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Endomyocardial Biopsy as Risk Factor in the Development of Tricuspid Insufficiency After Heart Transplantation
Endomyocardial Biopsy as Risk Factor in the Development of Tricuspid Insufficiency After Heart Transplantation A.I. Fiorelli, G.H.B. Coelho, J.L. Oliveira, Jr, V.D. Aiello, L.A. Benvenuti, A. Santos, A. Chi, A. Tallans, M.L. Igushi, F. Bacal, E.A. Bocchi, and N.A.G. Stolf
ABSTRACT Objective. Endomyocardial biopsy (EMB), which is used to monitor for rejection, may cause tricuspid regurgitation (TR) after orthotopic heart transplantation (OHT). The purpose of this investigation was to examine the occurrence of tricuspid valve tissue in myocardial specimens obtained by routine EMB performed after OHT. Patients and Methods. From January 2000 to July 2008, 125 of the patients who underwent OHT survived more than 1 month. Their follow-up varied from 1 month to 8.5 years (mean, 5.1 ⫾ 3.7 years). EMB was the gold standard examination and myocardial scintigraphy with gallium served as a screen to routinely monitor rejection. Results. Each of 428 EMB including 4 to 7 fragments, totaling 1715 fragments, were reviewed for this study. The number of EMB per patient varied from 3 to 8 (mean, 4.6 ⫾ 3.5). Histopathological analysis of these fragments showed tricuspid tissue in 4 patients (3.2%), among whom only 1 showed aggravation of TR. Conclusions. EMB remains the standard method to diagnose rejection after OLT. It can be performed with low risk. Reducing the number of EMB using gallium myocardial scintigraphy or other alternative methods as well as adoption of special care during the biopsy can significantly minimize trauma to the tricuspid valve.
T
RICUSPID REGURGITATION (TR) is a frequent complication after orthotopic heart transplantation (OHT). The etiology is multifactorial; however, a biopsyinduced flail leaflet is one of the most important mechanisms. Endomyocardial biopsy (EMB) is used to monitor for rejection. It may be one of the causes of TR. The presence of chordal tissue in EMB from heart transplant cases shows an intimate association with TR; it may lead to serious hemodynamic abnormalities. Various studies have retrospectively analyzed the occurrence of tricuspid tissue in EMB using echocardiographic findings of severe or mild TR.1–3 The purpose of this study was to investigate the occurrence of tricuspid valve tissue in myocardial specimens obtained by routine EMB performed after OHT for evaluation of rejection.
PATIENTS AND METHODS From January 2000 to July 2008, the 125 patients who underwent OHT and survived for more than 1 month were selected for this investigation. Their follow-up varied from 1 month to 8.5 years (mean, 5.1 ⫾ 3.7 years). All transplantations were performed by 2 © 2009 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 41, 935–937 (2009)
principal surgeons; we retrospectively analyzed information regarding the surgical technique. EMBs were performed seeking to follow a predefined classic schedule; however, after the patients acquired clinical stability we routinly used gallium scintigraphy as the screening method. Only 3 cardiac surgeons performed all EMBs via the percutaneous right internal jugular vein approach with a short sheath of 9 French ⫻ 12 cm in length into the right atrium. A long sheath passing through the tricuspid valve was less often used. The bioptome was threaded and directed under fluoroscopy toward the right interventricular septum to blind take 4 to 6 fragments at each procedure. When the EBM was performed in the intensive care unit, the bioptome was guided by echocardiography. For this study 2 observers who worked independently reviewed all EMBs using optical microscopy; uncertain cases were evaluated by a third professional. For cases that found tricuspid tissue, we reviewed the 2-dimensional and color Doppler echocardiographic From the Heart Institute, São Paulo University School of Medicine, São Paulo, Brazil. Address reprint requests to Alfredo I. Fiorelli, Rua Morgado de Mateus 126/81, São Paulo/SP, Brazil, CEP: 0415-050. E-mail: [email protected] 0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2009.02.011 935
936
FIORELLI, COELHO, OLIVEIRA ET AL
studies before and after EMB to evaluate tricuspid valve function. The TR degree was quantified as proposed by Mügge et al4 in 1990. The data analysis was not able to stratify the cases, because the number of biopsies with the lesion was small. Continuous data are presented as mean values ⫾ standard deviations.
