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Reprint requests: Professor Petar M. Seferović, MD, PhD, FESC, FACC, Vice-president, European Society of Cardiology, President, Heart failure Association of the ESC (2018-2020), Academician, Serbian Academy of Sciences and Arts, Professor of Cardiology, University of Belgrade Faculty of Medicine and, Heart Failure Center, Belgrade University Medical Center, President, Heart Failure Society of Serbia, Koste Todorovica 8, 11 000 Belgrade, Serbia, Phone/Fax: +381 11 361 47 38.
Department of Cardiology (CVK); and Berlin Institute of Health Center for Regenerative Therapies (BCRT); German Centre for Cardiovascular Research (DZHK) partner site Berlin; Charité Universitätsmedizin Berlin, Germany
Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, GermanyFraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany
Berlin Institute of Health (BIH) and Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Department of Cardiology, Campus Virchow Klinikum, Charite University, Berlin, Germany
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.
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.
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.
Subsequently, Sekiguchi described the use of EMB in diagnostic assessment of myocardial diseases such as glycogen storage disorders, sarcoidosis, and myocarditis.
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.
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.
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.
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.
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.
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.
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. 2Historical cornerstones in the development of endomyocardial biopsy. (1) Procedural technique. (2) Imaging guidance. (3) Myocardial tissue processing.
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.
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.
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
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.
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.
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.
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.
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.
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.
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. 3An artistic presentation of right ventricular endomyocardial biopsy. Endomyocardial biopsy samples are typically taken from the interventricular septum.
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.
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.
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)
Likewise, a small study suggested that directing EMB to the regions of late gadolinium enhancement on CMR can increase diagnostic usefulness in 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.
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.
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.
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]).
Areas of low-voltage or abnormal electrogram on electroanatomic voltage mapping have a high sensitivity and specificity to identify the pathologic substrate.
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.
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%).
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.
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.
Hospital volume and cardiac complications of endomyocardial biopsy: a retrospective cohort study of 9508 adult patients using a nationwide inpatient database in Japan.
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.
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%),
Comparative analysis of the complications of 5347 endomyocardial biopsies applied to patients after heart transplantation and with cardiomyopathies: a single-center study.
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.
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.
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.
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.
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.
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.
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
Disease
EMB PROCESSING/STAINING
POSSIBLE FINDINGS
Myocarditis, DCM
Histopathology
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 + Borrelia
Infection 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, ARVC
Histology 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 diseases
PAS, 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)
Tumors
Standard histopathology + immunohistochemistry for specific tumors
Differential diagnosis between benign and malignant tumors, and in malignant tumor subtyping
Cellular 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. 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).
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 Presentation
Endomyocardial Biopsy Finding
Suspected fulminant myocarditis or acute myocarditis with acute HF, LV dysfunction, and/or rhythm disorders. Suspected myocarditis in hemodynamically stable patients.
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.
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.
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.
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).
In addition, EMB can provide differential diagnosis in patients with severe clinical course, when noninvasive assessment is inconclusive or unfeasible.
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.
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.
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.
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.
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.
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.
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
Electrogram guidance: a method to increase the precision and diagnostic yield of endomyocardial biopsy for suspected cardiac sarcoidosis and myocarditis.
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,
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.
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.
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.
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%.
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.
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.
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.
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.
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.
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.
Electrogram guidance: a method to increase the precision and diagnostic yield of endomyocardial biopsy for suspected cardiac sarcoidosis and myocarditis.
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).
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%.
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.
Likewise, EMB in patients with systemic lupus erythematosus can provide confirmation of lupus myocarditis, hydroxychloroquine-induced cardiotoxicity and/or coronary vasculitis and vasculopathy.
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.
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.
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).
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.
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.
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.
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.
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 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.
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.
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.
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.
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.
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.
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.
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. 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.
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).
Comparison of utilization trends, indications, and complications of endomyocardial biopsy in native versus donor hearts (from the Nationwide Inpatient Sample 2002 to 2014).
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
T1-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 onset
CMR
T2-weighted imaging: imaging modality with the greatest diagnostic accuracy
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.
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.
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.
Furthermore, findings of ultrastructural changes, fibrosis, apoptosis, hypertrophy, vascular density, inflammation, and viral persistence may indicate adverse prognosis in DCM.
An analysis of EMB samples from 182 patients demonstrated an association between increased immune cell activity in the myocardium and poor long-term prognosis.
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
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.
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.
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.
In patients with myocarditis of unknown etiology, a clinical trial failed to demonstrate a beneficial effect of immunosuppression on LV function and survival.
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.
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.
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.
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.
In patients with active viral infection, several treatment options have been investigated, including intravenous immunoglobulins, interferon-alfa and -beta, ganciclovir, acyclovir, and valacyclovir.
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.
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.
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.
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.
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.
Comparative analysis of the complications of 5347 endomyocardial biopsies applied to patients after heart transplantation and with cardiomyopathies: a single-center study.
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.
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.
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%).
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.
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.
Complication rate of transfemoral endomyocardial biopsy with fluoroscopic and two-dimensional echocardiographic guidance: a 10-year experience of 228 consecutive procedures.
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
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.
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.
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.
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.
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T2 mapping cardiovascular magnetic resonance identifies the presence of myocardial inflammation in patients with dilated cardiomyopathy as compared to endomyocardial biopsy.
Hospital volume and cardiac complications of endomyocardial biopsy: a retrospective cohort study of 9508 adult patients using a nationwide inpatient database in Japan.
Comparative analysis of the complications of 5347 endomyocardial biopsies applied to patients after heart transplantation and with cardiomyopathies: a single-center study.
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.
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Are two tests better than one? combining donor derived cell-free DNA and gene expression profiling for non-invasive surveillance after heart transplantation.
Comparison of utilization trends, indications, and complications of endomyocardial biopsy in native versus donor hearts (from the Nationwide Inpatient Sample 2002 to 2014).
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.
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.
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.
Complication rate of transfemoral endomyocardial biopsy with fluoroscopic and two-dimensional echocardiographic guidance: a 10-year experience of 228 consecutive procedures.
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