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Pathology_Robbins. Endemic African KS typically occurs in younger (under 40 years of age) HIV-seronegative individuals and can follow an indolent or aggressive course; it involves lymph nodes much more frequently than in the classic variant. In combination with AIDS-associated KS (see later), KS is now the most common tumor in central Africa. A particularly severe form, with prominent lymph node and visceral involvement, occurs in prepubertal children; the prognosis is poor, with an almost 100% mortality within 3 years. Transplantation-associated KS occurs in solid organ transplant recipients in the setting of T-cell immunosuppression. In these patients, the risk for KS is increased 100-fold. It pursues an aggressive course and often involves lymph nodes, mucosa, and viscera; cutaneous lesions may be absent. Lesions often regress with attenuation of immunosuppression, but at the risk for organ rejection.


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Pathology_Robbins. AIDS-associated (epidemic) KS is an AIDS-defining illness; worldwide it represents the most common HIV-related malignancy (Chapter 5). Although the incidence of KS has fallen more than 80% with the advent of antiretroviral therapy, it still occurs in HIV-infected individuals with a 1000-fold higher incidence than in the general population, and afflicts 2% to 3% of the HIV-infected U.S. population. AIDS-associated KS often involves lymph nodes and disseminates widely to viscera early


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Pathology_Robbins. U.S. population. AIDS-associated KS often involves lymph nodes and disseminates widely to viscera early Fig. 10.29 Bacillaryangiomatosis.(A)Characteristiccutaneouslesion.(B)Histologicfeaturesarethoseofacuteinflammationandcapillaryproliferation.Inset, Modifiedsilver(Warthin-Starry)staindemonstratesclustersoftangledbacilli(black). (A, Courtesy of Richard Johnson, MD, Beth Israel Deaconess Medical Center, Boston, Massachusetts. B and inset, courtesy of Scott Granter, MD, Brigham and Women’s Hospital, Boston, Massachusetts.) http://ebooksmedicine.net inflammatorycells,sometimescontaininghemosiderin.These in its course. Most patients eventually die of opportu lesionscanbedifficulttodistinguishfromgranulationtissue. nistic infections rather than from KS. •Withtime,lesionsspreadproximallyandbecomelarger,vio-


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Pathology_Robbins. nistic infections rather than from KS. •Withtime,lesionsspreadproximallyandbecomelarger,vio- Virtually all KS lesions are infected by KSHV (HHV-8). Like Epstein-Barr virus, KSHV is a γ-herpesvirus. It is transmitted both through sexual contact and potentially via oral secretions and cutaneous exposures (of note, the prevalence of endemic African KS is inversely related to the wearing of shoes). KSHV and altered T-cell immunity probably are required for KS development; in older adults, diminished T-cell immunity may be related to aging. It also is probable that acquired somatic mutations in the cells of origin contribute to tumor development and progression.


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Pathology_Robbins. KSHV causes lytic and latent infections in ECs, both of which probably are important in KS pathogenesis. A virally encoded G protein induces VEGF production, stimulating endothelial growth, and cytokines produced by inflammatory cells recruited to sites of lytic infection also create a local proliferative milieu. In latently infected cells, KSHV-encoded proteins disrupt normal cellular proliferation controls (e.g., through synthesis of a viral homologue of cyclin D) and prevent apoptosis by inhibiting p53. Thus, the local inflammatory environment favors cellular proliferation, and latently infected cells have a growth advantage. In its early stages, only a few cells are KSHV-infected, but with time, virtually all of the proliferating cells carry the virus. As with EBV infection, early lesions are polyclonal but with accumulation of mutations the tumors become monoclonal.


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Pathology_Robbins. MORPHOLOGYInclassicKaposisarcoma(andsometimesinothervariants),the cutaneouslesionsprogressthroughthreestages:patch,plaque, andnodule. •Patches arepink,red,orpurplemacules,typicallyconfinedtothedistallowerextremities( Fig.10.30A ).Microscopicexaminationrevealsdilated,irregular,andangulatedbloodvesselslinedbyECsandaninterspersedinfiltrateofchroniclaceous, raised plaques ( Fig.10.30A )composedofdilated,jaggeddermalvascularchannelslinedandsurroundedbyplumpspindlecells.Otherprominentfeaturesincludeextravasatedredcells,hemosiderin-ladenmacrophages,andothermononuclearcells. •Eventuallynodular, moreovertlyneoplastic,lesionsappear.Thesearecomposedofplump,proliferatingspindlecells,mostlylocatedinthedermisorsubcutaneoustissues( Fig.


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Pathology_Robbins. The course of disease varies widely according to the clinical setting. Most primary KSHV infections are asymptomatic. Classic KS is—at least initially—largely restricted to the surface of the body, and surgical resection usually is adequate for an excellent prognosis. Radiation therapy can be used for multiple lesions in a restricted area, and chemotherapy yields satisfactory results for more disseminated disease, including nodal involvement. In KS associated with immunosuppression, withdrawal of therapy (with or without adjunct chemotherapy or radiotherapy) often is effective. For AIDS-associated KS, HIV anti-retroviral therapy generally is beneficial, with or without additional therapy. IFN-γ and angiogenesis inhibitors also have proved variably effective. Hemangioendotheliomas comprise a wide spectrum of borderline vascular neoplasms with clinical behaviors intermediate between those of benign, well-differentiated hemangiomas and aggressively malignant angiosarcomas


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Pathology_Robbins. Fig. 10.30 Kaposisarcoma.(A)Characteristiccoalescentcutaneousred-purplemaculesandplaques.(B)Histologicviewofthenodularstage,demonstratingsheetsofplump,proliferatingspindlecellsandslitlikevascularspaces.(Courtesy of Christopher D.M. Fletcher, MD, Brigham and Women’s Hospital, Boston, Massachusetts.) http://ebooksmedicine.net Epithelioid hemangioendothelioma is a tumor of adults arising in association with mediumto large-sized veins. The clinical course is highly variable. While excision is curative in a majority of the cases, up to 40% of the tumors recur; 20% to 30% eventually metastasize, and 15% of patients die of their tumors.


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Pathology_Robbins. Angiosarcomas are malignant endothelial neoplasms ranging from highly differentiated tumors resembling hemangiomas to wildly anaplastic lesions. Older adults are more commonly affected, without gender predilection; lesions can occur at any site, but most often involve the skin, soft tissue, breast, and liver. Clinically, angiosarcomas are aggressive tumors that invade locally and metastasize. Current 5-year survival rates are only about 30%. Angiosarcomas can arise in the setting of lymphedema, classically in the ipsilateral upper extremity several years after radical mastectomy (i.e., with lymph node resection) for breast cancer. In such instances, the tumor presumably arises from lymphatic vessels (lymphangiosarcoma). Angiosarcomas can also be induced by radiation and rarely are associated with long-term (years) indwelling foreign bodies (e.g., catheters).


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Pathology_Robbins. Hepatic angiosarcomas are associated with certain carcinogens, including arsenical pesticides and polyvinyl chloride (one of the best known examples of human chemical carcinogenesis). Multiple years typically transpire between exposure and subsequent tumor development. MORPHOLOGYIntheskin,angiosarcomasbeginassmall,sharplydemarcated,asymptomaticrednodules.Moreadvancedlesionsarelarge,fleshyred-tantogray-whitemasses( Fig.10.31A )withmarginsthatblendimperceptiblywithsurroundingstructures.Necrosisandhemorrhagearecommon. Onmicroscopicexamination,theextentofdifferentiationisextremelyvariable,rangingfromplumpatypicalECsthatformvascularchannels( Fig.10.31B )toundifferentiatedspindlecelltumorswithoutdiscerniblebloodvessels.TheECorigincanbedemonstratedinthepoorlydifferentiatedtumorsbystainingfortheECmarkersCD31andvonWillebrandfactor( Fig.10.31C Vascularectasiasarenotneoplasms,butratherdilationsofexistingvessels.


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Pathology_Robbins. http://ebooksmedicine.net The morphologic changes that occur in vessels following therapeutic intervention—balloon angioplasty, stenting, or bypass surgery—recapitulate many of the changes that occur in the setting of other forms of vascular injury. Local trauma (due to stenting), vascular thrombosis (after angioplasty), and abnormal mechanical forces (e.g., a saphenous vein inserted into the arterial circulation as a coronary artery bypass graft) all induce the same stereotypical healing responses—fibromuscular intimal hyperplastic lesions composed of SMCs and ECM. Thus, just as with atherosclerosis, interventions that injure the endothelium also tend to induce intimal thickening by recruiting SMCs and promoting ECM deposition.


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Pathology_Robbins. Arterial stenoses (especially those in coronary and carotid arteries) can be dilated by transiently inflating a balloon catheter to pressures sufficient to rupture the occluding plaque (balloon angioplasty); in doing so, a limited arterial dissection also is induced. Angioplasty can be complicated by abrupt reclosure resulting from compression of the lumen by an extensive circumferential or longitudinal dissection, or by thrombosis. In view of this well over 90% of endovascular coronary procedures involve both angioplasty and concurrent coronary stent placement.


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Pathology_Robbins. Coronary stents are expandable tubes of metallic mesh. They provide a larger and more regular lumen, “tack down” the intimal flaps and dissections that occur during angioplasty, and mechanically limit vascular spasm. Nevertheless, as a consequence of endothelial injury, thrombosis is an important immediate post-stenting complication; patients must receive potent anti-thrombotic agents (primarily platelet antagonists) to prevent acute catastrophic thrombotic occlusions until the stented region becomes endothelialized. The long-term success of angioplasty is limited by the development of proliferative in-stent restenosis. Such intimal thickening results in clinically significant luminal occlusion in up to one third of patients within 6 to 12 months of stenting (Fig. 10.32 ). The newest generation of drug-eluting stents is designed to avoid this complication by releasing anti-proliferative drugs (e.g., paclitaxel, sirolimus) into the adjacent vessel wall that block SMC activation. Use of


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Pathology_Robbins. of drug-eluting stents is designed to avoid this complication by releasing anti-proliferative drugs (e.g., paclitaxel, sirolimus) into the adjacent vessel wall that block SMC activation. Use of such stents reduces the incidence of restenosis at 1 year by 50% to 80%.


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Pathology_Robbins. Synthetic or autologous vascular grafts commonly are used to replace damaged vessels or bypass diseased arteries. Of the synthetic grafts, large-bore (12to 18-mm–diameter) conduits function well in high-flow locations such as the aorta, while small-bore artificial grafts (8 mm or less in diameter) generally fail as a result of acute thrombosis or late intimal hyperplasia, primarily at the junction of the graft and the native vasculature. Consequently, when small-bore vessel replacement is needed (e.g., for coronary artery bypass surgeries), the grafts are fashioned either from autologous saphenous vein (taken from the patient’s own leg) or left internal mammary artery. The long-term patency of saphenous vein grafts is only 50% at 10 years; these grafts occlude through thrombosis (typically early), intimal thickening (months to years postoperatively), and vein graft atherosclerosis. By contrast, more than 90% of internal mammary artery grafts are patent after 10 years. BA*.


