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The Impact and Outcome of Transplant Coronary Artery Disease in a Pediatric Population: A 9-Year Multi-institutional Study
PEDIATRIC TRANSPLANTATION
The Impact and Outcome of Transplant Coronary Artery Disease in a Pediatric Population: A 9-Year Multi-institutional Study Elfriede Pahl, MD,a David C. Naftel, PhD,b Micheal A. Kuhn, MD,c Robert E. Shaddy, MD,d William R. Morrow, MD,e Charles E. Canter, MD,f and James Kirklin, MD,b for the Pediatric Heart Transplant Study Background: Transplant coronary artery disease (TCAD) limits survival in heart transplant recipients; however, its incidence in children is unknown. The purpose of this study was to determine the angiographic incidence of TCAD, potential risk factors, and outcomes in a large pediatric cohort. Methods: From January 1993 to December 1, a total of 1,222 children, aged newborn to 17 years, underwent primary cardiac transplantation at 20 institutions. A total of 2,049 coronary angiograms were performed in 751 patients. All angiograms were graded for coronary disease and results were submitted to the Pediatric Heart Transplant Study database. We analyzed time-related freedom from graded severity and events from coronary disease, and we examined risk factors. Results: The incidence of angiographic abnormalities at 1, 3, and 5 years was 2%, 9%, and 17%, respectively; however, moderate-to-severe disease occurred in only 6% at 5 years, compared with 15% in the adult transplant database (p ⬍0.0001). The major risk factors were older recipient and donor age. Two or more episodes of rejection in the 1st year correlated with coronary disease (p ⫽ 0.05). Overall freedom from graft loss caused by primary TCAD was 99%, 96%, and 91% at 1, 5, and 9 years after heart transplantation, respectively. Death or graft loss occurred within 2 years of diagnosis in patients with severe disease; 24% of patients with any coronary disease died within 2 years. Conclusions: The incidence of TCAD in children is smaller than the incidence in adults, but increases with age. Graft loss is infrequent in children; however, severe coronary disease correlates with poor prognosis. J Heart Lung Transplant 2005;24:645–51. Copyright © 2005 by the International Society for Heart and Lung Transplantation.
Transplant coronary artery disease (TCAD) in the allograft limits survival in adult heart recipients as well as in children.1–3 In adults, risk factors have been identified and include immune and non-immune factors.4 Angiography remains the gold standard for detection, and in a large multicenter adult study of the Cardiac Transplant Research Database (CTRD), the risk factors for TCAD were older donor age, donor male sex, and donor hypertension; recipient risk factors included male sex and black race.5 From the aChildren’s Memorial Hospital, Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Chicago, Illinois; bUniversity of Alabama, Birmingham, Alabama; cLoma Linda University Medical Center, Loma Linda, California; dPrimary Children’s Medical Center, Salt Lake City, Utah; eArkansas Children’s Hospital, Little Rock, Arkansas; and fSt. Louis Children’s Hospital, Washington University Medical School, St. Louis, Missouri. This study was presented at the American Heart Association Annual Scientific Sessions in Chicago, November 2002. Reprint requests: Elfriede Pahl, MD, Children’s Memorial Hospital, Division of Cardiology, Box 21, 2300 Children’s Plaza, Chicago, Illinois 60611. Telephone: 773-880-8185. Fax: 773-880-8111. E-mail: [email protected] Copyright © 2005 by the International Society for Heart and Lung Transplantation. 1053-2498/05/$–see front matter. doi:10.1016/ j.healun.2004.03.021
Transplant coronary artery disease has been reported in pediatric recipients in survey and autopsy series; however, the angiographic incidence of TCAD in children has not been established, especially in a large population. Furthermore, risk factors for the development of TCAD in children have not been defined and may be different from adult risk factors, in which much older donors are used for transplantation. The purpose of this study was to determine the angiographic incidence of TCAD and, once detected, to determine the potential risk factors and outcomes in a pediatric heart transplant population. METHODS Patient Population From January 1, 1993, to December 31, 2001, a total of 1,222 patients, aged newborn to 17 years, underwent primary cardiac transplantation at 20 institutions in the Pediatric Heart Transplant Study (PHTS, Appendix A). A total of 2,049 coronary angiograms were performed in 751 patients who had ⱖ1 angiogram; the majority of recipients survived ⬎1 year and form the basis of this analysis. We reviewed all angiograms for the presence of TCAD and graded the presence as none, mild, moderate, or severe. We submitted the results to the 645
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Table 1. Classification of CAD CTRD class None Mild Moderate Severe
Table 3. Age Distribution for Routine Annual Angiograms Angio lesion
Possible
Normal ⬍50% in any branch segment ⱖ50% in 1 primary vessel or ⱖ50% in branch of 2 vessels ⱖ50% in 2 primary vessels OR ⱖ50% in branches of all 3 systems OR 50% left main
Age at Transplantation ⬍6 years 6–12 years ⬎12 years Total
n 1,843 434 706 2,983
Actual n 1,140 279 457 1,876
% 62% 64% 65% 63%
p value ⫽ 0.3.
CAD, coronary artery disease; CTRD, cardiac transplant research database.
