Endomyocardial biopsy in the clinical context: current indications and challenging scenarios

Endomyocardial biopsy (EMB) is an invasive procedure developed in 1960s initially for the early diagnosis and monitoring of heart transplant (HTx) rejection [1]. Since then, this technique has become an important tool for the diagnosis and evaluation of different cardiac disorders such as cardiomyopathies, myocarditis, infiltrative and storage diseases, and cardiac tumours. EMB incremental diagnostic, prognostic and therapeutic value has led to a wide diffusion of this technique over the years in different settings. Nevertheless, a significant heterogeneity exists in EMB use in clinical practice, probably due to its low sensitivity in specific scenarios, the development of non-invasive diagnostic techniques, the non-negligible risk of major complications especially in non-experienced centres and the limited availability of skilled cardio-pathologists for the interpretation of histological findings, outside referral centres [2].

In recent years, the use of advanced imaging modalities, as echocardiography with three-dimensional (3D) and myocardial strain analysis, cardiac magnetic resonance (CMR) and positron emission tomography (PET), has revolutionized the non-invasive approach to diagnosis and prognostic stratification of several cardiac diseases, resulting in an accurate selection of cases in which EMB may carry important both diagnostic and prognostic information (Table 1). Indeed, along with a full morphological and functional cardiac assessment, CMR imaging can provide a detailed characterization of the cardiac muscle composition, although it may not be feasible in patients with specific features (i.e. arrhythmias, poor breath-holding, non-conditioned cardiac devices) [3]. A remarkable example is the possibility to reach a non-invasive diagnosis of acute myocarditis (AM), according to the Lake Louise Criteria published in 2009 [4], updated in 2018 [5]. Furthermore, another promising tool for clinical practice is the measurement of myocardial strain, which can reveal subtle systolic dysfunction in patients with clinically suspected AM or anthracycline-induced cardiomyopathy presenting with apparently normal left ventricular ejection fraction (LVEF) [6, 7]. In addition, PET with 18F-fluorodeoxyglucose (18F-FDG) uptake could help to identify the involvement of the heart in cardiac sarcoidosis (CS) and to monitor treatment response [8]. Over the years, major technical advances in EMB, tissue processing and analysis, such as molecular diagnostics, proteomics and electron microscopy, increased the accuracy of this procedure and reduced the risk of major complications.

Therefore, it emerges the need to re-define the current role of EMB for diagnostic work-up and management of cardiovascular diseases, a task recently pursued by an international “Position statement on endomyocardial biopsy” [9]. The aim of this review is to summarize current knowledge on EMB in light of the most recent evidences and discuss current indications, including challenging scenarios encountered in clinical practice.

Providing essential information on myocardial histology, immunohistochemistry and molecular structure, EMB represents the gold-standard technique to reach a definite and etiological diagnosis in different cardiac disorders, to improve patients’ stratification and guide treatment options (Table 2) [10, 11]. Emerging imaging modalities (3D echocardyography, CMR, PET, electro anatomic voltage mapping) guiding cardiac sampling and the implementation of immunohistochemistry and polymerase chain reaction (PCR) to standard histologic evaluation have enhanced EMB diagnostic accuracy [12]. However, a significant variability in EMB diagnostic yield is conferred by the specific pattern of myocardial involvement (i.e. focal vs diffuse tissue) and centre’s expertise in samples’ collection, processing, analysis and interpretation.

EMB is a cornerstone in the management of patients with unexplained acute heart failure (HF) with haemodynamic compromise or ventricular arrhythmias/conduction disorders of unknown aetiology, clinically suspected AM, CS, storage and infiltrative diseases, cardiac masses and monitoring of HTx rejection status [10, 11].

Aside diagnostic information, viral search by PCR, reverse transcription (RT)-PCR and direct sequencing analysis on cardiac specimens have also therapeutic implications, as in the evaluation of possible candidates to immunosuppressive therapy [13]. While immunosuppression lacks conclusive prognostic evidence in virus-negative lymphocytic myocarditis, it is a recognized effective treatment option for other inflammatory cardiomyopathies, such as giant cell myocarditis (GCM), eosinophilic necrotizing myocarditis (ENM) and CS, which are associated with a poor outcome [13, 14]. Finally, during COVID-19 pandemic, although rarely indicated in suspected AM related to SARS-Cov-2, EMB has been used mainly for research purposes. In this setting, histopathological finings revealed an increased macrophage and lymphocytic tissue infiltration in the heart, without evidence of viral presence within cardiomyocytes [15].

The first technique of EMB using a bioptome designed for transvascular approach (Konno-Sakakibara bioptome) was reported in the early 1960 in Japan [1]. Over the last 60 years, EMB technique has been refined and the procedure has gained worldwide acceptance (Fig. 1). However, safety remains a concern when performing EMB; indeed, although rare, major complications (including cardiac tamponade necessitating pericardiocentesis, thromboembolism, severe arrhythmias/atrioventricular block, valvular trauma) occur in about 1% of cases [16, 17]. Haemodynamically unstable patients and those with large ventricles with thin walls may be at a higher risk of cardiac perforation, which is more frequently observed with right ventricle (RV) than with left ventricle (LV) EMB (Table 3). Of note, LV EMB is associated with a higher risk of stroke or systemic embolism. Therefore, when posing indications to EMB, the risk/benefit balance should be accurately evaluated and the procedure should be performed in high-volume centres with specific expertise to minimize the risk of such complications [2].

