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Tricuspid Valve Injury After Heart Transplantation Due toEndomyocardial Biopsy: An Analysis of 3550 Biopsies

A.I. Fiorelli, G.H.B. Coelho, V.D. Aiello, L.A. Benvenuti, J.F. Palazzo, V.P. Santos Júnior, B. Canizares,R.R. Dias, and N.A.G. Stolf

ABSTRACT

Introduction. Tricuspid regurgitation (TR) is the most commonly valvular dysfunctionfound after heart transplantation (HTx). It may be related to endomyocardial biopsy(EMB) performed for allograft rejection surveillance.Objective. This investigation evaluated the presence of tricuspid valve tissue fragmentsobtained during routine EMB performed after HTx and its possible effect on short-termand long-term hemodynamic status.Method. This single-center review included prospectively collected and retrospectivelyanalyzed data. From 1985 to 2010, 417 patients underwent 3550 EMB after HTx. Allmyocardial specimens were reviewed to identify the presence of tricuspid valve tissue by 2observers initially and in doubtful cases by a third observer. The echocardiographic andhemodynamic parameters were only considered for valvular functional damage analysis incases of tricuspid tissue inadvertently removed during EMB.Results. The 417 HTx patients to 3550 EMB, including 17,550 myocardial specimens.Tricuspid valve tissue was observed in 12 (2.9%) patients corresponding to 0.07% of theremoved fragments. The echocardiographic and hemodynamic parameters of thesepatients before versus after the biopsy showed increased TR in 2 cases (2/12; 16.7%)quantified as moderate without progression in the long term. Only the right atrial pressureshowed a significant increase (P � .0420) after tricuspid injury; however, the worsening ofthe functional class was not significant enough in any of the subjects. Thus, surgicalintervention was not required.Conclusions. Histological evidence of chordal tissue in EMB specimens is a real-worldproblem of relatively low frequency. Traumatic tricuspid valve injury due to EMB rarelyleads to severe valvular regurgitation; only a minority of patients develop significantclinical symptoms. Hemodynamic and echocardiographic alterations are also less often

observed in most patients.

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TRICUSPID regurgitation (TR), the most common val-vular dysfunction after heart transplantation (HTx),

has been related to multiple etiologic factors: pulmonaryarterial hypertension, surgical technique, right ventricleanatomic distortion, allograft ischemia time, acute cellularrejection, and endomyocardial biopsy (EMB).1–3 Despite arelative frequency of TR incidence, severe degree dysfunc-tion occurs only occasionally, nevertheless with a strongnegative impact on patient survival or life quality.3 Anchocardiography study showed the TR prevalence after

Tx to vary from 65%–85%. This valvular dysfunction

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

Transplantation Proceedings, 44, 2479–2482 (2012)

hich tends to increase over time may aggravate the clinicalicture producing symptoms of the right ventricular dys-unction and survival.4–7 This investigation had for its mainbjective to examine the role of EMB on the genesis of TRfter HTx using analysis of tissue fragments obtained from

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

Address reprint requests to Alfredo I. Fiorelli, Rua Morgado deMateus 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.2012.07.024

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2480 FIORELLI, COELHO, AIELLO ET AL

biopsies performed routinely to evaluate the presence ofrejection. We analyzed its possible role to affect long-termclinical status and hemodynamic performance.

