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Bradycardia and syncope as a presentation of cardiac allograft rejection involving the conducting system
Cardiovascular Pathology 19 (2010) 117 – 120
Case Report
Bradycardia and syncope as a presentation of cardiac allograft rejection involving the conducting system Carrie S. Knight a , José A. Tallaj b,c,⁎, Barry K. Rayburn b , Salpy V. Pamboukian b , Robert Bourge b , James K. Kirklin d , David McGiffin d , Silvio H. Litovsky a a
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA c Birmingham VA Medical Center, Birmingham, AL, USA d Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
b
Received 13 July 2008; received in revised form 16 September 2008; accepted 10 October 2008
Abstract Post-heart transplantation bradycardic syncope and arrest could be due to preferential rejection of the conduction system. We present six heart transplant patients with this presentation, two of whom died. The autopsy of one of those patients demonstrated severe rejection of the conduction system, with only mild rejection throughout the rest of the myocardium. We postulate that aggressive therapy for rejection and pacemaker placement may result in improved survival in heart transplant recipients with this clinical presentation. Published by Elsevier Inc. Keywords: Bradycardia; Heart transplant; Rejection; Conducting system
1. Introduction After cardiac transplantation, multiple factors may contribute to bradycardia. In the immediate post-transplantation period, bradycardia is a well-recognized phenomenon that is usually self-limited [1,2]. However, beyond the first 2 weeks post-transplant, new onset bradyarrhythmias should prompt evaluation for causes such as sinus node dysfunction, ischemia, rejection, allograft vasculopathy, or drug effects. Evaluation for rejection commonly includes endomyocardial biopsy. Biopsy-negative acute allograft rejection is a difficult entity to diagnose and to treat appropriately, with a more guarded prognosis than the more typical episode of rejection with biopsy findings [3]. Based on a series of patients followed at our institution and corresponding autopsy findings, we propose that rejection preferentially involving
⁎ Corresponding author. THT 338, 1900 University Blvd, Birmingham, AL 35294, USA. E-mail address: [email protected] (J.A. Tallaj). 1054-8807/08/$ – see front matter. Published by Elsevier Inc. doi:10.1016/j.carpath.2008.10.006
the conducting system is a potential cause for bradycardia which may be missed by endomyocardial biopsy. 2. Methods We identified six post-transplantation patients (five males, mean age 52 years) from our institution who presented between January 2000 and December 2007 with unexplained bradycardic syncope. This presentation occurred 42.5±26.5 months after transplantation (Table 1). Records were reviewed for history of rejection, clinical course, and anatomic pathologic findings. 3. Results Four patients had prior cellular rejection 18 to 82 months prior to admission as diagnosed by routine endomyocardial biopsy, but none had history of hemodynamically significant rejection. Left ventricular function was normal by echocardiography in all patients at presentation. Five patients had
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C.S. Knight et al. / Cardiovascular Pathology 19 (2010) 117–120
Table 1 Patients presenting with unexplained bradycardia and syncope after cardiac transplantation in order of presentation Patient
Age (years)
Gender
Time post-transplant (months)
Outcome
Treatment for acute rejection
Pacemaker?
Pathologic findings
1 2
49 61
F M
37 28
Survived Expired
No No
Yes Yes
3 4
58 23
M M
31 65
Survived Expired
Yes No
Yes No
5 6
69 56
M M
11 83
Survived Survived
Yes Yes
Yes Yes
Biopsy: ISHLT Grade 0 Biopsy: ISHLT Grade 0 Autopsy: mild acute cellular rejection involving the working myocardium; conducting system not histologically examined Biopsy: ISHLT Grade IA Biopsy: ISHLT Grade IB Autopsy: acute cellular rejection predominantly involving the conducting system, with only mild changes in the working myocardium Biopsy: ISHLT Grade 0 Biopsy: ISHLT Grade 0
endomyocardial biopsies, and none showed more than mild rejection [International Society for Heart and Lung Transplantation (ISHLT) Grade 0 to IB]. Five patients underwent permanent pacemaker placement for presumptive chronotropic incompetence. Three patients were treated empirically for rejection with augmentation of immunosuppression and survived the event. Of the three patients who were not treated for presumed rejection, two of them died suddenly. One collapsed in-hospital but did not survive resuscitative efforts, and the other died suddenly at home the day after discharge from the hospital after pacemaker placement. Autopsies were performed on the two deceased patients. The first patient's postmortem examination (Table 1, Patient 2) revealed mild acute allograft rejection in routine myocardial sections; the conducting system was not examined histologically. During postmortem examination of the second patient (Table 1, Patient 4), additional sections of the conduction system were obtained. This patient was a 23-year-old man with a history of dilated cardiomyopathy, who was 65 months post-transplant. He presented with unexplained episodes of syncope, although bradycardia was not documented during these initial episodes. He was again admitted for further evaluation when the episodes became more frequent. An echocardiogram showed normal right and left ventricular ejection fraction, and a right ventricular endomyocardial biopsy showed mild rejection (ISHLT Grade IB). While in the hospital, he had a bradycardic arrest and could not be resuscitated despite aggressive and prolonged efforts. Autopsy revealed acute cellular allograft rejection primarily involving the conducting system. Sections of the right and left ventricular myocardium showed only a mild, predominantly perivascular lymphocytic infiltrate. Sections from the cardiac conducting system, however, showed much more severe inflammation and damage. In the region of the sinoatrial node (Fig. 1A), there was a prominent lymphocytic infiltrate with associated myocyte damage. In the region of the atrioventricular node, there were vessels with significant inflammation and intimal
