Cardiology

Endomyocardial Biopsy

General description of procedure, equipment, technique

Endomyocardial biopsy (EMB) is a procedure that percutaneously obtains small amounts of myocardial tissue for diagnostic, therapeutic, and research purposes. It is primarily used to (1) follow the transplanted heart for myocardial rejection; (2) diagnose specific inflammatory, infiltrative, or familial myocardial disorders; and (3) sample unknown myocardial masses. EMB is the definitive procedure for examining the myocardium, but is limited by its invasiveness, sampling error and lack of generalized expertise in its performance.

Although not recommended for the routine evaluation of new onset heart failure, EMB is particularly useful when the index of suspicion for a specific disorder (e.g., amyloidosis) is increased.

EMB is almost always performed on an elective basis but may be considered urgently in the setting of hemodynamic collapse of uncertain origin.

EMB is especially useful in the diagnosis of myocardial rejection, myocarditis, amyloidosis, sarcoidosis, and hemochromatosis.

Indications and patient selection

The indications for EMB can be generally divided into two broad categories, transplant and nontransplant. In transplant patients:

  • Surveillance EMB is performed to identify allograft rejection before clinically relevant myocardial dysfunction occurs as a consequence of rejection.

  • Allograft rejection is more likely to occur in the first 6 to 12 months and is therefore performed as part of a protocol in the first year in most programs.

  • Although there is no standard or consensus schedule for surveillance biopsy, most centers perform frequent biopsies during the first 6 to 12 months; thereafter, the frequency is center-dependent.

  • Biopsies are also performed in the setting of clinical concerns for transplant rejection (e.g., asymptomatic fall in ejection fraction), and following significant changes in immunosuppression.

In nontransplant patients:

  • The predominant indication for EMB in the nontransplant setting is to confirm a clinically suspected condition rather than as part of a routine assessment of new onset cardiomyopathy or heart failure.

  • ACC/AHA Class I indications for EMB are directed toward identifying the cause of acute onset fulminant heart failure, most importantly giant cell myocarditis. Other forms of myocarditis, including lymphocytic and hypersensitivity, may also produce this clinical picture.

  • According to the ACC/AHA guidelines, the two Class I indications (described as clinical scenarios) include:

    • New-onset heart failure (<2 weeks duration) with hemodynamic compromise in the presence of normal or dilated left ventricle (LV).

    • New-onset heart failure of 2 to 12 weeks duration with new ventricular arrhythmias, second or third degree heart block, or failure to respond to usual care within 1 to 2 weeks of initiating treatment.

  • EMB is reasonable (e.g., Class II) in patients with a clinical suspicion for cardiac sarcoidosis, hypersensitivity myocarditis, anthracycline toxicity, and intracardiac tumors (excluding typical myxomas).

  • EMB is reasonable in unexplained cardiomyopathy in children and in unexplained restrictive cardiomyopathy.

  • EMB can be definitive in the diagnosis of amyloidosis, hemochromatosis, endocardial fibroelastosis, and Loeffler's syndrome when suspected clinically.

Contraindications

  • Routine use of EMB for new heart failure is not recommended by any society because the diagnostic yield is low and the clinical benefit is outweighed by the risk of the procedure.

  • Relative contraindications include uncorrected coagulopathies, thrombocytopenia, inadequate vascular access, and mechanical prosthetic tricuspid valve.

Details of how the procedure is performed

Preprocedural assessment

  • Review of the indications, alternative procedures, and risks/benefits of EMB should be reviewed and informed consent obtained from the patient or designated authority.

  • A comprehensive history and physical examination and recent laboratory evaluation (renal function, serum electrolytes, complete blood count, and coagulation profile) should be reviewed.

  • Prior EMB experiences of the patient are crucial, particularly in the case of transplantation when multiple serial procedures are performed.

  • Particular attention to vascular access site (e.g., jugular or femoral vein) is important. The right internal jugular (IJ) approach is favored due to the ability to guide the bioptome to specific locations within the heart and allows the patient to ambulate and be discharged soon after the procedure.

Patient preparation

  • Continuous noninvasive monitoring of blood pressure, oximetry, and heart rhythm is recommended.

  • Sedation is not always required for EMB. However, conscious sedation generally suffices if sedation is thought to be necessary.

