Continuing Education Activity

The role and utility of endomyocardial biopsy (EMB) in the work-up of cardiovascular diseases remains controversial and the practice varies widely in different centers. EMB is a diagnostic modality used to evaluate various cardiac diseases in which non-invasive testing is usually not able to formulate a clinical diagnosis. This activity describes the background, indications, complications, and the technique required to perform an endomyocardial biopsy and highlights the role of the interprofessional team in the care of patients that undergo this procedure.

Objectives:

• Identify the indications and contraindications of endomyocardial biopsy.
• Describe the equipment and technique in regards to endomyocardial biopsy.
• Review the potential complications of endomyocardial biopsy.
• Outline interprofessional team strategies for improving care coordination and communication to enhance the care of patients that undergo endomyocardial biopsy.

Introduction

The role and utility of endomyocardial biopsy (EMB) in the work-up of cardiovascular diseases remains controversial, and the practice varies widely in different centers. EMB is a diagnostic modality used to evaluate various cardiac diseases in which non-invasive testing is usually not able to formulate a clinical diagnosis. Performing a biopsy is not without complications, and less invasive diagnostic procedures such as cardiac magnetic resonance imaging (MRI) or positron emission tomography (PET) scans outcompete EMB for certain indications. However, there do exist certain conditions and scenarios in which doing an EMB is helpful in establishing the diagnosis when no other diagnostic test yields a substantial diagnosis. As with every diagnostic modality, the EMB procedure has unique characteristics in terms of sensitivity, specificity, and predictive values for different diseases. EMB is a multistep process consisting of deciding about indication, biopsy taking, sample handling, and interpretation. Apart from its clinical use, EMB also serves research purposes.[1]

Anatomy and Physiology

EMB can be performed in the right or left ventricle. However, the most common location for biopsy sampling is within the right ventricular septum. Right ventricular access is commonly performed via the right or left femoral vein, or through the right internal jugular vein (the most common approach used in the United States). Left ventricular access is granted via the right or left femoral artery or the right radial artery.[1]

Knowing the cardiac anatomy and the particular locations of localized involvement are important for proper sampling and reducing complications. For example, arrhythmogenic right ventricular dysplasia (ARVD) causes changes in the right ventricular free wall (which is especially prone to perforation during a biopsy) rather than the septum (which is the usual location of EMB sampling). Cardiac masses, on a similar note, also have a distinct location within the heart, depending on its primary origin and character. For example, myxomas are most often found within the left atrium, whereas secondary neoplasms are often located in the right heart chambers. It has also been established that the expression of interstitial fibrosis and cardiac collagen type I is more reliably found when the EMB is performed in the left ventricle.[2]

In order to decrease the sampling error in more diffuse processes, increasing the amount of EMBs taken has been established to decrease the sampling error. When deciding between which ventricle to biopsy, utilization of cardiovascular magnetic resonance imaging (CMRI) and electrocardiogram concurrently during EMB has been shown to aid in guiding the physician to taking samples from areas of the heart that are shown to be actively affected by myocarditis or cardiac sarcoidosis.[3]

Indications

EMB is not a commonly indicated test in the diagnosis of heart disease. However, under some special clinical scenarios, EMB has a particular diagnostic and prognostic significance. There are no randomized clinical studies to prove the utility of EMB in any cardiac disease, and the recommendations are based on retrospective analysis, case series, and expert opinion.

Broadly, EMB can be used to diagnose heart failure of unknown etiology, cardiac sarcoidosis, amyloidosis, inflammatory cardiomyopathies, storage diseases (such as hemochromatosis), cardiac masses, and antineoplastic side effects. It can also be used in the surveillance of patients with a heart transplant or to differentiate between constrictive pericarditis and restrictive cardiomyopathy or right ventricular myocarditis and arrhythmogenic right ventricular cardiomyopathy. 

Diagnostic Indications

Heart Failure of Unknown Etiology

A special role of EMB is in patients who develop acute decompensated heart failure (less than 2 weeks in duration). If other causes of heart failure are excluded, including coronary artery disease, obtaining an EMB has a unique prognostic significance. Fulminant lymphocytic myocarditis (FLM) has an excellent prognosis, while on the other hand, giant cell myocarditis (GCM) and necrotizing eosinophilic myocarditis (NEM) specify poor prognosis.

