Heart, Pericardium, and Blood Vessels





Heart


Cardiomyopathy


Clinical Features


Hypertrophic Cardiomyopathy





  • Myocardial disease characterized by left ventricular hypertrophy in the absence of systemic hypertension, aortic valve stenosis, or overt infiltrative diseases



  • Associated with normal systolic function and diastolic dysfunction; systolic dynamic obstruction of the left ventricular outflow tract occurs in 25%



  • Estimated prevalence of unexplained left ventricular hypertrophy on echocardiography compatible with a diagnosis of hypertrophic cardiomyopathy is 1 in 500



  • Clinical presentation varies from asymptomatic to congestive heart failure, syncope, dyspnea, chest pain, and sudden death



  • Associated with sudden death in athletes during exercise



Dilated Cardiomyopathy





  • Most common cause of congestive heart failure in young patients and one of the leading indications for heart transplantation



  • Patient presentation related to systolic dysfunction and progressive cardiac chamber enlargement with secondary mitral or tricuspid regurgitation and arrhythmias



  • Usually idiopathic, but can be caused by toxins, drugs, and metabolic derangements; can be associated with myocarditis, alcohol abuse, pregnancy, familial incidence, nutritional deficiencies, neuromuscular disorders, and endocrine abnormalities



  • Idiopathic dilated cardiomyopathy is a diagnosis of exclusion; heart failure is out of proportion to the presence of any concomitant coronary artery disease, systemic hypertension, or valvular heart disease



Restrictive Cardiomyopathy





  • Patients present with symptoms associated with diastolic dysfunction, reduced diastolic volume, and normal systolic function



  • Causes include: (a) endomyocardial scarring (idiopathic restrictive cardiomyopathy, endomyocardial fibrosis, Löffler syndrome, and endocardial fibroelastosis), (b) storage disease (hemochromatosis, glycogen storage disease, Fabry disease), or (c) myocardial infiltrate (amyloidosis, sarcoidosis, and radiation fibrosis)



  • Idiopathic restrictive cardiomyopathy




    • Rare entity with autosomal dominant transmission and associated with skeletal myopathy




  • Endomyocardial fibrosis




    • Recognized as a tropical disease, occurring most often in sub-Saharan Africa, affecting children and young adults




  • Löffler syndrome (Löffler endomyocarditis and endocarditis parietalis fibroplastica)




    • Occurs in older patients and in men (more often than women) who live in the temperate zone



    • Often associated with reactive or neoplastic eosinophilia




  • Endocardial fibroelastosis




    • Classified as primary or secondary; secondary form is much more common



    • Primary form may be related to intrauterine myocardial injury with left ventricular dilation



    • Secondary form is most often associated with congenital heart disease involving the left ventricle such as aortic stenosis, hypoplastic left heart syndrome, and coarctation of the aorta




  • Hemochromatosis




    • Primary hemochromatosis is an autosomal recessive disorder in which excessive iron absorption leads to iron overload



    • Secondary hemochromatosis is associated with ineffective erythropoiesis, chronic liver disease, or multiple blood transfusions




Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy





  • Inherited heart muscle disease that may present with arrhythmias, heart failure, or sudden death



  • Arrhythmias are usually of right ventricular origin associated with global or regional dysfunction of the right ventricle



  • Increasingly recognized as an important cause of sudden cardiac death



  • Clinical diagnosis is based on diagnostic criteria originally proposed in 1994 by the European Society of Cardiology and Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology and revised in 2010



Gross Pathology


Hypertrophic Cardiomyopathy





  • Left ventricular hypertrophy, which may be symmetrical or asymmetrical



  • Asymmetrical forms include thickening of subaortic ventricular septum (which is at least 1.5 times that of the left ventricular free wall), midventricular segment, or apical region



  • Systolic anterior motion of the anterior mitral leaflet leads to a contact lesion in the septum, seen as an area of endocardial fibroelastosis



  • Mechanical trauma to the anterior mitral leaflet and chordae results in thickening and fibrosis of the valve



  • Foci of small scars often observed in the septum do not correspond to areas supplied by the major epicardial coronary arteries



Dilated Cardiomyopathy





  • Increased cardiac weight with dilatation of the left or both ventricles, often with four-chamber dilation



  • Normal or decreased left ventricular wall thickness due to chamber dilation



  • Mural thrombi may be present



  • Endocardial thickening is focal and may be related to organized thrombus or jet lesions from valvular regurgitation



  • Valves are normal, or may exhibit secondary changes associated with insufficiency such as dilated annulus or thickening of free edges



  • Coronary arteries are normal, or may exhibit mild atherosclerotic change within limits expected for the patient’s age



Restrictive Cardiomyopathy





  • Idiopathic restrictive cardiomyopathy




    • Firm myocardium with normal left ventricular wall thickness



    • Normal left ventricular cavity size



    • Often biatrial dilation



    • Endocardium is not grossly thickened




  • Endomyocardial fibrosis




    • Thick, white scarring of the left ventricular endocardium at the inflow tract and apex with encasement of papillary muscles and subvalvular apparatus, resulting in valvular regurgitation



    • Fibrosis of right ventricular apex seen in half of the cases




  • Löffler syndrome




    • Fibrosis of endocardium, characteristically with large mural thrombi at the inflow tract and apex of both ventricles




  • Endocardial fibroelastosis




    • Left ventricle is usually contracted but may be dilated



    • Diffusely thickened pearly white endocardium that may obscure trabeculae carneae




  • Hemochromatosis




    • Left ventricular hypertrophy with rusty-brown discoloration of myocardium




Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy





  • Replacement of right ventricular myocardium by adipose and fibrous tissue



  • In early disease, these changes are segmental, and present in the apex, right ventricular inlet, and right ventricular outflow tract



  • Progressive loss of myocardium leads to diffuse involvement with right ventricular dilation and localized ventricular aneurysms



  • Left ventricular involvement usually minor and seen in advanced stages with preferential involvement of the posterolateral wall; less frequently there is equal biventricular involvement



Histopathology


Hypertrophic Cardiomyopathy





  • Hypertrophy and disarray of myocytes with interstitial fibrosis ( Figure 18.1A and B )




    Figure 18.1


    Hypertrophic cardiomyopathy.