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Pathology_Robbins. BA*. Fig. 10.32 Restenosisafterangioplastyandstenting.(A)Grossviewdemonstratingresidualatheroscleroticplaque(arrows) andanew,glisteningintimalproliferativelesion.(B)Histologicviewshowsathickenedneointimaoverlyingthestentwires(black diamond indicated by the arrow), whichencroachesonthelumen(asterisk). (B, Reproduced from Schoen FJ, Edwards WD: Pathology of cardiovascular interventions, including endovascular therapies, revascularization, vascular replacement, cardiac assist/replacement, arrhythmia control, and repaired congenital heart disease. In Silver MD, et al., editors: Cardiovascularpathology, ed 3, Philadelphia, 2001, Churchill Livingstone.) Bhutani M, Polizzotto MN, Uldrick TS, et al: Kaposi sarcoma-associated herpesvirus-associated malignancies: epidemiology, pathogenesis, and advances in treatment, Semin Oncol 42:247, 2015. [A solid and thorough review.]


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Pathology_Robbins. Coffman TM: Under pressure: the search for the essential mechanisms of hypertension, Nat Med 17:1402, 2011. [A well-written review of the current state of the field including recent translational advances.] Fishbein MC, Fishbein GA: Arteriosclerosis: facts and fancy, Cardiovasc Pathol 24:335, 2015. [A fun and thought-provoking revisit to topics of cardiovascular “conventional wisdom.”] Gillis E, Van Laer L, Loeys BL: Genetics of thoracic aortic aneurysm: at the crossroad of transforming growth factor-β signaling and vascular smooth muscle cell contractility, Circ Res 113:327, 2013. [An up-to-date discussion of the molecular and cellular basis for thoracic aneurysms and dissections.] Gimbrone MA Jr, Garcia-Cardeña G: Vascular endothelium, hemodynamics, and the pathobiology of atherosclerosis, Cardiovasc Pathol 22:9, 2013. [A well-written review on endothelial responses to mechanical forces from one of the leading groups in the field.]


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Pathology_Robbins. Grebe A, Latz E: Cholesterol crystals and inflammation, Curr Rheumatol Rep 15:313, 2013. [A review of the activation of the inflammasome by cholesterol crystals, and its role in atherosclerosis.] Hansson GK, Libby P, Tabas I: Inflammation and plaque vulnerability, J Intern Med 278:483, 2015. [An up-to-date review of the current concepts linking inflammation and plaque vulnerability.] Inoue T, Croce K, Morooka T, et al: Vascular inflammation and repair: implications for re-endothelialization, restenosis, and stent thrombosis, JACC Cardiovasc Interv 4:1057, 2011. [An excellent overview of the inflammatory pathways that influence the outcomes of percutaneous vessel interventions.] Jaffe R, Strauss B: Late and very late thrombosis of drug-eluting stents: evolving concepts and perspectives, J Am Coll Cardiol 50:119, 2007. [An even-handed discussion of the complications following coronary artery stent placement.]


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Pathology_Robbins. Jennette J, Falk R: Nosology of primary vasculitis, Curr Opin Rheumatol 19:10, 2007. [A classification of vasculitis based on pathogenic pathways and the vessels involved; provides a good organization to a complex and potentially confusing aspect of vascular pathology.] Jennette JC, Falk RJ: Pathogenesis of antineutrophil cytoplasmic autoantibody-mediated disease, Nat Rev Rheumatol 10:463, 2014. [A well-written and well-organized overview of the big picture in ANCA vasculitis.] Kim FY, Marhefka G, Ruggiero NJ, et al: Saphenous vein graft disease: review of pathophysiology, prevention, and treatment, Cardiol Rev 21:101, 2013. [A good overview of the pathogenesis and clinical issues of saphenous vein graft acute occlusion and chronic stenosis.]


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Pathology_Robbins. Libby P, Lichtman AH, Hansson GK: Immune effector mechanisms implicated in atherosclerosis: from mice to humans, Immunity 38:1092, 2013. [A superb review of the experimental and clinical literature describing the role of specific and adaptive immunity in atherosclerosis pathogenesis.] MacAlpin RN: Some observations on and controversies about coronary arterial spasm, Int J Cardiol 181:389, 2015. [A good clinical overview of coronary spasm and its sequelae.] Michel JB, Martin-Ventura JL, Egido J, et al: Novel aspects of the pathogenesis of aneurysms of the abdominal aorta in humans, Cardiovasc Res 90:18, 2011. [A good discussion of the molecular pathways underlying human abdominal aortic aneurysm formation.]


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Pathology_Robbins. Monahan-Earley R, Dvorak AM, Aird WC: Evolutionary origins of the blood vascular system and endothelium, J Thromb Haemost 11(Suppl 1):46, 2013. [An interesting discussion of the evolutionary basis for vascular development, including cogent explanations for endothelial heterogeneity.] Penel N, Marréaud S, Robin YM, et al: Angiosarcoma: state of the art and perspectives, Crit Rev Oncol Hematol 22:1266, 2011. [An extensive clinical summary of this aggressively malignant vascular tumor.] Ridker P: From C-reactive protein to interleukin-6 to interleukin-1: moving upstream to identify novel targets for atheroprotection, Circ Res 118:145, 2016. [A well-written opinion piece regarding how CRP links to other inflammatory mediators, and potentially identifies therapeutic targets.] http://ebooksmedicine.net studentconsult.com Other Causes of Myocardial Disease Cardiac Effects of Noncardiac Neoplasms


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Pathology_Robbins. The heart is a truly remarkable organ, beating more than 40 million times per year and pumping over 7500 liters of blood a day; in a typical lifespan, its cumulative output would fill three supertankers. The cardiovascular system is the first organ system to become functional in utero (at approximately 8 weeks of gestation); without a beating heart and vascular supply, development cannot proceed, and the embryo dies. When the heart fails during postnatal life, the results are equally catastrophic. Indeed, cardiovascular disease is the leading cause of mortality worldwide and accounts for one in four of all deaths in the United States—approximately 1 death every minute, or 610,000 deaths each year (a greater mortality rate than for all forms of cancer combined). The annual economic impact of cardiac disease exceeds $200 billion, with ischemic heart disease contributing well over half. Moreover, roughly one third of these deaths are “premature,” occurring in individuals younger than 75


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Pathology_Robbins. of cardiac disease exceeds $200 billion, with ischemic heart disease contributing well over half. Moreover, roughly one third of these deaths are “premature,” occurring in individuals younger than 75 years of age; thus, an additional economic burden is imposed through lost years of productivity.


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Pathology_Robbins. Although a wide range of diseases can affect the cardiovascular system, the pathophysiologic pathways that result in a “broken” heart distill down to six principal mechanisms: Failure of the pump. In the most common situation, the cardiac muscle contracts weakly and the chambers cannot empty properly—so-called “systolic dysfunction.” In some cases, the muscle cannot relax sufficiently to permit ventricular filling, resulting in diastolic dysfunction. Obstruction to flow. Lesions that prevent valve opening (e.g., calcific aortic valve stenosis) or cause increased ventricular chamber pressures (e.g., systemic hypertension or aortic coarctation) can overwork the myocardium, which has to pump against the obstruction. Regurgitant flow. Valve pathology that allows backward flow of blood results in increased volume workload and may overwhelm the pumping capacity of the affected chambers.


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Pathology_Robbins. Regurgitant flow. Valve pathology that allows backward flow of blood results in increased volume workload and may overwhelm the pumping capacity of the affected chambers. Shunted flow. Defects (congenital or acquired) that divert blood inappropriately from one chamber to another, or from one vessel to another, lead to pressure and volume overloads. Disorders of cardiac conduction. Uncoordinated cardiac impulses or blocked conduction pathways can cause arrhythmias that slow contractions or prevent effective pumping altogether. Rupture of the heart or major vessel. Loss of circulatory continuity (e.g., a gunshot wound through the thoracic aorta) may lead to massive blood loss, hypotensive shock, and death. http://ebooksmedicine.net


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Pathology_Robbins. http://ebooksmedicine.net Heart failure, often referred to as congestive heart failure (CHF), is the common end point for many forms of cardiac disease and typically is a progressive condition with a poor prognosis. In the United States alone, over 5 million individuals are affected, resulting in well over 1 million hospitalizations annually, and a financial burden in excess of $32 billion. Roughly one half of patients die within 5 years of receiving a diagnosis of CHF, and 1 in 9 deaths in the United States include heart failure as a contributory cause.


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Pathology_Robbins. CHF occurs when the heart cannot generate sufficient output to meet the metabolic demands of the tissues, or can only do so at higher-than-normal filling pressures; in a minority of cases, heart failure is a consequence of greatly increased tissue demands, as in hyperthyroidism, or decreased oxygen carrying capacity, as in anemia (highoutput failure). The onset of CHF is sometimes abrupt, as in the setting of a large myocardial infarct or acute valve dysfunction. In most cases, however, CHF develops gradually and insidiously owing to the cumulative effects of chronic work overload or progressive loss of myocardium.


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Pathology_Robbins. Heart failure may result from systolic or diastolic dysfunction. Systolic dysfunction results from inadequate myocardial contractile function, usually as a consequence of ischemic heart disease or hypertension. Diastolic dysfunction refers to an inability of the heart to adequately relax and fill, which may be a consequence of massive left ventricular hypertrophy, myocardial fibrosis, amyloid deposition, or constrictive pericarditis. Approximately one half of CHF cases are attributable to diastolic dysfunction, with a greater frequency seen in older adults, diabetic patients, and women. Heart failure may also be caused by valve dysfunction (e.g., due to endocarditis), or may occur following rapid increases in blood volume or blood pressure, even if the heart is normal.


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Pathology_Robbins. When, the failing heart can no longer efficiently pump blood, there is an increase in end-diastolic ventricular volumes, increased end-diastolic pressures, and elevated venous pressures. Thus, inadequate cardiac output— called forward failure—is almost always accompanied by increased congestion of the venous circulation—that is, backward failure. Although the root problem in CHF typically is deficient cardiac function, virtually every other organ is eventually affected by some combination of forward and backward failure.


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Pathology_Robbins. The cardiovascular system attempts to compensate for reduced myocardial contractility or increased hemodynamic burden through several homeostatic mechanisms: • The Frank-Starling mechanism. Increased end-diastolic filling volumes dilate the heart and cause increased cardiac myofiber stretching; these lengthened fibers contract more forcibly, thereby increasing cardiac output. If the dilated ventricle is able to maintain cardiac output by this means, the patient is said to be in compensated heart failure. However, ventricular dilation comes at the expense of increased wall tension and magnifies the oxygen requirements of an already-compromised myocardium. With time, the failing muscle is no longer able to propel sufficient blood to meet the needs of the body, and the patient develops decompensated heart failure. Activation of neurohumoral systems:


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Pathology_Robbins. Activation of neurohumoral systems: Release of the neurotransmitter norepinephrine by the autonomic nervous system increases heart rate and augments myocardial contractility and vascular resistance. Activation of the renin-angiotensin-aldosterone system spurs water and salt retention (augmenting circulatory volume) and increases vascular tone. Release of atrial natriuretic peptide acts to balance the renin-angiotensin-aldosterone system through diuresis and vascular smooth muscle relaxation. Myocardial structural changes, including augmented muscle mass. Cardiac myocytes adapt to increased workload by assembling new sarcomeres, a change that is accompanied by myocyte enlargement (hypertrophy) ( Fig. 11.1


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Pathology_Robbins. Fig. 11.1 In pressure overload states (e.g., hypertension or valvular stenosis), new sarcomeres tend to be added parallel to the long axis of the myocytes, adjacent to existing sarcomeres. The growing muscle fiber diameter thus results in concentric hypertrophy—the ventricular wall thickness increases without an increase in the size of the chamber. In volume overload states (e.g., valvular regurgitation or shunts), the new sarcomeres are added in series with existing sarcomeres, so that the muscle fiber length increases. Consequently, the ventricle tends to dilate, and the resulting wall thickness can be increased, normal, or decreased; thus, heart weight—rather than wall thickness—is the best measure of hypertrophy in volume-overloaded hearts.


