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Heart Failure Association, Heart Failure Society of America, and Japanese Heart Failure Society Position Statement on Endomyocardial Biopsy

      Abstract

      Endomyocardial biopsy (EMB) is an invasive procedure, globally most often used for the monitoring of heart transplant rejection. In addition, EMB can have an important complementary role to the clinical assessment in establishing the diagnosis of diverse cardiac disorders, including myocarditis, cardiomyopathies, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumors. Improvements in EMB equipment and the development of new techniques for the analysis of EMB samples has significantly improved the diagnostic precision of EMB. The present document is the result of the Trilateral Cooperation Project between the Heart Failure Association of the European Society of Cardiology, Heart Failure Society of America, and the Japanese Heart Failure Society. It represents an expert consensus aiming to provide a comprehensive, up-to-date perspective on EMB, with a focus on the following main issues: (1) an overview of the practical approach to EMB, (2) an update on indications for EMB, (3) a revised plan for heart transplant rejection surveillance, (4) the impact of multimodality imaging on EMB, and (5) the current clinical practice in the worldwide use of EMB.

      Graphical Abstract

      Keywords

      Endomyocardial biopsy (EMB) is an established invasive procedure most frequently used for the monitoring of heart transplant (HTx) rejection. EMB also has a complementary role to the clinical assessment in establishing the diagnosis of several cardiac disorders, including myocarditis, cardiomyopathies, drug-induced cardiotoxicity, amyloidosis, other infiltrative and storage disorders and cardiac tumors. Improvements in EMB equipment and significant progress in the analysis of EMB samples has led to an improvement in diagnostic precision of EMB. This document is the result of the Trilateral Cooperation Project between the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America, and the Japanese Heart Failure Society. It was developed during the first Trilateral Cooperation Workshop held in Munich, in March 2019.
      The role of EMB in the management of cardiovascular disorders has been discussed previously.
      • Cooper LT
      • Baughman KL
      • Feldman AM
      • Frustaci A
      • Jessup M
      • Kuhl U
      • et al.
      The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology.
      ,

      Leone O, Veinot JP, Angelini A, Baandrup UT, Basso C, Berry G, et al. 2011 Consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology. Cardiovasc Pathol 2012;21:245–74.

      The present document, based on the Trilateral Cooperative Project between the European Society of Cardiology- Heart Failure Association, the Heart Failure Society of America, and the Japanese Heart Failure Society, represents an expert consensus aiming to provide a comprehensive, up-to-date perspective on EMB, with a focus on the following main issues: (1) an overview of the practical approach to EMB, (2) an update on the indications for EMB, (3) a revised plan for HTx rejection surveillance, (4) the impact of multimodality imaging on EMB, and (5) the current clinical practice in the worldwide use of EMB. All the relevant points are summarized in the Graphical Abstract.

      Historical Milestones

      Konno and Sakakibara first reported percutaneous EMB procedure (Fig. 1), using a flexible bioptome with sharpened cusps that allowed EMB by pinching, as opposed to the surgical cutting technique used since 1950.
      • Konno S
      • Sakakibara S.
      Endo-myocardial Biopsy.
      ,
      • Sakakibara S
      • Konno S.
      Endomyocardial biopsy.
      Subsequently, Sekiguchi described the use of EMB in diagnostic assessment of myocardial diseases such as glycogen storage disorders, sarcoidosis, and myocarditis.
      • Sekiguchi M
      • Konno S.
      Histopathological differentiation employing endomyocardial biopsy in the clinical assessment of primary myocardial disease.
      He proposed a systematic histopathologic classification, including an analysis of cardiomyocyte hypertrophy, degeneration, disarrangement, and/or fragmentation of muscle bundles, as well as the extent of interstitial fibrosis and endocardial thickening.
      • Sekiguchi M
      • Konno S.
      Histopathological differentiation employing endomyocardial biopsy in the clinical assessment of primary myocardial disease.
      ,
      • Sekiguchi M
      • Konno S.
      Diagnosis and classification of primary myocardial disease with the aid of endomyocardial biopsy.
      Fig 1
      Fig. 1(A) Original illustration by Konno and Sakakibara of the percutaneous technique EMB. (B) Opening and closing of the cutting claw at the tip of the catheter.
      • Konno S
      • Sakakibara S.
      Endo-myocardial Biopsy.
      Reproduced with permission: Konno S, Sakakibara S Endo-myocardial biopsy. Chest 1983;44:346–347. Copyright Elsevier 1983.
      Caves and Schultz modified the Konno-Sakakibara forceps to allow percutaneous biopsies through the right internal jugular vein under local anesthesia with rapid tissue extraction.
      • Caves PK
      • Stinson EB
      • Graham AF
      • Billingham ME
      • Grehl TM
      • Shumway NE.
      Percutaneous transvenous endomyocardial biopsy.
      The reusable Stanford Caves–Schultz bioptome and its subsequent modifications became the standard device for EMB for approximately 2 decades, predominantly used for monitoring of HTx rejection.
      • Kawai C
      • Kitaura Y.
      New endomyocardial biopsy catheter for the left ventricle.
      ,
      • Richardson PJ.
      King's endomyocardial bioptome.
      Since then, the use of EMB had extended to diverse cardiac diseases, including myocarditis, cardiomyopathies, drug-induced cardiotoxicity, amyloidosis, other infiltrative and storage disorders and cardiac tumors.
      Simultaneously, the long sheath technique was developed, which improved feasibility and safety of the procedure. In 1974, a flexible King's College bioptome was introduced by Richardson.
      • Richardson PJ.
      King's endomyocardial bioptome.
      This bioptome, and its subsequent modifications, could be inserted through the long sheath using either the jugular or subclavian veins, femoral veins, or right and left femoral arteries. The first study on radial approach using sheetless guiding catheters for left ventricular (LV) EMB was reported by Bagur et al.
      • Bagur R
      • Bertrand OF
      • Béliveau P
      • Gaudreault V
      • Potvin JM
      • Fillion N
      • et al.
      Feasibility of using a sheathless guiding catheter for left ventricular endomyocardial biopsy performed by transradial approach.
      The safety of EMB was established both for the right ventricle (RV) and the LV.
      • Yilmaz A
      • Kindermann I
      • Kindermann M
      • Mahfoud F
      • Ukena C
      • Athanasiadis A
      • et al.
      Comparative evaluation of left and right ventricular endomyocardial biopsy: differences in complication rate and diagnostic performance.
      With the improvement of the technique and tissue processing, EMB has gradually gained worldwide acceptance. Besides the significant progress in the technique, various imaging modalities were introduced for EMB guidance, and several new techniques were developed for tissue processing and viral genome detection (Fig. 2).
      Fig 2
      Fig. 2Historical cornerstones in the development of endomyocardial biopsy. (1) Procedural technique. (2) Imaging guidance. (3) Myocardial tissue processing.

      Practical Approach to EMB

       Selection of the Access Site

      EMB is usually performed in a cardiac catheterization laboratory, under fluoroscopic guidance, using the jugular, femoral, or brachial veins, or the femoral or radial arteries for vascular access.
      • Harwani N
      • Chukwu E
      • Alvarez M
      • Thohan V.
      Comparison of brachial vein versus internal jugular vein approach for access to the right side of the heart with or without myocardial biopsy.
      Patient monitoring (heart rhythm, noninvasive blood pressure, and blood oxygen saturation monitoring) is mandatory during the procedure. To minimize the risk of bleeding, an international normalized ratio should be ≤1.5–1.8 and the platelet count ≥50 × 109/L.
      • Patel IJ
      • Rahim S
      • Davidson JC
      • Hanks SE
      • Tam AL
      • Walker TG
      • et al.
      Society of Interventional Radiology consensus guidelines for the periprocedural management of thrombotic and bleeding risk in patients undergoing percutaneous image-guided interventions-part II: recommendations: endorsed by the Canadian Association for Interventional Radiology and the Cardiovascular and Interventional Radiological Society of Europe.
      The internal jugular vein is the most common access site for RV EMB in HTx patients, whereas the right femoral vein is most frequently used in non-HTx patients. Other access sites include brachial venous access for RV EMB
      • Harwani N
      • Chukwu E
      • Alvarez M
      • Thohan V.
      Comparison of brachial vein versus internal jugular vein approach for access to the right side of the heart with or without myocardial biopsy.
      and the right femoral and radial arteries for LV EMB. Radial access is associated with fewer vascular complications, earlier ambulation, and lower costs; however, radial thrombosis may occur if the inner vessel diameter is small (≤2.5 mm) and the peak systolic velocity is low.
      EMB is most commonly performed as a single procedure in HTx patients, whereas in non-HTx patients it can be combined with right heart catheterization, coronary angiography, and/or electrophysiologic study for the purpose of electroanatomic voltage mapping–guided procedure.
      • Schleifer JW
      • Manocha KK
      • Asirvatham SJ
      • Noseworthy PA
      • Gulati R
      • Friedman PA
      • et al.
      Feasibility of performing radiofrequency catheter ablation and endomyocardial biopsy in the same setting.

       The Number of EMB Procedures per Operator for the Maintenance of Procedural Skill

      The number of EMBs per operator required to maintain the procedural skill may vary between institutions and is not defined accurately. Training and yearly volumes for operators should be consistent with the recommendations of the appropriate medical societies. The opinion of the Trilateral Cooperative Project experts is that a range between 20 and 50 procedures per operator, per year may be reasonable. The Report of the American College of Cardiology Competency Management Committee recommends 50 EMBs per operator per year.
      • Jessup M
      • Drazner MH
      • Book W
      • Cleveland Jr., JC
      • Dauber I
      • Farkas S
      • et al.
      2017 ACC/AHA/HFSA/ISHLT/ACP advanced training statement on advanced heart failure and transplant cardiology (revision of the ACCF/AHA/ACP/HFSA/ISHLT 2010 clinical competence statement on management of patients with advanced heart failure and cardiac transplant): a report of the ACC Competency Management Committee.
      In addition to the procedural skill, it is essential that an experienced cardiac pathologist is available for the timely analysis and communication of EMB findings.
      Details of EMB technique are described in Appendix 1 and a video tutorial on EMB procedure as it is performed in expert centers in Europe, the United States, and Japan is available online (Supplementary Video).

       Selection of EMB Site, Sampling Error, and Biopsy of Noncardiac Tissues

      The most common site of EMB is the RV EMB (Fig. 3), but occasionally, LV (Fig 4) or biventricular EMB may be needed. The decision on EMB site should be based on the clinical indication, findings of preprocedural imaging, and on the operator's expertise.
      • Chimenti C
      • Frustaci A.
      Contribution and risks of left ventricular endomyocardial biopsy in patients with cardiomyopathies: a retrospective study over a 28-year period.
      A study of 755 patients with suspected myocarditis and nonischemic cardiomyopathy (including infiltrative and storage disorders) indicated that biventricular EMB can increase diagnostic accuracy compared with selective LV or RV EMB.
      • Yilmaz A
      • Kindermann I
      • Kindermann M
      • Mahfoud F
      • Ukena C
      • Athanasiadis A
      • et al.
      Comparative evaluation of left and right ventricular endomyocardial biopsy: differences in complication rate and diagnostic performance.
      Sampling error is the major limitation of the diagnostic usefulness of EMB. It is suggested that at least 5 samples should be taken from different sites in the RV and LV to decrease the risk of sampling error in the setting of diseases with focal pattern or intracardiac tumours.
      • Cooper LT
      • Baughman KL
      • Feldman AM
      • Frustaci A
      • Jessup M
      • Kuhl U
      • et al.
      The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology.
      ,
      • Caforio AL
      • Pankuweit S
      • Arbustini E
      • Basso C
      • Gimeno-Blanes J
      • Felix SB
      • 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.
      Fig 3
      Fig. 3An artistic presentation of right ventricular endomyocardial biopsy. Endomyocardial biopsy samples are typically taken from the interventricular septum.
      Fig 4
      Fig. 4An artistic presentation of left ventricular endomyocardial biopsy. Endomyocardial biopsy samples are typically taken from the ventricular apex.
      In patients with infiltrative and storage disorders affecting multiple organs, biopsies taken from the most affected organ are most likely to provide the diagnosis, but occasionally their usefulness may be hampered by low sensitivity. In patients with amyloidosis, abdominal fat pad biopsies have a sensitivity of 75% for immunoglobulin light-chain amyloidosis, but the sensitivity is significantly lower in both hereditary and wild-type transthyretin amyloidosis (approximately 45% and approximately 15%, respectively) and thus, a negative result does not rule out cardiac involvement.
      • Quarta CC
      • Gonzalez-Lopez E
      • Gilbertson JA
      • Botcher N
      • Rowczenio D
      • Petrie A
      • et al.
      Diagnostic sensitivity of abdominal fat aspiration in cardiac amyloidosis.

