Chapter 5 |
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INTRODUCTION |
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This chapter summarizes pathologic considerations most relevant to surgery in the major forms of acquired cardiovascular disease. Both clinicopathologic correlations and pathophysiologic mechanisms are emphasized. In view of space limitations, several relevant areas (e.g., aortic disease) are necessarily omitted from discussion and others (e.g., cardiac assist devices) are attenuated as they are discussed in greater detail elsewhere in the text. Moreover, although we have not included the key pathologic considerations herein, we are mindful that the number of adults with congenital heart disease is increasing rapidly and that they have unique and important pathological issues.2 Many of these considerations have recently been summarized in another venue.3
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GENERAL CONSIDERATIONS |
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Cardiac hypertrophy is the compensatory response of the myocardium to increased work (Fig. 5-1).4 Myocardial hyperfunction induces an increase in the overall mass and size of the heart that reflects increased size of myocytes through addition of contractile elements (sarcomeres) and mitochondria. Cardiac myocyte diameters, normally approximately 15 µm, can increase to 25 µm or more in hypertrophy.5 Since cardiac myocytes are terminally differentiated cells that cannot divide, functional augmentation of myocyte number (hyperplasia) does not occur in the adult heart. Since the vasculature does not proliferate commensurate with increased cardiac mass, hypertrophied myocardium is usually relatively deficient in blood vessels. Moreover, myocardial fibrous tissue is often increased.
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Molecular changes that initially mediate enhanced function in hypertrophied hearts may subsequently contribute to the development of heart failure.6–9 Hemodynamic overload alters myocardial gene expression, leading to reexpression of a pattern of protein synthesis similar to that of proliferating cells in general and of fetal cardiac myocytes during development. Proteins comprising contractile elements and those involved in excitation-contraction coupling and energy utilization are altered quantitatively or through production of different isoforms; the variant proteins may be less functional than the normal. Hypertrophied and/or failing myocardium may have additional abnormalities that include reduced adrenergic responsiveness, decreased calcium availability, impaired mitochondrial function, and microcirculatory spasm. Apoptosis of cardiac myocytes, potentially triggered by the same mechanical forces, neurohormonal activation, hypoxia, or cytokines that prompted the adaptive changes, also plays a role in the development of heart failure.10,11 A further understanding of myocyte apoptosis may lead to novel therapeutic strategies for the treatment of heart failure.
The mechanical changes described above initially enhance function and are thereby adaptive, but they may ultimately become deleterious and contribute to cardiac failure. Thus, cardiac hypertrophy comprises a tenuous balance between adaptive characteristics and potentially deleterious structural, functional, and biochemical/molecular alterations including enlarged muscle mass with enhanced metabolic requirements, synthesis of abnormal proteins, decreased capillary/myocyte ratio, fibrosis, microvascular spasm, and impaired contractile mechanisms. Hypertrophy (with or without chamber dilation) also decreases myocardial compliance and may thereby hinder diastolic filling. In addition, left ventricular hypertrophy is an independent risk factor for cardiac mortality and morbidity, especially for sudden death.12
Left ventricular hypertrophy is reversible in many cases following removal of the stimulus,13 but it is uncertain to what extent hypertrophy is capable of resolution in individual patients. However, the hemodynamic adjustment that occurs following cardiac valve surgery is not always accompanied by reversal of the myocardial changes secondary to the valvular disorder, and progressive cardiac failure may ensue despite valve replacement or repair (Fig. 5-2). Even in ventricles that are well compensated postoperatively, regression of hypertrophy often is incomplete with some degree of hypertrophy persisting for decades. In addition, the increased cardiac muscle mass in many patients requiring cardiac surgery, with its attendant global ischemia, renders intraoperative myocardial preservation difficult to achieve and the heart thereby particularly susceptible to ischemic damage.
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Atherosclerosis is a chronic, progressive, multifocal disease of the vessel wall intima whose characteristic lesion is the atheroma or plaque that forms through the key processes of intimal thickening (mediated predominantly by smooth muscle cell proliferation) and lipid accumulation (mediated primarily by monocyte phagocytosis).14–17 Atherosclerosis primarily affects the large elastic arteries and large and medium-sized muscular arteries of the systemic circulation, particularly at points of branches, sharp curvatures, and bifurcations. Atherosclerosis of native coronary arteries generally is limited to the large epicardial vessels, especially the proximal portions of the left anterior descending (LAD) and circumflex, and the right coronary diffusely, and does not involve their intramural branches. In contrast, the arteriosclerosis that affects the coronary arteries of transplanted hearts is a diffuse process that involves distal, intramural vessels as well as the larger epicardial vessels. Venous bypass grafts interposed within branches of the arterial system can develop rapidly progressive intimal thickening and ultimately atherosclerotic obstructions, yet arterial grafts such as the internal mammary artery are largely spared. Atheromas in the coronary arteries may be either concentric (25%–30%) or eccentric (70%–75%), with a plaque-free segment often comprising a substantial fraction of the vessel wall. In early lesions, the plaque bulges outward at the expense of the media with the arterial lumen remaining circular in cross-section at essentially the same original diameter (a process termed vascular remodeling).18,19
The prevailing theory of atherogenesis and atherosclerosis (termed the response-to-injury hypothesis) centers around interactions between endothelial cells and smooth muscle cells of the arterial wall, monocytes and platelets in the bloodstream, and plasma lipoproteins (Fig. 5-3).20–22 Endothelial cell injury from chronic hypercholesterolemia, homocystinemia, chemicals in cigarette smoke, viruses, localized hemodynamic forces, systemic hypertension, hyperglycemia, or the local effects of cytokines causes endothelial activation. Endothelial activation that causes maladaptive processes leading to disease (such as atherosclerosis or hypertension) is called endothelial dysfunction. Endothelial dysfunction is manifested by: (1) vasoconstriction due to decreased production of the vasodilator nitric oxide, (2) increased permeablilty to lipoproteins, (3) expression of tissue factor leading to thrombosis, and (4) expression of certain injury-induced adhesion molecules leading to adherence of platelets and inflammatory cells.23,24 Progression through an early, subendothelial lesion (often called a fatty streak) to a mature, complex atheromatous plaque results from (1) monocyte adherence to endothelial cells, migration into the subendothelial space, and transformation into tissue macrophages; (2) smooth muscle cell migration from the media into the intima, and proliferation and secretion of collagen and other extracellular matrix constituents; (3) lipid accumulation, both intracellularly (foam cells) in macrophages and smooth muscle cells as well as extracellularly; (4) lipoprotein oxidation in the vessel wall leading to generation of potent biological stimuli such as chemoattractants and cytotoxins; (5) persistent chronic inflammation, especially at the junction with the uninvolved arterial wall (the "shoulder"); and (6) cell death with release of intracellular lipids (mostly cholesterol esters), and subsequent calcification.
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The clinical manifestations of advanced atherosclerosis in the coronary arteries are generally due to their encroachment of the lumen leading to progressive stenosis, or to acute plaque disruption with thrombosis (see later discussion in section on ischemic heart disease) (Fig. 5-4). However, slowly developing occlusions over time may stimulate collateral vessels that protect against distal myocardial ischemia and infarction even with an eventual high-grade stenosis. Aneurysms may form secondary to atherosclerosis as a result of atrophy or necrosis of the media, but this process is more common in the aorta than in the coronary circulation.
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Cardiac ischemia occurs when there is inadequate perfusion to meet the metabolic needs of the tissue.31 It is most often caused by inadequate local coronary blood flow resulting from obstruction or narrowing secondary to atherosclerosis, thrombosis, embolism, or spasm. Decreased coronary perfusion also follows systemic hypotension, in shock, and during cardiopulmonary bypass leading to global hypoperfusion. Moreover, ischemia is potentiated when the oxygen supply is decreased secondary to anemia, hypoxia, or cardiac failure. Ischemia can also result from increased cardiac demand secondary to exercise, tachycardia, hyperthyroidism, or ventricular hypertrophy and/or dilation. The consequences of ischemia depend on its severity and duration, and on the preexisting adaptive and nutritional/metabolic state of the affected cells and tissues. Infarction, a loss of cardiac myocytes by necrosis, is caused by severe prolonged ischemia. However, chronic ischemia insufficient to cause infarction may lead to the development of collateral vessels, while brief periods of ischemia followed by reperfusion lead to changes in myocyte metabolism (ischemic preconditioning) that are protective against more severe ischemic events.32 Ischemic myocardium salvaged by reperfusion may remain viable but suffer transient (hours to days) contractile dysfunction; this condition is termed stunned myocardium or postischemic dysfunction. The progressive effects of ischemia and salvage by reperfusion are discussed below.
Intracellular changes following the onset of myocardial ischemia are sequential and complex (Table 5-1).33,34 Cardiac myocyte ischemia induces anaerobic glycolysis within seconds, leading to inadequate production of high-energy phosphates such as ATP and the accumulation of metabolites such as lactic acid leading to intracellular acidosis. Myocardial function is exquisitely sensitive to these biochemical consequences of severe ischemia; following the onset of ischemia, a contractility defect is evident within seconds with total loss of contraction within 2 minutes. Ischemic changes in an individual cell are initially sublethal and potentially reversible if the duration of ischemic injury is short and perfusion is restored prior to the onset of irreversible changes (15–20 min). Irreversible (lethal) injury of cardiac myocytes with cell membrane structural defects occurs only after 20 to 40 minutes within the most severely ischemic area. When ischemic injury is of sufficient severity and duration, groups of involved cells die, and myocardial infarction results.
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Within a few minutes of the onset of ischemia, reversible ultrastructural changes can be observed using transmission electron microscopy, including glycogen depletion, cellular and mitochondrial swelling, myofibrillar relaxation, and margination of nuclear chromatin. This is followed by the development of amorphous mitochondrial densities and sarcolemmal disruption as evidence of necrosis. However, neither reversible ischemia nor necrosis existing less than at least 6 or more hours before patient death can be detected grossly or microscopically. On gross examination at autopsy of a patient who died at least 2 to 3 hours following the onset of infarction, the presence of a necrotic region may often be indicated as a staining defect with triphenyl tetrazolium chloride (TTC), a dye that turns viable myocardium a brick-red color on reaction with intact myocardial dehydrogenases.37 However, these and other changes occurring less than about 6 hours prior to death are not visible on routine light microscopic evaluation. The earliest light microscopic features include clusters of necrotic myocytes that exhibit intense eosinophilia, nuclear pyknosis and loss, and stretched and wavy myocytes. Inflammatory exudation with polymorphonuclear leukocytes can usually be seen after 6 to 12 hours and peaks within 1 to 3 days. The inflammatory reaction continues with removal of necrotic tissue by macrophages (3–5 days) and is followed by a fibroblastic reparative response accompanied by neovascularization (granulation tissue) beginning after 1 to 2 weeks at the margins of preserved tissue. The infarcted tissue is replaced by scar that reaches maturity by about 6 weeks.
Healing of myocardial ischemic injury may be slowed by anti-inflammatory agents administered following myocardial infarction, as a component of immunosuppressive therapy following transplantation, or in otherwise debilitated or malnourished patients.38,39 Sublethal but chronic ischemic injury may be revealed by myocyte vacuolization, usually most prevalent in the subendocardium. Overall, the repair sequence following an infarct is similar to that which follows tissue injury of diverse causes and at various noncardiac anatomic sites.
Although cardiac myocytes are not traditionally thought capable of regeneration, mitotic activity has been reported at the viable borders of myocardial infarcts.40 In addition, myocytes bearing a Y chromosome have been found in the heart of female donors transplanted to male recipients, raising the possibility that endogenous primitive stem cells, either circulating or resident, may play a role in repair of myocardial infarcts.41
The progression of myocardial ischemic injury can be modified by restoration of blood flow (reperfusion) to jeopardized myocardium. Reperfusion occurring before the onset of irreversibility (about 20 minutes in the most severely ischemic regions) may substantially limit infarct size or prevent cell death altogether. Later reperfusion up to 6 to 12 hours does not prevent infarction entirely, but does salvage myocytes located at the leading edge of the "wavefront" that are only reversibly injured. The potential for recovery decreases with increasing severity and duration of ischemia (Fig. 5-5). Late reperfusion beyond the interval at which myocyte salvage continues to be possible may also lead to functional benefits by mechanisms that are yet poorly understood.42,43
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Reperfusion may actually damage some of the ischemic but viable myocytes (reperfusion injury), but the amount of salvaged myocardium usually outweighs the extent of this damage.46,47 Reperfusion injury is mediated primarily by toxic oxygen species (such as free radicals) that are overproduced by myocytes or polymorphonuclear leukocytes upon restoration of oxygen supply to the tissues, but complement activation may also contribute. Consequently, injury may be reduced by free radical scavengers such as superoxide dismutase and catalase, inhibitors of polymorphonuclear leukocyte endothelial cell adhesion, or drugs that regulate complement.48–50 Arrhythmias also may occur after reperfusion, possibly secondary to myocyte damage by oxygen free radicals and/or increased intracellular calcium.
Metabolic and functional recovery of successfully reperfused myocardium is not instantaneous, with contractile dysfunction persisting for hours to days following brief periods of ischemia; this dysfunction is termed myocardial stunning.51,52 Myocardial stunning may occur after angioplasty, thrombolysis, cardiopulmonary bypass, or even ischemia related to unstable angina or stress. The use of cardiac assist devices may allow the stunned myocardium to recover in these situations of reversible cardiac failure.53–55 The mechanism of myocardial stunning likely involves the generation of oxygen radicals, alterations of calcium metabolism, and changes in the sarcomere.
Viable regions of myocardium with chronically impaired function in the setting of chronically reduced coronary blood flow are termed hibernating myocardium.56,57 Myocardial hibernation is characterized by: (1) persistent wall motion abnormality; (2) low myocardial blood flow; and (3) evidence of viability of at least some of the affected areas. Contractile function of hibernating myocardium improves if blood flow returns toward normal or if oxygen demand is reduced. Correction of this abnormality is likely responsible for the reversal of long-standing defects in ventricular wall motion that may be observed following coronary bypass graft surgery or angioplasty. Efforts are underway to image hibernating myocardium and therefore identify those patients who would benefit from restoration of adequate coronary blood flow.58,59
Adaptation to short-term transient ischemia may induce tolerance against subsequent, more severe ischemic insults in a process termed ischemic preconditioning.60 A short (5-min) period of cardiac ischemia followed by reperfusion is capable of protecting the affected myocardium against injury from a more intense period of subsequent ischemia. The mechanism of this protection is uncertain, but stimulation of adenosine receptors when adenosine is released during ischemia, enhanced expression of heat-shock proteins (which makes the heart more resistant to prolonged ischemia), and involvement of protein kinase C and ATP-dependent potassium channels have been suggested.61,62 Pharmacologic stimulation of these pathways is under investigation to derive the benefits of preconditioning without actually subjecting the myocardium to ischemia.
