Author + information
- Received January 28, 2014
- Revision received February 24, 2014
- Accepted March 7, 2014
- Published online October 1, 2014.
- Jackson J. Liang, DO∗,
- Virginia B. Hebl, MD†,
- Christopher V. DeSimone, MD, PhD†,
- Malini Madhavan, MBBS†,
- Sudip Nanda, MBBS†,
- Suraj Kapa, MD†,
- Joseph J. Maleszewski, MD‡,
- William D. Edwards, MD‡,
- Guy Reeder, MD†,
- Leslie T. Cooper, MD† and
- Samuel J. Asirvatham, MD†,§∗ ()
- ∗Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
- †Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
- ‡Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota
- §Department of Pediatrics and Adolescent Medicine Mayo Clinic, Rochester, Minnesota
- ↵∗Reprint requests and correspondence:
Dr. Samuel J. Asirvatham, Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905.
Objectives The aim of this study was to describe the method used to perform electrogram-guided EMB and correlate electrogram characteristics with pathological and clinical outcomes.
Background Endomyocardial biopsy (EMB) is valuable in determining the underlying etiology of a cardiomyopathy. The sensitivity, however, for focal disorders, such as lymphocytic myocarditis and cardiac sarcoidosis (CS), is low. The sensitivity of routine fluoroscopically guided EMB is low. Abnormal intracardiac electrograms are seen at sites of myocardial disease. However, the exact value of electrogram-guided EMB is unknown.
Methods We report 11 patients who underwent electrogram-guided EMB for evaluation of myocarditis and CS.
Results Of 40 total biopsy specimens taken from 11 patients, 19 had electrogram voltage <5 mV, all of which resulted in histopathologic abnormality (100% specificity and positive predictive value). A voltage amplitude cutoff value of 5 mV had substantially higher sensitivity (70% vs. 26%) and negative predictive value (62%) than 1.5 mV. Abnormal electrogram appearance at biopsy site had good sensitivity (67%) and specificity (92%) in predicting abnormal myocardium. Normal signals with voltage >5 mV signified normal myocardium with no significant diagnostic yield. Biopsy results guided therapy in all patients, including 5 with active myocarditis or CS, all of whom subsequently received immunosuppressive therapy. There were no procedural complications.
Conclusions In patients with suspected myocarditis or CS, electrogram-guided EMB targeting sites with abnormal or low-amplitude electrograms may increase the diagnostic yield for detecting abnormal pathological findings.
Endomyocardial biopsy (EMB) is a useful tool to define the etiology of heart failure when a specific diagnosis is suspected and if establishing a histopathologic diagnosis would influence therapy (1,2). A major drawback of standard EMB with fluoroscopic or intracardiac echocardiographic guidance is the low sensitivity and high rate of false negatives, particularly in cardiomyopathies such as cardiac sarcoidosis (CS), lymphocytic myocarditis, and arrhythmogenic right ventricular cardiomyopathy (ARVC), which often only involve focal areas of the endomyocardium (3). Additionally, affected myocardium may closely approximate or involve critical cardiac structures, such as the conduction system or tricuspid valve cords, which may lead to complications such as ventricular and supraventricular arrhythmias, conduction abnormalities, or tricuspid regurgitation if biopsied (4).
The utility of electroanatomic mapping to guide EMB in the evaluation of suspected CS, ARVC, and lymphocytic myocarditis has been described in case reports (5–8) but has not been well studied. We have been using electrogram guidance at our institution to target diseased tissue and therefore increase the diagnostic yield of EMB in certain suspected disease processes. As shown in Table 1, we hypothesized that areas with normal electrograms will unlikely harbor abnormal pathology because they consist of normal myocardium. Meanwhile, we hypothesized that abnormal and low-voltage electrograms will signify underlying scar tissue and that areas with fragmented signals without isoelectric segments (noted in either sinus or ventricular paced rhythm) are likely to show active disease. We believe that targeting sites with abnormal electrograms and fragmented signals with EMB will result in the highest diagnostic yield.
We correlated pre-biopsy electrogram characteristics with histopathologic findings and clinical outcomes in 11 sequential patients undergoing electrogram-guided EMB at our institution. Approval to conduct this study was granted by the Mayo Clinic Institutional Review Board.
