fig.11.19A )forming1-to2-mmvegetations—verrucae—thatcauselittledisturbanceincardiacfunction. Chronic rheumatic heart disease ischaracterizedbyorganizationofacuteinflammationandsubsequentscarring.Aschoffbodiesarereplacedbyfibrousscarsothattheselesionsarerarelyseeninchronicdisease.Mostcharacteristically,valvecuspsandleafletsbecomepermanentlythickenedandretracted.Classically,themitralvalvesexhibitleaflet thickening, commissural fusion and shortening,and thickening and fusion of the chordae tendineae ( Fig.11.19CtoE ).Fibrousbridgingacrossthevalvularcommissuresandcalcificationcreate“fishmouth”or“buttonhole”stenoses( Fig.11.19C ).Microscopicexaminationshowsneovascularization(visiblyevidentin Fig. 11.19D )anddiffusefibrosisthatobliteratesthenormalleafletarchitecture.


Pathology_Robbins

Pathology_Robbins. Acute rheumatic fever occurs most often in children; the principal clinical manifestation is carditis. Nevertheless, http://ebooksmedicine.net


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Pathology_Robbins. From Schoen FJ, St John-Sutton M: Contemporary issues in the pathology of valvular heart disease, HumPathol18:568, 1967.) about 20% of first attacks occur in adults, with arthritis being the predominant feature. Symptoms in all age groups typically begin 2 to 3 weeks after streptococcal infection and are heralded by fever and migratory polyarthritis— one large joint after another becomes painful and swollen for a period of days, followed by spontaneous resolution with no residual disability. Although cultures are negative for streptococci at the time of symptom onset, serum titers of antibodies against one or more streptococcal antigens (e.g., streptolysin O or DNAase) usually are elevated. The clinical signs of carditis include pericardial friction rubs and arrhythmias; myocarditis may be sufficiently severe to cause cardiac dilation and resultant functional mitral insufficiency and CHF. Nevertheless, less than 1% of patients die of acute rheumatic fever.


Pathology_Robbins

Pathology_Robbins. The diagnosis of acute rheumatic fever is made based on serologic evidence of previous streptococcal infection in conjunction with two or more of the Jones criteria: (1) carditis; (2) migratory polyarthritis of large joints; (3) subcutaneous nodules; (4) erythematous annular rash (erythema marginatum) in the skin; and (5) Sydenham chorea, a neurologic disorder characterized by involuntary purposeless, rapid movements (also called St. Vitus dance). Minor criteria such as fever, arthralgias, EKG changes, or elevated acute phase reactants also can help support the diagnosis.


Pathology_Robbins

Pathology_Robbins. After an initial attack and the generation of immunologic memory, patients are increasingly vulnerable to disease reactivation with any subsequent streptococcal infections. Carditis is likely to worsen with each recurrence, and the damage is cumulative. However, chronic rheumatic carditis usually is not clinically evident until years or even decades after the initial episode of rheumatic fever. At that time, the signs and symptoms of valvular disease depend on which cardiac valve(s) is involved. In addition to various cardiac murmurs, cardiac hypertrophy and dilation, and CHF, patients with chronic rheumatic heart disease often have arrhythmias (particularly atrial fibrillation in the setting of mitral stenosis), and thromboembolic complications due to atrial mural thrombi. In addition, scarred and deformed valves are more susceptible to infective endocarditis. The long-term prognosis is highly variable. In some cases, a relentless cycle of valvular deformity ensues, yielding


Pathology_Robbins

Pathology_Robbins. scarred and deformed valves are more susceptible to infective endocarditis. The long-term prognosis is highly variable. In some cases, a relentless cycle of valvular deformity ensues, yielding hemodynamic abnormality, which begets further deforming fibrosis. Surgical repair or replacement of diseased valves—mitral valvuloplasty—has greatly improved the outlook for patients with rheumatic heart disease.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Infective endocarditis (IE) is a microbial infection of the heart valves or the mural endocardium that leads to the formation of vegetations composed of thrombotic debris and organisms, often associated with destruction of the underlying cardiac tissues. The aorta, aneurysmal sacs, other blood vessels, and prosthetic devices also may become infected. Although fungi, rickettsiae (agents of Q fever), and chlamydial species can cause endocarditis, the vast majority of cases are caused by extracellular bacteria. Infective endocarditis is classified into acute and subacute forms based on the tempo and severity of the clinical course; the distinctions are related to the virulence of the responsible microbe and whether underlying cardiac disease is present. Of note, a clear delineation between acute and subacute endocarditis is not always possible, and many cases fall somewhere along the spectrum between the two forms.


Pathology_Robbins

Pathology_Robbins. Acute endocarditis refers to tumultuous, destructive infections, frequently involving a highly virulent organism attacking a previously normal valve. It is associated with of substantial morbidity and mortality, even with appropriate antibiotic therapy and/or surgery. Subacute endocarditis refers to infections by organisms of low virulence affecting a previously abnormal heart, especially scarred or deformed valves. The disease typically appears insidiously and—even if untreated— follows a protracted course of weeks to months; most patients recover after appropriate antibiotic therapy.


Pathology_Robbins

Pathology_Robbins. Infective endocarditis can develop on previously normal valves, but cardiac abnormalities predispose to such infections; rheumatic heart disease, mitral valve prolapse, bicuspid aortic valves, and calcific valvular stenosis are all common substrates. Prosthetic heart valves (discussed later) now account for 10% to 20% of all cases of IE. Sterile platelet-fibrin deposits at sites of pacemaker lines, indwelling vascular catheters, or endocardium damage by flow “jets” stemming from preexisting cardiac disease all can be foci for bacterial seeding and development of endocarditis. Host factors such as neutropenia, immunodeficiency, malignancy, diabetes mellitus, and alcohol or intravenous drug abuse also increase the risk for IE and adversely affect outcomes.


Pathology_Robbins

Pathology_Robbins. The causative organisms differ depending on the underlying risk factors; 50% to 60% of cases occurring on damaged or deformed valves are caused by Streptococcus viridans, a relatively banal group of normal oral flora. By contrast, the more virulent S. aureus (common to skin) can attack healthy as well as deformed valves and is responsible for 10% to 20% of cases overall; it also is the major offender in infections occurring in intravenous drug abusers. Additional bacterial agents include enterococci and the so-called “HACEK group” (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella), all commensal in the oral cavity. More rarely, gram-negative bacilli and fungi are involved. In about 10% of all cases of endocarditis, no organism is isolated from the blood (“culture-negative” endocarditis) because of previous antibiotic therapy, difficulty in isolating the offending agent, or because deeply embedded organisms within the enlarging vegetation are not readily released


Pathology_Robbins

Pathology_Robbins. endocarditis) because of previous antibiotic therapy, difficulty in isolating the offending agent, or because deeply embedded organisms within the enlarging vegetation are not readily released into the blood.


