Myocarditis refers to an inflammatory response within the myocardium that is not secondary to ischemic events or cardiac rejection in the setting of transplantation. The presence of myocyte necrosis is required for certain types of myocarditis, specifically lymphocytic myocarditis that is triggered by viruses and augmented by autoimmunity, and the myocyte damage is believed to be mediated both by direct invasion of the myocardium and postimmune insult. Histologically, some overlap exists among categories of myocarditis, and no finding is specific for a single etiology (see Microscopic Findings). In general, the histologic patterns can be divided into lymphocytic (including viral and autoimmune forms), eosinophilic (in which hypersensitivity myocarditis is the most common, followed by cases of hypereosinophilic syndrome), granulomatous (sarcoid and giant cell myocarditis [GCM]), neutrophilic (bacterial, fungal, and early forms of viral myocarditis), and reperfusion type/contraction band necrosis (present in catecholamine-induced injury and reperfusion injury). However, a pathologic classification is complicated because often tissue biopsies are not obtained and a presumptive clinical diagnosis is sometimes confirmed by indirect methods such as serology. The true incidence of myocarditis is difficult to determine, and most cases are believed to be subclinical. Laboratory tests are nonspecific, and endomyocardial biopsy is not performed in most cases. One study of military recruits that used ECG changes, clinical symptoms, and cardiac enzyme elevation estimated the incidence at 17 per 100,000 population annually.1,2 Less than 2% of all cases are fatal, and these are the cases that are commonly presented to pathologists. Fatal myocarditis cases often manifest as sudden or rapid death and have the highest incidence in infants and young adults. A slight male predominance is seen. Myocarditis cases usually fall into 4 main categories: infection, postviral autoimmune related, autoimmunity (lupus myocarditis, giant cell myocarditis [GCM]), and associated with drugs (hypersensitivity and toxic myocarditis). In over 50% of the cases, myocarditis is considered idiopathic and is believed to be postviral immune related, even in the absence of demonstrable viral antigens. Cases of viral myocarditis have an identifiable infectious organism ranging from 10-100% in several studies.3,4,5,6,7,8 Several factors influence the yield detection, including stage of the disease, the methods used to detect the infectious agent, sample studied (eg, heart from endomyocardial biopsy [EMB], autopsy material, or indirectly from serum), amount of available tissue, and interpretation of the results. Myocarditis associated with drugs is histologically defined as hypersensitivity myocarditis. A list of medications associated with myocarditis includes clozapine, penicillin, ampicillin, hydrochlorothiazide, methyldopa, and sulfonamide drugs. Radiation therapy and insect bites are reported to cause heart injury as well. Toxic myocarditis relates to drug-induced injury that is not mediated by hypersensitivity and persists after the cessation of the drug. It is also associated with later inflammatory stages of catecholamine-induced myocardial injury. Myocarditis associated with connective tissue disease has been reported in lupus, mixed connective tissue disease, rheumatoid arthritis, and others. Giant cell myocarditis [GCM] is considered idiopathic. Myocarditis most often refers to diffuse inflammation of the myocardium, although cases of focal myocarditis in either right or left ventricle have been reported. Cases of sudden death due to myocarditis show a diffuse infiltrate in all sections examined. However, areas of normal heart can be seen; this may explain the low sensitivity rate of endomyocardial biopsies. Patients with myocarditis may be asymptomatic, have very mild nonspecific symptoms, such as fever, chills, and dyspnea, or more severe symptoms like palpitations, syncope, and sudden death. Most cases of myocarditis are acute self-limiting cases. Those patients typically have EKG alterations, cardiac enzymes elevation and some evidence of systemic inflammatory process (arthralgias, malaise, pharyngitis, tonsillitis, and upper respiratory tract infections). In these cases, infectious is the most common cause, viral infections being by far the most prevalent. Associated pericarditis is common. Most often, no indication for endomyocardial biopsy (EMB) exists, and the diagnosis is assigned clinically. Some cases follow a rapid deterioration and have been named acute fulminant myocarditis. Fever is common. The presentation is acute with rapid onset of heart failure that may cause sudden death. The involvement of the myocardium is often diffuse, yielding a high sensitivity in EMB. In these cases, the histologic findings are usually lymphocytic, with a minor proportion showing eosinophilia typical of hypersensitivity myocarditis. Giant cell myocarditis (GCM) also occurs in rapid cases. Overall, these patients also have a good prognosis if early immunosuppression therapy is introduced. Antiviral agents do not seem to be of any value, because, in most cases, the viruses had been cleared from the organism. A third scenario that is uncommon is that of chronic evolution to cardiomyopathy. These patients have a low detection of inflammation by EMB. The prognosis is poor, with some cases requiring heart transplantation. Incidental myocarditis seen at autopsy that shows a focal lymphocytic process is another common situation. In these cases, lymphocytic myocarditis is again the most frequent finding, but hypersensitivity myocarditis is also common. Endomyocardial biopsy is generally indicated if heart failure exists; therefore, most suspected cases of myocarditis are not biopsied. Biopsy may be warranted when giant cell myocarditis (GCM) is suspected, to exclude