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Pathology_Robbins. Compensatory hypertrophy comes at a cost. The oxygen requirements of hypertrophic myocardium are amplified owing to increased myocardial cell mass. Because the myocardial capillary bed does not expand in step with the increased myocardial oxygen demands, the myocardium becomes vulnerable to ischemic injury. Hypertrophy also typically is associated with altered patterns of gene expression reminiscent of fetal myocytes, such as changes in the dominant form of myosin heavy chain produced. Altered gene expression may contribute to changes in myocyte function that lead to increases in heart rate and force of contraction, both of which improve cardiac output, but which also lead to higher cardiac oxygen consumption. In the face of ischemia and chronic increases in workload, other pathologic changes eventually supervene, including myocyte apoptosis, cytoskeletal alterations, and increased extracellular matrix (ECM) deposition.


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Pathology_Robbins. Pathologic compensatory cardiac hypertrophy is correlated with increased mortality; indeed, cardiac hypertrophy is an independent risk factor for sudden cardiac death. By contrast, the volume-loaded hypertrophy induced by regular aerobic exercise (physiologic hypertrophy) typically is accompanied by an increase in capillary density, with decreased resting heart rate and blood http://ebooksmedicine.net


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Pathology_Robbins. Fig. 11.1 Leftventricularhypertrophy.(A)Pressurehypertrophyduetoleftventricularoutflowobstruction.Theleftventricleisonthelower right inthisapicalfour-chamberviewoftheheart.(B)Leftventricularhypertrophywithandwithoutdilation,viewedintransverseheartsections.Comparedwithanormalheart(center), thepressure-hypertrophiedhearts(left and in A) haveincreasedmassandathickleftventricularwall,whilethehypertrophied,dilatedheart(right) hasincreasedmassandanormalwallthickness.(C)Normalmyocardium.(D)Hypertrophiedmyocardium(panelsC andD arephotomicrographsatthesamemagnification).Notetheincreasesinbothcellsizeandnuclearsizeinthehypertrophiedmyocytes.(A and B, Reproduced with permission from Edwards WD: Cardiac anatomy and examination of cardiac specimens. In Emmanouilides GC, et al, editors: MossandAdamsheartdiseaseininfants,children,andadolescents:includingthefetusandyoungadults,ed 5,Philadelphia,1995,Williams & Wilkins,p 86.) pressure. These physiologic adaptations reduce overall


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Pathology_Robbins. MORPHOLOGYcardiovascular morbidity and mortality. In comparison, static exercise (e.g., weight lifting) is associated with pressure hypertrophy and may not have the same beneficial effects. Heart failure can affect predominantly the left or the right side of the heart or may involve both sides. The most common causes of left-sided cardiac failure are ischemic heart disease (IHD), systemic hypertension, mitral or aortic valve disease, and primary diseases of the myocardium (e.g., amyloidosis). The morphologic and clinical effects of left-sided CHF stem from diminished systemic perfusion and elevated back-pressures within the pulmonary circulation.


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Pathology_Robbins. http://ebooksmedicine.net Dyspnea (shortness of breath) on exertion is usually the earliest and most significant symptom of left-sided heart failure; cough is also common as a consequence of fluid transudation into air spaces. As failure progresses, patients experience dyspnea when recumbent (orthopnea); this occurs because the supine position increases venous return from the lower extremities and also elevates the diaphragm. Orthopnea typically is relieved by sitting or standing, so patients usually sleep in a semi-seated position. Paroxysmal nocturnal dyspnea is a particularly dramatic form of breathlessness, awakening patients from sleep with extreme dyspnea bordering on feelings of suffocation.


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Pathology_Robbins. Other manifestations of left ventricular failure include an enlarged heart (cardiomegaly), tachycardia, a third heart sound (S3), and fine ráles at the lung bases, caused by the opening of edematous pulmonary alveoli. With progressive ventricular dilation, the papillary muscles are displaced outward, causing mitral regurgitation and a systolic murmur. Subsequent chronic dilation of the left atrium can cause atrial fibrillation, manifested by an “irregularly irregular” heartbeat. Such uncoordinated, chaotic atrial contractions reduce the atrial contribution to ventricular filling, thus reducing the ventricular stroke volume. Atrial fibrillation also causes stasis of the blood (particularly in the atrial appendage), frequently leading to the formation of thrombi that can shed emboli and cause strokes and manifestations of infarction in other organs.


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Pathology_Robbins. Diminished cardiac output leads to decreased renal perfusion that in turn triggers the renin-angiotensin-aldosterone axis, increasing intravascular volume and pressures (Chapters 4 and 10). Unfortunately, with a failing heart, these compensatory effects exacerbate the pulmonary edema. With further progression of CHF, prerenal azotemia may supervene, with impaired excretion of nitrogenous wastes and increasing metabolic derangement. In severe CHF, diminished cerebral perfusion may manifest as hypoxic encephalopathy marked by irritability, diminished cognition, and restlessness that can progress to stupor and coma.


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Pathology_Robbins. Treatment for CHF is typically focused—at least initially—on correcting the underlying cause, for example a valvular defect or inadequate cardiac perfusion. In lieu of such options, the clinical approach includes salt restriction or pharmacologic agents that variously reduce volume overload (e.g., diuretics), increase myocardial contractility (so-called “positive inotropes”), or reduce afterload (adrenergic blockade or inhibitors of angiotensin-converting enzymes). Angiotensin-converting enzyme inhibitors appear to benefit patients not only by opposing aldosteronemediated salt and water retention, but also by limiting cardiomyocyte hypertrophy and remodeling through uncertain mechanisms. Although cardiac resynchronization therapy (exogenous pacing of both the right and left ventricles) and cardiac contractility modulation (exogenous stimulation of cardiac muscle) have recently augmented the cardiologist’s armamentarium, CHF remains a serious cause of human morbidity and mortality.


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Pathology_Robbins. Right-sided heart failure is usually the consequence of left-sided heart failure, since any pressure increase in the pulmonary circulation inevitably produces an increased burden on the right side of the heart. Consequently, the causes of right-sided heart failure include all of those that induce left-sided heart failure. Isolated right-sided heart failure is infrequent and typically occurs in patients with one of a variety of disorders affecting the lungs; hence it is often referred to as cor pulmonale. Besides parenchymal lung diseases, cor pulmonale also may arise secondary to disorders that affect the pulmonary vasculature, for example, primary pulmonary hypertension (Chapter 13), recurrent pulmonary thromboembolism, or conditions that cause pulmonary vasoconstriction (obstructive sleep apnea). The common feature of these disorders is pulmonary hypertension (discussed later), which results in hypertrophy and dilation of the right side of the heart. In cor pulmonale, myocardial


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Pathology_Robbins. sleep apnea). The common feature of these disorders is pulmonary hypertension (discussed later), which results in hypertrophy and dilation of the right side of the heart. In cor pulmonale, myocardial hypertrophy and dilation generally are confined to the right ventricle and atrium, although bulging of the ventricular septum to the left can reduce cardiac output by causing outflow tract obstruction.


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Pathology_Robbins. The major morphologic and clinical effects of pure right-sided heart failure differ from those of left-sided heart failure in that engorgement of the systemic and portal venous systems typically is pronounced and pulmonary congestion is minimal. MORPHOLOGYLiver and Portal System. Theliverusuallyisincreasedinsizeandweight(congestive hepatomegaly). Acutsectiondisplaysprominentpassive congestion, apatternreferredtoasnutmeg liver (Chapter4);congestedcentrilobularareasaresurroundedbyperipheralpaler,noncongestedparenchyma.Whenleft-sidedheartfailureisalsopresent,severecentralhypoxiaproducescentrilobular necrosis inadditiontothesinusoidalcongestion.Withlong-standingsevereright-sidedheartfailure,thecentralareascanbecomefibrotic,creatingso-calledcardiac cirrhosis.


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Pathology_Robbins. Subcutaneous Tissues. Edemaofdependentportionsofthebody,especiallythefeetandlowerlegs,isahallmarkofright-sidedCHF.Inchronicallybedriddenpatients,theedemamaybeprimarilypresacral. Unlike left-sided heart failure, pure right-sided heart failure typically is not associated with respiratory symptoms. Instead, the clinical manifestations are related to systemic and portal venous congestion and include hepatic and splenic enlargement, peripheral edema, pleural effusion, and ascites. Venous congestion and hypoxia of the kidneys and brain due to right-sided heart failure can produce deficits comparable to those caused by the hypo-perfusion of left-sided heart failure.


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Pathology_Robbins. Of note, cardiac decompensation is often marked by the appearance of biventricular CHF, encompassing features of both right-sided and left-sided heart failure. As CHF progresses, patients may become frankly cyanotic and acidotic, as a consequence of decreased tissue perfusion resulting from both diminished cardiac output and increasing congestion. CHFoccurswhentheheartisunabletoprovideadequateperfusiontomeetthemetabolicdemandsofperipheraltissues;inadequatecardiacoutputusuallyisaccompaniedbycongestionofthevenouscirculation. Left-sidedheartfailureismostcommonlysecondarytoischemicheartdisease,systemichypertension,mitraloraorticvalvedisease,orprimarydiseasesofthemyocardium;symptomsaremainlyaconsequenceofpulmonarycongestionandedema,althoughsystemichypoperfusioncancauserenalandcerebraldysfunction. Right-sidedheartfailureisduemostoftentoleft-sidedheartfailureand,lesscommonly,toprimarypulmonarydisorders;signsandsymptomsarerelatedchieflytoperipheraledemaandvisceralcongestion.


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Pathology_Robbins. Right-sidedheartfailureisduemostoftentoleft-sidedheartfailureand,lesscommonly,toprimarypulmonarydisorders;signsandsymptomsarerelatedchieflytoperipheraledemaandvisceralcongestion. Congenital heart diseases are abnormalities of the heart or great vessels that are present at birth. They account for 20% to 30% of all birth defects and include a broad Table 11.1 Frequency of Congenital Cardiac Malformations* *Summaryof44publishedstudies.Percentagesdonotaddto100%becauseofrounding.DatafromHoffmanJI,KaplanS:Theincidenceofcongenitalheartdisease,J Am Coll Cardiol 39:1890,2002.


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Pathology_Robbins. spectrum of malformations, ranging from severe anomalies incompatible with intrauterine or perinatal survival, to lesions that produce few or no symptoms, some of which go completely unrecognized during life. Congenital heart disease affects nearly 1% of newborns (or roughly 40,000 infants per year in the United States). The incidence is higher in premature infants and in stillborns, approximately one fourth of which have significant cardiac malformations. Defects that permit live birth usually involve only single chambers or regions of the heart. Twelve entities account for 85% of congenital heart disease; their frequencies are shown in Table 11.1


Pathology_Robbins

Pathology_Robbins. Table 11.1 Thanks to surgical advances, the number of patients surviving with congenital heart disease is increasing rapidly and is currently estimated at over 2 million individuals in the United States alone. Although surgery may correct the hemodynamic abnormalities, the repaired heart may not be completely normal, since the myocardial hypertrophy and cardiac remodeling brought about by the congenital defect may be irreversible; in addition, virtually all cardiac surgery results in some degree of myocardial scarring. Such changes can lead secondarily to arrhythmias and myocardial dysfunction, which occasionally appear many years after surgical correction.


