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Introduction

Technique

Use of EMB in Special Situations

Discussion

Future Directions

References

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Role of endomyocardial biopsies in advanced heart failure care

 

Nandini Nair MD, PhD, Enrique Gongora, MD

Providence Sacred Heart Medical Center, Spokane,USA. Memorial Cardiac and Vascular Institute , Hollywood, USA

 

Abstract

Endomyocardial biopsy has had an interesting evolution that has spanned decades. The advent of a transvascular approach remarkably reduced the complications. This review updates its use in advanced heart failure care to diagnose diseases of the endocardium and myocardium. With modifications in technique and instrumentation EMB today is safe when performed by experienced operators. EMB can be performed to procure tissue from the right as well as left ventricles. The safety and diagnostic accuracy was equal. Endomyocardial biopsy is not recommended for routine use of new-onset heart failure as per the guidelines. Benefit of the procedure is limited to specific clinical scenarios especially where the test has a high positive predictive value. In rejection surveillance status post cardiac transplantation EMB is the standard of care for lack of any specific non-invasive /laboratory tests. Cytokine profiling is not recommended for the first 60 days post cardiac transplantation hence EMB is the only alternative. EMB specimens are used for complement activation as a screen for vascular rejection and to guide therapy. It is also used for assessing inflammatory burden for defining prognosis in this setting. In future endomyocardial biopsy (EMB) will likely be used in conjunction with other imaging techniques to confer safety and specificity. With the advent of molecular markers and need for their localization in tissues EMB would serve as an important technique to aid in diagnosis and prognosis. Key Words: endomyocardial biopsy; cardiomyopathy; rejection; hydroxychloroquine

Introduction

Endomyocardial biopsy (EMB) continues to be the gold standard in the diagnosis of acute rejection in transplanted hearts. EMB has also remained the technique of choice in assessing the etiology and pathophysiology of cardiac diseases where tissue samples are required for a definitive diagnosis, prognosis and plan of therapy. The yield of the technique in diagnosis varies but still remains the only option to procure tissue samples from the heart. This review addresses its use in advanced heart failure care to diagnose diseases of the endocardium and myocardium. The evolution of the technique of EMB is interesting and has spanned decades. Prior to 1962 the only approach to obtaining cardiac biopsy specimens was via a mini thoracotomy which was accompanied by a greater risk and complications that included cardiac tamponade, pulmonary infarcts, coronary artery damage and also death in some cases.1,2 The Sakakibara and Konno technique put forth in 1962 opened the doors for a transvascular approach.3 The transvascular technique showed no major complications in a 450 patient study.4 Following this a modified bronchoscope bioptome was developed which showed variable results but had the same safety profile as the Konno bioptome.5,6 The current day bioptome that is widely used globally is the commercial modification of the Stanford Caves-Shulz bioptome.7 With modifications in technique and instrumentation EMB today is safe when performed by experienced operators. This review presents an update of the technique in the present day and its multiple uses in the diagnosis and prognosis of a number of other conditions besides rejection of the cardiac allograft. Endomyocardial biopsy remains the mainstay in diagnosis of inflammatory cardiac diseases such as myocarditis of various etiologies, infiltrative diseases such as amyloidosis, sarcoidosis, hemochromatosis, hypertrophic cardiomyo-pathies, storage diseases such as Fabry’s disease and all cardiac tumors which need a definitive tissue diagnoses.