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Pathology_Robbins. Foremost among the factors predisposing to endocarditis is seeding of the blood with microbes. The mechanism or portal of entry of the agent into the bloodstream may be an obvious infection elsewhere, a dental or surgical procedure that causes a transient bacteremia, injection of contaminated material directly into the bloodstream by intravenous drug abusers, an occult source from the gut, or oral cavity, or trivial injuries. Recognition of predisposing anatomic substrates and clinical conditions causing bacteremia allows appropriate antibiotic prophylaxis. MORPHOLOGYInbothacuteandsubacuteformsofthedisease,friable,bulky,andpotentiallydestructivevegetationscontainingfibrin,inflammatorycells,andmicroorganismsarepresentontheheartvalves(


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYInbothacuteandsubacuteformsofthedisease,friable,bulky,andpotentiallydestructivevegetationscontainingfibrin,inflammatorycells,andmicroorganismsarepresentontheheartvalves( Figs.11.20 11.21 ).The aortic and mitral valves are the most common sites of infection, although the tricuspid valve is a frequent target in the setting of intravenous drug abuse. Vegetationsmaybesingleormultipleandmayinvolvemorethanonevalve;theycansometimeserodeintotheunderlyingmyocardiumtoproduceanabscesscavity(ring abscess) ( Fig.11.21B ).Sheddingofemboli iscommonbecauseofthefriablenatureofthevegetations.Sincethefragmentedvegetationscontainlargenumbersoforganisms,abscessesoftendevelopatthesiteswhereembolilodge,leadingtodevelopmentofseptic infarcts andaneurysmsresultingfrombacterialinfectionofthearterialwall(mycotic aneurysms).


Pathology_Robbins

Pathology_Robbins. Subacuteendocarditistypicallycauseslessvalvulardestructionthanacuteendocarditis.Onmicroscopicexamination,thevegetationsofsubacuteendocarditisoftenhavegranulationtissueattheirbases(suggestingchronicity),promotingdevelopmentofchronicinflammatoryinfiltrates,fibrosis,andcalcificationovertime. Fever is the most consistent sign of infective endocarditis.


Pathology_Robbins

Pathology_Robbins. Fever is the most consistent sign of infective endocarditis. However, in subacute disease (particularly in older adults), fever may be absent, and the only manifestations may be nonspecific fatigue, weight loss, and a flulike syndrome; splenomegaly also is common in subacute cases. By contrast, acute endocarditis often manifests with rapidly developing fever, chills, weakness, and lassitude. Murmurs are present in 90% of patients with left-sided lesions. In those who are not treated promptly, microemboli are formed, which can give rise to petechia, nail bed (splinter) hemorrhages, retinal hemorrhages (Roth spots), painless palm or sole erythematous lesions (Janeway lesions), or painful fingertip nodules (Osler nodes); diagnosis is confirmed by positive blood cultures and echocardiographic findings.


Pathology_Robbins

Pathology_Robbins. Prognosis depends on the infecting organism and the development of complications. Adverse sequelae generally begin within the first weeks after onset of the infectious process and can include glomerulonephritis due to glomerular trapping of antigen-antibody complexes, with http://ebooksmedicine.net


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. hematuria, albuminuria, or renal failure (Chapter 14). Clinical features of septicemia, arrhythmias (suggesting extension to underlying myocardium and conduction system), and systemic embolization bode ill for the patient. Left untreated, IE generally is fatal. However, with appropriate long-term (6 weeks or more) antibiotic therapy and/or valve replacement, mortality is reduced. For infections with low-virulence organisms (e.g., Streptococcus viridans or Streptococcus bovis), the cure rate is 98%, and for enterococci and Staphylococcus aureus infections, cure rates range from 60% to 90%; however, infections with aerobic gram-negative bacilli or fungi are associated with fatality rate of approximately 50%.


Pathology_Robbins

Pathology_Robbins. Nonbacterial thrombotic endocarditis (NBTE) is characterized by the deposition of sterile thrombi on cardiac valves, typically in those with an underlying hypercoagulable state. Although NBTE can occur in otherwise healthy individuals, a wide variety of diseases associated with general debility or wasting are associated with an increased risk for NBTE—hence the alternate term marantic endocarditis. In contrast to infective endocarditis, the sterile valvular lesions of NBTE are nondestructive ( Fig. 11.22


Pathology_Robbins

Pathology_Robbins. Fig. 11.22 The vegetations in NBTE are typically small (1 to 5 mm in diameter) and valvular damage is not a prerequisite. Indeed, the condition usually occurs on previously normal valves. Rather, hypercoagulable states are the usual precursor to NBTE; such conditions include chronic disseminated intravascular coagulation, hyperestrogenic states, and those associated with underlying malignancy, particularly mucinous adenocarcinomas. This last association probably relates to the procoagulant effect of circulating mucin and/or tissue factor elaborated by these tumors. Endocardial trauma, such as from an indwelling catheter, also is a well-recognized predisposing condition.


Pathology_Robbins

Pathology_Robbins. Although the local effect on the valve usually is trivial, NBTE lesions can become clinically significant by giving rise to emboli that can cause infarcts in the brain, heart, and other organs. NBTE also can serve as a potential nidus for bacterial colonization and the consequent development of infective endocarditis. Fig. 11.21 Infectiveendocarditis.(A)SubacuteendocarditiscausedbyStreptococcus viridans onapreviouslymyxomatousmitralvalve.Thelarge,friablevegetationsaredenotedbyarrows. (B)AcuteendocarditiscausedbyStaphylococcus aureus onacongenitallybicuspidaorticvalvewithextensivecuspaldestructionandringabscess(arrow). http://ebooksmedicine.net Fig. 11.22 Nonbacterialthromboticendocarditis(NBTE).(A)Smallthromboticvegetationsalongthelineofclosureofthemitralvalveleaflets(arrows). (B)PhotomicrographofNBTElesion,showingblandthrombus,withvirtuallynoinflammationinthevalvecusp(C) orthethromboticdeposit(t).Thethrombusisonlylooselyattachedtothecusp(arrow).


Pathology_Robbins

Pathology_Robbins. (B)PhotomicrographofNBTElesion,showingblandthrombus,withvirtuallynoinflammationinthevalvecusp(C) orthethromboticdeposit(t).Thethrombusisonlylooselyattachedtothecusp(arrow). Endocarditis in Systemic Lupus Erythematosus: Libman-Sacks Endocarditis Libman-Sacks endocarditis is characterized by the presence of sterile vegetations on the valves of patients with systemic lupus erythematosus. It occurs in about 10% of patients with SLE. The lesions probably develop as a consequence of immune complex deposition and thus exhibit associated inflammation, often with fibrinoid necrosis of the valve adjacent to the vegetation; subsequent fibrosis and serious deformity can result in lesions that resemble chronic rheumatic heart disease. These can occur anywhere on the valve surface, on the cords, or even on the atrial or ventricular endocardium (see Fig. 11.20 ). Similar lesions can occur in the setting of anti-phospholipid antibody syndrome (Chapter 4).