Pathology_Robbins

Pathology_Robbins. Congenital heart disease most commonly arises from faulty embryogenesis during gestational weeks 3 through 8, when major cardiovascular structures develop. The cause is unknown in almost 90% of cases. Of the accepted etiologic factors, environmental exposures, including congenital rubella infection, teratogens, and maternal diabetes, and genetic factors are best characterized. Genetic factors include specific loci implicated in familial forms of congenital heart disease and certain chromosomal abnormalities (e.g., trisomies 13, 15, 18, and 21, and Turner syndrome). http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Cardiac morphogenesis involves multiple genes that work together to choreograph a complex series of tightly regulated events. Key steps include commitment of progenitor cells to the myocardial lineage, formation and looping of the heart tube, segmentation and growth of the cardiac chambers, cardiac valve formation, and connection of the great vessels to the heart. Proper orchestration of these remarkable transformations depends on networks of transcription factors and several signaling pathways and molecules, including the Wnt, vascular endothelial growth factor (VEGF), bone morphogenetic protein (BMP), transforming growth factor-β (TGF-β), fibroblast growth factor, and Notch pathways. Also essential for cardiac morphogenesis is the mechanical force imparted by flowing pulsatile blood, which is sensed by the cells of the developing heart and vessels.


Pathology_Robbins

Pathology_Robbins. Since crafting a normal heart involves many steps, even subtle perturbations can adversely influence the outcome. Most of the known genetic defects are autosomal dominant mutations causing loss (or sometimes gain) of function of a particular factor. Several mutations involve transcription factors. For example, atrial septal defects (ASDs) and ventricular septal defects (VSDs) and/or conduction defects may be caused by transcription factor mutations, such as TBX5 mutations in the Holt-Oram syndrome. Other disorders (e.g., Noonan syndrome) are associated with mutations in intracellular signaling cascades that cause constitutive activation. MicroRNAs, as well as epigenetic changes (e.g., DNA methylation), also are increasingly recognized as important contributors. It is likely that even transient environmental stresses at critical junctures early in pregnancy can cause subtle changes in transcription factor activity that may recapitulate defects produced by heritable mutations.


Pathology_Robbins

Pathology_Robbins. The various structural anomalies in congenital heart disease can be assigned to three major groups based on their hemodynamic and clinical consequences: (1) malformations causing a left-to-right shunt; (2) malformations causing a right-to-left shunt (cyanotic congenital heart diseases); and (3) malformations causing obstruction. A shunt is an abnormal communication between chambers or blood vessels. Depending on pressure relationships, shunts permit the flow of blood from the left to the right side of the heart (or vice versa). With right-to-left shunt, a dusky blueness of the skin (cyanosis) results because the pulmonary circulation is bypassed and poorly oxygenated blood collected from the venous system enters the systemic arterial circulation.


Pathology_Robbins

Pathology_Robbins. By contrast, left-to-right shunts increase blood flow into the pulmonary circulation and are not associated (at least initially) with cyanosis. However, they expose the low-pressure, low-resistance pulmonary circulation to high pressures and increased volumes; these alterations lead to adaptive changes that increase lung vascular resistance to protect the pulmonary bed, resulting in right ventricular hypertrophy and—eventually rightsided—failure. With time, increased pulmonary resistance also can cause shunt reversal (right to left) and late-onset cyanosis. • Some congenital anomalies obstruct vascular flow by narrowing the chambers, valves, or major blood vessels. A malformation characterized by complete obstruction is called an atresia. In some disorders (e.g., tetralogy of Fallot), an obstruction (pulmonary stenosis) also is associated with a shunt (right-to-left, through a VSD).


Pathology_Robbins

Pathology_Robbins. The altered hemodynamics of congenital heart disease usually lead to chamber dilation or wall hypertrophy. However, some defects result in a reduced muscle mass or chamber size; this is called hypoplasia if it occurs before birth and atrophy if it develops postnatally. Disorders associated with Left-to-right shunts are the most common types of congenital cardiac malformations. They include atrial septal defects (ASDs), ventricular septal defects (VSDs), and patent ductus arteriosus (PDA) ( Fig. 11.2 ). ASDs typically increase only right ventricular and pulmonary outflow volumes, while VSDs and PDAs cause both increased pulmonary blood flow and pressure. Manifestations of these shunts range from completely asymptomatic to fulminant heart failure.


Pathology_Robbins

Pathology_Robbins. Cyanosis is not an early feature of these defects. However, as discussed earlier, prolonged left-to-right shunting may eventually give rise to pulmonary hypertension and right-to-left shunting of unoxygenated blood into the systemic circulation, a change marked by the appearance of cyanosis (Eisenmenger syndrome). Once significant pulmonary hypertension develops, the structural defects of congenital heart disease are considered irreversible. This is the rationale for early intervention, in most cases surgically. Fig. 11.2 Commoncongenitalcausesofleft-to-rightshunts(arrows indicatedirectionofbloodflow).(A)Atrialseptaldefect(ASD).(B)Ventricularseptaldefect(VSD).(C)Patentductusarteriosus(PDA).Ao, Aorta;LA, leftatrium;LV, leftventricle;PT, pulmonarytrunk;RA, rightatrium;RV, rightventricle. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. During normal cardiac development, patency is maintained between the right and left atria by a series of fenestrations (ostium primum and ostium secundum) that eventually become the foramen ovale. This arrangement allows oxygenated blood from the maternal circulation to flow from the right to the left atrium, thereby sustaining fetal development. At later stages of intrauterine development, tissue flaps (septum primum and septum secundum) grow to occlude the foramen ovale, and in 80% of cases, the higher left-sided pressures in the heart that occur at birth permanently fuse the septa against the foramen ovale. In the remaining 20% of cases, a patent foramen ovale results; although the flap is of adequate size to cover the foramen, the unsealed septa can allow transient right-to-left blood flow, such as with a Valsalva maneuver during sneezing or straining during bowel movements. Although this typically has little significance, it occasionally manifests as paradoxical embolism, defined


Pathology_Robbins

Pathology_Robbins. flow, such as with a Valsalva maneuver during sneezing or straining during bowel movements. Although this typically has little significance, it occasionally manifests as paradoxical embolism, defined as venous emboli (e.g., from deep leg veins) that enter the systemic arterial circulation via a foramen ovale defect.


Pathology_Robbins

Pathology_Robbins. In contrast to patent foramen ovale, an ASD is an abnormal fixed opening in the atrial septum that allows unrestricted blood flow between the atrial chambers. A majority (90%) of ASDs are so-called “ostium secundum” defects in which growth of the septum secundum is insufficient to occlude the second ostium. MORPHOLOGYOstium secundum ASDs(90%ofASDs)aresmooth-walleddefectsneartheforamenovale,typicallywithoutotherassociatedcardiacabnormalities.Hemodynamicallysignificantlesionsareaccompaniedbyrightatrialandventriculardilation,rightventricularhypertrophy,anddilationofthepulmonaryartery,reflectingtheeffectsofachronicallyincreasedvolumeload. Ostium primum ASDs(accountingfor5%ofthesedefects)occuratthelowestpartoftheatrialseptumandcanbeassociatedwithmitralandtricuspidvalveabnormalities,reflectingthecloserelationshipbetweendevelopmentoftheseptumprimumandtheendocardialcushions.Inmoreseverecases,additionaldefectsmayincludeaVSDandacommon atrioventricular canal.


Pathology_Robbins

Pathology_Robbins. Sinus venosus ASDs (accountingforanother5%ofthecases)arelocatedhighintheatrialseptumandoftenareaccompaniedbyanomalousdrainageofthepulmonaryveinsintotherightatriumorsuperiorvenacava.


Pathology_Robbins

Pathology_Robbins. ASDs usually are asymptomatic until adulthood. Although VSDs are more common, many close spontaneously. Consequently, ASDs—which are less likely to spontaneously close—are the most common defects to be first diagnosed in adults. ASDs initially cause left-to-right shunts, due to lower pressures in the pulmonary circulation and the right side of the heart. In general, these defects are well tolerated, especially if they are less than 1 cm in diameter; even larger lesions do not usually produce any symptoms in childhood. Over time, however, chronic volume and pressure overloads can cause pulmonary hypertension. Surgical or intravascular ASD closure is thus performed to preempt the development of heart failure, paradoxical embolization, and irreversible pulmonary vascular disease. Mortality is low, and postoperative survival is comparable to that for an unaffected population.


Pathology_Robbins

Pathology_Robbins. Defects in the ventricular septum allow left-to-right shunting and constitute the most common congenital cardiac anomaly at birth (see Table 11.1 Fig. 11.3 ). The ventricular septum normally is formed by a muscular ridge that grows upward from the heart apex fusing with a thinner membranous partition that grows downward from the endocardial cushions. The basal (membranous) region is the last part of the septum to develop and is the site of approximately 90% of VSDs. Most VSDs close spontaneously in childhood, but only 20% to 30% of VSDs occur in isolation; the remainder are associated with other cardiac malformations.


Pathology_Robbins

Pathology_Robbins. Fig.11.3 ),rangingfromminutedefectsinthemembranousseptumtolargedefectsinvolvingvirtuallytheentireinterventricularwall.Indefectsassociatedwithasignificantleft-to-rightshunt,therightventricleishypertrophiedandoftendilated.Thediameterofthepulmonaryarteryisincreased,owingtotheincreasedrightventricularoutputandhigherrightsidedpressures.Vascularchangestypicalofpulmonaryhypertensionarecommon(Chapter13). Fig. 11.3 Ventricularseptaldefectofthemembranoustype(arrow).(Cour-tesy of William D. Edwards, MD, Mayo Clinic, Rochester, Minnesota.) http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 11.3 Ventricularseptaldefectofthemembranoustype(arrow).(Cour-tesy of William D. Edwards, MD, Mayo Clinic, Rochester, Minnesota.) http://ebooksmedicine.net Small VSDs may be asymptomatic; half of those in the muscular portion of the septum close spontaneously during infancy or childhood. Larger defects, however, result in chronic left-to-right shunting, often complicated by pulmonary hypertension and CHF. Progressive pulmonary hypertension, with resultant reversal of the shunt and cyanosis, occurs earlier and more frequently with VSDs than with ASDs. Early surgical correction is therefore indicated for such lesions. Small-or medium-sized defects that produce jet lesions in the right ventricle cause endothelial damage and increase the risk for infective endocarditis.


Pathology_Robbins

Pathology_Robbins. The ductus arteriosus arises from the left pulmonary artery and joins the aorta just distal to the origin of the left subclavian artery. During intrauterine life, it permits blood to flow from the pulmonary artery to the aorta, bypassing the unoxygenated lungs. Within 1 to 2 days of birth in healthy term infants, the ductus constricts and closes; these changes occur in response to increased arterial oxygenation, decreased pulmonary vascular resistance, and declining local levels of prostaglandin E2. Complete obliteration occurs within the first few months of extrauterine life, leaving only a strand of residual fibrous tissue known as the ligamentum arteriosum. Ductal closure can be delayed (or even absent) in infants with hypoxia (related to respiratory distress or heart disease). PDAs account for about 7% of congenital heart lesions (see Table 11.1 Fig. 11.2 ); the great majority of these (90%) are isolated defects.