PHTS database. Severity of TCAD seen with angiograms was defined by published CTRD criteria, shown in Table 1.6 We analyzed time-related freedom from graded severity of TCAD and TCAD events and examined risk factors (Appendix B). Intracoronary ultrasound is not routine at most PHTS centers and was not assessed in this study. Choice of immunosuppression was left to individual centers; some centers used lympholytic therapy for induction, and others did not. The use of statins for lipid-decreasing effect and the use of anti-hypertensive regimens were individualized for each patient and were not standardized. Categorization of TCAD Primary vessel refers to the proximal or mid-33% of the left anterior descending, left circumflex, and dominant or codominant right coronary artery.6 Table 1 shows in detail the classification of TCAD. Therefore, the classification as mild, moderate, or severe is based on involvement of the left main, primary vessel stenosis, or branch vessel stenosis, with the class determined by the most severe TCAD reported in each coronary angiogram. An “event” refers to death or retransplantation caused by TCAD. Indications for Angiograms The majority of angiograms were performed for routine surveillance (95.5%), and most patients underwent selective coronary angiography (Table 2). Some programs perform angiography yearly, others perform angiography every 2 years, and a few do not perform routine Table 2. Indication for Angiogram N ⫽ 2,049 Routine, per protocol Selective R & L Evidence of graft dysfunction/CAD Symptoms (CHF or angina) Prior non-invasive test: CAD Other Total
n 1,956 1,895 41 32 5 15 2,049
% 95.5% 92.4% 2.0% 1.6% 0.2% 0.7% 100.0%
CAD, coronary artery disease; CHF, congestive heart failure; L, left; R, right.
angiography, thus the difference in number of studies available per patient. We observed no difference in the number of routine angiograms (62%– 65%) performed among the age groups of ⬍6 years, 6 to 12 years, or ⬎12 years (Table 3). Data Collection Appendix B lists the potential donor and recipient risk factors analyzed. We analyzed the presence and degree of TCAD using the data collection forms that the investigator at each participating center provided and that reflected the results of the coronary angiograms, usually performed at regular intervals as determined by the individual centers. The data collection form also included findings at autopsy, if available, as well as a comment as to whether death or retransplantation were the result of TCAD as a primary or contributing cause. Statistical Methods We examined the data using standard descriptive statistics, including means, standard deviations, and standard errors. We compared sub-groups using contingency tables and t-tests. Time to disease was characterized by actuarial (Kaplan-Meier) methods and by parametric methods. We identified risk factors for coronary disease by multivariable risk factor, forward, stepwise analysis in the multiphase hazard domain. All participating centers had approval from their institutional review boards to participate in this study. RESULTS Incidence and Development of TCAD Table 4 lists the percentage of angiograms graded as normal, mild, moderate, or severe TCAD. The majority (92%) showed no TCAD. Table 5 lists grading for the Table 4. Allograft CAD—All Angiograms Allograft CAD None Mild Moderate Severe Total angios CAD, coronary artery disease.
n 1,876 116 39 18 2,049
% 92 6 2 0.9 100
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Table 5. TCAD: Last Angiogram (751 patients) Allograft CAD None Mild Moderate Severe Total patients
n 681 40 17 13 751
% 91% 5% 2% 2% 100%
CAD, coronary artery disease; TCAD, transplant CAD.
most recent angiogram, which was similar. Again the majority (91%) had no TCAD, and only 2% had severe grade of TCAD. Figure 1 shows the distribution of the percentage of patients with TCAD by the years after transplantation, showing a gradual increase from 1 to 8 years. However, if only donors ⬎30 years are considered, the presence of TCAD increased greatly after 2 years after transplantation (Figure 2). The incidence of any angiographic abnormalities at 1, 3, and 5 years was 2%, 9%, and 17%, respectively (Figure 3). However, moderate-to-severe TCAD occurred in only 1%, 2%, and 5% at 1, 3 and 5 years, respectively (Figure 4) compared with 15% in the published analysis of the adult CTRD (p ⬍ 0.0001). Figure 5 portrays the effect of recipient age on presence of angiographic TCAD. We obtained data for patients ⱖ18 years old from the CTRD. We found a marked increase in the incidence of TCAD with older recipient age. Similarly, the incidence of TCAD is much greater in older donors (Figure 6). Risk Factors for TCAD The major pre-transplant risk factor that correlated with the development of TCAD was older recipient age (p ⬍ 0.0001). Recipients ⱖ12 years old had 2.9-fold the likelihood of having TCAD within 5 years compared with children ⱕ5 years (p ⫽ 0.0003). Additionally, in donors ⬎30 years of age, the risk of TCAD occurring
Figure 1. Bar graph demonstrating percentage of patients in which coronary angiography showed any evidence of coronary artery disease (CAD), with a fairly stable incidence from Years 3 to 8. PHTS, Pediatric Heart Transplant Study.
