Ann Thorac Surg 1995;60:1263-1266
© 1995 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Permanent Pacemaker for Rejection Episodes After Heart Transplantation: A Poor Prognostic Sign
Carlos Blanche, MD,
Lawrence S. C. Czer, MD,
Michael C. Fishbein, MD,
Johanna J. M. Takkenberg, MD,
Alfredo Trento, MD
Department of Cardiothoracic Surgery, Cedars-Sinai Medical Center, Los Angeles, California
Accepted for publication June 12, 1995.
 |
Abstract
|
|---|
Background. The development of arrhythmias early or late after heart transplantation has been associated with acute and chronic rejection. This study aims to document the importance of this relationship and its value as a prognostic sign in those patients who required a permanent pacemaker for rejection episodes.
Methods. A retrospective analysis of 158 orthotopic heart transplantations performed in 157 patients between December 1988 and April 1995 was done. The clinical course and the outcome of 6 patients who underwent insertion of a permanent pacemaker for bradyarrhythmias caused by acute or chronic allograft rejection were compared with the course and outcome of 9 patients who had pacemaker placement as a result of sinus node dysfunction not associated with rejection.
Results. The mortality rate was 100% for patients whose indication for permanent pacing was severe acute or chronic rejection. Conversely, 8 of the 9 patients who underwent pacemaker placement for sinus node dysfunction not associated with rejection are long-term survivors; the one late death was due to a noncardiac cause.
Conclusions. We observed a strong relationship between bradyarrhythmias requiring a permanent pacemaker and severe acute or chronic allograft rejection. This association suggests a poor prognosis and indicates that these patients should be managed aggressively. Such management includes close immunologic surveillance for cellular and humoral rejection, increased frequency of endomyocardial biopsies and coronary angiography, and early consideration for retransplantation.
|
Introduction
|
|---|
The occurrence of severe bradyarrhythmias early or late in the posttransplantation period has previously been considered a marker of acute or chronic rejection [1–4]. Although the predictors of permanent pacing after heart transplantation are multiple, the presence of a rejection episode has been implicated as a major factor [5]. However, the prognostic importance of this relationship is uncertain.
To explore the association between acute or chronic rejection and the need of permanent pacing after transplantation, we retrospectively reviewed our experience with heart transplant patients who required a permanent pacemaker. In particular, we analyzed the cases of patients whose indication for permanent pacing was an episode of acute cellular or humoral rejection or accelerated allograft atherosclerosis (chronic rejection). This analysis focused on the importance of this relationship and its value as a prognostic sign.
|
Material and Methods
|
|---|
Between December 1988 and April 1995, 158 orthotopic heart transplantations were performed in 157 patients at Cedars-Sinai Medical Center. The first 64 consecutive patients underwent transplantation with the standard operative technique as originally described by Shumway and colleagues [6]. The subsequent patients had transplantation with an alternative technique previously described [7].
Immunosuppression consisted of OKT3 induction therapy (5 mg/d for 14 days in the first 112 patients and for 7 days in the last 45 patients) with concomitant administration of cyclosporine (5 mg•kg-1•d-1 for a level of 120 to 200 ng/mL by fluorescence polarization immunoassay started postoperatively once the serum creatinine level was < 2.0 mg/dL), azathioprine (4 mg/kg preoperatively and 2 mg•kg-1•d-1 postoperatively), and steroids (methylprednisolone sodium succinate [Solu-Medrol], 1 g intraoperatively at removal of the aortic cross-clamp and then 125 µg intravenously every 8 hours for three doses postoperatively, followed by prednisone, 0.25 mg•kg-1•d-1 during OKT3 therapy, increased to 0.5 mg•kg-1•d-1, and then tapered in the subsequent 3 to 8 months).