    A, Movat-stained histologic section shows disorganization in the arrangement of myocyte bundles with interstitial fibrosis. B, Disarray can also be observed in the myofibrils of individual myocytes. C, Dysplastic small intramural coronary arteries are often observed with a narrowed lumen, irregularly thickened wall, and adventitial fibrosis.



  • Disarray involves at least 10% of the myocardium and is maximal in the middle or deeper region of the interventricular septum



  • Intramural small coronary arteries are dysplastic with narrowed lumens, due to medial hyperplasia with or without intimal thickening (see Figure 18.1C )



  • Replacement fibrosis and myocardial scars



  • Should not be diagnosed on the basis of a right ventricular endomyocardial biopsy as disarray is common in the trabeculae of the right ventricle



Dilated Cardiomyopathy





  • Histopathologic findings are nonspecific



  • Myocyte hypertrophy with enlarged hyperchromatic nuclei, mixed with myocyte atrophy and degeneration



  • Varying extent of interstitial fibrosis sometimes associated with sparse inflammatory cell infiltrates



Restrictive Cardiomyopathy





  • Idiopathic restrictive cardiomyopathy




    • Diffuse interstitial fibrosis that surrounds individual myocytes




  • Endomyocardial fibrosis




    • Hyalinized collagen scarring of the endocardium with few mesenchymal cells



    • Fibrosis extends into the inner myocardium




  • Löffler syndrome




    • Three stages have been described



    • Once the fibrotic stage is reached, the distinction between endomyocardial fibrosis and Löffler syndrome based on pathologic features may not be possible




      • Acute necrotic stage: shows intense eosinophilic infiltrate in myocardium with arteritis



      • Thrombotic stage: characterized by superimposed thrombosis on thickened endocardium and thrombi in intramyocardial vessels



      • Fibrotic stage: shows thick endocardium with loosely arranged vascularized fibrous tissue in the deepest layer; vessels show intimal thickening and perivascular fibrosis





  • Endocardial fibroelastosis




    • Diffuse fibrosis of endocardium with prominent elastic fibers




  • Hemochromatosis




    • Hemosiderin deposition within myocytes ( Figure 18.2A )




      Figure 18.2


      Hemochromatosis.

      A, Iron deposits in the form of hemosiderin accumulate in the sarcoplasm of the myocytes as brown pigment, usually in the perinuclear region of the sarcoplasm where secondary lysosomes accumulate. In contrast to lipofuscin pigment, which is yellow, the hemosiderin pigment is brown and may be birefringent upon polarization. B, Perls Prussian blue stain highlights ferric iron in these secondary lysosomes, which are seen in the perinuclear and peripheral areas of the myocyte sarcoplasm.




Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy





  • Transmural extensive fatty replacement of the myocardium with fibrosis and myocyte atrophy ( Figure 18.3A )




    Figure 18.3


    Arrhythmogenic right ventricular cardiomyopathy.

    A, Histologic section of right ventricular wall shows a markedly thinned myocardium with fatty infiltration of the wall. B, Movat stain shows fibrous replacement of the myocytes.



  • Lymphocytic infiltrates associated with myocyte damage may be present



Special Stains and Immunohistochemistry





  • Masson trichrome highlights interstitial fibrosis and myofibrillar loss



  • Movat pentachrome highlights fibrosis and elastosis (see Figure 18.3B )



  • Prussian blue highlights iron deposition in myocytes and macrophages (see Figure 18.2B )



  • Periodic acid–Schiff (PAS) with and without diastase highlights glycogen accumulation in myocytes, including basophilic degeneration



Other Techniques for Diagnosis


Dilated Cardiomyopathy





  • Electron microscopy: myocyte degeneration with myofibrillar loss in some myocytes and myocyte hypertrophy in others; dilation of T tubules, increased number of mitochondria, and increased glycogen, lipid vacuoles, myelin figures, and phagolysosomes



Toxic Cardiomyopathy





  • Grading of endomyocardial biopsies for anthracycline-induced cardiotoxicity requires at least three pieces of myocardium and examination of 10 plastic-embedded semithin sections stained with toluidine blue




    • Grade 0: normal myocardium by light and electron microscopy



    • Grade 1: occasional isolated myocytes with myofibrillar loss or vacuolar degeneration (distended sarcoplasmic reticulum and T-tubular system) involving less than 5% of cells



    • Grade 1.5: scattered, single myocytes with myofibrillar loss or vacuolar degeneration affecting 5% to 15% of myocytes



    • Grade 2: clusters of affected myocytes affecting 16% to 25% of cells



    • Grade 2.5: 26% to 35% of myocytes affected



    • Grade 3: diffuse myocyte damage affecting more than 35% of cells; myocyte cell necrosis (total loss of contractile elements, loss of organelles, and mitochondrial and nuclear degeneration)




  • Chloroquine and hydroxychloroquine cardiotoxicity




    • Electron microscopy: Sarcoplasm contains numerous myelin figures, curvilinear bodies, and secondary lysosomes




Metabolic Cardiomyopathy





  • Fabry disease




    • Electron microscopy: electron-dense intracellular lamellar bodies or myelin figures corresponding to the accumulation of glycolipids




  • Mitochondrial cardiomyopathy




    • Electron microscopy: proliferation of mitochondria, which are pleomorphic in size and shape and have abnormal cristae and paracrystalline inclusions




  • Glycogen storage disease




    • Electron microscopy: markedly increased sarcoplasmic free glycogen; glycogen in lysosomes; vacuoles containing autophagic material




Differential Diagnosis


Hypertrophic Cardiomyopathy Versus Metabolic Cardiomyopathy





  • Myocyte sarcoplasmic vacuolization or granularity should raise suspicion for storage disease and mitochondrial abnormalities, which cause phenotype similar to hypertrophic cardiomyopathy; electron microscopy is necessary for complete evaluation



  • Fabry disease due to mutations in lysosomal α-galactosidase A



  • Adult-onset glycogen storage disease with left ventricular hypertrophy and Wolff-Parkinson-White syndrome due to mutations in the γ2 regulatory subunit of the adenosine monophosphate–activated protein kinase (PRKAG2)



  • X-linked hypertrophic cardiomyopathy (Danon disease) with skeletal myopathy and mental retardation due to mutations in lysosome-associated membrane protein (LAMP2)