Figure 2. Bar graph showing incidence of any coronary artery disease (CAD) in recipients who had donors that were ⬎30 years of age; each bar shows the percentage of abnormal studies at the annual evaluation and shows a significant increase between 2 and 3 years. PHTS, Pediatric Heart Transplant Study.
within 5 years increased by 3 times compared with the risk in younger donors (p ⬍ 0.0001). Two or more episodes of rejection in the 1st year were associated with TCAD (p ⫽ 0.06, Figure 7). The use of statins increased with time after transplantation; however, in 5-year survivors, ⬍25% were receiving anti-lipid agents. Therefore, the use of statins was not routine (Figure 8). We found no apparent difference in the incidence of TCAD in patients who acquired cytomegalovirus infection, who received lympholytics as induction, or who varied in demographics such as race or sex. Progression and Outcome After Diagnosis of Severe TCAD Among 10 patients with severe TCAD, 4 died and 5 underwent retransplantation; 6 of these events occurred within 2 years of diagnosis. Transplant coronary artery disease as the primary cause of death or of graft
Figure 3. Actuarial freedom from the presence of any coronary artery disease (CAD), mild, moderate, or severe, detected by coronary angiography after heart transplantation.
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Figure 4. Actuarial freedom from the presence of moderate-to-severe coronary artery disease (CAD) detected by coronary angiography performed later than 6 months after heart transplantation.
loss is portrayed by years since transplantation (Table 4, Figures 9 and 10). Overall, freedom from graft loss caused by primary TCAD was 99%, 96%, and 91% at 1, 5, and 9 years, respectively after transplantation (Figure 9). However, 24% of patients with any TCAD died within 2 years, and 50% of patients with moderate-tosevere TCAD died within 2 years (Table 6). DISCUSSION This study is the 1st reported angiographic incidence of TCAD in children, and is an analysis of 2,049 angiograms performed in 751 pediatric patients from 20 centers. This is the largest series published to date, and the study evaluated the incidence of risk factors as well as potential risk factors. The incidence of TCAD in this study was quite small and much smaller than the incident reported in adults. Furthermore, patients who did not undergo angiography or who died suddenly
Figure 5. Actuarial freedom from the presence of moderate-to-severe transplant coronary artery disease (CAD) detected by coronary angiography and stratified by recipient age. *CTRD involves the lowest curve of patients who are in the Cardiac Transplant Research Database at UAB and represents adults ⬎18 years at time of heart transplantation.
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Figure 6. Actuarial freedom from the presence of any coronary artery disease (CAD), mild, moderate, or severe, and stratified by donor age. PHTS, Pediatric Heart Transplant Study.
may have had TCAD but were not considered in the incidence and analysis. Donor and recipient age were the primary risk factors identified and probably are linked. Pre-existing donor disease may account for the increased incidence of TCAD in patients receiving transplants from donors ⬎30 years; however, routine coronary angiography early after transplantation was not performed, and this cannot be determined conclusively. The youngest recipients had the smallest incidence of TCAD. The greater incidence of TCAD in older recipients could be caused by the greater incidence of rejection in older children, or to non-compliance that may have affected immune risk factors. Certainly, we found that rejection was a risk factor for the development of TCAD, and previous studies confirm that rejection, especially with hemodynamic compromise, is a risk factor.7–11
Figure 7. Actuarial freedom from the presence of any transplant coronary artery disease (TCAD) stratified by number of rejection episodes during 1st year, includes patients who survived and had no CAD at 1 year.
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Figure 8. Bar graph demonstrating percentage of all patients receiving statins at the time of annual visits. CAD, coronary artery disease; PHTS, Pediatric Heart Transplant Study.
Because the incidence of TCAD in our study was fairly small, other risk factors not apparent in our study may play a role. The use of induction prophylaxis with lympholytics did not affect the incidence of TCAD. We also did not demonstrate that cytomegalovirus infection was a risk factor in this study, as has been shown in several adult studies.12 Additionally, our study did not assess the impact of lipids, of statin use,13 or of immunosuppressive regimen, specifically the type of calcineurin inhibitor used; the use of steroids; or the impact of mycophenolate mofetil, everolimus, or azathioprine.14,15 Prospective studies will be important to determine whether these play a role, and we will need to re-assess the incidence of TCAD in 3 to 5 years to see whether it increases as patients are observed even longer. Patients diagnosed with moderate-to-severe TCAD had a poor prognosis, with a greater incidence of death or retransplantation. If TCAD is detected, patients should be considered for retransplantation as the only
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Figure 10. Outcome after diagnosis of moderate or severe coronary artery disease (CAD) in 30 recipients, showing freedom from death or graft loss. PHTS, Pediatric Heart Transplant Study.
therapy that may improve survival.16,17 Interventional techniques have been shown to palliate symptoms but do not prolong survival.18,19 In the current era, angiography is the gold standard; however, experience is increasing with intracoronary ultrasound in children.20 –22 In our study, ⬍50% of patients underwent serial coronary angiography annually. Some centers screen only patients with abnormal graft function and rely on echocardiography for surveillance. The optimal frequency and appropriate type of investigation are debated. A recent adult study questioned the utility of routine angiographic surveillance to detect TCAD.23 However, Smart et al24 demonstrated the insensitivity of non-invasive tests to detect TCAD. We believe angiography complements other studies, including functional studies. We and others have shown that dobutamine stress echocardiography is useful prognostically if TCAD is identified and is useful to screen for significant TCAD, but will not detect subtle-to-mild TCAD.25,26 Newer imaging modalities, including tissue Doppler and cardiac magnetic resonance imaging, are in development. The use of intracoronary ultrasound may become more common in children20 –22 and would be especially useful in prospective studies of potential interventions. Table 6. Allograft CAD: Morbidity and Mortality
Figure 9. Actuarial survival of graft with the event represented as death or retransplantation with coronary artery disease (CAD) as the primary cause.
