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Endomyocardial biopsy and cardiomyopathy final
- 1. Endomyocardial biopsy and cardiomyopathy Presenter : Dr Suma H V Moderator : Dr S Shivakumar
- 2. Contents • Endomyocardial biopsy – Introduction – History – Indications – Instruments – Procedure – Complications
- 3. • Cardiomyopathy – Definition – Classification – Morphology • References
- 5. Introduction • Technique by which heart tissue is sampled from the patients with suspected cardiac disorders for microscopic evaluation and diagnosis of the lesions. • Gold standard mode of investigation for diagnosing cardiac diseases.
- 6. Historical aspects • Open surgical biopsies of heart - 1950’s Using Vim-silverman’s needle through thoracotomy / trans-thoracic approach. • 1st trans-venous biopsy –Bioptome in Japan in 1962
- 7. • Modified bioptome- CAVES-SCHULTZ- STANFORD bioptome – Stanford -1972
- 9. Indications • To diagnosis – Myocarditis – Transplant rejection – cardiomyopathies • To evaluate – Drug toxicity (anthracycline, doxorubicin) – Unexplained CCF
- 10. Instruments • Flexible bioptomes • Commonly used bioptomes are: – Novatome- single use 50cm – Argon forceps – Bipal bioptome • Fluoroscopy is the imaging modality
- 12. Patient preparation • Routine lab tests • ECG • Chest x-ray. • Nil per oral for 6hrs. • Cardiac Catheterization lab.
- 13. Procedure • Performed through the transvascular approach • Right ventricle is preferred -Easier and safer to biopsy -Representative site in diffuse diseases. • Left ventricle is preferred in sarcoidosis and done via arterial approach
- 14. • A flexible, plastic tube called a “sheath” is inserted into the vein in the neck or groin • Insertion of “pulmonary artery catheter” into the right side of heart • Catheter is removed.
- 15. • Bioptome is guided through the sheath into the heart. • Biopsy forceps can easily be taken upto the apical portion of Right ventricular septum. • 3-4 tissue samples of 2-3 mm size are obtained. • Then the bioptome and sheath are removed.
- 16. • Flexible, disposable bioptomes- presently available. • Availability of catheters and bioptome forceps of different sizes and designs • Apical curvature- for easy sampling and grip on the tissue.
- 18. Procedure
- 19. Tissue Processing • 4-5 biopsy fragments are processed routinely and 1 fragment for EM exam. • Transplant biopsies- if vascular rejection is suspected, 1 fragment is frozen for immunofluorescence. • Anthracycline, Chloroquine and Amiodarone toxicity- All fragments are processed for EM.
- 20. PROBLEMS DURING INTERPRETATION • Sampling error-due to focal nature of disease • Crush artifacts • Contraction bands • Focal interstitial fibrosis
- 21. PROBLEMS DURING INTERPRETATION cont…. • Interstitial mesenchymal cells closely resemble lymphocytes. • Endocardial thickening • Adipose tissue
- 22. Complications • PERFORATION – Chest pain and pericardial effusion as judged by transthoracic echocardiography or TEE • The risk of perforation can be reduced by using a specially curved sheath to guide the biopsy forceps toward the interventricular septum.
- 23. • Air embolism • Myocardial infarction • Transmission of infections • Damage to valves • Chest pain, hematoma • Arrythmias(AF/VF) • Pneumothorax • Haemopericardium
- 24. Cardiac transplantation • Worldwide about 1 lakh adult and 11000 pediatric heart transplantation have been performed • Survival rate is 88% at 1st year, 80% at 2nd year 75% at 3rd year
- 25. Grading of transplant rejection
- 28. CARDIOMYOPATHY
- 29. Introduction • Heterogeneous group of diseases • Mechanical &/or electrical dysfunction • Ventricular hypertrophy or dilatation • Variety of causes that frequently are genetic. • Cardiomyopathies either are confined to the heart or are a part of generalized systemic disorders
- 30. Functional classification • Dilated cardiomyopathy • Hypertrophic cardiomyopathy • Restrictive cardiomyopathy • Arrhthymogenic Right Ventricular disease(ARVD)
- 31. Morphological classification of cardiomyopathies • Primary cardiomyopathies – Dilated cardiomyopathy – Hypertrophic cardiomyopathy – Restrictive cardiomyopathy – RV arrhythmogenic cardiomyopathy • Inflammatory cardiomyopathy / myocarditis
- 32. • Secondary cardiomyopathy – Infiltrative – Storage disorder – Toxic/ drug related – Peripartal cardiomyopathy
- 34. Definition • Primary cardiomyopathy that principally affects the myocardium leading to LV dilation and systolic dysfunction.