hyperplasia (Fig. 1B and C), as well as evidence of both acute and chronic myocyte damage including areas of interstitial fibrosis. Immunohistochemical stains for T-cell, B-cell, and histiocytic markers revealed the infiltrate to be composed predominantly of T cells, with scattered B cells and macrophages (Fig. 1D, staining for CD4). These histologic findings within the conducting system were indicative of much more severe rejection than seen elsewhere in the myocardium, suggesting that this patient's presentation with unexplained bradycardia may have been secondary to rejection preferentially involving the conducting system.
4. Discussion The unexpected finding of rejection preferentially involving the conducting system may represent one mechanism of post-transplant bradycardic syncope and sudden death. Unexplained bradycardic syncope due to damage to the cardiac conducting system may be a manifestation of allograft rejection. Several previous investigators have examined changes in the conducting system in cardiac allograft rejection. Stovin and Hewitt [4] examined 11 transplanted hearts at autopsy for noncardiac death or retransplantation and found involvement of the conduction tissue by rejection which was no more severe than in the adjacent myocardium. They found little evidence of permanent structural damage to the AV tissues by recurrent episodes of mild to moderate rejection [4]. In a series of 21 hearts studied by Chang et al. [5], six showed more severe rejection in the working myocardium than in the conducting system, but there were no cases in which the opposite was identified. In a Norwegian series by Foerster [6], the conduction system was involved in 8 of 11 allografts with acute cellular rejection, including one case with a history of AV block in which infiltrates were seen almost exclusively in atrioventricular tissue. Foerster identified most of the cells composing these infiltrates as T
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119
Fig. 1. Autopsy sections obtained from Patient 4, in the region of the sinoatrial node (A, 2×), atrioventricular node (B, 2×), with the artery of the AV node expanded (C, 10×), all showing significant vascular and perivascular mononuclear inflammation; CD4 immunohistochemical staining demonstrates prominent infiltration (D, 40×).
lymphocytes, with lesser numbers of macrophages and B cells, and found no morphological differences between findings in patients treated with cyclosporine and prednisolone with or without the addition of azathioprine [6]. Other investigators, using extensive serial histologic sections, have demonstrated that the conducting system may be involved by changes of acute and chronic allograft rejection [7,8], and these changes may be associated with electrocardiographic abnormalities [7]. Chan et al. [5] recently reported a case of rejection primarily involving the conducting system in a 15-month-old girl who had received heart transplantation due to congestive heart failure from a congenital heart block. The patient did not have electrocardiographic findings of heart block postoperatively, but 6 weeks after transplantation she developed sudden-onset bradycardia and died. Similar to one of our patients, her autopsy showed severe acute cellular rejection involving primarily the conduction system [9]. Our findings differ from this case in that (a) this phenomenon was observed late in the post-transplantation period, when the incidence of acute and severe rejection is less frequent and
(b) our patient did not have a history of heart block prior to transplantation. Although our findings correlate bradycardia with preferential rejection of the conduction system, the mechanism of such a presentation is unknown. One possibility may be that the conducting system, composed of altered myocytes, may contain unique antigens that may themselves be targets for cellular rejection. A paucity of similar cases in earlier series suggests that this occurrence is either rare in or of itself, or possibly develops rarely because of current patient monitoring and immunosuppressive protocols. This case series illustrates that presentation with unexplained bradycardia and syncope in cardiac allograft recipients heralds a poor prognosis. Aggressive treatment similar to that for hemodynamically significant rejection should be strongly considered even if not indicated by standard right ventricular biopsy. At our center, we have adopted a standard protocol of treating post-transplant patients with unexplained syncope aggressively for rejection, including plasmapheresis and steroid boluses, followed by photopheresis. We also implant permanent pacemakers in these patients in the event of
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recurrence after treatment. The justification of this approach is underscored by the survival of the patients who were treated aggressively vs. the sudden death of those who were treated conservatively, and the impossibility of obtaining randomized, controlled data for this rare and potentially unrecognized clinical entity. References [1] Goldstein DR, Coffey CS, Benza RL, Nanda NC, Bourge RC. Relative perioperative bradycardia does not lead to adverse outcomes after cardiac transplantation. Am J Transplant 2003;3:484–91. [2] Miyamoto Y, Curtiss EI, Kormos RL, Armitage JM, Hardesty RL, Griffith BP. Bradyarrhythmia after heart transplantation. Incidence, time course, and outcome. Circulation 1990;82(Suppl 5):IV313–7. [3] Fishbein MC, Kobashigawa J. Biopsy-negative cardiac transplant rejection: etiology, diagnosis, and therapy. Curr Opin Cardiol 2004;19:166–9.