       Imaging Guidance

      In most centers, EMB is performed using fluoroscopic guidance; however, novel guidance modalities have emerged aiming to improve the feasibility and enable targeted EMB. The role of imaging in EMB guidance is 2-fold. First, preprocedural imaging with echocardiography, cardiac magnetic resonance imaging (CMR), computed tomography and/or position emission tomography (PET) can be used to direct EMB to the specific sites of myocardial disease. Second, procedural imaging (eg, real-time 3-dimensional echocardiography) can be performed simultaneously with fluoroscopy to improve the accuracy of EMB procedure.
      • Platts D
      • Brown M
      • Javorsky G
      • West C
      • Kelly N
      • Burstow D.
      Comparison of fluoroscopic versus real-time three-dimensional transthoracic echocardiographic guidance of endomyocardial biopsies.
      Intracardiac echocardiography has also been successfully employed to guide EMB of cardiac tumours.
      • Zanobini M
      • Dello Russo A
      • Saccocci M
      • Conti S
      • De Camilli E
      • Vettor G
      • et al.
      Endomyocardial biopsy guided by intracardiac echocardiography as a key step in intracardiac mass diagnosis.
      Preprocedural diagnostics with CMR has been demonstrated to improve diagnostic performance of EMB in several cardiac disorders. CMR-directed EMB can improve procedural accuracy in diseases with focal pattern (eg, sarcoidosis)
      • Kandolin R
      • Lehtonen J
      • Graner M
      • Schildt J
      • Salmenkivi K
      • Kivistö SM
      • et al.
      Diagnosing isolated cardiac sarcoidosis.
      and in the setting of soft tissue masses, which may be difficult to visualize on fluoroscopy.
      • McGuirt D
      • Mazal J
      • Rogers T
      • Faranesh AZ
      • Schenke W
      • Stine A
      • et al.
      X-ray fused with magnetic resonance imaging to guide endomyocardial biopsy of a right ventricular mass.
      Likewise, a small study suggested that directing EMB to the regions of late gadolinium enhancement on CMR can increase diagnostic usefulness in myocarditis.
      • Mahrholdt H
      • Wagner A
      • Deluigi CC
      • Kispert E
      • Hager S
      • Meinhardt G
      • et al.
      Presentation, patterns of myocardial damage, and clinical course of viral myocarditis.
      However, a larger study failed to confirm this finding, perhaps because late gadolinium enhancement is a nonspecific sign, which may correspond with both acute necrosis and inflammation, as well as fibrosis in myocarditis.
      • Yilmaz A
      • Kindermann I
      • Kindermann M
      • Mahfoud F
      • Ukena C
      • Athanasiadis A
      • et al.
      Comparative evaluation of left and right ventricular endomyocardial biopsy: differences in complication rate and diagnostic performance.
      Because T2 mapping has a greater sensitivity for detecting inflammation, this technique may be explored further for directing EMB to the most affected regions of the heart in myocarditis and other inflammatory disorders.
      • Spieker M
      • Katsianos E
      • Gastl M
      • Behm P
      • Horn P
      • Jacoby C
      • et al.
      T2 mapping cardiovascular magnetic resonance identifies the presence of myocardial inflammation in patients with dilated cardiomyopathy as compared to endomyocardial biopsy.
      However, small cohort studies of patients with cardiomyopathies indicate that the concordance between CMR and EMB findings is only partial and that these procedures have a complementary role in diagnostic assessment.
      • Dickerson JA
      • Raman SV
      • Baker PM
      • Leier CV.
      Relationship of cardiac magnetic resonance imaging and myocardial biopsy in the evaluation of nonischemic cardiomyopathy.
      ,
      • Yoshida A
      • Ishibashi-Ueda H
      • Yamada N
      • Kanzaki H
      • Hasegawa T
      • Takahama H
      • et al.
      Direct comparison of the diagnostic capability of cardiac magnetic resonance and endomyocardial biopsy in patients with heart failure.
      Electroanatomic voltage mapping has been used for the guidance of EMB in diseases with focal pattern associated with ventricular arrhythmias (myocarditis, sarcoidosis, and arrhythmogenic right ventricular cardiomyopathy [ARVC]).
      • Vaidya VR
      • Abudan AA
      • Vasudevan K
      • Shantha G
      • Cooper LT
      • Kapa S
      • et al.
      The efficacy and safety of electroanatomic mapping-guided endomyocardial biopsy: a systematic review.
      ,
      • Seizer P
      • Klingel K
      • Stickel J
      • Dorn C
      • Horger M
      • Kandolf R
      • et al.
      Left ventricular site-directed biopsy guided by left ventricular voltage mapping: a proof of principle.
      Areas of low-voltage or abnormal electrogram on electroanatomic voltage mapping have a high sensitivity and specificity to identify the pathologic substrate.
      • Vaidya VR
      • Abudan AA
      • Vasudevan K
      • Shantha G
      • Cooper LT
      • Kapa S
      • et al.
      The efficacy and safety of electroanatomic mapping-guided endomyocardial biopsy: a systematic review.
      The EMB procedure may be further facilitated by using bioptomes with an integrated electrode at the tip, as well as with the use of 3-dimensional electroanatomic voltage mapping systems and intracardiac echocardiography.
      • Casella M
      • Dello Russo A
      • Vettor G
      • Lumia G
      • Catto V
      • Sommariva E
      • et al.
      Electroanatomical mapping systems and intracardiac echo integration for guided endomyocardial biopsy.
      ,
      • Konecny T
      • Noseworthy PA
      • Kapa S
      • Cooper LT
      • Mulpuru SK
      • Sandhu GS
      • et al.
      Endomyocardial biopsy-integrating electrode at the bioptome tip.

       Complications

      EMB is associated with a low rate of major complications (approximately 1%),
      • Yilmaz A
      • Kindermann I
      • Kindermann M
      • Mahfoud F
      • Ukena C
      • Athanasiadis A
      • et al.
      Comparative evaluation of left and right ventricular endomyocardial biopsy: differences in complication rate and diagnostic performance.
      ,
      • Chimenti C
      • Frustaci A.
      Contribution and risks of left ventricular endomyocardial biopsy in patients with cardiomyopathies: a retrospective study over a 28-year period.
      which can be classified as major or minor (Table 1). Patient characteristics, EMB site, procedural volume and operator expertise are the most important determinants of EMB risk (details in Supplementary Table 1). The risk of major complications is lower in HTx recipients compared with non-HTx patients (0.19% vs 0.70%).
      • Shah Z
      • Vuddanda V
      • Rali AS
      • Pamulapati H
      • Masoomi R
      • Gupta K.
      National trends and procedural complications from endomyocardial biopsy: results from the National Inpatient Sample, 2007-2014.
      Hemodynamically unstable patients with acute or advanced heart failure (HF) and those with dilated ventricles may be at a higher risk of cardiac perforation, tamponade, and malignant arrhythmias.
      • William Wijns PWS
      • Vahanian Alec
      • Eeckhout Eric
      • Rodney De Palma
      • Sambeek Marc van
      The PCR-EAPCI Textbook Percutaneous interventional cardiovascular medicine Toulouse.
      Cardiac perforation and tamponade are more frequently observed with RV than with LV EMB,
      • Chimenti C
      • Frustaci A.
      Contribution and risks of left ventricular endomyocardial biopsy in patients with cardiomyopathies: a retrospective study over a 28-year period.
      but LV EMB is more frequently complicated by stroke or systemic embolism. High-volume centers have a lower complications rate compared with low-volume centers, and high procedural volume has been identified as an independent predictor of a lower risk of major complications.
      • Isogai T
      • Yasunaga H
      • Matsui H
      • Ueda T
      • Tanaka H
      • Horiguchi H
      • et al.
      Hospital volume and cardiac complications of endomyocardial biopsy: a retrospective cohort study of 9508 adult patients using a nationwide inpatient database in Japan.
      Table 1Major and Minor Complications of Endomyocardial Biopsy
      Major ComplicationsMinor Complications
      Death (0%–0.07%)Chest pain (transient) (0%–1.8%)
      Cardiac perforation, hemopericardium, tamponade (0%–6.9%)Deep vein thrombosis (0.23%–3.8%)
      Pneumothorax, air embolism (0%–0.8%)Puncture site hematoma, nerve palsy (0%–0.64%)
      Thromboembolism (0%–0.32%)Hypotension, vasovagal syncope (0%–4.3%)
      Valvular trauma (0.02%–1.10%)Arterial trauma, vascular damage, fistulae (0.32%–2.80%)
      Severe arrhythmias, atrioventricular block (0%–11%)
      Detailed description of complications according to the center volume, access site, type of endomyocardial biopsy procedure and patient characteristics as well as references are provided in Supplementary Table 1.
      There is a risk of tricuspid valve damage during EMB, both at the valvular and subvalvular levels.
      • Fiorelli AI
      • Coelho GH
      • Aiello VD
      • Benvenuti LA
      • Palazzo JF
      • Santos Júnior VP
      • et al.
      Tricuspid valve injury after heart transplantation due to endomyocardial biopsy: an analysis of 3550 biopsies.
      The risk of complication can be minimized by using a correctly located long sheath across the tricuspid valve with the tip in the RV, to avoid repeated exposure of the valve leaflets to the bioptome. Infection and sepsis are very rare risks with EMB if the procedure follows recommendations for the aseptic technique.
      The risk of periprocedural mortality is low (0–0.07%),
      • Chimenti C
      • Frustaci A.
      Contribution and risks of left ventricular endomyocardial biopsy in patients with cardiomyopathies: a retrospective study over a 28-year period.
      ,
      • Fiorelli AI
      • Benvenuti L
      • Aielo V
      • Coelho AQ
      • Palazzo JF
      • Rossener R
      • et al.
      Comparative analysis of the complications of 5347 endomyocardial biopsies applied to patients after heart transplantation and with cardiomyopathies: a single-center study.
      and most frequently caused by stroke, malignant arrhythmias, high-degree atrioventricular block, and cardiac tamponade.
      • 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.
      The risk of stroke and systemic embolism can be decreased by identification of a thrombus (an absolute contraindication for EMB) and administration of low-dose heparin during the procedure in patients with high thromboembolic risk.
      • Cooper LT
      • Baughman KL
      • Feldman AM
      • Frustaci A
      • Jessup M
      • Kuhl U
      • et al.
      The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology.
      The management of cardiac perforation during EMB includes immediate pericardiocentesis and autotransfusion from the pericardium to a large central vein (femoral or jugular) until the bleeding has stopped.
      • Ristić AD
      • Imazio M
      • Adler Y
      • Anastasakis A
      • Badano LP
      • Brucato A
      • et al.
      Triage strategy for urgent management of cardiac tamponade: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.
      If cardiac perforation has occurred, these patients require close monitoring and consultation with a cardiac surgical service. Urgent surgical repair of the perforation site may be required in patients with on-going bleeding or instability related to the perforation.

       Evaluation of EMB Samples

      The choice of the technique for the analysis of EMB specimens depends on the clinical presentation and suspected underlying cardiac disorder.
      • Cooper LT
      • Baughman KL
      • Feldman AM
      • Frustaci A
      • Jessup M
      • Kuhl U
      • et al.
      The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology.
      The pathologist performing the analysis should be well-trained in specimen processing and proficient in analyses techniques. Standardized diagnostic criteria for histopathologic analyses (eg, Dallas criteria for myocarditis) should be used to minimize EMB reporting variability.

      Leone O, Veinot JP, Angelini A, Baandrup UT, Basso C, Berry G, et al. 2011 Consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology. Cardiovasc Pathol 2012;21:245–74.

      The use of vital stains is indicated to demonstrate myocyte hypertrophy and patterns of myocyte disarray or vacuolization. Infiltrative disorders such as amyloidosis can be characterized by Congo red stain, immunohistochemistry, immunogold electron microscopy, and mass spectroscopy. Immunostaining can be used to quantify resident and infiltrating macrophages, myofibroblasts, and lymphocytes. Quantitative polymerase chain reaction (PCR), reverse transcription PCR and direct sequencing should be used to identify infectious agents.
      • Tschope C
      • Cooper LT
      • Torre-Amione G
      • Van Linthout S.
      Management of myocarditis-related cardiomyopathy in adults.
      Simultaneously, blood samples should be assessed with PCR to identify systemic infection, and to exclude potential contamination of heart tissue by persistently or latently infected blood cells.
      • Caforio AL
      • Pankuweit S
      • Arbustini E
      • Basso C
      • Gimeno-Blanes J
      • Felix SB
      • 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.
      Electron microscopy is useful to detect and quantify changes in cardiomyopathies and storage disease.
      The most frequent indication for a repeat EMB procedure is the follow-up of graft rejection status after HTx. Rarely, a repeat EMB may be considered if sampling error is suspected in a patient with unexplained deterioration of HF and/or malignant rhythm disorders, when EMB findings may provide information pertinent to further management.
      • Caforio AL
      • Pankuweit S
      • Arbustini E
      • Basso C
      • Gimeno-Blanes J
      • Felix SB
      • 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.
      Details on EMB sample processing and analyses are presented in Table 2 and considered in Appendix 2. In addition, typical histopathologic findings of the normal myocardium, lymphocytic myocarditis, HTx rejection, and cardiac amyloidosis are presented in Fig. 5.
      Table 2Sample Processing, Analysis, and Characteristic Findings According to Clinical Presentation
      DiseaseEMB PROCESSING/STAININGPOSSIBLE FINDINGS
      Myocarditis, DCMHistopathology
      Hematoxylin and eosin, Mason or Mallory trichrome, Elastic van Gieson, PAS, Heidenhein`s AZAN, and Methylene blue stain (Trypanosoma cruzii)Dallas criteria for myocarditis: inflammatory infiltrates associated with myocyte degeneration and necrosis of nonischemic origin (active or borderline)

      Lymphocytic myocarditis: Patchy or diffuse inflammatory infiltrate mostly of lymphocytes and macrophages (viral infections, immune-mediated myocarditis [systemic lupus erythematosus, polymyositis/dermatomyositis, rheumatoid arthritis, organ-specific autoimmune disorders etc]).

      Giant cell myocarditis: Myocyte necrosis and diffuse or multifocal inflammatory infiltrates, with T lymphocytes, macrophage-derived multinucleated giant cells and eosinophilic granulocytes.

      Granulomatous myocarditis: Non-necrotizing granulomas with macrophages and multinucleated giant cells, surrounded by fibrosis and a lymphocytic infiltrate (sarcoidosis).

      Eosinophilic myocarditis: Interstitial inflammatory infiltrate dominated by eosinophils, often without myocyte damage, frequently accompanied by peripheral eosinophilia (hypersensitivity, parasitic infection, Churg-Strauss syndrome, endomyocardial fibrosis)
      Quantitative real-time PCR for enteroviruses, adenoviruses, herpesviruses (cytomegalovirus, herpes simplex, Epstein-Barr, human herpesvirus 6), parvovirus B19, influenza A and B, and SARS-CoV-2 virus + BorreliaInfection confirmed or not by RT- PCR
      Immunohistochemistry

      CD3 (T cells), CD68 (macrophages), MHC II, alpha SM-myofibroblasts
      Myocarditis confirmed by immunohistochemistry: ≥14 leucocytes/mm2 including ≤4 monocytes/mm2 with the presence of CD3 positive T lymphocytes ≥7 cells/mm2

      DCM, ARVCHistology and PCR as above, additional immunohistochemical stains for lamin A/C, dystrophin, and plakoglobin (ARVC)DCM: Nonspecific histopathology including hypertrophy and vacuolar changes of myocytes, interstitial fibrosis, foci of microscarring.