Pathology_Robbins

Pathology_Robbins. Fig. 11.20 ). Similar lesions can occur in the setting of anti-phospholipid antibody syndrome (Chapter 4). •Valvepathologycanleadtoocclusion(stenosis) and/orregurgitation(insufficiency); acquiredaorticormitralvalvestenosisaccountsforapproximatelytwothirdsofallvalvedisease. Valvecalcificationtypicallyresultsinstenosis;abnormalmatrixsynthesisandturnoverleadstomyxomatousdegenerationandinsufficiency. Inflammatoryvalvediseasescausepostinflammatoryneovascularizationandscarring.Rheumaticheartdiseaseresultsfromanti-streptococcalantibodiesthatcross-reactwithcardiactissues;itmostcommonlyaffectsthemitralvalveandisresponsibleforalmostallcasesofacquiredmitralstenosis. Infectiveendocarditiscanrapidlydestroynormalvalves,orcanbeindolentandminimallydestructiveofpreviouslyabnormalvalves.Systemicembolizationcanproducesepticinfarcts. Nonbacterialthromboticendocarditisoccursonpreviouslynormalvalvesasaresultofhypercoagulablestates;embolizationisanimportantcomplication.


Pathology_Robbins

Pathology_Robbins. Nonbacterialthromboticendocarditisoccursonpreviouslynormalvalvesasaresultofhypercoagulablestates;embolizationisanimportantcomplication. Cardiac diseases due to intrinsic myocardial dysfunction are termed cardiomyopathies (literally, “heart muscle diseases”); these can be primary—that is, principally confined to the myocardium—or secondary presenting as the cardiac manifestation of a systemic disorder. Cardiomyopathies are thus a diverse group that includes inflammatory disorders (e.g., myocarditis), immunologic diseases (e.g., sarcoidosis), systemic metabolic disorders (e.g., hemochromatosis), muscular dystrophies, and genetic disorders of myocardial fibers. In many cases, the cardiomyopathy is of unknown etiology and thus is termed idiopathic; however, a number of previously “idiopathic” cardiomyopathies have been shown to be the consequence of specific genetic abnormalities in cardiac energy metabolism or in structural and contractile proteins.


Pathology_Robbins

Pathology_Robbins. Cardiomyopathies can be classified according to a variety of criteria, including the underlying genetic basis of dysfunction; indeed, some of the arrhythmia-inducing channelopathies that are included in some classifications of cardiomyopathy were alluded to earlier. For purposes of general diagnosis and therapy, however, three time-honored clinical, functional, and pathologic patterns are recognized ( Fig. 11.23 Table 11.5 Of the three major patterns, DCM is most common (90% of cases), and restrictive cardiomyopathy is the least frequent. Within each pattern, there is a spectrum of clinical severity, and in some cases clinical features overlap among the groups. In addition, each of these patterns can be caused by a specific identifiable cause, or can be idiopathic (see Table 11.5


Pathology_Robbins

Pathology_Robbins. Table 11.5 Dilated cardiomyopathy (DCM) is characterized by progressive cardiac dilation and contractile (systolic) dysfunction, usually with concurrent hypertrophy; regardless of the cause, the clinicopathologic patterns are similar. http://ebooksmedicine.net Fig. 11.23 Thethreemajorformsofcardiomyopathy.Dilatedcardiomyopathyleadsprimarilytosystolicdysfunction,whereasrestrictiveandhypertrophiccardiomyopathiesresultindiastolicdysfunction.Notethechangesinatrialand/orventriculardilationandinventricularwallthickness.Ao, Aorta;LA, leftatrium;LV, leftventricle. Although many individuals with DCM have a familial (genetic) form, DCM can also result from various acquired myocardial insults. These include the following: • Myocarditis (an inflammatory disorder that precedes the development of cardiomyopathy in at least some cases, and is sometimes caused by viral infections) Table 11.5 Cardiomyopathies: Functional Patterns, Causes


Pathology_Robbins

Pathology_Robbins. Table 11.5 Cardiomyopathies: Functional Patterns, Causes Toxicities, including adverse effects of chemotherapeutic agents and chronic alcoholism, a history of which can be elicited in 10% to 20% of patients Pregnancy, so-called “peripartum cardiomyopathy” By the time it is diagnosed, DCM has frequently already progressed to end-stage disease; the heart is dilated and poorly contractile, and at autopsy or cardiac transplant, fails to reveal any specific pathologic features. Nevertheless, genetic and epidemiologic studies suggest that at least five general pathways can lead to end-stage DCM ( Fig. 11.24


Pathology_Robbins

Pathology_Robbins. Genetic causes. DCM has a hereditary basis in 20% to 50% of cases. Over 50 genes are known to be mutated in this form of cardiomyopathy, with autosomal dominant inheritance being the predominant pattern; mutations affecting cytoskeletal proteins or proteins that link the sarcomere to the cytoskeleton (e.g., α-cardiac actin) are most commonly involved. X-linked DCM is most frequently associated with mutatons in dystrophin, a cell membrane protein that physically couples the intracellular cytoskeleton to the ECM (Chapter 22). Uncommon forms of DCM are caused by mutations of mitochondrial proteins involved in oxidative phosphorylation or fatty acid β-oxidation, presumably leading to defective ATP generation. Other genetic forms of DCM include those with mutations in cytoskeletal proteins such as desmin (the principal intermediate filament protein in cardiac myocytes), and the nuclear lamins A and C. Since contractile myocytes and conduction fibers share a common developmental pathway,


Pathology_Robbins

Pathology_Robbins. as desmin (the principal intermediate filament protein in cardiac myocytes), and the nuclear lamins A and C. Since contractile myocytes and conduction fibers share a common developmental pathway, congenital conduction abnormalities also can be a feature of inherited forms of DCM.


Pathology_Robbins

Pathology_Robbins. Infection. The nucleic acid “footprints” of coxsackievirus B and other enteroviruses can occasionally be detected in the myocardium from late-stage DCM patients. Moreover, sequential endomyocardial biopsies have documented instances in which infectious myocarditis progressed to DCM. Simply finding viral transcripts or demonstrating elevated anti-viral antibody titers may be sufficient to invoke a myocarditis that was “missed” in its early stages. Consequently, many cases of DCM are attributed to viral infections, even though inflammation is absent from the end-stage heart. Alcohol or other toxic exposure. Alcohol abuse is strongly associated with the development of DCM. Alcohol and http://ebooksmedicine.net Toxic (e.g., alcohol) 20-50% genetic causes Various proteins (cell membrane, cytoskeleton, sarcomere, nuclear envelope, or mitochondrial) Defect in force generation, force transmission, and/or myocyte signaling


Pathology_Robbins

Pathology_Robbins. Defect in force generation, force transmission, and/or myocyte signaling Defect in energy transfer from mitochondria to sarcomere and/or direct sarcomeric dysfunction Hypertrophy, marked Fibrosis, interstitial and replacement • Hypertrophy • Dilation • Fibrosis, interstitial • Intracardiac thrombi Dilated cardiomyopathy phenotype • Heart failure • Sudden death • Atrial fibrillation • Stroke Clinical Fig. 11.24 Causesandconsequencesofdilatedandhypertrophiccardiomyopathy.Asignificantfractionofdilatedcardiomyopathies—andvirtuallyallhyper-trophiccardiomyopathies—haveageneticorigin.Dilatedcardiomyopathiescanbecausedbymutationsincytoskeletal,sarcomeric,nuclearenvelope,ormitochondrialproteins;hypertrophiccardiomyopathiestypicallyarecausedbysarcomericproteinmutations.Althoughthetwoformsofcardiomyopathydifferincauseandmorphology,theyhavecommonclinicalendpoints.LV, Leftventricle.