Biomaterials and Tissue Engineering
Biomaterials are synthetic or modified biologic materials that are used in implanted or extracorporeal medical devices that augment or replace body structures and functions.63,64 Examples of such biomaterials include polymers, metals, ceramics, carbons, processed collagen, and chemically treated animal or human tissues, the latter exemplified by glutaraldehyde-preserved heart valves, pericardium, and blood vessels. The first generation of biomedical materials (e.g., metals used for early valve substitutes and orthopedic hardware) was generally designed to be inert; the goal was to reduce the host inflammatory responses to the implanted material. By the mid-1980s, a second generation of bioactive biomaterials was emerging that could interact with the host in a beneficial manner (e.g., hydroxyapatite ceramics, biodegradable polymer sutures). With a greater understanding of material-tissue interactions at the cellular and molecular levels, a third generation of materials is being designed to stimulate specific cellular and tissue responses at the molecular level.65
Comprising effects of both the implant on the host tissues and the host on the implant, biomaterial-tissue interactions are important in mediating prosthetic device complications (Fig. 5-7). 66 Major morphologic effects of biomaterials on tissues are illustrated in Figure 5-8. Complications of cardiovascular medical devices, irrespective of anatomic site of implantation, can be grouped into six major categories: (1) thrombosis and thromboembolism; (2) device-associated infection; (3) exuberant or defective healing; (4) degeneration, fracture, or other biomaterials failure; (5) adverse local tissue interaction, such as toxicity or traumatic hemolysis; and (6) adverse effects distant from the intended site of the device, such as biomaterials migration or systemic hypersensitivity.
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Thromboembolic complications of cardiovascular devices cause significant mortality and morbidity.68 Thrombotic deposits can impede the function of a prosthetic heart valve, vascular graft, or blood pump, or cause distal emboli. As in the cardiovascular system in general, surface thrombogenicity, hypercoagulability, and locally static blood flow (Virchow's triad), present individually or in combination, determine the relative propensity toward thrombus formation and location of thrombotic deposits with specific devices. Considerable evidence implicates a primary role for blood platelets in the thrombogenic response to artificial surfaces (see Fig. 5-8A).69 However, the clinical approach to control of thrombosis in cardiovascular devices uses systemic anticoagulants, particularly coumadin (warfarin). This agent inhibits thrombin formation but does not inhibit platelet-mediated thrombosis. The specific physical and chemical characteristics of materials that regulate the outcomes of blood-surface interaction are incompletely understood.
Coagulation proteins, complement products, other proteins, and platelets also are activated, damaged, and consumed by blood-material interactions. For example, blood contact with the large areas of synthetic surfaces during the extracorporeal perfusion of cardiopulmonary bypass (CPB) may have at least four consequences: (1) activation and resultant dysfunction of platelets; (2) progressive denaturation of plasma proteins and lipoproteins; (3) activation of coagulation proteins and the fibrinolytic system and, through interaction with inflammatory pathways, production of various bioactive molecules, including bradykinin, a potent vasodilator; and (4) activation of complement through the alternative pathway, with production of C3a and C5a, inducing polymorphonuclear leukocyte stasis in the pulmonary circulation with the occasional sequelae of acute pulmonary hypertension and inflammatory lung injury.
Hemolysis (damage to red blood cells) in implants and extracorporeal circulatory systems results from both blood-surface interactions and turbulence. Erythrocytes have reduced survival following cardiopulmonary bypass. Also, with earlier model heart valve prostheses, renal tubular hemosiderosis or cholelithiasis occurred in many patients, indicative of chronic hemolysis. With contemporary valves, hemolysis generally is modest and well compensated, but may be accentuated by valve dysfunction.
Synthetic biomaterials typically are not immunogenic, but they elicit a foreign body reaction, a special form of nonimmune inflammatory response with an infiltrate predominantly composed of macrophages.70,71 Although immunologic reactions have been proposed rarely for synthetic biomaterial-tissue interactions, they are theoretically possible with tissue-derived biomaterials, and antibodies can be elicited by implantation of some materials in finely pulverized form.72,73 Nevertheless, clinical cardiovascular device failure owing to immunologic reactivity is rare. For most biomaterials implanted into solid tissue, encapsulation by a relatively thin fibrous tissue capsule (composed of collagen and fibroblasts) resembling a scar ultimately occurs, often with a fine capillary network at its junction with normal tissue (see Fig. 5-8B). An ongoing inflammatory infiltrate consisting of monocytes/macrophages and multinucleated foreign body giant cells in the vicinity of a foreign body generally suggests persistent tissue irritation (see Fig. 5-8C).
The healing of fabric prostheses or components within the cardiovascular system can yield exuberant fibrous tissue at the anastomosis as an overactive but physiologic repair response (Fig. 5-9).74 Synthetic and biological vascular grafts often fail because of generalized or anastomotic narrowing mediated by connective tissue proliferation in the intima, and heart valve prostheses can have excessive pannus that occludes the orifice. Intimal hyperplasia results primarily from smooth muscle cell migration, proliferation, and extracellular matrix elaboration following and possibly mediated by acute or ongoing endothelial cell injury. Contributing factors include: (1) surface thrombogenesis; (2) delayed or incomplete endothelialization of the fabric; (3) disturbed flow across the anastomosis; and (4) mechanical factors at the junction of implant and host tissues.
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Humans have a limited ability to spontaneously endothelialize cardiovascular prostheses, and full endothelialization of clinical grafts (yielding an intact neointima) usually does not occur. Luminal coverage develops relatively slowly and incompletely. For uncertain reasons, endothelial cell coverage generally is restricted to a zone near an anastomosis, typically 10 to 15 mm, thereby allowing healing of intracardiac fabric patches and prosthetic valve sewing rings, but not long vascular grafts. Thus, except adjacent to an anastomosis, a compacted platelet-fibrin aggregate (pseudointima) comprises the inner lining of clinical fabric grafts, even after long-term implantation. Because firm adherence of such linings to the underlying graft may be impossible, dislodgment of the lining and formation of a flap-valve can occur and cause acute obstruction.76 Current research centers on the design of novel vascular graft materials that enhance endothelial cell attachment, grafts preseeded with unmodified or genetically engineered endothelial cells, and attempts to block smooth muscle cell proliferation.77–81
Infection occurs in as many as 5% to 10% of patients with implanted prosthetic devices and is a frequent source of morbidity and mortality.82 Because medical devices usually are coated with platelet-fibrin thrombus and are remote from capillary vessels, associated infections often are difficult to treat with antibiotics and are resistant to host defenses. Consequently, such infections generally persist until the devices are removed.
Early implant infections (less than 1–2 months postoperatively) most likely result from intraoperative contamination or early postoperative wound infection. In contrast, late infections generally occur by a hematogenous route, and can be initiated by bacteremia induced by therapeutic dental or genitourinary procedures. Antibiotics given prophylactically at device implantation and shortly before subsequent diagnostic and therapeutic procedures may protect against implant infection. Infections associated with foreign bodies are characterized microbiologically by a high prevalence of coagulase-negative staphylococci, including Staphylococcus epidermidis, an organism with low virulence, and an infrequent cause of non–prosthesis-associated deep infections, as well as other more virulent staphylococci, especially S. aureus, and less virulent strains of streptococci.83,84
The presence of a foreign body potentiates infection in several ways. Microorganisms may inadvertently be introduced by device contamination, provided access to deeper tissue by damage to natural barriers against infection during implantation or subsequent device function, and permitted to survive adjacent to the implant. Many strains of bacteria, particularly S. epidermidis, are adept at adhering to synthetic surfaces and creating a biofilm that protects against the host humoral and cellular immune defenses.85 Moreover, an implanted foreign body could limit phagocyte migration into infected tissue or interfere with inflammatory cell phagocytic mechanisms, by release of soluble implant components or surface-mediated interactions.
Despite the large numbers of implants used clinically over an extended duration, neoplasms occurring at the site of implanted cardiovascular and other medical devices are exceedingly rare.86,87
A logical future thrust of biomaterials science, tissue engineering combines the principles and methods of the life sciences with those of engineering to develop implantable medical devices that use living cells together with extracellular components (either natural or synthetic).88–91 Tissue engineering utilizes third-generation biomaterials, designed to stimulate specific cellular responses at the molecular level and thereby providing the scientific foundation for molecular design of scaffolds that can be seeded with cells in vitro for subsequent implantation or specifically attract functional cells in vivo.
In implantable medical devices that use cells together with extracellular components, the cells are either transplanted or induced in the recipient by implantation of an appropriate bioresorbable substrate. In the usual approach to engineering tissues, the first step involves the seeding of cells on a synthetic polymer or natural material (such as collagen or chemically treated tissue) scaffold, and a tissue is matured in vitro. A typical scaffold is a bioresorbable polymer in a porous configuration, adhesive for cells in the desired geometry for the engineered tissue. The cells are either differentiated cells, or undifferentiated "stem cells."92 When placed in a metabolically and mechanically supportive environment with growth media (in a bioreactor), the cells proliferate and elaborate extracellular matrix in the form of a "new" tissue (the construct). In the second step, the construct is implanted in the appropriate anatomic location. Remodeling of the construct in vivo following implantation is intended to recapitulate normal functional architecture of an organ or tissue. Progress has already been made toward tissue engineered heart valves,93,94 vascular grafts,95–97 and segments of myocardium.98
Another approach to myocardial tissue engineering is cell transplantation into the myocardium as a means of augmentation. Numerous investigators have injected autologous or allogenic fetal cardiomyocytes, myoblasts, or isolated skeletal muscle satellite, and bone marrow stromal cells or mesenchymal stem cells have been studied.99 Injection of bone-marrow–derived cells into myocardium following ischemic injury resulted in improved function and replacement of dead myocardial tissue by cells that expressed cardiac muscle-specific proteins.100
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ISCHEMIC HEART DISEASE |
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ROLE OF FIXED CORONARY OBSTRUCTIONS
In the absence of significant pathology, coronary arterial flow provides adequate myocardial perfusion at rest, and compensatory vasodilation provides flow reserve that is more than sufficient to accommodate the increased metabolic demands during vigorous exertion. When the luminal cross-sectional area is decreased by 75% or more, coronary blood flow generally becomes limited with exertion; with 90% or greater reduction, coronary flow may be inadequate even at rest. Over 90% of patients with ischemic heart disease have advanced stenosing coronary atherosclerosis (fixed obstructions), and most myocardial infarcts occur in patients with coronary atherosclerosis.101 Most have one or more lesions causing at least 75% reduction of the cross-sectional area in one or more of the major epicardial arteries. Thus, the clinical effects of stable advanced atherosclerotic plaques in the coronary arteries are due to their encroachment on the lumen, leading to stenosis.
However, the onset and prognosis of ischemic heart disease and other complications of atherosclerosis are not well predicted by the angiographically determined extent and severity of fixed anatomic disease.102–105 Dynamic vascular changes are largely responsible for the conversion of chronic stable angina or an asymptomatic state to acute ischemic heart disease. The most common such acute event leading to coronary occlusion is fracture of the fibrous cap leading to hemorrhage into the plaque, followed by platelet aggregation and thrombosis.
Nonatherosclerotic causes of coronary artery obstruction can also occur; the most common causes are infectious disease (e.g., tuberculosis), autoimmune diseases (e.g., SLE and rheumatoid arthritis), vasculitis (e.g., Buergers disease and Kawasaki disease), fibromuscular dysplasia, and dissection, spasm, embolism. Obstruction of the small intramural coronary arteries is seen in several disease states, including diabetes, deposition diseases such as Fabry disease and amyloidosis, progressive systemic sclerosis (scleroderma), and as a proliferative intimal lesion in the coronary arteries of cardiac allografts.
The acute coronary syndromes (unstable angina, acute myocardial infarction, and sudden ischemic death) usually are precipitated by atherosclerotic plaque disruption with hemorrhage, fissuring, and/or ulceration. Fissures and ruptures most frequently occur at the lateral portions of the fibrous cap, with stresses highest at its junction with the adjacent plaque-free segment of the arterial wall.106 Vasospasm, tachycardia, hypercholesterolemia, and intraplaque hemorrhage are likely contributors, as are stresses induced by blood flow and/or coronary intramural pressure or tone in plaque.
Plaque alterations precipitating the acute coronary syndrome span a broad morphologic range from minimal surface erosions to lacerations that extend deep within the plaque. In some cases, coronary artery thrombosis results from a superficial erosion of the intima without a frank rupture through the plaque fibrous cap. Endothelial cells may undergo apoptosis in response to inflammatory mediators, and this loss of endothelial cells can uncover the thrombogenic subendothelial matrix.107 Even in the absence of actual sloughing of endothelial cells, an altered balance between prothrombotic and fibrinolytic properties of the endothelium may provoke thrombosis in situ. Regardless of the extent of injury, the result is flow disruption and exposure of the luminal blood to a thrombogenic surface (collagen, lipid, or necrotic debris), thereby setting the stage for mural or total thrombosis (see Fig. 5-4B).
Pathologic and clinical studies show that plaques that undergo abrupt disruption leading to coronary occlusion often are those that previously produced only mild to moderate luminal stenosis.102–105 Overall, approximately two thirds of plaques that rupture with subsequent occlusive thrombosis cause occlusion of only 50% or less before plaque rupture, and in 85% of patients, stenosis is initially less than 70%. It is presently impossible to reliably predict plaque disruption or subsequent thrombosis in an individual patient.
Coronary artery imaging is an area of current interest and importance.108,109 Although x-ray coronary angiography remains the gold standard, a noninvasive test that would reduce the procedural risk of this invasive modality is highly desirable. Calcification of the coronary arteries can be detected noninvasively by electron beam computed tomography. Radiographically visible calcium in the epicardial coronary arteries predicts the extent of atherosclerotic disease, but cannot identify features of plaque instability. However, since plaque burden correlates with cardiovascular risk, coronary calcium tends to be a good prognostic indicator of future myocardial ischemic events.110 In contrast, three-dimensional coronary magnetic resonance angiography may permit reliable detection of coronary artery disease, whether or not calcification is present, as this technique has the potential to visualize both the coronary lumen and the atherosclerotic plaques in the arterial wall.111 Intravascular ultrasound (IVUS) is an invasive technique that can provide precise information about the degree of stenosis, and the location and nature of atherosclerotic plaque.
The events that trigger abrupt changes in plaque configuration and superimposed thrombosis are complex and poorly understood. Influences both intrinsic (e.g., plaque structure and composition) and extrinsic to the plaque (e.g., blood pressure, platelet reactivity) are likely important. Surface erosions, fissures, and ruptures are more likely to occur in soft and eccentric plaques than in hard and concentric lesions. Similarly, plaques contain large areas of foam cells and extracellular lipid, and those in which the fibrous caps are thin or contain clusters of inflammatory cells are more susceptible to rupture.112–114 Plaques that are prone to rupture are termed vulnerable plaques. There is evidence that lipid lowering by diet or drugs such as statins can reduce the onset of coronary thrombotic complications by stabilizing plaque through reducing accumulation of macrophages expressing matrix-degrading enzymes and tissue factor, and reducing activation of smooth muscle cells and endothelial cells.115 The pronounced circadian periodicity for the time of onset of acute myocardial infarction and other acute coronary syndromes, with a peak incidence between 9:00 A.M. and 11:00 A.M., suggests that the physiologic morning surge in blood pressure and heightened platelet reactivity may contribute to plaque disruption.