      ARVC: progressive myocyte atrophy/loss with fibrous or fibro-fatty myocardial replacement

      Storage diseasesPAS, Congo Red, sulfate Alcian blue, or S/T thioflavin, Sudan black or Oil Red O (lipid deposits), Prussian Blue (iron), TEM (Anderson-Fabry, Danon)PAS+ sarcoplasmic vacuoles and lysosomal glycogen accumulation (Pompe disease); PAS+ and LAMP2 absence, autophagic granules in TEM (Danon disease), PAS+ and lamellar bodies (Anderson–Fabry), Congo Red+ and interstitial deposits (amyloidosis); brownish perinuclear granules in myocytes highlighted in blue by Prussian Blue stain (iron storage disease)
      TumorsStandard histopathology + immunohistochemistry for specific tumorsDifferential diagnosis between benign and malignant tumors, and in malignant tumor subtyping
      Heart transplantationHematoxylin and eosin, Giemsa, Movat, Masson trichrome, Weigert-Van Gieson, Ziehl Nielsen, PAS, Gram, Gomori, CD31, CD34, CD45, CD68, C4dCellular rejection: Grade 0R (no rejection); Grade 1R (mild) Interstitial and/or perivascular infiltrate with up to 1 focus of myocyte damage; Grade 2R (moderate), ≥2 foci of infiltrate with associated myocyte damage; Grade 3R (severe) diffuse infiltrate with multifocal myocyte damage, oedema, hemorrhage, or vasculitis

      Humoral rejection: capillary injury, endothelial cell swelling and aggregation of intravascular macrophages (positive staining for C4d or C3d fragments of complement by endothelial cells)
      ARVC, arrhythmogenic right ventricular cardiomyopathy; CD, cluster of differentiation; DCM, dilated cardiomyopathy; EMB, endomyocardial biopsy; LAMP2, lysosome-associated membrane protein 2; MHC II, major histocompatibility complex type II; PAS, periodic acid Schiff; PCR, polymerase chain reaction; RT-PCR, reverse transcriptase polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TEM, transmission electron microscopy.
      Fig 5
      Fig. 5Typical histopathologic findings of the normal myocardium (A), lymphocytic myocarditis (B), cardiac amyloidosis (C) and cellular HTx rejection (D). (A) Normal myocardium: no myocyte necrosis, inflammation or fibrosis. (B) Acute lymphocytic myocarditis: many necrotic myocytes (light pink) and numerous CD3+ T cells and other immune cells (eg, CD68+ macrophages). (C) Acute cellular HTx rejection: significant amounts of inflammatory cells including CD3+ T cells. (D) Cardiac amyloidosis: Congo red staining and subtyping by immunohistochemistry defines cardiac amyloidosis. (Presented in the figure: transthyretin amyloidosis).

      Indications for EMB

      EMB can provide important histologic, immunohistochemical, and molecular information about the heart. Because EMB is an invasive procedure with limited availability, the risk and benefits of the procedure should be taken into account. In establishing an indication for EMB, it is important to identify clinical situations in which EMB can complement the diagnostic process to confirm clinically suspected diagnosis and provide information relevant for the management. Diagnostic value of EMB also depends on the myocardial disease (ie, a lower sensitivity in diseases with focal involvement) and on the center's proficiency in sample processing and analysis. The most frequent indications for EMB are summarized in Table 3.
      Table 3Indications for Endomyocardial Biopsy
      Clinical PresentationEndomyocardial Biopsy Finding
      Suspected fulminant myocarditis or acute myocarditis with acute HF, LV dysfunction, and/or rhythm disorders.

      Suspected myocarditis in hemodynamically stable patients.
      Myocarditis type:

       Lymphocytic myocarditis

       Eosinophilic myocarditis

       Giant cell myocarditis

       Granulomatous myocarditis
      Dilated cardiomyopathy with recent onset HF, moderate-to-severe LV dysfunction, refractory to standard treatment (after the exclusion of specific etiologies).Myocyte abnormalities, focal or diffuse fibrosis and inflammatory infiltrates (inflammatory cardiomyopathy).
      Suspected ICI-mediated cardiotoxicity: acute HF with/without haemodynamic instability early after drug initiation (approximately first 4 cycles)ICI-mediated myocarditis
      High-degree atrioventricular block, syncope, and/or unexplained ventricular arrhythmias (ventricular fibrillation, ventricular tachycardia, frequent multifocal premature ventricular complexes), refractory to treatment, without obvious cardiac disease or with minimal structural abnormalities.Myocarditis

      Arrhythmogenic right ventricular cardiomyopathy

      Cardiac sarcoidosis
      Autoimmune disorders with progressive HF unresponsive to treatment with/without sustained ventricular arrhythmias and/or conduction abnormalities.Autoimmune myocarditis

      Viral myocarditis

      Vasculitis/vasculopathy
      MINOCA/takotsubo syndrome with progressive LV dysfunction and HF with/without ventricular arrhythmias or conduction abnormalities.Differential diagnosis of myocarditis
      Unexplained restrictive or hypertrophic cardiomyopathy.Amyloidosis

      Infiltrative/storage disorders (Anderson–Fabry disease, glycogen storage diseases, sarcoidosis, haemochromatosis)
      Cardiac tumorsHistopathologic diagnosis
      Routine surveillance EMB

      Symptom-triggered EMB
      HTx rejection status
      EMB, endomyocardial biopsy; HF, heart failure; HTx, heart transplantation; ICI, immune checkpoint inhibitors; LV, left ventricular; MINOCA, myocardial infarction without obstructive coronary artery disease

       Clinically Suspected Myocarditis

      EMB is indicated in patients with fulminant or acute myocarditis presenting with cardiogenic shock or acute HF and LV dysfunction, with or without malignant ventricular arrhythmias and/or conduction abnormalities. It may also be considered in hemodynamically stable patients with clinical symptoms and diagnostic criteria (electrocardiogram abnormalities, elevated troponin levels, and imaging findings) suggestive of myocarditis, in the absence of significant coronary artery disease.
      • Caforio AL
      • Pankuweit S
      • Arbustini E
      • Basso C
      • Gimeno-Blanes J
      • Felix SB
      • 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.
      A retrospective registry-based analysis of 220 patients (mean age 42 years) from the United States, Europe, and Japan with acute myocarditis and LV dysfunction has shown that patients with fulminant myocarditis have significantly worse short-term (60-day mortality/HTx rate: 27.7% vs 1.8%) and long-term prognosis (7-year mortality/HTx rate: 43.0% vs 9.0%) compared with nonfulminant course and that EMB-proven diagnosis of giant cell myocarditis carries the worst prognosis.
      • Ammirati E
      • Veronese G
      • Brambatti M
      • Merlo M
      • Ciprani M
      • Potena L
      • et al.
      Fulminant versus acute nonfulminant myocarditis in patients with left ventricular systolic dysfunction.
      A recent analysis of 443 individuals with suspected myocarditis has shown that among high-risk patients with LV dysfunction, sustained ventricular arrhythmias and/or haemodynamic instability (n = 118, EMB performed in 56 patients) EMB-established diagnosis (89.3%) offered information relevant for the management and prognosis (eg, institution of immunosuppressive therapy in giant cell myocarditis, sarcoidosis, or eosinophilic myocarditis).
      • Ammirati E
      • Cipriani M
      • Moro C
      • Raineri C
      • Pini D
      • Sormani P
      • et al.
      Clinical presentation and outcome in a contemporary cohort of patients with acute myocarditis.
      In addition, EMB can provide differential diagnosis in patients with severe clinical course, when noninvasive assessment is inconclusive or unfeasible.
      • Ammirati E
      • Cipriani M
      • Moro C
      • Raineri C
      • Pini D
      • Sormani P
      • et al.
      Clinical presentation and outcome in a contemporary cohort of patients with acute myocarditis.
      Accordingly, in unexplained acute HF with hemodynamic compromise, a cohort study of 851 patients demonstrated that EMB provided a diagnosis in 39%, and that the most common finding was acute myocarditis.
      • Bennett MK
      • Gilotra NA
      • Harrington C
      • Rao S
      • Dunn JM
      • Freitag TB
      • et al.
      Evaluation of the role of endomyocardial biopsy in 851 patients with unexplained heart failure from 2000-2009.
      In this study, EMB-based diagnosis resulted in a change of therapy in almost a third of patients, and most clinical decisions concerned the institution or withholding of immunosuppressive medications.
      • Bennett MK
      • Gilotra NA
      • Harrington C
      • Rao S
      • Dunn JM
      • Freitag TB
      • et al.
      Evaluation of the role of endomyocardial biopsy in 851 patients with unexplained heart failure from 2000-2009.
      The common histologic types of myocarditis include lymphocytic, eosinophilic, giant cell, and granulomatous myocarditis (cardiac sarcoidosis). The most prevalent is lymphocytic myocarditis caused by viral infection, autoimmunity, or drug toxicity, which is frequently associated with HF of various severity. Eosinophilic myocarditis is characterized by eosinophilic infiltrates in the heart and is often accompanied by peripheral blood eosinophilia. Giant cell myocarditis is rare (approximately 1% of acute myocarditis cases), but it may take the fulminant course and carries a poor prognosis.
      • Ammirati E
      • Veronese G
      • Brambatti M
      • Merlo M
      • Ciprani M
      • Potena L
      • et al.
      Fulminant versus acute nonfulminant myocarditis in patients with left ventricular systolic dysfunction.
      EMB has a high sensitivity (80%) and positive predictive value (71%) for giant cell myocarditis, especially if performed within 2–4 weeks of symptom onset.
      • Shields RC
      • Tazelaar HD
      • Berry GJ
      • Cooper Jr., LT
      The role of right ventricular endomyocardial biopsy for idiopathic giant cell myocarditis.
      Noncaseating granulomatous myocarditis is the usual histopathologic finding in patients with cardiac sarcoidosis.
      • Okura Y
      • Dec GW
      • Hare JM
      • Kodama M
      • Berry GJ
      • Tazelaar HD
      • et al.
      A clinical and histopathologic comparison of cardiac sarcoidosis and idiopathic giant cell myocarditis.
      An EMB may be indicated in suspected cardiac sarcoidosis (electrocardiographic abnormalities, unexplained syncope or palpitations), if imaging studies (echocardiography, CMR, 18fluorodeoxyglucose-PET) and lymph node or lung biopsy render inconclusive results, as well as in cases of isolated cardiac involvement.
      • Birnie DH
      • Sauer WH
      • Bogun F
      • Cooper JM
      • Culver DA
      • Duvernoy CS
      • et al.
      HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis.
      The major drawback is the low sensitivity of EMB owing to the focal nature of myocardial involvement, revealing noncaseating granulomatous infiltrates in approximately 25% of patients.
      • Birnie DH
      • Sauer WH
      • Bogun F
      • Cooper JM
      • Culver DA
      • Duvernoy CS
      • et al.
      HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis.
      Small case series have suggested that sensitivity can be improved with an electrogram-guided approach targeting areas with low amplitude and/or abnormal electrogram appearance
      • Liang JJ
      • Hebl VB
      • DeSimone CV
      • Madhavan M
      • Nanda S
      • Kapa S
      • et al.
      Electrogram guidance: a method to increase the precision and diagnostic yield of endomyocardial biopsy for suspected cardiac sarcoidosis and myocarditis.
      or with preprocedural CMR-guided EMB.
      • Kandolin R
      • Lehtonen J
      • Graner M
      • Schildt J
      • Salmenkivi K
      • Kivistö SM
      • et al.
      Diagnosing isolated cardiac sarcoidosis.
      EMB is rarely indicated with individuals with suspected coronavirus disease 2019 myocarditis. EMB and autopsy findings support the presence of severe acute respiratory syndrome coronavirus 2 in the myocardium,
      • Tavazzi G
      • Pellegrini C
      • Maurelli M
      • Belliato M
      • Sciutti F
      • Bottazzi A
      • et al.
      Myocardial localization of coronavirus in COVID-19 cardiogenic shock.
      ,
      • Puelles VG
      • Lütgehetmann M
      • Lindenmeyer MT
      • Sperhake JP
      • Wong MN
      • Allweiss L
      • et al.
      Multiorgan and renal tropism of SARS-CoV-2.
      and histopathologic studies suggest that increased interstitial macrophage infiltration and lymphocytic myocarditis are the most common findings.
      • Tavazzi G
      • Pellegrini C
      • Maurelli M
      • Belliato M
      • Sciutti F
      • Bottazzi A
      • et al.
      Myocardial localization of coronavirus in COVID-19 cardiogenic shock.
      ,
      • Basso C
      • Leone O
      • Rizzo S
      • De Gaspari M
      • van der Wal AC
      • Aubry M-C
      • et al.
      Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study.
      The diagnostic value of EMB in clinically suspected myocarditis increases if the procedure is performed 2–4 weeks after symptom onset,
      • Cooper LT
      • Baughman KL
      • Feldman AM
      • Frustaci A
      • Jessup M
      • Kuhl U
      • et al.
      The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology.
      ,
      • Caforio AL
      • Pankuweit S
      • Arbustini E
      • Basso C
      • Gimeno-Blanes J
      • Felix SB
      • 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.
      and the sample is analyzed with the use of immunohistochemistry. A recent meta-analysis (61 publications with a total of 10,491 patients) indicated that the use of immunohistochemistry can increase the detection rate of inflammation in EMB specimens to approximately 51%.

       Dilated Cardiomyopathy

      In patients with dilated cardiomyopathy (DCM), EMB may be indicated in the setting of decompensated HF with moderate-to-severe LV dysfunction, refractory to standard HF treatment, with a recent onset of the clinical syndrome, exclusion of other specific etiologies, absence of severe LV remodeling, and negative familial history and/or genetic testing for cardiomyopathy. In this setting, EMB can be used to confirm inflammatory cardiomyopathy with a higher sensitivity compared with CMR.
      • Katzmann JL
      • Schlattmann P
      • Rigopoulos AG
      • Noutsias E
      • Bigalke B
      • Pauschinger M
      • et al.
      Meta-analysis on the immunohistological detection of inflammatory cardiomyopathy in endomyocardial biopsies.
      EMB may also have a role in the assessment of Borrelia burgdorferi involvement in unexplained DCM in regions endemic for Lyme disease.
      • Kubánek M
      • Šramko M
      • Berenová D
      • Hulínská D
      • Hrbáčková H
      • Malušková J
      • et al.
      Detection of Borrelia burgdorferi sensu lato in endomyocardial biopsy specimens in individuals with recent-onset dilated cardiomyopathy.
      A study of 110 individuals with recent-onset DCM has demonstrated that the Borrelia burgdorferi genome was present in 20% of EMB samples.
      • Kuchynka P
      • Palecek T
      • Havranek S
      • Vitkova I
      • Nemecek E
      • Trckova R
      • et al.
      Recent-onset dilated cardiomyopathy associated with Borrelia burgdorferi infection.