RESULTS
During the investigation, 125 patients underwent OHT, including 22 patients (17.6%) with an atrial anastomosis and a bicaval anastomosis with prophylactic donor heart tricuspid annuloplasty 86 (68.8%) versus without annuloplasty in 17 (13.6%). The technique was determined by surgeon preference and the transplantation era. There were 428 EBMs performed for rejection control, each one including 4 to 7 fragments, totaling 1715 fragments, all of which were reviewed for this study. The number of EMB per patient varied from 3 to 8 (mean, 4.6 ⫾ 3.5). Meticulous histopathological analysis of these fragments identified tricuspid tissue in 4 patients (3.2%), among whom only 1 experienced aggravation of TR (case 1). Table 1 shows the echocardiographic findings. DISCUSSION
Severe intraoperative TR predicts poor late survival following OHT. Fortunately, severe valvar regurgitation does not occur in many cases. Several groups have applied prophylactic tricuspid annuloplasty of the donor heart, because severe late complications and reduced survival may arise from TR development.5–7 TR is the most common valvular abnormality after OHT with an extremely variable prevalence between 25% and 45%.1,5 Multiple factors play important roles in this process such as regurgitation classification, operative technique, follow-up time, pulmonary artery pressure, allograft behavior, right ventricular function, frequency/severity of rejection episodes, female donor, donor age, weight mismatch, ischemia time, and, not the least important, the number and technique of the EMB.1,3,5 EMB remains the gold standard to monitor and diagnose allograft rejection after OHT. It may have a direct impact on the development of TR, although the strength of this association is controversial.1–3 Most patients with evide-
nce of significant TR after chordal tissue biopsy continue clinically asymptomatic, showing no significant change in hemodynamics. Moreover, there are many reports demonstrating a strong relationship between the number of EMB performed per patient and the development of flail tricuspid leaflets or chordal rupture. Nguyen et al1 in 2005 strongly suggested a cutoff of ⬍31 EMB to reduce the risk for severe TR. Mielniczuk et al2 in 2005 reported 19/98 (19.4%) OHT patients displayed significant TR by echocardiogram during a 6-year follow-up. Among 205 biopsies in 19 patients (mean 10.7 ⫾ 4.2), chordal tissue was found in 9 (9.2%). Similar results have been noted by other authors.1–3 Probably if all the pieces of the biopsy were analyzed, the incidence would have been higher, because many patients remain asymptomatic. In the present study, the incidence of traumatic injury to the tricuspid valve secondary to a biopsy was small. Perhaps some factors significantly contributed to it: the biopsies by a surgeon; the reliance on myocardial scintigraphy with gallium as a screening method to reduce the number of EMB; and the use of a long sheath that could reach the right ventricle through the tricuspid valve. This approach has been applied at our institution for several years because it has reducted the routine EMB by ⬎50%.7–9 At the beginning of our experience in 1985, findings of tricuspid tissue in biopsies were more frequent, because we were passing through the learning curve. Furthermore, these observations confirmed the involvement of other risk factors in the genesis of TR; they were equally or more important than EMB alone. Only 1 patient (1/385; 0.3%) who was not part of this research developed severe tricuspid insufficiency requiring a valve replacement at 4 years after OHT. In conclusion, EMB remains the standard method to diagnose rejection after heart transplantation. It can be performed with low risk. A reduced number of EMB using screening with gallium myocardial scintigraphy or other alternative methods as well the adoption of special care during the biopsy can significantly minimize trauma to the tricuspid valve.
Table 1. Echocardiographic Changes Before and After Tricuspid Chordal Tissue Disruption From the Routine EMB Case 1 Before
No. of EMB Tricuspid Mitral Pulmonary Aortic RV LV EF LV (%) PAPs (mm Hg)
2 2 0 0 SH Normal 56 36
Case 2 After
3 3 2 1 SH Normal 56 25
Case 3
Before
After
1 0 0 0 Normal Normal 65 36
1 0 0 0 Normal Normal 64 35
Before
1 1 0 0 DH Normal 67 29
Case 4 After
1 1 0 0 DH Normal 50 31
Before
After
0 0 0 0 Normal Normal 61 35
0 0 0 0 Normal Normal 74 34
RV, right ventricle; LV, left ventricle; EF LV, ejection fraction left ventricle; PAPs, pulmonary arterial systolic pressure; SH, severe hypocontractility; DH, discrete hypocontractility. Valvar insufficiency degree was quantified as: 0 ⫽ absent; 1 ⫽ mild; 2 ⫽ moderate; and 3 ⫽ severe.