METHOD

This single-center review included prospectively collected andretrospectively analyzed data from 1985 to 2010. The 417 HTxpatients had a mean age of 42.6 � 15.1 years (range, 3–69) due toterminal heart failure from the following etiologies: 35.7% (149)idiopathic, 29.6% (123) ischemic; 25.6% (107) Chagas disease;4.3% (18) rheumatic; 1.7% (7) restrictive; 1.2% (5) right ventricu-lar arrhythmogenic dysplasia; 0.7% (3) retransplantation; and 1.2%(5) other causes. During this period we performed 3550 EMB(8.5 � 10.2 EMB/patient) for rejection evaluation with withdrawalof 3 to 8 fragments at each session (5.1 � 2.9) resulting in 17,550myocardial specimens. All specimens were initially reviewed by 2independent observers to identify the possible presence of tricuspidvalve tissue or chordae tendineae; doubtful cases were reviewed bya third observer. Chordae tendineae were characterized as ananatomic structure formed by thread-like bands of fibrous tissuewith myocardium fixed at one end. Primarily, histological rejectionstatus was graded in accordance with the criteria of the Interna-tional Society for Heart and Lung Transplantation,8 only speci-mens with tricuspid valve tissue were examined herein.

The echocardiographic and hemodynamic parameters were re-viewed only for patients in whom the tricuspid tissue was inadver-tently removed during the EMB. Right-sided heart catheterizationwas routinely performed at EMB using a Swan-Ganz catheter tomeasure hemodynamic variables. At the beginning of the HTxprogramme rejection control was performed solely by EMB obey-ing a predefined traditional schedule; later the frequency of thisprocedure was decreased due to the introduction of Gallium-67scintigraphy for the screening method.9 All procedures wereperformed by a single surgical team. The TR degree by two-dimensional echocardiography was stratified as proposed byMügge et al.10

Statistical Analysis

The data analysis was not able to apply an extensive stratifiedstatistical analysis because fortunately the number of EMB con-taining tricuspid tissue was small. Continuous variables werecompared using an unpaired Student t-test; categorical variableswere compared using Fisher exact test. Data are presented as meanvalues and standard deviations with P � .05 considered to besignificant.

RESULTS

From 1985 to 2010, we analyzed the EMB per patient per5-year period as follows: 29.7, 6.2, 4.0, 3.9, 2.6, and 3.1. Weobserved a more than 10-fold significant reduction in EMBper patient due to Gallium-67 scintigraphy for screening.Preferential venous access to the right ventricle EMB was apercutaneous puncture of the right internal jugular veinfollowed by the contralateral jugular vein and femoral andsubclavian vein. Fluoroscopy was used in most cases(97.6%) for bioptome guidance; however, 84 EMB (2.4%)were performed using two-dimensional echocardiography.Analysis of 17,550 myocardial specimens removed from

3550 EMB revealed tricuspid valve tissue in only 12 (2.9%)

atients corresponding to 0.07% of removed fragments.he primary cardiomyopathies of affected patients were

diopathic (n � 5);, Chagas disease (n � 4), and ischemicn � 3).

The echocardiographic and hemodynamic parameterstudied before and after the EMB considered culpable areescribed in Table 1. There was an important aggravationf TR quantified as severe in only 2 cases (cases 2 and 6),evertheless without long-term progression. These 2 casesontained tricuspid valve chordae tendineae fragments.one of these 12 cases had a significant deterioration of the

unctional class. For this reason, surgical interventions wereot used.

DISCUSSION

Percutaneous transvenous EMB remains the gold standardmethod to diagnose cardiac rejection after HTx because itallows early identification of histopathologic alterationsbefore allograft dysfunction.8 This therapeutic interventionfor rejection is effective, achieving a greater chance of abenign evolution. However, EMB is an invasive procedurewith potential morbidity of ventricular perforation, pneu-mothorax, and tricuspid valve injury.1,2,5 TR is the mostfrequent valvular dysfunction after HTx with multifactorialetiology, including increased pulmonary arterial pressure,right ventricle anatomic distortion, tricuspid annulus geom-etry alterations, asynchronous contraction between the al-lograft and recipient atrial remnant, and damage at thetricuspid subvalvular apparatus.4,6,11

Various noninvasive methods have sought to replace theEMB: however, all present limitations due to lack ofspecificity and sensitivity; none of them is able to overcomethe advantages of histological analysis.12,13 In our institu-ion we developed a rigid protocol to investigate theenefits of Gallium-67 scintigraphy as a screening methodo indicate the need for EMB.9,13 The use of this method

has resulted in favorable outcomes, with an approximately10-fold reduction among EMB without prejudice for allo-graft rejection control. EMB is indicated preferentially forpatients with positive Gallium-67 concentrations at scintig-raphy.