       Cardiotoxicity of Cancer Therapy

      Immune checkpoint inhibitors (ICI) represent a novel, highly effective class of antineoplastic drugs but their use can result in cardiac toxicity in up to 5% of cases, including myocarditis, noninflammatory LV dysfunction, myocardial infarction, and arrhythmias.
      • Lyon AR
      • Yousaf N
      • Battisti NML
      • Moslehi J
      • Larkin J.
      Immune checkpoint inhibitors and cardiovascular toxicity.
      ICI-mediated myocarditis and pericarditis occur early (>75% cases in first 4 cycles), more frequently in patients on combined ICIs and can be severe or fatal in up to 50%.
      • Mahmood SS
      • Fradley MG
      • Cohen JV
      • Nohria A
      • Reynolds KL
      • Heinzerling LM
      • et al.
      Myocarditis in patients treated with immune checkpoint inhibitors.
      ,
      • Escudier M
      • Cautela J
      • Malissen N
      • Ancedy Y
      • Orabona M
      • Pinto J
      • et al.
      Clinical features, management, and outcomes of immune checkpoint inhibitor-related cardiotoxicity.
      EMB is indicated in suspected ICI-mediated cardiotoxicity, if CMR or 18F-fluorodeoxyglucose PET-computed tomography yield uncertain findings and/or the patients cannot undergo noninvasive assessment owing to haemodynamic instability.
      • Zhang L
      • Awadalla M
      • Mahmood SS
      • Nohria A
      • Hassan MZO
      • Thuny F
      • et al.
      Cardiovascular magnetic resonance in immune checkpoint inhibitor-associated myocarditis.
      In patients with confirmed ICI-mediated myocarditis, ICI treatment should be discontinued and high-dose immunosuppression should be instituted, in addition to standard HF care.
      • Lyon AR
      • Yousaf N
      • Battisti NML
      • Moslehi J
      • Larkin J.
      Immune checkpoint inhibitors and cardiovascular toxicity.
      If active inflammation has been ruled out by EMB, then ICI treatment rechallenge may be considered once LV function has stabilized or recovered with standard HF drugs.
      • Lyon AR
      • Yousaf N
      • Battisti NML
      • Moslehi J
      • Larkin J.
      Immune checkpoint inhibitors and cardiovascular toxicity.
      EMB has been used to document and assess the degree of anthracycline-related cardiotoxicity.
      • Billingham ME
      • Mason JW
      • Bristow MR
      • Daniels JR.
      Anthracycline cardiomyopathy monitored by morphologic changes.
      However, EMB is not routinely recommended in patients with anthracycline-related cardiotoxicity and HF when there is a clear causal relationship. EMB may be considered in rare cases when there is clinical uncertainty as to the cause of HF (eg, suspected myocarditis). The role of EMB in cyclophosphamide-induced cardiotoxicity, and other cancer therapy-induced HF is less well-established.
      • Kusumoto S
      • Kawano H
      • Hayashi T
      • Satoh O
      • Yonekura T
      • Eguchi M
      • et al.
      Cyclophosphamide-induced cardiotoxicity with a prolonged clinical course diagnosed on an endomyocardial biopsy.
      and EMB is not indicated.

       Unexplained Ventricular Arrhythmias, Conduction Disorders, and Syncope

      EMB may be indicated in patients with unexplained ventricular arrhythmias or syncope (ventricular fibrillation or tachycardia, frequent multifocal ventricular premature complexes, or nonsustained ventricular tachycardia), refractory to treatment, and without obvious cardiac disease or with minimal structural changes to identify potentially treatable etiologies, such as myocarditis, ARVC, or sarcoidosis.
      • Birnie DH
      • Sauer WH
      • Bogun F
      • Cooper JM
      • Culver DA
      • Duvernoy CS
      • et al.
      HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis.
      ,
      • Vasichkina E
      • Poghosyan H
      • Mitrofanova L
      • Tatarsky R
      • Lebedev D.
      Right ventricular endomyocardial biopsy in children and adolescents with drug-refractory arrhythmia.
      ,
      • Vignola PA
      • Aonuma K
      • Swaye PS
      • Rozanski JJ
      • Blankstein RL
      • Benson J
      • et al.
      Lymphocytic myocarditis presenting as unexplained ventricular arrhythmias: diagnosis with endomyocardial biopsy and response to immunosuppression.
      Ventricular arrhythmias may be the only symptom of myocarditis and sarcoidosis,
      • Birnie DH
      • Sauer WH
      • Bogun F
      • Cooper JM
      • Culver DA
      • Duvernoy CS
      • et al.
      HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis.
      ,
      • Peretto G
      • Sala S
      • Rizzo S
      • De Luca G
      • Campochiaro C
      • Sartorelli S
      • et al.
      Arrhythmias in myocarditis: state of the art.
      as well as the first presentation of ARVC in patients with subtle structural abnormalities, that may challenge diagnostic evaluation. Given the focal nature of cardiac sarcoidosis and ARVC, undirected EMB can be falsely negative and electroanatomic voltage mapping guidance may be considered to increase the diagnostic yield.
      • Liang JJ
      • Hebl VB
      • DeSimone CV
      • Madhavan M
      • Nanda S
      • Kapa S
      • et al.
      Electrogram guidance: a method to increase the precision and diagnostic yield of endomyocardial biopsy for suspected cardiac sarcoidosis and myocarditis.
      ,
      • Casella M
      • Dello Russo A
      • Bergonti M
      • Catto V
      • Conte E
      • Sommariva E
      • et al.
      Diagnostic yield of electroanatomic voltage mapping in guiding endomyocardial biopsies.
      EMB may be useful in patients with new-onset bradycardia and conduction abnormalities, when clinical presentation is suggestive of a treatable etiology (eg, myocarditis, amyloidosis, or sarcoidosis).
      • Frustaci A
      • Letizia C
      • Adamo F
      • Grande C
      • Verardo R
      • Chimenti C.
      A-V block as presentation of cardiac amyloid: prominent infiltration of conduction tissue revealed by endomyocardial biopsy.
      ,
      • Kusumoto FM
      • Schoenfeld MH
      • Barrett C
      • Edgerton JR
      • Ellenbogen KA
      • Gold MR
      • et al.
      2018 ACC/AHA/HRS guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.
      Electroanatomic voltage mapping guidance may be useful, as suggested by a cohort of patients with unexplained atrioventricular block, where a comprehensive evaluation, including electroanatomic voltage mapping guided–EMB, demonstrated cardiac sarcoidosis in 34%.
      • Nery PB
      • Beanlands RS
      • Nair GM
      • Green M
      • Yang J
      • McArdle BA
      • et al.
      Atrioventricular block as the initial manifestation of cardiac sarcoidosis in middle-aged adults.

       Autoimmune Disorders

      EMB is rarely indicated in autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, polymyositis, dermatomyositis, etc), but it may be considered in patients with progressive HF unresponsive to usual treatment, as well as in patients with sustained ventricular arrhythmias and/or conduction abnormalities, when there is a high clinical suspicion of myocarditis or vasculitis. In a small study of patients with systemic sclerosis and HF, a greater extent of EMB-detected inflammation and fibrosis correlated with serious adverse events.
      • Mueller KA
      • Mueller II
      • Eppler D
      • Zuern CS
      • Seizer P
      • Kramer U
      • et al.
      Clinical and histopathological features of patients with systemic sclerosis undergoing endomyocardial biopsy.
      Likewise, EMB in patients with systemic lupus erythematosus can provide confirmation of lupus myocarditis, hydroxychloroquine-induced cardiotoxicity and/or coronary vasculitis and vasculopathy.
      • Nord JE
      • Shah PK
      • Rinaldi RZ
      • Weisman MH.
      Hydroxychloroquine cardiotoxicity in systemic lupus erythematosus: a report of 2 cases and review of the literature.
      ,
      • Sakaguchi Y
      • Nakamura Y
      • Sutani T
      • Tsuchihashi M
      • Yamano S
      • Hashimoto T
      • et al.
      [Immunohistochemical study of the endomyocardial biopsy of systemic lupus erythematosus].

       Myocardial Infarction Without Obstructive Coronary Artery Disease and Takotsubo Syndrome

      EMB is rarely indicated in myocardial infarction without obstructive coronary artery disease or in Takotsubo syndrome. In may be considered for the purpose of a differential diagnosis of myocarditis in the setting of progressive LV dysfunction and HF despite standard therapy, with or without life-threatening ventricular arrhythmias or conduction abnormalities.
      • Agewall S
      • Beltrame JF
      • Reynolds HR
      • Niessner A
      • Rosano G
      • Caforio ALP
      • et al.
      ESC working group position paper on myocardial infarction with non-obstructive coronary arteries.

       Restrictive and Hypertrophic Cardiomyopathy

      EMB may be considered in patients with restrictive and hypertrophic cardiomyopathy if the etiology of cardiomyopathy remains inconclusive after noninvasive assessment, and there is clinical suspicion of infiltrative or storage disorder (amyloidosis, sarcoidosis, Anderson Fabry, and glycogen storage diseases) with available treatment options.
      • Frustaci A
      • Russo MA
      • Chimenti C.
      Diagnostic contribution of left ventricular endomyocardial biopsy in patients with clinical phenotype of hypertrophic cardiomyopathy.
      • Elliott PM
      • Anastasakis A
      • Borger MA
      • Borggrefe M
      • Cecchi F
      • Charron P
      • et al.
      2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).
      • Smid BE
      • van der Tol L
      • Cecchi F
      • Elliott PM
      • Hughes DA
      • Linthorst GE
      • et al.
      Uncertain diagnosis of Fabry disease: consensus recommendation on diagnosis in adults with left ventricular hypertrophy and genetic variants of unknown significance.
      In patients with cardiac amyloidosis, differentiating between immunoglobulin light chain and wild-type or hereditary transthyretin amyloidosis has important therapeutic implications.
      • Siddiqi OK
      • Ruberg FL.
      Cardiac amyloidosis: an update on pathophysiology, diagnosis, and treatment.
      EMB is highly sensitive and specific for cardiac amyloidosis,
      • Rubin J
      • Maurer MS.
      Cardiac amyloidosis: overlooked, underappreciated, and treatable.
      and may be considered if noninvasive assessment provides inconclusive or discordant results (eg, abnormal serum free light chain assay and a positive 99mTc 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy), or in patients with plasma cell dyscrasia and ambiguous imaging results.
      • Siddiqi OK
      • Ruberg FL.
      Cardiac amyloidosis: an update on pathophysiology, diagnosis, and treatment.
      ,
      • Lee J
      • Kim K
      • Choi J-O
      • Kim SJ
      • Jeon E-S
      • Choi JY.
      99mTc-DPD scintigraphy and SPECT/CT in patients with AL and ATTR type amyloidosis: potential clinical implications.
      Congo red staining and immunohistochemistry are the standard techniques used to characterize the type of amyloid fibrils in EMB specimens, but newer technologies, such as immunoelectron microscopy and laser dissection mass spectrometry, seem to be superior to immunohistochemistry in identifying amyloid protein type.
      • Rezk T
      • Gilbertson JA
      • Mangione PP
      • Rowczenio D
      • Rendell NB
      • Canetti D
      • et al.
      The complementary role of histology and proteomics for diagnosis and typing of systemic amyloidosis.
      ,
      • Witteles RM
      • Bokhari S
      • Damy T
      • Elliott PM
      • Falk RH
      • Fine NM
      • et al.
      Screening for transthyretin amyloid cardiomyopathy in everyday practice.
      In individuals with LV hypertrophy and suspected Anderson–Fabry disease who do not meet all diagnostic criteria, EMB can be performed to confirm the diagnosis.
      • Smid BE
      • van der Tol L
      • Cecchi F
      • Elliott PM
      • Hughes DA
      • Linthorst GE
      • et al.
      Uncertain diagnosis of Fabry disease: consensus recommendation on diagnosis in adults with left ventricular hypertrophy and genetic variants of unknown significance.
      Rarely, EMB may be indicated in the presence of iron overload and unequivocal imaging results to confirm cardiac hemochromatosis.
      • Olson LJ
      • Edwards WD
      • Holmes DR
      • Miller FA
      • Nordstrom LA
      • Baldus WP.
      Endomyocardial biopsy in hemochromatosis: clinicopathologic correlates in six cases.

       Tumors of the Heart

      In patients with cardiac tumors, multimodality imaging plays the pivotal role in identification and characterization of cardiac masses. EMB may be indicated in patients with primary or metastatic cardiac tumors when noninvasive assessment and/or biopsy of noncardiac tissues have been inconclusive, and histologic diagnosis is relevant for the prognosis and treatment.
      • Cooper LT
      • Baughman KL
      • Feldman AM
      • Frustaci A
      • Jessup M
      • Kuhl U
      • et al.
      The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology.
      EMB is not indicated for intracardiac masses with a high embolic potential, such as left-sided tumors or typical cardiac myxomas. EMB guidance with transthoracic, transesophageal, and intracardiac echocardiography can improve the efficacy and safety of the procedure.
      • Zanobini M
      • Dello Russo A
      • Saccocci M
      • Conti S
      • De Camilli E
      • Vettor G
      • et al.
      Endomyocardial biopsy guided by intracardiac echocardiography as a key step in intracardiac mass diagnosis.
      ,
      • Nguyen CT
      • Lee E
      • Luo H
      • Siegel RJ.
      Echocardiographic guidance for diagnostic and therapeutic percutaneous procedures.

      Monitoring of HTx Rejection Status

      Despite advances in cardiac imaging and availability of novel biomarkers, EMB remains the gold standard for the detection of HTx rejection. EMB after HTx can be scheduled according to a protocol for routine surveillance EMB (rsEMB) in asymptomatic patients, and it is also performed in patients with worsening clinical status, as a symptom triggered EMB.
      At present, there is a lack of consensus on the optimal timing and frequency of rsEMB. In the era of potent immunosuppressive regimens, a decrease in diagnostic usefulness was observed with surveillance protocols that utilize frequent rsEMB procedures. A diagnostic yield of 1.39% for detecting clinically silent acute rejection was described with a protocol of 14 rsEMB procedures per patient in the first year after HTx.
      • Hamour IM
      • Burke MM
      • Bell AD
      • Panicker MG
      • Banerjee R
      • Banner NR.
      Limited utility of endomyocardial biopsy in the first year after heart transplantation.
      Another study reported a diagnostic yield of approximately 3% in the first 6 months after HTx and of 0% in the next 6 months, with a protocol involving an average of 8.7 ± 3.7 rsEMB procedures in months 0–6, and 2.0 ± 2.1 rsEMB procedures in months 6–12.
      • Shah KB
      • Flattery MP
      • Smallfield MC
      • Merinar G
      • Tang DG
      • Sheldon EH
      • et al.
      Surveillance endomyocardial biopsy in the modern era produces low diagnostic yield for cardiac allograft rejection.
      Recently, a low-frequency protocol for rsEMB was tested in 282 HTx patients and demonstrated morbidity and mortality comparable with the high-frequency protocol data in the International Society for Heart and Lung Transplantation Registry.
      • Weckbach LT
      • Maurer U
      • Schramm R
      • Huber BC
      • Lackermair K
      • Weiss M
      • et al.
      Lower frequency routine surveillance endomyocardial biopsies after heart transplantation.
      In this study, rsEMB was performed monthly for the first 6 months (with the first rsEMB being scheduled 1 month after HTx), and subsequently at months 9 and 12. Despite this relatively low frequency of rsEMB procedures, only 6 unscheduled symptom triggered EMB procedures were required, resulting in a change of treatment in only 2 patients.