Pathology_Robbins

Pathology_Robbins. its metabolites (especially acetaldehyde) have a direct toxic effect on the myocardium. Moreover, chronic alcoholism can be associated with thiamine deficiency, introducing an element of beriberi heart disease (Chapter 8). DCM also can develop after exposure to other toxic agents, such as cobalt, and particularly doxorubicin (Adriamycin), a chemotherapeutic drug.


Pathology_Robbins

Pathology_Robbins. Peripartum cardiomyopathy occurs late in gestation or several weeks to months postpartum. The etiology is multifactorial, including pregnancy-associated hypertension, volume overload, nutritional deficiency, metabolic derangements (e.g., gestational diabetes), and/or immunologic responses. Recent work suggests that the primary defect is impaired angiogenesis within the myocardium leading to ischemic injury. Antiangiogenic cleavage products of the hormone prolactin (which rises late in pregnancy) and placental-derived antagonists to the VEGF have been implicated. Fortunately, approximately one half of these patients spontaneously recover normal function.


Pathology_Robbins

Pathology_Robbins. Iron overload in the heart can result either from hereditary hemochromatosis (Chapter 16) or from multiple transfusions. Iron overload also can cause restrictive cardiomyopathy due to interstitial fibrosis, but DCM is the most common manifestation; it has been attributed to interference with metal-dependent enzyme systems or to injury caused by iron-mediated production of reactive oxygen species. MORPHOLOGYTheheartinDCMcharacteristicallyisenlarged(uptotwotothreetimesthenormalweight)andflabby, withdilationofallchambers( Fig.11.25 ).Becauseofthewallthinningthataccompaniesdilation,theventricularthicknessmaybelessthan,equalto,orgreaterthannormal.Mural thrombi areoftenpresentandmaybeasourceofthromboemboli.Bydefinition,valvularandvascularlesions(e.g.,atheroscleroticcoronaryarterydisease)thatcancausecardiacdilationsecondarilyareabsent.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. The fundamental defect in DCM is ineffective contraction. Thus, in end-stage DCM, the cardiac ejection fraction typically is less than 25% (normal is 50% to 65%). Secondary mitral regurgitation and abnormal cardiac rhythms are common, and embolism from intracardiac (mural) thrombi can occur. DCM most commonly is diagnosed between 20 and 50 years of age. It typically manifests with signs of slowly progressive CHF, including dyspnea, easy fatigability, and poor exertional capacity. One half of patients die within 2 years and only 25% survive longer than 5 years; death is usually due to progressive cardiac failure or arrhythmia. Cardiac transplantation is the only definitive treatment, although implantation of long-term ventricular assist devices is increasingly utilized; in some patients, a course of mechanical assistance can produce durable regression of cardiac dysfunction. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 11.25 Dilatedcardiomyopathy(DCM).(A)Four-chamberdilationandhypertrophyareevident.Asmallmuralthrombuscanbeseenattheapexoftheleftventricle(arrow).(B)ThenonspecifichistologicpictureintypicalDCM,withmyocytehypertrophyandinterstitialfibrosis.(Collagenisblue inthisMassontrichrome–stainedpreparation.) Arrhythmogenic right ventricular cardiomyopathy is an autosomal dominant disorder that classically manifests with right-sided heart failure and rhythm disturbances, which can cause sudden cardiac death. Its prevalence in the general adult population is close to 1 in 5000 in a study from Italy. Similar prevalence is likely in the US where it seems to be under reported. Almost 10% of cases of sudden deaths in athletes have been ascribed to this entity. Morphologically, the right ventricular wall is severely thinned owing to myocyte replacement by fatty infiltration and lesser amounts of fibrosis (


Pathology_Robbins

Pathology_Robbins. Fig. 11.26 ). Many of the causative mutations involve genes encoding desmosomal junctional proteins at the intercalated disk (e.g., plakoglobin), as well as proteins that interact with the desmosome (e.g., the intermediate filament desmin). It’s thought that myocyte death is caused by desmosomal detachment, particularly during strenuous exercise. Hypertrophic cardiomyopathy (HCM) is characterized by myocardial hypertrophy, defective diastolic filling, and— in one third of cases—ventricular outflow obstruction. The heart is thick-walled, heavy, and hypercontractile, in striking contrast to the flabby, poorly contractile heart in DCM. Systolic function usually is preserved in HCM, but the myocardium does not relax and therefore exhibits primary diastolic dysfunction. HCM needs to be distinguished clinically from disorders causing ventricular stiffness (e.g., amyloid deposition) and ventricular hypertrophy (e.g., aortic stenosis and hypertension).


Pathology_Robbins

Pathology_Robbins. Most cases of HCM are caused by missense mutations in one of several genes encoding proteins that form the contractile apparatus. The usual pattern of transmission is autosomal dominant, with variable expression. Although more than 400 causative mutations in nine different genes have been identified, all have one unifying feature: they all affect sarcomeric proteins and increase myofilament function. This results in myocyte hypercontractility, increased energy use, and a net negative energy balance. Of the various sarcomeric proteins, β-myosin heavy chain is most frequently involved, followed by myosin-binding protein C and troponin T. Mutations in these three genes account for 70% to 80% of all cases of HCM. Some of the genes mutated in HCM also are mutated in DCM (e.g., beta-myosin), but in DCM the mutations depress motor function as opposed to the gain of function seen in HCM. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Although HCM can present at any age, it typically manifests during the postpubertal growth spurt. The clinical symptoms can be best understood in the context of the functional abnormalities. It is characterized by massive left ventricular hypertorphy associated with (paradoxically) a markedly reduced stroke volume. This latter occurs as a consequence of impaired diastolic filling and overall smaller chamber size. In addition, roughly 25% of patients have dynamic obstruction to the left ventricular outflow by the anterior leaflet of the mitral valve. Reduced cardiac output and a secondary increase in pulmonary venous pressure cause exertional dyspnea, with a harsh systolic ejection murmur. A combination of massive hypertrophy, high left ventricular pressures, and compromised intramural arteries frequently leads to myocardial ischemia (with angina), even in the absence of concomitant CAD. Major clinical problems include atrial fibrillation with mural thrombus formation, ventricular


Pathology_Robbins

Pathology_Robbins. arteries frequently leads to myocardial ischemia (with angina), even in the absence of concomitant CAD. Major clinical problems include atrial fibrillation with mural thrombus formation, ventricular fibrillation leading to sudden cardiac death, infectious endocarditis of the mitral valve, and CHF. Most patients’ symptoms are improved by therapy that promotes ventricular relaxation; partial surgical excision or controlled alcohol-induced infarction of septal muscle also can relieve the outflow tract obstruction. As mentioned earlier, HCM is an important cause of sudden cardiac death. In almost one third of cases of sudden cardiac death in athletes younger than 35 years of age, the underlying cause is HCM.