ENDOMYOCARDIAL BIOPSY AS RISK FACTOR
REFERENCES 1. Nguyen V, Cantarovich M, Cecere R, et al: Tricuspid regurgitation after cardiac transplantation: how many biopsies are too many? J Heart Lung Transplant 24(7 suppl):S227, 2005 2. Mielniczuk L, Haddad H, Davies RA, et al: Tricuspid Valve chordal tissue in endomyocardial biopsy specimens of patients with significant tricuspid regurgitation. J Heart Lung Transplant 24: 1586, 2005 3. Sahar G, Stamler A, Erez E, et al: Etiological factors influencing the development of atrioventricular valve incompetence after heart transplantation. Transplant Proc 29:2675, 1997 4. Mügge A, Daniel WG, Herrmann G, et al: Quantification of tricuspid regurgitation by Doppler color flow mapping after cardiac transplantation. Am J Cardiol 66:884, 1990
937 5. Jeevanandam V, Russell H, Mather P, et al: Donor tricuspid annuloplasty during orthotopic heart transplantation: long-term results of a prospective controlled study. Ann Thorac Surg 82:2089, 2006 6. Anderson CA, Shernan SK, Leacche M, et al: Severity of intraoperative tricuspid regurgitation predicts poor late survival following cardiac transplantation. Ann Thorac Surg 78:1635, 2004 7. Fiorelli AI, Stolf NA, Abreu Filho CA, et al: Prophylactic donor tricuspid annuloplasty in orthotopic bicaval heart transplantation. Transplant Proc 39:2527, 2007 8. Meneguetti JC, Camargo EE, Soares J Jr, et al: Gallium-67 imaging in human heart transplantation: correlation with endomyocardial biopsy. J Heart Transplant 6:171, 1987 9. Camargo PR, Mazzieri R, Snitcowsky R, et al: Correlation between gallium-67 imaging and endomyocardial biopsy in children with severe dilated cardiomyopathy. Int J Cardiol 28:293, 1990
ABSTRACT Objective. Endomyocardial biopsy (EMB), which is used to monitor for rejection, may cause tricuspid regurgitation (TR) after orthotopic heart transplantation (OHT). The purpose of this investigation was to examine the occurrence of tricuspid valve tissue in myocardial specimens obtained by routine EMB performed after OHT. Patients and Methods. From January 2000 to July 2008, 125 of the patients who underwent OHT survived more than 1 month. Their follow-up varied from 1 month to 8.5 years (mean, 5.1 ⫾ 3.7 years). EMB was the gold standard examination and myocardial scintigraphy with gallium served as a screen to routinely monitor rejection. Results. Each of 428 EMB including 4 to 7 fragments, totaling 1715 fragments, were reviewed for this study. The number of EMB per patient varied from 3 to 8 (mean, 4.6 ⫾ 3.5). Histopathological analysis of these fragments showed tricuspid tissue in 4 patients (3.2%), among whom only 1 showed aggravation of TR. Conclusions. EMB remains the standard method to diagnose rejection after OLT. It can be performed with low risk. Reducing the number of EMB using gallium myocardial scintigraphy or other alternative methods as well as adoption of special care during the biopsy can significantly minimize trauma to the tricuspid valve.
T
RICUSPID REGURGITATION (TR) is a frequent complication after orthotopic heart transplantation (OHT). The etiology is multifactorial; however, a biopsyinduced flail leaflet is one of the most important mechanisms. Endomyocardial biopsy (EMB) is used to monitor for rejection. It may be one of the causes of TR. The presence of chordal tissue in EMB from heart transplant cases shows an intimate association with TR; it may lead to serious hemodynamic abnormalities. Various studies have retrospectively analyzed the occurrence of tricuspid tissue in EMB using echocardiographic findings of severe or mild TR.1–3 The purpose of this study was to investigate the occurrence of tricuspid valve tissue in myocardial specimens obtained by routine EMB performed after OHT for evaluation of rejection.