Technique

Access, risk and complications
Endomyocardial biopsies of the right ventricle (RV) were exclusively done via an internal jugular approach however with the availability of the 105 cm long flexible bioptomes a femoral vein approach came into vogue with comparable safety and complication profile. The right internal jugular is preferred due to ease of access into the RV. The left ventricle is often accessed safely via the femoral artery. Table 1 shows a variety of approaches and the corresponding incidence of complication rates.8-13 In the femoral vein approach using a guiding sheath reduces the rate of complications. Protection of the tricuspid valve is also achieved by introducing the bioptome in a closed position via a guiding sheath beyond the valve.12 The brachial vein approach as compared to the internal jugular approach appeared to be superior in terms of the complication rates. In > 1100 cases studied the complication rate appeared to be 0% with the brachial vein access.14 Guiding sheaths that are steerable may be positioned beyond the tricuspid valve into the right ventricle and used to steer the bioptome in the desired direction to obtain samples. This approach avoids the removal of samples from the same site leading to fibrosis of the area especially in the transplanted hearts. Some of the acute risks such as pneumothorax are decreased by a high internal jugular approach. In patients with a preexistent left bundle-branch block there is a risk of a transient complete heart block which very rarely requires temporary pacing. Permenant pacing is often not required. Administration of lidocaine intravenously into the internal jugular vein can result in Horner syndrome, vocal cord paresis, and rarely in diaphragmatic weakness. These complications are noted to last only until the lidocaine is effective.

Table 1

Imaging
Endomyocardial biopsy is almost always done under fluoroscopy.  However echocardiography can be used to entirely guide the procedure or may be used in combination with fluoroscopy. The advantage of using echo guidance is reduction in risk of radiation exposure to patient and operator. Duration of the entire procedure is comparable, and can be performed at the bedside.  In a study comparing fluoroscopic versus echo guided protocols the presence of epicardium or pericardium suggests that inadvertent sampling from the right ventricular free wall cannot be avoided despite more accurate placement of bioptome.  Echo guided EMB in transplant patients who have undergone bicaval anastomosis should be with caution as the superior vena suture line in not well visualized by echocardiography and if any resistance is felt passing the bioptome via the internal jugular immediate use of fluoroscopy is recommended.15,16
In a more recent study real time 3D echocardiography (RT3DE) was noted to be a superior technique that was safe in which both the sheath tip and the bioptome tip could be well visualized. In about half the patients the sheath had to be repositioned when visualized under RT3DE due to suboptimal sheath orientation under fluorography.17 In a third of the cases, the bioptome tip had to be repositioned just prior to sampling as imaging using RT3DE indicated the biopsy would be obtained from an unsatisfactory site if only fluorography was used.

Site
Most endomyocardial biopsies are performed on the right ventricle. For a few indications the left ventricle is used and if performed on both ventricles the yield of diagnosis may be optimized.18,19 Both RV and LV biopsies have been considered safe if performed by experienced operators.  In the study by Yilmaz et al the diagnostic yield for myocarditis was not improved if specific sites were targeted using gadolinium enhancement on cardiac magnetic resonance imaging.  More evidence now exists for a trans radial approach to procure specimens from the left ventricle.20 
In a study of 189 patients  on whom echo-guided right ventricular endomyocardial biopsies were performed a 4% complication rate of acute procedural thrombus formation in the right ventricle was noted.  On retrospective analysis it appeared that this was particularly in patients with a history of thrombosis.  Immediate thrombus aspiration and post procedure anticoagulation were the treatments used in the study . In this setting a role for procedural echocardiography would be beneficial for early detection and treatment.21 Left ventricular biopsy is an important diagnostic tool for pathological processes limited to the left ventricle22 In a more recent retrospective study spanning 28 years, left ventricular biopsy was found to be a safe procedure with very low transient complications and especially useful in diagnosing myocarditis. The diagnostic accuracy was equal for RVEMB and LVEMB in detecting infiltrative diseases.23

Indications and Uses
EMB is not recommended for routine use of new-onset heart failure as per the guidelines.24-27 Benefit of the procedure is limited to specific clinical scenarios being most beneficial where the testing has a high positive predictive value.   EMB is recommended only in two scenarios as a class 1 recommendation: 1) patients who have fulminant heart failure with unexplained new-onset heart failure of less than two weeks’ duration associated with a normal-sized or dilated left ventricle with hemodynamic compromise.  2) Patients who have early AV block, arrhythmias, or refractory heart failure with unexplained new-onset HF of two weeks to three months’ duration associated with a dilated left ventricle and new ventricular arrhythmias, Mobitz type II second-degree atrioventricular (AV) block, third-degree AV block, or failure to respond to usual care within one to two weeks.