Mapping and biopsy procedure
The general approach of electrogram-guided EMB at our institution involves establishing 8-F access in the right femoral vein, through which a Blazer 4-mm mapping catheter (Boston Scientific, Natick, Massachusetts) may be inserted. When ablation is planned following EMB, an ablation catheter is introduced instead. Access via 7-F catheter is established in the right internal jugular vein (preferably) or a groin access site in preparation for bioptome insertion. Under fluoroscopic guidance, areas of fractionated low-voltage electrograms are identified. Next, with the mapping catheter held at a site with abnormal electrograms to target, a flexible, modified bioptome (Cordis Corporation, Bridgewater, New Jersey) is advanced using fluoroscopy (Figure 1) and intracardiac echocardiography. Multiple biopsies are taken as close to the catheter tip as possible from areas with abnormal electrograms. Additionally, specimens are taken from standard biopsy sites (e.g., mid-ventricular septum or apical septum) with the catheter positioned nearby to determine the electrogram characteristics in these locations. Where abnormal electrograms are identified along the right ventricular (RV) free wall, biopsies are not taken from these sites because of the concern for possible cardiac perforation. After biopsy is performed, intracardiac ultrasound is used to evaluate for the presence of post-procedural pericardial effusion. Due to the concern for bleeding complications with EMB, care is taken to assure that the patient does not experience anticoagulation during the procedure. For those patients in whom ablation is also planned, intravenous heparin is commenced only after pericardial effusion has been ruled out following EMB.
Definitions of abnormal versus normal electrogram voltage and morphology
Prior studies proposed a bipolar electrogram voltage amplitude of 1.5 mV to be the lower limit of normal in the RV and <0.5 mV to suggest the presence of densely scarred endocardium (9–11). For this study, we arbitrarily defined electrogram amplitude as being “normal voltage” when >5 mV, “low voltage” when <5 mV, and “very low voltage” when <1.5 mV.
We considered the morphology of RV bipolar endocardial electrograms to be normal when there was a single deflection with duration <70 ms. We defined the morphology of electrograms to be “abnormal” if they were either double/split potentials (2 clearly separated deflections separated by at least 10 ms) or fractionated (polyphasic, primarily low-amplitude deflection) in appearance (Figure 2).
Biopsy specimens were reviewed by cardiovascular pathologists (J.J.M. and W.D.E.). Results of pathological analysis were considered to be “abnormal” if they showed active myocardial inflammation or fibrosis. Although nonspecific, we considered biopsy specimens with fibrosis as being “abnormal” for analysis because despite not being diagnostic for active myocarditis, in this cohort of high-risk patients with suspected inflammation, fibrosis may have represented healed myocarditis or other cardiomyopathic processes and thus may be clinically significant. Biopsies demonstrating normal myocardium or only mild to moderate myocyte hypertrophy were considered to be “normal.”
Eleven patients underwent electrogram-guided EMB for evaluation of suspected myocarditis or CS, and 41 biopsy specimens were submitted for histopathologic evaluation. The corresponding electrogram for 1 specimen was not saved; therefore, it was excluded from the analysis.
Electrogram amplitude was <5 mV at 19 of 40 biopsy sites (47.5%) and <1.5 mV at 7 of 40 sites (17.5%). Electrograms were considered “abnormal” in appearance in 19 of 40 biopsy sites (47.5%). Overall, 27 of 40 biopsy specimens (67.5%) resulted in abnormal pathology, consistent with active myocarditis or fibrosis. Sensitivity and specificity as well as positive and negative predictive values based on voltage and/or abnormal electrogram appearance, were calculated and are reported in Table 2.
Very low (<1.5 mV) and low (<5 mV) electrogram amplitudes had 100% specificity and positive predictive value for identifying abnormal myocardial tissue. Increasing the voltage cutoff from 1.5 mV to 5 mV decreased the sensitivity (70.4% to 25.9%) and negative predictive value (61.9% to 39.4%). The presence of abnormal electrogram appearance had a high specificity (92.3%) and positive predictive value (94.7%) for detecting abnormal myocardium. Of the 4 biopsy specimens (11%) taken at sites with severe fragmentation without a discernible electrogram, all exhibited histopathologic abnormality (2 showed active inflammation, 1 showed healed myocarditis, and 1 showed severe focal fibrosis).
A diagnosis of active myocarditis or CS was determined by electrogram-guided EMB in 5 patients (Online Appendix), and treatment was directed by electrogram-guided EMB results in all 11 patients. The relationships between electrogram characteristics and EMB results for all patients are documented in Table 3. Figure 3 shows the correlation between electrogram and biopsy histopathology in 1 patient in whom electrogram-guided biopsy led to the diagnosis of a mixed-disease process consistent with both CS and giant cell myocarditis (GCM).
In the 6 patients without active inflammation on microscopic evaluation, immunosuppression was withheld. In 3 of these patients without evidence of active inflammation, no fragmented signals were identified and all 3 remain off immunosuppression to date. In 1 patient with fragmented electrogram signals, focal interstitial fibrosis and features of healed myocarditis were identified histopathologically, and immunosuppression was withheld. Three years later she was diagnosed clinically and radiographically with CS and commenced on immunosuppression.