RV EMB is performed by jugular, femoral or brachial veins. Transradial artery access is emerging as an alternative access route for LV EMB [18, 19], non‐inferior to transfemoral artery access in terms of major complications [20] and possibly leading to fewer access-site bleedings compared to the femoral access [21]. However, LV EMB is still usually performed by femoral arteries. In LV EMB, intravenous heparin is given to reach an ACT > 200 s to reduce the risk of embolism. From femoral access, long sheath technique is predominantly used for semi-flexible bioptomes also to avoid repeated exposure of the valve leaflets to the bioptome. The long sheath is introduced in the ventricle over a pigtail catheter which advances over a 0.035 wire under fluoroscopy guidance. Then, the mid LV cavity position of the tip of the sheath is confirmed in right and left anterior oblique projection in order to avoid the apex and to be far from valvular apparatus. At this stage, performing a ventriculography (Video 1) can facilitate the positioning of the catheter and additional angiographic views can be used for specific site of sample collection. Pigtail catheter is then removed and the bioptome is advanced into the LV. The forceps should be already in the “opened” position inside the distal segment of the long sheath and have to remain open until contact with the ventricular wall. The bioptome forceps are closed when a slight resistance is sensed by the operator; ventricular beat or non-sustained ventricular tachycardia is common while the bioptome is in contact with the myocardium. The bioptome is then removed from the sheath and the sheath is aspirated and flushed to prevent air or tissue embolism. Once the patient’s hemodynamic stability has been ascertained, heparin is antagonized with protamine sulphate and the introducer removed by closure devices. The general advice about steering the bioptome holds true for both LV and RV EBM. Of note, in RV EMB, samples are usually taken from different sites of the interventricular septum (Videos 2 and 3) to reduce the risk of perforation.

A successful procedure should provide at least ≥ 5 samples for histological evaluation, immunohistochemistry and viral PCR analyses [11, 22]. The diagnostic yield of EMB may be optimized when samples from both ventricles are available [16]; however, LV EMB appears diagnostically more informative than RV EMB [17] in patients with clinically uninvolved RV. The best approach should be identified based on an accurate clinical query: LV biopsy is preferred in suspected AM with primary LV involvement and CS. While the diagnostic accuracy of EMB is high in diffuse cardiac diseases, such as CA, collection of specimens from multiple cardiac sites should be considered in focal diseases as in CS [23]. Of note, increasing the number of collected samples is paralleled by a higher risk of complications [24]. Pre-operative third-level imaging techniques as CMR and 18F-FD PET may identify the sites with myocardial fibrosis (LGE and T1 mapping), cardiac edema (T2 mapping), and inflammation where the probability of an informative EMB result is higher. Moreover, the use of intra-procedural electroanatomic mapping may detect ventricular segments with fragmented or low voltages [5] which may indicate the most diseased area for sample collection [8]. Further studies are needed to evaluate the ability of imaging techniques and electroanatomic mapping to guide EMB and improve the safety and the diagnostic yield of the procedure.

Clinical indications to EMB have been based on empirical decisions and expert opinions, often heterogeneous worldwide and dynamic over time, mostly due to the invasive nature of this technique and the lack of specific clinical trials and guidelines (Table 2). Previously published international Scientific Statements [10, 11] did not result in a standardized use of EMB in clinical practice. Currently, in the latest guidelines on the diagnosis and treatment of HF from the European Society of Cardiology (ESC), EMB is indicated with a class IIa recommendation in the context of rapidly progressive HF despite standard therapy, when there is a probability of a specific diagnosis requiring specific treatments, which can be confirmed only in myocardial samples [25].

Furthermore, the recent position Statement by Seferovic et al. [9] identified with a standardized approach 9 specific clinical scenarios in which EMB should be considered to reach the final diagnosis and to guide decision-making (Table 4).

It should be always considered that EMB is an invasive procedure to be used after careful consideration of risks and benefits [24]. EMB has some limitations [2] : (a) its accuracy is not 100% and inconclusive results are possible in clinical practice, (b) it is associated with a modest, but still relevant, risk of potential major procedural complications, (c) the presence of mild myocardial histological changes is not always clinically relevant and does not address a specific therapeutic approach, and (d) it requires cardiac pathologists with experience in the interpretation of histological findings. Finally, some absolute contraindications to EMB should be considered such as the presence of intracardiac thrombus, ventricular aneurysm, severe tricuspid, pulmonary or aortic stenosis and tricuspid or aortic prosthesis [9].

A careful candidate selection with a stepwise and comprehensive approach is recommended in challenging scenarios (Table 5). Of note, this approach to EMB indication is supported by the 2021 guidelines for the diagnosis and treatment of acute and chronic HF from the ESC [25].

Although a consensus exists about the clinical indications to EMB, this exam gains particular relevance (a) in acute cardiac syndromes, refractory to standard therapies, (b) when non-invasive assessment is not feasible (i.e. CMR not feasible because of frequent arrhythmias, etc..) or yields inconclusive results, (c) for surveillance indications (i.e. reject after HTx) and (d) in selected cases of chronic hemodynamically stable patients with inconclusive non-invasive tests and suspicion of inflammatory disease (i.e. persistently or relapsing increased serum troponin values, ventricular arrhythmias, development of severe LV dysfunction) or underlying cardiomyopathies (i.e. HCM “phenocopies”) (Fig. 3).

Of note, EMB should be performed in centres with specific expertise in evaluating patients with cardiomyopathies and interpreting the immunohistopathological and bio-molecular histological findings. In this perspective, the organization of a “hub-spoke” network should be fully supported in the near future. This approach would allow an accurate selection of best candidates to EMB after consideration of the risk–benefit balance, avoiding taking unnecessary procedural risks. CMR findings such as LGE or increased T values/ECV, the analysis of the genetic background [43] and knowledge of the disease-specific mechanisms of cardiac injury [44] are promising fields of future investigation to refine patients selection.