The fibrous cap is a highly dynamic tissue that can undergo continuous remodeling. The inflammatory process largely controls the balance of collagen synthetic and degradative activity, which determines stability and prognosis. Lesions prone to rupture have a thin collagen layer and few smooth muscle cells. These cells are responsible for the repair and maintenance of the all-important collagenous matrix and are a rich source of extracellular matrix macromolecules in the artery wall.114 Smooth muscle cells and macrophages can undergo apoptosis within the plaque induced by proinflammatory cytokines and fas ligand, factors overexpressed in atherosclerotic plaques. Cytokines induce production of matrix metalloproteinases by macrophages; these enzymes degrade the collagen that lends strength to the fibrous cap. Inflammation may also contribute to coronary thrombosis by altering the balance between prothrombotic and fibrinolytic properties of the endothelium. For example, endothelial cells exposed to proinflammatory cytokines express tissue factor procoagulant, and plaque rupture may expose necrotic and apoptotic cells and cell debris to the circulating blood. It is thus not surprising that several serum markers of inflammation such as C-reactive protein and pregnancy-associated plasma protein A (PAPP-A) have been linked to atherosclerosis and the acute coronary syndromes.116–118 C-reactive protein has multiple direct atherothrombotic effects and increases risk of acute coronary events, while PAPP-A, a metalloproteinase and prothrombotic inflammatory marker, is expressed in ruptured and eroded but not stable plaque.
Potential outcomes for unstable lesions include thrombotic occlusion, nonocclusive thrombosis, healing at the site of plaque erosion, athero- or thromboembolization, organization of mural thrombus (plaque progression), and organization of the occlusive mass with recanalization. Among these outcomes, the most common fate is plaque progression, owing either to resealing of the plaque fissure or to organization of a nonocclusive mural thrombus. Indeed, asymptomatic plaque rupture and its subsequent healing is likely an important mechanism of stenosis progression.
Pathology of Coronary and Myocardial Interventions
Revascularization by thrombolysis in early acute myocardial infarction limits infarct size and improves function cardiac and survival.119–122 The pathophysiologic basis of thrombolytic therapy is as follows: (1) Untreated thrombotic occlusion of a coronary artery causes transmural infarction; (2) the extent of necrosis during an evolving myocardial infarction progresses as a wavefront and becomes complete only 6 hours or more following coronary occlusion (see Fig. 5-5); (3) both early- and long-term mortality following acute myocardial infarction correlate strongly with the amount of residual functioning myocardium; and (4) early reperfusion rescues some jeopardized myocardium. The benefits of thrombolytic therapy depend on and are assessed by the amount of myocardium salvaged, recovery of left ventricular function, and resultant reduction in mortality. These important clinical end points are largely determined by the time interval between onset of symptoms and a successful intervention, adequacy of early coronary reflow, and the degree of residual stenosis of the infarct vessel. Recanalization rates vary from 60% to 90%, where the best efficacy relates to the earliest time of infusion of thrombolytic agents such as streptokinase, urokinase, or tissue-derived plasminogen activator. The maximal time for substantial myocardial salvage is approximately 4 hours for intracoronary and 3 hours for intravenous administration, but some studies suggest that some benefit can occur following later reperfusion, usually within 12 hours of symptoms. Spontaneous recanalization, presumably owing to inherent thrombolysis, can be beneficial to left ventricular function within 24 hours of infarct initiation. However, spontaneous thrombolysis with reperfusion probably occurs in fewer than 10% of patients within the critical 3 to 4 hours after symptom onset.
Successful thrombolytic therapy often reestablishes antegrade flow in the infarct-related coronary artery but does not reverse factors responsible for initiating the original thrombosis, such as advanced atherosclerotic plaque, intimal rupture, enhanced platelet adhesiveness, or coronary spasm. High-grade residual stenosis and the persistence of the nidus of the original thrombosis are likely to be associated with recurrent ischemic events as evidenced by postinfarction angina or recurrent infarction. Thus, balloon angioplasty and stent placement or surgical revascularization during infarct evolution constitutes a more effective management of the underlying disease process than thrombolysis alone.123
The most common complications of thrombolytic reperfusion are failure to achieve clot lysis, reperfusion arrhythmias, coronary rethrombosis, and myocardial and systemic hemorrhage. Failure of thrombolytic therapy occurs in 20% to 30% of patients and is related to the presence of critical and disrupted plaques with complex geometry, plaque rupture with luminal obstruction by thromboatheromatous debris, and old organizing thrombus. Acute reocclusion occurs in 15% to 35% of patients and appears to be related to incomplete thrombolysis and the unstable nature of the underlying atherosclerotic plaque. Other complications include coronary embolism and hemopericardium. The most frequent and potentially the most serious complication of thrombolytic therapy is bleeding, with hemorrhage at sites of vascular punctures the most common (> 70%) and intracranial hemorrhage (approximately 1%) the most dreaded.
ANGIOPLASTY, ATHERECTOMY, AND STENTS
Percutaneous transluminal coronary angioplasty (PTCA) is used in patients with stable angina, unstable angina, or acute myocardial infarction.124 Angioplasty has also been applied to obstructions in saphenous vein grafts, internal mammary artery grafts, and coronary arteries in transplanted hearts. PTCA is successful in 85% to 95% of cases (including vein grafts and internal mammary arteries) and is associated with a mortality rate of 1%.
In PTCA, the progressive and substantial expansile force induced by the inflated balloon causes the plaque to split at its weakest point, a site not necessarily most severely involved with atherosclerosis.125 Structural/stress analysis based on intravascular ultrasound imaging can predict the location of plaque fracture that accompanies angioplasty. The split extends at least to the intimal-medial border and often into the media, with consequent circumferential and longitudinal dissection of the media (Fig. 5-11). Acute dissection may contribute to the propensity for acute closure that occurs in up to 5% of patients. For example, a dissection that involves a considerable portion of the circumference can generate a flap that may impinge on the lumen. Alternatively, a dissection that involves a substantial proximal-to-distal segment of the vessel, which traverses a large plaque-free wall segment, can induce compression of the vessel at a point of minimal disease.
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Thus, the key vascular consequences of angioplasty are plaque fracture, medial dissection, and stretching of the media beyond the dissection. These are accompanied by local flow abnormalities and generation of new, thrombogenic blood-contacting surfaces (similar to what is observed with spontaneously disrupted plaque) and can lead to platelet deposition and occlusive thrombosis. The immediate postangioplasty healing process is not well understood, but dissolution of soft atheromatous material, retraction of the split plaque, thrombus formation, and intimal healing with reendothelialization likely occur.
The long-term success of angioplasty is limited by the development of progressive, proliferative restenosis, which occurs in 30% to 40% of patients, most frequently within the first 4 to 6 months (Fig. 5-12). Although vessel wall recoil and organization of thrombus likely contribute, the major process leading to restenosis is excessive medial smooth muscle proliferation as an exaggerated response to angioplasty-induced injury, similar in some respects to the processes of atherosclerosis and vascular graft healing. Medial smooth muscle cells migrate to the intima where, along with existing plaque smooth muscle cells, they proliferate and secrete abundant extracellular matrix. Early lesions have a loose myxoid matrix in which numerous stellate smooth muscle cells are haphazardly arranged. Over weeks to months, the extracellular matrix becomes more densely collagenous, and the neointima becomes less cellular, with scattered spindle-shaped cells in a more laminar arrangement. Moreover, following prominent thrombus formation or in a hyperlipidemic patient, the site of healing may contain foam cells and cholesterol crystals, resembling a mature fibrofatty atheroma. Interest in locally delivered pharmacologic and molecular therapies to mitigate restenosis has been longstanding; regrettably, success has been limited.126–130
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Metallic balloon-expandable and self-expanding coronary stents have had an immense impact on the outcome of catheter-based therapies. As expandable tubes of metallic mesh that are inserted percutaneously at the time of PTCA to preserve luminal patency in both native coronary arteries and vein grafts, such devices provide a larger and more regular lumen by acting as a scaffold to support the intimal dissections that occur in PTCA. They mechanically prevent vascular spasm and increase blood flow, all of which minimize thrombus formation and reduce the impact of postangioplasty restenosis.133–135 Stenting has recently been shown to be superior to angioplasty alone in patients with acute myocardial infarction.136 The complications and limitations of stenting include initial failure, early thrombosis, and late restenosis. Subacute stent thrombosis occurs in 1% to 3% of patients, usually within 7 to 10 days of the procedure; antiplatelet treatment minimizes this risk.
Stent implantation is accompanied by damage to the endothelial
lining and stretching of the vessel wall, stimulating early
adherence and accumulation of platelets and leukocytes. Covered
initially by a variable platelet-fibrin coating, stent wires
may eventually become completely covered by an endothelium-lined
neointima, with the wires embedded in a layer of intimal thickening
consisting of 
-actin
positive smooth muscle cells in a collagenous matrix.137–139
Nevertheless, the neointima may thicken, and proliferative restenosis
can occur even in the presence of a stent (Fig.
5-13).140
In-stent restenosis correlates with disruption of the internal
elastic lumina, protrusion of struts into lipid-laden portions of the
plaque, and intimal neovascularization. Although the clinical
paradigm has suggested that a larger lumen after angioplasty
diminishes angiographic and clinical restenosis, intimal growth is
greater when struts penetrate more deeply into the lipid core of the
plaque.141
Attempts to reduce in-stent restenosis include intracoronary
radiotherapy, the delivery of recombinant vascular endothelial growth
factor with a balloon catheter to speed endothelialization of a
stent, gene therapy, and local drug delivery.142–146
Antiproliferative agents such as sirolimus and paclitaxel released in
a controlled fashion from coated stents have shown impressive promise
in reducing the neointimal proliferation that causes stent
restenosis.146,147
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Coronary artery bypass graft (CABG) surgery improves survival in patients with significant left main coronary artery disease, with three-vessel disease, or with reduced ventricular function.148–151 CABG surgery prolongs and improves the quality of life in patients with left main equivalent disease (proximal left anterior descending and proximal left circumflex), but does not protect them from the risk of subsequent myocardial infarction. The main mechanism for these benefits is the reperfusion of hibernating (viable, but poorly functioning owing to low flow) myocardium leading to increased left ventricular function. Over 90% of appropriately selected patients report a reduction in angina pectoris after CABG surgery.
The hospital mortality rate for CABG surgery is approximately 1% in low-risk patients, with less than 3% of patients suffering perioperative myocardial infarction. The most consistent predictors of mortality after CABG are urgency of operation, age, prior cardiac surgery, female sex, low left ventricular ejection fraction, degree of left main stenosis, and number of vessels with significant stenoses. The benefit of CABG is greatest in the highest, risk patients with the most severe disease; it is not surprising, therefore, that a recent increase in morbidity and mortality has accompanied an increase in CABG performed in an older and sicker population. In low- and moderate-risk patients, however, medical therapy and PTCA have results similar to CABG.
The most common mode of death after CABG is acute cardiac failure. The underlying cause of this acute failure leading to low output or arrhythmias is unclear in many cases. Many such patients have no detectable myocardial necrosis either clinically or at autopsy, and in others, the extent of necrosis noted at autopsy seems insufficient to account for the profound ventricular dysfunction encountered clinically. Possible explanations include: (1) evolving myocardial necrosis either undetectable clinically or too recent to detect at autopsy; (2) postischemic dysfunction of viable myocardium, for which no morphologic markers of the dysfunctional state are known; or (3) a metabolic cause, such as hypokalemia, for which there is no morphologic counterpart. Therefore, although established myocardial necrosis causes cardiac dysfunction in some patients with postoperative failure, it may not be the predominant lesion or the cause of death. When such necrosis is detected at autopsy, it may indicate that a potentially larger volume of adjacent morphologically normal myocardium was dysfunctional.
Perioperative infarction usually is caused by either hypotensive episodes during anesthesia induction or inadequate intraoperative regional preservation due to severe obstruction of the feeding artery and poor collaterals. Such necrosis usually predominates in the subendocardium and often has the morphology of necrosis with contraction bands. As in cardiac surgery in general, perioperative myocardial infarction is more likely to occur in patients with cardiomegaly than in those with normal-sized hearts.
Early thrombotic occlusion of the graft vessel may occur, with inadequate distal run-off from extremely small distal native coronaries (often further compromised by atherosclerosis) comprising the major mechanism. Additional factors include acute graft dissection at the anastomotic site, atherosclerosis or arterial branching at the anastomotic site, distortion of a graft that is too short or too long for the intended bypass, as well as patient factors including continued hyperlipidemia or smoking. In some cases, thrombosis occurring early postoperatively involves only the distal portion of the graft, suggesting that early graft thrombosis is frequently initiated at the distal anastomosis. Antiplatelet therapy has resulted in improved patency rates, and graft thromboses account for only a minority of early cardiac deaths; most patients who die early have patent grafts.
The patency of saphenous vein grafts is reported as 60% at 10 years, due to several pathologic mechanisms such as early thrombosis, progressive intimal thickening, and obstructive atherosclerosis.152,153 Between 1 month and 1 year, graft stenosis is usually caused by intimal hyperplasia with excessive smooth muscle proliferation and extracellular matrix production similar to that seen following angioplasty. Atherosclerosis becomes more the dominant mechanism in graft occlusion 1 to 3 years after CABG. As in the coronary arteries, atherosclerosis in bypass grafts can cause myocardial ischemia through progressive luminal stenosis or plaque rupture with secondary thrombotic obstruction. The potential for disruption and embolization of atherosclerotic lesions in vein grafts exceeds that for native coronary atherosclerotic lesions. Plaques in grafts generally involve dilated segments, often have poorly developed fibrous caps with large necrotic cores, and develop secondary dystrophic calcific deposits that may extend to the lumen (Fig. 5-14). Thus, atheroembolization is a major risk, often with catastrophic results; balloon angioplasty or intraoperative manipulation of grafts may stimulate atheroembolism.154
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Transmyocardial laser revascularization (TMR) is used in selected patients with coronary artery disease that is refractory to conventional revascularization techniques and to maximal medical therapy.157,158 Performed on a beating heart through a left thoracotomy, the operation employs a high-energy laser to bore transmural channels into the left ventricle. The hypothesis is that blood will flow directly from the left ventricular chamber into the channels and then into the intramyocardial vascular plexus, thereby restoring perfusion to potentially viable myocardium in a manner reminiscent of normal reptilian hearts. Although some clinical trials report a decrease in anginal symptoms after TMR, the morphologic basis for success is yet uncertain.159–161
Intramyocardial channels generated by TMR initially have a central region of destroyed myocardium surrounded by a thin rim of necrotic tissue (Fig. 5-16). Over the first 24 hours, the channels fill with blood and fibrin and are surrounded by myocardium with contraction band necrosis (see Fig. 5-16A). After 2 to 3 weeks, the channels are filled with vascularized granulation tissue in keeping with the general time course of wound healing (see Fig. 5-16B). Clinical studies and examinations of hearts from patients who have died at various postmortem intervals fail to reveal patent channels.162,163 The leading hypothesis for the reported efficacy of TMR is the stimulation of neovascularization in the vicinity of the channels164,165; denervation of these areas may also play a role in the reduction of symptomatic angina. Ongoing studies are directed at elucidating the mechanisms of action of TMR and clinical indications for its use.
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Coronary atherosclerosis with acute plaque rupture and superimposed thrombosis typically results in a transmural infarct, where ischemic necrosis involves at least half and usually the full or nearly full thickness of the ventricular wall in the distribution of the involved coronary artery. In contrast, a subendocardial (nontransmural) infarct constitutes an area of ischemic necrosis limited to the inner third or at most half of the ventricular wall. This process can be multifocal, often extending laterally beyond the perfusion territory of a single coronary artery. Subendocardial infarcts are commonly associated with diffuse stenosing coronary atherosclerosis without acute plaque rupture or superimposed thrombosis in the setting of episodic hypotension, global ischemia, or hypoxemia. A subendocardial infarct can also result from a coronary thrombus that is nonocclusive or becomes lysed before the progressive myocardial necrosis becomes transmural. In both transmural and subendocardial infarcts, a 1- to 2-mm rim of subendocardium may survive due to diffusion of oxygen and nutrients from the blood in the ventricular cavity.