This carries a clinical significance as patients with FLM have the probability of recovering on their own while those with GCM and NEM should be considered for immunosuppressive therapies as well as mechanical circulatory support if needed.

Another recommendation to performing EMB is heart failure of 2 weeks to months in duration with dilated left ventricle and associated arrhythmias (high-grade heart blocks, ventricular arrhythmias) and failure to respond to usual care. The concern here is GCM, which has a poor prognosis and usually requires immunosuppression and heart transplant in certain cases.[4]

Cardiac Sarcoidosis

In cases of cardiac sarcoidosis, misdiagnosis of patients with other similar-presenting conditions, particularly idiopathic granulomatous myocarditis and GCM, is highly possible. However, due to its patchy involvement, the diagnostic yield of EMB is low (20% to 30%), even in patients with full-blown features of sarcoidosis. The use of cardiac magnetic resonance imaging to localize the areas of involvement may improve the diagnostic yield of biopsy.[5][6] It is important to distinguish sarcoidosis from GCM as both have giant cells. The transplant-free survival at 1-year is much higher for sarcoidosis than for GCM. Also, patients with sarcoidosis usually respond to steroids, and an implantable cardioverter-defibrillator (ICD) can treat ventricular arrhythmias in these patients.

Hypersensitivity Myocarditis

Hypersensitivity myocarditis (HSM) is an uncommon disorder with the most common presentation being a chronic dilated cardiomyopathy (DCM) though rapidly progressive and fatal CM may also be seen. Eosinophilic cardiomyopathy (ECM) is a type of HSM that is associated with hypereosinophilic syndrome. It typically presents as biventricular failure developing over the course of weeks to months. It may be idiopathic or associated with allergic reactions, parasite infections, or malignancies.

Both HSM and ECM are important to recognize as treatment of the offending parasite, allergy, or avoidance of the allergens may treat the underlying CM. It also distinguishes these entities from other fatal cardiomyopathies (CM) like GCM and NEM.

Suspected Anthracycline Cardiomyopathy

Given its invasive nature, EMB in patients treated with chemotherapeutic agents (anthracycline) may be best suited for situations in which there is a question as to the cause of cardiac dysfunction, as well as in select cases in which ultimate administration of greater than the usual upper limit of an agent is believed to be desirable, and in clinical studies of chemotherapeutic-related toxicity of newer agents and regimens.

Heart Failure With a Restrictive Pattern

Restrictive cardiomyopathy (RCM) can be infiltrative, non-infiltrative, or could be due to storage diseases. Idiopathic restrictive CM is a unique form of RCM in which the etiology is uncertain with non-invasive diagnostic testing, but EMB may show mild myocyte hypertrophy with myofibrillary disarray which helps to formulate the diagnosis. Since RCM may mimic constrictive pericarditis clinically and hemodynamically, a cardiac computed tomogram (CT) or CMR should be pursued in uncertain cases. If a clear rim of calcification is identified surrounding the heart, then there is no indication for EMB. Similarly, in amyloidosis, apple-green birefringence of any misfolded amyloid protein when visualized under polarized microscopy after staining the specimen with congo red stain is virtually diagnostic.[7][8]

Cardiac Tumors

In diagnosing cardiac tumors except for typical myxomas (as they have the potential to embolize from manipulation), EMB may be a reasonable choice. Though numerous tumors have been reported to have been diagnosed with EMB, lymphomas are the most commonly reported in the literature.

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

The role of EMB in ARVC is controversial as there is a concern for perforation of the already thinned out right ventricular wall. Some experts believe that non-invasive testing may be utilized, while others think that a fibrofatty replacement of myocardium on cardiac biopsy may provide certainty to the diagnosis. A reasonable approach is to employ non-invasive tests as the first-line option, considering EMB for cases of diagnostic uncertainty.  