Permanent pacemakers were implanted in 15 patients, all of whom had transplantation by the standard technique [6]. The indications for permanent pacing were symptomatic bradyarrhythmias (rate <50 beats/min) that persisted for more than 15 days after transplantation.
|
Results
|
|---|
Nine patients received a pacemaker for sinus node dysfunction not associated with acute or chronic rejection (mean time to pacemaker implantation, 15 days; range, 6 to 34 days). Eight of them are clinically well (mean follow-up, 51 months; range, 39 to 58 months), and 1 died of sertraline (Roerig, New York, NY) toxicity 44 months after transplantation; no rejection was observed at postmortem examination.
Three patients underwent pacemaker implantation that was associated with an episode of severe acute cellular or humoral rejection or both (mean time after transplantation, 82 days; range, 17 to 208 days), and 3 patients received a pacemaker because of chronic rejection (mean time after transplantation, 17 months; range, 3.2 to 35.4 months). The mean interval between pacemaker placement and death was 10 days for the patients with acute rejection and 18.6 months for the patients with chronic rejection. All 6 patients died as a consequence of rejection, and their case reports follow.
Patient 1
A 64-year-old man underwent uneventful heart transplantation for end-stage ischemic cardiomyopathy. Eight months later, he was seen with syncope that was due to prolonged sinus arrest (>8 seconds) with slow junctional escape rhythm, which necessitated insertion of a permanent DDD pacemaker. The endomyocardial biopsy specimen showed severe acute cellular rejection, and pulsed steroid therapy was instituted. Soon thereafter, the patient experienced multiple intractable ventricular arrhythmias and died. Postmortem examination confirmed severe acute rejection with marked involvement of the conduction system (Fig 1
).
View larger version (152K):
[in this window]
[in a new window]
|
Fig 1. . Histologic section of atrioventricular node showing evidence of acute cellular rejection; inflammatory infiltrate and interstitial edema separating myocytes are observed. (Hematoxylin and eosin; x25 before 35% reduction.) (C = central fibrous body.)
|
|
Patient 2
A 42-year-old man underwent heart transplantation for end-stage dilated cardiomyopathy. Symptomatic junctional bradycardia (45 beats/min) required insertion of a permanent AAI pacemaker 17 days after transplantation. The endomyocardial biopsy specimen revealed severe acute cellular and humoral rejection. During pulsed steroid therapy, intractable ventricular arrhythmias developed, and the patient died. Postmortem examination confirmed severe acute cellular and humoral rejection with marked involvement of the conduction system.
Patient 3
A 50-year-old man underwent heart transplantation for end-stage dilated cardiomyopathy. Early in the postoperative course, heart failure caused by severe acute cellular and humoral rejection developed; an intraaortic balloon pump was inserted. Complete atrioventricular block with slow junctional escape rhythm required insertion of a permanent DDD pacemaker 3 weeks after transplantation. Despite institution of antirejection therapy, the patient died prior to retransplantation. Postmortem examination confirmed marked involvement of the conduction system in the rejection response (Fig 2).
View larger version (143K):
[in this window]
[in a new window]
|
Fig 2. . Histologic section of atrioventricular node showing intense inflammatory infiltrate within both the node and the atrioventricular node artery (*), which also shows pronounced intimal thickening. (Hematoxylin and eosin; x13 before 35% reduction.) (C = central fibrous body.)
|
|
Patient 4
A 42-year-old woman underwent heart transplantation for end-stage ischemic heart disease. The postoperative course was complicated by recurrent episodes of cytomegalovirus infection as well as multiple episodes of severe cellular and humoral rejection. Sudden symptomatic bradycardia (<40 beats/min) necessitated insertion of a permanent VVI pacemaker 3 months after transplantation. Coronary angiography demonstrated accelerated allograft atherosclerosis. The patient died 36 months after transplantation of chronic allograft failure resulting from multiple rejection episodes. Postmortem examination confirmed accelerated allograft atherosclerosis with extensive diffuse interstitial fibrosis and thickening of the endocardium. There was prominent fibrosis in the conduction tissue (Fig 3).