The electrocardiographic findings of a transmural infarct usually involve ST segment elevations and the development of abnormal Q waves, while subendocardial infarcts have ST segment and T-wave changes without abnormal Q waves. Q-wave infarcts are generally larger both by enzyme elevations and pathologic determination and carry a less favorable short-term prognosis than non–Q-wave infarcts.
The short-term mortality rate from acute myocardial infarction has declined from 30% in the 1960s to 10% to 13% today. The rate is even lower, about 7%, for patients who receive aggressive reperfusion and pharmacologic therapy. However, half of all deaths from myocardial infarction occur within the first hour after the onset of symptoms, often before the individuals reach the hospital. Poor prognostic factors include advanced age, female gender, diabetes mellitus, and a previous myocardial infarction. The most important factors in long-term prognosis are left ventricular function and the extent of obstructive lesions in vessels perfusing viable myocardium. The overall mortality rate following myocardial infarction is 30% in the first year, with survivors having an additional 3% to 4% mortality per year thereafter.
Important and frequent complications of myocardial infarction include ventricular dysfunction, cardiogenic shock, arrhythmias, myocardial rupture, infarct extension and expansion, papillary muscle dysfunction, right ventricular involvement, ventricular aneurysm, pericarditis, and systemic arterial embolism.166 About one half of patients with myocardial infarction will experience one or more of these complications, with the specific complication and prognosis dependent on infarct size, location, and transmurality. Patients with anterior infarcts are at greatest risk for regional dilation and mural thrombi and have a substantially worse clinical course than those with inferior-posterior infarcts. In contrast, inferior-posterior infarcts are more likely to have serious conduction blocks and right ventricular involvement. Mechanical complications are more frequent and significant in patients with transmural lesions.
Many patients have cardiac rhythm abnormalities following myocardial infarction, even though histologic evidence of direct conduction system involvement is present only in a minority. These abnormalities require aggressive treatment when they impair hemodynamics as can occur with either brady- or tachyarrhythmias, compromise myocardial viability by increasing oxygen requirements, or predispose to malignant ventricular tachycardia or fibrillation. The proposed mechanisms for generation of arrhythmias include the presence of electrically unstable ischemic myocardium at the edge of an infarct causing a micro-reentry phenomenon, and the release of arrhythmogenic metabolites such as lactic acid and potassium from necrotic tissue.167,168 Autopsy studies of sudden death victims and clinical studies of resuscitated survivors show that only a minority develop a full-blown acute myocardial infarction. Thus, ischemia caused by severe chronic coronary arterial stenosis can lead directly to lethal arrhythmias. Heart block following myocardial infarction usually is transient, but persistent heart block in the proximal atrioventricular conduction system may necessitate pacemaker implantation. Tachyarrhythmias usually originate in areas of severely ischemic or necrotic myocardium. Arrhythmias that develop long after infarction likely originate at the junction between scar tissue and viable myocardium.
Myocardial infarcts produce functional abnormalities approximately proportional to their size. Large infarcts have a higher probability of cardiogenic shock, arrhythmias, and late congestive heart failure. Nonfunctional scar tissue resulting from previous infarctions and areas of stunned or hibernating myocardium may also contribute to overall ventricular dysfunction. Cardiogenic shock occurs in 10% to 15% of patients following myocardial infarction and is generally indicative of a large infarct (often >40% of the left ventricle). The high mortality of myocardial dysfunction and cardiogenic shock has been alleviated somewhat in recent years by the use of intra-aortic balloon pumps and ventricular assist devices to bridge patients through phases of prolonged but reversible functional abnormalities after myocardial infarction.
Frequently catastrophic, cardiac rupture syndromes include three entities: (1) rupture of the ventricular free wall (most common), usually with hemopericardium and cardiac tamponade; (2) rupture of the ventricular septum (less common), leading to an acquired ventricular septal defect with a left-to-right shunt; and (3) papillary muscle rupture (least common), resulting in the acute onset of severe mitral regurgitation. Cardiac rupture is the cause of death in 8% to 10% of patients with fatal acute transmural myocardial infarcts. Ruptures tend to occur relatively early following infarction (mean interval of 4–5 days, range of 1–10 days) with as many as 25% presenting within 24 hours of myocardial infarction. Even though they can be associated with large or small infarcts, free-wall and septal ruptures almost always involve transmural infarcts.169 Although the lateral wall is the least common site for left ventricular infarction, it is the most common site for postinfarction free-wall rupture. Acute free-wall ruptures usually are rapidly fatal; repair is rarely possible.170,171
A fortuitously located pericardial adhesion that arrests the rapidly moving blood front and aborts a rupture may result in the formation of a false aneurysm, defined as a contained rupture with a hematoma communicating with the ventricular cavity.172 False aneurysms contain no myocardial elements in their walls, consisting only of epicardium and adherent parietal pericardium and thrombus; half eventually rupture.
Acute ventricular septal defects secondary to postinfarction septal rupture complicate 1% to 2% of infarcts. Infarct-related septal defects are of two types: (1) single or multiple sharply localized, jagged, linear passageways that connect the ventricular chambers (simple type), usually involving the anteroapical aspect of the septum; and (2) defects that tunnel serpiginously through the septum to a somewhat distant opening on the right side (complex type), usually involving the basal inferoseptal wall.173 In simple lesions, neither gross hemorrhage nor peripheral laceration is present. In complex lesions, the tract may extend into regions remote from the site of the infarct. Without surgery, the prognosis following infarct-related septal rupture is poor; 50% of patients die within the first week (half of these within 24 hours), and only 15% to 20% percent survive beyond 2 months.
Mitral regurgitation secondary to either subendocardial or transmural myocardial infarction reflects loss of the structural or functional integrity of the mitral valve apparatus, usually at the level of the papillary muscle. Mitral regurgitation in this setting has an acute onset, and its severity varies depending on the location and extent of papillary muscle disruption. If only part of a papillary muscle group is involved, the degree of regurgitation will be less severe than if the entire muscle group ruptures. Since chordae tendineae arise from the heads of the papillary muscles and provide continuity with each of the valve leaflets, interference with the structure or function of either papillary muscle can result in dysfunction of both mitral valve leaflets.
Papillary muscles are perfused with blood vessels that have traversed the entire transmural extent of the myocardium, and thus are particularly vulnerable to ischemic injury. Since the collateral circulation of the posterior myocardium is not as extensive as it is in the anterolateral segments, the posterior medial papillary muscle is more susceptible to widespread necrosis and is more commonly (85%) the site of rupture.174,175 Papillary muscle rupture can occur later than other rupture syndromes (as late as 1 month after MI), since local healing can be delayed because of the limited vasculature and resultant inaccessibility of inflammatory cells.
Other mechanisms can produce mitral regurgitation in the setting of chronic ischemic heart disease. These mechanisms include an ischemic papillary muscle that fails to tighten the chordae during systole, and a fibrotic, shortened papillary muscle that fixes the chordae deeply within the ventricle. Ventricular dilation secondary to left ventricular failure can cause stretching of the mitral annulus and malalignment of the papillary muscle axes, leading to functional mitral regurgitation.176
Isolated right ventricular infarction is rare. However, involvement of the right ventricle by extension of an inferoseptal infarct occurs in approximately 10% of transmural infarcts and can have important functional consequences, including right ventricular failure with or without tricuspid regurgitation and arrhythmias.177,178
Infarct extension is characterized by new or recurrent necrosis in the same distribution as a completed recent infarct, associated with an increase in the amount of necrotic myocardium.179,180 Extension most often occurs between 2 to 10 days after the original infarction, forms along the lateral and subepicardial borders, and histologically appears younger than the necrotic myocardium of the original infarct.
In contrast, infarct expansion is a disproportionate thinning and dilation of the infarcted region occurring through a combination of (1) slippage between muscle bundles, reducing the number of myocytes across the infarct wall; (2) disruption of the normal myocardial cells; and (3) tissue loss within the necrotic zone.181 This regional dilation contributes to a significant increase in ventricular volume, increasing the wall stress and workload of noninfarcted myocardium and predisposing to late aneurysm formation. In addition, extension predisposes to intracardiac mural thrombus formation via myocardial contractility abnormalities causing stasis and endocardial damage causing thrombogenicity. Patients with infarct expansion, which can be detected by echocardiography in 30% of transmural infarcts, have increased morbidity and mortality.
Following myocardial infarction, structural changes occur both in the necrotic zone and uninvolved areas of the heart.182–185 The composite process, called ventricular remodeling, occurs by a combination of left ventricular dilation, wall thinning by infarct expansion, compensatory hypertrophy of noninfarcted myocardium, and potentially late aneurysm formation.186,187 Ventricular remodeling begins at the time of acute infarction and probably continues for months to years, until either a stable hemodynamic state is achieved or progressively severe cardiac decompensation occurs. Compensatory hypertrophy of noninfarcted myocardium is initially hemodynamically beneficial, but late decreases in ventricular performance with depression of regional and global contractile function may reflect degenerative changes. This congestive heart failure secondary to coronary artery disease occurs when the overall function of nonscarred myocardium can no longer maintain an adequate cardiac output. Moreover, the vulnerability of regions of hyperfunctioning residual myocardium to additional ischemic episodes may be increased.188
A ventricular aneurysm most commonly results from a large transmural infarct that undergoes expansion and heals as scar tissue that paradoxically bulges during ventricular systole.189 In contrast to false aneurysms, and even though their walls are frequently as thin as 1 mm, true ventricular aneurysms rarely rupture because of their tough fibrous or fibrocalcific nature.190 Markedly hypertrophied myocardial remnants as well as mummified myocardium (necrotic but inadequately healed) often are present in aneurysm walls, indicating incomplete healing of an infarct. Although 50% of patients with chronic fibrous aneurysms have mural thrombus contained within the ventricle, systemic embolization occurs in only approximately 5% of cases. Some pharmacologic approaches to limiting infarct size, such as steroids and other anti-inflammatory agents, could exacerbate infarct expansion and aneurysm formation.
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VALVULAR HEART DISEASE |
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Structure-Function Correlations in Normal Valves
The anatomy of the mitral and aortic valves is illustrated in Figure 5-17.
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Of the two leaflets of the mitral valve (see Fig. 5-17A), the anterior (also called septal, or aortic) leaflet is roughly triangular and deep, with the base inserting on approximately one third of the annulus. The posterior (also called mural, or ventricular) leaflet, although more shallow, is attached to about two thirds of the annulus and typically has a scalloped appearance. The mitral leaflets have a combined area approximately twice that of the annulus; they meet during systole with apposition to approximately 50% of the depth of the posterior leaflet and 30% that of the anterior leaflet. Each leaflet receives chordae tendineae from both the anterior and posterior papillary muscles.
The mitral valve orifice is D-shaped, with the flat anteromedial portion comprising the attachment of the anterior mitral leaflet in the subaortic region. This part of the annulus is fibrous and noncontractile; the posterolateral portion of the annulus is muscular and contracts during systole to asymmetrically reduce the area of the orifice. The edges of the mitral leaflets are held in or below the plane of the orifice by the chordae tendineae, which are pulled from below by the contracting papillary muscles during systole. This serves to draw the leaflets to closure and maintain competence. The orifice of the tricuspid valve is larger and less distinct than that of the mitral; its three leaflets (anterior, posterior, and septal) are larger and thinner than those of the mitral valve.
The three aortic valve cusps (left, right, and noncoronary) attach to the aortic wall in a semilunar fashion, ascending to the commissures and descending to the base of each cusp (see Fig. 5-17B). Commissures are spaced approximately 120 degrees apart and occupy the three points of the annular crown, representing the site of separation between adjacent cusps. Behind the valve cusps are dilated pockets of aortic root, called the sinuses of Valsalva, from which the right and left coronary arteries arise from individual orifices behind the right and left cusps, respectively. At the midpoint of the free edge of each cusp is a fibrous nodule called the nodule of Arantius. A thin, crescent-shaped portion of the cusp on either side of the nodule, termed the lunula, defines the surface of apposition of the cusps when the valve is closed (approximately 40% of the cuspal area). Fenestrations (holes) near the free edges commonly occur as a developmental or degenerative abnormality. They generally are small (less than 2 mm in diameter) and have no functional significance, since the lunular tissue does not contribute to separating aortic from ventricular blood during diastole. In contrast, cuspal defects below the lunula are not only associated with functional incompetence, but also suggest previous or active infection. The pulmonary valve cusps and surrounding tissues have architectural similarity to but are more delicate than those of the corresponding aortic components, and lack coronary arterial origins.
All cardiac valves essentially have the same microscopically inhomogeneous architecture, consisting of four well-defined tissue layers. Using the aortic valve as an example (see Fig. 5-17C), the thin ventricular layer (ventricularis) faces the left ventricular chamber, and is comprised predominantly of collagenous fibers with radially aligned elastic fibers covered by an endothelial lining. The rich elastin of the ventricularis enables the cusps to have minimal surface area when the valve is open but stretch during diastolic back pressure to form a large coaptation area. The spongiosa is centrally located and is composed of loosely arranged collagen and abundant proteoglycan. This layer has negligible structural strength, but accommodates the shape changes of the cusp during the cardiac cycle, lubricates relative movement between layers, and absorbs shock during closure. The fibrosa is a thick fibrous layer that provides structural integrity and mechanical stability and is composed predominantly of circumferentially aligned, densely packed collagen fibers, largely arranged parallel to the cuspal free edge. Finally, the aortalis is a thin layer that consists of a few collagen fibers lined by endothelial cells along the aortic surface of the cusps. Normal human aortic and pulmonary valve cusps have few blood vessels; they are sufficiently thin to be perfused from the surrounding blood. In contrast, the mitral and tricuspid leaflets contain a few capillaries in their most basal thirds.
During valve closure, cusps and leaflets do not touch along only their free edges like closing double doors. Rather, adjacent cusps coapt with a substantial area of surface-to-surface contact. This involves, for example, approximately a third of the atrioventricular valve leaflets. Thus, normal cusp and leaflet areas are substantially greater than are needed to simply close the valve orifice.
The orientation of architectural elements is nonrandom in the plane of the cusp, yielding unequal mechanical properties of the valve cusps in different directions (anisotropic behavior). Consequently, although the pressure differential across the closed aortic valve during the diastolic phase induces a large load on the cusps, the geometry of the whole valve and the fibrous network within the cusps effectively transfers the resultant stresses to the annulus and aortic wall. With specializations that include crimp of collagen fibers along their length, and bundles of collagen in the fibrous layer oriented toward commissures that produce grossly visible corrugations, cusps are extremely soft and pliable when unloaded, but taut and stiff during the closed phase. This minimizes sagging of the cusp centers, preserves maximum coaptation, and prevents regurgitation. For the mitral valve, the subvalvular apparatus including tendinous cords and papillary muscles is critical to maintain valve competency.
Etiology and Pathologic Anatomy of Valvular Heart Disease
Cardiac valve operations usually are undertaken for dysfunction caused by calcification, fibrosis, fusion, retraction, perforation, rupture, stretching, dilation, or congenital malformations of the valve leaflets/cusps or associated struts. Valvular stenosis, defined as inhibition of forward flow secondary to obstruction caused by failure of a valve to open completely, is almost always caused by a primary cuspal abnormality and a chronic disease process. In contrast, valvular insufficiency, defined as reverse flow caused by failure of a valve to close completely, may result from either intrinsic disease of the valve cusps or from damage to or distortion of the supporting structures (e.g., the aorta, mitral annulus, chordae tendineae, papillary muscles, and ventricular free wall) without primary cuspal pathology. Regurgitation may appear either acutely, as with rupture of cords, or chronically, as with leaflet scarring and retraction. Both stenosis and insufficiency can coexist in a single valve, usually with one process predominating. The most commonly encountered morphologies of valvular heart disease are illustrated in Figures 5-18 and 5-19.