Pathology_Robbins

Pathology_Robbins. Table 11.1 Fig. 11.2 ); the great majority of these (90%) are isolated defects. PDAs are high-pressure left-to-right shunts that produce harsh, “machinery-like” murmurs. A small PDA generally causes no symptoms, although larger defects eventually can lead to Eisenmenger syndrome with cyanosis and congestive heart failure. High-pressure shunts also predispose patients to developing infective endocarditis. While isolated PDAs should be closed as early in life as is feasible, preservation of ductal patency (by administering prostaglandin E) can be lifesaving when a PDA is the only means to sustain systemic or pulmonary blood flow (e.g., in infants with aortic or pulmonic atresia).


Pathology_Robbins

Pathology_Robbins. Cardiac malformations associated with right-to-left shunts are distinguished by early cyanosis. This occurs because poorly oxygenated blood from the right side of the heart flows directly into the arterial circulation. Two of the most important conditions associated with cyanotic congenital heart disease are tetralogy of Fallot and transposition of the great vessels ( Fig. 11.4 ). Clinical consequences of severe, systemic cyanosis include clubbing of the tips of the fingers and toes (hypertrophic osteoarthropathy), polycythemia, and paradoxical embolization. Tetralogy of Fallot Tetralogy of Fallot is the most common cause of cyanotic congenital heart disease. It accounts for about 5% of all Fig.11.4 Commoncongenitalright-to-leftshunts(cyanoticcongenitalheartdisease).(A)TetralogyofFallot(arrow indicatesdirectionofbloodflow). (B)TranspositionofthegreatvesselswithandwithoutVSD.Ao, Aorta;LA, leftatrium;LV, leftventricle;PT, pulmonarytrunk;RA, rightatrium;RV, rightventricle.


Pathology_Robbins

Pathology_Robbins. (B)TranspositionofthegreatvesselswithandwithoutVSD.Ao, Aorta;LA, leftatrium;LV, leftventricle;PT, pulmonarytrunk;RA, rightatrium;RV, rightventricle. Table 11.1 ). The four cardinal features are ( Fig. 11.4A Overriding of the VSD by the aorta All of the features of tetralogy of Fallot result from anterosuperior displacement of the infundibular septum leading to abnormal septation between the pulmonary trunk and the aortic root.


Pathology_Robbins

Pathology_Robbins. All of the features of tetralogy of Fallot result from anterosuperior displacement of the infundibular septum leading to abnormal septation between the pulmonary trunk and the aortic root. MORPHOLOGYTheheartisenlargedand“boot-shaped”asaconsequenceofright ventricular hypertrophy; theproximalaortaisdilated,whilethepulmonarytrunkishypoplastic.Theleft-sidedcardiacchambersareofnormalsize,whiletherightventricularwallismarkedlyhypertrophied,sometimesevenexceedingthethicknessoftheleftventricle.TheVSD usuallyislargeandliesinthevicinityofthemembranousportionoftheinterventricularseptum;theaorticvalveliesimmediatelyovertheVSD(overriding aorta) andisthemajorsiteofegressforbloodflowfrombothventricles.Theobstructionoftherightventricularoutflowmostoftenisduetonarrowingoftheinfundibulum(subpulmonic stenosis) butalsocanbecausedbypulmonaryvalvestenosisorcompleteatresiaofthevalveandtheproximalpulmonaryarteries.Insuchcases,apersistentPDAordilatedbronchialarteriesaretheonlyrouteforbloodtoreachthelungs.


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Pathology_Robbins. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. The hemodynamic consequences of tetralogy of Fallot are right-to-left shunting, decreased pulmonary blood flow, and increased aortic volumes. The clinical severity largely depends on the degree of the pulmonary outflow obstruction; even untreated, some patients can survive into adult life. Thus, if the pulmonic obstruction is mild, the condition resembles an isolated VSD because the high left-sided pressure causes only a left-to-right shunt with no cyanosis. More commonly, more severe degrees of pulmonic stenosis cause early cyanosis. Moreover, as the child grows and the heart increases in size, the pulmonic orifice does not expand proportionately, leading to progressive worsening of the stenosis. Fortuitously, the pulmonic outflow stenosis protects the pulmonary vasculature from pressure and volume overloads, so that pulmonary hypertension does not develop, and right ventricular failure is rare. Nevertheless, patients develop the typical sequelae of cyanotic heart disease, such as


Pathology_Robbins

Pathology_Robbins. and volume overloads, so that pulmonary hypertension does not develop, and right ventricular failure is rare. Nevertheless, patients develop the typical sequelae of cyanotic heart disease, such as hypertrophic osteoarthropathy and polycythemia (due to hypoxia) with attendant hyperviscosity; right-to-left shunting also increases the risk for infective endocarditis and systemic embolization. Complete surgical repair is possible with classic tetralogy of Fallot but is more complicated in the setting of pulmonary atresia.


Pathology_Robbins

Pathology_Robbins. Transposition of the Great Arteries Transposition of the great arteries is a discordant connection of the ventricles to their vascular outflow. The embryologic defect is an abnormal formation of the truncal and aortopulmonary septa so that the aorta arises from the right ventricle and the pulmonary artery emanates from the left ventricle ( Fig. 11.4B ). The atrium-to-ventricle connections, however, are normal (concordant), with the right atrium joining the right ventricle and the left atrium emptying into the left ventricle. The functional outcome is separation of the systemic and pulmonary circulations, a condition incompatible with postnatal life unless a shunt (such as a VSD) allows delivery of oxygenated blood to the aorta. Indeed, VSDs occur in one third of cases (see


Pathology_Robbins

Pathology_Robbins. Fig. 11.4, B ). There is marked right ventricular hypertrophy, since that chamber functions as the systemic ventricle; the left ventricle is hypoplastic, since it pumps only to the low-resistance pulmonary circulation. Some newborns with transposition of the great arteries have a patent foramen ovale or PDA that allows oxygenated blood to reach the aorta, but these tend to close; such infants typically require emergent surgical intervention within the first few days of life. The dominant manifestation is cyanosis, with the prognosis depending on the magnitude of shunting, the degree of tissue hypoxia, and the ability of the right ventricle to maintain systemic pressures. Without surgery (even with stable shunting), most patients with uncorrected transposition of the great arteries die within the first months of life. However, improved surgical techniques now permit definitive repair, and such patients often survive into adulthood.


Pathology_Robbins

Pathology_Robbins. Congenital obstruction of blood flow can occur at the level of the heart valves or more distally within a great vessel. Obstruction can also occur proximal to the valve, as with subpulmonic stenosis in tetralogy of Fallot. Relatively common examples of congenital obstructions are pulmonic valve stenosis, aortic valve stenosis or atresia, and coarctation of the aorta. Coarctation (narrowing, or constriction) of the aorta is a common form of obstructive congenital heart disease (see Table 11.1 ). Males are affected twice as often as females, although females with Turner syndrome frequently have coarctation. There are two classic forms (Fig. 11.5 An “infantile” preductal form featuring hypoplasia of the aortic arch proximal to a PDA An “adult” postductal form consisting of a discrete ridgelike infolding of the aorta, adjacent to the ligamentum arteriosum


Pathology_Robbins

Pathology_Robbins. An “adult” postductal form consisting of a discrete ridgelike infolding of the aorta, adjacent to the ligamentum arteriosum Coarctation can occur as a solitary defect, but in more than half of the cases is accompanied by a bicuspid aortic valve. Aortic valve stenosis, ASD, VSD, or mitral regurgitation also can be present. Coarctation of aorta Fig. 11.5 Coarctationoftheaortawith(“infantile”orpreductalform)andwithoutapatentductusarteriosus(PDA)(“adult”orpostductalform);arrow indicatesdirectionofbloodflow.Ao, Aorta;LA, leftatrium;LV, leftventricle;PT, pulmonarytrunk;RA, rightatrium;RV, rightventricle. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 11.6 Coarctationoftheaorta,postductaltype.Thecoarctationisasegmentalnarrowingoftheaorta(arrow).Suchlesionstypicallymanifestlaterinlifethanpreductalcoarctations.Thedilatedascendingaortaandmajorbranchvesselsaretotheleftofthecoarctation.Thelowerextremitiesareperfusedpredominantlybywayofdilated,tortuouscollateralchannels.(Courtesy of Sid Murphree, MD, Department of Pathology, University of Texas Southwestern Medical School, Dallas,Texas.) MORPHOLOGYPreductal coarctation ischaracterizedbycircumferentialnarrowingoftheaorticsegmentbetweentheleftsubclavianarteryandtheductusarteriosus;theductustypicallyispatentandisthemainsourceof(unoxygenated)blooddeliveredtothedistalaorta.Thepulmonarytrunkisdilatedtoaccommodatetheincreasedbloodflow;becausetherightsideoftheheartnowperfusesthebodydistaltothenarrowedsegment(“coarct”),therightventricletypicallyishypertrophied.


Pathology_Robbins

Pathology_Robbins. Inthemorecommon“adult” postductal coarctation, theaortaissharplyconstrictedbyatissueridgeadjacenttothenonpatentligamentumarteriosum( Fig.11.6 ).Theconstrictedsegmentismadeupofsmoothmuscleandelasticfibersderivedfromtheaorticmedia.Proximaltothecoarctation,theaorticarchanditsbranchvesselsaredilatedandtheleftventricleishypertrophied. Clinical manifestations depend on the severity of the narrowing and the patency of the ductus arteriosus. Preductal coarctation with a PDA usually presents early in life, classically as cyanosis localized to the lower half of the body; without intervention, most affected infants die in the neonatal period.


Pathology_Robbins

Pathology_Robbins. Postductal coarctation without a PDA usually is asymptomatic, and the disease may remain unrecognized well into adult life. Classically, there is upper-extremity hypertension paired with weak pulses and relative hypotension in the lower extremities, associated with symptoms of claudication and coldness. Exuberant collateral circulation “around” the coarctation often develops through markedly enlarged intercostal and internal mammary arteries; expansion of the flow through these vessels can lead to radiographically visible “notching” of the ribs. In most cases, significant coarctations are associated with systolic murmurs and occasionally palpable thrills. Balloon dilation and stent placement or surgical resection with end-to-end anastomosis (or replacement of the affected aortic segment by a prosthetic graft) yields excellent results.


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Pathology_Robbins

Pathology_Robbins. Obstructivelesionsincludeformsofaorticcoarctation;theclinicalseverityoftheselesionsdependsonthedegreeofstenosisandthepatencyoftheductusarteriosus. Ischemic heart disease (IHD) is a broad term encompassing several closely related syndromes caused by myocardial ischemia—an imbalance between cardiac blood supply (perfusion) and myocardial oxygen and nutritional requirements. Since cardiac myocytes generate energy almost exclusively through mitochondrial oxidative phosphorylation, cardiac function is strictly dependent upon the continuous flow of oxygenated blood through the coronary arteries. Despite dramatic improvements in therapy in the past quarter century, IHD in its various forms remains the leading cause of mortality in the United States and other developed nations, accounting for 7.5 million deaths worldwide each year.