There were no complications directly caused by electrogram-guided EMB in our series. However, 1 patient returned to the hospital after discharge with dyspnea and hypotension and was found to have anemia, a small right hemothorax, and a hemodynamically insignificant hemopericardium. Nevertheless, the complication was attributed to cardiac resynchronization therapy–defibrillator upgrade rather than the EMB procedure itself because she had undergone placement of right atrial and coronary sinus leads after her uncomplicated EMB. She was managed medically, discharged after 3 days, and had no further complications.
Although currently most commonly used for rejection monitoring after cardiac transplantation, EMB is an important diagnostic procedure in the evaluation of selected patients with cardiomyopathy (1–3). Bennett et al. (12) recently reported their single-center 851-patient experience with EMB for unexplained heart failure, finding that EMB provided a diagnostic result in 25.5% of cases and changed clinical course in 22.6%. All of our patients fit “clinical scenario #3” from the 2007 American Heart Association/American College of Cardiology Foundation/European Society of Cardiology scientific statement (1), which states that EMB is reasonable to perform in patients with unexplained heart failure of more than 3 months’ duration when associated with dilated left ventricle (LV) and new ventricular arrhythmias, high-grade atrioventricular (AV) block, or failure to respond to normal heart failure therapy within 1 to 2 weeks. EMB is particularly helpful to diagnose conditions for which management differs dramatically depending on the underlying process (i.e., immunosuppression for CS, lymphocytic myocarditis, and GCM vs. screening of family members for ARVC).
Limitations of contemporary EMB
One of the major limitations of EMB is its low sensitivity in detection of certain disorders that do not diffusely involve the myocardium. Sensitivity with EMB in detection of lymphocytic myocarditis, which varies depending on duration of disease, may be as low as 10% to 35% (1,13,14). For CS, EMB sensitivity ranges from 20% to 30% (1,15), whereas sensitivity tends to be much higher (80% to 85%) with fulminant GCM (16). In a study by Kandolin et al. (17), which examined 72 patients under age 55 years who underwent pacemaker implantation for initially unexplained high-grade AV block, EMB later established the diagnoses of CS and GCM in 14 (19%) and 4 (6%) patients, respectively. The 25% positive biopsy rate in these patients with unexplained high-grade AV block suggests that EMB should be reasonable in similarly presenting patients (18). Due to the low sensitivity of contemporary EMB, previous recommendations had suggested that only positive findings be considered diagnostic when lymphocytic myocarditis was suspected (19). Repeating EMB after negative results when suspicion for underlying process may increase the sensitivity, as has been reported with GCM (68% with single biopsy vs. 93% after up to 2 repeat procedures) (20). This, however, places patients at risk for procedural complications associated with each additional EMB.
Electrogram guidance to increase diagnostic yield
EMB using an electrogram-guided approach may be beneficial in diagnosing certain disease processes. Areas of active inflammation or chronic fibrosis will have abnormal electrogram morphology and amplitude, allowing the operator to avoid biopsying normal myocardium, potentially increasing diagnostic yield. Furthermore, when biopsies taken from areas of low-voltage electrograms only demonstrate fibrosis without active inflammation, active disease can be more confidently ruled out, allowing for aggressive immunosuppression to be withheld. Although the addition of electrogram guidance increases procedural and fluoroscopic time associated with EMB, it may increase the sensitivity and specificity of EMB, potentially curtailing the need for repeated biopsy procedures to establish a diagnosis in certain patients.
Successful EMB guided by electroanatomic mapping has been previously described in the diagnosis of ARVC (5,6) and isolated CS (7). Recently, Seizer et al. (8) described the diagnosis of acute lymphocytic myocarditis in a patient using site-directed EMB at the location of an abnormal electrogram in the LV via transseptal puncture, whereas RV septal biopsies from sites of normal electrograms were unremarkable in the same patient. CS and ARVC (particularly in early stages) may have focal cardiac involvement and electrogram guidance may identify low-voltage areas of myocardium that have been replaced by fibrous or adipose tissue, allowing for targeted biopsy. CS classically involves the base of the heart; therefore, standard mid-ventricular or apical biopsies may be unrevealing. Although it is technically more difficult to biopsy at the base (particularly near the outflow tract), the presence of basal fractionated signals should prompt the operator to target these areas for EMB. Chimenti and Frustaci (21) recently reported that RV EMB alone had a high diagnostic yield (96.5%) when RV involvement was seen on pre-EMB imaging. However, when abnormalities were limited to the LV on pre-EMB imaging, they found that LV EMB was safe when performed by skilled providers and significantly increased diagnostic yield compared with RV biopsy alone (97.8% vs. 53%). Therefore, pre-procedural imaging to localize areas of inflammation should be used as an adjunctive tool because it may prompt consideration for electrogram-guided biopsy of the LV or even epicardium.