  • Mitochondrial cardiomyopathy due to mutations in mitochondrial DNA



Symmetrical Hypertrophic Cardiomyopathy Versus Physiologic Hypertrophy in Response to Exercise (“Athlete’s Heart”)





  • Differentiation of physiologic cardiac hypertrophy induced by athletic training from those with structural disease may require extensive non-invasive and invasive clinical screening tests



Hypertrophic Cardiomyopathy Versus Age-Related Subaortic Bulging of the Interventricular Septum (Sigmoid or Catenoid Septum)





  • Anatomic variant commonly seen in elderly patients, which may be accentuated by concomitant systemic hypertension, simulating asymmetrical hypertrophic cardiomyopathy



Hypertrophic Cardiomyopathy Versus Diseases Associated With Left Ventricular Hypertrophy in Infants and Young Children





  • Infiltrative cardiomyopathies including type II Pompe disease, Hunter disease, and Hurler disease



  • Noonan syndrome resulting from PTPN11 (protein- tyrosine phosphatase, nonreceptor type 11) gene mutation presenting with cardiofacial abnormalities, including pulmonic valve stenosis and atrial septal defect




    • Infants of insulin-dependent diabetic mothers




Restrictive Cardiomyopathy Versus Constrictive Pericarditis





  • Diastolic filling is restricted in constrictive pericarditis by rigid, thickened pericardium with fibrous pericardial adhesions



  • Endomyocardial biopsy has proved useful in establishing diagnosis of infiltrative cardiomyopathies



  • A normal endomyocardial biopsy would direct the clinical workup to reevaluate the pericardium



Pearls





  • Cardiomyopathies are a heterogeneous group of diseases, manifesting as mechanical or electrical dysfunction of the heart, that frequently have a genetic cause.



  • Traditional functional classification of cardiomyopathies has been challenged as the genetic basis of a number of cardiomyopathies has become evident; moreover, hypertrophic cardiomyopathy and some infiltrative diseases may progress to a dilated form late in the course of the disease



  • Hypertrophic cardiomyopathy




    • Familial in at least 60% of cases, with autosomal dominant mode of inheritance but variable clinical expression in age of onset and severity



    • Sometimes referred to as disease of the sarcomere because mutations are most common in genes that encode sarcomeric proteins



    • Most common gene mutations involve the β-myosin heavy chain (MYH7, chromosome locus 14q12) and myosin-binding protein C (MYBPC3, chromosome locus 11p11.2)



    • Endomyocardial biopsy is almost never diagnostic but can be helpful to rule out other diagnoses



    • Disarray may be absent in small myectomy specimens, but presence of intramural coronary artery dysplasia and replacement or interstitial fibrosis is suggestive of hypertrophic cardiomyopathy




  • Dilated cardiomyopathy




    • Studies indicate that at least 30% of dilated cardiomyopathy cases may be familial



    • Pattern of inheritance is variable and includes autosomal dominant, autosomal recessive, and X-linked



    • Mutations are more varied and are found in genes encoding sarcomeric proteins, particularly titin, intermediate filaments, dystrophin-associated protein complex components, nuclear membrane proteins, and phospholamban




  • Arrhythmogenic right ventricular dysplasia/cardiomyopathy




    • Familial occurrence in about 30% to 50% of cases, with predominantly autosomal dominant pattern of inheritance and incomplete penetrance



    • Most common mutations are in genes encoding desmosomal proteins (desmoplakin, plakophilin-2, desmoglein-2, desmocollin-2, and plakoglobin)




  • There are considerable overlaps and variations in the phenotypic expression of genetic mutations associated with cardiomyopathies



  • Endomyocardial biopsy is able to establish the diagnosis in patients with unexplained cardiomyopathy with a high degree of sensitivity and specificity





Selected References




  • Arad M., Maron B.J., Gorham J.M., et. al.: Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med 2005; 352: pp. 362-372.



  • Gandjbakhch E., Redheuil A., Pousset F., et. al.: Clinical diagnosis, imaging, and genetics of arrhythmogenic right ventricular cardiomyopathy/dysplasia: JACC state-of-the-art review. J Am Coll Cardiol 2018; 72: pp. 784-804.



  • Elliott P., Andersson B., Arbustini E., et. al.: Classification of the cardiomyopathies: a position statement from the European Society of Cardiology working group on myocardial and pericardial diseases. Eur Heart J 2008; 29: pp. 270-276.



  • McNally E.M., Mestroni L.: Dilated cardiomyopathy: genetic determinants and mechanisms. Circ Res 2017; 121: pp. 731-748.



  • Leone O., Veinot J.P., Angelini A., et. al.: 2011 consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology. Cardiovasc Pathol 2012; 21: pp. 245-274.



  • Maron B.J., Towbin J.A., Thiene G., et. al.: Contemporary definitions and classification of the cardiomyopathies: an American Heart Association scientific statement from the council on clinical cardiology, heart failure and transplantation committee; quality of care and outcomes research and functional genomics and translational biology interdisciplinary working groups; and council on epidemiology and prevention. Circulation 2006; 113: pp. 1807-1816.



  • Olsen E.G., Spry C.J.: Relation between eosinophilia and endomyocardial disease. Prog Cardiovasc Dis 1995; 27: pp. 241-254.


Myocarditis


Clinical Features


Lymphocytic Myocarditis





  • Frequently asymptomatic, or having a subclinical course that later progresses to dilated cardiomyopathy



  • May present as chest pain, unexplained acute onset of congestive heart failure, ventricular arrhythmias, or sudden death



  • Viruses are the most common cause of myocarditis, particularly in children



Giant Cell Myocarditis





  • Typically affects young and middle-aged adults



  • Most patients present with rapidly progressive heart failure, often with refractory ventricular arrhythmia, rarely with heart block or chest pain mimicking myocardial infarction



  • Poor prognosis and often fatal if untreated



Eosinophilic Myocarditis





  • Hypersensitivity myocarditis




    • Believed to be an allergic delayed hypersensitivity reaction to diverse pharmacologic drugs and nutritional supplements



    • Reported complication of smallpox vaccination in young individuals



    • Associated with prolonged continuous administration of vasopressors, particularly dobutamine



    • Signs and symptoms are nonspecific and include typical allergic reaction (fever, rash, and blood eosinophilia), arrhythmias, sudden death, and congestive heart failure