 

Use of EMB in Special Situations

Cardiac Transplantation:
Acute cellular rejection: In acute rejection surveillance status post cardiac transplantation EMB is the standard of care for lack of any specific non-invasive /laboratory tests.  Cytokine profiling is not recommended for the first 60 days post cardiac transplantation .28,29
Antibody mediated rejection: EMB specimens are used for complement activation as a screen for vascular rejection and to guide therapy.  It is also used for assessing inflammatory burden for prognostication purposes.30,31

Viral Myocarditis and Inflammatory cardiomyopathy
The technique recommended for confirmation of inflammatory diseases currently is EMB.  A number of systemic inflammatory diseases such as systemic lupus erythematosus, sarcoidosis, systemic sclerosis, Churg-Strauss disease and rheumatoid arthritis affect the myocardium leading to inflammation , arrhythmias , sudden cardiac death and end stage heart failure if not effectively diagnosed and treated.32,33 Tissue diagnosis of viral infections is best obtained in endomyocardial biopsy specimen.  EMB is useful in determining the etiology, especially with the advent of the polymerase chain reaction for diagnoses of a wide variety of diseases including cytomegalovirus, adenovirus, Coxsackie virus and Borrelia infections.34-36 The sensitivity of routine fluoroscopically guided EMB for focal diseases such as lymphocytic myocarditis is low. Hence foci of myocardial disease detected by intracardiac electrograms increase the sensitivity of diagnosis.37 

Hypertrophic cardiomyopathy
In primary hypertrophic cardiomyopathy EMB is not required for diagnosis but if it is secondary to conditions like Fabry’s disease / amyloidosis / mitochondrial or other musculosketetal diseases patients would benefit from a definitive diagnosis to guide therapy and for prognostication.  The decision to perform endomyocardial biopsies should be based on clinical suspicion where testing has a high positive predictive value .38-42

Infiltrative Diseases
In hemochromatosis the role of EMB is vital for diagnosis but more recently it is also complemented by weighted T2 imaging used to detect iron deposits in the heart and also to monitor response to therapy .43
Diagnosis of cardiac amyloidosis requires tissue biopsy confirmation by endomyocardial biopsy and further biochemical characterization of the type of amyloidosis for guiding therapy.  The pathophysiology and treatment will then require further testing correlated with clinical findings.  Imaging techniques will complement the use of EMB in diagnosis and prognosis.44 -47
Focal infiltrative diseases such as cardiac sarcoidosis have less diagnostic yield by EMB. Hence use of intracardiac electrograms increase the sensitivity of diagnosis.  In a voltage guided EMB study of 40 biopsies done in 11 patients, 19 studies had electrogram voltage <5 mV, all of which resulted in histopathologic abnormality (100% specificity and positive predictive value).  Voltage less than 5 mV had substantially higher sensitivity (70% vs. 26%) and negative predictive value (62%) than 1.5 mV.  This is suggestive of better diagnostic yield in suspected cases.37   In sarcoidosis only about 25% have positive routine cardiac biopsies for non-caseating  granulomas. The patients with a positive endomyocardial biopsy have a poorer prognosis.19 

Cardiomyopathy secondary to drug therapy for Connective Tissue Diseases
Hydroxychloroquine used in the treatment of systemic lupus erythematosus, rheumatoid arthritis, and other connective tissue disorders has a spectrum of toxicity including cardiomyopathy.  Endomyocardial biopsy in addition to cardiac MRI is a valuable tool to confirm the diagnosis of hydroxychloroquine-induced cardiomyopathy.48 

Arrhythmogenic right ventricular cardiomyopathy
In arrhythmogenic right ventricular cardiomyopathy (ARVC) diagnostic yield may be increased by using 3D electroanatomic voltage mapping to identify affected areas but such diagnostic patterns may not be present in early disease despite increased risk for sudden cardiac death.  Hence EMB may have a role in identifying potential tissue biomarkers that arise early in the disease process and occur diffusely throughout the myocardium.49,50 Myocardium from 11 patients with ARVC  of whom 8 were positive for desmosomal mutations were compared by Asimaki et al with myocardium obtained from 10 subjects with no clinical or pathological evidence of heart disease at autopsy to serve as controls.49  All ARVC patients showed a significant reduction in immunoreactive levels for plakoglobin .  Other desmosomal proteins showed variable changes, but the nondesmosomal adhesion molecule N-cadherin showed consistently normal levels in ARVC patients.  Plakoglobin levels were tested in hypertrophic / dilated / ischemic cardiomyopathies and found to be within normal levels suggesting that plakoglobin is specific for ARVC .  The studies by Azimaki et al showed a sensitivity of 91%, a specificity of 82%, a positive predictive value of 83%, and a negative predictive value of 90%. Analysis of conventional EMB using such biomarkers could improve diagnostic value.49,50

