Endomyocardial biopsy

Endomyocardial biopsy is an invasive procedure used routinely to obtain small samples of heart muscle in order to diagnose various heart diseases in which non-invasive testing is usually not able to formulate a clinical diagnosis and it is primarily used for monitoring of allograft rejection of a donor heart following heart transplantation and is considered the “gold standard” for the diagnosis of myocarditis ¹. Endomyocardial biopsy is mandatory only for the diagnosis of a small number of diseases, including anthracycline-induced cardiomyopathy, cardiac allograft rejection, sarcoidosis, giant cell myocarditis and hypereosinophilic syndrome. Many diseases diagnosed by endomyocardial biopsy are often suspected before the procedure is performed and a specific tissue diagnosis is achieved only in a minority of cases because histological findings are frequently non-­specific ². Despite that, its use is still controversial because of concerns about the risk of complications due to the invasive nature of the procedure, the uncertain diagnostic contribution and the practice varies widely in different centers ³. Several recent studies showed that endomyocardial biopsy is a safe procedure with very low transient complications if performed by experienced interventionists. In addition, its diagnostic contribution in the clinical suspicion of myocarditis is crucial. The application of immunohistochemical and molecular biology techniques allows the etiologic definition of the myocardial inflammation (i.e., viral or autoimmune) with important therapeutic and prognostic implications.

Performing a endomyocardial biopsy is not without complications, and less invasive diagnostic procedures such as cardiac magnetic resonanceimaging (MRI) or positron emission tomography (PET) scans outcompete endomyocardial biopsy for certain indications ³. However, there do exist certain conditions and scenarios in which doing an endomyocardial biopsy is helpful in establishing thediagnosis when no other diagnostic test yields a substantial diagnosis. As every diagnostic modality, the endomyocardial biopsyprocedure has unique characteristics in terms of sensitivity, specificity, and predictive values for different diseases.endomyocardial biopsy is a multistep process consisting of deciding about indication, biopsy taking, sample handling, andinterpretation. Apart from its clinical use, endomyocardial biopsy also serves research purposes ⁴.

The rate of complication during endomyocardial biopsy is reported to be as less than 6% in most case series ⁵. These include access site hematoma or carotid puncture, pneumothorax or haemothorax, transient right bundle branch block, transient arrhythmias, ­tricuspid regurgitation and occult pulmonary embolism. ­Life-threatening complications include right ventricular perforation with pericardial effusion and eventually cardiac tamponade (less than 1%), malignant arrhythmias and tension pneumothorax.

Patients undergoing repeated endomyocardial biopsy during a prolonged period of time (i.e. rejection surveillance) are at risk of long-term complications ⁶. Serious late complications from endomyocardial biopsy can include coronary artery-to-right ventricular fistula and severe tricuspid valve regurgitation. Tricuspid valve regurgitation occurs relatively frequently with reported rates of symptomatic regurgitation up to 23% and, unfortunately, it seems that even asymptomatic endomyocardial biopsy-induced tricuspid regurgitation could increase late mortality ⁷. However, tricuspid echo-color Doppler during the procedure allows to reduce this complication; in fact, a endomyocardial biopsy registry reports a post-procedural tricuspid valve regurgitation of less than 10%.

Endomyocardial biopsy 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 ⁴.

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 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 endomyocardial biopsy 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 endomyocardial biopsy is performed in the left ventricle ⁸.

In order to decrease the sampling error in more diffuse processes, increasing the amount of endomyocardial biopsy’s taken has been established to decrease the sampling error. When deciding between which ventricle to biopsy, utilization of cardiovascular magnetic resonance imaging and electrocardiogram concurrently during endomyocardial biopsy 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 ⁹.

Endomyocardial biopsy guidelines

The indications for endomyocardial biopsy according to current guidelines are: surveillance heart transplant rejection, diagnosis of unexplained cardiomyopathies (suspected myocarditis or cardiomyopathy) and cardiac tumors, detection of suspected anthracycline toxicity and use in research when necessary ¹⁰.

Endomyocardial biopsy is not a commonly indicated test in the diagnosis of heart disease ¹¹. However, under some special clinical scenarios, endomyocardial biopsy has a particular diagnostic and prognostic significance. There are no randomized clinical studies to prove the utility of endomyocardial biopsy in any cardiac disease, and the recommendations are based on retrospective analysis, case-series, and expert opinion ¹¹. The clinical significance of endomyocardial biopsy depends on two factors which are, role in diagnosis and implication for treatment.

Broadly, endomyocardial biopsy can be used to:

1. Diagnose heart failure of unknown etiology, cardiac sarcoidosis, amyloidosis, inflammatory cardiomyopathies, storage diseases such as hemochromatosis, cardiac masses, and antineoplastic side effects.
2. Surveillance of heart transplant patients,
3. To differentiate between constrictive pericarditis and restrictive cardiomyopathy or right ventricular myocarditis and arrhythmogenic right ventricular cardiomyopathy.