sarcoidosis, in addition to unexplained recent onset of heart failure. The rate of myocarditis in biopsies for new onset of heart failure has been reported between 5% and 15%;9,10 although, according to one study, 12% of patients with new onset heart failure were given a clinical diagnosis of myocarditis.11 The Dallas criteria for the biopsy diagnosis of myocarditis, established in 1987, consist of myocyte necrosis and inflammation. A positive biopsy, however, does not correlate with clinical symptoms; for example, fulminant from chronic myocarditis, which is diagnosed clinically and may respond to immunosuppressive therapy, may show only minimal inflammation because of sampling. The Dallas criteria include a “borderline” category for the first biopsy and “resolving myocarditis” for subsequent ones with no necrosis.12 Currently, any chronic inflammation in heart biopsy for new onset heart failure is diagnostic of myocarditis. The inflammatory cells are most frequently mature T-lymphocytes with a large population of accompanying macrophages. The T-cells are a mixture of CD4+ and CD8+ cells. Immunohistochemical and in-situ hybridization assays are available for the identification of a multitude of microorganisms that comprise viruses, bacteria, and parasites (including T gondii and T cruzi).8 Several studies have documented the use of PCR in EMB and autopsy tissue in the detection of parvovirus, adenovirus, enterovirus (most often coxsackievirus), Epstein-Barr virus, Lyme borreliosis, and others.4,8,14,15,16,17 Great interest has recently arisen on the finding of etiologic microbiologic agents in cases of myocarditis using endomyocardial biopsy or autopsy material. However, the identification of organisms, especially viruses, in clinical samples is problematic because of a high range of reported positivity. Polymerase chain reaction has been used to detect viruses and other pathogens in biopsy and autopsy samples of myocarditis and cardiomyopathy PCR in EMB and autopsy, including parvovirus, adenovirus, enterovirus (most often coxsackievirus), Epstein-Barr virus, and Lyme borreliosis.7,16,18 However, positive PCR results in control tissues hamper interpretation of the findings.19,20 Most cases of lymphocytic myocarditis are subclinical and never present to medical attention. Most patients resolve spontaneously with no known sequela. As stated above, a small percentage of patients, mostly children and young adults, present as fulminant disease onset and may progress rapidly to sudden death. In these patients, the infiltrates are usually diffuse. Another subset of patients who develop congestive heart failure may have late morbidity related to the degree of left ventricular dysfunction. Cases of giant cell myocarditis are usually severe, with a higher percentage progressing to death in a short period of time. Heart transplantation in association with immunosuppressive therapy is one of the only ways of saving most of these patients Patients with hypersensitivity myocarditis and heart failure can improve and heal if the drug is discontinued, but some patients may require heart transplantation. More frequently, the pathologist sees incidental hypersensitivity at autopsy or explant that is asymptomatic. For example, in heart transplant patients, who are often on multiple medications, the incidence is 7%, as diagnosed histologically in the explanted heart.20 Cardiac lymphomaMyocarditis
Definition
Lymphocytic myocarditis. Intermediate magnification of myocardium with diffuse infiltrates composed mostly of lymphocytes but also some neutrophils, macrophages, and plasma cells.
Epidemiology
Etiology
Location
Clinical Features
Gross Findings
The gross findings of fatal myocarditis cases are nonspecific and include normal or chamber dilatation. Softening and pallor of the ventricles can be present. Accompanied pericardial effusion and pericarditis can be part of viral or bacterial myocarditis cases. Late stages of myocarditis can show fibrosis that can be focal or diffuse, but the distribution is often random, as opposed to the subendocardial fibrosis typically seen in ischemia.
Myocarditis with scarring, autopsy. The image is a short axis gross photograph of an 8-year-old child with clinical myocarditis showing scarring of both ventricles, more prominent in the left. The fibrosis shows a random distribution with epicardial, myocardium, and pericardial involvements.
Microscopic Findings
Endomyocardial biopsy of a 4-year-old child with clinical suspicion for myocarditis. This image is a low magnification of myocardium with lymphocytic infiltrate within myocardial fibers. The histologic findings are consistent with myocarditis and compatible with the clinical history, even in the absence of myocyte necrosis.
Immunohistochemical stained section of the biopsy illustrated in the prior figure showing positivity for CD3 confirming a T-cell phenotype.
Lymphocytic myocarditis as seen at autopsy is rich in T cells and macrophages, and the inflammation is usually diffuse, with focal myocyte necrosis. In early phases of viral myocarditis, a neutrophilic infiltrate can occur and not be mistaken for bacterial etiology. The latter often shows numerous neutrophils, lymphocytes, and macrophages with prominent necrosis and occasional microabscesses, which are prominent in cases of fungal myocarditis. Inflammation due to ischemia is a major differential diagnosis at autopsy, especially at the edge of reperfusion infarcts, where a diffuse interstitial neutrophilic infiltrate may be present. Subendocardial location, a large proportion of neutrophils, extensive necrosis in relation to inflammation, and zonal necrosis in the case of nonreperfusion infarcts are features of ischemia.Lymphocytic myocarditis. Intermediate magnification of myocardium with diffuse infiltrates composed mostly of lymphocytes but also some neutrophils, macrophages, and plasma cells.