[4] Stovin PG, Hewitt S. Conduction tissue in the transplanted human heart. J Pathol 1986;149:183–9. [5] Chang AC, Hruban RH, Levin HR, Baughman KL, Baumgartner WA, Reitz BA, Hutchins GM. Comparison of rejection in the atrioventricular node and bundles with the working myocardium in transplanted hearts. J Heart Lung Transplant 1991;10:915–20. [6] Foerster A. The conduction system in human cardiac allografts: a histological and immunopathological study. Pathol Res Pract 1992;188: 783–90. [7] Calzolari V, Angelini A, Basso C, Livi U, Rossi L, Thiene G. Histologic findings in the conduction system after cardiac transplantation and correlation with electrocardiographic findings. Am J Cardiol 1999;84: 756–9. [8] Bharati S, Billingham M, Lev M. The conduction system in transplanted hearts. Chest 1992;102:1182–8. [9] Chan JB, Levi DS, Lai CK, Alejos JC, Fishbein MC. Cellular rejection of the conduction system after orthotopic heart transplantation for congenital atrioventricular block. J Heart Lung Transplant 2006;25: 1371–5.
Case Report
Bradycardia and syncope as a presentation of cardiac allograft rejection involving the conducting system Carrie S. Knight a , José A. Tallaj b,c,⁎, Barry K. Rayburn b , Salpy V. Pamboukian b , Robert Bourge b , James K. Kirklin d , David McGiffin d , Silvio H. Litovsky a a
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA c Birmingham VA Medical Center, Birmingham, AL, USA d Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
b
Received 13 July 2008; received in revised form 16 September 2008; accepted 10 October 2008
Abstract Post-heart transplantation bradycardic syncope and arrest could be due to preferential rejection of the conduction system. We present six heart transplant patients with this presentation, two of whom died. The autopsy of one of those patients demonstrated severe rejection of the conduction system, with only mild rejection throughout the rest of the myocardium. We postulate that aggressive therapy for rejection and pacemaker placement may result in improved survival in heart transplant recipients with this clinical presentation. Published by Elsevier Inc. Keywords: Bradycardia; Heart transplant; Rejection; Conducting system
1. Introduction After cardiac transplantation, multiple factors may contribute to bradycardia. In the immediate post-transplantation period, bradycardia is a well-recognized phenomenon that is usually self-limited [1,2]. However, beyond the first 2 weeks post-transplant, new onset bradyarrhythmias should prompt evaluation for causes such as sinus node dysfunction, ischemia, rejection, allograft vasculopathy, or drug effects. Evaluation for rejection commonly includes endomyocardial biopsy. Biopsy-negative acute allograft rejection is a difficult entity to diagnose and to treat appropriately, with a more guarded prognosis than the more typical episode of rejection with biopsy findings [3]. Based on a series of patients followed at our institution and corresponding autopsy findings, we propose that rejection preferentially involving
⁎ Corresponding author. THT 338, 1900 University Blvd, Birmingham, AL 35294, USA. E-mail address: [email protected] (J.A. Tallaj). 1054-8807/08/$ – see front matter. Published by Elsevier Inc. doi:10.1016/j.carpath.2008.10.006
the conducting system is a potential cause for bradycardia which may be missed by endomyocardial biopsy. 2. Methods We identified six post-transplantation patients (five males, mean age 52 years) from our institution who presented between January 2000 and December 2007 with unexplained bradycardic syncope. This presentation occurred 42.5±26.5 months after transplantation (Table 1). Records were reviewed for history of rejection, clinical course, and anatomic pathologic findings. 3. Results Four patients had prior cellular rejection 18 to 82 months prior to admission as diagnosed by routine endomyocardial biopsy, but none had history of hemodynamically significant rejection. Left ventricular function was normal by echocardiography in all patients at presentation. Five patients had
118
C.S. Knight et al. / Cardiovascular Pathology 19 (2010) 117–120
Table 1 Patients presenting with unexplained bradycardia and syncope after cardiac transplantation in order of presentation Patient
Age (years)
Gender
Time post-transplant (months)
Outcome
Treatment for acute rejection
Pacemaker?