TR is the most common valvular abnormality after HTxwith a prevalence and severity greater than that in thegeneral population. In some cases it may be linked directlyto EMB because this procedure is invasive and not totallyfree of risks.1,5,11 Fortunately, TR with severe clinicalsymptoms occurs in a significant minority of patients whodevelop debilitating clinical symptoms of right-sided heartfailure necessitating tricuspid valve surgery. In the presentinvestigation the 2 patients who developed severe TR didnot experience right heart failure and did not requiresurgical intervention.

Several studies have demonstrated the TR prevalence toincrease over the time after HTx from 5% at 1 year to 50%at 4 years of follow-up.2–4,14,15 Most studies have reported

a close correlation between TR incidence and EMB num-

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TRICUSPID VALVE INJURY 2481

ber but not all are supported by histopathologic studies.15 Asmaller number of publications of long term series, haveidentified the risk of tricuspid injury produced byEMB,1,2,11 showing the EMB technique, bioptome type,

nd team experience to be important factors in theevelopment of the valvular lesion. The operator mustave certainty that bioptome tip is leaning against the rightall of the interventricular septum to avoid inadvertent

emoval of tricuspid tissue.8

EMB may produce or aggravate TR by accidental re-moval of tricuspid tissue that worsens the clinical evolutionof the recipient. Many investigations have reporting TR tobe caused by iatrogenic injury during EMB in 6%–32% ofcases.1,3,10 EMB number, technical aspects, bioptome type,method of bioptome guidance, and access route are amongthe main factors responsible for TR. Mielniczuk et al

Table 1. Echocardiographic and Hemodynamic ParametersTissue

Case No. EMB* Rejection TR† MR†

1 Before 0R 0 0After 0R 1 0

2 Before*** 1R 2 1After 2R 3 1

3 Before 1R 1 0After 2R 1 0

4 Before 2R 0 1After 1R 1 1

5 Before 1R 1 0After 0R 1 0

6 Before‡ 2R 2 2After 2R 3 3

7 Before 0R 1 0After 1R 1 0

8 Before 1R 1 1After 2R 1 1

9 Before 1R 1 1After 1R 1 1

0 Before 2R 0 1After 1R 1 1

1 Before 1R 1 1After 2R 1 1

2 Before 1R 0 0After 1R 0 0

ean � SDBefore 0R � 2 0.9 � 0.8 0.6 � 0.7

1R � 72R � 3

After 0R � 2 1.3 � 1.0 0.7 � 1.01R � 52R � 5

P — 0.4064 1.0000

Abbreviations: DH, Discrete hypertrophy; FE, Ejection fraction; LV, left ventriclright atrium pressure; RV, right ventricle; SH, severe hypertrophy; SD, standerejection.

*All EMB were guided by fluoroscopy.†Valvular regurgitation degree quantified as follows: 0, absent; 1, mild; 2, m‡Tricuspid valve chordae tendineae was found at myocardium specimens.

observed a significant correlation between occurrence of

ricuspid valve injury and EMB number performed peratient.2 The authors identified the presence of chordaeendineae in 47% of the patients with significant TR asonfirmed by echocardiogram, showing the important notef EMB in the genesis of this valvular injury. This investi-ation had as a starting point a myocardial histologicalnalysis only among patients selected due to clinical signs ofevere TR. Our study had another focus: to identify tricus-id valve injury risk among all myocardial fragments recov-red by EMB at a single center to determine its real clinicalignificance.