Pathology_Robbins

Pathology_Robbins. In more than 90% of cases, IHD is a consequence of reduced coronary blood flow secondary to obstructive atherosclerotic vascular disease (Chapter 10). Thus, unless otherwise specified, IHD usually is synonymous with coronary artery disease (CAD). In most cases, the various syndromes of IHD are consequences of coronary atherosclerosis that has been gradually progressing for decades (beginning even in childhood or adolescence). In the remaining cases, cardiac ischemia may be the result of increased demand (e.g., with increased heart rate or hypertension); diminished blood volume (e.g., with hypotension or shock); diminished oxygenation (e.g., due to pneumonia or CHF); or diminished oxygen-carrying capacity (e.g., due to anemia or carbon monoxide poisoning). http://ebooksmedicine.net The manifestations of IHD are a direct consequence of the insufficient blood supply to the heart. The clinical presentation may include one or more of the following cardiac syndromes:


Pathology_Robbins

Pathology_Robbins. The manifestations of IHD are a direct consequence of the insufficient blood supply to the heart. The clinical presentation may include one or more of the following cardiac syndromes: Angina pectoris (literally, “chest pain”). Ischemia induces pain but is insufficient to cause myocyte death. Angina can be stable (occurring predictably at certain levels of exertion), can be caused by vessel spasm (Prinzmetal angina), or can be unstable (occurring with progressively less exertion or even at rest). Myocardial infarction (MI). This occurs when the severity or duration of ischemia is sufficient to cause cardiomyocyte death. Chronic IHD with CHF. This progressive cardiac decompensation, which occurs after acute MI or secondary to accumulated small ischemic insults, eventually precipitates mechanical pump failure.


Pathology_Robbins

Pathology_Robbins. Chronic IHD with CHF. This progressive cardiac decompensation, which occurs after acute MI or secondary to accumulated small ischemic insults, eventually precipitates mechanical pump failure. Sudden cardiac death (SCD). This can occur as a consequence of tissue damage from MI, but most commonly results from a lethal arrhythmia without myocyte necrosis (see “ ” later in the chapter). The term acute coronary syndrome is applied to any of the three catastrophic manifestations of IHD—unstable angina, MI, and SCD.


Pathology_Robbins

Pathology_Robbins. More than 700,000 Americans experience a MI each year, and roughly half of those affected die. As troubling as this toll is, it represents a spectacular advance; since peaking in 1963, the mortality related to IHD in the United States has declined by 50%. The improvement is largely attributed to interventions that have diminished cardiac risk factors (behaviors or conditions that promote atherosclerosis; (Chapter 10), in particular smoking cessation programs, hypertension and diabetes treatment, and use of cholesterol-lowering agents. To a lesser extent, diagnostic and therapeutic advances also have contributed; these include aspirin prophylaxis, better arrhythmia control, establishment of coronary care units, thrombolysis for MI, angioplasty and endovascular stenting, and coronary artery bypass graft surgery. Maintaining this downward trend in mortality will be particularly challenging given the predicted longevity of “baby boomers,” as well as the epidemic of obesity that is


Pathology_Robbins

Pathology_Robbins. artery bypass graft surgery. Maintaining this downward trend in mortality will be particularly challenging given the predicted longevity of “baby boomers,” as well as the epidemic of obesity that is sweeping the United States and other parts of the world.


Pathology_Robbins

Pathology_Robbins. IHD is a consequence of inadequate coronary perfusion relative to myocardial demand, usually as a consequence of a preexisting (“fixed”) atherosclerotic occlusion of the coronary arteries and new, superimposed thrombosis and/ or vasospasm. Atherosclerotic narrowing can affect any of the coronary arteries—left anterior descending (LAD), left circumflex (LCX), and right coronary artery (RCA)— singly or in combination. Clinically significant plaques tend to occur within the first several centimeters of the LAD and LCX takeoff from the aorta, and along the entire length of the RCA. Sometimes, secondary branches also are involved (i.e., diagonal branches of the LAD, obtuse marginal branches of the LCX, or posterior descending branch of the RCA).


Pathology_Robbins

Pathology_Robbins. Fixed obstructions that occlude less than 70% of a coronary vessel lumen typically are asymptomatic, even with exertion. In comparison, lesions that occlude more than 70% of a vessel lumen—resulting in so-called “critical stenosis”—generally cause symptoms in the setting of increased demand; with critical stenosis, certain levels of exertion predictably cause chest pain, and the patient is said to have stable angina. A fixed stenosis that occludes 90% or more of a vascular lumen can lead to inadequate coronary blood flow with symptoms even at rest—one of the forms ofunstable angina (see “ ” later in the chapter).


Pathology_Robbins

Pathology_Robbins. Of importance, if an atherosclerotic lesion progressively occludes a coronary artery at a sufficiently slow rate over years, other coronary vessels may undergo remodeling and provide compensatory blood flow to the area at risk; such collateral perfusion can subsequently protect against MI, even if the original vessel becomes completely occluded. Unfortunately, with acute coronary blockage, there is no time for collateral flow to develop and infarction results. The following elements contribute to the development and consequences of coronary atherosclerosis:


Pathology_Robbins

Pathology_Robbins. The following elements contribute to the development and consequences of coronary atherosclerosis: Inflammation plays an essential role at all stages of atherosclerosis, from inception to plaque rupture (Chapter 10). It begins with the interaction of endothelial cells and circulating leukocytes, resulting in T-cell and macrophage recruitment and activation. These cells drive subsequent smooth muscle cell accumulation and proliferation, with associated matrix production, superimposed on an atheromatous core of lipid, cholesterol, calcification, and necrotic debris. At later stages, destabilization of atherosclerotic plaque can occur through macrophage metalloproteinase secretion.


Pathology_Robbins

Pathology_Robbins. Thrombosis associated with an eroded or ruptured plaque triggers the acute coronary syndromes. Partial vascular occlusion by a newly formed thrombus on a disrupted atherosclerotic plaque can wax and wane with time and lead to unstable angina or sudden death; alternatively, even partial luminal occlusion by a thrombus can compromise blood flow sufficiently to cause a infarction of the innermost zone of the myocardium (subendocardial infarct). Organizing thrombi produce potent activators of smooth muscle proliferation, which can contribute to the growth of atherosclerotic lesions. Mural thrombi in a coronary artery can also embolize; indeed, small emboli can be found in the distal intramyocardial circulation (along with associated microinfarcts) at autopsy of patients with unstable angina. In the most serious case, completely obstructive thrombus over a disrupted plaque can cause massive MI.


Pathology_Robbins

Pathology_Robbins. Vasoconstriction directly compromises lumen diameter; moreover, by increasing local mechanical shear forces, vessel spasm can potentiate plaque disruption. Vasoconstriction in atherosclerotic plaques can be stimulated by the following: Imbalance between endothelial cell–relaxing factors (e.g., nitric oxide) and –contracting factors (e.g., endothelin) due to endothelial dysfunction http://ebooksmedicine.net Onset of myocardial ischemia depends not only on the extent and severity of fixed atherosclerotic disease but also on dynamic changes in coronary plaque morphology. In most patients, unstable angina, infarction, and sudden cardiac death occur because of abrupt plaque change followed by thrombosis—hence the term acute coronary syndrome ( Fig. 11.7 The initiating event is typically a sudden disruption (ranging from erosion to rupture) of a partially occlusive plaque. More than one mechanism of injury may be involved: rupture, fissuring, or ulceration of plaques expose


Pathology_Robbins

Pathology_Robbins. OBSTRUCTION/? EMBOLI (Acute transmural myocardial (Unstable angina, or acute infarction or sudden death) subendocardial myocardial infarction or sudden death) Fig. 11.7 Diagramofsequentialprogressionofcoronaryarterylesionsleadingtovariousacutecoronarysyndromes.(Modified and redrawn from Schoen FJ: Interventionalandsurgicalcardiovascularpathology:clinicalcorrelationsandbasicprinciples,Philadelphia, 1989, Saunders, p 63.) highly thrombogenic constituents or underlying subendothelial basement membrane, leading to rapid thrombosis. In addition, hemorrhage into the core of plaques can expand plaque volume, thereby acutely exacerbating the degree of luminal occlusion.


Pathology_Robbins

Pathology_Robbins. Factors that trigger plaque erosion include endothelial injury and apoptosis, likely attributable to some combination of inflammatory and toxic exposures. Acute plaque rupture, on the other hand, involves factors that influence plaque susceptibility to disruption by mechanical stress. These include intrinsic aspects of plaque composition and structure (Chapter 10) and extrinsic factors, such as blood pressure and platelet reactivity:


Pathology_Robbins

Pathology_Robbins. Plaques that contain large atheromatous cores or have thin overlying fibrous caps are more likely to rupture and are therefore termed vulnerable. Fissures frequently occur at the junction of the fibrous cap and the adjacent normal plaque-free arterial segment, where the mechanical stresses are highest and the fibrous cap is thinnest. Fibrous caps also are continuously remodeling; their overall balance of collagen synthesis versus degradation determines mechanical strength and plaque stability. Collagen is produced by smooth muscle cells and degraded by the action of metalloproteases elaborated by macrophages. Consequently, atherosclerotic lesions with a paucity of smooth muscle cells or large numbers of inflammatory cells are vulnerable to rupture. Of interest, statins (inhibitors of hydroxymethylglutaryl Co-A reductase, a key enzyme in cholesterol synthesis) can provide additional benefit in CAD and IHD by reducing plaque inflammation and increasing plaque stability, effects distinct


Pathology_Robbins

Pathology_Robbins. Co-A reductase, a key enzyme in cholesterol synthesis) can provide additional benefit in CAD and IHD by reducing plaque inflammation and increasing plaque stability, effects distinct from and their primary cholesterol-lowering activity.


Pathology_Robbins

Pathology_Robbins. Influences extrinsic to the plaque also are important. Adrenergic stimulation can put physical stress on the plaque by causing hypertension or local vasospasm. Indeed, the surge in adrenergic stimulation associated with awakening and rising may underlie the observation that the incidence of acute MI is highest between 6 AM and 12 noon. Intense emotional stress also leads to adrenergic stimulation, explaining the association of natural catastrophes such as earthquakes and floods with secondary waves of MIs in susceptible individuals.


Pathology_Robbins

Pathology_Robbins. In a majority of cases, the “culprit lesion” in patients who suffer an MI was not critically stenotic or even symptomatic before its rupture. As noted previously, anginal symptoms typically occur with fixed lesions exhibiting greater than 70% chronic occlusion. Pathologic and clinical studies show that two thirds of ruptured plaques are less than or equal to 50% stenotic before plaque rupture, and 85% exhibit initial stenotic occlusion of less than or equal to 70%. Thus, the worrisome conclusion is that a large number of asymptomatic adults are at significant risk for a catastrophic coronary event. At present, it is impossible to predict plaque rupture in any given patient. Plaque disruption and ensuing non-occlusive thrombosis also are common, repetitive, and often clinically silent complications of atheromas. The healing of such subclinical plaque disruption and overlying thrombosis is an important mechanism by which atherosclerotic lesions progressively enlarge (


Pathology_Robbins

Pathology_Robbins. Fig. 11.7 http://ebooksmedicine.net Angina pectoris is an intermittent chest pain caused by transient, reversible myocardial ischemia. The pain is a consequence of the ischemia-induced release of adenosine, bradykinin, and other molecules that stimulate autonomic nerves. The following three variants are recognized: Typical or stable angina is predictable episodic chest pain associated with particular levels of exertion or some other increased demand (e.g., tachycardia). The pain is described as a crushing or squeezing substernal sensation that often radiates down the left arm or to the left jaw (referred pain). The pain usually is relieved by rest (reducing demand) or by drugs such as nitroglycerin, a vasodilator that increases coronary perfusion.