- 35. Incidence and prognosis • Prevalence – 36/1,00,000 • 3rd most common cause of heart failure • Most frequent cause of heart transplantation • Complete recovery is rare • 50% die within 2yrs
- 36. Causes • Genetic – Autosomal dominant – Mutations in genes encoding dystrophin,δ sarcoglycan, troponin T, β MHC etc • Myocarditis • Alcohol and other toxins • Childbirth (peripartum cardiomyopathy)
- 37. Clinical features • Peak incidence in middle age • Symptoms may be gradual in onset • Acute presentation – Misdiagnosed as viral URI in young adults
- 38. • Symptoms/Signs of heart failure – Pulmonary congestion (left heart failure), dyspnea, orthopnea – Systemic congestion (right heart failure), edema, nausea, abdominal pain, nocturia – Low cardiac output – Hypotension, tachycardia, tachypnea – Fatigue and weakness • Arrhythmia – Atrial fibrillation, conduction delays, sudden death
- 40. Morphology • Heart enlarged, heavy, flabby • Mural thrombi • Dilatation of all chambers, both ventricular hypertrophy
- 42. Microscopy • Hypertrophic myocardial fibres • Cardiac myocytes show degenerative changes • Interstitial and endocardial fibrosis
- 43. Peripartum cardiomyopathy • Four criteria: three clinical and one echocardiographic 1. Development of heart failure during last trimester of pregnancy or first six months post partum. 2. Absence of any identifiable cause for cardiac failure. 3. Absence of any recognizable heart disease prior to last trimester of pregnancy.
- 44. 4. Echocardiographic criteria - Demonstrable proof of left ventricular systolic dysfunction. - Ejection fraction less than 45%, -Left ventricular end- diastolic dimension >2.7cm/m square of body surface area.
- 46. • Most common genetic disorder of heart • Prevalence : 1 in 500 adults • Characterised by myocyte hypertrophy in the absence of hypertension, stenotic valvular disorder or infiltrative disorders
- 47. Pathogenesis • Autosomal dominant • Remaining are sporadic • Mutations are mostly missense • Mutations causing HCM found in genes encoding β MHC, cardiac TnT, α tropomyosin, myosin binding protein C
- 48. Pathophysiology • Impaired diastolic filling ↓ reduced stroke volume • Reduced CO and increase in pulmonary venous pressure ↓ exertional dyspneoa
- 49. Clinical features • Asymptomatic • Symptomatic – Dyspnea – Chest pain – Fatigue, pre-syncope, syncope – Palpitation, PND, CHF, dizziness
- 51. • Begins during early adolescence and stops when growth has finished • Left ventricle almost always affected. • Hypertrophy is usually greatest in the septum
- 52. • Asymmetric septal hypertrophy with obstruction to the outflow of blood from the heart may occur. The mitral valve touches the septum, blocking the outflow tract. Some blood is leaking back through the mitral valve causing mitral regurgitation
- 54. Mimicking Hypertrophic Cardiomyopathy • Cardiac amyloidosis • Athlete's heart • Fabry disease • Apical hypertrophy - apical cavity obliteration caused by hypereosinophilic syndrome
- 55. Athlete's Heart Vs Hypertrophic Cardiomyopathy HCM HCM • Can be asymmetric • Wall thickness: > 15 mm • LA: > 40 mm • Diastolic function: always abnormal Athletic heart • Concentric & regresses • < 15 mm • < 40 mm • Normal
- 57. Introduction • Rigid ventricular wall with impaired ventricular filling • Contractile functions are normal • Abnormal diastolic function • Less common
- 58. CAUSES • Primaryidiopathic • Secondary associated with – Radiation fibrosis – Amyloidosis – Sarcoidosis – Metastatic tumors – Metabolic deposition diseases
- 59. Clinical manifestations • Symptoms of right and left heart failure • Echo-Doppler – Abnormal mitral inflow pattern -Prominent E wave (rapid diastolic filling) • Almost invariably progresses to congestive heart failure,10% survive for 10 yrs
- 60. Morphology • Ventricles are of normal size • Cavities are not dilated • Myocardium is firm and non compliant • Biatrial dilatation is common • Patchy/diffuse interstitial fibrosis
- 63. Arrhythmogenic right ventricular cardiomyopathy • Inherited disease of cardiac muscle • RVF, rhytm disturbances, ventricular tachycardia, fibrillation • Right ventricular wall is thinned, extensive fatty infiltration and fibrosis • Autosomal dominant inheritence