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DEGENERATIVE CALCIFIC AORTIC VALVE STENOSIS
The most frequent valvular abnormality requiring surgery, acquired aortic stenosis (AS) usually is the consequence of age-related calcium phosphate deposition in either anatomically normal aortic valves or in congenitally bicuspid valves as a result of accelerated wear (see Fig. 5-18A).193–195 Stenotic, previously normal tricuspid valves come to clinical attention primarily in the eighth to ninth decades of life, while bicuspid valves with superimposed age-related degenerative calcification generally become symptomatic earlier (usually sixth to seventh decades). Calcific degeneration affects men and women equally.
Nonrheumatic, calcific aortic stenosis is characterized by heaped-up, calcified masses initiated in the cuspal fibrosa at the points of maximal cusp flexion (the margins of attachment); they protrude distally from the aortic aspect into the sinuses of Valsalva, inhibiting cuspal opening. The dystrophic calcification process does not involve the free cuspaledges and largely preserves the microscopic layered architecture. In contrast to rheumatic aortic stenosis, appreciable commissural fusion is absent in calcific aortic stenosis and the mitral valve generally is uninvolved. Aortic valve sclerosis comprises a common, earlier, and hemodynamically less significant stage of the calcification process. Nevertheless, aortic sclerosis is associated with an increase of approximately 50% in the risk of death from cardiovascular causes and the risk of myocardial infarction, even in the absence of hemodynamically significant obstruction of left ventricular outflow.196
Aortic valves are congenitally bicuspid in approximately 1% to 2% of the population, with men affected 3 to 4 times more frequently than are women. The two cusps are typically of unequal size, with the larger (conjoined) cusp having a midline raphe, representing an incomplete separation or congenital fusion of two cusps. Less frequently, the cusps are of equal size, and a raphal ridge may or may not be identifiable (see Figs. 5-18B and 5-18C). When a raphe is present, the most commonly fused cusps are the right and left, accounting for about 75% of cases. Neither stenotic nor symptomatic at birth or throughout early life, bicuspid valves are predisposed to accelerated calcification, with about 85% becoming stenotic. About 15% of the time, they become purely incompetent, complicated by infective endocarditis, or associated with acute aortic dissection. Usually, an uncomplicated bicuspid valve is encountered at autopsy.
Aortic stenosis leads to a gradually increasing pressure gradient across the valve, which may reach 75 to 100 mg Hg in severe cases, with a left ventricular pressure of 200 mg Hg or more. Cardiac output is maintained by the development of concentric left ventricular hypertrophy secondary to pressure overload. The onset of symptoms such as angina, syncope, or heart failure in aortic stenosis heralds the exhaustion of compensatory cardiac hyperfunction, and carries a poor prognosis if not treated by aortic valve replacement (>50% mortality within 3–5 years). If cardiac output is low, as may occur in heart failure or in the elderly, then neither the gradient nor the resultant murmur may appear significant and aortic stenosis can be missed clinically. Other complications of calcific aortic stenosis include embolization that may occur spontaneously or during interventional procedures, hemolysis, and extension into the ventricular septum causing conduction abnormalities.
Degenerative calcific deposits also can develop in the ring (annulus) of the mitral valve; elderly individuals, especially women, are most commonly affected, although annular calcification can accompany mitral valve myxomatous degeneration. Although generally asymptomatic, the calcific nodules may lead to regurgitation by interference with systolic contraction of the mitral valve ring or, very rarely, stenosis by impairing opening of the mitral leaflets. Occasionally, the calcium deposits may penetrate sufficiently deeply to impinge on the atrioventricular conduction system and produce arrhythmias (and rarely sudden death). Patients with mitral annular calcification have an increased risk of stroke, and the calcific nodules can be the nidus for thrombotic deposits or infective endocarditis.197
Rheumatic fever is an acute, often recurrent, inflammatory disease that generally follows a pharyngeal infection with group A beta-hemolytic streptococci, principally in children.198,199 In the past several decades, rheumatic fever and rheumatic heart disease have declined markedly but not disappeared in the United States and other developed countries. Evidence strongly suggests that rheumatic fever is the result of an immune response to streptococcal antigens, inciting either a cross-reaction to tissue antigens, or a streptococcal-induced autoimmune reaction to normal tissue antigens.200 The cardiac surgical implications of rheumatic fever primarily relate to chronic rheumatic heart disease, characterized by chronic, progressive, deforming valvular disease (particularly mitral stenosis) that produces permanent dysfunction and severe, sometimes fatal, cardiac failure decades later.
Chronic rheumatic heart disease most frequently affects the mitral and to a lesser extent the aortic and/or the tricuspid valves. Chronic rheumatic valve disease is characterized by fibrous or fibrocalcific distortion of leaflets or cusps, valve commissures, and chordae tendineae, with or without annular or papillary muscle deformities (see Figs. 5-19A and 5-19B). Stenosis results from leaflet and chordal fibrous thickening and from commissural and chordal fusion, with or without secondary calcification. Regurgitation entails related mechanisms, including scarring-induced retraction of chordae and leaflets and, less commonly, fusion of a commissure in an opened position. Chordal rupture only very rarely involves a rheumatic valve. Combinations of lesions may yield valves that are both stenotic and regurgitant. Although considered the pathognomonic inflammatory myocardial lesions in acute rheumatic fever, Aschoff nodules are found infrequently in myocardium sampled at autopsy or at valve replacement surgery, most likely reflecting an extended interval from acute disease to critical functional impairment.201
MYXOMATOUS DEGENERATION OF THE MITRAL VALVE (MITRAL VALVE PROLAPSE)
Myxomatous mitral valve disease is the most frequent cause of chronic, pure, isolated mitral regurgitation.202,203 One or both mitral leaflets are enlarged, redundant, or floppy and will prolapse, or balloon back into the left atrium during ventricular systole (see Fig. 5-19C). The three characteristic anatomic changes in mitral valve prolapse are: (1) interchordal ballooning (hooding) of the mitral leaflets or portions thereof (most frequently involving the posterior leaflet), sometimes accompanied by elongated, thinned, or ruptured cords; (2) rubbery diffuse leaflet thickening that hinders adequate coaptation and interdigitation of leaflet tissue during valve closure; and (3) substantial annular dilation, with diameters and circumferences that may exceed 3.5 and 11.0 cm, respectively (see Fig. 5-19D).204,205 Pathological mitral annular enlargement is usually confined to the posterior leaflet, since the anterior leaflet is firmly anchored by the fibrous tissue at the aortic valve end and is far less distensible. The key microscopic change in myxomatous degeneration is attenuation or focal disruption of the fibrous layer (with loss of collagen) of the valve,206 on which the structural integrity of the leaflet depends. This is accompanied by focal or diffuse thickening of the spongy layer by proteoglycan deposition. These changes weaken the leaflet. Deposited amorphous extracellular matrix gives the tissue an edematous, blue appearance on routine hematoxylin and eosin staining, an appearance called myxomatous by pathologists. Concomitant involvement of the tricuspid valve is present in 20% to 40% of cases, and the aortic and pulmonary valves also may be affected. Myxomatous tricuspid valve may be associated with primary pulmonary disease owing to altered right-sided hemodynamics.
Secondary changes may occur, including: (1) focal pad-like fibrous thickening along both surfaces of the valve leaflets; (2) linear thickening of the subjacent mural endocardium of the left ventricle as a consequence of friction-induced injury by cordal hamstringing of the prolapsing leaflets; (3) thrombi on the atrial surfaces of the leaflets, particularly in the recesses behind the ballooned leaflet segments; (4) calcification along the base of the posterior mitral leaflet; and (5) chordal thickening and fusion with some features that resemble postrheumatic disease. The pathogenesis of myxomatous degeneration is uncertain, but this valvular abnormality is a common feature of Marfan syndrome and occasionally occurs with other hereditary disorders of connective tissues such as Ehlers-Danlos syndrome, suggesting an analogous but localized connective tissue defect. Excessive remodeling of connective tissue marks the disease, but it is yet unknown whether this is causal or secondary.206
In a subgroup of affected individuals that is largely unidentifiable beforehand, mitral valve prolapse is associated with infective endocarditis, stroke, or other manifestation of thromboembolism, progressive congestive heart failure, or sudden death. Distinction should be made between the clinical diagnosis of mitral valve prolapse in young people and the pathologic diagnosis of a myxomatous mitral valve in mature individuals. The former generally is associated with a competent and minimally distorted valve and occurs in women more frequently than in men. The latter, in contrast, affects men more often than women and usually is associated with a severely regurgitant valve that is structurally deformed. More important, only a small fraction of young people with clinically detected mitral valve prolapse will develop severely distorted and incompetent mitral valves as they grow older.
Infective endocarditis is characterized by colonization or invasion of the heart valves, mural endocardium, aorta, aneurysmal sacs, or other blood vessels by a microbiologic agent, leading to the formation of friable vegetations laden with organisms.207 Virtually any type of microbiologic agent can cause infective endocarditis, but most cases are bacterial.
The so-called Duke criteria provide a standardized assessment of patients with suspected infective endocarditis that integrates factors predisposing patients to the development of infective endocarditis, blood-culture evidence of infection, echocardiographic findings, and clinical and laboratory information.208 The previously important clinical findings of petechiae, subungual hemorrhages, Janeway lesions, Osler's nodes, and Roth's spots in the eyes (secondary to retinal microemboli) have now become uncommon owing to the shortened clinical course of the disease as a result of antibiotic therapy.
The clinical classification into acute and subacute forms is based on the range of severity of the disease and its tempo, on the virulence of the infecting microorganism, and on the presence of underlying cardiac disease. Acute endocarditis is a destructive infection, often involving a previously normal heart valve, with a highly virulent organism, and leads to death within days to weeks in over 50% of patients. In contrast, in a more indolent lesion often called subacute endocarditis, organisms of low virulence cause infection on previously deformed valves; the infection pursues a protracted course of weeks to months and may be undetected and untreated.
Vegetations in both acute and subacute endocarditis are composed of fibrin, inflammatory cells, and organisms. Staphylococcus aureus is the leading cause of acute endocarditis and produces necrotizing, ulcerative, invasive, and highly destructive valvular infections. The subacute form is usually caused by Streptococcus viridans. Cardiac abnormalities, such as rheumatic heart disease, congenital heart disease (particularly anomalies that have small shunts or tight stenoses creating high-velocity jet streams), myxomatous mitral valves, mildly calcified bicuspid aortic valves, and artificial valves and their sewing rings, predispose to endocarditis. In intravenous drug abusers, left-sided lesions predominate, but right-sided valves are commonly affected; the usual organism is S. aureus.209 In about 5% to 20% of all cases of endocarditis, no organism can be isolated from the blood (culture-negative endocarditis), often because of prior antibiotic therapy.
The complications of endocarditis include valvular insufficiency (or rarely stenosis), abscess of the valve annulus (ring abscess), suppurative pericarditis, and embolization. With appropriate antibiotic therapy, vegetations may undergo healing, with progressive sterilization, organization, fibrosis, and occasionally calcification. Regurgitation generally occurs on the basis of cusp or leaflet perforation, chordal rupture, or fistula formation from a ring abscess into an adjacent cardiac chamber or great vessel. Ring abscesses tend to be associated with virulent organisms, are technically difficult to deal with surgically, and are associated with a relatively high mortality rate.
Reconstructive procedures to eliminate mitral insufficiency of various etiologies and to minimize the severity of rheumatic mitral stenosis are now highly effective and commonplace, accounting presently for over 70% of mitral valve operations.210,211 Reconstructive therapy of selected patients with aortic insufficiency and aortic dilation may also be done,212,213 but repair of aortic stenosis has been notably less successful.214,215 The major advantages of repair over replacement relate to the elimination of both prosthesis-related complications and the need for chronic anticoagulation. Other reported advantages include a lower hospital mortality, better long-term function, and a lower rate of postoperative endocarditis. Figure 5-20 illustrates the pathologic anatomy of various mitral valve reconstruction procedures, and Figure 5-21 illustrates aortic valve repairs.
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The hemodynamic disturbances in most forms of mitral valve disease are the result of structural deformities at different and often multiple levels within the complex mitral apparatus. Identification of each component of the anatomic lesion and an underlying understanding of normal valve anatomy and function are essential to adequate valve reconstruction (see Fig. 5-20).216
In general, reconstructive techniques are more easily applied to mitral valves with nonrheumatic disease than those affected by rheumatic disease. The fibrosis and shortening of both chordae and leaflets that cause mitral stenosis and are the result of an advanced rheumatic process makes gaining adequate mobility and adequate leaflet area difficult. Commissurotomy may be employed in the operative repair of some stenotic mitral valves. Since the annular portions of the leaflet are normally devoid of chordal support, splitting them to 2 to 3 mm from the annulus may avoid the potential complication of a new or residual regurgitant jet. Anterior leaflet mobility often is sufficient to allow an acceptable mitral opening despite posterior leaflet immobility, and pliable leaflets can partially compensate for a rigid subvalvar apparatus. Five factors compromise the late functional results of mitral commissurotomy: (1) left ventricular dysfunction; (2) pulmonary venous hypertension and right-sided cardiac factors, including right ventricular failure, tricuspid regurgitation, or a combination of these; (3) systemic embolization; (4) other coexistent cardiac disorders, such as coronary artery or aortic valve diseases; and (5) residual or progressive mitral valve disease. Late deterioration following mitral commissurotomy may occur owing to restenosis of the valve, residual (unrelieved) stenosis, or regurgitation induced at operation. Leaflet calcification, subvalvar (predominantly chordal) fibrotic changes, and significant regurgitation owing to scar retraction limit the ability to perform reconstructive surgical repair, and thereby necessitate valve replacement of a stenotic mitral valve.
Structural defects seen in mitral regurgitation include: (1) dilation of the mitral annulus; (2) elongation or rupture of chordae tendineae, permitting leaflet prolapse into the atrium; (3) redundancy and deformity of leaflets; (4) leaflet perforations or defects; (5) restricted leaflet motion as a result of commissural fusion in an opened position, and leaflet retraction, chordal shortening or thickening or both. Necrosis without rupture of a papillary muscle following an acute myocardial infarction generally does not itself induce insufficiency. More frequently, mitral regurgitation results from the underlying necrotic and nonfunctional free-wall segment or distortion of the papillary muscle geometry by ventricular dilation, where lateral movement of the papillary muscles alters the axis of their tension on the cords.
Leaflet abnormalities causing mitral regurgitation include retraction, redundancy, and perforation. The posterior leaflet is more delicate, has a shorter annulus-to-free-edge dimension than the anterior, and is therefore more prone to postinflammatory fibrous retraction. Following resection of excess anterior or posterior leaflet tissue in valves with redundancy, annuloplasty with or without a prosthetic ring is used to reduce the annulus dimension to correspond to the amount of leaflet tissue available. Tissue substitutes such as glutaraldehyde-pretreated xenograft or autologous pericardium can be used to repair or enlarge leaflets. Ruptured or elongated chordae may be repaired by shortening or replacement with pericardial tissue or thick suture material.
