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Comparative Analysis of the Complications of 5347 EndomyocardialBiopsies Applied to Patients After Heart Transplantation and WithCardiomyopathies: A Single-center Study

A.I. Fiorelli, L. Benvenuti, V. Aielo, A.Q. Coelho, J.F. Palazzo, R. Rossener, A.C.P. Barreto, C. Mady,F. Bacal, E. Bocchi, and N.A.G. Stolf

ABSTRACT

Introduction. Endomyocardial biopsy (EMB) plays an important role in allograft sur-veillance to screen an acute rejection episode after heart transplantation (HT), to diagnosean unknown cause of cardiomyopathies (CMP) or to reveal a cardiac tumor. However, theprocedure is not risk free.Objective. The main objective of this research was to describe our experience with EMBduring the last 33 years comparing surgical risk between HT versus no-HT patients.Method. We analyzed retrospectively the data of 5347 EMBs performed from 1978 to2011 (33 years). For surveillance of acute rejection episodes after HT we performed 3564(66.7%), whereas 1777 (33.2%) for CMP diagnosis, and 6 (1.0%) for cardiac tumoridentification.Results. The main complications due to EMB were divided into 2 groups to facilitateanalysis: major complications associated with potential death risk, and minor complica-tions. The variables that showed a significant difference in the HT group were as follows:tricuspid Injury (.0490) and coronary fistula (.0000). Among the no-HT cohort they wereinsufficient fragment (.0000), major complications (.0000) and total complications (.0000).Conclusions. EMB can be accomplished with a low risk of complications and higheffectiveness to diagnose CMP and rejection after HT. However, the risk is great amongpatients with CMP due to their anatomic characteristics. Children also constitute a riskgroup for EMB due to their small size in addition to the heart disease. The risk of injury

to the tricuspid valve was higher among the HT group.

ENDOMYOCARDIAL biopsy (EMB) is an invasiveprocedure to obtain myocardial tissue samples for

histological and other analyses. This procedure plays animportant role in allograft surveillance to detect an acuterejection episode after heart transplantation (HT), in thediagnosis of an unknown cause of cardiomyopathy(CMP) or to uncover a cardiac tumor.1–3 EMB allowsdentification of morphological alterations before allo-raft ventricular dysfunction. The method is used forlinical follow-up after HT. Multiple noninvasive meth-ds have arisen to detect an acute rejection episode;owever, none of them substitute EMB as the goldtandard examination for the diagnosis of this immuno-

ogic phenomenon inherent to HT.2

© 2012 by Elsevier Inc. All rights reserved.360 Park Avenue South, New York, NY 10010-1710

Transplantation Proceedings, 44, 2473–2478 (2012)

After 1980, the surgical risk of EMB decreased substan-tially because it became a routine examination that wassystematized with the use of flexible bioptomes.4–6 EMBusually employs fluoroscopy to guide the bioptome tiptoward the right interventricular septum. More recently,two-dimensional echocardiography has allowed examina-tion of patients confined to bed or as a hybrid method toobtain myocardial samples from specific locations.7–9 Even

From the Heart Institute of Sao Paulo University MedicalSchool, Sao Paulo, Brazil.

Address reprint requests to Alfredo Inácio Fiorelli, Rua Mor-gado de Mateus 126/81, Sao Paulo/SP, Brazil, CEP: 04015-050.

E-mail: fiorelliai@uol.com.br

0041-1345/–see front matterhttp://dx.doi.org/10.1016/j.transproceed.2012.07.023

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2474 FIORELLI, BENVENUTI, AIELO ET AL

in experienced hands EMB is not free of complications.Therefore, its indications must be well defined based on arigid protocol.5,6 The most feared complication during the

MB is ventricular perforation followed by cardiac tampon-de due to a high risk of death if diagnosis and treatmentre not performed promptly. Other minor complicationsay be more frequent; nevertheless, they do not require

urgical intervention. The main objective of this researchas to describe our experience with EMB over the last 33ears comparing the surgical risk between patients with HTersus CMP.