Total deaths: Primary cause CAD/infarction: Secondary cause CAD/infarction: Total Retransplantations: Primary cause CAD/infarction: Secondary cause CAD/infarction: Total grafts lost due to CAD/infarction: Primary cause Secondary cause CAD, coronary artery disease.
275 19 18 36 11 1 49 30 19
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Limitations We recognize several limitations to this analysis. The diagnosis of TCAD was based on angiographic detection of coronary abnormalities in the epicardial vessels, and in most cases, the pediatric cardiologists who read the angiograms had less experience in reviewing angiograms than did adult cardiologists. Interpretations were qualitative rather than quantitative. Thus, the presence and severity of abnormalities may have been underestimated; furthermore, contrast coronary angiography underestimates allograft TCAD,27 and few patients underwent intravascular ultrasound. In the patients identified with TCAD, no functional assessment or exercise or other stress modalities were reported to assess the impact of TCAD on allograft function. Furthermore, the incidence and severity of TCAD may have been underestimated because no autopsies were performed to determine cause in 50% of all patients; sudden deaths probably were caused by TCAD but were not counted as coronary deaths if autopsies were not performed. The small incidence of TCAD in this study makes it difficult to identify risk factors in the multivariable analysis. This study did not address the impact of medical therapies such as statins, calcium channel blockers, or type of immunosuppression on the development of TCAD. This would require a multicenter prospective study. CONCLUSIONS The incidence of TCAD in children is smaller than that in adults but increases significantly with recipient and donor age. Rejection may be a risk factor. Although graft loss was infrequent, the presence of moderate or severe TCAD was associated with poor prognosis. Prospective studies that assess the impact of different medical therapies, as well as continued follow-up of this cohort, will be necessary to follow the impact of TCAD in children. REFERENCES 1. Boucek MM, Edwards LB, Keck BM, et al. The Registry of the International Society for Heart and Lung Transplantation: Fifth Official Pediatric Report—2001 to 2002. J Heart Lung Transplant 2002;21:827– 40. 2. Pahl E, Zales VR, Fricker FJ, Addonizio LJ. Posttransplant coronary artery disease in children. A multicenter national survey. Circulation 1994;90:56 – 60. 3. Luyt CE, Drobinski G, Dorent R, et al. Prognosis of moderate coronary artery lesions in heart transplant patients. J Heart Lung Transplant 2003;22:130 – 6. 4. Johnson MR. Transplant coronary disease: nonimmunologic risk factors. J Heart Lung Transplant 1992;11:S124 –32.
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5. Costanzo-Nordin MR. Cardiac allograft vasculopathy: relationship with acute cellular rejection and histocompatibility. J Heart Lung Transplant 1992;11:S90 –103. 6. Costanzo MR, Naftel DC, Pritzker MR, et al. Heart transplant coronary artery disease detected by coronary angiography: a multiinstitutional study of preoperative donor and recipient risk factors. Cardiac Transplant Research Database. J Heart Lung Transplant 1998;17: 744 –53. 7. Kobashigawa JA. Postoperative management following heart transplantation. Transplant Proc 1999;31:2038 – 46. 8. Michaels PJ, Espejo ML, Kobashigawa J, et al. Humoral rejection in cardiac transplantation: risk factors, hemodynamic consequences and relationship to transplant coronary artery disease. J Heart Lung Transplant 2003;22:58 – 69. 9. Addonizio LJ. Current status of cardiac transplantation in children. Curr Opin Pediatr 1996;8:520 – 6. 10. Uretsky BF, Murali S, Reddy PS, et al. Development of coronary artery disease in cardiac transplant patients receiving immunosuppressive therapy with cyclosporine and prednisone. Circulation 1987;76:827–34. 11. Pahl E, Naftel DC, Canter CE, Frazier EA, Kirklin JK, Morrow WR. Death after rejection with severe hemodynamic compromise in pediatric heart transplant recipients: a multi-institutional study. J Heart Lung Transplant 2001;20:279 – 87. 12. Valantine HA. Role of CMV in transplant coronary artery disease and survival after heart transplantation. Transpl Infect Dis 1999;1(Suppl 1):25–30. 13. Kobashigawa JA, Katznelson S, Laks H, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1995;333:621–7. 14. Gao SZ, Alderman EL, Schroeder JS, Silverman JF, Hunt SA. Accelerated coronary vascular disease in the heart transplant patient: coronary arteriographic findings. J Am Coll Cardiol 1988;12:334 – 40. 15. Tuzcu EM, Schoenhagen P, Starling RC, et al. Impact of everolimus on allograft vasculopathy the SDZ RAD/Heart Intravascular Ultrasound Study. J Heart Lung Transplant 2002;21:68. 16. Michler RE, Edwards NM, Hsu D, et al. Pediatric retransplantation. J Heart Lung Transplant 1993;12(6 Pt 2): S319 –27. 17. Razzouk AJ, Chinnock RE, Dearani JA, et al. Cardiac retransplantation for graft vasculopathy in children: should we continue to do it? Arch Surg 1998;133:881–5. 18. Aranda JM Jr, Hill J. Cardiac transplant vasculopathy. Chest 2000;118:1792– 800. 19. Halle AA III, DiSciascio G, Massin EK, et al. Coronary angioplasty, atherectomy and bypass surgery in cardiac transplant recipients. J Am Coll Cardiol 1995;26:120 – 8. 20. Kuhn MA, Jutzy KR, Deming DD, et al. The medium-term findings in coronary arteries by intravascular ultrasound in infants and children after heart transplantation. J Am Coll Cardiol 2000;36:250 – 4. 21. Dent CL, Canter CE, Hirsch R, Balzer DT. Transplant coronary artery disease in pediatric heart transplant recipients. J Heart Lung Transplant 2000;19:240 – 8.