Procedure

  • Right ventricular biopsies are most commonly performed via the right IJ approach followed by right or left femoral vein; subclavian access and left IJ approaches can also be used. Left ventricular biopsies are most commonly performed via a femoral artery approach.

  • EMB can be performed via fluoroscopic or echocardiographic guidance.

  • The right IJ vein can be accessed by identifying the clavicular and sternal heads of the sternocleidomastoid muscle (SCM) with the patient's head turned to the left; asking the patient to lift his or her head off the table facilitates identification of these muscle groups. The carotid artery should also be identified by palpation.

  • 1% Xylocaine is used to locally anesthetize the apex of the triangle created by the heads of the SCM. A single wall puncture needle is directed just lateral to the palpated carotid artery and toward the ipsilateral nipple.

  • Success for IJ cannulation may be increased with ultrasound guidance, providing direct visualization of the vein. A micropuncture needle is favored by some operators to decrease the consequences of inadvertent puncture of the carotid artery.

  • Once cannulated, an 11 cm 7-Fr sheath that sits within the IJ vein and superior vena cava is placed to facilitate passage of a pulmonary arterial catheter and bioptome. Some centers use longer sheaths that transverse the tricuspid valve (TV) to avoid TV trauma.

  • Hemodynamics can be obtained prior to the actual biopsy if so desired.

  • A disposable, preshaped, semirigid, 50-cm bioptome is inserted through the vascular sheath under fluoroscopic guidance into the right atrium and optimally pointed toward the right atrial (RA) lateral wall.

  • As the bioptome is advanced within the right atrium, a counterclockwise motion directs the bioptome anteriorly toward and across the TV into the right ventricle (RV). Further counterclockwise rotation and advancement positions the bioptome toward the apical septum.

  • Position in the RV should be confirmed by premature ventricular contractions; apical position should be assessed in the right anterior oblique (RAO) projection; septal positioning should be confirmed in the 60-degree left anterior oblique (LAO) projection with the bioptome pointed posteriorly.

  • Once properly positioned, the bioptome is withdrawn slightly with the jaws open and then readvanced to the septum until slight resistance is met and PVCs occur. The jaws are then closed to obtain the specimen. The bioptome is then withdrawn from the sheath and the sample is removed and placed in a fixation solution.

  • Biopsies are optimally taken from the apical RV septum from multiple passes with the bioptome. Optimally, the specimens should be 2 to 3 mm3 in size. Myocardial tissue can generally be distinguished from either fat or scar macroscopically by its beefy red appearance.

  • At least 3 to 5 biopsy samples should be taken for adequate sampling; more may be necessary depending on the study indication.

  • Specimens are routinely sent for staining and histological examination. In special circumstances, electron microscopy and/or protein or molecular analysis may be requested.

  • Specific tissue stains for particular conditions (e.g., Congo red for amyloid) should be ordered at time of biopsy and communication with the cardiac pathologist is essential. Electron microscopy may be particularly important in conditions such as Fabry's disease and muscular dystrophies.

Femoral vein approach

  • The femoral vein can be accessed by palpating the femoral artery pulse at the femoral head identified fluoroscopically and inserting the needle approximately 1 cm inferior and medial from the pulse.

  • A long, 7-Fr preformed sheath with a primary distal curve is placed into the apex of the RV, facilitated by the use of a pigtail catheter placed within the long sheath. Once properly positioned, the pigtail catheter is withdrawn, leaving the preformed sheath in place.

  • With the femoral vein approach, sampling is limited to the sheath's distal position since the bioptome cannot be steered independent of the sheath tip's location.

  • After flushing of the long sheath, a long (105 cm) flexible bioptome is advanced through the sheath into the RV. The jaws are opened as soon as it exits the sheath to avoid RV perforation and advanced to the septum. Samples are then obtained as described above.

Postprocedure

  • The central venous pressure (CVP) and blood pressure should be obtained postbiopsy, before the venous sheath is removed. A dramatic increase in the CVP and loss of the Y descent when compared to preprocedural values should raise concern for RV perforation and tamponade.

  • Routine postprocedural echocardiographic imaging is not required.

  • Most patients following a right IJ procedure can be discharged after a brief period of observation.