MATERIALS AND METHOD

We analyzed retrospectively the data of 5347 EMBs from 1978 to2011 (33 years). To analyze acute rejection surveillance after HTwe performed 3564 biopsies (66.7%) whereas 1777 (33.2%), wereperformed for diagnosis of CMP of unknown etiology, and 6(1.0%) for cardiac tumor identification. Fluoroscopy was used asthe guidance method for the bioptome in 5254 (98.3%) examina-tions, two-dimensional echocardiography was used in 87 (1.6%),and a hybrid method of fluoroscopy associated with two-dimensional echocardiography was used in 6 (1.0%) patients todiagnose intracardiac masses. The total number of EMBs guided bytwo-dimensional echocardiography was 93 (1.7%), including 69(74.1%) in critically ill patients performed at the bedside. In 10(10.8%) subjects the procedure was accomplished simultaneouslywith fluoroscopy for safety’s sake during the learning period; in 8(8.6%) patients, fluoroscopy was impractical; in 6 (6.5%), weadopted a hybrid method to diagnose an intracardiac tumor. Themain indications for these examinations were rejection control(n � 64; 68.8%) CMP diagnosis before HT (n � 12; 12.9%);ejection control myocarditis diagnosis in the presence of cardio-enic shock (n � 11; 11.8%); and diagnosis of right chamber tumorn � 6; 6.5%).

The right internal jugular vein was the route used for bioptomentroduction in 5169 (96.7%) procedures, followed by the leftnternal jugular vein (n � 32; 0.6%), femoral (n � 29; 0.5%), or

subclavian approach (n � 15; 0.3%). In 102 (1.9%) proceduresthere was no registry of the access route. All EMBs were performedby the same surgical team. The procedure was performed withoutpremedication in adult patients and with general anesthesia orsedation among children and young adolescents. All patients werecontinuously monitored during the EMB by cardiac rhythm andperipheral oxygen saturation. The children with dilated CMPunderwent intraoperative mechanical ventilation because of thehigher surgical risk. The surgical technique for cardiac transplan-tation, biatrial or bicaval, as well as tricuspid valve prophylacticannuloplasty on the heart donor did not hamper the realization ofEMB guided either by fluoroscopy or two-dimensional echocardi-ography. Heterotopic HT required an operator with more experi-ence; metal clips placed at the superior vena caval anastomosisfacilitated identification of the access into the allograft.

When necessary, the right chamber pressures and the cardiacoutput were easily obtained after the conclusion of the EMB withthe introduction of the Swan-Ganz catheter through the samevenous access. After EMB the patients stayed in clinical observa-tion from 2 to 6 hours in the day clinic or intensive care unit.Complications resulting from the procedure were classified as

major or minor according to the risk of death.

Statistical Analysis

Categorical variables were presented as absolute values and per-centages with chi-square tests to compare HT and no-HT groups.The level of statistical significance was P � .05.

RESULTS

The main complications that occurred among 5347 EMBswere divided into 2 groups: major, those with potential riskof death, and minor complications (Table 1). Both atrialand ventricular arrhythmias occurred for a short time anddid not require cardioversion. EMB indications for CMPand histopathologic findings observed in HT are describedin Table 2.

DISCUSSION

Advances in myocarditis treatment and CMP have beenbased on viral identification, histological analysis, and im-munohistochemistry or biomolecular analysis of myocardialfragments obtained from EMBs. Recent studies have dem-onstrated the beneficial effects of biopsy-based treatment inrelation to immunosuppressive or antiviral therapies.1,10,11

Thus, EMB has become the gold standard to establish theetiologic diagnosis of myocarditis and CMP of indetermi-nate origin because sometimes the data of anamnesis andnoninvasive examinations are not efficiently specific toelucidate the nature of the cardiac disease.

EMB has acquired wider dissemination and greatersafety to be incorporated into routine follow-up after HTfor acute allograft rejection surveillance. It has a highsensitivity and specificity for the diagnosis of acute cellularrejection.2

EMB was introduced in our country in 1962 initially usingtransthoracic access and in 1967 were used classic percuta-neous venous access.12,13 To facilitate the analysis of re-sults, we divided the complications into major and minor,and the patients into HT or CMP diagnosis. The risk ofmajor complications was relatively low (0.3%) comparedwith other centers considering that were included patientsfrom various groups of ages and forms of heart disease. Theevents considered to be major complications were categor-ical variables with occurrences leading the patient to risk ofdeath. They appeared in such a low frequency that did notpermit a multivariate analysis to detect risk factors for theevents.