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22. Costello JM, Wax DF, Binns HJ, Backer CL, Mavroudis C, Pahl E. A comparison of intravascular ultrasound with coronary angiography for evaluation of transplant coronary disease in pediatric heart transplant recipients. J Heart Lung Transplant 2003;22:44 –9. 23. Sechtem U. Do heart transplant recipients need annual coronary angiography? Eur Heart J 2001;22:895–7. 24. Smart FW, Ballantyne CM, Cocanougher B, et al. Insensitivity of noninvasive tests to detect coronary artery vasculopathy after heart transplant. Am J Cardiol 1991;67: 243–7. 25. Pahl E, Crawford SE, Swenson JM, et al. Dobutamine stress echocardiography: experience in pediatric heart transplant recipients. J Heart Lung Transplant 1999;18: 725–32. 26. Larsen RL, Applegate PM, Dyar DA. Dobutamine stress echocardiography for assessing coronary artery disease after transplantation in children. J Am Coll Cardiol 1998; 32:515–20. 27. Rickenbacher PR, Kemna MS, Pinto FJ, Hunt SA. Coronary artery intimal thickening in the transplanted heart. An in vivo intracoronary ultrasound study of immunologic and metabolic risk factors. Transplantation 1996;61:46 –53.
APPENDIX Appendix A Pediatric Heart Transplant Study, Participating Institutions 1. Arkansas Children’s Hospital, Little Rock, Arkansas, W. Robert Morrow, MD 2. Children’s Hospital, Boston, Massachusetts, Elizabeth D. Blume, MD 3. Cleveland Clinic Foundation, Cleveland, Ohio, Maryann R. K. Chrisant, MD 4. Children’s Hospital Medical Center, Cincinnati, Ohio, Robert Spicer, MD 5. Cardinal Glennon Children’s Hospital, St. Louis, Missouri, Ian Balfour, MD 6. Children’s Hospital of Michigan, Detroit, Michigan, Tajinder P. Singh, MD
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7. Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, Steve Webber, MD 8. Children’s Memorial Hospital, Chicago, Illinois, Elfriede Pahl, MD 9. Columbia University/Babies Hospital, New York, New York, Linda J. Addonizio, MD 10. Egleston Children’s Hospital, Atlanta, Georgia, Kirk R. Kanter, MD 11. University of Florida/Shands Hospital, Jay Fricker, MD 12. Hospital for Sick Children, Toronto, Ontario, Lori West, MD 13. Loma Linda University Medical Center, Loma Linda, California, Richard E. Chinnock, MD 14. Primary Children’s Medical Center, Salt Lake City, Utah, Robert Shaddy, MD 15. St. Louis Children’s Hospital, St. Louis, Missouri, Charles E. Canter, MD 16. Stanford University Medical Center, Palo Alto, California, Daniel Bernstein, MD 17. University of Alabama at Birmingham, Birmingham, Alabama, James K. Kirklin, MD 18. University of Colorado/The Children’s Hospital, Denver, Colorado, Bill Pietra, MD 19. University of Iowa Hospitals and Clinics, Iowa City, Iowa, R. Erik Edens, MD 20. University of South Florida/All Children’s Hospital, St. Petersburg, Florida, Robert Boucek, MD
Appendix B Multivariate Analysis for Development of Angiographic Coronary Disease–Variables Examined 1. 2. 3. 4. 5. 6. 7.
Recipient demographics Donor variables Clinical variables Rejection history Surgical variables Recipient/donor mismatch variables Institution
The Impact and Outcome of Transplant Coronary Artery Disease in a Pediatric Population: A 9-Year Multi-institutional Study Elfriede Pahl, MD,a David C. Naftel, PhD,b Micheal A. Kuhn, MD,c Robert E. Shaddy, MD,d William R. Morrow, MD,e Charles E. Canter, MD,f and James Kirklin, MD,b for the Pediatric Heart Transplant Study Background: Transplant coronary artery disease (TCAD) limits survival in heart transplant recipients; however, its incidence in children is unknown. The purpose of this study was to determine the angiographic incidence of TCAD, potential risk factors, and outcomes in a large pediatric cohort. Methods: From January 1993 to December 1, a total of 1,222 children, aged newborn to 17 years, underwent primary cardiac transplantation at 20 institutions. A total of 2,049 coronary angiograms were performed in 751 patients. All angiograms were graded for coronary disease and results were submitted to the Pediatric Heart Transplant Study database. We analyzed time-related freedom from graded severity and events from coronary disease, and we examined risk factors. Results: The incidence of angiographic abnormalities at 1, 3, and 5 years was 2%, 9%, and 17%, respectively; however, moderate-to-severe disease occurred in only 6% at 5 years, compared with 15% in the adult transplant database (p ⬍0.0001). The major risk factors were older recipient and donor age. Two or more episodes of rejection in the 1st year correlated with coronary disease (p ⫽ 0.05). Overall freedom from graft loss caused by primary TCAD was 99%, 96%, and 91% at 1, 5, and 9 years after heart transplantation, respectively. Death or graft loss occurred within 2 years of diagnosis in patients with severe disease; 24% of patients with any coronary disease died within 2 years. Conclusions: The incidence of TCAD in children is smaller than the incidence in adults, but increases with age. Graft loss is infrequent in children; however, severe coronary disease correlates with poor prognosis. J Heart Lung Transplant 2005;24:645–51. Copyright © 2005 by the International Society for Heart and Lung Transplantation.