View larger version (135K):
[in this window]
[in a new window]
|
Fig 3. . Histologic section of atrioventricular node showing myocytes separated by interstitial collagen deposition. (Hematoxylin and eosin; x50 before 35% reduction.) (C = central fibrous body.)
|
|
Patient 5
A 58-year-old man underwent heart transplantation for end-stage ischemic cardiomyopathy. The postoperative course was complicated by multiple episodes of cellular rejection with slow deterioration of cardiac function. Accelerated allograft atherosclerosis (chronic rejection) was demonstrated on coronary angiography. The patient required insertion of a permanent DDD pacemaker for symptomatic sinus bradycardia 35 months after transplantation. He had a progressively downhill course and died suddenly 5 months later.
Patient 6
A 56-year-old man underwent heart transplantation for end-stage ischemic heart disease. The postoperative course was complicated by the development of accelerated allograft atherosclerosis (chronic rejection), demonstrated on coronary cineangiography. He required insertion of a permanent DDD pacemaker for sinus arrest and slow (<50 beats/min) junctional escape rhythm 13 months after transplantation. The patient died of chronic rejection 24 months after transplantation. Postmortem examination revealed severe chronic rejection with diffuse interstitial and endocardial fibrosis.
|
Comment
|
|---|
In the early days of heart transplantation, the Stanford group reported that 40% of clinical rejection episodes were preceded or accompanied by arrhythmias and that almost invariably, there was resolution of the arrhythmia with rejection treatment. For instance, atrial arrhythmias such as atrial fibrillation and flutter, premature atrial contractions, and junctional rhythm were detected in 72% of patients after transplantation and were frequently associated with acute or chronic rejection episodes [1]. Complex premature ventricular contractions have also been cited as an indicator of chronic rejection [8]. Park and colleagues [2] reported that a significant proportion of patients with supraventricular and ventricular tachyarrhythmias experience a rejection episode along with the initial episode of arrhythmia after heart transplantation. Ventricular tachyarrhythmias in particular were usually associated with the eventual discovery of chronic rejection. Most importantly, patients with postoperative arrhythmias have shown decreased allograft survival.
In addition to clinical studies documenting a relationship between arrhythmias and rejection, electrophysiologic studies have demonstrated that right ventricular refractoriness may be considered a marker of early rejection. In animal models, the most sensitive measurement of acute rejection is the atrioventricular conduction time [9]. Histopathologic studies have shown that there is no anatomic dividing line between the conduction and nonconduction tissues at the sinoatrial node, although the distinction can be made more precisely at the atrioventricular node. Our findings indicate that the conduction tissue is not selectively involved or spared in the rejection response. In addition, the arteries to the sinoatrial and atrioventricular nodes are frequently involved in both acute and chronic rejection [10].
Permanent pacemakers are required in approximately 4% to 15% of patients after heart transplantation [5, 11, 12]. In the majority of patients, the indication is sinus node dysfunction, although high-degree atrioventricular block can occur as well. In our experience, rejection was the indication in 6 (40%) of 15 patients. In 3 patients, permanent pacing was associated with severe acute rejection. Although other factors may have played a role in the pathogenesis of their severe bradyarrhythmias, autopsy results revealed marked involvement of the conduction system in the rejection response; the final event was intractable and refractory ventricular arrhythmias. An additional 3 patients who had no previously documented sinus node dysfunction underwent placement of a permanent pacemaker late in the posttransplantation period, which was associated with angiographically documented accelerated allograft atherosclerosis. Two of these patients died of heart failure caused by chronic rejection, which was confirmed at postmortem examination. In the other patient, even though no postmortem examination was performed, it is not unreasonable to assume that the patient experienced ventricular arrhythmias resulting from chronic rejection as the final event.
The immunosuppression regimen, except for minor modifications, has basically remained unchanged for all patients. However, a new surgical technique [7] that involves total excision of the recipient atria with cardiac allograft implantation using bicaval and pulmonary venous anastomoses was used in the last 93 patients. The advantages of this approach are that it preserves the geometric configuration, anatomic size, and physiologic function of the atria, including preservation of the conduction system. It should be noted that all 6 patients reported here underwent transplantation using the standard technique [6], and their deaths were related to allograft rejection rather than anatomic or technical factors. Nonetheless, these patients could represent historic and learning-curve variables that are difficult to identify.