Focal lymphocytic myocarditis; intermediate magnification of myocardium with focal lymphocyte-rich infiltrate. Compare this with the diffuse process in Media file 1. The significance of focal inflammation at autopsy is often unclear, as such focal lesions can be found incidentally.
Lymphocytic myocarditis; high magnification of myocardium showing myocyte necrosis with lymphohistiocytic infiltrates.
Medium magnification of fungal myocarditis showing nonseptate hyphae within myocardium capillaries in association with lymphocytes and neutrophils.
The presence of giant cells and granulomas brings the differential diagnosis of giant cell myocarditis and sarcoid involving the heart. Some authors have used the term “granulomatous myocarditis” to illustrate any case with giant cells, such as in giant cell myocarditis and sarcoid. The cardiac findings of sarcoidosis are similar to other organs. The diagnosis is established by the presence of epithelioid granulomas with giant cell formation and associated with a variety of inflammatory cells consisting of activated T lymphocytes with increased CD4/CD8 ratios and activated monocytes and macrophages.
Giant cell myocarditis is characterized by diffuse infiltration of myocardium by a heterogeneous infiltrate composed of abundant lymphocytes, some eosinophils and plasma cells, occasional neutrophils and scattered prominent giant cells. T lymphocytes are more numerous than B cells, with a predominance of CD8 T lymphocytes. Myocyte degenerative changes and myocyte necrosis, especially in early stages of the disease, are invariably present. Contrasted with CS, in GCM the giant cells are not part of well-formed granulomas, are associated with myocyte necrosis, and do not involve the interstitium and epicardium. Eosinophils can be easily found in GCM, and they are rare in CS.13Giant cell myocarditis; intermediate magnification in a sudden death case. Diffuse with numerous giant cells, lymphocytes, neutrophils, and eosinophils is present. Myocyte damage is also present.
Cardiac sarcoidosis; low magnification of autopsy case with numerous giant cells and lymphocytes in a background of fibrosis and scarring. In addition to the cardiac findings, this patient had extensive involvement of mediastinal lymph nodes by sarcoidosis.
Eosinophilic myocarditis is usually related to hypersensitivity myocarditis and is described as infiltrates rich in macrophages and eosinophils. In this setting, myocyte necrosis is usually not present, and scattered poorly formed granulomas can be seen. This histologic pattern is more frequent as incidental findings in explants from heart transplant candidates, or at autopsy, with no history of any symptoms. The differential diagnosis is eosinophilic endomyocardial disease (Loeffler syndrome), which is characterized by extensive necrosis and mural and intravascular thrombi and is not considered myocarditis in either clinical or pathological settings. Rarely, hypersensitivity myocarditis can result in myocyte damage and severe clinical symptoms; this condition is important to diagnose by biopsy because cardiac function may improve or normalize when the offending drug is withheld.Hypersensitivity myocarditis; high magnification of myocardium with perivascular infiltrates rich in eosinophils. This patient had a clinical history compatible with drug-induced hypersensitivity myocarditis.
Immunohistochemistry
However, other studies have also shown the presence of organisms when cardiac tissue lacks evidence of inflammation, raising questions about the specificity of the detection and reinforcing the need for clinic-pathological correlation and accurate histologic diagnosis of myocarditis.18,19Molecular/Genetics
Prognosis and Predictive Factors
Differentials
Heart Transplantation
Heart transplantation rejection
Inflammation induced by ischemiaMultimedia
Media file 1: Lymphocytic myocarditis. Intermediate magnification of myocardium with diffuse infiltrates composed mostly of lymphocytes but also some neutrophils, macrophages, and plasma cells. Media file 2: Focal lymphocytic myocarditis; intermediate magnification of myocardium with focal lymphocyte-rich infiltrate. Compare this with the diffuse process in Media file 1. The significance of focal inflammation at autopsy is often unclear, as such focal lesions can be found incidentally. Media file 3: Giant cell myocarditis; intermediate magnification in a sudden death case. Diffuse with numerous giant cells, lymphocytes, neutrophils, and eosinophils is present. Myocyte damage is also present. Media file 4: Lymphocytic myocarditis; high magnification of myocardium showing myocyte necrosis with lymphohistiocytic infiltrates. Media file 5: Medium magnification of fungal myocarditis showing nonseptate hyphae within myocardium capillaries in association with lymphocytes and neutrophils. Media file 6: Cardiac sarcoidosis; low magnification of autopsy case with numerous giant cells and lymphocytes in a background of fibrosis and scarring. In addition to the cardiac findings, this patient had extensive involvement of mediastinal lymph nodes by sarcoidosis. Media file 7: Hypersensitivity myocarditis; high magnification of myocardium with perivascular infiltrates rich in eosinophils. This patient had a clinical history compatible with drug-induced hypersensitivity myocarditis. Media file 8: Myocarditis with scarring, autopsy. The image is a short axis gross photograph of an 8-year-old child with clinical myocarditis showing scarring of both ventricles, more prominent in the left. The fibrosis shows a random distribution with epicardial, myocardium, and pericardial involvements. Media file 9: Endomyocardial biopsy of a 4-year-old child with clinical suspicion for myocarditis. This image is a low magnification of myocardium with lymphocytic infiltrate within myocardial fibers. The histologic findings are consistent with myocarditis and compatible with the clinical history, even in the absence of myocyte necrosis. Media file 10: Immunohistochemical stained section of the biopsy illustrated in the prior figure showing positivity for CD3 confirming a T-cell phenotype.