  • Acute necrotizing eosinophilic myocarditis




    • Thought to represent the most severe form of hypersensitivity myocarditis but can also be associated with viral infections, cancer, connective tissue diseases, and Churg-Strauss syndrome



    • Presents with fulminant heart failure and can be rapidly fatal




  • Hypereosinophilic syndrome




    • Characterized by eosinophilia in the blood and bone marrow and tissue infiltration with eosinophils in multiple organs



    • Predominantly affects males between 20 and 50 years old



    • Cardiac involvement is most common and can present with restrictive physiology



    • Mural thrombi are frequently formed and can lead to systemic embolization




Gross Pathology





  • Variable degrees of cardiac hypertrophy and possible chamber dilation may be seen



  • Affected myocardium appears as pale foci, sometimes with minute hemorrhages



  • Irregular and geographic fibrous scars without predilection to particular sites, and affecting both ventricles and interventricular septum, develop in giant cell myocarditis if patient survives



  • In hypereosinophilic syndrome, endocardial damage leads to mural thrombosis



  • Associated fibrinous pericarditis and pericardial effusion



Histopathology


Lymphocytic Myocarditis





  • Focal to diffuse interstitial mononuclear cell infiltrate, predominantly lymphocytes, with associated myocyte necrosis ( Figure 18.4 )




    Figure 18.4


    Lymphocytic myocarditis.

    Histologic section shows interstitial infiltrate of lymphocytes with rare eosinophils. Note the thinning of the myocytes in areas of myocyte necrosis.



  • In endomyocardial biopsies, sparse lymphocytic infiltrate not associated with myocyte damage is diagnosed as borderline myocarditis, based on the Dallas criteria



  • Repeat biopsies showing persistent lymphocytic infiltrate is called persistent myocarditis , a less intense infiltrate is resolving myocarditis , and absence of inflammatory infiltrate is resolved myocarditis



Giant Cell Myocarditis





  • Multifocal-to-diffuse infiltrate consisting of lymphocytes and macrophages with multinucleated giant cells ( Figure 18.5A and B )




    Figure 18.5


    Giant cell myocarditis.

    A, Histologic section shows extensive areas of myocyte dropout with a mixed inflammatory infiltrate. B, Conspicuous giant cells admixed with macrophages, lymphocytes, and eosinophils do not form discrete granulomas.



  • Eosinophils are often present



  • Occasional poorly formed granuloma-like structures may be seen



  • Geographic areas of myocyte damage or necrosis with varying degrees of fibrosis are evident on low magnification



Eosinophilic Myocarditis





  • Patchy interstitial and perivascular infiltrates consisting of many eosinophils mixed with histiocytes, lymphocytes, and plasma cells



  • May involve the endocardium and epicardium



  • Lesions are all of the same age



  • Usually only minimal myocyte necrosis and interstitial fibrosis



  • Acute necrotizing eosinophilic myocarditis shows intense and diffuse infiltrates with extensive myocyte necrosis



  • Hypereosinophilic syndrome also shows eosinophilic infiltrates with myocyte necrosis



  • Charcot-Leyden crystals can be seen



Special Stains and Immunohistochemistry





  • Gram, Gomori methenamine silver (GMS), PAS, and Ziehl-Neelsen stains to demonstrate causative organisms in infectious myocarditis



  • The utility of immunohistochemical staining and quantitation of inflammatory cells using T- and B-cell markers, CD68, and HLA-DR is not yet firmly established



Other Techniques for Diagnosis





  • In situ hybridization and polymerase chain reaction for viral detection; most commonly detected viruses are enteroviruses (Coxsackie B), parvovirus B19, adenovirus, human herpesvirus type 6, cytomegalovirus, influenza virus A and B, Epstein-Barr virus, and hepatitis C virus (HCV)



Differential Diagnosis


Lymphocytic Myocarditis





  • Myocarditis associated with infectious agents including Lyme disease, leptospirosis, typhoid fever, syphilis, chlamydia and rickettsial infections, and AIDS



  • Myocarditis associated with collagen vascular disease and autoimmune disorders



  • Myocarditis associated with cancer immunotherapies including immune checkpoint inhibitors



  • Toxic myocarditis




    • Includes toxin-induced myocardial injury (e.g., diphtheria exotoxin) and dose-related, direct toxic effects of drugs on the myocardium



    • Small foci of myocardial necrosis with contraction bands can be seen in patients who are on vasopressor agents, have elevated endogenous catecholamines, or are cocaine abusers



    • Inflammatory infiltrates are predominantly macrophages



    • Lesions are of varying ages




  • Microbiologic, serologic, and clinical correlation help make the diagnosis



Giant Cell Myocarditis





  • Sarcoidosis




    • Dense fibrous scars toward the base of the heart involving the septum more heavily than the free wall of the left or right ventricle can be seen in sarcoidosis



    • Characterized by well-formed granulomas and fibrosis with few or no eosinophils ( Figure 18.6 )




      Figure 18.6


      Cardiac sarcoidosis.

      Epithelioid granulomas with multinucleated giant cells are seen in areas of replacement fibrosis. Unlike giant cell myocarditis, the granulomas are discrete in a background of dense fibrous tissue.



    • Generally lacks active myocyte necrosis



    • Rarely present as isolated cardiac involvement; lymph node or lung involvement almost always present




  • Rheumatic myocarditis




    • Endocardial and interstitial Aschoff granulomas with giant cells




  • Infectious granulomatous diseases




    • Giant cells may be seen in tuberculosis, cryptococcosis, syphilitic myocarditis, or measles myocarditis



    • Myocardial involvement is rarely isolated



    • Special stains for microorganisms should be performed




  • Foreign-body reaction




    • Birefringent material under polarized light



    • Myocardial reaction to pacemaker leads, assist devices




Eosinophilic Myocarditis





  • Parasitic infestation with peripheral eosinophilia (e.g., Trichinella species)



Neutrophilic Infiltrates





  • Usually seen in systemic bacterial and fungal infections in the immunocompromised host or spread by direct extension




    • Focal neutrophilic infiltrates with myocyte necrosis and microabscesses




  • Myocardial infarction




    • A zone of necrosis with neutrophilic infiltration at the periphery corresponding to a territory supplied by an epicardial coronary artery