Heart Transplant

Another indication for EMB is heart transplantation. In patients who undergo heart transplants, routine surveillance EMBs within the first year of transplant is performed to detect any evidence of transplant rejection, which may require further management by appropriate titration and adjustments of immunosuppressants.[8]

Contraindications

Since EMB is an invasive procedure, it has both absolute and relative contraindications. Absolute contraindications to EMB include valvular diseases such as vegetations or stenosis and vascular pathologies such as aneurysm and thrombosis. Atrial myxomas have high embolic potential and should not be routinely biopsied. Relative contraindications include coagulopathy, the use of dual antiplatelet therapy, or therapeutic anticoagulants. In situations of contraindication, alternatives to endomyocardial biopsy are needed, which include tissue doppler echocardiography, scintigraphy, and cardiac magnetic resonance imaging (CMRI).

Equipment

A bioptome is used to obtain a cardiac biopsy. The procedure can be performed under fluoroscopy (more commonly used) or echocardiography. Different bioptomes are now available, which are more flexible and finer than the early versions. Vascular access for right or left heart biopsy is achieved through venous (internal jugular or femoral vein) or arterial puncture (radial or femoral artery), respectively. The bioptome is advanced through a sheath that has been placed using the Seldinger technique.[9]

Personnel

An interventional cardiologist with experience doing EMBs is required to minimize the risk of complications. Additionally, a skilled interprofessional team of nurses and technologists in the cardiac catheterization lab should be utilized. Interpreting cardiac tissue samples requires knowledge and experience. Cardiac pathologists are specially trained pathologists and interpret histologic samples which stem from EMB or autopsy.[10]

Preparation

Guiding the bioptome can be done through fluoroscopy in the catheterization laboratory or via intracardiac or transthoracic/transesophageal echocardiography at the bedside.[11] Echocardiography guidance offers a comparable alternative to radiography in terms of complications and procedure time. Besides anatomic orientation, specific targeting can be achieved with voltage-mapping and CMR, thus decreasing sampling error. Real-time CMR-guided EMB requires MR-conditional devices. Voltage mapping can be used to identify certain pathologic areas (i.e., scar) characterized by conduction changes. Preprocedural imaging to locate areas of interest can increase the success of EMB.[12]

Technique or Treatment

Before an endomyocardial biopsy, the patient should have discontinued any anticoagulation therapy for 16 hours prior to the procedure, as well as for 12 hours post-procedure. The patient's INR (international normalized ratio) must also be less than 1.5 before the procedure. After the patient is provided with anesthesia and sedation, they should be put into a supine position with a 3-lead electrocardiogram (ECG), blood pressure cuff, and oxygen saturation monitoring.

To reduce discomfort during the procedure, analgesia and sedation are necessary. The biopsy procedure takes several minutes on average. To reduce sampling error, several tissue samples should be taken. The preparation of histologic samples begins just after the biopsy sample is taken. The different tissue samples are stored in formaldehyde, glutaraldehyde, and liquid nitrogen for evaluation using light microscopy, electron microscopy, immunofluorescence, or viral nucleic acid studies. For histologic examination, the samples are stained using hematoxylin-eosin, Masson trichrome, Congo red for identifying amyloidosis, and Prussian blue to detect iron deposition. The following characteristic changes are identified:[13]

• Inflammation (myocarditis)
• Myocyte hypertrophy and disarray (idiopathic restrictive cardiomyopathy)
• Myocyte degradation and necrosis (necrotizing myocarditis)
• Fibrosis (ischemic or non-ischemic insults)
• Fibrofatty infiltration (ARVC)
• Iron deposition (hemochromatosis)
• Amyloid deposition (amyloidosis)
• Vascular abnormalities (vasculitis)
• Artifacts (no clinical significance)

To quantify the extent of inflammation, a severity index has been defined, which includes the number of mononuclear cells (CD3, CD45, CD68) and HLA activation (HLA-ABC, HLA-DR). Frozen tissue samples are analyzed for viral nucleic acid using the polymerase chain reaction (PCR) technique to identify cardiotropic strains of enteroviruses (coxsackievirus and echovirus), parvovirus, adenovirus, and herpes simplex virus.[14]

The International Society for Heart and Lung Transplantation (ISHLT) grading evaluates cardiac transplant tissue samples for signs of inflammation and myocyte damage allowing classification of allograft rejection reaction and better interobserver agreement.[15] A unique phenomenon can be observed following transplantation. Quilty lesions are the dense accumulation of lymphocytes confined to the endocardium (Quilty A lesion) or spreading to the myocardium (Quilty B Lesion).[16]