CATHETER BALLOON VALVULOPLASTY
Percutaneous transluminal balloon dilation of stenotic valves has been used successfully to relieve some congenital and acquired stenoses of native pulmonary, aortic, and mitral valves, and stenotic right-sided porcine bioprosthetic valves.217–219 Mitral valvuloplasty yields favorable results in elderly patients with mitral stenosis complicated by pulmonary hypertension, a difficult group of patients to manage surgically. For acquired calcific aortic stenosis, individual functional responses to balloon dilation vary considerably and data suggest a modest incremental benefit, high early mortality, and high restenosis rate.220 Some patients have dramatic improvement in valvular and ventricular function, whereas others show little change. The major complications of balloon valvuloplasty include cerebrovascular accident secondary to embolism, massive regurgitation owing to valve trauma, cardiac perforation with tamponade, and, with mitral valvuloplasty, creation of an atrial septal defect owing to septal dilation.
Improvement following catheter balloon valvuloplasty of aortic stenosis derives from commissural separation, fracture of calcific deposits, and displacing and stretching of the valve cusps (see Fig. 5-21A). Fractured calcific nodules can themselves prove dangerous (see Figs. 5-21B and C).221 In pediatric cases in which the cusps are generally pliable, cuspal stretching, tearing, or avulsion may also occur. In the relief of mitral stenosis, balloon valvuloplasty largely involves commissural separation; thus, this procedure is unlikely to provide significant alteration in the subvalvular pathology of the chordae and papillary muscles of patients with rheumatic mitral stenosis. Commissural splitting generally is successful only in valves with little or no commissural calcification. Thus, balloon valvuloplasty has been far more applicable in third world countries in which rheumatic mitral stenosis is commonly severe but noncalcific at a young age, rather than in the United States, in which the disease is usually only severe and calcific in middle-aged or elderly adults.
Since valvular aortic stenosis in most patients over 60 years of age is characterized by calcific deposits superimposed upon a valve largely free of either congenital or rheumatic deformities, such valves are stenotic simply because the leaflets are immobilized by extensive deposits of calcium. However, because the calcific deposits arise deep in the valve fibrous layer (see Figs. 5-18D and E), their removal by sharp dissection or ultrasonic debridement generally requires surgical dissection that removes the fibrosa and may cause damage to the spongiosa, resulting in severe compromise of cuspal mechanical integrity (see Figs. 4-21D and E).222 In some cases, vegetations of infective endocarditis may be surgically debrided.
Severe symptomatic valvular heart disease other than pure mitral stenosis or incompetence is most frequently treated by excision of the diseased valve(s) and replacement by a functional substitute. Five factors principally determine the results of valve replacement in an individual patient: (1) technical aspects of the procedure; (2) intraoperative myocardial ischemic injury; (3) irreversible and chronic structural alterations in the heart and lungs secondary to the valvular abnormality; (4) coexistent obstructive coronary artery disease; and (5) valve prosthesis reliability and host-tissue interactions.
VALVE TYPES AND PROGNOSTIC CONSIDERATIONS
Cardiac valvular substitutes are of two generic types, mechanical and biological tissue (Fig. 5-22 and Table 5-2).223–225 Prostheses function passively, responding to pressure and flow changes within the heart. Mechanical valves are usually composed of nonphysiologic biomaterials that employ a rigid, mobile occluder (pyrolytic carbon disk) in a metallic cage (cobalt-chrome or titanium alloy) as in the Bjork-Shiley, Hall-Medtronic, or OmniScience valves, or two carbon hemidisks in a carbon housing as in the St. Jude Medical, Edwards-Duromedics, or CarboMedics CPHV prostheses. Pyrolytic carbon has high strength and fatigue and wear resistance, with exceptional biocompatibility including thromboresistance.227 In contrast, tissue valves are more anatomically similar to natural valves. The major advantages of tissue valves compared to mechanical prostheses are their pseudoanatomic central flow and relative nonthrombogenicity, usually not requiring anticoagulant therapy. It is estimated that slightly more than half of all valves implanted in the present era are mechanical (mostly bileaflet tilting disk); the remainder are bioprosthetic, mostly xenografts fabricated from porcine aortic valve or bovine pericardium, which have been preserved in a dilute glutaraldehyde solution, with a small percentage of cryopreserved allografts. In the past decade, innovations in tissue valve technologies and design have caused this segment of the market to grow disproportionately and expanded indications for their use (Fig. 5-23).228
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Improvement in late outcome has derived from earlier referral of patients for valve replacement, decreased intraoperative myocardial damage, and improved surgical technique and cardiac valve prostheses. Following valve replacement with currently used devices, the probability of 5-year survival is about 80% and of 10-year survival about 70%, dependent on overall functional state, preoperative left ventricular function, left ventricular and left atrial size, and extent and severity of coronary artery disease. Preservation of the subvalvular apparatus has also been an important advance.230
Prosthetic valve–associated pathology becomes an important consideration beyond the early postoperative period. The few randomized studies available show that with contemporary mechanical prosthetic and bioprosthetic valves, approximately 60% or more patients have an important device-related complication within 10 years postoperatively.213–215,231,232 However, thrombotic and thromboembolic problems that frequently complicate mechanical valves tend to occur earlier than the structural failures that complicate tissue valve prostheses.233 Valve-related complications frequently necessitate reoperation, now accounting for approximately 5% to 15% of all valve procedures, and they may cause death. Late death following valve replacement results predominantly from either cardiovascular pathology not related to the substitute valve or prosthesis-associated complications. Moreover, late death is caused by a device-related complication in 25% to 61% of patients.229,234 As might be expected, autopsy studies generally reveal a higher rate of valve-related pathology than clinical investigations. One fifth or more of valve recipients will ultimately die suddenly; in one autopsy study of a highly selected referral population, 40% of valve recipients who died suddenly had a valve-related cause.235
Four categories of valve-related complications are most important: thromboembolism and related problems, infection, structural dysfunction (i.e., failure or degeneration of the biomaterials comprising a prosthesis), and nonstructural dysfunction (i.e., miscellaneous complications and modes of failure not encompassed in the previous groups) (Table 5-2).226,236–243 The clinicomorphologic features of these problems have been widely described in the literature. The relative performance and risk of complications of various types of widely used substitute heart valve types are summarized in Table 5-3. The risk of some valve-related complications (particularly thromboembolism) is potentiated by preoperative or postoperative functional impairment.
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As with other devices in which nonphysiologic artificial surfaces are exposed to blood at high fluid shear stresses, platelet deposition dominates initial blood-surface interaction and prosthetic valve thromboembolism correlates strongly with altered platelet function.246 Nevertheless, although platelet-suppressive drugs largely normalize indices of platelet formation and partially reduce the frequency of thromboembolic complications in patients with mechanical prosthetic valves, antiplatelet therapy alone is insufficient to adequately prevent thromboembolism. The friability and susceptibility to embolization of thrombi that form on bioprosthetic or mechanical valves are prolonged because lack of adjacent vascular tissue retards their histologic organization. For similar reasons, the age of such thrombi is difficult to determine microscopically. Moreover, in selected circumstances, thrombolytic therapy may be a practical nonsurgical option.247,248
Prosthetic valve infective endocarditis (Fig. 5-25) occurs in 3% to 6% of recipients of substitute valves.207,249 Infection is generally categorized into early (usually less than 60 days postoperative) and late.250–255 The microbial etiology of early prosthetic valve endocarditis is dominated by the staphylococcal species S. epidermidis and S. aureus, even though prophylactic regimens used today are targeted against these microorganisms. The clinical course of early prosthetic valve endocarditis tends to be fulminant, with rapid deterioration of hemodynamic status due to valvular or annular destruction or persistent bacteremia. In late endocarditis, a probable source of infection can be found in 25% to 80% of patients, the most frequent initiators being dental procedures, urologic infections and interventions, and indwelling catheters. The most common organisms in these late infections are S. epidermidis, S. aureus, Streptococcus viridans, and enterococci. Surgical reintervention usually is indicated for large highly mobile vegetations or cerebral thromboembolic episodes. Transesophageal echocardiography enhances diagnosis of prosthetic valve endocarditis and its intracardiac complications.253 Rates of infection of bioprostheses and mechanical valves are similar, but previous endocarditis as the original indication for valve replacement markedly increases the risk.
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Prosthetic valve dysfunction owing to materials degradation can necessitate reoperation or cause prosthesis-associated death (Fig. 5-26). Durability considerations vary widely for mechanical valves and bioprostheses, for specific types of each, for different models of a particular prosthesis (utilizing different materials or having different design features), and even for the same model prosthesis placed in the aortic rather than the mitral site. Moreover, although mechanical valve failure is often catastrophic and may be life-threatening, bioprosthetic valve failure generally causes slowly progressive symptomatic deterioration, often permitting reoperation.
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In contrast, structural dysfunction of tissue valves is the major cause of failure of the most widely used bioprostheses (flexible-stent-mounted, glutaraldehyde-preserved porcine aortic valves, and bovine pericardial valves) (see Figs. 5-26B and 5-26C). 259 Within 15 years following implantation, 30% to 50% of porcine aortic valves implanted as either mitral or aortic valve replacements require replacement because of primary tissue failure.260 Cuspal mineralization is the major responsible pathologic process with regurgitation through secondary tears the most frequent failure mode.226,238,243,259 There is increasing recognition that noncalcific structural damage owing to collagen fiber disruption is an important mode of bioprosthetic heart valve failure.261 Pure stenosis owing to calcific cuspal stiffening and noncalcific cuspal tears or perforations (reflecting direct mechanical destruction of collagen) occurs less frequently. Calcific deposits are usually localized to cuspal tissue (intrinsic calcification), but calcific deposits extrinsic to the cusps may occur in thrombi or endocarditic vegetations. Calcification is markedly accelerated in younger patients, with children and adolescents having an especially accelerated course.
Bovine pericardial valves suffer primarily design-related tearing, with calcification frequent but less limiting.263,264 Abrasion of the pericardial tissue is an important contributing factor.265
The morphology and determinants of calcification of bioprosthetic valve tissue have been widely studied in experimental models. The process is initiated primarily within residual membranes and organelles of the nonviable connective tissue cells that have been devitalized by glutaraldehyde pretreatment procedures.259,266–269 This dystrophic calcification mechanism involves reaction of calcium-containing extracellular fluid with membrane-associated phosphorus, causing calcification of the collagen. The determinants of accelerated calcification include recipient metabolic factors such as young age, valve factors such as glutaraldehyde fixation, and increased mechanical stress. The function of the native cardiac valve is contingent on a highly adapted, complex, and dynamic architecture in which cells and extracellular matrix elements support substantial repetitive movement and ongoing repair of injury.270 Substantial changes are induced by the preservation and manufacture of a bioprosthesis, these rendering the tissue different in many respects from that of a native valve. The pathological changes in bioprosthetic valves that occur following implantation are, to a large extent, rationalized on the basis of these differences and the superimposed alterations that occur following implantation,271 as discussed below. They include:
Commissural region dehiscence of the aortic wall tissue from the inside of porcine bioprosthetic valve stents causing insufficiency has been described in several valve models (Fig. 5-27).272,273
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Hemolysis owing to turbulent flow and blood–material surface interactions is an ever-present risk. It was more common with earlier model heart valve prostheses and resulted in renal tubular hemosiderosis or cholelithiasis in many patients. Although severe hemolytic anemia is unusual with contemporary valves, paravalvular leaks or dysfunction owing to materials degeneration may induce clinically important hemolysis.
Extrinsic factors can mediate late prosthetic valve stenosis or regurgitation, including a large mitral annular calcific nodule, septal hypertrophy, exuberant overgrowth of fibrous tissue (Fig. 5-28B), interference by retained valve remnants (such as a retained posterior mitral leaflet or components of the submitral apparatus; Fig. 5-28C), or unraveled, long, or looped sutures or knots (Figs. 4-28D, E, and F). For bioprosthetic valves, cuspal motion can be restricted by sutures looped around stents, and suture ends cut too long may erode into or perforate a bioprosthetic valve cusp.
VALVULAR ALLOGRAFTS/HOMOGRAFTS
Aortic or pulmonary valves (with or without associated vascular conduits) transplanted from one individual to another have exceptionally good hemodynamic profiles, a low incidence of thromboembolic complications without chronic anticoagulation, and a low reinfection rate following valve replacement for endocarditis.276,277 Early valvular allografts sterilized and/or preserved with chemicals (using propriolactone or ethylene oxide) or irradiation suffered a high rate of leaflet calcification and rupture, resulting in failure rates of nearly 50% at 10 to 12 years and 50% to 90% at 15 to 20 years.278 Pathologic examination of such valves revealed variable host fibrous tissue overgrowth and marked structural changes, including loss of architectural elements and cellularity, fibrosis, calcification, and often cuspal ruptures.279
Subsequent technical developments have led to cryopreserved allografts, in which freezing is performed with protection from crystallization by dimethyl-sulfoxide; storage until valve use is done at -196°C in liquid nitrogen. Contemporary allograft valves yield freedom from degeneration and have durability equal to or better than those of conventional porcine bioprosthetic valves (approximately 50%–90% valve survival at 10–15 years compared with 40%–60% for bioprostheses).
Some studies suggest that a fraction of viable cells may remain at the time of implantation of grafts cryopreserved using current technology.280 However, unknown are the extent of residual cells and their functional activity and whether allograft cell viability at implantation is actually an important determinant of long-term durability. While cellular preservation may enhance both thromboresistance and durability, the presence of viable cells could have deleterious consequences, via immunologic reactivity.
We studied 33 explanted left- and right-sided cryopreserved human allograft heart valves/conduits in place several hours to 9 years in children and adults.281 Cryopreserved human allograft heart valves/conduits implanted more than 1 day had progressively severe loss of normal structural demarcations. Long-term explants were generally devoid of both surface endothelium and deep connective tissue cells and had hyalinized collagen, laminated elastin, and minimal inflammatory cellularity (Fig. 5-29). No morphological evidence of immunologic rejection was noted. Our studies and most others demonstrate that cryopreserved allograft heart valves/conduits are morphologically nonviable; the structural basis for their favorable function seems primarily related to the largely preserved collagen. Allograft valves do not have the capacity to grow, remodel, or exhibit active metabolic functions, and their degeneration generally is not secondary to immunologic responses.
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Often called the Ross operation in recognition of its originator, pulmonary autograft replacement of the aortic valve is technically difficult but yields excellent hemodynamic performance, avoids anticoagulation, carries a low risk of thromboembolism, and is purported to permit growth of the autograft proportional to the somatic growth of a child or young adult.282–285 The risk of late valve failure requiring reoperation for either the autograft valve or the homograft right ventricular outflow tract reconstruction is low. Ross et al have reported freedom from autograft replacement of 85% at 20 years and a freedom from all valve-related events of 70% at 20 years.282 With the more recently used implantation of the autograft as a root replacement and the cryopreserved pulmonary homograft for right ventricular outflow tract reconstruction, actuarial freedom from reoperation (autograft or homograft) was 89% ± 3% at 5 years, and 92% ± 3% for the autograft alone. Late autograft valve failure was most frequently due to aortic annulus dilation and less frequently to degeneration. Autograft dysfunction can be corrected by autograft repair in patients with central insufficiency and aortic annular dilation.