Pathologic findings
1 2
49 61
F M
37 28
Survived Expired
No No
Yes Yes
3 4
58 23
M M
31 65
Survived Expired
Yes No
Yes No
5 6
69 56
M M
11 83
Survived Survived
Yes Yes
Yes Yes
Biopsy: ISHLT Grade 0 Biopsy: ISHLT Grade 0 Autopsy: mild acute cellular rejection involving the working myocardium; conducting system not histologically examined Biopsy: ISHLT Grade IA Biopsy: ISHLT Grade IB Autopsy: acute cellular rejection predominantly involving the conducting system, with only mild changes in the working myocardium Biopsy: ISHLT Grade 0 Biopsy: ISHLT Grade 0
endomyocardial biopsies, and none showed more than mild rejection [International Society for Heart and Lung Transplantation (ISHLT) Grade 0 to IB]. Five patients underwent permanent pacemaker placement for presumptive chronotropic incompetence. Three patients were treated empirically for rejection with augmentation of immunosuppression and survived the event. Of the three patients who were not treated for presumed rejection, two of them died suddenly. One collapsed in-hospital but did not survive resuscitative efforts, and the other died suddenly at home the day after discharge from the hospital after pacemaker placement. Autopsies were performed on the two deceased patients. The first patient's postmortem examination (Table 1, Patient 2) revealed mild acute allograft rejection in routine myocardial sections; the conducting system was not examined histologically. During postmortem examination of the second patient (Table 1, Patient 4), additional sections of the conduction system were obtained. This patient was a 23-year-old man with a history of dilated cardiomyopathy, who was 65 months post-transplant. He presented with unexplained episodes of syncope, although bradycardia was not documented during these initial episodes. He was again admitted for further evaluation when the episodes became more frequent. An echocardiogram showed normal right and left ventricular ejection fraction, and a right ventricular endomyocardial biopsy showed mild rejection (ISHLT Grade IB). While in the hospital, he had a bradycardic arrest and could not be resuscitated despite aggressive and prolonged efforts. Autopsy revealed acute cellular allograft rejection primarily involving the conducting system. Sections of the right and left ventricular myocardium showed only a mild, predominantly perivascular lymphocytic infiltrate. Sections from the cardiac conducting system, however, showed much more severe inflammation and damage. In the region of the sinoatrial node (Fig. 1A), there was a prominent lymphocytic infiltrate with associated myocyte damage. In the region of the atrioventricular node, there were vessels with significant inflammation and intimal
hyperplasia (Fig. 1B and C), as well as evidence of both acute and chronic myocyte damage including areas of interstitial fibrosis. Immunohistochemical stains for T-cell, B-cell, and histiocytic markers revealed the infiltrate to be composed predominantly of T cells, with scattered B cells and macrophages (Fig. 1D, staining for CD4). These histologic findings within the conducting system were indicative of much more severe rejection than seen elsewhere in the myocardium, suggesting that this patient's presentation with unexplained bradycardia may have been secondary to rejection preferentially involving the conducting system.
4. Discussion The unexpected finding of rejection preferentially involving the conducting system may represent one mechanism of post-transplant bradycardic syncope and sudden death. Unexplained bradycardic syncope due to damage to the cardiac conducting system may be a manifestation of allograft rejection. Several previous investigators have examined changes in the conducting system in cardiac allograft rejection. Stovin and Hewitt [4] examined 11 transplanted hearts at autopsy for noncardiac death or retransplantation and found involvement of the conduction tissue by rejection which was no more severe than in the adjacent myocardium. They found little evidence of permanent structural damage to the AV tissues by recurrent episodes of mild to moderate rejection [4]. In a series of 21 hearts studied by Chang et al. [5], six showed more severe rejection in the working myocardium than in the conducting system, but there were no cases in which the opposite was identified. In a Norwegian series by Foerster [6], the conduction system was involved in 8 of 11 allografts with acute cellular rejection, including one case with a history of AV block in which infiltrates were seen almost exclusively in atrioventricular tissue. Foerster identified most of the cells composing these infiltrates as T
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119
Fig. 1. Autopsy sections obtained from Patient 4, in the region of the sinoatrial node (A, 2×), atrioventricular node (B, 2×), with the artery of the AV node expanded (C, 10×), all showing significant vascular and perivascular mononuclear inflammation; CD4 immunohistochemical staining demonstrates prominent infiltration (D, 40×).