The procedure of EMB may influence microscopic findings and cause artifacts. These include contraction bands, mitochondrial massing, sarcolemmal folding, cell swelling, and membrane disruption with the displacement of glycogen and lipids. Contraction bands can be produced artificially by biopsy taking, whereas in the postmortem study, it can reflect pathology.[17]

Complications

Complications can be divided into acute and chronic. Dreaded acute complications include pneumothorax, arrhythmias, perforation, pericardial effusion, pericardial tamponade, fistulas, heart block, arterial puncture, pulmonary embolization, nerve block/injury, hematoma, arteriovenous fistula, deep vein thrombosis, and tricuspid valve injury. Tricuspid injury, in particular, can be seen in patients undergoing multiple EMB procedures for transplant surveillance. The majority of regurgitation is tolerable and does not often progress to requiring valve replacement. However, care should be taken to minimize tricuspid valve tissue sampling during biopsies in patients who are known to expect frequent EMB procedures. The overall complication rate and the number of inconclusive samples are rather low, with severe adverse events in less than 1% and minor incidents up to 6% of procedures.[18]

Delayed complications include access site bleeding, damage to the tricuspid valve, pericardial tamponade, and deep venous thrombosis.

The risks of EMB depend on the clinical state of the patient, the experience of the operator, and the availability of expertise in cardiac pathology. If a patient with an indication for EMB presents at a medical center where expertise in EMB and cardiac pathology is unavailable, transfer of the patient to a medical center with such experience should be seriously considered. Additionally, patients with cardiogenic shock or unstable ventricular arrhythmias may require the care of specialists for the management of heart failure, including ventricular assist device placement and potentially heart transplantation.[19][20]

Clinical Significance

The clinical significance of endomyocardial biopsy depends on two factors which are, role in diagnosis and implication for treatment. EMB is relevant and applicable in selected clinical cases. EMB is essential to diagnose the diverse disease processes underlying cardiomyopathy presenting as heart failure. But sometimes, the therapeutic consequence of EMB is limited.[21] Regarding the interpretation of histologic changes, the difference between structure and function should be remembered.[22] Histopathologic appearance does not necessarily relate to symptoms.

In certain cases, the use of additional methodologies besides light microscopy and staining such as electron microscopy and immunohistochemistry, and molecular analysis is recommended. For example, in hemochromatosis and some other storage diseases, there is diffuse involvement of the heart, and simple light microscopy of EMB specimens may not be diagnostic. When the index of suspicion of these diseases is high as suggested by symptoms and results of other diagnostic testing, special staining techniques (to detect iron and other substances infiltrating the heart) and molecular analysis may help diagnose the underlying disease. 

The role of EMB to diagnose pathologic entities is changing over the years. The Dallas criteria have been discussed controversially since many patients that do not fulfill the Dallas criteria have been finally diagnosed to have myocarditis.[23] Apart from myocarditis, EMB suffers from low sensitivity, which is 25% for lymphocytic myocarditis and 35% cardiac sarcoidosis.[24] The poor sensitivity but good specificity makes EMB the diagnostic modality of choice in specific diseases. Thus high pretest probability is required. In patients with low pretest probability, other tests to rule out pathology should be preferred. These may include scintigraphy (indium-111, gallium-67).[25][26] The combination of CMR and EMB has synergistic value in the diagnosis of myocarditis.[27]

Enhancing Healthcare Team Outcomes

An interprofessional team should be involved in the care of patients that undergo EMB. This team includes interventional cardiologists, cardiac pathologists, radiologists, and cardiology nurses and technicians. Decision-making regarding EMB should balance the risk of this invasive procedure, its treatment implication, and its diagnostic power compared to other diagnostic methods. EMB is one part of the evaluation of cardiac pathology. As histology illustrates cellular appearance, science evolves with trying to take a more detailed look at the subcellular and molecular levels. The findings of the genetic basis of cardiac diseases led to the common pathway hypothesis of hypertrophic and dilated cardiomyopathy and long QT syndromes.[28][29]