Pearls





  • Lymphocytic myocarditis




    • Detection of viral genome, specifically enteroviruses, is an independent predictor of poor clinical outcome in patients with dilated cardiomyopathy



    • Detection of autoantibodies directed against myocardial structural, sarcoplasmic, or sarcolemmal proteins suggests immune-mediated myocarditis




  • Giant cell myocarditis




    • Up to 20% of patients have other inflammatory diseases, especially inflammatory bowel disease or autoimmune disorders



    • Most commonly associated tumor is thymoma



    • Giant cell myocarditis is known to recur in transplanted hearts




  • Hypersensitivity myocarditis




    • Diagnosis requires high clinical index of suspicion



    • Endomyocardial biopsy necessary to establish the diagnosis



    • No correlation between the duration and dose of the drug and the severity of myocarditis



    • Treatment requires removal of the offending substance; immunosuppressive therapy may be indicated in severe cases






Selected References




  • Caforio A.L., Pankuweit S., Arbustini E., et. al.: Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2013; 34: pp. 2636-2648. 2648a–2648d



  • Calabrese F., Thiene G.: Myocarditis and inflammatory cardiomyopathy: microbiological and molecular biological aspects. Cardiovasc Res 2003; 60: pp. 11-25.



  • Champion S.N., Stone J.R.: Immune checkpoint inhibitor associated myocarditis occurs in both high-grade and low-grade forms. Mod Pathol 2020; 33: pp. 99-108.



  • Ginsberg F., Parrillo J.E.: Eosinophilic myocarditis. Heart Fail Clin 2005; 1: pp. 419-429.


Amyloidosis


Clinical Features





  • Amyloid deposition in the cardiovascular system may be local (isolated atrial, valvular, or aortic amyloidosis) or be part of a systemic involvement



  • When symptomatic, patients can present with restrictive cardiomyopathy, congestive heart failure, atypical chest pain, and arrhythmias



  • Preponderance of male patients



Gross Pathology





  • Cardiac amyloidosis usually leads to cardiomegaly with biventricular hypertrophy



  • Cut surface may show a variable appearance, ranging from normal to firm and rubbery myocardium, depending on extent of amyloid deposition



  • Tiny, semitranslucent, waxy yellow-ochre nodules may be seen on the endocardium, more prominent in the left atrium; in severe cases, they are visible in all chambers and on the valvular endocardium



Histopathology





  • Characteristic interstitial deposition of extracellular eosinophilic material surrounding individual myocytes results in atrophy and loss of myocytes ( Figure 18.7A )




    Figure 18.7


    Amyloidosis.

    A, Abundant eosinophilic material is deposited around myocytes, which show marked variation in size on cross section, indicating hypertrophy and degeneration . B, Individual myocytes are outlined by amyloid deposits that fluoresce with thioflavin stain. C, Immunohistochemical staining with λ light chains is positive in this case.



  • Other patterns of infiltration are nodular, subendocardial, vascular, and mixed



  • Mononuclear inflammatory cell infiltrates can be found and correlate with poor prognosis



Special Stains and Immunohistochemistry





  • Congo red: apple-green birefringence under polarized light, bright orange-red fluorescence using Texas red filter visualized under ultraviolet light



  • Thioflavin T or thioflavin S: ultraviolet fluorescence of the amyloid deposits (see Figure 18.7B )



  • Sulfated alcian blue: highlights green-staining amyloid surrounding individual myocytes and red-staining interstitial fibrosis



  • Immunohistochemical staining by immunoperoxidase or immunofluorescence method with the following antibodies is useful in cardiac amyloidosis: transthyretin, κ and λ light chains, heavy chains, amyloid A, and atrial natriuretic peptide (see Figure 18.7C )



Other Techniques for Diagnosis





  • Electron microscopy: interstitial expansion by extracellular, nonbranching, randomly oriented fibrils measuring 8 to 10 nm in diameter



  • Laser microdissection and tandem mass spectrometry–based proteomic analysis can be useful in establishing the type of amyloid



Differential Diagnosis


Hyalinized Collagen





  • May appear similar to amyloid on hematoxylin and eosin-stained sections but exhibits periodic banding pattern on polarization



  • Congo red may have false-positive birefringence in collagen if staining method is not optimal



  • Blue collagen fibers can be differentiated from the blue-gray hue of amyloid on Masson trichrome stain



Pearls





  • Amyloidosis involving the heart can be divided into primary (light and heavy chains), secondary (amyloid A), hereditary (mutant transthyretin), senile systemic (wild-type transthyretin), isolated atrial (atrial natriuretic peptide), and hemodialysis-related (β 2 -microglobulin)



  • Deposits in the heart are most common in primary (immunoglobulin light chain) and transthyretin amyloidosis



  • Localized forms of amyloidosis in the atria, valves, and aorta are generally incidental findings not associated with significant clinical disease



  • Endomyocardial biopsy is a safe method to establish the diagnosis



  • In early disease, amyloid deposits may be visible only with electron microscopy



  • The type of protein needs to be identified by immunophenotyping or by mass spectroscopy, as it has prognostic and therapeutic implications



  • Thioflavin T or S is more sensitive than Congo red and easy to perform but requires fluorescence microscopy





Selected References




  • Tan C.D., Rodríguez E.R.: Cardiac amyloidosis.Picken M.M.Herrera G.A.Dogan A.Amyloid and Related Disorders: Surgical Pathology and Clinical Correlations.2015.Humana PressNew York, NY:pp. 391-411.



  • Vrana J.A., Gamez J.D., Madden B.J., et. al.: Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens. Blood 2009; 114: pp. 4957-4959.