Endocarditis refers to endothelial damage with thrombosis on endocardial surfaces, typically on the heart valves (see the image below). Two major types of endocarditis exist: infectious endocarditis, which has a microbial etiology, and noninfectious endocarditis.
The population-based incidence of endocarditis is 4-10 per 100,000 per year, with a slightly higher rate in men.1,2The death rate due to endocarditis has been estimated at 1 per 100,000 per year, and it is greater than 10 times that amount in an urban population with a high rate of intravenous drug abuse (IVDA).3 Endocarditis accounts for about 0.75 admissions per 1000 per year in large community hospitals.4 Endocarditis begins as endothelial damage and sterile surface microthrombus, which, in the absence of bacteremia, regresses or grows into macrothrombi (noninfectious endocarditis).
The rate of culture-negative endocarditis varies from 7% to 33% and is increased in community-acquired infections because of antibiotic treatment before diagnosis.6 No association exists between culture negativity and underlying etiology or risk factors. If a full work-up is performed at a tertiary reference center, including serology and culture for esoteric organisms and polymerase chain reaction (PCR), an etiology is found in over 75% of cases of endocarditis with an initial negative culture. The most common organisms are C burnetii and Bartonella species.7 Endocarditis generally refers to inflammation on the valve leaflets, although the endocardial lining of the atrium and ventricles may also be involved, especially after surgery. The process tends to begin on the lines of closure, where the pressure is greatest (atrial surfaces of the atrioventricular valves and the ventricular surface of the semilunar valves).
The clinical symptoms of infectious endocarditis may be general (related to the infectious agent) or specific (related to the site or heart valve affected) and related to valvular insufficiency, with concomitant infectious symptoms. The classic signs of Osler nodes and Janeway lesions are increasingly uncommon, but microembolic phenomena such as splinter hemorrhages, Roth spots, and glomerulonephritis are still frequently observed in patients in the 21st century. Previously, infectious endocarditis has been diagnosed using clinical criteria (Duke criteria), dividing cases into possible and probable endocarditis. Current imaging modalities, especially transesophageal echocardiography and computed tomography (CT) scanner, have largely supplanted other tests. Treatment of infectious endocarditis includes antibiotics, and surgery if the valve is irreversibly insufficient. Surgical options include replacement, and repair if possible. In general, between 14% and 37% of cases require surgery. In infectious endocarditis, the valve may appear hemorrhagic and roughened, in early or treated lesions, with vegetations that may be inconspicuous or large. Especially bulky vegetations are typical of fungal endocarditis. Perforation of the valve leaflet is nearly pathognomonic for a later stage endocarditis, because only infectious processes result in significant valve tissue destruction. In autopsy specimens, discrete areas of endocardial fibrosis, or jet lesions, may be seen on the atrial surfaces in cases of atrioventricular valve endocarditis, or the ventricular outflow in aortic or pulmonary endocarditis.
Two features are always present in infectious endocarditis: inflammation and surface thrombus. Depending on the duration of the infection and treatment, the inflammation may be primarily neutrophilic or mostly chronic. Macrophage giant cells are common, especially toward the luminal surface. Organizing and organized thrombi with fibrosis are common in lesions that have been present for weeks or more. In acute lesions, clusters of organisms are frequently found, often gram-positive cocci, with the acute exudate and surface thrombus. See the following images.
Immunohistochemistry (IHC) has been used for the detection of fastidious bacteria in cases of culture-negative endocarditis, specifically for Coxiella and Legionella infection. Immunohistochemical studies of these organisms are generally restricted to reference laboratories with special expertise in identifying infectious agents. See the image below.
Polymerase chain reactions have been used for the detection of DNA specific for fastidious bacteria in culture-negative bacteria. Specific organisms that have been tested in this way include rickettsia (Coxiella, Bartonella, andTropheryma whipplei [Whipple disease]). The overall mortality of infectious endocarditis is approximately 20-25%, and it is increased with advanced patient age, left-sided disease, methicillin-resistant S aureus (MRSA) infection, and chronic renal failure. For staphylococcal endocarditis, mortality is associated with age 60 years or older, female sex, community-acquired infection, absence of heart murmur, presence of congestive heart failure, and central nervous system involvement.9The mortality rate of MRSA endocarditis in hemodialysis patients is as high as 90%.10 The long-term prognosis of patients with negative blood culture infective endocarditis has been found to be similar to that of patients with positive blood culture infective endocarditis across all age ranges.Infectious Endocarditis
Definition
Mitral valve: endocarditis with valve destruction and vegetation. Note the posterior leaflet of the mitral valve, with an irregular vegetation on the atrial surface, resulting in valve destruction at the commissure between the anterior leaflet and the posterior leaflet.