- 65. Cardiac Amyloidosis • Deposition of abnormal protein amyloid • Characterised by :congestive heart failure myocardial dysfunction
- 66. Types 1. Immunoglobulin associated amyloidosis 2. Familial/heriditary amyloidosis 3. Senile amyloidosis
- 67. Morphology • Ventricles - Normal to dilated - thinned walls (DCM) - thickened LV walls with small chambers (HCM) • Cut surface – waxy appearance • Can also involve endocardium, myocardium, pericardium, valves and vessels
- 69. Pompe disease • - deficiency of acid maltase - Autosomal recessive -hepatomegaly, failure to thrive, hypotonia, macroglossia, massive cardiomegaly - heart is enlarged and mimics HCM
- 71. Fabry’s disease • Storage disorder • Deficiency of alpha galactosidase A enzyme ↓ Glycophospholipid accumulation • X – linked disorder • Ventricular hypertrophy, heart failure, arrhythmia, conduction defects
- 73. Hemochromatosis • Mc inheritable metabolic disorder • Prevalence 1:200-400 • Increased iron deposition in heart, liver, pituitary gland, pancreas and skin. • Autosomal recessive • HFE- mc mutation
- 75. Drug related cardiomyopathy • Anthracyclin antibiotics- doxorubicin, daunorubicin • Precipitated by infection, pregnancy or surgery • Congestive heart failure, arrhythmia – common
- 76. Microscopy • Tissue is fixed and processed in glutaraldehyde solution • 10 plastic blocks is required for assessing numerical grade • One micron sections are cut and stained by toluidine blue stain and assessed under light microscopy for distribution and extent of cell injury
- 77. • Myocytes appear shrunken with homogenous pale cytoplasm and cytoplasmic vacuolization
- 78. Electron microscope • Myofibrillary loss • Partial/complete loss of fibrils
- 79. Grading of chronic anthracycline cardiotoxicity • Grade 0 – normal ultrastructural appearance of myocytes • Grade 1.0 – isolated or scattered myocytes showing sarcotubular distension or early myofibrillar loss; damage to <5% of all cells • Grade 1.5 – changes as grade 1 but involving 6%-15% of all cells
- 80. • Grade 2 – clusters of myocytes with myofibrillary loss or sarcotubular distension involving 16-25% of all cells • Grade 2.5 – numerous damaged myocytes (26-35%) showing characterised changes • Grade 3 – diffuse/confluent myocyte damage of >35% of cells, necrotic cells may be seen
- 81. Inflammatory cardiopathy (Myocarditis) • Definition: Myocardial process characterized by the presence of both an inflammatory infiltrate and myocyte damage or necrosis not typical of the myocardial damage of ischemic heart disease.
- 82. Etiology • Idiopathic myocarditis • Drug induced • Myocarditis associated with systemic disease • Sarcoidosis • Idiopathic giant cell myocarditis
- 83. Myocarditis • Both inflammation and myocyte damage are present. • Depending on the composition of the cellular infiltrate the specific type of myocarditis.
- 85. Drug- related myocarditis • Hypersensitivity myocarditis • Toxic myocarditis • Drug-induced cardiomyopathy (e.g., anthracycline, chloroquine) • Giant cell myocarditis
- 86. Hypersensitivity Myocarditis • Most common form of acute drug-related myocardial injury • Antibiotics, diuretics, and antihypertensive drugs • Clinical signs : rash, fever, peripheral eosinophilia, and occasionally arrhythmias, sudden death, and congestive heart failure.
- 87. • The histopathologic features include uniform lesions distributed in the subendocardial, perivascular, and interstitial tissues between bundles of myocytes.
- 89. Toxic Myocarditis • Uncommon • Characterized by direct myocyte cytotoxicity. • Causative agents - antineoplastic drugs • The lesions are focal and temporally heterogeneous.
- 91. Sarcoidosis • Cardiac involvement in sarcoidosis is 25% to 60%. • Include classic noncaseating granulomatous inflammation, lymphocytic myocarditis, DCM and normal myocardium. • Diffuse myocardial involvement progresses to myocyte hypertrophy and interstitial fibrosis resembling DCM
- 92. Gross • Firm, white nodules forming discrete masses within the interventricular septum, LV free wall, or papillary muscle
- 94. Idiopathic giant cell myocarditis • Rare • Fatal form of myocarditis that occurs in previously healthy young adults. • Clinical onset is abrupt • Characterized by rapidly progressive heart failure and/or arrhythmias.