       Revised Schedule for HTx Rejection Surveillance

      Currently, most HTx protocols suggest performing rsEMB every week during the first month, every second week for the next several months, and then once monthly for the first 12 months. Thereafter, rsEMB are often continued at variable frequency for years, despite a low risk of late rejection and with a low cost-effectiveness.
      • Lampert BC
      • Teuteberg JJ
      • Shullo MA
      • Holtz J
      • Smith KJ.
      Cost-effectiveness of routine surveillance endomyocardial biopsy after 12 months post-heart transplantation.
      Recently, noninvasive surveillance of HTx rejection with the combined use of novel techniques, such as gene expression profiling and donor-derived cell-free DNA, has shown high negative predictive validity for acute graft rejection, which may decrease the need for rsEMB.
      • Purewal S
      • Moayedi Y
      • Runeckles K
      • Fan C
      • Gordon J
      • Henricksen EJ
      • et al.
      Are two tests better than one? combining donor derived cell-free DNA and gene expression profiling for non-invasive surveillance after heart transplantation.
      In the future, multicenter prospective clinical trials should be planned to test the optimal approach to rsEMB after HTx. Based on the available data on diagnostic yield of EMB according to the time after HTx, the schedule for rsEMB is suggested in Fig. 6.
      Fig 6
      Fig. 6Recommended schedule for the routine surveillance endomyocardial biopsies (rsEMB) in the monitoring of transplant rejection status. High pretest diagnostic probability is highlighted in green, intermediate in yellow and low in blue. *If rsEMB reveals more than grade 1 rejection or if there is on-going clinical concern for the patient, a follow-up EMB should be considered.

      Contraindications

      In most instances, contraindications for EMB are consistent with contraindications for cardiac catheterization (Table 4). Additional caution is required in patients with recent pacemaker implantation (increased risk of lead dislodgement for RV EMB), marked ventricular wall thinning and hypercontractility (high risk of ventricular perforation).
      • Singh V
      • Mendirichaga R
      • Savani GT
      • Rodriguez A
      • Blumer V
      • Elmariah S
      • et al.
      Comparison of utilization trends, indications, and complications of endomyocardial biopsy in native versus donor hearts (from the Nationwide Inpatient Sample 2002 to 2014).
      Table 4Contraindications for Endomyocardial Biopsy
      Absolute contraindications
       Intracardiac thrombus
       Ventricular aneurysm
       Severe tricuspid, pulmonary or aortic stenosis
       Aortic and tricuspid mechanical prosthesis
      Relative contraindications
       Active bleeding
       Infection and fever
       Infective endocarditis
       Pregnancy
       Recent cerebrovascular accident/TIA (<1 month)
       Uncontrolled hypertension
       Thin ventricular wall (for the biopsy of the myocardium)
       Coagulopathy
       Contrast media hypersensitivity*
       Uncooperative patient
      TIA; transitory ischaemic attack.
      *Contrast media is rarely used for endomyocardial biopsy and is an infrequent contraindication for the procedure.

      Multimodality Imaging and EMB

      Multimodality imaging—including standard 2-dimensional, 3-dimensional, speckle-tracking, and intracardiac echocardiography, CMR, computed tomography, and nuclear imaging techniques (eg, 18F-fluorodeoxyglucose PET)—represent key noninvasive diagnostic tools in the evaluation of patients with suspected myocarditis, cardiomyopathies, cardiotoxicity, infiltrative or storage disorders, and cardiac tumors. These imaging techniques allow for the identification of cardiac structural and functional alterations, tissue characterization, exclusion of significant coronary artery disease or pericardial involvement, and the assessment of myocardial perfusion and metabolism (Table 5). In most instances, modern imaging techniques in combination with laboratory analyses, biomarkers, genetic testing, and/or biopsy of noncardiac tissues can provide the diagnosis without a requirement for EMB, thus narrowing the scope of clinical situations in which EMB may be necessary.
      Table 5Sensitivity and Specificity of Magnetic Resonance and Nuclear Imaging Techniques in Myocarditis, Amyloidosis, and Sarcoidosis
      DiseaseMethodFindingSensitivitySpecificity
      Myocarditis
      • Ferreira VM
      • Schulz-Menger J
      • Holmvang G
      • Kramer CM
      • Carbone I
      • Sechtem U
      • et al.
      Cardiovascular magnetic resonance in nonischemic myocardial inflammation: expert recommendations.
      • Friedrich MG
      • Sechtem U
      • Schulz-Menger J
      • Holmvang G
      • Alakija P
      • Cooper LT
      • et al.
      Cardiovascular magnetic resonance in myocarditis: a JACC White Paper.
      • Lurz P
      • Luecke C
      • Eitel I
      • Föhrenbach F
      • Frank C
      • Grothoff M
      • et al.
      Comprehensive cardiac magnetic resonance imaging in patients with suspected myocarditis: the MyoRacer-trial.
      Early phase (<14 days from symptom onset)CMRT1-weighted imaging: early gadolinium enhancement is suggestive of hyperemia and capillary leak. LGE is suggestive of cell necrosis and fibrosis.

      T2-weighted imaging: presence of myocardial edema (typically subepicardial)
      67%91%
      Late phase (>14 days after symptom onsetCMRT2-weighted imaging: imaging modality with the greatest diagnostic accuracy71%72%
      Amyloidosis
      • Zhao L
      • Tian Z
      • Fang Q.
      Diagnostic accuracy of cardiovascular magnetic resonance for patients with suspected cardiac amyloidosis: a systematic review and meta-analysis.
      ,
      • Castaño A
      • Manson DK
      • Maurer MS
      • Bokhari S.
      Transthyretin cardiac amyloidosis in older adults: optimizing cardiac imaging to the corresponding diagnostic and management goal.
      CMRIncreased T1-weighted imaging, ECV

      Diffuse global subendocardial LGE
      85%92%
      Nuclear imaging (99mTc pyrophosphate, or 99mTc-hydroxymethylene-diphosphonate full body scan)Typical finding: positive uptake in ATTR cardiac amyloidosis.>90%>90%
      Sarcoidosis
      • Bravo PE
      • Singh A
      • Di Carli MF
      • Blankstein R.
      Advanced cardiovascular imaging for the evaluation of cardiac sarcoidosis.
      ,
      • Zhang J
      • Li Y
      • Xu Q
      • Xu B
      • Wang H.
      Cardiac magnetic resonance imaging for diagnosis of cardiac sarcoidosis: a meta-analysis.
      18F-fluorodeoxyglucose positron emission tomographyActive inflammation and scar.89%78%
      CMRT2-weighted imaging:

      inflammation, focal wall thickening, myocardial fibrosis.

      Typical finding: subepicardial and mid wall LGE on basal septum and/or inferolateral wall.
      93%85%
      AL, light chain amyloidosis; ATTR, transthyretin amyloidosis; CMR, cardiac magnetic resonance imaging; ECV, extracellular volume; LGE, late gadolinium enhancement.
      Nevertheless, EMB cannot be fully substituted by cardiac imaging. CMR and nuclear imaging are often limited by access issues and well-recognized contraindications to CMR and cannot be applied in hemodynamically unstable or claustrophobic patients. Also, EMB may be the only viable diagnostic option in patients with malignant ventricular arrhythmias, frequent ventricular ectopic beats, and fast atrial fibrillation with irregular R-R intervals, as well as in those with rapid or relentless disease progression, in whom establishing histologic diagnosis can impact further treatment significantly (eg, fulminant myocarditis).

      The Role of EMB in Prognosis and Risk Assessment

      Available data indicate that EMB may have a role in the evaluation of prognosis and the risk stratification of patients with several cardiac disorders. EMB-confirmed lymphocytic myocarditis is associated with a more favorable outcome in comparison with giant cell myocarditis, which confers a poor prognosis.
      • Ammirati E
      • Veronese G
      • Brambatti M
      • Merlo M
      • Ciprani M
      • Potena L
      • et al.
      Fulminant versus acute nonfulminant myocarditis in patients with left ventricular systolic dysfunction.
      Viral persistence in the myocardium in patients with LV dysfunction is associated with a deterioration in LV function, whereas spontaneous viral elimination usually leads to a significant recovery.
      • Kühl U
      • Pauschinger M
      • Seeberg B
      • Lassner D
      • Noutsias M
      • Poller W
      • et al.
      Viral persistence in the myocardium is associated with progressive cardiac dysfunction.
      EMB-detected morphologic changes in the myocardium may also inform on the prognosis in DCM. Focal derangement and diffuse myofilament lysis in EMB samples are predictors of readmissions for worsening HF in patients with DCM, whereas diffuse myofilament lysis is as an independent predictor of mortality.
      • Saito T
      • Asai K
      • Sato S
      • Takano H
      • Mizuno K
      • Shimizu W.
      Ultrastructural features of cardiomyocytes in dilated cardiomyopathy with initially decompensated heart failure as a predictor of prognosis.
      Furthermore, findings of ultrastructural changes, fibrosis, apoptosis, hypertrophy, vascular density, inflammation, and viral persistence may indicate adverse prognosis in DCM.
      • Saito T
      • Asai K
      • Sato S
      • Takano H
      • Mizuno K
      • Shimizu W.
      Ultrastructural features of cardiomyocytes in dilated cardiomyopathy with initially decompensated heart failure as a predictor of prognosis.
      ,
      • Kanzaki M
      • Asano Y
      • Ishibashi-Ueda H
      • Oiki E
      • Nishida T
      • Asanuma H
      • et al.
      A development of nucleic chromatin measurements as a new prognostic marker for severe chronic heart failure.
      An analysis of EMB samples from 182 patients demonstrated an association between increased immune cell activity in the myocardium and poor long-term prognosis.
      • Nakayama T
      • Sugano Y
      • Yokokawa T
      • Nagai T
      • Matsuyama TA
      • Ohta-Ogo K
      • et al.
      Clinical impact of the presence of macrophages in endomyocardial biopsies of patients with dilated cardiomyopathy.
      EMB remains the gold standard for the surveillance of graft rejection in HTx recipients, with implications for the treatment and long-term prognosis.
      • Colvin MM
      • Cook JL
      • Chang P
      • Francis G
      • Hsu DT
      • Kiernan MS
      • et al.
      Antibody-mediated rejection in cardiac transplantation: emerging knowledge in diagnosis and management: a scientific statement from the.
      • Costanzo MR
      • Dipchand A
      • Starling R
      • Anderson A
      • Chan M
      • Desai S
      • et al.
      The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients.
      • Kobashigawa J
      • Zuckermann A
      • Macdonald P
      • Leprince P
      • Esmailian F
      • Luu M
      • et al.
      Report from a consensus conference on primary graft dysfunction after cardiac transplantation.
      • Orrego CM
      • Cordero-Reyes AM
      • Estep JD
      • Loebe M
      • Torre-Amione G.
      Usefulness of routine surveillance endomyocardial biopsy 6 months after heart transplantation.

      Therapeutic Implications of EMB

      EMB can provide information valuable for the treatment of several cardiac disorders. Data from the few randomised trials in patients with myocarditis support institution of immunosuppressive therapy in the setting of EMB-proven, virus-negative myocarditis with circulating cardiac autoantibodies
      • Frustaci A
      • Chimenti C
      • Calabrese F
      • Pieroni M
      • Thiene G
      • Maseri A.
      Immunosuppressive therapy for active lymphocytic myocarditis: virological and immunologic profile of responders versus nonresponders.
      and in giant cell myocarditis.
      • Cooper Jr, LT
      • Hare JM
      • Tazelaar HD
      • Edwards WD
      • Starling RC
      • Deng MC
      • et al.
      Usefulness of immunosuppression for giant cell myocarditis.
      Based on small observational cohorts, clinical experience, and expert opinion, immunosuppressive therapy can be instituted in virus-negative eosinophilic myocarditis, ICI-mediated myocarditis, cardiac sarcoidosis, and myocarditis associated with autoimmune diseases.
      • Lyon AR
      • Yousaf N
      • Battisti NML
      • Moslehi J
      • Larkin J.
      Immune checkpoint inhibitors and cardiovascular toxicity.
      ,
      • Cooper LT
      • Baughman KL
      • Feldman AM
      • Frustaci A
      • Jessup M
      • Kuhl U
      • et al.
      The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology.
      • Caforio AL
      • Pankuweit S
      • Arbustini E
      • Basso C
      • Gimeno-Blanes J
      • Felix SB
      • 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.
      • Bleeker JS
      • Syed FF
      • Cooper LT
      • Weiler CR
      • Tefferi A
      • Pardanani A.
      Treatment-refractory idiopathic hypereosinophilic syndrome: pitfalls and progress with use of novel drugs.
      • Rosenthal DG
      • Parwani P
      • Murray TO
      • Petek BJ
      • Benn BS
      • Marco TD
      • et al.
      Long-term corticosteroid-sparing immunosuppression for cardiac sarcoidosis.
      In patients with myocarditis of unknown etiology, a clinical trial failed to demonstrate a beneficial effect of immunosuppression on LV function and survival.
      • Mason JW
      • O'Connell JB
      • Herskowitz A
      • Rose NR
      • McManus BM
      • Billingham ME
      • et al.
      A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators.
      In patients with DCM, therapeutic implications of EMB-proven virus-negative myocardial inflammation (ie, inflammatory cardiomyopathy) have been addressed in 2 randomised trials. In the TIMIC study (n = 85), 6 months of prednisone and azathioprine treatment resulted in a significant improvement in LV function compared with placebo without major adverse effects.
      • Frustaci A
      • Russo MA
      • Chimenti C.
      Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy: the TIMIC study.
      Another trial (n = 84) reported that 3 months of immunosuppressive therapy vs placebo provided a significant improvement in LV ejection fraction that was maintained at the 2-year follow-up, although there was no difference in survival.
      • Wojnicz R
      • Nowalany-Kozielska E
      • Wojciechowska C
      • Glanowska G
      • Wilczewski P
      • Niklewski T
      • et al.
      Randomized, placebo-controlled study for immunosuppressive treatment of inflammatory dilated cardiomyopathy.
      A propensity score–matched retrospective analysis of patients receiving immunosuppressive therapy (n = 90) vs standard care (n = 90) also demonstrated beneficial effects of immunosuppression on HTx-free survival and improvement in LV function after a median follow-up of 12 months.
      • Merken J
      • Hazebroek M
      • Van Paassen P
      • Verdonschot J
      • Van Empel V
      • Knackstedt C
      • et al.
      Immunosuppressive therapy improves both short- and long-term prognosis in patients with virus-negative nonfulminant inflammatory cardiomyopathy.
      In an observational study of 110 patients with Lyme disease–associated cardiomyopathy, an improvement in cardiac function was described with antibiotic treatment in addition to standard HF medications.
      • Kuchynka P
      • Palecek T
      • Havranek S
      • Vitkova I
      • Nemecek E
      • Trckova R
      • et al.
      Recent-onset dilated cardiomyopathy associated with Borrelia burgdorferi infection.
      In patients with active viral infection, several treatment options have been investigated, including intravenous immunoglobulins, interferon-alfa and -beta, ganciclovir, acyclovir, and valacyclovir.
      • Van Linthout S
      • Elsanhoury A
      • Klein O
      • Sosnowski M
      • Miteva K
      • Lassner D
      • et al.
      Telbivudine in chronic lymphocytic myocarditis and human parvovirus B19 transcriptional activity.
      • Kuhl U
      • Lassner D
      • von Schlippenbach J
      • Poller W
      • Schultheiss HP.
      Interferon-Beta improves survival in enterovirus-associated cardiomyopathy.
      • Escher F
      • Kuhl U
      • Gross U
      • Westermann D
      • Poller W
      • Tschope C
      • et al.
      Aggravation of left ventricular dysfunction in patients with biopsy-proven cardiac human herpesvirus A and B infection.
      • Krueger GR
      • Ablashi DV.
      Human herpesvirus-6: a short review of its biological behavior.
      A phase II randomised trial of 143 patients with EMB-proven enterovirus, adenovirus, and/or parvovirus B19 presence in the myocardium has demonstrated that 24 weeks of interferon beta-1b vs placebo resulted in effective viral clearance or a decrease in the viral load.
      • Schultheiss HP
      • Piper C
      • Sowade O
      • Waagstein F
      • Kapp JF
      • Wegscheider K
      • et al.
      Betaferon in chronic viral cardiomyopathy (BICC) trial: effects of interferon-β treatment in patients with chronic viral cardiomyopathy.
      Likewise, rituximab has shown promising results in a small series of patients with cardiomyopathy and CD20+ B lymphocytes in EMB samples.
      • Tschöpe C
      • Van Linthout S
      • Spillmann F
      • Posch M
      • Reinke P
      • Volk H-D
      • et al.
      Targeting CD20+ B lymphocytes in inflammatory dilated cardiomyopathy with rituximab improves clinical course: a case series.
      Presently, recommendations for the routine clinical use cannot be given for these medications, pending further clinical evaluation.
      EMB findings also have therapeutic implications for individuals with storage disorders for which specific enzyme replacement therapies are available (Anderson–Fabry disease, glycogen storage disorders), as well as in the management of amyloidosis and in HTx rejection.