The frequency of complications, especially minimal, isvariable in the literature. They depend on the extent andquality of information, the included heart diseases, and theoperative technique. Nevertheless, major complicationsgenerally considered by the majority of studies range be-tween 0.09% and 5.2%, and minor complications between0.2% and 6.9%. Table 3 shows the largest experiences withEMB described recently in the literature.

Cardiac perforation is one of the most terrible complica-tions due to the death risk up to 0.31%. Among 3048 EMBs,Holzmann et al reported 0.08% of cases with pericardial

tamponade that were solved only with pericardiocentesis;

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ENDOMYOCARDIAL BIOPSY 2475

there was no death.14 They attributed the favorable resultso the exclusive use of femoral access and to the team’sxperience. Other large series, also using the femoralpproach, were not exempt from deaths probably becausehe procedure is invasive and other factors play importantoles.5,15 Pophal et al described a 5.2% incidence of cardiac

perforation and 0.6% mortality rate among 154 childrenundergoing EMB, considering the age to be a risk factor(5). During this investigation, 7 (0.39%) patients withdilated CMP experienced cardiac perforation, including 4(0.23%) with favorable resolutions through pericardiocen-tesis and 3 (0.17%) who needed urgent cardiac surgery.Nevertheless, 2 (0.26%) subjects died as a result of theheart injury and pre-existent ventricular dysfunction.5 Oneof the patients (0.06%) who died was a 1-year-old child with

Table 1. Main Complications Observed Due to EM

HT - 3564 EMB

Scope Echo

Biopsy No. 3500* 64inor complicationsLocal pain 54 (1.5%) 1 (1.2%)Insufficient material 32 (0.9%) 0Puncture failure 39 (1.1%) 2 (2.6%)Change of the puncturesite

26 (0.7%) 2 (2.6%)

Tricuspid injury 12 (0.3%) 0Arterial puncture -hematoma

11 (0.3%) 1 (1.2%)

Prolonged VA† 4 (0.1%) 0Vasovagal reaction† 3 (0.08%) 0Prolonged atrial fibrillation† 1 (0.02%) 0Coronary fistula 1 (0.02%) 0Arteriovenous fistula 1 (0.02%) 0Superior vena cava injury 1 (0.02%) 0Guide-wire intointravascular

1 (0.02%) 0

Neurological complications 0 0Temporary AV block 0 0

Total 186 (5.3%) 6 (7.6%)Major complications

Hemopericardium‡ 1 (0.02%) 0Cardiac tamponade§ 1 (0.02%) 0Hemothorax/pneumothorax 1 (0.02%) 0Ventricular fibrillation 0 0Permanent AV block 0 0Septicemia after biopsy� 1 (0.02%)# 0Mortality 1 (0.02%) 0

Total 5 (0.1%) 0Total of complications 191 (5.5%) 6 (7.6%)

Abbreviations: AV, atrioventricular; Echo, echocardiography; Scope, fluorosc*3 patients had heterotopic heart transplantation.†Required clinical treatment.‡No surgery.§Surgical treatment.�Aspergillum infection.¶2 deaths.#1 death.

severe dilated CMP. v

Thinning of the right ventricular wall due to cardiachamber dilation at CMP is one factor responsible for anncreased risk of perforation during EMB. None of theatients with HT experienced a ventricular perforationuring EMB, perhaps because of the cardioprotective ef-ects of right ventricular hypertrophy or surgical adhesions.n this present study, some with long-surviving HT recipi-nts underwent more than 30 EMBs without complications,howing that the procedure can be repeated with safety.he literature reports incidences of serious complicationsuring EMB that vary from 0.3% to 0.7% due to the

nherent invasiveness of the method.4,6,15,16 Thus, indica-ion for EMB must be well considered to have the capacityo change the patient’s therapy or prognosis.