- 95. Morphology • Multifocal areas of necrosis are easily observed in the heart. • The heart weight is normal or slightly increased. All chambers of the heart are uniformly involved in most cases.
- 97. Conclusion • Endomyocaedial biopsy is helpful is diagnosing many cardiac disorders
- 98. References • Sternberg, s diagnostic surgical pathology. • Silverberg’s principle and practice of surgical pathology and cytopathology. • Cardiovascular pathology • Journals on cardiovascular pathology
- 99. Thank you
Editor's Notes
- Bioptome – small pincer shaped cutting/grasping instrument
- A novatome – 2-3mm tip, 9F sheath, single use B argon endomyocardial forceps – 8mm tip that requires a 7-F sheath C Bipal 7 bioptome, 50cm and 104cm – 2-3mm tip, 7F sheath D 8 –F transseptal mullens sheath when using the longer Bipal 7 bioptome through right femoral vein access to improve tip control and placement
- ( under fluoroscopic guidance), which measures the pressures inside the heart.
- Internal jugular vein
- Eg myocarditis - mechanical trauma (AMI, Mechanical trauma) (non- specific finding)
- 1. 2(non specific finding) 3 (normal in rt ventr biopsy) 0- 1.3cm
- 10% Fever, shortness of breath, new chest pain/ tenderness, increased BP Cardiac allograft specimen,s are high and EMB is the gold standard for diagnosing acute transplant rejection
- 1990ISHLT SCHEME- international society for heart and lung transplantation 2004 revised ISHLT – 1A, 1B, 2 – mild rejectuion (1R) 3A – moderate rejection (2R) 3B, 4 – severe rejection (3R) Acute cardiac rejection – ag-ab raection Chronic rejection – blockage in intramural and epicardila vessels
- No rejection (0) Focal mild rejection (1A) : perivascular interstitial infiltrate without myocyte damage Diffuse mild rejection (1B) : interstitial infiltrate without myocyte damage Focal moderate (2) : solitary focus of infiltrate associated with myocyte damage Multifoacl moderate rejection (3A) : 2/more foci of infiltrates associated with myocyte damage
- Diffuse moderate rejection (3B) : diffuse, often polymorphous inflammatory infiltrates in many biopsy pieces with conspicuous myocyte damage Severe rejection (4) : finding of 3B rejectioin + interstitial edema, hemorrhage +/- small vessel vasculitis
- “a heterogeneous group of diseases of the myocardium associated with mechanical &/or electrical dysfunction that usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilatation and are due to a variety of causes that frequently are genetic.” Cardiomyopathies either are confined to the heart or are a part of generalized systemic disorders
- Infiltrative (amyloidosis, gaucher’s Storage disorder (fabry’s disease, glycogen storage, hemochromatosis ) Toxic/ drug / therapy related (anthracycline, cyclophosphamide)
- Mc indication for cardiac transplantation
- MHC- myosin heavy chain
- Increased in weight, globular in shape, all chambers dilated, mural thrombi, endocardial fibrous thickrning over septrum of LV, reduced free wall thickness
- Hypertrophic myocytes Cytoplasmic vacuolations Interstitium is expanded by collagen fibres – trichrome stain? Lymphocytic infiltration at the interstsitium
- - Ejection fraction less than 45%, - left ventricular fractional shortening less than 30% or left ventricular end- diastolic dimension >2.7cm/m square of body surface area.
- Diastolic dysfunction Impaired diastolic filling, increased filling pressure
- Asymptomatic -Echocardiographic finding only Systolic ejection murmur , Atrial fibrillation, thromboembolism
- Short axis method of dissection The major abnormality of the heart in HCM -- excessive thickening of the muscle
- . Thickening usually begins during early adolescence and stops when growth has finished. uncommon for thickening to progress after this age left ventricle almost always affected. Hypertrophy is usually greatest in the septum, associated with obstruction to the flow of blood into the aorta
- Extensive myocyte hypertrophy Myocyte Disarray Interstitial and replacement fibrosis
- LVEDD : < 45 mm > 45 mm
- Normal weight of heart, Ventricles are of normal size Cavities are not dilated Myocardium is firm and non compliant Biatrial dilatation is common Patchy/diffuse interstitial fibrosis
- Myocyte hypertrophy, interstitial fibrosis Interstitial fibrosis highlighted by trichrome stain
- Characterized by deposition of IG light chain – poor prognosis
- 1. Most common type - immunoglobulin associated amyloidosis (AL type), Seen in primary amyloidosis, plasma cell dyscrasias 2. AD- mutation in transthyretin protein(TTR), transplantation is definitive traetment 3. Deposition of wild type transthyretin , occurs in middle and old men
- • Amyloid deposition is most prominent in interstitial, perivascular and endocardial regions. Pale, finely fibrillar eosinphilic ,material Masson trichrome stain – distuinguishes from amyloid by gray –blue Zeis medium / normal medium - fixation
- Cardiac enlargement without ventricular dilatation • Ventricular walls are thickened and rubbery • Amyloid deposition is most prominent in interstitial, perivascular and endocardial regions. Pale, finely fibrillar eosinphilic ,material Masson trichrome stain – distuinguishes from amyloid by gray –blue from collagen Zeis medium / normal medium - fixation
- Group of inherited enzymatic deficiencies for the synthesis or utilization of glycogen 12 types
- Enlarged myocytes Vacuolated cytoplasm Cytoplasm filled with glycogen To differentiate from vacuolization of normal myocytes – dis is uniformly massive and diffuse vacuolization
- Marked LV hypertrophy mimics HCM both macroscopically and functionally.