lymphocytes, with lesser numbers of macrophages and B cells, and found no morphological differences between findings in patients treated with cyclosporine and prednisolone with or without the addition of azathioprine [6]. Other investigators, using extensive serial histologic sections, have demonstrated that the conducting system may be involved by changes of acute and chronic allograft rejection [7,8], and these changes may be associated with electrocardiographic abnormalities [7]. Chan et al. [5] recently reported a case of rejection primarily involving the conducting system in a 15-month-old girl who had received heart transplantation due to congestive heart failure from a congenital heart block. The patient did not have electrocardiographic findings of heart block postoperatively, but 6 weeks after transplantation she developed sudden-onset bradycardia and died. Similar to one of our patients, her autopsy showed severe acute cellular rejection involving primarily the conduction system [9]. Our findings differ from this case in that (a) this phenomenon was observed late in the post-transplantation period, when the incidence of acute and severe rejection is less frequent and
(b) our patient did not have a history of heart block prior to transplantation. Although our findings correlate bradycardia with preferential rejection of the conduction system, the mechanism of such a presentation is unknown. One possibility may be that the conducting system, composed of altered myocytes, may contain unique antigens that may themselves be targets for cellular rejection. A paucity of similar cases in earlier series suggests that this occurrence is either rare in or of itself, or possibly develops rarely because of current patient monitoring and immunosuppressive protocols. This case series illustrates that presentation with unexplained bradycardia and syncope in cardiac allograft recipients heralds a poor prognosis. Aggressive treatment similar to that for hemodynamically significant rejection should be strongly considered even if not indicated by standard right ventricular biopsy. At our center, we have adopted a standard protocol of treating post-transplant patients with unexplained syncope aggressively for rejection, including plasmapheresis and steroid boluses, followed by photopheresis. We also implant permanent pacemakers in these patients in the event of
120
C.S. Knight et al. / Cardiovascular Pathology 19 (2010) 117–120
recurrence after treatment. The justification of this approach is underscored by the survival of the patients who were treated aggressively vs. the sudden death of those who were treated conservatively, and the impossibility of obtaining randomized, controlled data for this rare and potentially unrecognized clinical entity. References [1] Goldstein DR, Coffey CS, Benza RL, Nanda NC, Bourge RC. Relative perioperative bradycardia does not lead to adverse outcomes after cardiac transplantation. Am J Transplant 2003;3:484–91. [2] Miyamoto Y, Curtiss EI, Kormos RL, Armitage JM, Hardesty RL, Griffith BP. Bradyarrhythmia after heart transplantation. Incidence, time course, and outcome. Circulation 1990;82(Suppl 5):IV313–7. [3] Fishbein MC, Kobashigawa J. Biopsy-negative cardiac transplant rejection: etiology, diagnosis, and therapy. Curr Opin Cardiol 2004;19:166–9.
[4] Stovin PG, Hewitt S. Conduction tissue in the transplanted human heart. J Pathol 1986;149:183–9. [5] Chang AC, Hruban RH, Levin HR, Baughman KL, Baumgartner WA, Reitz BA, Hutchins GM. Comparison of rejection in the atrioventricular node and bundles with the working myocardium in transplanted hearts. J Heart Lung Transplant 1991;10:915–20. [6] Foerster A. The conduction system in human cardiac allografts: a histological and immunopathological study. Pathol Res Pract 1992;188: 783–90. [7] Calzolari V, Angelini A, Basso C, Livi U, Rossi L, Thiene G. Histologic findings in the conduction system after cardiac transplantation and correlation with electrocardiographic findings. Am J Cardiol 1999;84: 756–9. [8] Bharati S, Billingham M, Lev M. The conduction system in transplanted hearts. Chest 1992;102:1182–8. [9] Chan JB, Levi DS, Lai CK, Alejos JC, Fishbein MC. Cellular rejection of the conduction system after orthotopic heart transplantation for congenital atrioventricular block. J Heart Lung Transplant 2006;25: 1371–5.