Sarcoidosis


Clinical Features





  • Affects young or middle-aged adults of either sex



  • Lung, lymph nodes, skin, and eyes commonly involved; rarely, isolated cardiac involvement has been reported



  • Cardiac involvement present in about 25% of sarcoidosis patients in autopsy series, with less than 5% having associated symptoms



  • Patients present with arrhythmias, heart block, heart failure, or sudden death



Gross Pathology





  • Granulomatous infiltration may be visible as patchy, irregular white firm areas



  • Transmural myocardial scars not associated with coronary atherosclerosis represent healed granulomas



  • Preferential sites of involvement, in decreasing order of frequency, are left ventricular free wall at the base of and including papillary muscles, basal and cephalic portion of interventricular septum, and right ventricular free wall



Histopathology





  • Noncaseating, well-formed granulomas composed of epithelioid histiocytes and multinucleated giant cells with or without lymphocytic infiltrates and no stainable microorganisms (see Figure 18.6 )



  • Granulomas may involve the endocardium, myocardium, epicardium, and pericardium



  • Typically minimal associated active myocyte necrosis



  • Collagenous stroma around granulomas



  • Myocardial scars with few or no residual granulomas in burned-out or treated cases



Special Stains and Immunohistochemistry





  • Noncontributory



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Giant Cell Myocarditis





  • Poorly formed granulomas with greater extent of myocyte necrosis and increased eosinophils compared with sarcoidosis



  • Appears clinically distinct with a more fulminant course and shorter time from symptom onset to death or transplantation



Infectious Myocarditis





  • Infectious etiology should be excluded by performing stains for fungi and mycobacteria



Myocardial Infarction





  • Scarring and thinning of the ventricle may be mistaken for healed myocardial infarcts, but normal coronary arteries should rule out ischemic heart disease



Pearls





  • Endomyocardial biopsy has poor sensitivity in detecting cardiac sarcoidosis; therefore, a negative endomyocardial biopsy does not exclude the diagnosis of sarcoidosis



  • Extensive myocardial scarring and ventricular aneurysm may be related to the natural history of the disease or previous corticosteroid therapy





Selected References




  • Ardehali H., Howard D.L., Hariri A., et. al.: A positive endomyocardial biopsy result for sarcoid is associated with poor prognosis in patients with initially unexplained cardiomyopathy. Am Heart J 2005; 150: pp. 459-463.



  • Okura Y., Dec G.W., Hare J.M., et. al.: A clinical and histopathologic comparison of cardiac sarcoidosis and idiopathic giant cell myocarditis. J Am Coll Cardiol 2003; 41: pp. 322-329.



  • Roberts W.C., McAllister H.A., et. al.: Sarcoidosis of the heart: a clinicopathologic study of 35 necropsy patients (group 1) and review of 78 previously described necropsy patients (group 11). Am J Med 1977; 63: pp. 86-108.


Valvular Diseases


Morphologic and Functional Correlations


Stenotic Valves With or Without Regurgitation





  • Diffuse fibrous thickening with a variable amount of calcification



  • No valvular tissue loss, perforations, or vegetations



  • No valvular tissue excess



  • Fusion of valve commissures



  • Chordae tendineae are fibrotic, fused, and shortened



  • Attached papillary muscle is normal



Purely Regurgitant Valves





  • Usually mild and focal fibrous thickening and absent calcification



  • Perforations or vegetations may be present



  • Excess valvular tissue may be present



  • No commissural fusion



  • Chordae tendineae are elongated or ruptured



  • Attached papillary muscle may be ruptured



Etiology of Valvular Dysfunction


Mitral Valve





  • Mitral stenosis




    • Congenital



    • Acquired




      • Postinflammatory and rheumatic



      • Mitral annular calcification





  • Mitral regurgitation




    • Congenital



    • Acquired




      • Mitral valve prolapse



      • Postinflammatory and rheumatic



      • Mitral annular calcification



      • Infective endocarditis



      • Ruptured papillary muscle



      • Papillary muscle dysfunction secondary to ischemia and infarct



      • Distortion of left ventricular geometry





Aortic Valve





  • Aortic stenosis




    • Congenital



    • Acquired




      • Unicuspid aortic valve



      • Calcification of bicuspid aortic valve



      • Senile calcific aortic stenosis



      • Postinflammatory and rheumatic





  • Aortic regurgitation




    • Congenital



    • Acquired




      • Bicuspid aortic valve



      • Postinflammatory and rheumatic



      • Infective endocarditis



      • Aortic dilation and aneurysm



      • Aortic dissection





Clinical Features


Rheumatic Heart Disease





  • Findings of acute rheumatic fever include pericardial friction rubs, weak heart sounds, tachycardia, and arrhythmias; usually occur 10 days to 6 weeks after the pharyngitis episode



  • Findings in chronic rheumatic heart disease include evidence of valvular stenosis or regurgitation, congestive heart failure, arrhythmias, thromboembolic complications, and infective endocarditis; usually occur 20 to 25 years after the acute disease



Mitral Valve Prolapse





  • Prevalence is estimated at 2% to 3% of the population, with equal distribution among men and women



  • Most patients do not develop symptoms



  • Prolapse occurs most commonly in the middle scallop of the posterior mitral valve leaflet as identified on echocardiography



  • Commonly idiopathic



  • Known association with connective tissue disorders including Marfan syndrome, Ehlers-Danlos syndrome, osteogenesis imperfecta, and pseudoxanthoma elasticum



  • Men appear to have a higher incidence of complications, which include severe mitral regurgitation, infective endocarditis, thromboembolic events, and sudden death



Calcific Aortic Valve Disease





  • Senile calcific aortic stenosis is more common in males, with a peak incidence in the seventh and eighth decades of life



  • Calcification of a congenital bicuspid aortic valve peaks in the fifth and sixth decades of life



  • Calcific disease of the aortic valve results in left ventricular hypertrophy, with symptoms including angina, syncope, and congestive heart failure



Mitral Annular Calcification





  • More common and more severe in women, primarily those older than 60 years



  • Associated with aging, hypertension, diabetes, aortic stenosis, chronic renal disease, and atherosclerosis



  • Often asymptomatic, but potential complications include acquired mitral stenosis or regurgitation, conduction system disturbances, endocarditis, and systemic embolism



Pure Aortic Regurgitation





  • Pure aortic insufficiency can be due to lesions of the valve or the aorta



  • Aortic root dilation is currently the most common cause of aortic insufficiency, followed by congenital bicuspid valve associated with ascending aortic aneurysm



Carcinoid Heart Disease





  • Carcinoid syndrome is characterized by episodic bronchospasm, flushing of the skin, telangiectasia, and diarrhea, usually associated with gastrointestinal carcinoid tumors that have metastasized to the liver



  • Cardiac involvement manifests as right-sided valvular disease that progresses to right-sided heart failure



  • Valvular dysfunction results in pure regurgitation of the tricuspid valve and predominantly regurgitation of the pulmonic valve



  • Left-sided involvement is rare and associated with the presence of right-to-left shunt, pulmonary metastases, or bronchial carcinoids



Gross Pathology


Rheumatic Heart Disease





  • Involves, in descending order of frequency, mitral, aortic, tricuspid, and pulmonic valves



  • Acute rheumatic fever may show small verrucous vegetations along the lines of closure



  • Chronic rheumatic heart disease shows diffuse thickening and fibrous retraction of valve leaflets with or without calcification, fusion of the commissures, and shortened, fused, and thickened chordae ( Figure 18.8 )




    Figure 18.8


    Mitral valve.