Marchlinski et al. (11) described bipolar voltage amplitude to be >1.44 mV in 95% of all RV signals recorded during sinus rhythm using the Carto system in patients with drug-refractory ventricular tachycardia. Based on their findings, an RV bipolar electrogram voltage amplitude of >1.5 mV has since been widely accepted to be “normal,” whereas an amplitude <0.5 mV has been correlated with “densely scarred” endomyocardium (9,10). However, the presence of abnormal myocardial pathology in 20 of 33 biopsy specimens (60.6%) at sites of electrogram voltage >1.5 mV in our series suggests that abnormal myocardium can exist in areas of apparently higher voltage. Due to the low sensitivity and negative predictive value of such a low voltage cutoff, an amplitude of <5 mV and/or the presence of abnormal electrogram appearance may more accurately predict abnormal myocardium at sites where EMB should be targeted. All biopsies taken at areas with low-voltage electrograms in our series exhibited histopathologic abnormality, suggesting that electrogram guidance is particularly helpful in identifying areas that would be low yield and unlikely to harbor myocardium with active inflammation or fibrosis. Although positive electrogram-guided biopsy findings demonstrating active myocarditis or CS is helpful in confirming a diagnosis, negative results do not completely rule out active disease.
Safety of electrogram-guided EMB
With contemporary EMB, complications related to sheath insertion and biopsy have been reported to occur in 1% to 6% of cases (1,4). The risk of cardiac perforation (0.2%) and vascular (1.2%) or embolic (0.4%) complications from catheter manipulation during electrophysiological studies is low (22). Additionally, electrograms characteristic of the conduction system identify sites to avoid with the bioptome, thus minimizing electrical complications, including arrhythmia and conduction abnormalities that have been previously reported to occur in 1% of cases with contemporary EMB (4).
We acknowledge that one major limitation of our study was the small sample size, which makes the results difficult to extrapolate to a larger population. Despite this, we believe we were able to show “proof of concept” of a promising electrogram-guided biopsy technique. We hope our findings will encourage other investigators to conduct larger population and prospective studies to determine the true benefit of electrogram guidance for EMB. Although we attempted to achieve optimal approximation between the ablation catheter and bioptome, we had to make sure that there was no direct contact between the ablation catheter and bioptome because that would result in noise, impairing electrogram interpretation. As such, it is possible that the region from which the biopsy was taken may not have corresponded exactly with the area from which the signal was recorded because small differences in location between the bioptome and ablation catheter may account for differences in location, particularly in focal disease processes and along the border zones of abnormal tissues. Factors such as movement artifact and filtering may cause bipolar electrograms to appear fractionated in the absence of underlying diseased myocardium (23). Additionally, although bipolar recording is not as sensitive to remote activity compared with unipolar recording, remote activation may still interfere.
We described 11 patients who successfully underwent electrogram-guided EMB without complications. In each patient, areas with abnormal electrograms were targeted for biopsy where present. In 5 patients, biopsies taken at areas with fragmented signal revealed active myocarditis, prompting treatment with aggressive immunosuppressive therapy. Areas with normal electrogram appearance and amplitude >5 mV likely harbor normal myocardium, and biopsies should not be taken from these locations when the intent is to detect myocardial inflammation or fibrosis.
Normal voltage and electrogram appearance do not significantly yield results to identify abnormal myocardium. As a result, randomly acquired, fluoroscopically guided EMB where such sites may be sampled had suboptimal diagnostic yield. Further prospective studies, preferably randomized between electrogram-guided versus routine RV-septal biopsies, are needed to demonstrate the exact value for electrogram-guided biopsy.
Dr. Asirvatham has received honoraria/consulting fees from Abiomed, Atricure, Biotronik, Biosense Webster, Boston Scientific, Medtronic, Spectranetics, St. Jude, Sanofi-Aventis, Wolters Kluwer, and Elsevier and is a copatent holder and may receive future royalties from Aegis, ATP, Nevro, Sanovas, and Sorin Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- arrhythmogenic right ventricular cardiomyopathy
- cardiac sarcoidosis
- endomyocardial biopsy
- giant cell myocarditis
- left ventricular/ventricle
- right ventricular/ventricle
- Received January 28, 2014.
- Revision received February 24, 2014.
- Accepted March 7, 2014.
- American College of Cardiology Foundation
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