PATIENTS AND METHODS From January 2000 to July 2008, the 125 patients who underwent OHT and survived for more than 1 month were selected for this investigation. Their follow-up varied from 1 month to 8.5 years (mean, 5.1 ⫾ 3.7 years). All transplantations were performed by 2 © 2009 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 41, 935–937 (2009)
principal surgeons; we retrospectively analyzed information regarding the surgical technique. EMBs were performed seeking to follow a predefined classic schedule; however, after the patients acquired clinical stability we routinly used gallium scintigraphy as the screening method. Only 3 cardiac surgeons performed all EMBs via the percutaneous right internal jugular vein approach with a short sheath of 9 French ⫻ 12 cm in length into the right atrium. A long sheath passing through the tricuspid valve was less often used. The bioptome was threaded and directed under fluoroscopy toward the right interventricular septum to blind take 4 to 6 fragments at each procedure. When the EBM was performed in the intensive care unit, the bioptome was guided by echocardiography. For this study 2 observers who worked independently reviewed all EMBs using optical microscopy; uncertain cases were evaluated by a third professional. For cases that found tricuspid tissue, we reviewed the 2-dimensional and color Doppler echocardiographic From the Heart Institute, São Paulo University School of Medicine, São Paulo, Brazil. Address reprint requests to Alfredo I. Fiorelli, Rua Morgado de Mateus 126/81, São Paulo/SP, Brazil, CEP: 0415-050. E-mail: [email protected] 0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2009.02.011 935
936
FIORELLI, COELHO, OLIVEIRA ET AL
studies before and after EMB to evaluate tricuspid valve function. The TR degree was quantified as proposed by Mügge et al4 in 1990. The data analysis was not able to stratify the cases, because the number of biopsies with the lesion was small. Continuous data are presented as mean values ⫾ standard deviations.
RESULTS
During the investigation, 125 patients underwent OHT, including 22 patients (17.6%) with an atrial anastomosis and a bicaval anastomosis with prophylactic donor heart tricuspid annuloplasty 86 (68.8%) versus without annuloplasty in 17 (13.6%). The technique was determined by surgeon preference and the transplantation era. There were 428 EBMs performed for rejection control, each one including 4 to 7 fragments, totaling 1715 fragments, all of which were reviewed for this study. The number of EMB per patient varied from 3 to 8 (mean, 4.6 ⫾ 3.5). Meticulous histopathological analysis of these fragments identified tricuspid tissue in 4 patients (3.2%), among whom only 1 experienced aggravation of TR (case 1). Table 1 shows the echocardiographic findings. DISCUSSION
Severe intraoperative TR predicts poor late survival following OHT. Fortunately, severe valvar regurgitation does not occur in many cases. Several groups have applied prophylactic tricuspid annuloplasty of the donor heart, because severe late complications and reduced survival may arise from TR development.5–7 TR is the most common valvular abnormality after OHT with an extremely variable prevalence between 25% and 45%.1,5 Multiple factors play important roles in this process such as regurgitation classification, operative technique, follow-up time, pulmonary artery pressure, allograft behavior, right ventricular function, frequency/severity of rejection episodes, female donor, donor age, weight mismatch, ischemia time, and, not the least important, the number and technique of the EMB.1,3,5 EMB remains the gold standard to monitor and diagnose allograft rejection after OHT. It may have a direct impact on the development of TR, although the strength of this association is controversial.1–3 Most patients with evide-
nce of significant TR after chordal tissue biopsy continue clinically asymptomatic, showing no significant change in hemodynamics. Moreover, there are many reports demonstrating a strong relationship between the number of EMB performed per patient and the development of flail tricuspid leaflets or chordal rupture. Nguyen et al1 in 2005 strongly suggested a cutoff of ⬍31 EMB to reduce the risk for severe TR. Mielniczuk et al2 in 2005 reported 19/98 (19.4%) OHT patients displayed significant TR by echocardiogram during a 6-year follow-up. Among 205 biopsies in 19 patients (mean 10.7 ⫾ 4.2), chordal tissue was found in 9 (9.2%). Similar results have been noted by other authors.1–3 Probably if all the pieces of the biopsy were analyzed, the incidence would have been higher, because many patients remain asymptomatic. In the present study, the incidence of traumatic injury to the tricuspid valve secondary to a biopsy was small. Perhaps some factors significantly contributed to it: the biopsies by a surgeon; the reliance on myocardial scintigraphy with gallium as a screening method to reduce the number of EMB; and the use of a long sheath that could reach the right ventricle through the tricuspid valve. This approach has been applied at our institution for several years because it has reducted the routine EMB by ⬎50%.7–9 At the beginning of our experience in 1985, findings of tricuspid tissue in biopsies were more frequent, because we were passing through the learning curve. Furthermore, these observations confirmed the involvement of other risk factors in the genesis of TR; they were equally or more important than EMB alone. Only 1 patient (1/385; 0.3%) who was not part of this research developed severe tricuspid insufficiency requiring a valve replacement at 4 years after OHT. In conclusion, EMB remains the standard method to diagnose rejection after heart transplantation. It can be performed with low risk. A reduced number of EMB using screening with gallium myocardial scintigraphy or other alternative methods as well the adoption of special care during the biopsy can significantly minimize trauma to the tricuspid valve.