Pathology_Robbins

Pathology_Robbins. Restrictive cardiomyopathy is characterized by a primary decrease in ventricular compliance, resulting in impaired ventricular filling during diastole (simply put, the wall is stiffer). This form of cardiomyopathy may be idiopathic or may be associated with systemic diseases that affect the myocardium, for example, radiation fibrosis, amyloidosis, sarcoidosis, or products of inborn errors of metabolism. Three forms of restrictive cardiomyopathy merit brief mention:


Pathology_Robbins

Pathology_Robbins. Three forms of restrictive cardiomyopathy merit brief mention: Amyloidosis is caused by the deposition of extracellular proteins with a predilection for forming insoluble β-pleated sheets (Chapter 5). Cardiac amyloidosis can occur in the setting of systemic amyloidosis (e.g., multiple myeloma) or can be predominantly restricted to the heart (e.g., senile cardiac amyloidosis). In the latter case, deposition of normal (or mutant) forms of transthyretin (a liver-synthesized circulating protein that transports thyroxine and retinol) in the hearts of older adult patients results in a restrictive cardiomyopathy. Four percent of African Americans carry a specific mutation of transthyretin that increases the risk of cardiac amyloidosis in that population over fourfold. Besides depositing as amyloid, immunoglobulin light-chains in AL-type amyloid also are directly cardiotoxic and can induce myocardial dysfunction.


Pathology_Robbins

Pathology_Robbins. Endomyocardial fibrosis is principally a disease of children and young adults in Africa and other tropical areas. It is http://ebooksmedicine.net Fig. 11.27 Hypertrophiccardiomyopathywithasymmetricseptalhypertrophy.(A)Theseptalmusclebulgesintotheleftventricularoutflowtract,givingrisetoa“banana-shaped”ventricularlumen,andtheleftatriumisenlarged.Theanteriormitralleaflethasbeenmovedawayfromtheseptumtorevealafibrousendocardialplaque(arrow) (seetext).(B)Histologicappearancedemonstratingdisarray,extremehypertrophy,andcharacteristicbranchingofmyocytes,as wellasinterstitialfibrosis.


Pathology_Robbins

Pathology_Robbins. characterized by dense diffuse fibrosis of the ventricular endocardium and subendocardium, often involving the tricuspid and mitral valves. The fibrous tissue markedly diminishes the volume and compliance of affected chambers, resulting in a restrictive physiology. Endomyocardial fibrosis has been linked to nutritional deficiencies and/or inflammation related to helminthic infections (e.g., hypereosinophilia); worldwide, it is the most common form of restrictive cardiomyopathy.


Pathology_Robbins

Pathology_Robbins. • Loeffler endomyocarditis also exhibits endocardial fibrosis, typically associated with formation of large mural thrombi. It has no geographic or population predilection. It is characterized by peripheral hypereosinophilia and eosinophilic tissue infiltrates; release of eosinophil granule contents, especially major basic protein, probably engenders endocardial and myocardial necrosis, followed by scarring, layering of the endocardium by thrombus, and finally thrombus organization. Of interest, some patients have an underlying hypereosinophilic myeloproliferative neoplasm driven by gene rearrangements that lead to expression of constitutively active tyrosine kinases (Chapter 12). Treatment of such patients with tyrosine kinase inhibitors can result in hematologic remission and reversal of the endomyocardial lesions.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYInrestrictivecardiomyopathy,theventriclesareofapproximatelynormalsizeoronlyslightlyenlarged,thecavitiesarenotdilated,andthemyocardiumisfirm.However,bothatriaaretypicallydilatedasaconsequenceofrestrictedventricularfillingandpressureoverloads.Microscopicexaminationrevealsvariabledegreesofinterstitialfibrosis.Althoughgrossmorphologicfindingsaresimilarforrestrictivecardiomyopathyofdisparatecauses,endomyocardialbiopsyoftencanrevealaspecificetiology. Myocarditis encompasses a diverse group of clinical entities in which infectious agents and/or inflammatory processes target the myocardium. It is important to distinguish myocarditis from conditions such as IHD, where the inflammatory process is secondary to some other cause of myocardial injury. In the United States, viral infections are the most common cause of myocarditis, with coxsackieviruses A and B and other enteroviruses accounting for a majority of the cases.


Pathology_Robbins

Pathology_Robbins. In the United States, viral infections are the most common cause of myocarditis, with coxsackieviruses A and B and other enteroviruses accounting for a majority of the cases. Cytomegalovirus (CMV), human immunodeficiency virus (HIV), influenza virus, and others are less common pathogens. Offending agents can be identified by serologic studies that show rising antibody titers or through molecular diagnostic techniques using infected tissues. While some viruses cause direct cell death, in most cases the injury results from an immune response directed against virally infected cells; this is analogous to the damage inflicted by virus-specific T cells on hepatitis virus–infected liver cells (Chapter 16). In some cases, viruses trigger a reaction against cross-reacting proteins such as myosin heavy chain.


Pathology_Robbins

Pathology_Robbins. The nonviral infectious causes of myocarditis run the entire gamut of the microbial world. The protozoan Trypanosoma cruzi is the agent of Chagas disease. Although uncommon in the northern hemisphere, Chagas disease affects up to one half of the population in endemic areas of South America, with myocardial involvement in the vast majority. About 10% of the patients die during an acute attack; others can enter a chronic immune-mediated phase with development of progressive signs of CHF and arrhythmia 10 to 20 years later. Toxoplasma gondii (household cats are the most common vector) also can cause myocarditis, particularly in immunocompromised individuals. http://ebooksmedicine.net Trichinosis is the most common helminthic disease associated with cardiac involvement.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Trichinosis is the most common helminthic disease associated with cardiac involvement. Myocarditis occurs in approximately 5% of patients with Lyme disease, a systemic illness caused by the bacterial spirochete Borrelia burgdorferi (Chapter 9). Lyme myocarditis manifests primarily as self-limited conduction system disease, frequently requiring temporary pacemaker insertion. Noninfectious causes of myocarditis include systemic diseases of immune origin, such as systemic lupus erythematosus and polymyositis. Drug hypersensitivity reactions affecting the heart (hypersensitivity myocarditis) may occur with exposure to a wide range of agents; such reactions typically are benign and only in rare circumstances lead to CHF or sudden death. MORPHOLOGYInacutemyocarditis,theheartmayappearnormalordilated;inadvancedstages,themyocardiumtypicallyisflabbyandoftenmottledwithpaleandhemorrhagicareas.Muralthrombimaybepresent.