Several terms have been used for these conditions, including (subacute) bacterial endocarditis for infectious endocarditis, and nonbacterial thrombotic endocarditis (NBTE) or marantic endocarditis for noninfectious endocarditis. The term NBTE is still in current use, but this term and subacute bacterial endocarditis are to be discouraged, as not all infections are caused by bacteria.Epidemiology
Etiology
Malformed stenotic valves, or especially regurgitant valves, are predisposed to endocarditis. In the presence of bacteremia or fungemia, even transient or those with low microbe counts, microthrombi become infected, by adhesion and colonization of the thrombotic surfaces. Growth of organisms results in an inflammatory response, with neutrophil infiltration, enlargement of the thrombus, recruitment of matrix metalloproteinases (MMPs), and eventual destruction of collagen and cusp perforation. In approximately 25% of patients, however, neither structural valve abnormalities nor predisposing conditions are evident.
Congenital valve abnormalities, acquired valve disease, prostheses, and previous cardiac surgery for structural congenital heart disease increase the risk for endocarditis and are indications for antibiotic prophylaxis for dental and other invasive procedures. In nosocomial endocarditis, bacteremic conditions are present in nearly 40% of cases and include intravenous drug abuse, hemodialysis, catheterizations, and intravascular devices.5
The organisms responsible for most cases of infectious endocarditis are gram-positive cocci: streptococci and, increasingly, staphylococci. The most common microbial infection is staphylococcus. Hospital-acquired infectionis often associated with hemodialysis, prosthetic valvular infection, malignancies, and vascular interventions. Some cases of culture-negative endocarditis are caused by fastidious gram-negative organisms of the Haemophilus parainfluenzae, Actinobacillus, Actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae (HACEK) group, which constitute approximately 1-3% of cases of community-acquired endocarditis on native and prosthetic valves, and may have a relatively good prognosis.
Organisms causing community-acquired endocarditis include the following:
Organisms responsible for nosocomial endocarditis include the following:
Location
The valves most commonly infected are left-sided valves, with approximately equal frequency between the mitral and aortic valves. Vegetations on the mitral valve can extend onto the noncoronary and left cusps of the aortic valve, as they are contiguous, and double aortic and mitral valve replacements are not rare. Left-sided valve endocarditis is more frequent, even in drug addicts, than right-sided endocarditis,3 although infections of the tricuspid and pulmonary valves are highly suspicious of intravenous drug abuse. Tricuspid valve endocarditis may occur in community-acquired infection, usually in intravenous drug addicts, or hospital-acquired infections fromimplanted devices. Isolated pulmonary valve endocarditis is rare (except in patients with congenital heart disease) and may cause confusing clinical symptoms.Clinical Features and Imaging
Gross Findings
Upon autopsy, or with complete valve replacement, many valves demonstrate underling pathology such as bicuspid aortic valve, mitral valve prolapse, or postinflammatory valve disease, predisposing the patient to endocarditis. See the images below.
Aortic valve: healed endocarditis. Note the gaping hole with the fibrous rim, and a small strand at the free edge. The hole is at the line of closure. The affected valve is the left cusp. Note the right noncoronary cusp (immediate to the left in this image) demonstrates a small, multichanneled fenestration, at the commissure, immediately adjacent to similar fenestrations in the left coronary cusp. These are physiologic lesions occurring with age and are unrelated to endocarditis.
Aortic valve: bicuspid, with infectious endocarditis. In this excised valve, note the bulky vegetations on the ventricular surfaces, with distortion of the valve surfaces.
Mitral valve: postrheumatic, with infectious endocarditis. A defect is seen in the scarred valve, with focal surface hemorrhage. The patient also underwent aortic valve replacement, as there was contiguous infection.
Microscopic Findings
The surface of the valves, in most cases, demonstrates areas of acute neutrophilic inflammation with admixed fibrin and platelets. Degenerated bacterial colonies are seen at the left. Also, areas of microcalcification may mimic bacterial deposits.
Infectious endocarditis, subacute phase. Hemorrhage and prominent granulation tissue with neovascularity is apparent throughout. This aortic valve showed fibrin exudate on the ventricular surface (below), with more prominent organization and granulation on the aortic surface (above).
Infectious endocarditis, surface of valve leaflet with fibrin; higher magnification of previous image. A chronic infiltrate is seen, just under the denuded thrombosed surface, with primarily macrophages and focal macrophage giant cells.