Pathology_Robbins

Pathology_Robbins. Prinzmetal or variant angina occurs at rest and is caused by coronary artery spasm. Although such spasms typically occur on or near existing atherosclerotic plaques, a completely normal vessel can be affected. Prinzmetal angina typically responds promptly to vasodilators such as nitroglycerin and calcium channel blockers. Unstable angina (also called crescendo angina) is characterized by increasingly frequent pain, precipitated by progressively less exertion or even occurring at rest. Unstable angina is associated with plaque disruption and superimposed thrombosis, distal embolization of the thrombus, and/or vasospasm; it can be a harbinger of MI, portending complete vascular occlusion.


Pathology_Robbins

Pathology_Robbins. Myocardial infarction (MI), also commonly referred to as “heart attack,” is necrosis of the heart muscle resulting from ischemia. The major underlying cause of IHD is atherosclerosis; while MIs can occur at virtually any age, the frequency rises progressively with aging and with increasing risk factors for atherosclerosis (Chapter 10). Nevertheless, approximately 10% of MIs occur before 40 years of age, and 45% occur before 65 years of age. Blacks and whites are equally affected. Men are at greater risk than women, although the gap progressively narrows with age. In general, women tend to be protected against MI during their reproductive years. However, menopause—with declining estrogen production—is associated with exacerbation of coronary artery disease, and IHD is the most common cause of death in older adult women. The vast majority of MIs are caused by acute thrombosis within coronary arteries (


Pathology_Robbins

Pathology_Robbins. Fig. 11.7 ). In most instances, disruption or erosion of preexisting atherosclerotic plaque serves as the nidus for thrombus generation, vascular occlusion, and subsequent infarction of the perfused myocardium. In 10% of MIs, however, transmural infarction occurs in the absence of occlusive atherosclerotic vascular disease; such infarcts are mostly ascribed to coronary artery vasospasm or to embolization from mural thrombi (e.g., in the setting of atrial fibrillation) or from valve vegetations. Occasionally, especially with infarcts limited to the innermost (subendocardial) myocardium, thrombi or emboli are absent. In such cases, severe fixed coronary atherosclerosis leads to marginal perfusion of the heart. In this setting, a prolonged period of increased demand (e.g., due to tachycardia or hypertension) can lead to ischemic necrosis of endomyocardium, the portion of the heart that is most distal to the epicardial vessels. Finally, ischemia without detectable atherosclerosis or


Pathology_Robbins

Pathology_Robbins. or hypertension) can lead to ischemic necrosis of endomyocardium, the portion of the heart that is most distal to the epicardial vessels. Finally, ischemia without detectable atherosclerosis or thromboembolic disease can be caused by disorders of small intramyocardial arterioles, including vasculitis, amyloid deposition, or stasis, as in sickle cell disease.


Pathology_Robbins

Pathology_Robbins. In a typical MI, the following sequence of events takes place: An atheromatous plaque is eroded or suddenly disrupted by endothelial injury, intraplaque hemorrhage, or mechanical forces, exposing subendothelial collagen and necrotic plaque contents to the blood. Platelets adhere, aggregate, and are activated, releasing thromboxane A2, adenosine diphosphate (ADP), and serotonin—causing further platelet aggregation and vasospasm (Chapter 4). Activation of coagulation by exposure of tissue factor and other mechanisms adds to the growing thrombus. Within minutes, the thrombus can evolve to completely occlude the coronary artery lumen.


Pathology_Robbins

Pathology_Robbins. Activation of coagulation by exposure of tissue factor and other mechanisms adds to the growing thrombus. Within minutes, the thrombus can evolve to completely occlude the coronary artery lumen. The evidence for this scenario derives from autopsy studies of patients dying of acute MI, as well as imaging studies demonstrating a high frequency of thrombotic occlusion early after MI. Angiography performed within 4 hours of the onset of MI demonstrates coronary thrombosis in almost 90% of cases. When angiography is performed 12 to 24 hours after onset of symptoms, however, evidence of thrombosis is seen in only 60% of patients, even without intervention. Thus, at least some occlusions clear spontaneously through lysis of the thrombus or relaxation of spasm. This sequence of events in a typical MI also has therapeutic implications: early thrombolysis and/or angioplasty can be highly successful in limiting the extent of myocardial necrosis.


Pathology_Robbins

Pathology_Robbins. Loss of blood supply has profound functional, biochemical, and morphologic consequences for the myocardium. Within seconds of vascular obstruction, aerobic metabolism ceases, leading to a drop in adenosine triphosphate (ATP) and accumulation of potentially noxious metabolites (e.g., lactic acid) in the cardiac myocytes. The functional consequence is a rapid loss of contractility, occurring within a minute or so of the onset of ischemia. Ultrastructural changes (including myofibrillar relaxation, glycogen depletion, cellular and mitochondrial swelling) are also seen. These early changes are reversible. Only prolonged ischemia lasting at least 20 to 40 minutes causes irreversible damage and coagulative necrosis of myocytes (Chapter 2). With longer periods of ischemia, vessel injury ensues, leading to superimposed microvascular thrombosis.


Pathology_Robbins

Pathology_Robbins. Thus, if blood flow is restored before irreversible injury occurs, myocardium can be preserved; this is the goal of early diagnosis and prompt intervention by thrombolysis or angioplasty. However, as discussed later, reperfusion can have deleterious effects. Even if reperfusion is timely, postischemic myocardium can be profoundly dysfunctional for a number of days due to persistent abnormalities in cellular biochemistry that result in a noncontractile state (stunned myocardium). Such stunning can be severe enough to produce transient but reversible cardiac failure. http://ebooksmedicine.net PulmonaryarteryAortaLeft circumflex coronary artery Right coronary artery Left anterior descending coronary artery Acute coronary arterial occlusion Zone of perfusion (area at risk) Cross-section of myocardium Obstructed coronary artery Endocardium Zone of perfusion (area at risk) Zone of necrosis Zone of necrosis Completed infarct involving nearly the entire area at risk 0 hr 2 hr 24 hr


Pathology_Robbins

Pathology_Robbins. Fig. 11.8 Progressionofmyocardialnecrosisaftercoronaryarteryocclusion.Atransmuralsegmentofmyocardiumthatisdependentontheoccludedvesselforperfusionconstitutestheareaatrisk(outlined). Necrosisbeginsinthesubendocardialregioninthecenteroftheischemiczoneandwithtimeexpandstoinvolvetheentirewallthickness.Notethataverynarrowzoneofmyocardiumimmediatelybeneaththeendocardiumissparedfromnecrosisbecauseitcanbeoxygenatedbydiffusionfromtheventricle. Myocardial ischemia also contributes to arrhythmias, probably by causing electrical instability (irritability) of ischemic regions of the heart. Although massive myocardial damage can cause a fatal mechanical failure, sudden cardiac death in the setting of myocardial ischemia most often (in 80% to 90% of cases) is due to ventricular fibrillation caused by myocardial irritability. Irreversible injury of ischemic myocytes first occurs in the subendocardial zone (


Pathology_Robbins

Pathology_Robbins. Irreversible injury of ischemic myocytes first occurs in the subendocardial zone ( Fig. 11.8 ). As already mentioned, this region is especially susceptible to ischemia because it is the last area to receive blood delivered by the epicardial vessels, and also because it is exposed to relatively high intramural pressures, which act to impede the inflow of blood. With more prolonged ischemia, a wavefront of cell death moves through other regions of the myocardium, driven by progressive tissue edema and myocardial-derived reactive oxygen species and inflammatory mediators. An infarct usually achieves its full extent within 3 to 6 hours; in the absence of intervention, an infarct caused by occlusion of an epicardial vessel can involve the entire wall thickness (transmural infarct). Clinical intervention within this critical window of time can lessen the size of the infarct within the “territory at risk.”


Pathology_Robbins

Pathology_Robbins. The location, size, and morphologic features of an acute myocardial infarct depend on multiple factors: Size and distribution of the involved vessel ( Fig. 11.9 Rate of development and duration of the occlusion Metabolic demands of the myocardium (affected, for example, by blood pressure and heart rate) Extent of collateral supply Acute occlusion of the proximal left anterior descending (LAD) artery is the cause of 40% to 50% of all MIs and http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 11.9 Dependenceofmyocardialinfarctiononthelocationandnatureofthediminishedperfusion.Left, Patternsoftransmuralinfarctionresultingfrommajorcoronaryarteryocclusion.Therightventriclemaybeinvolvedwithocclusionoftherightmaincoronaryartery(not depicted). Right, Patternsofinfarc-tionresultingfrompartialortransientocclusion(top), globalhypotensionsuperimposedonfixedthree-vesseldisease(middle), orocclusionofsmallintra-myocardialvessels(bottom). Posterior Restoration of flow (reperfusion) LVRV Permanent occlusion of left anterior descending branch Transient/partial obstruction regionalsubendocardial infarct Permanent occlusion of left circumflex branch Global hypotension circumferentialsubendocardial infarct Permanent occlusion of the posterior descending branch of the right coronary artery Small intramural vessel occlusions microinfarcts Anterior typically results in infarction of the anterior wall of the left ventricle, the anterior two thirds of the ventricular septum, and most of the


Pathology_Robbins

Pathology_Robbins. intramural vessel occlusions microinfarcts Anterior typically results in infarction of the anterior wall of the left ventricle, the anterior two thirds of the ventricular septum, and most of the heart apex; more distal occlusion of the same vessel may affect only the apex. Similarly, acute occlusion of the proximal left circumflex (LCX) artery (seen in 15% to 20% of MIs) causes necrosis of the lateral left ventricle, and proximal right coronary artery (RCA) occlusion (30% to 40% of MIs) affects much of the right ventricle. Coronary occlusion in the proximal left anterior descending artery has been dubbed the “widow maker” because so much myocardial territory is perfused by that vessel, and acute obstructions are often fatal.


Pathology_Robbins

Pathology_Robbins. The posterior third of the septum and the posterior left ventricle are perfused by the posterior descending artery. The posterior descending artery can arise from either the RCA (in 90% of individuals) or the LCX. By convention, the coronary artery—either RCA or LCX—that gives rise to the posterior descending artery and thereby perfuses portions of the inferior/posterior left ventricle and the posterior third of the septum is considered the dominant vessel. Thus, in a right dominant heart, occlusion of the RCA can lead to posterior septal and posterior wall ischemic injury. In comparison, in a left dominant heart, where the posterior descending artery arises from the circumflex artery, occlusion of the LCX generally affects the left lateral wall as well as the posterior third of the septum, and the inferior and posterior wall of the left ventricle.


Pathology_Robbins

Pathology_Robbins. Occlusions also can occur within secondary branches, such as the diagonal branches of the LAD artery or marginal branches of the LCX artery. Interestingly, atherosclerosis is primarily a disease of epicardial vessels; significant atherosclerosis or thrombosis of penetrating intramyocardial branches of coronary arteries is rare—although these can be affected by vasculitis or vasospasm, and can be occluded by embolization.