Table 1. Echocardiographic Changes Before and After Tricuspid Chordal Tissue Disruption From the Routine EMB Case 1 Before
No. of EMB Tricuspid Mitral Pulmonary Aortic RV LV EF LV (%) PAPs (mm Hg)
2 2 0 0 SH Normal 56 36
Case 2 After
3 3 2 1 SH Normal 56 25
Case 3
Before
After
1 0 0 0 Normal Normal 65 36
1 0 0 0 Normal Normal 64 35
Before
1 1 0 0 DH Normal 67 29
Case 4 After
1 1 0 0 DH Normal 50 31
Before
After
0 0 0 0 Normal Normal 61 35
0 0 0 0 Normal Normal 74 34
RV, right ventricle; LV, left ventricle; EF LV, ejection fraction left ventricle; PAPs, pulmonary arterial systolic pressure; SH, severe hypocontractility; DH, discrete hypocontractility. Valvar insufficiency degree was quantified as: 0 ⫽ absent; 1 ⫽ mild; 2 ⫽ moderate; and 3 ⫽ severe.
ENDOMYOCARDIAL BIOPSY AS RISK FACTOR
REFERENCES 1. Nguyen V, Cantarovich M, Cecere R, et al: Tricuspid regurgitation after cardiac transplantation: how many biopsies are too many? J Heart Lung Transplant 24(7 suppl):S227, 2005 2. Mielniczuk L, Haddad H, Davies RA, et al: Tricuspid Valve chordal tissue in endomyocardial biopsy specimens of patients with significant tricuspid regurgitation. J Heart Lung Transplant 24: 1586, 2005 3. Sahar G, Stamler A, Erez E, et al: Etiological factors influencing the development of atrioventricular valve incompetence after heart transplantation. Transplant Proc 29:2675, 1997 4. Mügge A, Daniel WG, Herrmann G, et al: Quantification of tricuspid regurgitation by Doppler color flow mapping after cardiac transplantation. Am J Cardiol 66:884, 1990
937 5. Jeevanandam V, Russell H, Mather P, et al: Donor tricuspid annuloplasty during orthotopic heart transplantation: long-term results of a prospective controlled study. Ann Thorac Surg 82:2089, 2006 6. Anderson CA, Shernan SK, Leacche M, et al: Severity of intraoperative tricuspid regurgitation predicts poor late survival following cardiac transplantation. Ann Thorac Surg 78:1635, 2004 7. Fiorelli AI, Stolf NA, Abreu Filho CA, et al: Prophylactic donor tricuspid annuloplasty in orthotopic bicaval heart transplantation. Transplant Proc 39:2527, 2007 8. Meneguetti JC, Camargo EE, Soares J Jr, et al: Gallium-67 imaging in human heart transplantation: correlation with endomyocardial biopsy. J Heart Transplant 6:171, 1987 9. Camargo PR, Mazzieri R, Snitcowsky R, et al: Correlation between gallium-67 imaging and endomyocardial biopsy in children with severe dilated cardiomyopathy. Int J Cardiol 28:293, 1990