Although the analysis of these patients is retrospective and perhaps observational, and the number of patients is limited for statistical validation, it is noteworthy that the mortality rate was 100% for those patients whose indication for permanent pacing was severe acute or chronic rejection. Conversely, 8 of the 9 patients who underwent pacemaker placement for sinus node dysfunction not associated with rejection are long-term survivors, and the other died of a noncardiac cause.
Thus, we have observed a strong pathogenic relationship between bradyarrhythmias requiring a permanent pacemaker and episodes of severe acute or chronic allograft rejection. This association suggests a poor prognosis, as all our patients died as a consequence of allograft rejection. On the basis of this experience, we have modified our approach when treating this patient population. The approach includes close immunologic surveillance for cellular and humoral rejection, increased frequency of endomyocardial biopsies and coronary angiography, the assumption that unexplained bradyarrhythmias in the posttransplantation period most likely represent ongoing rejection, and early consideration for retransplantation. Since the adoption of these modifications, we have not encountered bradyarrhythmias requiring permanent pacemaker insertion in the last 93 consecutive heart transplant patients.
|
Acknowledgments
|
|---|
We thank Kathleen Farrington and Marilyn Sanders for their expertise in the preparation of the manuscript.
|
Footnotes
|
|---|
Address reprint requests to Dr Blanche, Heart Transplantation Program, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Suite 6215, Los Angeles, CA 90048.
|
References
|
|---|
- Schroeder JS, Berke DK, Graham AF, Rider AK, Harrison DC. Arrhythmias after cardiac transplantation. Am J Cardiol 1974;33:604–7.[Medline]
- Park JK, Hsu DT, Hordof AJ, Addonizio LJ. Arrhythmias in pediatric heart transplant recipients: prevalence and association with death, coronary artery disease, and rejection. J Heart Lung Transplant 1993;12:956–64.[Medline]
- Blanche C, Czer LSC, Trento A, et al. Bradyarrhythmias requiring pacemaker implantation after orthotopic heart transplantation: association with rejection. J Heart Lung Transplant 1992;11:446–52.[Medline]
- Jacquet L, Ziady G, Stein K, et al. Cardiac rhythm disturbances early after orthotopic heart transplantation: prevalence and clinical importance of the observed abnormalities. J Am Coll Cardiol 1990;16:832–7.[Abstract]
- Cooper MM, Smith CR, Rose EA, Schneller SJ, Spotnitz HM. Permanent pacing following cardiac transplantation. J Thorac Cardiovasc Surg 1992;104:812–6.[Abstract]
- Shumway NE, Lower RR, Stofer RC. Transplantation of the heart. Adv Surg 1966;2:265–84.[Medline]
- Blanche C, Valenza M, Aleksic I, Czer LSC, Trento A. Technical considerations of a new technique for orthotopic heart transplantation: total excision of recipient's atria with bicaval and pulmonary venous anastomoses. J Cardiovasc Surg (Torino) 1994;35:283–7.[Medline]
- Romhilt DW, Doyle M, Sagar KB, et al. Prevalence and significance of arrhythmias in long-term survivors of cardiac transplantation. Circulation 1982;66(Suppl 1):219–22.
- Wnuk-Wojnar AM, Zembala M, Regila Z, et al. Electrophysiologic properties of transplanted human heart with and without rejection. J Heart Lung Transplant 1992;11:435–41.[Medline]
- Stovin PGI, Hewit S. Conduction tissue in the transplanted human heart. J Pathol 1986;149:183–9.[Medline]
- Montero JA, Anguita M, Concha M, et al. Pacing requirements after orthotopic heart transplantation: incidence and related factors. J Heart Lung Transplant 1992;11:799–802.[Medline]
- 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):313–7.[Medline]
Top
Abstract
Introduction