Endomyocardial biopsy is relevant and applicable in selected clinical cases. Endomyocardial biopsy is essential to diagnose the diverse disease processes underlying cardiomyopathy presenting as heart failure. But sometimes, the therapeutic consequence of endomyocardial biopsy is limited ¹². Regarding the interpretation of histologic changes, the difference between structure and function should be remembered ¹³. 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 endomyocardial biopsy 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 endomyocardial biopsy 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 ¹⁴. Apart from myocarditis, endomyocardial biopsy suffers from low sensitivity, which is 25% for lymphocytic myocarditis and 35% cardiac sarcoidosis ¹⁵. The poor sensitivity but good specificity makes endomyocardial biopsy 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) ¹⁶. The combination of cardiac magnetic resonance imaging (MRI) and endomyocardial biopsy has synergistic value in the diagnosis of myocarditis ¹⁷.

Heart failure of unknown cause

A special role of endomyocardial biopsy 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 endomyocardial biopsy has a unique prognostic significance. Fulminant lymphocytic myocarditis has an excellent prognosis, while on the other hand, giant cell myocarditis and necrotizing eosinophilic myocarditis specify poor prognosis.

This carries a clinical significance as patients with fulminant lymphocytic myocarditis have the probability of recovering on their own while those with giant cell myocarditis and necrotizing eosinophilic myocarditis should be considered for immunosuppressive therapies as well as mechanical circulatory support if needed.

Another recommendation to performing endomyocardial biopsy 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 giant cell myocarditis, which has a poor prognosis and usually requires immunosuppression and heart transplant in certain cases ¹⁸.

Cardiac sarcoidosis

In cases of cardiac sarcoidosis, misdiagnosis of patients with other similar-presenting conditions, particularly idiopathic granulomatous myocarditis and giant cell myocarditis, is highly possible. However, due to its patchy involvement, the diagnostic yield of endomyocardial biopsy is low (20% to 30%), even in patients with full-blown features of sarcoidosis. Use of cardiac magnetic resonance imaging (MRI) to localize the areas of involvement may improve the diagnostic yield of biopsy ¹⁹. It is important to distinguish sarcoidosis from giant cell myocarditis as both have giant cells. The transplant-free survival at 1-year is much higher for sarcoidosis then for giant cell myocarditis. Also, patients with sarcoidosis usually respond to steroids, and an implantable cardioverter-defibrillator (ICD) can treat ventricular arrhythmias in sarcoidosis patients.

Hypersensitivity myocarditis

Hypersensitivity myocarditis is an uncommon disorder with the most common presentation being a chronic dilated cardiomyopathy though rapidly progressive and fatal cardiomyopathy may also be seen. Eosinophilic cardiomyopathy is a type of hypersensitivity myocarditis 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 hypersensitivity myocarditis and eosinophilic cardiomyopathy are important to recognize as treatment of the offending parasite, allergy, or avoidance of the allergens may treat the underlying cardiomyopathy. It also distinguishes these entities from other fatal cardiomyopathies like giant cell myocarditis and necrotizing eosinophilic myocarditis.

Suspected anthracycline cardiomyopathy

Given its invasive nature, endomyocardial biopsy 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 can be infiltrative, non-infiltrative, or could be due to storage diseases. Idiopathic restrictive cardiomyopathy is a unique form of restrictive cardiomyopathy in which the cause is uncertain on the non-invasive diagnostic testing, but endomyocardial biopsy may show mild myocyte hypertrophy with myofibrillary disarray helping in formulating the diagnosis. Since restrictive cardiomyopathy may mimic constrictive pericarditis clinically and hemodynamically, so a cardiac computed tomogram (CT) or cardiac magnetic resonance imaging (MRI) should be pursued in uncertain cases. If a clear rim of calcification is identified surrounding the heart, then there is no indication for endomyocardial biopsy. 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 ²⁰.

Cardiac tumors

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

Arrhythmogenic right ventricular cardiomyopathy

The role of endomyocardial biopsy in Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) in 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 endomyocardial biopsy for cases of diagnostic uncertainty.

Heart transplant

Another indication for endomyocardial biopsy is in post-heart transplantation is to identify rejection, determine the presence of infection, if any, and determine the development of any post-transplant neoplasia or post-transplant lymphoproliferative disease. In patients who undergo heart transplants, routine surveillance endomyocardial biopsys 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 ²⁰.

The identification of heart transplant rejection is based on the presence of mononuclear inflammatory cells in the interstitium, away from previous biopsy sites and not associated with Quilty lesions, which are flat lesions due to the infiltrates of endocardial mononuclear cells that grow into the endocardium and appear as nodular lesions confined to the endocardium (Quilty A) or into the myocardium (Quilty B) ²¹.

The most widely used classification of heart transplant rejection was that ideated by Margaret Billingham. In 1990, the International Society for Heart and Lung Transplantation grading system was introduced for an effort of standardization (Table 1) and reviewed in 2006 by the newer grading system (Table 2) ²². If there is no evidence of cellular rejection, clinical features would suggest rejection, antibody-mediated rejection should be investigated. The C4dpar stains the capillary endothelial cell membrane in paraffin-embedded tissues. Unfortunately, there is not a codified classification of this type of rejection ²³.