Pathology_Robbins

Pathology_Robbins. Inhypersensitivity myocarditis, interstitialandperivascularinfiltratesarecomposedoflymphocytes,macrophages,andahighproportionofeosinophils( Fig.11.28B ).Giant cell myocarditis isamorphologicallydistinctiveentitycharacterizedbywidespreadinflammatorycellinfiltratescontainingmultinucleategiantcells(formedbymacrophagefusion).Giantcellmyocarditisprobablyrepresentstheaggressiveendofthespectrumoflymphocyticmyocarditis,andthereisatleastfocal—andfrequentlyextensive—necrosis (Fig.11.28C ).Thisvariantcarriesapoorprognosis. Chagas myocarditis ischaracterizedbytheparasitizationofscatteredmyofibersbytrypanosomesaccompaniedbyaninflammatoryinfiltrateofneutrophils,lymphocytes,macrophages,andoccasionaleosinophils( Fig.11.28D


Pathology_Robbins

Pathology_Robbins. Fig.11.28D The clinical spectrum of myocarditis is broad; at one end, the disease is asymptomatic, and patients recover without sequelae. At the other extreme is the precipitous onset of heart failure or arrhythmias, occasionally with sudden death. Between these extremes are many levels of involvement associated with a variety of signs and symptoms, including fatigue, dyspnea, palpitations, pain, and fever. The clinical features of myocarditis can mimic those of acute MI. Clinical progression from myocarditis to DCM occasionally is seen.


Pathology_Robbins

Pathology_Robbins. Cardiac complications of cancer therapy are an important clinical problem. Cardiotoxicity can be associated with conventional chemotherapeutic agents, targeted drugs such as tyrosine kinase inhibitors, and certain forms of immunotherapy (e.g., immune checkpoint blockade for cancer). The anthracyclines doxorubicin and daunorubicin are the chemotherapeutic agents that are most frequently associated with toxic myocardial injury, which often takes the form of a dilated cardiomyopathy and heart failure. Anthracycline toxicity is dose-dependent (cardiotoxicity becomes progressively more frequent above a total dose of 500 mg/m2) and is attributed primarily to peroxidation of lipids in myocyte membranes.


Pathology_Robbins

Pathology_Robbins. Many other agents, such as lithium, phenothiazines, and chloroquine, have been implicated in myocardial injury and sometimes sudden death. Common findings in hearts injured by many of these chemicals and drugs (including diphtheria exotoxin and doxorubicin) are myofiber swelling, cytoplasmic vacuolization, and fatty change. Discontinuing such agents can lead to complete resolution, with no apparent sequelae. Sometimes, however, more extensive damage produces myocyte necrosis and leads to a dilated cardiomyopathy.


Pathology_Robbins

Pathology_Robbins. Foci of myocardial necrosis with contraction bands, often associated with a sparse mononuclear inflammatory infiltrate (mostly macrophages), can occur in individuals with pheochromocytoma, a tumor that elaborates catecholamines (Chapter 20). Similar changes can occur with a variety of agents—endogenous or exogenous—under the rubric of “catecholamine effect.” These include cocaine, high doses of ephedrine (an adrenergic agent in many cold and allergy formulations), intense autonomic stimulation secondary to intracranial lesions, or vasopressor agents such as dopamine. The mechanism of catecholamine cardiotoxicity is uncertain, but seems to relate either to a direct toxicity of catecholamines on cardiac myocytes via calcium overload or to vasoconstriction in the face of an increased heart rate. The mononuclear cell infiltrate is probably a reaction to microscopic foci of myocyte cell death.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Pericardial lesions typically are associated with a pathologic process elsewhere in the heart or surrounding structures, or are secondary to a systemic disorder. Pericardial disorders include effusions and inflammatory conditions, sometimes resulting in fibrous constriction. Normally, the pericardial sac contains less than 50 cc of thin, clear, straw-colored fluid. Under various circumstances, the pericardial sac may be distended by accumulations of serous fluid (pericardial effusion), blood (hemopericardium), or pus (purulent pericarditis). Pericardial effusions and their causes include the following: Serous: Congestive heart failure, hypoalbuminemia of any cause Serosanguineous: Blunt chest trauma, malignancy, ruptured MI, or aortic dissection Chylous: Mediastinal lymphatic obstruction


Pathology_Robbins

Pathology_Robbins. Serous: Congestive heart failure, hypoalbuminemia of any cause Serosanguineous: Blunt chest trauma, malignancy, ruptured MI, or aortic dissection Chylous: Mediastinal lymphatic obstruction With long-standing cardiac enlargement or with slowly accumulating fluid, the pericardium has time to dilate. This permits chronic pericardial effusions to become quite large without interfering with cardiac function. Thus, with chronic effusions of less than 500 cc in volume, the only clinical significance is a characteristic globular enlargement of the heart shadow on chest radiograph. In contrast, rapidly developing fluid collections of as little as 200 to 300 cc (e.g., due to hemopericardium caused by a ruptured MI or aortic dissection) can produce clinically devastating compression of the thin-walled atria and venae cavae, or the ventricles themselves; cardiac filling is thereby restricted, producing potentially fatal cardiac tamponade.


Pathology_Robbins

Pathology_Robbins. Primary pericarditis is uncommon. It is typically due to viral infection (often with concurrent myocarditis), http://ebooksmedicine.net although bacteria, fungi, or parasites may also be involved. In most cases, pericarditis is secondary to acute MI or cardiac surgery (so-called “Dressler’s syndrome”), radiation to the mediastinum, or processes involving other thoracic structures (e.g., pneumonia or pleuritis). Uremia is the most common systemic disorder associated with pericarditis. Less common secondary causes include rheumatic fever, systemic lupus erythematosus, and metastatic malignancies. Pericarditis can (1) cause immediate hemodynamic complications if it elicits a large effusion (resulting in cardiac tamponade), (2) resolve without significant sequelae, or 3) progress to a chronic fibrosing process.


Pathology_Robbins

Pathology_Robbins. Chronic pericarditis maybeassociatedwithdelicateadhesionsordense,fibroticscarsthatobliteratethepericardialspace.Inextremecases,theheartissocompletelyencasedbydensefibrosisthatitcannotexpandnormallyduringdiastole—resultingintheconditionknownasconstrictive pericarditis. Pericarditis classically manifests with atypical chest pain (not related to exertion and worse in recumbency), and a prominent friction rub. When associated with significant fluid accumulation, acute pericarditis can cause cardiac tamponade, which leads to declining cardiac output and consequent shock. Chronic constrictive pericarditis produces a combination of right-sided venous distention and low cardiac output, similar to the clinical picture in restrictive cardiomyopathy.


Pathology_Robbins

Pathology_Robbins. Primary cardiac tumors are uncommon; moreover, most also are (fortunately) benign. The five most common have no malignant potential and account for 80% to 90% of all primary heart tumors. In descending order of frequency, these are myxomas, fibromas, lipomas, papillary fibroelastomas, and rhabdomyomas. Angiosarcomas constitute the most common primary malignant tumor of the heart. Only the myxomas and rhabdomyomas merit further mention here. Fig. 11.29 Acutesuppurative(purulent,exudative)pericarditis,causedbyextensionfromapneumonia. Myxomas are the most common primary tumors of the adult heart ( Fig. 11.30 ). Roughly 90% are atrial, with the left atrium accounting for 80% of those.