- In EMB sections, the myocytes and endothelial cells are diffusely vacuolated with pinpoint weakly positive predigested PAS granules within these spaces (Fig. 29.15). The diagnosis is confirmed at the ultrastructural level by the presence of membrane-bound electron-dense lamellar myelin (“zebra”) bodies
- HFE gene – chromosome 6 C282y, H63D
- Dark brown granular deposition v/s lipofuchsin
- Hematolymphoid malignancies, efficacy is limited due to cardiotoxicity
- Shrunken bcoz of myofibrillary loss Vacuoloization bcoz of sacrotubular dilatation
- Retention of Z- band remnants
- 1 – therapy continues 1.5 – continued 2 – continues wid close cardiac assessment 2.5 – one more dose of anthracycline 3 - discontinued
- The distribution of inflammatory infiltrate may be focal, confluent, or diffuse; the severity ranges from mild to severe. The most difficult challenge is the determination of myocyte damage in the biopsy specimen. In our experience, florid myocytolysis and necrosis are not common biopsy patterns.
- myocarditis (e.g., lymphocytic, eosinophilic, neutrophilic, giant cell, granulomatous, or mixed cell types). The distribution of inflammatory infiltrate may be focal, confluent, or diffuse; the severity ranges from mild to severe. The most difficult challenge is the determination of myocyte damage in the biopsy specimen. In our experience, florid myocytolysis and necrosis are not common biopsy patterns.
- mononuclear cells that encroaches into the sarcolemmal membrane of myocytes Fragmentation of myocytes with remnants of cytoplasm or “bare nuclei,” architectural displacement or distortion of myocytes by inflammatory cells, or partial replacement of myocytes by inflammatory cells.
- The predominant inflammatory cells are eosinophils, but variable numbers of histiocytes and scattered lymphocytes are also found. Myocyte necrosis is absent. No giant cells
- The inflammatory infiltrates are polymorphous with lymphocytes, plasma cells, and neutrophils, but eosinophils are rare or absent. Example is the acute form of doxorubicin cardiotoxicity presenting as acute myocarditis
- The inflammatory infiltrates are polymorphous with lymphocytes, plasma cells, and neutrophils, but eosinophils are rare or absent. Example is the acute form of doxorubicin cardiotoxicity presenting as acute myocarditis
- Classic granulomatous pattern is characterized by
- Tan white foci within myocardium Discrete granuloma embedded in fibrous scar tissue granulomas composed of epithelioid histiocytes and multinucleated giant cells arranged in round or oval aggregates. These can be found as isolated lesions or may coalesce to form larger zones within the myocardium. Endocardial and pericardial involvement is observed in some cases. Scattered around and within the granulomas are mature The epithelioid histiocytes express CD68, and the infiltrating lymphocytes are almost exclusively T cells with a predominance of CD4+ cells lymphocytes, but eosinophils are absent or sparse in number. Mature collagenous fibrosis is present and surrounds the granulomas, but active myocyte necrosis is uncommon.
- . Death occurs within weeks or months of onset of symptoms unless aggressive immunosuppression and cardiac transplantation are implemented 20% of patients have an associated autoimmune disorder such as ulcerative colitis, cryofibrinogenemia, rheumatoid arthritis, myasthenia gravis, hyperthyroidism, and hypothyroidism
- Active/ acute phase : Widespread myocyte dmage which is replaced by mixed inflammatory cells Multinucleate giant cell, lympho, eosino, histiocytes Healed / resolved phase : Trichrome stain-healed idiopathic giant cell myocarditis with outer half of myocardium replaced by mature collagen