Interpretation of results

  • Preprocedural planning of sample processing is critical and may include histological, electron microscopic, and/or protein/molecular examination.

  • Biopsy results may have both prognostic and/or therapeutic implications.

  • Interpreting the results of a test depends on the pretest clinical suspicion and the known clinical yield of EMB for that clinical entity; therefore, biopsy results are most helpful when a specific cause of ventricular dysfunction is suspected a priori.

  • Tissue analysis should be performed by an experienced cardiac pathologist. Pathologic interpretation is best obtained in a clinical context, so the clinician should review the relevant case details with the cardiac pathologist.

Transplant-specific pathology

The International Society for Heart and Lung Transplantation (ISHLT) grading system for cardiac allograft rejection is used for assessing transplant biopsies.

  • Posttransplant findings can be grouped into three categories: (1) cellular rejection, (2) antibody-mediated rejection, and (3) incidental findings.

  • Acute cellular rejection (ACR)

    • Grade 0 (no rejection): no mononuclear infiltrates present.

    • Grade 1R (mild rejection): one focus of interstitial and/or perivascular infiltrate with associated myocyte damage.

    • Grade 2R (moderate rejection): two or more foci of infiltrates with associated myocyte damage.

    • Grade 3R (severe rejection): diffuse infiltrate with multifocal myocyte damage ± edema ± hemorrhage ± vasculitis

  • Antibody-mediated rejection (AMR)

    • AMR 0: No features of AMR.

    • AMR 1: Histologic features and/or immunohistochemical findings of AMR.

    • Histological features include myocardial capillary injury characterized by endothelial cell swelling, intravascular macrophage accumulation, and myocyte necrosis without lymphocyte infiltration.

    • Immunohistochemical analysis includes staining for immunoglobulin and complement deposition (e.g., C4d) as well as macrophages (CD64+).

  • Incidental, nonrejection related findings:

    • Ischemic injury

      • Ischemic changes that occur within 6 weeks of transplant reflect perioperative ischemia and are characterized by myocyte damage out of proportion to inflammatory cell infiltrate (the opposite of which is seen in rejection). The infiltrate is classically heterogeneous and includes neutrophils, plasma cells, and eosinophils rather than the homogenous infiltrate of mononuclear cells seen in ACR.

      • Ischemic changes that occur after 6 weeks posttransplant reflect cardiac allograft vasculopathy (CAV) and are characterized by subendothelial myocyte vacuolization and microinfarcts.

    • Quality effect: nodular endocardial infiltrates (primarily B-lymphocytes and plasma cells) with little to no clinical significance.

    • Infections: organisms such as cytomegalovirus (CMV) and toxoplasmosis can produce a lymphocytic infiltration that can be distinguished from rejection by looking for CMV inclusion bodies or Toxoplasma organisms.

    • Posttransplant lymphoproliferative disorders (PTLDs): distinguished by a B-cell infiltrate without associated myocyte necrosis in contrast to rejection, which is primarily a T-cell infiltrate.

Nontransplant pathology

  • Myocarditis

    • EMB is the gold-standard for the diagnosis of all forms of myocarditis.

    • Lymphocytic myocarditis: lymphocyte and histiocyte infiltrates with an area of myocyte necrosis. Absence of myocyte necrosis is interpreted as borderline myocarditis.

    • Virus identification: cardiotropic viruses can be detected by PCR using EMB samples. However, the clinical value of virus detection in EMBs is unclear.

    • Giant cell myocarditis: lymphocyte and eosinophil infiltrates with multinucleated giant cells and myocyte loss.

    • Eosinophilic myocarditis: interstitial and perivascular infiltration of eosinophils, lymphocytes, histiocytes, and plasma cells.

  • Infiltrative cardiomyopathies

    • Amyloidosis demonstrates interstitial deposition of extracellular amorphous material and myocyte loss; amyloid deposits are green with Congo red staining.

    • Hemochromatosis is characterized by hemosiderin deposition within myocytes and can be confirmed with special iron stains.

    • Sarcoidosis is characterized by noncaseating granulomas made up of histiocytes and multinucleated giant cells and can be difficult to distinguish from giant cell myocarditis.

  • Cardiotoxins: classically, anthracycline toxicity is associated with myofibrillar loss and cytoplasmic vacuolization.