Transplant coronary artery disease (TCAD) in the allograft limits survival in adult heart recipients as well as in children.1–3 In adults, risk factors have been identified and include immune and non-immune factors.4 Angiography remains the gold standard for detection, and in a large multicenter adult study of the Cardiac Transplant Research Database (CTRD), the risk factors for TCAD were older donor age, donor male sex, and donor hypertension; recipient risk factors included male sex and black race.5 From the aChildren’s Memorial Hospital, Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Chicago, Illinois; bUniversity of Alabama, Birmingham, Alabama; cLoma Linda University Medical Center, Loma Linda, California; dPrimary Children’s Medical Center, Salt Lake City, Utah; eArkansas Children’s Hospital, Little Rock, Arkansas; and fSt. Louis Children’s Hospital, Washington University Medical School, St. Louis, Missouri. This study was presented at the American Heart Association Annual Scientific Sessions in Chicago, November 2002. Reprint requests: Elfriede Pahl, MD, Children’s Memorial Hospital, Division of Cardiology, Box 21, 2300 Children’s Plaza, Chicago, Illinois 60611. Telephone: 773-880-8185. Fax: 773-880-8111. E-mail: [email protected] Copyright © 2005 by the International Society for Heart and Lung Transplantation. 1053-2498/05/$–see front matter. doi:10.1016/ j.healun.2004.03.021
Transplant coronary artery disease has been reported in pediatric recipients in survey and autopsy series; however, the angiographic incidence of TCAD in children has not been established, especially in a large population. Furthermore, risk factors for the development of TCAD in children have not been defined and may be different from adult risk factors, in which much older donors are used for transplantation. The purpose of this study was to determine the angiographic incidence of TCAD and, once detected, to determine the potential risk factors and outcomes in a pediatric heart transplant population. METHODS Patient Population From January 1, 1993, to December 31, 2001, a total of 1,222 patients, aged newborn to 17 years, underwent primary cardiac transplantation at 20 institutions in the Pediatric Heart Transplant Study (PHTS, Appendix A). A total of 2,049 coronary angiograms were performed in 751 patients who had ⱖ1 angiogram; the majority of recipients survived ⬎1 year and form the basis of this analysis. We reviewed all angiograms for the presence of TCAD and graded the presence as none, mild, moderate, or severe. We submitted the results to the 645
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Table 1. Classification of CAD CTRD class None Mild Moderate Severe
Table 3. Age Distribution for Routine Annual Angiograms Angio lesion
Possible
Normal ⬍50% in any branch segment ⱖ50% in 1 primary vessel or ⱖ50% in branch of 2 vessels ⱖ50% in 2 primary vessels OR ⱖ50% in branches of all 3 systems OR 50% left main
Age at Transplantation ⬍6 years 6–12 years ⬎12 years Total
n 1,843 434 706 2,983
Actual n 1,140 279 457 1,876
% 62% 64% 65% 63%
p value ⫽ 0.3.
CAD, coronary artery disease; CTRD, cardiac transplant research database.
PHTS database. Severity of TCAD seen with angiograms was defined by published CTRD criteria, shown in Table 1.6 We analyzed time-related freedom from graded severity of TCAD and TCAD events and examined risk factors (Appendix B). Intracoronary ultrasound is not routine at most PHTS centers and was not assessed in this study. Choice of immunosuppression was left to individual centers; some centers used lympholytic therapy for induction, and others did not. The use of statins for lipid-decreasing effect and the use of anti-hypertensive regimens were individualized for each patient and were not standardized. Categorization of TCAD Primary vessel refers to the proximal or mid-33% of the left anterior descending, left circumflex, and dominant or codominant right coronary artery.6 Table 1 shows in detail the classification of TCAD. Therefore, the classification as mild, moderate, or severe is based on involvement of the left main, primary vessel stenosis, or branch vessel stenosis, with the class determined by the most severe TCAD reported in each coronary angiogram. An “event” refers to death or retransplantation caused by TCAD. Indications for Angiograms The majority of angiograms were performed for routine surveillance (95.5%), and most patients underwent selective coronary angiography (Table 2). Some programs perform angiography yearly, others perform angiography every 2 years, and a few do not perform routine Table 2. Indication for Angiogram N ⫽ 2,049 Routine, per protocol Selective R & L Evidence of graft dysfunction/CAD Symptoms (CHF or angina) Prior non-invasive test: CAD Other Total
n 1,956 1,895 41 32 5 15 2,049
% 95.5% 92.4% 2.0% 1.6% 0.2% 0.7% 100.0%
CAD, coronary artery disease; CHF, congestive heart failure; L, left; R, right.