Despite the wide use of the Ross procedure, the structural features,
cell viability, and extracellular matrix (ECM) remodeling of
pulmonary autograft (PA) valves have not been described. We
have studied pulmonary autografts in place for 15 days to 6
years (E Rabkin, FJ Schoen, unpublished data). The pulmonary
autograft cusps showed (1) near-normal trilaminar structure,
(2) near-normal collagen architecture, (3) viable endothelium
and interstitial cells, (4) usual outflow surface corrugations,
(5) sparse inflammatory cells, and (6) absence of calcification
and thrombus. They often also had an irregular layer of intimal
thickening (up to 1 mm), particularly on the ventricular aspect.
Long-term explants were markedly hypercellular. Interstitial
cells of short-term explants were largely myofibroblasts of
vimentin/-actin
phenotype and showed strong metalloproteinase (in the form of MMP-13)
activity indicative of active collagen remodeling (likely due to
mechanical adaptation). In contrast, long-term explants were stained
predominantly for vimentin and had weaker expression of MMP-13,
resembling quiescent fibroblast-like cells of normal valves. It
remains unknown whether the cuspal changes represent adaptation to
the altered mechanical or other conditions of the aortic site or a
response to injury engendered by the procedure. The arterial walls
showed considerable transmural damage (probably ischemic injury
caused by disruption of vasa vasorum) with scaring and loss of medial
SMC and elastin. Thus, pulmonary autograft valve cusps undergo early
remodeling but maintain remarkably preserved semilunar valve
morphology, cell viability, and collagen microstructure up to 6
years. The early necrosis and healing with probable resultant loss of
strength/elasticity of the "new" aortic wall may potentiate late
dilation.
STENTLESS PORCINE AORTIC VALVE BIOPROSTHESES
Nonstented (stentless) porcine aortic valve bioprostheses comprise glutaraldehyde-pretreated pig aortic root and valve cusps that have no supporting stent. Two such models were approved by the U.S. FDA in 1997 for insertion into the aortic site: St. Jude Medical Toronto SPV (St. Jude Medical Inc., St. Paul, MN) and Medtronic Freestyle (Medtronic Heart Valves, Santa Ana, CA) bioprostheses.286,287 They differ slightly in overall configuration (particularly the amount of aortic wall included), details of glutaraldehyde pretreatment conditions, and overall fabrication, and whether anticalcification technology is used (the FreeStyle valve is treated with 2-amino-oleic acid [AOA]). Other variants of this concept are also in clinical trials.288 The principal advantage of a stentless porcine aortic valve is that it allows for the implantation of a larger bioprosthesis (than stented) in any given aortic root, which may enhance hemodynamics and thereby ventricular remodeling and patient survival.289
The potential and observed complications with nonstented bioprostheses are comparable to those of stented valves. However, nonstented porcine aortic valves have greater portions of aortic wall exposed to blood than in currently used stented valves, and calcification of the aortic wall is potentially deleterious. Indeed, allograft valved conduits frequently fail because of calcific stenosis, with prominent deposits in the wall.290 Calcification of the wall portion of a stentless valve could stiffen the root, altering hemodynamic efficiency; cause nodular calcific obstruction or wall rupture; or provide a nidus for emboli. Important in this respect is the observation that some anticalcification agents (see below), including AOA and ethanol, prevent experimental cuspal but not aortic wall calcification. In an initial pathology analysis of nonstented valves, aortic wall calcification was not a problem.291
Methods are being actively studied and some are being used clinically to prevent calcification in bioprosthetic valves.292–296 Other approaches to provide improved valves include modifications of bioprosthetic valve stent design and tissue-mounting techniques to reduce cuspal stresses, tissue treatment alternatives to glutaraldehyde to enhance durability and postimplantation biocompatibility, nonstented porcine valves, minimally cross-linked autologous pericardial valves, flexible trileaflet polymeric (polyurethane) prostheses, and mechanical and tissue valves with novel design features to improve hemodynamics, enhance durability, and reduce thromboembolism.
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MYOCARDIAL DISEASE |
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There are three functional/pathophysiologic/anatomic patterns: dilated, hypertrophic, and restrictive. The cause of a specific cardiomyopathy is often revealed by light and/or electron microscopic examination, whereas the morphology is nonspecifically abnormal in idiopathic cardiomyopathy. Moreover, in idiopathic dilated cardiomyopathy, the severity of the morphologic changes does not necessarily correlate with the severity of dysfunction or the patient's prognosis. The understanding and potential treatment of myocardial disease have advanced substantially over the last decade as a result of genetic studies and their correlations with clinical features.299–302
Endomyocardial biopsy is used in the diagnosis and management of patients with myocardial disease and in the ongoing surveillance of cardiac transplant recipients.303 The bioptome, inserted into the right internal jugular or femoral vein and advanced under fluoroscopic or echocardiographic guidance through the tricuspid valve, obtains 1- to 3-mm fragments of endomyocardium, most frequently from the apical half of the right side of the ventricular septum. Interpretation of right-sided biopsy specimens assumes that this location produces representative pathology. Since most myocardial diseases affect both ventricles, correlation between right- and left-sided findings generally is good.
The most common variants of cardiomyopathy are the dilated and hypertrophic types. Both are illustrated in Figure 5-30.
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Dilated cardiomyopathy is characterized by hypertrophy, dilation,
and systolic ventricular dysfunction. Dilated cardiomyopathy
has a familial basis in approximately 30% to 40% of cases, with
autosomal dominant (most common), autosomal recessive, and X-linked
and mitochondrial inheritance all described.300,301,304
Mutations in several different genes can cause autosomal dominant
dilated cardiomyopathy, including the cytoskeletal
protein-encoding genes ß- and -sarcoglycan, dystrophin, and lamin A/C,
as well as the sarcomeric protein-encoding genes actin, ß-myosin
heavy chain, cardiac troponin T, and -tropomyosin. These mutations are
thought to cause disease through force transmission abnormalities
leading to reduced force generation by the cardiac myocytes. A
history of chronic alcoholism can be elicited in 20% of patients, and
biopsy-proven myocarditis precedes the development of cardiomyopathy
in 5% to 10%. Pregnancy-associated nutritional deficiency or
immunologic reaction is another possible contributory factor.
The primary functional abnormality in dilated cardiomyopathy is impairment of left ventricular systolic function, as measured by the ejection fraction (< 25% in end-stage, normal approximately 50% to 65%). Pathologic findings include cardiomegaly with heart weight two to three times normal and four-chamber dilation (see Fig. 5-30A). Cardiac mural thrombi, a potential source of thromboemboli, are sometimes present and predominate in the left ventricle but may occur in any chamber. The histologic changes comprise myocyte hypertrophy and interstitial and endocardial fibrosis of variable degree, but they do not reflect an etiologic agent (see Fig. 5-20B). Moreover, the myocardial histology in dilated cardiomyopathy is indistinguishable from that in myocardial failure secondary to ischemic or valvular heart disease.
A recently described variant of dilated cardiomyopathy is arrhythmogenic right ventricular cardiomyopathy, characterized by a severely thinned right ventricular wall, with extensive fatty infiltration, loss of myocytes with compensatory myocyte hypertrophy, and interstitial fibrosis.300,305–307 Sometimes familial, this disorder is most commonly associated with right-sided and sometimes left-sided heart failure and various rhythm disturbances, particularly ventricular tachycardia and sudden death.308
Hypertrophic cardiomyopathy is characterized by a heavy, muscular, hypercontracting heart, in striking contrast to the flabby, hypocontracting heart of dilated cardiomyopathy. It represents a diastolic, rather than systolic, disorder.
The essential anatomic feature of hypertrophic cardiomyopathy is massive myocardial hypertrophy without dilation (see Fig. 5-30A). 309 The classic pattern is characterized by disproportionate thickening of the ventricular septum relative to the free wall of the left ventricle (ratio >1.5), termed asymmetric septal hypertrophy, and is usually localized to the subaortic region. When the basal septum is markedly thickened at the level of the mitral valve, the outflow of the left ventricle may be narrowed during systole. Endocardial thickening in the left ventricular outflow tract and thickening of the anterior mitral leaflet result from contact between the two during ventricular systole (observed by echocardiography as systolic anterior motion of the mitral valve), correlating with systolic left ventricular outflow tract obstruction. In about 10% of cases, left ventricular hypertrophy is symmetric, and in other cases disproportionate hypertrophy involves the midventricular or apical septum, extends onto the left ventricular free wall anteriorly or inferiorly, or causes right ventricular outflow tract obstruction.
The most important microscopic features in hypertrophic cardiomyopathy include: (1) disarray of myocytes and contractile elements within cells (myofiber disarray) typically involving 10% to 50% of the septum; (2) extreme myocyte hypertrophy, with transverse myocyte diameters frequently more than 40 µm (normal approximately 15–20 µm); and (3) interstitial and replacement fibrosis (see Fig. 5-30D).
Hypertrophic cardiomyopathy has an extremely variable course, with potential complications including atrial fibrillation with mural thrombus formation and embolization, infective endocarditis of the mitral valve, intractable cardiac failure, and sudden death. Sudden death occurs in approximately 2% to 3% of adults and 4% to 6% of children per year, is the most common cause of death from hypertrophic cardiomyopathy, and is particularly common in young males with familial hypertrophic cardiomyopathy or a family history of sudden death. The risk is related to the degree of hypertrophy.310,311 Cardiac failure from hypertrophic cardiomyopathy results from reduced stroke volume due to decreased diastolic filling of the massively hypertrophied left ventricle. Although symptoms are not solely a result of ventricular septal thickening, some patients benefit from thinning of the septum by surgical myotomy/myectomy.312,313 More recently, the technique of chemical septal ablation appears to be a safe and effective procedure, with hemodynamic and functional improvement.314,315 End-stage heart failure can be accompanied by dilation, for which cardiac transplantation may be recommended.
Hypertrophic cardiomyopathy has a genetic basis in most cases.300–302,309,312,316
In approximately half or more of patients the disease is familial,
and the pattern of transmission is autosomal dominant with variable
expression; remaining cases appear to be sporadic. Various mutations
have been identified in hypertrophic cardiomyopathy; all are
genes for sarcomeric proteins including ß-myosin heavy chain,
troponin T and I, -tropomyosin, and titin. The mechanism by which defective
sarcomeric proteins produce the phenotype of hypertrophic
cardiomyopathy is uncertain. Therefore, cardiac hypertrophy in HCM is
likely a "compensatory" phenotype due to increased cardiac myocyte
stress or altered Ca2+ sensitivity of the contractile
apparatus imparted by the mutant contractile proteins. Accordingly,
increased myocyte stress leads to expression of a variety of cardiac
genes that activate the transcription machinery leading to
hypertrophy and other phenotypes of HCM. This would suggest that the
pathogenesis of hypertrophy, a common programmed response of the
myocardium to any form of stress, whether caused by a genetic defect
or by an acquired condition, involves common pathways. Interestingly,
different responsible gene mutations carry vastly differing
prognoses, and certain genetic defects indicate a relatively high
likelihood of sudden death.317
Restrictive cardiomyopathy is characterized by impeded diastolic relaxation and left ventricular filling, with systolic function often unaffected. Any disorder that interferes with ventricular filling can cause restrictive cardiomyopathy (including eosinophilic endomyocardial disease, amyloidosis, hemochromatosis, or postirradiation fibrosis) or mimic it (constrictive pericarditis or hypertrophic cardiomyopathy). Morphologically, the ventricles are of approximately normal size or slightly enlarged, but the cavities are not dilated and the myocardium is firm. Biatrial dilation commonly is observed. Distinct morphologic patterns indicative of specific heart muscle disease may be revealed by light or electron microscopy of endomyocardial biopsy specimens, including deposition of amyloid or of products of an inborn error of metabolism such as trihexosylceramide in Fabry disease.318
Cardiac transplantation provides long-term survival and rehabilitation for many individuals with end-stage cardiac failure.319 Overall predicted 1-year survival is presently approximately 86% and 5-year survival is about 70%.320 The most common indications for cardiac transplantation, accounting for 90% of the patients, are idiopathic cardiomyopathy and end-stage ischemic heart disease; other recipients have congenital, other myocardial, or valvular heart disease.321,322
Hearts explanted at the time of transplantation typically have the expected pathologic features of the underlying diseases. However, previously undiagnosed conditions and unexpected findings may be encountered. Most frequent is eosinophilic or hypersensitivity myocarditis, seen in approximately 20% of explants and characterized by a focal or diffuse mixed inflammatory infiltrate, rich in eosinophils, and generally associated with minimal associated myocyte necrosis.323,324 In virtually all cases, the myocarditis represents hypersensitivity to one or more of the many drugs taken by transplant candidates, including dobutamine, and is unrelated to but superimposed on the original disease necessitating transplantation. Several diseases responsible for the original cardiac failure can recur in and cause dysfunction of the allograft, including amyloidosis, sarcoidosis, giant-cell myocarditis, acute rheumatic carditis, and Chagas' disease.321,322,325
Recipients of heart transplants undergo surveillance endomyocardial biopsies according to an institution-specific schedule, which typically evolves from weekly during the early postoperative period, to twice weekly until 3 to 6 months, and then approximately two to four times annually following 1 year, or at any time when there is a change in clinical state. Histologic findings of rejection frequently precede clinical signs and symptoms of acute rejection. Optimal biopsy interpretation requires four or more pieces of myocardial tissue; reviews of technical details and artifacts are available.321,322,326
The major sources of mortality and morbidity following cardiac transplantation are perioperative ischemic injury, infection, allograft rejection, lymphoproliferative disease, and obstructive graft vasculopathy. A particularly interesting recent finding is that of recipient cells that have migrated (presumably from the bone marrow) to the donor heart.327 The significance of these cells is yet unknown.
Ischemic injury can originate in the unavoidable ischemia that accompanies procurement and implantation of the donor heart. Several time intervals are potentially important: (1) the donor interval between brain death and heart removal, perhaps partially related to terminal administration of pressor agents or the release of norepinephrine and cytokines associated with brain death; (2) the interval of warm ischemia between donor cardiectomy to cold storage; (3) the interval during cold transport; and (4) the interval during warming, trimming, and reimplantation, or some combination of these. Existing hypertrophy and coronary obstructions tend to enhance injury, whereas decreased tissue temperature and cardioplegic arrest slow chemical reactions and thereby protect myocytes from progressive ischemic damage. However, when the heart is not filled with oxygenated blood during transport, the subendocardial myocytes normally perfused from the lumen are especially vulnerable to ischemic injury. As in other situations of transient myocardial ischemia, frank necrosis or prolonged ischemic dysfunction of viable myocardium or both may be present. Massive myocardial injury can cause potentially fatal low cardiac output in the perioperative period.
Perioperative myocardial ischemic injury as diagnosed by conventional histologic criteria is prevalent in endomyocardial biopsies early after heart transplantation.322,328,329 The histologic progression of healing of myocardial necroses in transplanted hearts, as noted on subsequent endomyocardial biopsies, is prolonged and the cellular infiltrate may be distorted owing to the anti-inflammatory effects of immunosuppressive therapy (Fig. 5-31). Therefore, the repair phase of perioperative myocardial necrosis frequently confounds the diagnosis of rejection in the first postoperative month, and in some cases, for as long as 6 weeks. In contrast, ischemic necrosis noted 3 to 6 months postoperatively is usually secondary to occlusive graft vasculopathy. It remains to be determined whether and to what degree early ischemic injury has a late impact on allograft dysfunction, possibly through loss of myocytes, accumulation of fibrosis, potentiation of rejection, or stimulation of graft vasculopathy.