Pathology_Robbins

Pathology_Robbins. Even though the three major coronary arteries are end arteries, these epicardial vessels are interconnected by numerous intercoronary anastomoses (collateral circulation). Although these channels are normally closed, gradual narrowing of one artery allows blood to flow from highto low-pressure areas through the collateral channels. In this manner, gradual collateral dilation can provide adequate perfusion to areas of the myocardium despite occlusion of an epicardial vessel. Based on the size of the involved vessel and the degree of collateral circulation, myocardial infarcts may take one of the following patterns:


Pathology_Robbins

Pathology_Robbins. Transmural infarctions involve the full thickness of the ventricle and are caused by epicardial vessel occlusion through a combination of chronic atherosclerosis and acute thrombosis; such transmural MIs typically yield ST segment elevations on the electrocardiogram (ECG) and can have negative Q waves with loss of R wave amplitude. These infarcts are also called ST-segment elevated MIs (STEMIs).


Pathology_Robbins

Pathology_Robbins. Subendocardial infarctions are MIs limited to the inner third of the myocardium; these infarcts typically do not exhibit ST segment elevations or Q waves on the ECG tracing (so-called “non–ST-segment elevated MIs” or “NSTEMIs”), although they can have ST-segment depressions or T wave abnormalities. As mentioned earlier, the subendocardial region is most vulnerable to hypoperfusion and hypoxia. Thus, in the setting of http://ebooksmedicine.net severe coronary artery disease, transient decreases in oxygen delivery (as from hypotension, anemia, or pneumonia) or increases in oxygen demand (as with tachycardia or hypertension) can cause subendocardial ischemic injury. This pattern also can occur when an occlusive thrombus lyses before a full-thickness infarction can develop.


Pathology_Robbins

Pathology_Robbins. • Microscopic infarcts occur in the setting of small-vessel occlusions and may not show any diagnostic ECG changes. These can occur in the setting of vasculitis, embolization of valve vegetations or mural thrombi, or vessel spasm due to elevated catecholamines, as may occur in extreme emotional stress, with certain tumors (e.g., pheochromocytoma), or as a consequence of cocaine use. MORPHOLOGYNearlyalltransmuralinfarcts(involving50%ormoreoftheventriclethickness)affectatleastaportionoftheleftventricleand/orinterventricularseptum.Roughly15%to30%ofMIsthatinvolvetheposteriororposteroseptalwallalsoextendintotherightventricle.Isolatedrightventricleinfarctsoccurinonly1%to3%ofcases.Evenintransmuralinfarcts,anarrowrim(approximately0.1mm)ofviablesubendocardialmyocardiumispreservedbydiffusionofoxygenandnutrientsfromtheventricularlumen.


Pathology_Robbins

Pathology_Robbins. ThegrossandmicroscopicappearanceofanMIdependsontheageoftheinjury.Areasofdamageprogressthroughahighlycharacteristicsequenceofmorphologicchangesfromcoagulativenecrosis,toacuteandthenchronicinflammation,tofibrosis( Table11.2 ).Myocardialnecrosisproceedsinvariablytoscarformationwithoutanysignificantregeneration;studieslookingatwhethertissuestemcellscanbeusedtoregeneratefunctionalmyocardiumareongoingbuthaveyettobearfruit. Grossand/ormicroscopicrecognitionofveryrecentmyocardialinfarctscanbechallenging,particularlywhendeathoccurswithinafewhours.Myocardial infarcts less than 12 hours old usually are not grossly apparent. However,infarctsmorethan3hoursoldcanbevisualizedbyexposingmyocardiumtovitalstains,suchastriphenyltetrazoliumchloride,asubstrateforlactatedehydrogenase.Becausethisenzymeisdepletedintheareaofischemicnecrosis(itleaksoutofthedamagedcells),theinfarctedareaisunstained(pale),whileoldscarsappearwhiteandglistening(


Pathology_Robbins

Pathology_Robbins. Fig.11.10 ).By 12 to 24 hours after MI, an infarct usually can be grossly identified by a red-blue discoloration caused by stagnated, trapped blood. Thereafter,infarctsbecomeprogressivelybetterdelineatedassoft,yellow-tanareas;by10to14days,infarctsarerimmedbyhyperemic(highlyvascularized)granulationtissue.Overthesucceedingweeks,theinfarctedtissueevolvestoafibrousscar. Table11.2 Fig.11.11 ).Typicalfeaturesofcoagulativenecrosis(Chapter2)becomedetectablewithin4to12hoursofinfarction.“Wavyfibers”alsocanbepresentattheedgesofaninfarct;thesereflectthestretchingandbucklingofnoncontractiledeadfibers.Sublethalischemiacanalsoinduceintracellularmyocyte vacuolization; suchmyocytesareviablebutfrequentlycontractpoorly. Necroticmyocardiumelicitsacuteinflammation(typicallymostprominent1to3daysafterMI),followedbyawaveofmacrophagesthatremovenecroticmyocytesandneutrophil


Pathology_Robbins

Pathology_Robbins. Necroticmyocardiumelicitsacuteinflammation(typicallymostprominent1to3daysafterMI),followedbyawaveofmacrophagesthatremovenecroticmyocytesandneutrophil Table 11.2 Evolution of Morphologic Changes in Myocardial Infarction 2–8weeksGray-whitescar,progressivefromIncreasedcollagendeposition,withdecreasedbordertowardcoreofinfarctcellularity http://ebooksmedicine.net Fig. 11.10 Acutemyocardialinfarctoftheposterolateralleftventricledemonstratedbyalackoftriphenyltetrazoliumchloridestaininginareasofnecrosis(arrow); theabsenceofstainingisduetoenzymeleakageaftercelldeath.Notetheanteriorscar(arrowhead), indicativeofremoteinfarction.Themyocardialhemorrhageattherightedgeoftheinfarct(asterisk) isduetoventricularrupture,andwastheacutecauseofdeathinthispatient(specimenisorientedwiththeposteriorwallatthetop).


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. The therapeutic goal in acute MI is restoration of tissue perfusion as quickly as possible (hence the adage “time is myocardium”). Such reperfusion is achieved by thrombolysis (dissolution of thrombus by tissue plasminogen activator), angioplasty, or coronary arterial bypass graft. Fig. 11.11 Microscopicfeaturesofmyocardialinfarctionanditsrepair.(A)One-day-oldinfarctshowingcoagulativenecrosisandwavyfibers,comparedwithadjacentnormalfibers(right). Necroticcellsareseparatedbyedemafluid.(B)Denseneutrophilicinfiltrateintheareaofa2-to3-day-oldinfarct.(C)Nearlycompleteremovalofnecroticmyocytesbyphagocyticmacrophages(7to10days).(D)Granulationtissuecharacterizedbylooseconnectivetissueandabundantcapillaries.(E)Healedmyocardialinfarctconsistingofadensecollagenousscar.Afewresidualcardiacmusclecellsarepresent.(D)and(E)areMasson’strichromestain,whichstainscollagenblue. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Unfortunately, while preservation of a viable (but at-risk) heart can improve both short-and long-term outcomes, reperfusion is not an unalloyed blessing. Indeed, late restoration of blood flow into ischemic tissues can incite greater local damage than might otherwise have occurred— so-called “reperfusion injury”. The factors that contribute to reperfusion injury include the following: Mitochondrial dysfunction. Ischemia alters the mitochondrial membrane permeability, which allows proteins to move into the mitochondria. This leads to swelling and rupture of the outer membrane, releasing mitochondrial contents that promote apoptosis. Myocyte hypercontracture. During periods of ischemia, the intracellular levels of calcium are increased as a result of impaired calcium cycling and sarcolemmal damage. After reperfusion, the contraction of myofibrils is augmented and uncontrolled, causing cytoskeletal damage and cell death.


Pathology_Robbins

Pathology_Robbins. Free radicals, including superoxide anion (•O− 2 ), hydrogen peroxide (H2O2), hypochlorous acid (HOCl), nitric oxide–derived peroxynitrite, and hydroxyl radicals (•OH). These are produced within minutes of reperfusion and cause damage to the myocytes by altering membrane proteins and phospholipids. Leukocyte aggregation may occlude the microvasculature and contribute to the “no-reflow” phenomenon. Further, leukocytes elaborate proteases and elastases that cause cell death. Platelet and complement activation also contribute to microvascular injury. Complement activation is thought to play a role in the no-reflow phenomenon by injuring the endothelium. The typical appearance of reperfused myocardium in the setting of an acute MI is shown in


Pathology_Robbins

Pathology_Robbins. The typical appearance of reperfused myocardium in the setting of an acute MI is shown in Figure 11.12 . Such infarcts are hemorrhagic as a consequence of vascular injury and leakiness. Microscopically, irreversibly damaged myocytes after reperfusion develop contraction band necrosis; in this pathologic process, intense eosinophilic bands of hypercontracted sarcomeres are created by an influx of calcium across plasma membranes that heightens actin-myosin interactions. In the absence of ATP, the sarcomeres cannot relax and get stuck in an agonal tetanic state. Thus, while reperfusion can salvage reversibly injured cells, it also alters the morphology of irreversibly injured cells.


Pathology_Robbins

Pathology_Robbins. The classic MI is heralded by severe, crushing substernal chest pain (or pressure) that can radiate to the neck, jaw, epigastrium, or left arm. In contrast to angina pectoris, the associated pain typically lasts several minutes to hours, and is not relieved by nitroglycerin or rest. However, in a substantialminorityofpatients(10%to15%),MIspresentwith the atypical signs and symptoms, and may even be entirely asymptomatic. Such “silent” infarcts are particularly common in patients with underlying diabetes mellitus (in which autonomic neuropathy may prevent perception of pain) and in older adults.


Pathology_Robbins

Pathology_Robbins. The pulse generally is rapid and weak, and patients are often diaphoretic (sweating) and nauseous (particularly with posterior wall MIs). Dyspnea is common, resulting from impaired myocardial contractility and dysfunction of the mitral valve apparatus, with resultant acute pulmonary congestion and edema. With massive MIs (involving more than 40% of the left ventricle), cardiogenic shock develops. Electrocardiographic abnormalities are important for the diagnosis of MI; these include Q waves, ST segment changes, and T wave inversions (the latter two representing abnormalities in myocardial repolarization). Arrhythmias caused by electrical abnormalities in the ischemic myocardium and conduction system are common; indeed, sudden cardiac death from a lethal arrhythmia accounts for the vast majority of MI-related deaths occurring before hospitalization.


Pathology_Robbins

Pathology_Robbins. The laboratory evaluation of MI is based on measuring blood levels of macromolecules that leak out of injured myocardial cells through damaged cell membranes ( Fig. 11.13 ). These molecules include myoglobin, cardiac troponins T and I (TnT, TnI), creatine kinase (CK; Fig. 11.12 Reperfusedmyocardialinfarction.(A)Thetransverseheartslice(stainedwithtriphenyltetrazoliumchloride)exhibitsalargeanteriorwallmyocardialinfarctionthatishemorrhagicbecauseofbleedingfromdamagedvessels.Theposteriorwallisatthetop. (B)Hemorrhageandcontractionbands,visibleasprominenthypereosinophiliccross-striationsspanningmyofibers(arrow), areseenmicroscopically. http://ebooksmedicine.net Relative concentration(=multiples of upper reference limit) Hours after onset of chest pain