angiography, thus the difference in number of studies available per patient. We observed no difference in the number of routine angiograms (62%– 65%) performed among the age groups of ⬍6 years, 6 to 12 years, or ⬎12 years (Table 3). Data Collection Appendix B lists the potential donor and recipient risk factors analyzed. We analyzed the presence and degree of TCAD using the data collection forms that the investigator at each participating center provided and that reflected the results of the coronary angiograms, usually performed at regular intervals as determined by the individual centers. The data collection form also included findings at autopsy, if available, as well as a comment as to whether death or retransplantation were the result of TCAD as a primary or contributing cause. Statistical Methods We examined the data using standard descriptive statistics, including means, standard deviations, and standard errors. We compared sub-groups using contingency tables and t-tests. Time to disease was characterized by actuarial (Kaplan-Meier) methods and by parametric methods. We identified risk factors for coronary disease by multivariable risk factor, forward, stepwise analysis in the multiphase hazard domain. All participating centers had approval from their institutional review boards to participate in this study. RESULTS Incidence and Development of TCAD Table 4 lists the percentage of angiograms graded as normal, mild, moderate, or severe TCAD. The majority (92%) showed no TCAD. Table 5 lists grading for the Table 4. Allograft CAD—All Angiograms Allograft CAD None Mild Moderate Severe Total angios CAD, coronary artery disease.
n 1,876 116 39 18 2,049
% 92 6 2 0.9 100
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Table 5. TCAD: Last Angiogram (751 patients) Allograft CAD None Mild Moderate Severe Total patients
n 681 40 17 13 751
% 91% 5% 2% 2% 100%
CAD, coronary artery disease; TCAD, transplant CAD.
most recent angiogram, which was similar. Again the majority (91%) had no TCAD, and only 2% had severe grade of TCAD. Figure 1 shows the distribution of the percentage of patients with TCAD by the years after transplantation, showing a gradual increase from 1 to 8 years. However, if only donors ⬎30 years are considered, the presence of TCAD increased greatly after 2 years after transplantation (Figure 2). The incidence of any angiographic abnormalities at 1, 3, and 5 years was 2%, 9%, and 17%, respectively (Figure 3). However, moderate-to-severe TCAD occurred in only 1%, 2%, and 5% at 1, 3 and 5 years, respectively (Figure 4) compared with 15% in the published analysis of the adult CTRD (p ⬍ 0.0001). Figure 5 portrays the effect of recipient age on presence of angiographic TCAD. We obtained data for patients ⱖ18 years old from the CTRD. We found a marked increase in the incidence of TCAD with older recipient age. Similarly, the incidence of TCAD is much greater in older donors (Figure 6). Risk Factors for TCAD The major pre-transplant risk factor that correlated with the development of TCAD was older recipient age (p ⬍ 0.0001). Recipients ⱖ12 years old had 2.9-fold the likelihood of having TCAD within 5 years compared with children ⱕ5 years (p ⫽ 0.0003). Additionally, in donors ⬎30 years of age, the risk of TCAD occurring
Figure 1. Bar graph demonstrating percentage of patients in which coronary angiography showed any evidence of coronary artery disease (CAD), with a fairly stable incidence from Years 3 to 8. PHTS, Pediatric Heart Transplant Study.
Figure 2. Bar graph showing incidence of any coronary artery disease (CAD) in recipients who had donors that were ⬎30 years of age; each bar shows the percentage of abnormal studies at the annual evaluation and shows a significant increase between 2 and 3 years. PHTS, Pediatric Heart Transplant Study.
within 5 years increased by 3 times compared with the risk in younger donors (p ⬍ 0.0001). Two or more episodes of rejection in the 1st year were associated with TCAD (p ⫽ 0.06, Figure 7). The use of statins increased with time after transplantation; however, in 5-year survivors, ⬍25% were receiving anti-lipid agents. Therefore, the use of statins was not routine (Figure 8). We found no apparent difference in the incidence of TCAD in patients who acquired cytomegalovirus infection, who received lympholytics as induction, or who varied in demographics such as race or sex. Progression and Outcome After Diagnosis of Severe TCAD Among 10 patients with severe TCAD, 4 died and 5 underwent retransplantation; 6 of these events occurred within 2 years of diagnosis. Transplant coronary artery disease as the primary cause of death or of graft
Figure 3. Actuarial freedom from the presence of any coronary artery disease (CAD), mild, moderate, or severe, detected by coronary angiography after heart transplantation.