Chemotherapy induced cardiomyopathy and diagnosis of cardiac tumors
Role of endomyocardial biopsies in chemotherapy-induced cardiotoxicity is not well substantiated.  Investigation of cardiac masses need correlation of clinical presentation with histopathology to define management hence endomyocardial biopsies play a role.   Use of molecular markers helps to obtain such information.51-52 However, risk of embolization precludes biopsies of tumors that have characteristics of a myxoma. So endomyocardial biopsy should be performed on myxomas only if adequate information cannot be obtained by non-invasive methods. 
Transesophageal/intracardiac echo or cardiac MRI guidance is recommended when performing biopsies on cardiac tumors.24,53

Detection of molecular markers in EMB specimens for prognosis
Additionally correlation studies of circulating versus tissue biomarkers are being used to help understand pathophysiology of diseases at the molecular level.  Most recently a study on role of Galectin-3 in fibrosis in heart failure secondary to hypertension showed that cardiac and systemic Gal-3 is increased but does not correlate with markers of fibrosis  such as collagen types I (C-terminal propeptide of procollagen type I, PICP) and III (N-terminal propeptide of procollagen type III, PIIINP).54 Detailed pathological evaluation of endomyocardial biopsy specimens showed a poorer overall  and cardiovascular mortality in the lymphocytic  versus eosinophilic types of myocarditis.  Presence of fibrosis was linked to the overall and cardiovascular mortality in patients with a diagnosis of borderline myocarditis by biopsy .55


Discussion

The role of EMB in diagnosis and prognosis has always been debated in the context of risk versus benefit analysis. A large retrospective analysis of a single–center data showed that 25.5% of EMBs provided a diagnostic result, and 22.6% of EMBs changed clinical course. This study evaluated 851 patients who underwent EMB from 2000-2009.56  The highlight of this work was that the analyses paralleled the 14 clinical scenarios addressed in the 2007 AHA/ACC/ESC guidelines. The study showed a benefit for acute onset unexplained cardiomyopathy. 
Interestingly utility was demonstrated for rare clinical scenarios such as suspected infiltrative disease and in the management of rare clinical scenarios, such as suspected hypersensitivity myocarditis, anthracycline cardiomyopathy, cardiac tumors, and arrhythmogenic right ventricular dysplasia/cardiomyopathy.54 The evolution of EMB techniques and instrumentation through the years have made the test safe when performed by experienced operators.  At present EMB still remains the test of choice for rejection surveillance in cardiac transplant recipients.

Conclusions

The use of EMB is not just limited to diagnosis of acute rejection in transplant patients. As delineated in this review there are multiple uses for this technique in diagnoses of infiltrative, hypertrophic, storage and metabolic diseases of the heart. Though detection of these cardiomyopathies may be achieved with existing powerful imaging techniques like cardiac MRI the actual tissue diagnosis is warranted for further characterization and to arrive at a strategic treatment plan most notably in diseases like amyloidosis, hemochromatosis, myocarditis of different etiologies. Such tissue characterization is useful to guide therapy and to monitor treatment efficacy. Additionally localization of molecular markers and specific diagnoses of cardiac tumors is entirely by EMB at this time especially in cases of primary cardiac lymphomas. 

Future Directions

The future of EMB will be most possibly in specific clinical scenarios where there is a high index of suspicion. It will likely be used in conjunction with other imaging techniques to confer safety and specificity. With the advent of molecular markers and need for their localization in tissues EMB would serve as an important technique to aid in diagnosis /prognosis and to formulate specific treatment plans.

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