  • Dilated cardiomyopathies: typically show myocyte hypertrophy and interstitial fibrosis, which are nonspecific but abnormal findings.

Performance characteristics of the procedure (applies only to diagnostic procedures)

  • The sensitivity and specificity for EMB varies based on the clinical entity that one is trying to identify. In general, specificity is high (e.g., amyloidosis) but sensitivity is low (e.g., sarcoidosis) for specific conditions.

  • A specific diagnosis based on biopsy results alone is made only 20% of the time, but increases when taking into account other clinical findings. True specificities and sensitivities are difficult to ascertain due to another "gold standard" to compare to.

  • Some literature-based sensitivities include: giant cell myocarditis >80%, lymphocytic myocarditis 10% to 35%, and cardiac sarcoidosis approximately 20%.

  • In general, both specificity and sensitivity of a certain diagnosis in the evaluation of dilated cardiomyopathy is low.

  • Sampling error decreases sensitivity of EMB. Some authorities recommend preprocedural cardiac MRI in order to improve sensitivity.

Alternative and/or additional procedures to consider

Cardiac magnetic resonance imaging (MRI)

  • In most instances, cardiac MRI is a useful adjuvant rather than an alternative to EMB.

  • MRI should be considered before proceeding to EMB in patients with suspected cardiac tumors.

  • MRI may improve the sensitivity of EMB if biopsy samples are taken from areas of contrast enhancement.

  • MRI with late gadolinium can be useful in the diagnosis of myocarditis (e.g. ,midwall, nonvascular hyperenhancement), but EMB is required to make specific histologic diagnoses (e.g., lymphocytic versus giant cell myocarditis).

  • MRI may be used as a gauge for treatment success in myocarditis patients.

  • MRI cannot replace EMB for monitoring of transplant rejection since specificity and sensitivity are poor.

  • MRI may be considered in the setting of a negative EMB if there is a strong suspicion for myocarditis or other conditions such as sarcoidosis.

Gene-expression profiling

  • In posttransplant patients at low risk for rejection, gene-expression profiling (e.g., Allomap) can be used for rejection surveillance.

Complications and their management

  • Complications rates are uncommon and rarely (<1%) fatal in experienced hands.

  • The most common complications are access-related injuries such as venous thrombosis, carotid cannulation, hematoma, nerve palsy, air embolism, and pneumothorax. Such complications may be reduced by the use of sonographic-guided access techniques.

  • Self-limited arrhythmias are often seen, most commonly premature atrial contractions (PACs), premature ventricular contractions (PVCs), and non-sustained ventricular tachycardia (NSVT), and rarely require intervention. Rarely ventricular tachycardia, ventricular fibrillation, atrial fibrillation, and AV block may occur.

  • Myocardial perforation is uncommon but should be suspected if chest pain or sudden hemodynamic instability occurs during the procedure.

  • Myocardial perforation is most effectively prevented by obtaining specimens from the RV apical septum and using biplane confirmation of bioptome position prior to closing the bioptome jaws. Echocardiographic-guidance may decrease this complication.

  • If myocardial perforation is suspected, confirmation should be obtained with fluoroscopy of the heart borders, echocardiography, and/or assessment of the right atrial pressure.

  • Although many patients with myocardial perforation can be managed conservatively with hospitalization and observation, cardiac tamponade will require emergent pericardiocentesis and urgent cardiac surgical consultation.

  • Tricuspid valve regurgitation may occur as a consequence of inadvertant biopsy of the valve leaflets or chordae, particularly after repeated procedures (e.g. following heart transplantation).

  • Using a longer sheath to bring the bioptome across the TV, echocardiographic guidance, and sampling from the RV apical septum help to decrease this complication.

  • Rare complications include inadvertent biopsy of another organ (e.g., liver), trauma to coronary sinus, and creation of septal perforator artery-to-right ventricle AV fistulas.

What’s the evidence?

Cooper, LT, Baughman, KL, Feldman, AM. "The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, American College of Cardiology, and European Society of Cardiology. Endorsed by the Heart Failure Society of America and Heart Failure Association of the European Society of Cardiology". J Am Coll Cardiol. vol. 50. 2007. pp. 1914-31.

(This is a position piece that outlines clinical scenarios in which EMB use is most appropriate.)