The most common valve lesion in patients with lupus is related to the antiphospholipid syndrome, and histologically they are indistinguishable from thrombi (nonbacterial thrombotic endocarditis or marantic endocarditis).8 True inflammatory autoimmune valvulitis is rare and has gone by the eponymic term Libman-Sacks endocarditis, in the case of lupus.Immunohistochemistry
Bioprosthetic valve with endocarditis. Note the large bacterial colony (staphylococci by culture) in the absence of significant inflammation; the xenograft tissue is not viable, and nuclear detail is not apparent.
Molecular/Genetics
Prognosis and Predictive Factors
Multimedia
Media file 1: Mitral valve: endocarditis with valve destruction and vegetation. Note the posterior leaflet of the mitral valve, with an irregular vegetation on the atrial surface, resulting in valve destruction at the commissure between the anterior leaflet and the posterior leaflet. Media file 2: Aortic valve: healed endocarditis. Note the gaping hole with the fibrous rim, and a small strand at the free edge. The hole is at the line of closure. The affected valve is the left cusp. Note the right noncoronary cusp (immediate to the left in this image) demonstrates a small, multichanneled fenestration, at the commissure, immediately adjacent to similar fenestrations in the left coronary cusp. These are physiologic lesions occurring with age and are unrelated to endocarditis. Media file 3: Aortic valve: bicuspid, with infectious endocarditis. In this excised valve, note the bulky vegetations on the ventricular surfaces, with distortion of the valve surfaces. Media file 4: Mitral valve: postrheumatic, with infectious endocarditis. A defect is seen in the scarred valve, with focal surface hemorrhage. The patient also underwent aortic valve replacement, as there was contiguous infection. Media file 5: The surface of the valves, in most cases, demonstrates areas of acute neutrophilic inflammation with admixed fibrin and platelets. Degenerated bacterial colonies are seen at the left. Also, areas of microcalcification may mimic bacterial deposits. Media file 6: Infectious endocarditis, subacute phase. Hemorrhage and prominent granulation tissue with neovascularity is apparent throughout. This aortic valve showed fibrin exudate on the ventricular surface (below), with more prominent organization and granulation on the aortic surface (above). Media file 7: Infectious endocarditis, surface of valve leaflet with fibrin; higher magnification of previous image. A chronic infiltrate is seen, just under the denuded thrombosed surface, with primarily macrophages and focal macrophage giant cells. Media file 8: Bioprosthetic valve with endocarditis. Note the large bacterial colony (staphylococci by culture) in the absence of significant inflammation; the xenograft tissue is not viable, and nuclear detail is not apparent.
Dilated cardiomyopathy (DCM) denotes global left ventricular systolic dysfunction in the absence of hypertension, valve disease, or significant coronary artery disease.1 Dilated cardiomyopathy is characterized by ventricular chamber enlargement and systolic dysfunction with normal left ventricular wall thickness (see the image below).2 Right ventricular dilatation and dysfunction may be present but are not necessary for the diagnosis. Dilated cardiomyopathy is a largely irreversible form of primary heart muscle disease with no clear cause. The estimated prevalence of dilated cardiomyopathy is 1:2500. This condition is among the most common causes of heart failure. The incidence of dilated cardiomyopathy discovered at autopsy is estimated to be 4.5 cases per 100,000 population per year, whereas the clinical incidence is 2.45 cases per 100,000 population per year.3 Dilated cardiomyopathy can be classified by cause as familial, primary without family history, or secondary (associated with or caused by other conditions). Approximately 2 of 3 patients have no known family history (sporadic dilated cardiomyopathy). About 15% of sporadic cases arise from chronic myocarditis, leading to scarring and heart failure. Viruses that cause myocarditis include coxsackievirus, adenovirus, parvovirus, andhuman immunodeficiency virus (HIV). Dilated cardiomyopathy is a diffuse process involving cardiomyocytes of both ventricles (see the image below); atrial function is also decreased. Dilated cardiomyopathy is a progressive, usually irreversible disease causing heart failure, left ventricular contractile dysfunction, ventricular and supraventricular arrhythmias, conduction system abnormalities,thromboembolism, and sudden death.2 Dilated cardiomyopathy may manifest clinically at a wide range of ages, but this condition most commonly occurs in the third or fourth decade of life. Dilated cardiomyopathy is usually identified when limiting symptoms are severe, but arrhythmias or sudden death are uncommonly early manifestations. In family screening studies with echocardiography, asymptomatic or mildly symptomatic relatives may be identified. In contrast to arrhythmogenic and hypertrophic cardiomyopathy, arrhythmias are typically prominent only after the onset of significant heart failure. The hallmark gross finding at autopsy is left ventricular dilatation, usually more than 4 cm. Cardiomegaly is usually considered a requisite for the diagnosis