      Worldwide Use of EMB: Current Clinical Practice

      There is a considerable international variability in the clinical practice of EMB. In most countries the procedure is more frequently used for the surveillance of HTx rejection than for other indications.
      • Costanzo MR
      • Dipchand A
      • Starling R
      • Anderson A
      • Chan M
      • Desai S
      • et al.
      The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients.
      ,
      • Haddad H
      • Isaac D
      • Legare JF
      • Pflugfelder P
      • Hendry P
      • Chan M
      • et al.
      Canadian Cardiovascular Society Consensus Conference update on cardiac transplantation 2008: executive summary.
      However, in Japan, EMB is more frequently performed in non-HTx patients because of the low rate of HTx procedures.
      • Kitamura S.
      Heart transplantation in Japan: a critical appraisal for the results and future prospects.
      ,
      • Fukushima N
      • Ono M
      • Saiki Y
      • Sawa Y
      • Nunoda S
      • Isobe M.
      Registry report on heart Transplantation tn Japan (June 2016).
      According to a nationwide study in Japan reporting on 9,508 adult patients (EMB performed in 2010–2013), the most common indication was DCM (35%), followed by sarcoidosis (7.3%), amyloidosis (4.2%), and myocarditis (3.4%), whereas HTx patients accounted for only 3.6% of EMB indications.
      • Isogai T
      • Yasunaga H
      • Matsui H
      • Ueda T
      • Tanaka H
      • Horiguchi H
      • et al.
      Hospital volume and cardiac complications of endomyocardial biopsy: a retrospective cohort study of 9508 adult patients using a nationwide inpatient database in Japan.
      By contrast, in a large US survey (2002–2014), the most frequent indication for EMB was HTx rejection surveillance (71%), followed by the assessment of cardiomyopathies, amyloidosis, myocarditis, and sarcoidosis.
      • Singh V
      • Mendirichaga R
      • Savani GT
      • Rodriguez A
      • Blumer V
      • Elmariah S
      • et al.
      Comparison of utilization trends, indications, and complications of endomyocardial biopsy in native versus donor hearts (from the Nationwide Inpatient Sample 2002 to 2014).
      Similarly, in a large single-center study from Brazil reporting on 5347 EMB procedures (1978–2011), HTx rejection surveillance was the most common indication in 67% of patients, whereas the assessment of cardiomyopathies and cardiac tumors accounted for 33% and 1% of EMB procedures, respectively.
      • Fiorelli AI
      • Benvenuti L
      • Aielo V
      • Coelho AQ
      • Palazzo JF
      • Rossener R
      • et al.
      Comparative analysis of the complications of 5347 endomyocardial biopsies applied to patients after heart transplantation and with cardiomyopathies: a single-center study.
      The overwhelming majority of EMB procedures are performed in tertiary or university hospitals (99% of HTx and 94% of non-HTx EMBs).
      • Shah Z
      • Rali A
      • Gupta K.
      National trends and procedural complications from endomyocardial biopsy: results from the National Inpatient Sample, 2007-2014.
      RV EMB is the most frequently used approach, while LV EMB is less frequent, especially in the United States. A large single-center European non-HTx study (n = 4,22, over 25 years) indicates that LV EMB can be safely performed (84% of patients) and provide incremental diagnostic information to RV EMB.
      • Chimenti C
      • Frustaci A.
      Contribution and risks of left ventricular endomyocardial biopsy in patients with cardiomyopathies: a retrospective study over a 28-year period.
      Guidance with fluoroscopy was used in 98% of the procedures in the Brazilian study, whereas 2-dimensional echocardiography and guidance with both fluoroscopy and 2-dimensional echocardiography were used significantly less often (1.6% and 1.0%, respectively), mostly for cardiac tumours.
      • Fiorelli AI
      • Benvenuti L
      • Aielo V
      • Coelho AQ
      • Palazzo JF
      • Rossener R
      • et al.
      Comparative analysis of the complications of 5347 endomyocardial biopsies applied to patients after heart transplantation and with cardiomyopathies: a single-center study.
      In this study, the right internal jugular vein was used as an access site in 97% of the procedures, followed by the left internal jugular vein (0.6%), femoral (0.5%), or subclavian approach (0.3%).
      • Fiorelli AI
      • Benvenuti L
      • Aielo V
      • Coelho AQ
      • Palazzo JF
      • Rossener R
      • et al.
      Comparative analysis of the complications of 5347 endomyocardial biopsies applied to patients after heart transplantation and with cardiomyopathies: a single-center study.
      A similar practice is followed in HTx centers in Germany, where the internal jugular vein is the prevailing vascular access site in 95% of EMB procedures, while femoral access is used in 4.6% of procedure.
      • Strecker T
      • Rösch J
      • Weyand M
      • Agaimy A.
      Endomyocardial biopsy for monitoring heart transplant patients: 11-years-experience at a German heart center.
      By contrast, most of the specialized centers in other countries report performing EMB in the non-HTx population using femoral veins and/or arteries.
      • Holzmann M
      • Nicko A
      • Kühl U
      • Noutsias M
      • Poller W
      • Hoffmann W
      • et al.
      Complication rate of right ventricular endomyocardial biopsy via the femoral approach: a retrospective and prospective study analyzing 3048 diagnostic procedures over an 11-year period.
      ,
      • Jang SY
      • Cho Y
      • Song JH
      • Cheon SS
      • Park SH
      • Bae MH
      • et al.
      Complication rate of transfemoral endomyocardial biopsy with fluoroscopic and two-dimensional echocardiographic guidance: a 10-year experience of 228 consecutive procedures.

      Future Perspectives

      EMB has gained global acceptance in the surveillance of HTx rejection and in diagnostic assessment of select patients with myocarditis, cardiomyopathies, cardiotoxicity of cancer drugs, infiltrative and storage disorders and cardiac tumors. In addition, EMB was instrumental in describing the pathophysiology of ICI-mediated cardiotoxicity
      • Lyon AR
      • Yousaf N
      • Battisti NML
      • Moslehi J
      • Larkin J.
      Immune checkpoint inhibitors and cardiovascular toxicity.
      and myocardial involvement in severe acute respiratory syndrome coronavirus 2 infection.
      • Basso C
      • Leone O
      • Rizzo S
      • De Gaspari M
      • van der Wal AC
      • Aubry M-C
      • et al.
      Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study.
      Future improvement in technologies is expected to provide more flexible and steerable guidance catheters, as well as the possibility of integrating EMB with high-resolution imaging modalities.
      • Unterberg-Buchwald C
      • Ritter CO
      • Reupke V
      • Wilke RN
      • Stadelmann C
      • Steinmetz M
      • et al.
      Targeted endomyocardial biopsy guided by real-time cardiovascular magnetic resonance.
      Innovations in cardiopathology, including new-generation PCR tools, confocal laser scanning microscopy, and super-resolution microscopy with high-contrast and high-resolution fluorescent imaging, will likely improve the diagnostic yield of EMB.
      • Crossman DJ
      • Ruygrok PN
      • Hou YF
      • Soeller C.
      Next-generation endomyocardial biopsy: the potential of confocal and super-resolution microscopy.
      Presently, there is an unmet need to develop a network of regional and national centers with a standardized expertise in EMB practice. This issue can be addressed through the implementation of Heart Failure Quality of Care Centers, providing multidisciplinary care of HF patients, including the availability of EMB in tertiary level centres.
      • Seferović PM
      • Piepoli MF
      • Lopatin Y
      • Jankowska E
      • Polovina M
      • Anguita-Sanchez M
      • et al.
      Heart Failure Association of the European Society of Cardiology Quality of Care Centres Programme: design and accreditation document.
      The high level of expertise provided by these centers will increase the diagnostic value of EMB, open new clinical perspectives, and decrease the risk of complications. These centers should build multidisciplinary teams with complementary competences in EMB procedure, evaluation of samples, interpretation of the results, and clinical expertise in patient management. The teams should include HF specialists, electrophysiologists, experts in imaging, cardiopathology, molecular biology, and clinical genetics.
      EMB has only partially fulfilled its earlier expectations. Its future role will be determined by advances made in noninvasive assessment of cardiac disorders, progress in translational sciences and the development of new, targeted therapeutic options.

      References

        • Cooper LT
        • Baughman KL
        • Feldman AM
        • Frustaci A
        • Jessup M
        • Kuhl U
        • et al.
        The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology.
        Eur Heart J. 2007; 28: 3076-3093
      1. Leone O, Veinot JP, Angelini A, Baandrup UT, Basso C, Berry G, et al. 2011 Consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology. Cardiovasc Pathol 2012;21:245–74.