Lindenfield, J, Albert, NM. "HFSA 2010 comprehensive heart failure practice guideline". J Card Fail. vol. 16. 2010. pp. e1-194.

(This describes the guidelines of the Heart Failure Society of America and comments on recommendations for EMB.)

Hunt, SA, Abraham, WT, Chin, MH. "2009 Focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the International Society for Heart and Lung Transplantation". J Am Coll Cardiol. vol. 53. 2009. pp. e1-90.

(ACC/AHA guidelines including recommendations on EMB.)

Deckers, JW, Hare, JM, Baughman, KL. "Complications of transvenous right ventricular endomyocardial biopsy in adult patients with cardiomyopathy: a seven-year survey of 546 consecutive diagnostic procedures in a tertiary referral center". J Am Coll Cardiol. vol. 19. 1992. pp. 43-7.

(Complication rates from a tertiary center.)

Shields, RC, Tazelaar, HD, Berry, GJ, Cooper, LT. "The role of right ventricular endomyocardial biopsy for idiopathic giant cell myocarditis". J Card Fail. vol. 8. 2002. pp. 74-8.

(Performance characteristics of EMB for giant cell myocarditis and lymphocytic myocarditis compared to pathology obtained from apical wedge, explantation, or autopsy.)

Uemura, A, Morimoto, S, Hiramitsu, S, Kato, Y, Ito, T, Hishida, H. "Histologic diagnostic rate of cardiac sarcoidosis: evaluation of endomyocardial biopsies". Am Heart J. vol. 138. 1999. pp. 299-302.

(Performance characteristics of EMB for sarcoidosis.)

Narula, J, Khaw, BA, Dec, GW. "Diagnostic accuracy of antimyosin scintigraphy in suspected myocarditis". J Nucl Cardiol. vol. 3. 1996. pp. 371-81.

(Performance characteristics of EMB for lymphocytic myocarditis.)

Costanzo, MR. "The Internation Society of Heart and Lung Transplantation guidelines for the care of heart transplant recipients". J Heart Lung Transplant. vol. 29. 2010. pp. 914-56.

Orrego, CM, Cordero-Reyes, AM, Estep, JD, Loebe, M, Torre-Amione, G. "Usefulness of routine surveillance endomyocardial biopsy 6 months after heart transplantation". J Heart Lung Transplant. vol. 31. 2012. pp. 845-9.

(Recommendations for the use of EMB in transplanted patients.)

Mahrholdt, H, Goedecke, C, Wagner, A. "Cardiovascular magnetic resonance assessment of human myocarditis: a comparison to histology and molecular pathology". Circulation. vol. 109. 2004. pp. 1250.

(This article demonstrates how MRI may improve sensitivity of EMB.)

Stewart, S, Winters, GL, Fishbein, MC. "Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection". J Heart Lung Transplant. vol. 24. 2005. pp. 1710.

(The classification of allograft rejection by biopsy findings.)

Lones, MA, Lawrence, SC, Alfredo, T, Deborah, HRN, Miller, JM, Fishbein, MC. "Clinical pathologic features of humoral rejection in cardiac allografts: a study of 81 consecutive patients". J Heart Lung Transplant. vol. 14. 1995. pp. 151-62.

(Describes the histopathological features of humoral rejection.)

Aretz, HT. "Myocarditis: the Dallas criteria". Hum Pathol. vol. 18. 1987. pp. 619-24.

(Dallas criteria of myocarditis determination.)

Pham, MX, Teuteberg, JJ, Kfoury, AG. "Gene-expression profiling for rejection surveillance after cardiac transplantation". N Engl J Med. vol. 362. 2010. pp. 1890-900.

(This trial investigated the use of Allomap gene-expression profiling for rejection surveillance in low-risk transplant patients.)

Felker, GM, Thompson, RE, Hare, JM. "Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy". N Engl J Med. vol. 342. 2000. pp. 1077-84.

(The classic series of 1230 patients who underwent EMB at The Johns Hopkins Hospital.)

Baughman, KL, Baim, DS. "Endomyocardial biopsy". Grossman’s Cardiac Catheterization, Angiography and Intervention. Lippincott, Williams, and Wilkins. 2006. pp. 395-411.

(A primer from two of the leading authorities on this procedure.)
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