Pathology_Robbins

Pathology_Robbins. Myxomas are the most common primary tumors of the adult heart ( Fig. 11.30 ). Roughly 90% are atrial, with the left atrium accounting for 80% of those. Rhabdomyomas are the most frequent primary tumors of the heart in infants and children; they frequently are discovered owing to valvular or outflow obstruction. Cardiac rhabdomyomas occur with high frequency in patients with tuberous sclerosis caused by mutations in the TSC1 or TSC2 tumor suppressor genes; loss of TSC-1 and TSC-2 activity leads to myocyte overgrowth. Because they often regress spontaneously (for unknown reasons), rhabdomyomas are sometimes considered to be hamartomas rather than true neoplasms. In keeping with this not all cardiac rhabdomyomas that occur in patients with tuberous sclerosis are clonal. MORPHOLOGYMyxomas arealmostalwayssingle,classicallyarisingintheregionofthefossaovalis(atrialseptum).Theycanbesmall(lessthan1cmindiameter)ormassive(upto10cmacross),sessileorpedunculatedmasses(


Pathology_Robbins

Pathology_Robbins. The major clinical manifestations of myxomas are due to valvular “ball-valve” obstruction, embolization, or a syndrome of constitutional signs and symptoms including fever and malaise. This syndrome is caused by elaboration of the cytokine interleukin-6 by the tumor cells, a major mediator of the acute-phase response. Echocardiography is the diagnostic modality of choice, and surgical resection is almost uniformly curative. With enhanced patient survival due to diagnostic and therapeutic advances, significant cardiovascular effects of non-cardiac neoplasms and their therapy are increasingly encountered ( Table 11.6 ). The pathologic consequences include direct tumor metastasis or infiltration, effects of circulating mediators, and therapeutic complications.


Pathology_Robbins

Pathology_Robbins. The most frequent metastatic tumors involving the heart are carcinomas of the lung and breast, melanomas, leukemias, and lymphomas. Metastases can reach the heart and pericardium by retrograde lymphatic extension (carcinomas), by hematogenous seeding (many tumors), by direct contiguous extension (primary carcinoma of the lung, breast, or esophagus), or by venous extension (tumors of the kidney or liver). Clinical symptoms are most often associated with pericardial spread, which can cause symptomatic pericardial effusions or a mass-effect that is sufficient to restrict cardiac filling. Bronchogenic carcinoma or malignant lymphoma may infiltrate the mediastinum extensively, causing encasement, compression, or invasion of the superior vena cava and obstruction to blood flow from the head and upper extremities (superior vena cava syndrome). Renal cell carcinoma often invades the renal vein and may grow as a continuous column of tumor up the inferior vena cava and into the right atrium,


Pathology_Robbins

Pathology_Robbins. upper extremities (superior vena cava syndrome). Renal cell carcinoma often invades the renal vein and may grow as a continuous column of tumor up the inferior vena cava and into the right atrium, blocking venous return to the heart.


Pathology_Robbins

Pathology_Robbins. Noncardiac tumors also may affect cardiac function indirectly, sometimes via circulating tumor-derived substances. The consequences include nonbacterial thrombotic endocarditis, carcinoid heart disease, pheochromocytomaassociated myocardial damage, and myeloma-associated AL-type amyloidosis. Complications of chemotherapy were discussed earlier in this chapter. Radiation used to treat breast, lung, or mediastinal neoplasms can cause pericarditis, pericardial effusion, myocardial fibrosis, and chronic pericardial disorders. Other cardiac effects of radiation therapy include accelerated coronary artery disease and mural and valvular endocardial fibrosis.


Pathology_Robbins

Pathology_Robbins. The carcinoid syndrome results from bioactive compounds such as serotonin released by carcinoid tumors (Chapter 15); systemic manifestations include flushing, diarrhea, dermatitis, and bronchoconstriction. Carcinoid heart disease refers to the cardiac manifestation caused by the bioactive compounds and occurs in one half of patients in whom the systemic syndrome develops. Cardiac lesions typically do not occur until there is a massive hepatic metastatic burden, since the liver normally inactivates circulating mediators before they can affect the heart. Classically, endocardium and valves of the right heart are primarily affected since they are the first cardiac tissues bathed by the mediators released by gastrointestinal carcinoid tumors. The left side of the heart is afforded some measure of protection because the pulmonary vascular bed degrades the mediators. However, left-sided heart carcinoid lesions can occur in the setting of atrial or ventricular septal defects and


Pathology_Robbins

Pathology_Robbins. some measure of protection because the pulmonary vascular bed degrades the mediators. However, left-sided heart carcinoid lesions can occur in the setting of atrial or ventricular septal defects and right-to-left flow, or they can arise in association with primary pulmonary carcinoid tumors.


Pathology_Robbins

Pathology_Robbins. Table 11.6 Cardiovascular Effects of Noncardiac Neoplasms ModifiedfromSchoenFJ,etal:Cardiaceffectsofnon-cardiacneoplasms,Cardiol Clin 2:657,1984. http://ebooksmedicine.net Fig. 11.31 Carcinoidheartdisease.(A)Characteristicendocardialfibrotic(light gray) lesion“coating”therightventricleandtricuspidvalve,andextendingontothechordaetendineae.(B)Microscopicappearanceofthethickenedendocardium,whichcontainssmoothmusclecellsandabundantacidmucopolysaccharides(blue-greeninthisMovatstain,whichcolorstheunderlyingendocardialelastictissueblack).


Pathology_Robbins

Pathology_Robbins. The mediators elaborated by carcinoid tumors include serotonin (5-hydroxytryptamine), kallikrein, bradykinin, histamine, prostaglandins, and tachykinins. Although it is not clear which of these is causative, plasma levels of serotonin and urinary excretion of the serotonin metabolite 5-hydroxyindoleacetic acid correlate with the severity of right-sided heart lesions. The valvular plaques in carcinoid syndrome also are similar to lesions that occur with the administration of fenfluramine (an appetite suppressant) or ergot alkaloids (for migraine headaches); of interest, these agents either affect systemic serotonin metabolism or directly bind to hydroxytryptamine receptors on heart valves. MORPHOLOGYThecardiovascularlesionsassociatedwiththecarcinoidsyndromearedistinctive,glisteningwhite,intimal,plaquelikethickeningsontheendocardialsurfacesofthecardiacchambersandvalveleaflets(


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYThecardiovascularlesionsassociatedwiththecarcinoidsyndromearedistinctive,glisteningwhite,intimal,plaquelikethickeningsontheendocardialsurfacesofthecardiacchambersandvalveleaflets( Fig.11.31 ).Thelesionsarecomposedofsmoothmusclecellsandsparsecollagenfibersembeddedinanacidmucopolysaccharide–richmatrix.Underlyingstructuresareintact.Withright-sidedinvolvement,typicalfindingsaretricuspidinsufficiencyandpulmonicstenosis. Although permanent ventricular assist device implantation is increasingly an option for management of end-stage heart disease, cardiac transplantation remains the treatment of choice for patients with intractable heart failure. Without transplantation, medically managed end-stage heart failure carries a 50% 1-year mortality rate, and less than 10% of patients survive 5 years. Over 5000 heart transplantation procedures are performed annually worldwide, mostly for DCM and IHD.