of dilated cardiomyopathy.6 The mean heart weight is about 600 g.7 Some patients with dilated cardiomyopathy have very little cardiac enlargement, and the diagnosis must be made on clinical grounds.4 Typically, 4-chamber dilatation that is greater in the ventricles than the atria is found. In patients with a history of atrial fibrillation, atrial dilatation may be prominent. At autopsy, measuring the chamber cavity at the level of the papillary muscles in a transverse cut best assesses left ventricular dilatation. Concomitant right ventricular dilatation results in the typical globular appearance of the heart. The histologic features of dilated cardiomyopathy are nonspecific; therefore, it is a microscopic diagnosis of exclusion. In biopsies, the findings range from minimal variation in myocyte size to typical features of myofiber loss, interstitial fibrosis (see the image below), and marked variation in myofiber size. The important features are negative findings, such as the lack of inflammation, amyloid, iron, and granulomas. The role of endomyocardial biopsy in the diagnosis of dilated cardiomyopathy is primarily to exclude secondary causes. Endomyocardial biopsy may establish a specific diagnosis in approximately 25% of patients; these have primarily been patients with amyloidosis, hemochromatosis, and adriamycin toxicity. Immunohistochemical (IHC) techniques are not useful for the diagnosis of dilated cardiomyopathy. Immunolocalization of sarcomeric and cytoskeletal proteins have demonstrated abnormal distribution in explanted hearts from patients with dilated cardiomyopathy. Tubulin and desmin are increased in amount and irregularly distributed.12 Titin, a member of the sarcomeric skeleton family, is reduced, usually in areas where contractile material is lacking.12 Connexin-43 is also decreased.13 Increased myocyte cell death and apoptosis is found,14along with regeneration of myocytes with the expression of proliferating cell nuclear antigen (PCNA) and Ki-67.15 Dilated cardiomyopathy is associated with a less than 50% survival at 10 years. With better supportive care, 5-year and 10-year survival has been reported.18 Heart transplantation is the treatment of choice. Peripartum cardiomyopathy may be reversible in up to 50% of patients but often recurs with subsequent pregnancy. There is also a negative association in dilated cardiomyopathy between survival and frequent ventricular tachyarrhythmias that required antiarrhythmic treatment or automated implantable cardioverter-defibrillator (AICD) placement.Dilated Cardiomyopathy
Definition
Gross heart specimen from a patient with dilated cardiomyopathy who died in end-stage heart failure. Defibrillator leads are in the right heart. The ventricles are dilated with normal ventricular wall thicknesses, imparting an appearance of thin ventricular walls. The ventricles are dilated more than the atria.
Epidemiology
Etiology
Noninflammatory etiologies and associations include alcoholism, anthracycline drugs, ingestion of metals, autoimmune and systemic disorders, and mitochondrial disorders. The distinction between primary and secondary dilated cardiomyopathy is sometimes blurred, as is the distinction between the cause and risk factor(s) for many of these associated conditions. Familial dilated cardiomyopathy, which is considered to compose at least 25% of patients,2 is usually autosomal dominant, with X-linked autosomal recessive and mitochondrial inheritance occurring less frequently.Location
Heart section from a cardiac explant in a patient with end-stage cardiomyopathy. Note the cardiomyocyte multinucleation. The change is nonspecific and can be seen in heart failure of any cause.
Clinical Features and Imaging
Dilated cardiomyopathy is defined as increased left ventricular diastolic dimension and decreased shortening fraction, usually less than 25%. Note that postmortem ventricular measurements might underestimate the diameter measurement, as precise end-diastolic measurements are impossible.
The term "mildly dilated cardiomyopathy" describes patients with advanced heart failure without restrictive hemodynamics or significant left ventricular dilatation. A family history of this condition is present in over 50% of these patients. The clinical picture and prognosis of mildly dilated cardiomyopathy are very similar to those of typical dilated cardiomyopathy.4 Differential Diagnosis
The clinical and pathologic differential diagnosis of dilated cardiomyopathy is to exclude secondary causes of heart failure. The distinction between coronary artery disease resulting in cardiomyopathy (ischemic cardiomyopathy) and primary dilated cardiomyopathy can be problematic. Some authors have suggested that the diagnosis of ischemic cardiomyopathy be made if coronary artery disease and concomitant global left ventricular dysfunction that is out of proportion to the coronary obstruction exists; for example, if an ejection fraction of less than 40% with less than or equal to 50% narrowing of a proximal artery or more than 50% narrowing of a distal artery is found. This definition of ischemic cardiomyopathy has been shown to be ineffective.5 The term ischemic cardiomyopathy is now generally reserved for patients with severe coronary disease and global left ventricular dysfunction, typically with a healed transmural infarct.