    In the upper specimen, postinflammatory scarring in rheumatic mitral valve disease results in commissural fusion and stenosis of the orifice. The chordae are fused, thickened, and shortened. Shown at the same magnification, the lower specimen, a segmental resection of a mitral valve, shows a diffusely thickened, expanded leaflet with mild billowing typical of mitral valve prolapse. The chordae are elongated and irregularly thickened, as seen on the ventricular aspect of the right lower specimen.



  • Narrowed valvular orifice due to commissural fusion



  • Calcific deposits are found at the commissures, which may become ulcerated



Mitral Valve Prolapse





  • Myxomatous degeneration may involve any valve but most frequently involves the posterior leaflet of the mitral valve



  • Diffuse leaflet thickening and redundancy with increased surface area (see Figure 18.8 )



  • Interchordal hooding or billowing (parachute) deformity may be seen



  • Cut surface reveals abundant gray translucent myxoid material in the spongiosa layer affecting the base, midportion, and free edge of the leaflet



  • Elongated chordae with irregular thickening are commonly seen, and sometimes rupture occurs



  • Often with annular dilation



Calcific Aortic Valve Disease





  • Senile calcific aortic stenosis shows fibrosis and calcification of the base and body of the cusps, often protruding into the sinuses of Valsalva and rarely involving the free edge ( Figure 18.9 )




    Figure 18.9


    Aortic valve.

    Only one commissure is identified in this surgically excised congenitally malformed unicommissural aortic valve with eccentrically located orifice (upper left) . A bicuspid aortic valve has two cusps with a slitlike opening of the valve. The larger of the cusps, termed the conjoined cusp, shows a calcified median raphe, which represents the site of failed cusp division. A fenestration is present in the smaller cusp (upper right) . Calcific aortic stenosis due to severe nodular calcification of all three cusps is shown (lower left) . Rheumatic aortic stenosis shows fusion of all the commissures with thick retracted cusps, resulting in a fixed triangular orifice (lower right) .



  • Calcification of a congenital bicuspid aortic valve typically begins in the median raphe or false commissure and extends to the body of the cusps



  • Absent or minimal commissural fusion is seen in degenerative aortic valve stenosis



Mitral Annular Calcification





  • Calcification develops in the annulus of the mitral valve, usually at the base of the posterior leaflet, forming a solid bar causing distortion and elevation of the posterior leaflet



  • Lesion may also extend into the myocardium and medially into the septum, where it may cause disruption of the bundle of His



  • Calcium mass may erode through the valve leaflet, ulcerate, and predispose to thrombosis and infection



  • Central softening and liquefaction of the calcification may occur and should not be mistaken for an abscess



Pure Aortic Regurgitation





  • Floppy valves are large, redundant, mildly thickened, and gelatinous in consistency



  • In aortic regurgitation secondary to dilation of the aortic root, the aortic cusps can be normal, with only focal and minimal fibrosis in the body; free edges are thickened; commissures are not fused



Carcinoid Heart Disease





  • White fibrotic plaques on the tricuspid and pulmonic valve, mural endocardium, and occasionally intima of great vessels



  • Fibrous plaques located predominantly on the ventricular aspect of tricuspid valve and almost exclusively on the arterial aspect of pulmonic valve



  • Plaques cause thickening and retraction of the leaflets



  • Plaques may also cause adherence of the valve to the mural endocardium of the right ventricle or intima of the pulmonary artery



Histopathology


Rheumatic Heart Disease





  • Acute rheumatic fever may show inflammation and Aschoff bodies in all layers of the heart, including valves and papillary muscles



  • Aschoff bodies consist of foci of fibrinoid degeneration surrounded by lymphocytes, occasional plasma cells, and Anitschkow or Aschoff cells



  • Anitschkow cells are macrophages with abundant cytoplasm and central round to oval vesicular nuclei with a central bar of condensed chromatin (caterpillar-like); may become multinucleated to form Aschoff giant cells



  • Chronic rheumatic heart disease shows diffuse fibrosis, neovascularization, or calcification of the valve



  • Focal chronic inflammatory cell infiltrate (mainly lymphocytic) may be seen



Mitral Valve Prolapse





  • Accumulation of mucopolysaccharides in the spongiosa layer with disruption of the collagenous bundles in the fibrosa and fragmentation of elastic fibers



  • Absence of neovascularization or inflammation



  • Mucopolysaccharide infiltration of the chordae tendineae



Calcific Aortic Valve Disease





  • Calcification begins in the fibrosa layer



  • Lipid deposits, neovascularization, and chronic inflammatory cell infiltrates are commonly found



  • Osseous metaplasia may develop in the calcium deposits



Mitral Annular Calcification





  • Calcification may be associated with mild inflammation and foreign-body giant cells



Pure Aortic Regurgitation





  • Fibrous thickening of the free edges



  • Myxomatous degeneration with accumulation of mucopolysaccharides in the spongiosa



Carcinoid Heart Disease





  • Plaque is cellular and contains fibroblasts, myofibroblasts, smooth muscle cells, and collagen embedded in a myxoid matrix



  • Plaques have a stuck-on appearance on the underlying valve and endocardium, which are intact



  • Usually there are no elastic lamellae (i.e., no fibroelastosis) within the carcinoid plaque



Special Stains and Immunohistochemistry





  • Movat delineates the different layers of the valve and highlights mucopolysaccharide accumulation, fibrosis, and disruption and fragmentation of elastic fibers



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis





  • Stenosis versus regurgitant: see “Morphologic and Functional Correlations” under “Valvular Diseases”



Pearls





  • An etiologic diagnosis can be formulated in most instances with careful gross evaluation of operatively excised valves



  • Histologic evaluation is necessary to establish diagnosis in infective endocarditis and metabolic diseases involving cardiac valves (e.g., Fabry disease, mucopolysaccharidoses, carcinoid syndrome)





Selected References




  • Feldman T.: Rheumatic heart disease. Curr Opin Cardiol 1996; 11: pp. 126-130.