Pathology_Robbins

Pathology_Robbins. The major complications of cardiac transplantation are acute cardiac rejection and allograft arteriopathy. The immunosuppression required for allograft survival also increases the risk for opportunistic infections and certain malignancies (e.g., Epstein-Barr virus–associated lymphoma). Rejection is characterized by interstitial lymphocytic inflammation, myocyte damage and a histologic pattern similar to that seen in viral myocarditis. Both T celland antibody responses to the allograft are involved in the rejection reaction. Allograft arteriopathy is the single most important longterm limitation for cardiac transplantation. It is marked by late, progressive, diffusely stenosing intimal proliferation in the coronary arteries, leading to ischemic injury. Despite these problems, the outlook for transplant recipients generally is good, with a 1-year survival rate of 90% and a 5-year survival rate of more than 70%.


Pathology_Robbins

Pathology_Robbins. Despite these problems, the outlook for transplant recipients generally is good, with a 1-year survival rate of 90% and a 5-year survival rate of more than 70%. Azaouagh A, Churzidse S, Konorza T, et al: Arrhythmogenic right ventricular cardiomyopathy/dysplasia: a review and update, Clin Res Cardiol 100:383, 2011. [An excellent look at this entity and its genetic causes.] Bruneau BG: The developmental genetics of congenital heart disease, Nature 451:943, 2008. [A succinct overview of the relationships between cardiac development and congenital heart disease.] Cerrone M, Priori SG: Genetics of sudden death: focus on inherited channelopathies, Eur Heart J 32:2109, 2011. [A well-organized description of the known ion channel disorders that cause sudden cardiac death.] Cooper LT Jr: Myocarditis, N Engl J Med 360:1526, 2009. [A nice review of etiology, pathogenesis, and clinical features.]


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Pathology_Robbins. Cooper LT Jr: Myocarditis, N Engl J Med 360:1526, 2009. [A nice review of etiology, pathogenesis, and clinical features.] Grozinsky-Glasberg S, Grossman AB, Gross DJ: Carcinoid heart disease: from pathophysiology to treatment—“something in the way it moves” Neuroendocrinology 101:263, 2015. [A good review of the pathophysiology, diagnosis, and treatment of this entity.] Guilherme L, Köhler KF, Kalil J: Rheumatic heart disease: mediation by complex immune events, Adv Clin Chem 53:31, 2011. [A well-written and scholarly discussion of the pathogenic mechanisms regarding rheumatic heart disease.] Hausenloy DJ, Yellon DM: Myocardial ischemia-reperfusion injury: a neglected therapeutic target, J Clin Invest 123:92, 2013. [A nice http://ebooksmedicine.net discussion of the mechanisms and possible therapeutic approaches in ischemia-reperfusion injury.]


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Pathology_Robbins. Heusch G, Libby P, Gersh B, et al: Cardiovascular remodelling in coronary artery disease and heart failure, Lancet 383:1933, 2014. [An excellent review of the pathophysiologic changes that occur as ischemic hearts develop CHF.] Hill EE, Herijgers P, Herregods MC, et al: Evolving trends in infective endocarditis, Clin Microbiol Infect 12:5, 2006. [A good, clinically oriented overview of the developments in microorganisms, diagnosis, and therapies for infective endocarditis.] Huang JB, Liu YL, Sun PW, et al: Molecular mechanisms of congenital heart disease, Cardiovasc Pathol 19:e183, 2010. [A comprehensive review of the genes and pathways underlying congenital heart disease.] Li C, Xu S, Gotlieb AI: The response to valve injury. A paradigm to understand the pathogenesis of heart valve disease, Cardiovasc Pathol 20:183, 2011. [A nice overview of pathologic concepts in valvular disease.]


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Pathology_Robbins. Mann DL, Zipes DP, Libby P, et al, editors: Braunwald’s heart disease: a textbook of cardiovascular medicine, ed 10, Philadelphia, 2015, Else-vier. [An outstanding and authoritative text, with excellent sections on heart failure and atherosclerotic cardiovascular disease.] Maron BJ, Towbin JA, Thiene G, et al: Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention, Circulation 113:1807, 2006. [A consensus document regarding an updated classification of cardiomyopathies, heavily weighted to genetic etiologies rather than pathophysiologic manifestations.]


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Pathology_Robbins. Mitchell RN: Graft vascular disease: immune response meets the vessel wall, Annu Rev Pathol 4:19, 2009. [A comprehensive overview of allograft arteriopathy, including animal models, pathogenic mechanisms, clinical diagnosis, and therapy.] New SE, Aikawa E: Molecular imaging insights into early inflammatory stages of arterial and aortic valve calcification, Circ Res 108:1381, 2011. [A good overview of the mechanisms leading to degenerative calcification on valves and vessels.] Ovize M, Baxter GF, Di Lisa F, et al: Postconditioning and protection from reperfusion injury: where do we stand? Position paper from the Working Group of Cellular Biology of the Heart of the European Society of Cardiology, Cardiovasc Res 87:406, 2010. [A good overview of the mechanisms and potential therapeutic interventions for ischemiareperfusion injury and for ischemic pre-conditioning in limiting infarct size.]


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Pathology_Robbins. Patten IS, Rana S, Shahul S, et al: Cardiac angiogenic imbalance leads to peripartum cardiomyopathy, Nature 485:333, 2012. [A new perspective on the mechanisms underlying pregnancy-associated cardiomyopathy.] Rasmussen TL, Raveendran G, Zhang J, et al: Getting to the heart of myocardial stem cells and cell therapy, Circulation 123:1771, 2011. [A well-written overview of the challenges and current state of the art regarding stem cell therapies in heart disease.] Seidman CE, Seidman JG: Identifying sarcomere gene mutations in hypertrophic cardiomyopathy: a personal history, Circ Res 108:743, 2011. [A well-written and authoritative overview of the genetics and pathophysiology of hypertrophic cardiomyopathy from one of the leading groups in the world.] Watkins H, Houman A, Redwood C: Inherited cardiomyopathies, N Engl J Med 364:1643, 2011. [An excellent review of the molecular basis of cardiomyopathies.]


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Pathology_Robbins. Watkins H, Houman A, Redwood C: Inherited cardiomyopathies, N Engl J Med 364:1643, 2011. [An excellent review of the molecular basis of cardiomyopathies.] Wu JC, Child JS: Common congenital heart disorders in adults, Curr Probl Cardiol 29:641, 2004. [A thorough overview of the congenital heart disorders seen in the adult population, often as a consequence of improved pediatric therapies.] http://ebooksmedicine.net studentconsult.com AnemiaofBloodLoss:Hemorrhage Trauma to Red Cells Anemia of Chronic Inflammation Thrombotic Microangiopathies:Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome Deficiencies of Factor VIII–von Willebrand Factor Complex Complications of Transfusion Disorders of the Spleen and Thymus