        • Konno S
        • Sakakibara S.
        Endo-myocardial Biopsy.
        Dis Chest. 1963; 44: 345-350
        • Sakakibara S
        • Konno S.
        Endomyocardial biopsy.
        Jpn Heart J. 1962; 3: 537-543
        • Sekiguchi M
        • Konno S.
        Histopathological differentiation employing endomyocardial biopsy in the clinical assessment of primary myocardial disease.
        Jpn Heart J. 1969; 10: 30-46
        • Sekiguchi M
        • Konno S.
        Diagnosis and classification of primary myocardial disease with the aid of endomyocardial biopsy.
        Jpn Circ J. 1971; 35: 737-754
        • Caves PK
        • Stinson EB
        • Graham AF
        • Billingham ME
        • Grehl TM
        • Shumway NE.
        Percutaneous transvenous endomyocardial biopsy.
        JAMA. 1973; 225: 288-291
        • Kawai C
        • Kitaura Y.
        New endomyocardial biopsy catheter for the left ventricle.
        Am J Cardiol. 1977; 40: 63-65
        • Richardson PJ.
        King's endomyocardial bioptome.
        Lancet. 1974; 1: 660-661
        • Bagur R
        • Bertrand OF
        • Béliveau P
        • Gaudreault V
        • Potvin JM
        • Fillion N
        • et al.
        Feasibility of using a sheathless guiding catheter for left ventricular endomyocardial biopsy performed by transradial approach.
        J Invasive Cardiol. 2014; 26: E161-E163
        • Yilmaz A
        • Kindermann I
        • Kindermann M
        • Mahfoud F
        • Ukena C
        • Athanasiadis A
        • et al.
        Comparative evaluation of left and right ventricular endomyocardial biopsy: differences in complication rate and diagnostic performance.
        Circulation. 2010; 122: 900-909
        • Harwani N
        • Chukwu E
        • Alvarez M
        • Thohan V.
        Comparison of brachial vein versus internal jugular vein approach for access to the right side of the heart with or without myocardial biopsy.
        Am J Cardiol. 2015; 116: 740-743
        • Patel IJ
        • Rahim S
        • Davidson JC
        • Hanks SE
        • Tam AL
        • Walker TG
        • et al.
        Society of Interventional Radiology consensus guidelines for the periprocedural management of thrombotic and bleeding risk in patients undergoing percutaneous image-guided interventions-part II: recommendations: endorsed by the Canadian Association for Interventional Radiology and the Cardiovascular and Interventional Radiological Society of Europe.
        J Vasc Interv Radiol. 2019; 30 (1168–84.e1)
        • Schleifer JW
        • Manocha KK
        • Asirvatham SJ
        • Noseworthy PA
        • Gulati R
        • Friedman PA
        • et al.
        Feasibility of performing radiofrequency catheter ablation and endomyocardial biopsy in the same setting.
        Am J Cardiol. 2018; 121: 1373-1379
        • Jessup M
        • Drazner MH
        • Book W
        • Cleveland Jr., JC
        • Dauber I
        • Farkas S
        • et al.
        2017 ACC/AHA/HFSA/ISHLT/ACP advanced training statement on advanced heart failure and transplant cardiology (revision of the ACCF/AHA/ACP/HFSA/ISHLT 2010 clinical competence statement on management of patients with advanced heart failure and cardiac transplant): a report of the ACC Competency Management Committee.
        Circ Heart Fail. 2017; 10e000021
        • Chimenti C
        • Frustaci A.
        Contribution and risks of left ventricular endomyocardial biopsy in patients with cardiomyopathies: a retrospective study over a 28-year period.
        Circulation. 2013; 128: 1531-1541
        • Caforio AL
        • Pankuweit S
        • Arbustini E
        • Basso C
        • Gimeno-Blanes J
        • Felix SB
        • 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 (48a–48d): 2636-2648
        • Quarta CC
        • Gonzalez-Lopez E
        • Gilbertson JA
        • Botcher N
        • Rowczenio D
        • Petrie A
        • et al.
        Diagnostic sensitivity of abdominal fat aspiration in cardiac amyloidosis.
        Eur Heart J. 2017; 38: 1905-1908
        • Platts D
        • Brown M
        • Javorsky G
        • West C
        • Kelly N
        • Burstow D.
        Comparison of fluoroscopic versus real-time three-dimensional transthoracic echocardiographic guidance of endomyocardial biopsies.
        Eur J Echocardiography. 2010; 11: 637-643
        • Zanobini M
        • Dello Russo A
        • Saccocci M
        • Conti S
        • De Camilli E
        • Vettor G
        • et al.
        Endomyocardial biopsy guided by intracardiac echocardiography as a key step in intracardiac mass diagnosis.
        BMC Cardiovasc Disord. 2018; 18: 15
        • Kandolin R
        • Lehtonen J
        • Graner M
        • Schildt J
        • Salmenkivi K
        • Kivistö SM
        • et al.
        Diagnosing isolated cardiac sarcoidosis.
        J Intern Med. 2011; 270: 461-468
        • McGuirt D
        • Mazal J
        • Rogers T
        • Faranesh AZ
        • Schenke W
        • Stine A
        • et al.
        X-ray fused with magnetic resonance imaging to guide endomyocardial biopsy of a right ventricular mass.
        Radiol Technol. 2016; 87: 622-626
        • Mahrholdt H
        • Wagner A
        • Deluigi CC
        • Kispert E
        • Hager S
        • Meinhardt G
        • et al.
        Presentation, patterns of myocardial damage, and clinical course of viral myocarditis.
        Circulation. 2006; 114: 1581-1590
        • Spieker M
        • Katsianos E
        • Gastl M
        • Behm P
        • Horn P
        • Jacoby C
        • et al.
        T2 mapping cardiovascular magnetic resonance identifies the presence of myocardial inflammation in patients with dilated cardiomyopathy as compared to endomyocardial biopsy.
        Eur Heart J Cardiovasc Imaging. 2018; 19: 574-582
        • Dickerson JA
        • Raman SV
        • Baker PM
        • Leier CV.
        Relationship of cardiac magnetic resonance imaging and myocardial biopsy in the evaluation of nonischemic cardiomyopathy.
        Congestive Heart Fail (Greenwich, Conn). 2013; 19: 29-38
        • Yoshida A
        • Ishibashi-Ueda H
        • Yamada N
        • Kanzaki H
        • Hasegawa T
        • Takahama H
        • et al.
        Direct comparison of the diagnostic capability of cardiac magnetic resonance and endomyocardial biopsy in patients with heart failure.
        Eur J Heart Fail. 2013; 15: 166-175
        • Vaidya VR
        • Abudan AA
        • Vasudevan K
        • Shantha G
        • Cooper LT
        • Kapa S
        • et al.
        The efficacy and safety of electroanatomic mapping-guided endomyocardial biopsy: a systematic review.
        J Interv Card Electrophysiol. 2018; 53: 63-71
        • Seizer P
        • Klingel K
        • Stickel J
        • Dorn C
        • Horger M
        • Kandolf R
        • et al.
        Left ventricular site-directed biopsy guided by left ventricular voltage mapping: a proof of principle.
        Int J Cardiol. 2013; 168: 3113-3114
        • Casella M
        • Dello Russo A
        • Vettor G
        • Lumia G
        • Catto V
        • Sommariva E
        • et al.
        Electroanatomical mapping systems and intracardiac echo integration for guided endomyocardial biopsy.
        Expert Rev Med Devices. 2017; 14: 609-619
        • Konecny T
        • Noseworthy PA
        • Kapa S
        • Cooper LT
        • Mulpuru SK
        • Sandhu GS
        • et al.
        Endomyocardial biopsy-integrating electrode at the bioptome tip.
        Ther Adv Cardiovasc Dis. 2015; 9: 66-69
        • Shah Z
        • Vuddanda V
        • Rali AS
        • Pamulapati H
        • Masoomi R
        • Gupta K.
        National trends and procedural complications from endomyocardial biopsy: results from the National Inpatient Sample, 2007-2014.
        Cardiology. 2018; 141: 125-131
        • William Wijns PWS
        • Vahanian Alec
        • Eeckhout Eric
        • Rodney De Palma
        • Sambeek Marc van
        The PCR-EAPCI Textbook.
        Europa Edition, France2012
        • Isogai T
        • Yasunaga H
        • Matsui H
        • Ueda T
        • Tanaka H
        • Horiguchi H
        • et al.
        Hospital volume and cardiac complications of endomyocardial biopsy: a retrospective cohort study of 9508 adult patients using a nationwide inpatient database in Japan.
        Clin Cardiol. 2015; 38: 164-170
        • Fiorelli AI
        • Coelho GH
        • Aiello VD
        • Benvenuti LA
        • Palazzo JF
        • Santos Júnior VP
        • et al.
        Tricuspid valve injury after heart transplantation due to endomyocardial biopsy: an analysis of 3550 biopsies.
        Transplant Proc. 2012; 44: 2479-2482
        • Fiorelli AI
        • Benvenuti L
        • Aielo V
        • Coelho AQ
        • Palazzo JF
        • Rossener R
        • et al.
        Comparative analysis of the complications of 5347 endomyocardial biopsies applied to patients after heart transplantation and with cardiomyopathies: a single-center study.
        Transplant Proc. 2012; 44: 2473-2478
        • 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. 1992; 19: 43-47
        • Ristić AD
        • Imazio M
        • Adler Y
        • Anastasakis A
        • Badano LP
        • Brucato A
        • et al.
        Triage strategy for urgent management of cardiac tamponade: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.
        Eur Heart J. 2014; 35: 2279-2284
        • Tschope C
        • Cooper LT
        • Torre-Amione G
        • Van Linthout S.
        Management of myocarditis-related cardiomyopathy in adults.
        Circ Res. 2019; 124: 1568-1583
        • Ammirati E
        • Veronese G
        • Brambatti M
        • Merlo M
        • Ciprani M
        • Potena L
        • et al.
        Fulminant versus acute nonfulminant myocarditis in patients with left ventricular systolic dysfunction.
        J Am Coll Cardiol. 2019; 74: 299-311
        • Ammirati E
        • Cipriani M
        • Moro C
        • Raineri C
        • Pini D
        • Sormani P
        • et al.
        Clinical presentation and outcome in a contemporary cohort of patients with acute myocarditis.
        Circulation. 2018; 138: 1088-1099
        • Bennett MK
        • Gilotra NA
        • Harrington C
        • Rao S
        • Dunn JM
        • Freitag TB
        • et al.
        Evaluation of the role of endomyocardial biopsy in 851 patients with unexplained heart failure from 2000-2009.
        Circ Heart Fail. 2013; 6: 676-684
        • Shields RC
        • Tazelaar HD
        • Berry GJ
        • Cooper Jr., LT
        The role of right ventricular endomyocardial biopsy for idiopathic giant cell myocarditis.
        J Card Fail. 2002; 8: 74-78
        • Okura Y
        • Dec GW
        • Hare JM
        • Kodama M
        • Berry GJ
        • Tazelaar HD
        • et al.
        A clinical and histopathologic comparison of cardiac sarcoidosis and idiopathic giant cell myocarditis.
        J Am Coll Cardiol. 2003; 41: 322-329
        • Birnie DH
        • Sauer WH
        • Bogun F
        • Cooper JM
        • Culver DA
        • Duvernoy CS
        • et al.
        HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis.
        Heart Rhythm. 2014; 11: 1305-1323
        • Liang JJ
        • Hebl VB
        • DeSimone CV
        • Madhavan M
        • Nanda S
        • Kapa S
        • et al.
        Electrogram guidance: a method to increase the precision and diagnostic yield of endomyocardial biopsy for suspected cardiac sarcoidosis and myocarditis.
        JACC Heart Fail. 2014; 2: 466-473
        • Tavazzi G
        • Pellegrini C
        • Maurelli M
        • Belliato M
        • Sciutti F
        • Bottazzi A
        • et al.
        Myocardial localization of coronavirus in COVID-19 cardiogenic shock.
        Eur J Heart Fail. 2020; 22: 911-915
        • Puelles VG
        • Lütgehetmann M
        • Lindenmeyer MT
        • Sperhake JP
        • Wong MN
        • Allweiss L
        • et al.
        Multiorgan and renal tropism of SARS-CoV-2.
        N Engl J Med. 2020; 383: 590-592
        • Basso C
        • Leone O
        • Rizzo S
        • De Gaspari M
        • van der Wal AC
        • Aubry M-C
        • et al.
        Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study.
        Eur Heart J. 2020; 41: 3827-3835
        • Katzmann JL
        • Schlattmann P
        • Rigopoulos AG
        • Noutsias E
        • Bigalke B
        • Pauschinger M
        • et al.
        Meta-analysis on the immunohistological detection of inflammatory cardiomyopathy in endomyocardial biopsies.
        Heart Fail Rev. 2020; 25: 277-294
        • Kubánek M
        • Šramko M
        • Berenová D
        • Hulínská D
        • Hrbáčková H
        • Malušková J
        • et al.
        Detection of Borrelia burgdorferi sensu lato in endomyocardial biopsy specimens in individuals with recent-onset dilated cardiomyopathy.
        Eur J Heart Fail. 2012; 14: 588-596
        • Kuchynka P
        • Palecek T
        • Havranek S
        • Vitkova I
        • Nemecek E
        • Trckova R
        • et al.
        Recent-onset dilated cardiomyopathy associated with Borrelia burgdorferi infection.
        Herz. 2015; 40: 892-897
        • Lyon AR
        • Yousaf N
        • Battisti NML
        • Moslehi J
        • Larkin J.
        Immune checkpoint inhibitors and cardiovascular toxicity.
        Lancet Oncol. 2018; 19: e447-ee58
        • Mahmood SS
        • Fradley MG
        • Cohen JV
        • Nohria A
        • Reynolds KL
        • Heinzerling LM
        • et al.
        Myocarditis in patients treated with immune checkpoint inhibitors.
        J Am Coll Cardiol. 2018; 71: 1755-1764
        • Escudier M
        • Cautela J
        • Malissen N
        • Ancedy Y
        • Orabona M
        • Pinto J
        • et al.
        Clinical features, management, and outcomes of immune checkpoint inhibitor-related cardiotoxicity.
        Circulation. 2017; 136: 2085-2087
        • Zhang L
        • Awadalla M
        • Mahmood SS
        • Nohria A
        • Hassan MZO
        • Thuny F
        • et al.
        Cardiovascular magnetic resonance in immune checkpoint inhibitor-associated myocarditis.
        Eur Heart J. 2020; 41: 1733-1743
        • Billingham ME
        • Mason JW
        • Bristow MR
        • Daniels JR.
        Anthracycline cardiomyopathy monitored by morphologic changes.
        Cancer Treat Rep. 1978; 62: 865-872
        • Kusumoto S
        • Kawano H
        • Hayashi T
        • Satoh O
        • Yonekura T
        • Eguchi M
        • et al.
        Cyclophosphamide-induced cardiotoxicity with a prolonged clinical course diagnosed on an endomyocardial biopsy.
        Intern Med. 2013; 52: 2311-2315
        • Vasichkina E
        • Poghosyan H
        • Mitrofanova L
        • Tatarsky R
        • Lebedev D.
        Right ventricular endomyocardial biopsy in children and adolescents with drug-refractory arrhythmia.
        Cardiol Young. 2017; 27: 435-442
        • Vignola PA
        • Aonuma K
        • Swaye PS
        • Rozanski JJ
        • Blankstein RL
        • Benson J
        • et al.
        Lymphocytic myocarditis presenting as unexplained ventricular arrhythmias: diagnosis with endomyocardial biopsy and response to immunosuppression.
        J Am Coll Cardiol. 1984; 4: 812-819
        • Peretto G
        • Sala S
        • Rizzo S
        • De Luca G
        • Campochiaro C
        • Sartorelli S
        • et al.
        Arrhythmias in myocarditis: state of the art.
        Heart Rhythm. 2019; 16: 793-801
        • Casella M
        • Dello Russo A
        • Bergonti M
        • Catto V
        • Conte E
        • Sommariva E
        • et al.
        Diagnostic yield of electroanatomic voltage mapping in guiding endomyocardial biopsies.
        Circulation. 2020; 142: 1249-1260
        • Frustaci A
        • Letizia C
        • Adamo F
        • Grande C
        • Verardo R
        • Chimenti C.
        A-V block as presentation of cardiac amyloid: prominent infiltration of conduction tissue revealed by endomyocardial biopsy.
        Amyloid. 2017; 24: 131-132
        • Kusumoto FM
        • Schoenfeld MH
        • Barrett C
        • Edgerton JR
        • Ellenbogen KA
        • Gold MR
        • et al.
        2018 ACC/AHA/HRS guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.
        Heart Rhythm. 2019; 16: e128-e226
        • Nery PB
        • Beanlands RS
        • Nair GM