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Improved immunosuppressive regimens in heart transplant patients have substantially decreased the incidence of serious rejection episodes. Nonetheless, rejection phenomena still cause cardiac failure or serious arrhythmias in some patients. Hyperacute rejection occurs rarely, most often when a major blood group incompatibility exists between donor and recipient, and acute rejection is unusual earlier than 2 to 4 weeks postoperatively. Acute rejection episodes occur largely but not exclusively in the first several months after transplantation. However, since rejection can occur years postoperatively, many transplant centers continue late surveillance biopsies at widely spaced intervals.330
The histologic features of acute rejection are an inflammatory cell infiltrate, with or without damage to cardiac myocytes; in late stages, vascular injury may become prominent (Fig. 5-32). The International Society for Heart and Lung Transplantation (ISHLT) working formulation, illustrated in Figure 5-33, is most widely accepted and used to guide immunosuppressive therapy in heart transplant recipients.331,332 In this grading system, grade 0 represents no evidence of rejection or healed rejection. Mild rejection (ISHLT grades 1A and 1B) is characterized by a focal or diffuse, respectively, mild perivascular (or interstitial) lymphocytic infiltrate without myocyte damage. Lymphocytic inflammatory infiltrates with associated myocyte encroachment or damage, generally called moderate rejection, can be limited to a single focus (ISHLT grade 2), present in a multifocal pattern (ISHLT grade 3A), or distributed diffusely (ISHLT grade 3B). In severe rejection (ISHLT grade 4), myocyte necrosis is more evident, there is often patchy interstitial hemorrhage owing to vascular damage, and vasculitis (usually arteriolitis) may be prominent. The increased inflammatory infiltrate often also includes neutrophils or eosinophils, presumably in response to myocyte necrosis or vascular damage.
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Apoptosis of myocytes occurs during rejection, with its prevalence paralleling the severity of rejection. The intensity of cellular infiltration correlates with the degree of apoptosis, which may be mediated by NO-dependent mechanisms. Apoptosis of other donor cells, including interstitial and endothelial cells, may influence the degree of vascular injury contributing to a deterioration of the transplant.335
The immunosuppressive therapy required in all heart transplant recipients confers an increased risk of infection with bacterial, fungal, protozoan, and viral pathogens, with cytomegalovirus (CMV) and Toxoplasma gondii remaining the most common opportunistic infections. Prophylaxis in the form of oral gancyclovir is typically given to patients at high risk of primary CMV infection (donor seropositive, recipient seronegative). Viral and parasitic infections can present a challenge in endomyocardial biopsies as the multifocal lymphocytic infiltrates with occasional necrosis seen with these infections can mimic rejection.
GRAFT VASCULOPATHY (GRAFT CORONARY ARTERIOSCLEROSIS)
Graft vasculopathy is the major limitation to long-term graft and recipient survival following heart transplantation.321,322,325,336,337 Up to 50% of recipients have angiographically evident disease 5 years after transplantation.338,339 However, graft vasculopathy may become significant at any time and can progress at variable rates. Nearly half of our posttransplant deaths owing to graft coronary disease at the Brigham and Women's Hospital have occurred within 6 to 12 months postoperatively.340
Graft vasculopathy (Fig. 5-35) represents a diffuse process that begins in small distal vessels and ultimately involves both intramyocardial and epicardial allograft vessels, leading to myocardial infarction, arrhythmias, congestive heart failure, or sudden death.321,326,341 Although this process has been called accelerated atherosclerosis, the morphology of the obstructive lesion of graft vasculopathy is distinctive in comparison to typical atherosclerosis (Table 5-5).342,343 The vessels involved have concentric occlusions characterized by marked intimal proliferation of myofibroblasts and smooth muscle cells with deposition of collagen, ground substance, and lipid. Lymphocytic infiltration varies from almost none to quite prominent, with the lymphocytes often noted in a subendothelial location. The internal elastic lamina often is almost completely intact, with only focal fragmentation. The resulting myocardial pathology includes subendocardial myocyte vacuolization (indicative of sublethal ischemic injury) and myocardial coagulation necrosis (indicative of infarction).
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Early diagnosis of graft vasculopathy is limited by the lack of clinical symptoms of ischemia in the denervated allograft, by the relative insensitivity of coronary angiography, which frequently underestimates the extent and severity of this diffuse disease, and by the exclusive or predominant involvement of small intramyocardial vessels. Histologic changes of chronic ischemia such as subendothelial myocyte vacuolization can be seen on surveillance biopsies and may suggest graft vasculopathy (Fig. 5-36). Coronary angiography is nevertheless performed for diagnosis and surveillance purposes and the presence of angiographically detectable disease is of prognostic relevance. Intravascular ultrasound (IVUS) allows exact delineation of vessel wall morphology and quantification of intimal thickness and vascular dimensions. The presence of severe intimal thickening by IVUS predicts cardiac events and early death in transplant recipients.346 Although not usually amenable to angioplasty, endarterectomy, or coronary artery bypass grafting because of their diffuse distribution, stenoses may be alleviated by these procedures in occasional cases. Pharmacologic therapy aimed at preventing disease progression with calcium antagonists, ACE inhibitors, and HMG-CoA reductase inhibitors has shown some benefit. For most cases, however, retransplantation is the only effective therapy for established graft atherosclerosis.
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Posttransplant lymphoproliferative disorders (PTLDs) are a well-recognized complication of the high-intensity long-term immunosuppressive therapy required to prevent rejection in cardiac allografts. Several factors increase the risk of developing PTLD, including pretransplant Epstein-Barr virus (EBV) seronegativity (10- to 75-fold increase), young recipient age, and cytomegalovirus infection or mismatching (donor-positive, recipient-negative).347,348 The incidence of PTLD in cardiac transplant recipients is approximately 3%, and the mortality can be as high as 80%.349
PTLDs can present as an infectious mononucleosis-like illness or with localized solid tumor masses, especially in extranodal sites (e.g., heart, lungs, gastrointestinal tract). The vast majority (>90%) of PTLDs derive from the B-cell lineage and are associated with EBV infection, although T- or NK-cell origin and late-arising EBV-negative lymphoid malignancies have been described. There is strong evidence that the lesions progress from polyclonal B-cell hyperplasias ("early lesions") to lymphomas ("monomorphic PTLDs") in a short period of time, in association with the appearance of cytogenetic abnormalities.350 Therapy centers on a stepwise approach of antiviral treatment and reduction of immunosuppression, and then progression to lymphoma chemotherapy. Monoclonal antibodies (rituximab) against the B-cell marker CD20 have yielded impressive initial results and may become an important component of PTLD therapy.351 As the understanding of the risk factors and pathogenesis of PTLDs has expanded, preemptive or prophylactic therapies may help prevent this complication of transplantation.
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CARDIAC ASSIST AND MECHANICAL REPLACEMENT |
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Cardiac Assist Devices and Total Artificial Hearts
First employed successfully by DeBakey in 1963, mechanical cardiac assist devices and artificial hearts have traditionally been used in two settings: for ventricular augmentation sufficient to permit a patient to survive postcardiotomy or postinfarction cardiogenic shock while ventricular recovery is occurring, and as a bridge to transplantation when ventricular recovery is not expected and the goal is hemodynamic support until a suitable donor organ is located.357–359 More recently, left ventricular assist devices (LVADs) have been shown to provide long-term cardiac support with survival and quality-of-life improvement over optimal medical therapy in patients with end-stage congestive heart failure who are not candidates for transplantation.360 LVADs are also being investigated as a "bridge-to-recovery" in patients with congestive heart failure to induce reverse ventricular remodeling leading to an improvement in cardiac function that would eventually allow device removal. The first total artificial heart implants in the United States since the mid-1980s are currently being evaluated (AbioCor, ABIOMED Corp.).361
The major complications of cardiac assist devices are hemorrhage, thrombosis/thromboembolism, and infection (Fig. 5-37).362–367 Hemorrhage continues to be a problem in device recipients, although the risk of major hemorrhage has been decreasing with improved therapies and methods. Many factors predispose to perioperative hemorrhage including: (1) coagulopathy secondary to hepatic dysfunction, poor nutritional status, and antibiotic therapy; (2) platelet dysfunction and thrombocytopenia secondary to cardiopulmonary bypass; and (3) the extensive nature of the required surgery.
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Infectious complications have been a major limiting factor in the prolonged use of cardiac assist devices. Infection can occur within the device but may also be associated with percutaneous drive lines (see Fig. 5-37C). Susceptibility to infection is not only potentiated by the usual prosthesis-associated factors, but also by the multisystem organ damage from the underlying disease, the periprosthetic culture medium provided by postoperative hemorrhage, and by prolonged hospitalization with the associated risk of nosocomial infections. These infections are a significant cause of morbidity and mortality and are often resistant to antibiotic therapy and host defenses. However, infection is not an absolute contraindication to subsequent cardiac transplantation.369 In the REMATCH trial, sepsis accounted for 17 of the 41 deaths among the 68 patients receiving LVADs.360
Other complications include hemolysis, pannus formation around anastomotic sites, calcification (see Figs. 5-37D and E), and device malfunction. Device failure can occur secondary to fracture or tear of one of the prosthetic valves within the device conduits, as this application provides a particularly severe test of valve durability (see Fig. 5-37F). Device failure can also occur secondary to damage or dehiscence to the pumping bladder (see Fig. 5-37G). These complications can be fatal, or make a patient ineligible for future transplantation.
Many pathophysiologic changes occur during the progression to end-stage heart failure, ranging from the subcellular (e.g., abnormal mitochondrial function and calcium metabolism) to the organ and system level (e.g., ventricular dilation, decreased ejection fraction, and neurohormonal changes), leading to the signs and symptoms of congestive failure. Implantation of an LVAD can reverse many of these changes ("reverse remodeling"), leading to increased cardiac output, decreased ventricular end-diastolic volume, and normalization of neurohormonal status such that a certain fraction of patients can be weaned from the device without the need for subsequent cardiac transplantation. Current research focuses on the mechanisms of cardiac recovery, identification of patients who could achieve recovery, and specifics such as the timing and duration of therapy.370–372
Skeletal Muscle Augmentation of Cardiac Function
Autologous skeletal muscle has been used to provide active cardiac assist in the form of both cardiomyoplasty and skeletal muscle ventricles for patients with heart failure.373–375 In cardiomyoplasty, the latissimus dorsi is wrapped around the ventricles, and this has been shown to stabilize left ventricular size and prevent further dilation. Skeletal muscle can adapt its physiological, biochemical, and structural characteristics to overcome fatigue and adjust to a more demanding pattern of use by increases in capillary density, activity of oxidative enzymes, and mitochondrial volume. While these procedures had some promising experimental and clinical results,373–376 interest in their application has waned due to several factors including the improvement in medical therapy for congestive heart failure, the development of the mechanical cardiac assist devices discussed above, and the hesitancy of clinicians to refer patients for this procedure given the alternative therapies.
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NEOPLASTIC HEART DISEASE |
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Myxomas are the most common primary tumor of the heart in adults, accounting for about 50% of all benign cardiac tumors.382 They typically arise in the left atrium (80%) along the interatrial septum near the fossa ovalis. Occasionally, myxomas arise in the right atrium (15%), the ventricles (3%–4%), or valves. These tumors arise more frequently in women and usually present between the ages of 50 and 70 years. Sporadic cases of myxoma are almost always single, while familial cases can be multiple and present at an earlier age. The Carney complex, a multiple neoplasia syndrome featuring cardiac and cutaneous myxomas, endocrine and neural tumors, as well as pigmented skin and mucosal lesions, is inherited as an autosomal dominant trait.383,384 A careful history and physical examination in patients with cardiac myxoma is important to identify other signs of the Carney complex as this diagnosis carries implications for family members of the patient.
Myxomas range from small (< 1 cm) to large (up to 10 cm) and form sessile or pedunculated masses that vary from globular and hard lesions mottled with hemorrhage to soft, translucent, papillary, or villous lesions having a myxoid and friable appearance (Fig. 5-38). The pedunculated form frequently is sufficiently mobile to move into or sometimes through the ipsilateral atrioventricular valve annulus during ventricular diastole, causing intermittent and often position-dependent obstruction. Sometimes, such mobility exerts a wrecking ball effect, causing damage to and secondary fibrotic thickening of the valve leaflets.
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Histologically, myxomas are composed of stellate or globular cells, often in formed structures that variably resemble poorly formed glands or vessels, endothelial cells, macrophages, mature or immature smooth muscle cells, and a variety of intermediate forms embedded within an abundant acid mucopolysaccharide matrix and covered by endothelium. Although it has long been questioned whether cardiac myxomas are hamartomas or organized thrombi, the weight of evidence is on the side of benign neoplasia. All the cell types present are thought to derive from differentiation of primitive multipotential mesenchymal cells.
Other Cardiac Tumors and Tumor-Like Conditions
Cardiac lipomas are discrete masses that are typically epicardial, but may occur anywhere within the myocardium or pericardium. Most are clinically silent, but some may cause symptoms such as arrhythmias, pericardial effusion, or intracardiac obstruction. Magnetic resonance imaging is useful in the diagnosis of adipocytic lesions due to its ability to identify fatty tissues. Histologically, these tumors are comprised of mature adipocytes, identical to lipomas elsewhere. A separate, non-neoplastic condition called lipomatous hypertrophy of the interatrial septum is characterized by accumulation of unencapsulated adipose tissue in the interatrial septum that can lead to arrhythmias.
Papillary fibroelastomas385 are usually solitary and located on the valves, particularly the ventricular surfaces of semilunar valves and the atrial surfaces of atrioventricular valves. They constitute a distinctive "sea anemone" cluster of hair-like projections up to 1 cm or more in length, and can mimic valvular vegetations echocardiographically (Fig. 5-39).386 Histologically, they are composed of a dense core of irregular elastic fibers, coated with myxoid connective tissue, and lined by endothelium. They may contain focal platelet-fibrin thrombus and serve as a source for embolization, commonly to cerebral or coronary arteries. Surgical excision is recommended to eliminate these embolic events. Although classified with neoplasms, fibroelastomas may represent organized thrombi, similar to the much smaller, usually trivial, whisker-like Lambl's excrescences that are frequently found on the aortic valves of older individuals.
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Cardiac fibromas, while also occurring predominantly in children and presenting with heart failure or arrhythmias, or incidentally, differ from rhabdomyomas in being solitary lesions that may show calcification on a routine chest radiograph. Fibromas are white, whorled masses that are typically ventricular. There is an increased risk of cardiac fibromas in patients with Gorlin syndrome (nevoid basal cell carcinoma syndrome), an autosomal dominant disorder characterized by skin lesions, odontogenic keratocysts of the jaw, and skeletal abnormalities. Gorlin syndrome is a result of germline mutations in the PTC gene on chromosome 9; the role of this gene product in myocardial growth and development is unknown. Histologically, fibromas consist of fibroblasts showing minimal atypia and collagen with the degree of cellularity decreasing with increasing age of the patient at presentation. While they are grossly well circumscribed, there is usually an infiltrating margin histologically. Calcifications and elastin fibers are not uncommon in these lesions.
Sarcomas, with angiosarcomas and rhabdomyosarcomas being the most common, are not distinctive from their counterparts in other locations. They tend to involve the right side of the heart, especially the right atrioventricular groove (Fig. 5-40). The clinical course is rapidly progressive as a result of local infiltration with intracavity obstruction and early metastatic events.
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REFERENCES |
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