The frequency of posttransplantation surveillance EMB

omparative Analysis Between the HT and No-HT

no-HT - 1783 EMB

Total P

CMP Tumor

Scope Echo Hybrid

1754 23 6 5347

3 (1.8%) 0 0 98 (1.8%) .36402 (2.3%) 0 0 74 (1.3%) .00009 (1.7%) 1 (11.1%) 0 71 (1.3%) —1 (1.4%) 1 (11.1%) 0 29 (0.2%) .6360

1 (0.05%) 0 0 12 (0.02%) .04906 (0.3%) 1 (11.1%) 0 19 (0.4%) .8670

3 (1.7%) 0 0 4 (0.07%) .59505 (0.3%) 0 0 3 (0.06%) .08101 (0.05%) 0 0 2 (0.04%) —

0 0 0 1 (0.02%) .00000 0 0 1 (0.02%) —

1 (0.05%) 0 0 2 (0.04%) —0 0 0 1 (0.02%) —

0 0 0 0 —0 0 0 0 —

3 (10.3%) 0 0 318 (5.9%)

3 (0.2%) 0 0 4 (0.07%) .07704 (0.2%)¶ 0 0 5 (0.09%) .02703 (0.2%)# 0 0 4 (0.07%) .07701 (0.05%) 0 0 1 (0.02%) —

0 0 0 0 —0 0 0 1 (0.02%) —

3 (0.2%) 0 0 4 (0.07%) .07704 (0.8%) 0 0 19 (0.3%) .00007 (11.1%) 0 0 337 (6.3%) .0000

nd VA, ventricular arrhythmia.

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2476 FIORELLI, BENVENUTI, AIELO ET AL

at our Institute, EMBs were performed with greaterfrequency. The introduction of heart scintigraphy usingGallium-67 as a triage method which has a high specificityand sensitivity to rejection has decreased the EMB number

Table 2. EMB Indication to CMP and Histopathologic FindingsObserved in HT

No. Percentage

CMP - 1783Idiopathic 1115 62.4%Myocarditis 335 18.7%Chagas disease 80 5.2%Insufficient material 42 2.3%Amyloidosis 37 2.1%Peripartum 37 2.1%Endomyocardial fibrosis 24 1.3%Acquired immune deficiency syndrome 15 0.8%Uremic 10 0.6%Sarcoidosis 9 0.5%Viral 9 0.5%Tumor 6 0.3%Hemochromatosis 5 0.3%Alcoholic 3 0.4%Scleroderma 1 0.1%Marfan syndrome 1 0.1%Other 96 5.3%

HT - 3564Rejection degree OR 1327 37.2%Rejection degree 1R 913 25.6%Rejection degree 2R 781 21.9%Rejection degree 3R 81 2.3%Acute antibody-mediated rejection – 0 51 3.0%Acute antibody-mediated rejection – 1 38 1.1%Rejection regression 209 5.7%Chagas disease reactivation 37 1.0%Insufficient material 32 0.9%Other 53 1.5%

Table 3. Experience Wit

Author Year Center Biopsy N

Deckers 1992 Single 546Hiramitsu 1998 Multi† 19,964

ophal 1999 Single 1000Felker 1999 Single 323Holzmann 2008 Single 3048

ilmaz 2010 Multi¶ 755uang 2010 Single 439araiva 2011 Single 2117iorelli 2011 Single 5347

Abbreviation: Multi, multicenter.*Values calculated from data of the manuscript.†213 centers.‡Only ventricular perforation.§Analysis of the 154 children.�Values of the different eras.¶2 centers, without HT.#

Left ventricle biopsy.**Right ventricle biopsy.

ramatically; EMB is now indicated only when this exami-ation is considered to be positive.17

Left bundle-branch block and left ventricular dimensionsabove 65 mm have been considered as risk factors fordeveloping ventricular arrhythmias as well as temporary orpermanent, complete atrioventricular block requiring car-diac pacing.3,4 We did not observe these complications; only

patient with dilated CMP developed ventricular fibrilla-ion and needed defibrillation.