Pathologically, the histologic features are nonspecific (see Microscopic Findings). Grossly, enlarged, dilated hearts can be seen in long-standing hypertensive heart disease, and valve disease and severe coronary disease should be excluded. At endomyocardial biopsy, amyloid, iron deposition, and significant inflammation should be excluded by routine staining supplemented by special stains. In addition, the clinical history that excludes other causes of heart failure should be elicited before a specific diagnosis of dilated cardiomyopathy is made.Gross Findings
Left ventricular wall thickness is often normal, in contrast to hypertensive cardiomyopathy with failure.8 Mitral insufficiency may result from papillary muscle dysfunction secondary to ventricular dilatation and changes in ventricular wall shape.6 In contrast, tricuspid regurgitation results from annular dilatation.7
Mural thrombi are common in patients who do not receive anticoagulation. Ventricular endocardial fibrous plaques, presumably a sequela of thrombi, occur in about 10% of cases.6 Mild diffuse or patchy endocardial fibrosis, especially toward the ventricular outflow tracts, is frequent and is likely a result of cardiac dilatation.Microscopic Findings
Heart section from a cardiac explant in a patient with end-stage cardiomyopathy. There is focal interstitial fibrosis. The change is nonspecific and can be seen in heart failure of any cause.
In explanted hearts, the findings are typically nonspecific diffuse findings of myocytes, including variation in size, nuclear variation (as seen in the following image), and interstitial fibrosis. Myofiber disarray and infiltrative processes such as amyloid are absent. Inflammatory cells, including mast cells that tend to be increased in areas of fibrosis, increase,9 but distinct infiltrates and myocyte necrosis are usually absent. Interstitial and replacement fibrosis are also common and correlate with inhomogeneous perfusion defects by single photon emission computed tomography (SPECT) scanning.10 Heart section from a cardiac explant in a patient with end-stage cardiomyopathy. Note the variation in nuclear size. The change is nonspecific and can be seen in heart failure of any cause.
Transmural scars may also occur in dilated cardiomyopathy. Quantitation of collagen has shown up to 4 times the normal collagen concentration, with a decrease in mature cross-linked collagen, correlating with an increase in neutrophil-type collagenase activity.11
Ultrastructurally,12 hypertrophied as well as atrophied myocytes exist, the volume density of myofibrils is reduced, and mitochondrial density is normal, but the mitochondria are more numerous and small.12
An image of a heart section in a patient who had end-stage cardiomyopathy is depicted below.Heart section from a cardiac explant in a patient with end-stage cardiomyopathy. Note the intracellular accumulation of amorphous material (basophilic degeneration). The change is nonspecific and can be seen in heart failure of any cause.
Immunohistochemistry
In patients with laminin-A mutations, ultrastructural immunolabeling showed absence of the nuclear envelope of patients with lamin A/C gene (LMNA) mutations.16 In cases of dystrophin-related dilated cardiomyopathy (up to 6% in males with dilated cardiomyopathy), immunohistochemical and molecular studies are essential to identify protein and gene defects.17Molecular/Genetics
Autosomal dominant forms of dilated cardiomyopathy are primarily caused by mutations in cytoskeletal proteins, and less commonly sarcomeric proteins, nuclear membrane, and transcriptional coactivator proteins, and intercalated disc protein genes. The most commonly identified are mutations of the LMNA gene, encoding the lamin A and C nuclear envelope proteins; these patients often have atrioventricular block.
The X-linked gene responsible for Emery-Dreifuss muscular dystrophy, emerin (another nuclear lamin protein), may also cause dilated cardiomyopathy. Other X-linked diseases associated with dilated cardiomyopathy include muscular dystrophies (eg, Becker and Duchenne); these patients are more likely to have elevated serum creatine kinase levels.17 Dilated cardiomyopathy may also occur in patients with mitochondrial myopathies and inherited metabolic disorders (eg, hemochromatosis).
Sarcomeric proteins are increasingly being identified in familial dilated cardiomyopathy. These include alpha-cardiac actin; alpha-tropomyosin; cardiac troponin T, I, and C; beta- and alpha-myosin heavy chain; myosin binding protein C; muscle LIM protein; alpha-actinin-2; ZASP, and titin.2 In some families with sarcomeric mutations, hypertrophic and dilated phenotypes overlap, highlighting the plasticity of these genes and occasional genotypic-phenotypic discordance. These findings also underline the importance of defining cardiomyopathy by morphologic and not genetic features.Prognosis and Predictive Factors
Multimedia
Media file 1: Gross heart specimen from a patient with dilated cardiomyopathy who died in end-stage heart failure. Defibrillator leads are in the right heart. The ventricles are dilated with normal ventricular wall thicknesses, imparting an appearance of thin ventricular walls. The ventricles are dilated more than the atria. Media file 2: Heart section from a cardiac explant in a patient with end-stage cardiomyopathy. Note the variation in nuclear size. The change is nonspecific and can be seen in heart failure of any cause. Media file 3: Heart section from a cardiac explant in a patient with end-stage cardiomyopathy. Note the cardiomyocyte multinucleation. The change is nonspecific and can be seen in heart failure of any cause. Media file 4: Heart section from a cardiac explant in a patient with end-stage cardiomyopathy. There is focal interstitial fibrosis. The change is nonspecific and can be seen in heart failure of any cause. Media file 5: Heart section from a cardiac explant in a patient with end-stage cardiomyopathy. Note the intracellular accumulation of amorphous material (basophilic degeneration). The change is nonspecific and can be seen in heart failure of any cause.