        • Green M
        • Yang J
        • McArdle BA
        • et al.
        Atrioventricular block as the initial manifestation of cardiac sarcoidosis in middle-aged adults.
        J Cardiovasc Electrophysiol. 2014; 25: 875-881
        • Mueller KA
        • Mueller II
        • Eppler D
        • Zuern CS
        • Seizer P
        • Kramer U
        • et al.
        Clinical and histopathological features of patients with systemic sclerosis undergoing endomyocardial biopsy.
        PLoS One. 2015; 10e0126707
        • Nord JE
        • Shah PK
        • Rinaldi RZ
        • Weisman MH.
        Hydroxychloroquine cardiotoxicity in systemic lupus erythematosus: a report of 2 cases and review of the literature.
        Semin Arthritis Rheum. 2004; 33: 336-351
        • Sakaguchi Y
        • Nakamura Y
        • Sutani T
        • Tsuchihashi M
        • Yamano S
        • Hashimoto T
        • et al.
        [Immunohistochemical study of the endomyocardial biopsy of systemic lupus erythematosus].
        J Cardiol. 1995; 25: 181-188
        • Agewall S
        • Beltrame JF
        • Reynolds HR
        • Niessner A
        • Rosano G
        • Caforio ALP
        • et al.
        ESC working group position paper on myocardial infarction with non-obstructive coronary arteries.
        Eur Heart J. 2016; 38: 143-153
        • Frustaci A
        • Russo MA
        • Chimenti C.
        Diagnostic contribution of left ventricular endomyocardial biopsy in patients with clinical phenotype of hypertrophic cardiomyopathy.
        Hum Pathol. 2013; 44: 133-141
        • Elliott PM
        • Anastasakis A
        • Borger MA
        • Borggrefe M
        • Cecchi F
        • Charron P
        • et al.
        2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).
        Eur Heart J. 2014; 35: 2733-2779
        • Smid BE
        • van der Tol L
        • Cecchi F
        • Elliott PM
        • Hughes DA
        • Linthorst GE
        • et al.
        Uncertain diagnosis of Fabry disease: consensus recommendation on diagnosis in adults with left ventricular hypertrophy and genetic variants of unknown significance.
        Int J Cardiol. 2014; 177: 400-408
        • Siddiqi OK
        • Ruberg FL.
        Cardiac amyloidosis: an update on pathophysiology, diagnosis, and treatment.
        Trends Cardiovasc Med. 2018; 28: 10-21
        • Rubin J
        • Maurer MS.
        Cardiac amyloidosis: overlooked, underappreciated, and treatable.
        Annu Rev Med. 2020; 71: 203-219
        • Lee J
        • Kim K
        • Choi J-O
        • Kim SJ
        • Jeon E-S
        • Choi JY.
        99mTc-DPD scintigraphy and SPECT/CT in patients with AL and ATTR type amyloidosis: potential clinical implications.
        Medicine. 2020; 99 (e18905-e)
        • Rezk T
        • Gilbertson JA
        • Mangione PP
        • Rowczenio D
        • Rendell NB
        • Canetti D
        • et al.
        The complementary role of histology and proteomics for diagnosis and typing of systemic amyloidosis.
        J Pathol Clin Res. 2019; 5: 145-153
        • Witteles RM
        • Bokhari S
        • Damy T
        • Elliott PM
        • Falk RH
        • Fine NM
        • et al.
        Screening for transthyretin amyloid cardiomyopathy in everyday practice.
        JACC Heart Fail. 2019; 7: 709-716
        • Olson LJ
        • Edwards WD
        • Holmes DR
        • Miller FA
        • Nordstrom LA
        • Baldus WP.
        Endomyocardial biopsy in hemochromatosis: clinicopathologic correlates in six cases.
        J Am Coll Cardiol. 1989; 13: 116-120
        • Nguyen CT
        • Lee E
        • Luo H
        • Siegel RJ.
        Echocardiographic guidance for diagnostic and therapeutic percutaneous procedures.
        Cardiovasc Diagn Ther. 2011; 1: 11-36
        • Hamour IM
        • Burke MM
        • Bell AD
        • Panicker MG
        • Banerjee R
        • Banner NR.
        Limited utility of endomyocardial biopsy in the first year after heart transplantation.
        Transplantation. 2008; 85: 969-974
        • Shah KB
        • Flattery MP
        • Smallfield MC
        • Merinar G
        • Tang DG
        • Sheldon EH
        • et al.
        Surveillance endomyocardial biopsy in the modern era produces low diagnostic yield for cardiac allograft rejection.
        Transplantation. 2015; 99: e75-e80
        • Weckbach LT
        • Maurer U
        • Schramm R
        • Huber BC
        • Lackermair K
        • Weiss M
        • et al.
        Lower frequency routine surveillance endomyocardial biopsies after heart transplantation.
        PLoS One. 2017; 12e0182880
        • Lampert BC
        • Teuteberg JJ
        • Shullo MA
        • Holtz J
        • Smith KJ.
        Cost-effectiveness of routine surveillance endomyocardial biopsy after 12 months post-heart transplantation.
        Circ Heart Fail. 2014; 7: 807-813
        • Purewal S
        • Moayedi Y
        • Runeckles K
        • Fan C
        • Gordon J
        • Henricksen EJ
        • et al.
        Are two tests better than one? combining donor derived cell-free DNA and gene expression profiling for non-invasive surveillance after heart transplantation.
        J Heart Lung Transplant. 2020; 39: S71
        • Singh V
        • Mendirichaga R
        • Savani GT
        • Rodriguez A
        • Blumer V
        • Elmariah S
        • et al.
        Comparison of utilization trends, indications, and complications of endomyocardial biopsy in native versus donor hearts (from the Nationwide Inpatient Sample 2002 to 2014).
        Am J Cardiol. 2018; 121: 356-363
        • Kühl U
        • Pauschinger M
        • Seeberg B
        • Lassner D
        • Noutsias M
        • Poller W
        • et al.
        Viral persistence in the myocardium is associated with progressive cardiac dysfunction.
        Circulation. 2005; 112: 1965-1970
        • Saito T
        • Asai K
        • Sato S
        • Takano H
        • Mizuno K
        • Shimizu W.
        Ultrastructural features of cardiomyocytes in dilated cardiomyopathy with initially decompensated heart failure as a predictor of prognosis.
        Eur Heart J. 2015; 36: 724-732
        • Kanzaki M
        • Asano Y
        • Ishibashi-Ueda H
        • Oiki E
        • Nishida T
        • Asanuma H
        • et al.
        A development of nucleic chromatin measurements as a new prognostic marker for severe chronic heart failure.
        PLoS One. 2016; 11e0148209
        • Nakayama T
        • Sugano Y
        • Yokokawa T
        • Nagai T
        • Matsuyama TA
        • Ohta-Ogo K
        • et al.
        Clinical impact of the presence of macrophages in endomyocardial biopsies of patients with dilated cardiomyopathy.
        Eur J Heart Fail. 2017; 19: 490-498
        • Colvin MM
        • Cook JL
        • Chang P
        • Francis G
        • Hsu DT
        • Kiernan MS
        • et al.
        Antibody-mediated rejection in cardiac transplantation: emerging knowledge in diagnosis and management: a scientific statement from the.
        Circulation. 2015; 131: 1608-1639
        • Costanzo MR
        • Dipchand A
        • Starling R
        • Anderson A
        • Chan M
        • Desai S
        • et al.
        The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients.
        J Heart Lung Transplant. 2010; 29: 914-956
        • Kobashigawa J
        • Zuckermann A
        • Macdonald P
        • Leprince P
        • Esmailian F
        • Luu M
        • et al.
        Report from a consensus conference on primary graft dysfunction after cardiac transplantation.
        J Heart Lung Transplant. 2014; 33: 327-340
        • 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. 2012; 31: 845-849
        • Frustaci A
        • Chimenti C
        • Calabrese F
        • Pieroni M
        • Thiene G
        • Maseri A.
        Immunosuppressive therapy for active lymphocytic myocarditis: virological and immunologic profile of responders versus nonresponders.
        Circulation. 2003; 107: 857-863
        • Cooper Jr, LT
        • Hare JM
        • Tazelaar HD
        • Edwards WD
        • Starling RC
        • Deng MC
        • et al.
        Usefulness of immunosuppression for giant cell myocarditis.
        Am J Cardiol. 2008; 102: 1535-1539
        • Cooper LT
        • Baughman KL
        • Feldman AM
        • Frustaci A
        • Jessup M
        • Kuhl U
        • et al.
        The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology.
        J Am Coll Cardiol. 2007; 50: 1914-1931
        • Caforio AL
        • Pankuweit S
        • Arbustini E
        • Basso C
        • Gimeno-Blanes J
        • Felix SB
        • 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 (48a–48d): 2636-2648
        • Bleeker JS
        • Syed FF
        • Cooper LT
        • Weiler CR
        • Tefferi A
        • Pardanani A.
        Treatment-refractory idiopathic hypereosinophilic syndrome: pitfalls and progress with use of novel drugs.
        Am J Hematol. 2012; 87: 703-706
        • Rosenthal DG
        • Parwani P
        • Murray TO
        • Petek BJ
        • Benn BS
        • Marco TD
        • et al.
        Long-term corticosteroid-sparing immunosuppression for cardiac sarcoidosis.
        J Am Heart Assoc. 2019; 8e010952
        • Mason JW
        • O'Connell JB
        • Herskowitz A
        • Rose NR
        • McManus BM
        • Billingham ME
        • et al.
        A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators.
        N Engl J Med. 1995; 333: 269-275
        • Frustaci A
        • Russo MA
        • Chimenti C.
        Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy: the TIMIC study.
        Eur Heart J. 2009; 30: 1995-2002
        • Wojnicz R
        • Nowalany-Kozielska E
        • Wojciechowska C
        • Glanowska G
        • Wilczewski P
        • Niklewski T
        • et al.
        Randomized, placebo-controlled study for immunosuppressive treatment of inflammatory dilated cardiomyopathy.
        Circulation. 2001; 104: 39-45
        • Merken J
        • Hazebroek M
        • Van Paassen P
        • Verdonschot J
        • Van Empel V
        • Knackstedt C
        • et al.
        Immunosuppressive therapy improves both short- and long-term prognosis in patients with virus-negative nonfulminant inflammatory cardiomyopathy.
        Circ Heart Fail. 2018; 11e004228
        • Van Linthout S
        • Elsanhoury A
        • Klein O
        • Sosnowski M
        • Miteva K
        • Lassner D
        • et al.
        Telbivudine in chronic lymphocytic myocarditis and human parvovirus B19 transcriptional activity.
        ESC Heart Fail. 2018; 5: 818-829
        • Kuhl U
        • Lassner D
        • von Schlippenbach J
        • Poller W
        • Schultheiss HP.
        Interferon-Beta improves survival in enterovirus-associated cardiomyopathy.
        J Am Coll Cardiol. 2012; 60: 1295-1296
        • Escher F
        • Kuhl U
        • Gross U
        • Westermann D
        • Poller W
        • Tschope C
        • et al.
        Aggravation of left ventricular dysfunction in patients with biopsy-proven cardiac human herpesvirus A and B infection.
        J Clin Virol. 2015; 63: 1-5
        • Krueger GR
        • Ablashi DV.
        Human herpesvirus-6: a short review of its biological behavior.
        Intervirology. 2003; 46: 257-269
        • Schultheiss HP
        • Piper C
        • Sowade O
        • Waagstein F
        • Kapp JF
        • Wegscheider K
        • et al.
        Betaferon in chronic viral cardiomyopathy (BICC) trial: effects of interferon-β treatment in patients with chronic viral cardiomyopathy.
        Clin Res Cardiol. 2016; 105: 763-773
        • Tschöpe C
        • Van Linthout S
        • Spillmann F
        • Posch M
        • Reinke P
        • Volk H-D
        • et al.
        Targeting CD20+ B lymphocytes in inflammatory dilated cardiomyopathy with rituximab improves clinical course: a case series.
        Eur Heart J Case Rep. 2019; 3: ytz131
        • Haddad H
        • Isaac D
        • Legare JF
        • Pflugfelder P
        • Hendry P
        • Chan M
        • et al.
        Canadian Cardiovascular Society Consensus Conference update on cardiac transplantation 2008: executive summary.
        Can J Cardiol. 2009; 25: 197-205
        • Kitamura S.
        Heart transplantation in Japan: a critical appraisal for the results and future prospects.
        Gen Thorac Cardiovasc Surg. 2012; 60: 639-644
        • Fukushima N
        • Ono M
        • Saiki Y
        • Sawa Y
        • Nunoda S
        • Isobe M.
        Registry report on heart Transplantation tn Japan (June 2016).
        Circ J. 2017; 81: 298-303
        • Shah Z
        • Rali A
        • Gupta K.
        National trends and procedural complications from endomyocardial biopsy: results from the National Inpatient Sample, 2007-2014.
        Cardiology. 2019; 142: 223
        • Strecker T
        • Rösch J
        • Weyand M
        • Agaimy A.
        Endomyocardial biopsy for monitoring heart transplant patients: 11-years-experience at a German heart center.
        Int J Clin Exp Pathol. 2013; 6: 55-65
        • Holzmann M
        • Nicko A
        • Kühl U
        • Noutsias M
        • Poller W
        • Hoffmann W
        • et al.
        Complication rate of right ventricular endomyocardial biopsy via the femoral approach: a retrospective and prospective study analyzing 3048 diagnostic procedures over an 11-year period.
        Circulation. 2008; 118: 1722-1728
        • Jang SY
        • Cho Y
        • Song JH
        • Cheon SS
        • Park SH
        • Bae MH
        • et al.
        Complication rate of transfemoral endomyocardial biopsy with fluoroscopic and two-dimensional echocardiographic guidance: a 10-year experience of 228 consecutive procedures.
        J Korean Med Sci. 2013; 28: 1323-1328
        • Unterberg-Buchwald C
        • Ritter CO
        • Reupke V
        • Wilke RN
        • Stadelmann C
        • Steinmetz M
        • et al.
        Targeted endomyocardial biopsy guided by real-time cardiovascular magnetic resonance.
        J Cardiovasc Magn Reson. 2017; 19: 45
        • Crossman DJ
        • Ruygrok PN
        • Hou YF
        • Soeller C.
        Next-generation endomyocardial biopsy: the potential of confocal and super-resolution microscopy.
        Heart Fail Rev. 2015; 20: 203-214
        • Seferović PM
        • Piepoli MF
        • Lopatin Y
        • Jankowska E
        • Polovina M
        • Anguita-Sanchez M
        • et al.
        Heart Failure Association of the European Society of Cardiology Quality of Care Centres Programme: design and accreditation document.
        Eur J Heart Fail. 2020; 22: 763-774
        • Ferreira VM
        • Schulz-Menger J
        • Holmvang G
        • Kramer CM
        • Carbone I
        • Sechtem U
        • et al.
        Cardiovascular magnetic resonance in nonischemic myocardial inflammation: expert recommendations.
        J Am Coll Cardiol. 2018; 72: 3158-3176
        • Friedrich MG
        • Sechtem U
        • Schulz-Menger J
        • Holmvang G
        • Alakija P
        • Cooper LT
        • et al.
        Cardiovascular magnetic resonance in myocarditis: a JACC White Paper.
        J Am Coll Cardiol. 2009; 53: 1475-1487
        • Lurz P
        • Luecke C
        • Eitel I
        • Föhrenbach F
        • Frank C
        • Grothoff M
        • et al.
        Comprehensive cardiac magnetic resonance imaging in patients with suspected myocarditis: the MyoRacer-trial.
        J Am Coll Cardiol. 2016; 67: 1800-1811
        • Zhao L
        • Tian Z
        • Fang Q.
        Diagnostic accuracy of cardiovascular magnetic resonance for patients with suspected cardiac amyloidosis: a systematic review and meta-analysis.
        BMC Cardiovasc Disord. 2016; 16: 129
        • Castaño A
        • Manson DK
        • Maurer MS
        • Bokhari S.
        Transthyretin cardiac amyloidosis in older adults: optimizing cardiac imaging to the corresponding diagnostic and management goal.
        Curr Cardiovasc Risk Rep. 2017; : 11
        • Bravo PE
        • Singh A
        • Di Carli MF
        • Blankstein R.
        Advanced cardiovascular imaging for the evaluation of cardiac sarcoidosis.
        J Nucl Cardiol. 2019; 26: 188-199
        • Zhang J
        • Li Y
        • Xu Q
        • Xu B
        • Wang H.
        Cardiac magnetic resonance imaging for diagnosis of cardiac sarcoidosis: a meta-analysis.
        Can Respir J. 2018; 20187457369