Saraiva et al published their experience of 2217 EMB forejection control using preferentially femoral access93.5%). They observed tricuspid valve tissue in 19 patients10.8%), which was 0.9% of the procedures.1 Only 2

patients developed mild TR without increased pulmonary

re and After the EMB Considered as Culpable for Tricuspidption

RV LV FE %RAP

mm Hg PASP

N N 56 6 29N N 60 8 31SH N 59 5 31SH N 60 13 29DH N 63 6 28DH N 59 9 30DH N 65 7 27DH N 65 9 29DH N 61 3 31DH N 64 6 32SH N 56 8 36SH N 56 12 25N N 65 8 36N N 64 7 35DH N 67 10 29DH N 50 8 31DH N 60 10 31DH N 55 9 30N N 66 11 30N N 62 8 28DH N 65 11 28DH N 59 10 31N N 61 9 35N N 74 11 34

N � 4 N � 10 61.4 � 3.9 6.9 � 2.1 31.3 � 3.5DH � 6SH � 2N � 4 N � 10 61.3 � 6.7 9.2 � 2.3 30.7 � 2.9DH � 6SH � 2

— — 0.9660 0.0420 0.6690

mitral regurgitation; N, normal; PASP, pulmonary artery systolic pressure; RAP,tion; 0R, no rejection; 1R, mild rejection; 2R, moderate rejection; 3R, severe

e; 3, severe.

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artery systolic pressure. In this investigation, the preferen-

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2482 FIORELLI, COELHO, AIELLO ET AL

tial access was the right internal jugular vein (97.6%) andthe incidence of valvular lesion was small, perhaps due tothe mode of advancing the bioptome through the tricuspidvalve using a longer sheath. The data showed that theprocedure performed in experienced hands was extremelysafe.

Two-dimensional echocardiography has advantages overother imaging modalities allowing the performance of EMBat the bedside. The method provides real-time images withadequate spatial orientation and anatomic definition.16,17,18

Two-dimensional echocardiography to guide EMB showeda protective effect on TR development in our experience.No myocardium fragment obtained from EMB guided bytwo-dimensional echocardiography (84/3550, 2.3%) showedtricuspid valve tissue withdrawn inadvertently.

Only 2 patients (cases 2 and 6) showed severe TR and atendency toward an increase in right atrial pressure. One ofthem (case 6, Chagas disease) died at 6 years after HTx dueto infection; anatomopathological examination of the heartconfirmed a chordae tendineae rupture that had occurred 4years prior. There were no significant differences in rightpulmonary systolic pressure obtained from right-sided heartcatheterization or echocardiographic parameters at thetime of EMB. Only the right atrial pressure showed asignificant increase (P � .0420) after tricuspid injury with-

ut clinical expression. Chagas disease reactivation afterTx was not a risk factor to promote tricuspid valve injury;

t was not possible to identify any risk for cardiomyopathy.eevanandam et al proposed prophylactic tricuspid valvennuloplasty in the allograft to minimize deleterious effectsf valvular regurgitation with good results.18 The methodas also introduced into our group because anatomicistortion of the tricuspid annulus has a high impact factoror TR development.19 This procedure was useful to con-

tain the TR, hindering neither the realization of EMB norincreasing the risk of injury to the tricuspid valve.

The study limitations included the investigation beingperformed at a single center with predominant venousaccess. The data were collected prospectively and analyzedretrospectively.

In conclusion, histological evidence of chordal tissueamong EMB specimens is a real-world problem, albeit witha relatively low frequency. Traumatic tricuspid valve injurydue to EMB rarely leads to severe valvular regurgitation.Only a significant minority of patients develop clinicalsymptoms. Hemodynamic and echocardiographic altera-tions are also less often observed in most affected patients.

ACKNOWLEDGMENT

We acknowledge the Pathology Department of the Heart Institute

of Sao Paulo University, Sao Paulo, Brazil.

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donor tricuspid annuloplasty in orthotopic bicaval heart transplan-tation. Transplant Proc 39:2527, 2007