Table 1. 1990 International Society for Heart and Lung Transplantation standardized cardiac biopsy grading: acute cellular rejection

Table 2. 2004 International Society for Heart and Lung Transplantation standardized cardiac biopsy grading: acute cellular rejection

Endomyocardial biopsy contraindications

Since endomyocardial biopsy is an invasive procedure, it has both absolute and relative contraindications. Absolute contraindications to endomyocardial biopsy 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, 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.

Endomyocardial biopsy complications

Endomyocardial biopsy complications can be divided into acute and chronic. The dreaded acute complications of endomyocardial biopsy 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 endomyocardial biopsy procedures for transplant surveillance. The majority of regurgitation, however, 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 endomyocardial biopsy procedures. The overall complication rate and the number of inconclusive samples is rather low, with severe adverse events in less than 1% and minor incidents up to 6% of procedures ²⁴.

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

The risks of endomyocardial biopsy 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 endomyocardial biopsy presents at a medical center where expertise in endomyocardial biopsy 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 ²⁵.

Endomyocardial biopsy procedure

Endomyocardial biopsy procedure can be performed under fluoroscopy (more commonly used) or echocardiography. A ‘bioptome’ is used to obtain a cardiac biopsy. 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 ²⁶.

Before an endomyocardial biopsy, it must be seen that the patient discontinues 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 put under anesthesia and sedation, the patient must be put into a supine position with 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 ²⁷:

• Inflammation (myocarditis)
• Myocyte hypertrophy and disarray (idiopathic restrictive cardiomyopathy)
• Myocyte degradation and necrosis (necrotizing myocarditis)
• Fibrosis (ischemic or non-ischemic insults)
• Fibrofatty infiltration (arrhythmogenic right ventricular cardiomyopathy)
• 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 PCR technique to identify cardiotropic strains of enteroviruses (coxsackievirus and echovirus), parvovirus, adenovirus, and herpes simplex virus ²⁸.

The International Society for Heart and Lung Transplantation grading evaluates cardiac transplant tissue samples for signs of inflammation and myocyte damage allowing classification of allograft rejection reaction and better interobserver agreement ²⁹. 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) ³⁰.

The procedure of endomyocardial biopsy 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 ³¹.

Endomyocardial biopsy technique

The common access site for endomyocardial biopsy has been the right internal jugular vein since the introduction of the flexible bioptome³². However, there have been described procedures conducted through right femoral ³³, subclavian ³⁴ or brachial veins ³⁵ and femoral or the radial arteries ³⁶ to access the right and left ventricles, respectively.

Endomyocardial biopsy is performed in the supine position; the patient must be monitored by continuous ECG, non-invasive blood pressure measurement and pulse oximetry. In patients receiving anticoagulation therapy, an international normalized ratio of less than 1.5 is required.

After the preparation of an appropriate sterile field, the jugular vein puncture is performed under local anaesthesia (2% lidocaine) followed by the insertion of a 9-Fr sheath with the Seldinger technique. A bioptome (9-Fr/50 cm) is then advanced slowly, through the sheath, to the right ventricle. Under echocardiographic control, doctors (interventional cardiologists) usually harvest four specimens of myocardial tissue from the apical segment of the right side of the interventricular septum.

Guiding the bioptome can be done through fluoroscopy in the catheterization laboratory or via intracardiac or transthoracic/transesophageal echocardiography at the bedside ³⁷. 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 cardiac magnetic resonance, thus decreasing sampling error. Real-time cardiac magnetic resonance-guided endomyocardial biopsy requires magnetic resonance-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 endomyocardial biopsy ³⁸.

Interventional cardiologists routinely use transthoracic echocardiogram during the execution of the endomyocardial biopsy, not only to steer the tip of bioptome, but also to assess incidental acute complications, such as tricuspid valve injury and pericardial effusion. In fact, great care is paid to avoid damage to the tricuspid valve or the free wall of the right ventricle by forceps manipulation. For this reason, color flow mapping of tricuspid valve flows during and after the procedure is mandatory. To gain ideal visualization of the tip of the bioptome in both the right atrium and the right ventricle, a parasternal long-axis view or, in slim patients, subcostal projection is typically used.

At the end of the procedure, a chest X-ray is performed to exclude the presence of pneumothorax or hemothorax.

Specimens are stored in 10% neutral-buffered formalin and processed on the same day. For histological assessment, tissue sections from different cutting levels were prepared from the paraffin block, mounted on glass slides and stained routinely with haematoxylin and eosin and/or with connective stains. Perivascular or interstitial cellular aggregates and evidence of myocyte damage are used for assigning a rejection grade according to both the old and the revised International Society for Heart and Lung Transplantation classifications. Specimens can also be collected for immunohistochemical studies to assess specific type of rejection, as C4d staining for identification of antibody-mediated rejection (AMR), or for detection of viruses in the diagnostic iter of myocarditis, by means of polymerase chain reaction of the nucleic acids. In the latter case, fresh specimens are immersed in a specific aqueous tissue storage solution that rapidly permeates to stabilize and protect RNA.

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