Multiple samples of the right interventricular septumhould be withdrawn during EMB because acute cellularejection is not evenly distributed in the transplanted heart.his principle is equally applicable to CMP; the inflamma-

ory reaction is not homogeneously distributed throughouthe heart. It has been demonstrated that the acute rejectionalse-negative rate decreases from 5%–2% when the num-er of fragments obtained during EMB increases from 3 to, respectively.16,17

Contaminated material may represent a potential sourceof infection during EMB, causing greater impact when thepatient is more susceptible to infectious agents as occurswith the use of immunosuppression.18,19 In 1998, Aziz et aleported a 2.1% incidence of bacteremia and endocarditis,s confirmed by laboratory investigations, after EMB re-uiring prolonged antibiotic therapy.20 Rosenheim et al, in

2006, published a case of the nosocomial transmission ofhepatitis B virus associated with EMB.21 In this series, 1healthy patient after a routine EMB for the surveillance ofan acute rejection episode developed a more severe clinicalsituation with a generalized infection pattern followed byrespiratory insufficiency, fulminant shock, and death within24 hours. The necropsy detected the presence of Aspergillusinfection as the etiologic agent responsible for the death.Most probably, the infection source was contaminatedmaterial.

B for Different Authors

Complications (%)

Mortality (%)Minor Major

6.9* 1.2* 0.4— 0.7‡ 0.05— 5.2§ 0.6§

0.320.2–5.5� 0.12–0� 0

2.9#–5.1** 0.6#–0.8** 00.23 — 00.7 0.09 05.9 0.3 0.07

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ENDOMYOCARDIAL BIOPSY 2477

A coronary fistula to the right ventricle, an uncommoncomplication, generally shows a benign evolution, as de-scribed in a case report.5 One woman with a HT in ourseries displayed an asymptomatic right coronary arteryfistula diagnosed by routine cinecoronariography. Anotherpatient experienced arteriovenous fistula at the puncturesite of the right internal jugular vein, which was small andasymptomatic.

In 2010, Yilmaz et al noted that EMB performed in bothventricles was safe and increased the efficiency of thediagnosis of CMP procedure.22 However, preferential bi-opsy in regions showing late gadolinium enhancement oncardiovascular magnetic resonance did not increase thepositivity of myocarditis diagnoses. Our experience with leftventricular EMB is small, not exceeding 5 cases.

Two-dimensional echocardiography used to guide theprocedure has been used for critical patients who cannot goto the catheterization room and require a procedure per-formed at the bedside. This portable method is also usefulfor patients with contraindications to radiation or for thediagnosis of intracardiac masses. It provides real-time im-ages with adequate spatial orientation and anatomic defi-nition. Han et al reported 3 cases (3.3%) of ventricularperforation with echocardiographic guided EMB via afemoral approach.23 Recently, we have published our expe-rience with the method emphasizing the reproducibility andsafety of the technique with no major complications8,9

(Table 1).The EMB has been suggested to be one of the factors

responsible for development of tricuspid regurgitation afterHT. In 2005, Mielniczuk et al showed tricuspid valvechordal tissue in 9 (9.2%) of 205 EMBs.24 Similar observa-ions but with different incidences has been reported byther authors.6,22,25–27 These histopathologic findings have

variable clinical significance; it depends on the extent ofvalvular injury. After review of all biopsy materials by 2observers, we noted a small incidence of tricuspid tissue; itwas higher among HT than non-HT group perhaps becausethe tricuspid annulus and right ventricular cavity are smallerin HT facilitating the withdrawal of valvular tissue duringthe EMB.

In conclusion, EMB can be performed with a low risk ofcomplications and high effectiveness for the diagnosis ofCMP or rejection after HT. However, the risk is greateramong patients with CMP due to anatomic characteristics.Children also constitute a risk group for EMB due to thesmall size in addition to the heart disease. The risk of injuryto the tricuspid valve was higher among HT patients.

ACKNOWLEDGMENTS

We thank medical student Marcelo Fiorelli Alexandrino da Silvafor his help in data collection.

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