  • Hayek E., Gring C.N., Griffin B.P.: Mitral valve prolapse. Lancet 2005; 365: pp. 507-518.



  • Roberts W.C., Ko J.M.: Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement for aortic stenosis, with or without associated aortic regurgitation. Circulation 2005; 111: pp. 920-925.



  • Simula D.V., Edwards W.D., Tazelaar H.D., et. al.: Surgical pathology of carcinoid heart disease: a study of 139 valves from 75 patients spanning 20 years. Mayo Clin Proc 2002; 77: pp. 139-147.



  • Waller B., Howard J., Fess S.: General concepts in the morphologic assessment of operatively excised cardiac valves. Part I. Clin Cardiol 1994; 17: pp. 41-46.



  • Waller B., Howard J., Fess S.: General concepts in the morphologic assessment of operatively excised cardiac valves. Part II. Clin Cardiol 1994; 17: pp. 208-214.


Infective Endocarditis


Clinical Features





  • Risk factors for infective endocarditis are structural valvular abnormalities, congenital heart diseases, prosthetic heart valves, and injection drug use



  • Staphylococcus aureus has become the most common cause of infective endocarditis owing to nosocomial infections and medical and surgical interventions, including indwelling catheters and devices



  • Most subacute cases of native valve endocarditis are due to viridans group Streptococci and Enterococci



  • Prosthetic valve endocarditis is usually caused by Staphylococci, viridans group Streptococci and Enterococci



  • Endocarditis caused by fastidious Gram-negative bacilli of the HACEK group ( Haemophilus parainfluenzae, Aggregatibacter (formerly Haemophilus ) aphrophilus, H. paraphrophilus, H. influenzae, Aggregatibacter (formerly Actinobacillus ) actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae , and K. denitrificans ) accounts for about 5% to 10% of native valve community-acquired endocarditis in patients who are not injection drug users



  • Fungal endocarditis is commonly caused by Candida , Aspergillus , and Histoplasma



  • Potential risk of Mycobacterium chimaera endocarditis following open heart surgery due to contamination of cardiopulmonary bypass machines



  • Symptoms are nonspecific and include fever, chills, fatigue, and weight loss



  • Special attention to potential sources of bacteremia, new regurgitant murmurs, and embolic phenomena, including septic lung emboli, is emphasized



  • Infection of a mechanical prosthetic valve may lead to valve dehiscence or paravalvular leak



Gross Pathology





  • Aortic and mitral valves are most commonly affected



  • Vegetations cause destruction or perforation of the cusp or leaflet and bulky vegetations prevent proper coaptation, both leading to valvular insufficiency ( Figure 18.10A )




    Figure 18.10


    Infective endocarditis.

    A, An aortic cusp shows perforation with large yellow-red vegetations on the ventricular aspect. B, Vegetation shows fibrin with acute inflammatory exudate with bacterial colonies in a case of staphylococcal endocarditis. C, Granulation tissue with neovascularization and neutrophilic infiltrates is commonly seen in streptococcal endocarditis.



  • Cusp or leaflet may have an irregular, ulcerated free border or perforation of the body and ruptured chordae



  • Healed endocarditis may result in aneurysms or perforation with smooth borders



  • Tissue prosthetic valve usually shows vegetations on both inflow and outflow surfaces



  • Mechanical prosthetic valve infection starts at the sewing ring and results in a periprosthetic or ring abscess



Histopathology





  • Acute vegetations consist of fibrin, platelets, neutrophils, and bacteria (see Figure 18.10B )



  • Subacute vegetations have granulation tissue at the base with both acute and chronic inflammatory cells, as well as histiocytes and occasionally multinucleated giant cells (see Figure 18.10C )



Special Stains and Immunohistochemistry





  • Gram, PAS, GMS, Warthin-Starry, Fite, and Ziehl-Neelsen stains are useful in detecting microorganisms in tissues



  • Antibodies to Tropheryma, Chlamydia, Bartonella , and Coxiella species are available only in specialized laboratories



Other Techniques for Diagnosis





  • Serologic tests are useful for the diagnosis of Bartonella, Coxiella , and Legionella endocarditis



  • Polymerase chain reaction followed by direct sequencing of 16S recombinant RNA genes from valve tissue are also used to detect Tropheryma, Bartonella , and Coxiella species and other etiologic agents of culture-negative endocarditis



Differential Diagnosis


Nonbacterial Thrombotic Endocarditis





  • Usually occurs in association with chronic inflammatory disease, hypercoagulable state, and underlying malignancy, especially adenocarcinomas



  • Aseptic vegetation may embolize or serve as a substrate for infection



  • Aortic and mitral valves are most commonly affected



  • Right-sided lesions are usually associated with intravenous catheters



  • Vegetations are present on the atrial surfaces of atrioventricular valves and ventricular surfaces of semilunar valves



  • Small (1- to 5-mm), multiple, nondestructive vegetations are loosely attached to the underlying valve leaflets, usually on previously normal valves



  • Composed of platelets mixed with fibrin and a few red blood cells



  • Inflammatory reaction is absent



  • Organization may be seen at the base of the lesion with fibroblastic proliferation



Libman-Sacks Endocarditis





  • Occurs in patients with systemic lupus erythematosus (SLE)



  • Only 6% to 20% of cases are symptomatic



  • Rare source of emboli



  • Most often develops on mitral and tricuspid valves



  • Relatively adherent, sessile, small (3- to 4-mm), pink to yellow-tan vegetations occurring singly or in clusters on the atrial and ventricular surfaces of the valve, anywhere from the free edge to the base, with extension onto the endocardium, chordae tendineae, and papillary muscles



  • Sterile vegetations consist of fibrin and mononuclear cells with fibroblastic proliferation and neovascularization



  • Necrosis with hematoxylin bodies rarely seen



  • Healed endocarditis results in fibrous plaque


Mar 11, 2021 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Heart, Pericardium, and Blood Vessels
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