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Figure 4. Actuarial freedom from the presence of moderate-to-severe coronary artery disease (CAD) detected by coronary angiography performed later than 6 months after heart transplantation.
loss is portrayed by years since transplantation (Table 4, Figures 9 and 10). Overall, freedom from graft loss caused by primary TCAD was 99%, 96%, and 91% at 1, 5, and 9 years, respectively after transplantation (Figure 9). However, 24% of patients with any TCAD died within 2 years, and 50% of patients with moderate-tosevere TCAD died within 2 years (Table 6). DISCUSSION This study is the 1st reported angiographic incidence of TCAD in children, and is an analysis of 2,049 angiograms performed in 751 pediatric patients from 20 centers. This is the largest series published to date, and the study evaluated the incidence of risk factors as well as potential risk factors. The incidence of TCAD in this study was quite small and much smaller than the incident reported in adults. Furthermore, patients who did not undergo angiography or who died suddenly
Figure 5. Actuarial freedom from the presence of moderate-to-severe transplant coronary artery disease (CAD) detected by coronary angiography and stratified by recipient age. *CTRD involves the lowest curve of patients who are in the Cardiac Transplant Research Database at UAB and represents adults ⬎18 years at time of heart transplantation.
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Figure 6. Actuarial freedom from the presence of any coronary artery disease (CAD), mild, moderate, or severe, and stratified by donor age. PHTS, Pediatric Heart Transplant Study.
may have had TCAD but were not considered in the incidence and analysis. Donor and recipient age were the primary risk factors identified and probably are linked. Pre-existing donor disease may account for the increased incidence of TCAD in patients receiving transplants from donors ⬎30 years; however, routine coronary angiography early after transplantation was not performed, and this cannot be determined conclusively. The youngest recipients had the smallest incidence of TCAD. The greater incidence of TCAD in older recipients could be caused by the greater incidence of rejection in older children, or to non-compliance that may have affected immune risk factors. Certainly, we found that rejection was a risk factor for the development of TCAD, and previous studies confirm that rejection, especially with hemodynamic compromise, is a risk factor.7–11
Figure 7. Actuarial freedom from the presence of any transplant coronary artery disease (TCAD) stratified by number of rejection episodes during 1st year, includes patients who survived and had no CAD at 1 year.
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Figure 8. Bar graph demonstrating percentage of all patients receiving statins at the time of annual visits. CAD, coronary artery disease; PHTS, Pediatric Heart Transplant Study.
Because the incidence of TCAD in our study was fairly small, other risk factors not apparent in our study may play a role. The use of induction prophylaxis with lympholytics did not affect the incidence of TCAD. We also did not demonstrate that cytomegalovirus infection was a risk factor in this study, as has been shown in several adult studies.12 Additionally, our study did not assess the impact of lipids, of statin use,13 or of immunosuppressive regimen, specifically the type of calcineurin inhibitor used; the use of steroids; or the impact of mycophenolate mofetil, everolimus, or azathioprine.14,15 Prospective studies will be important to determine whether these play a role, and we will need to re-assess the incidence of TCAD in 3 to 5 years to see whether it increases as patients are observed even longer. Patients diagnosed with moderate-to-severe TCAD had a poor prognosis, with a greater incidence of death or retransplantation. If TCAD is detected, patients should be considered for retransplantation as the only
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Figure 10. Outcome after diagnosis of moderate or severe coronary artery disease (CAD) in 30 recipients, showing freedom from death or graft loss. PHTS, Pediatric Heart Transplant Study.
therapy that may improve survival.16,17 Interventional techniques have been shown to palliate symptoms but do not prolong survival.18,19 In the current era, angiography is the gold standard; however, experience is increasing with intracoronary ultrasound in children.20 –22 In our study, ⬍50% of patients underwent serial coronary angiography annually. Some centers screen only patients with abnormal graft function and rely on echocardiography for surveillance. The optimal frequency and appropriate type of investigation are debated. A recent adult study questioned the utility of routine angiographic surveillance to detect TCAD.23 However, Smart et al24 demonstrated the insensitivity of non-invasive tests to detect TCAD. We believe angiography complements other studies, including functional studies. We and others have shown that dobutamine stress echocardiography is useful prognostically if TCAD is identified and is useful to screen for significant TCAD, but will not detect subtle-to-mild TCAD.25,26 Newer imaging modalities, including tissue Doppler and cardiac magnetic resonance imaging, are in development. The use of intracoronary ultrasound may become more common in children20 –22 and would be especially useful in prospective studies of potential interventions. Table 6. Allograft CAD: Morbidity and Mortality
Figure 9. Actuarial survival of graft with the event represented as death or retransplantation with coronary artery disease (CAD) as the primary cause.
Total deaths: Primary cause CAD/infarction: Secondary cause CAD/infarction: Total Retransplantations: Primary cause CAD/infarction: Secondary cause CAD/infarction: Total grafts lost due to CAD/infarction: Primary cause Secondary cause CAD, coronary artery disease.
275 19 18 36 11 1 49 30 19
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Limitations We recognize several limitations to this analysis. The diagnosis of TCAD was based on angiographic detection of coronary abnormalities in the epicardial vessels, and in most cases, the pediatric cardiologists who read the angiograms had less experience in reviewing angiograms than did adult cardiologists. Interpretations were qualitative rather than quantitative. Thus, the presence and severity of abnormalities may have been underestimated; furthermore, contrast coronary angiography underestimates allograft TCAD,27 and few patients underwent intravascular ultrasound. In the patients identified with TCAD, no functional assessment or exercise or other stress modalities were reported to assess the impact of TCAD on allograft function. Furthermore, the incidence and severity of TCAD may have been underestimated because no autopsies were performed to determine cause in 50% of all patients; sudden deaths probably were caused by TCAD but were not counted as coronary deaths if autopsies were not performed. The small incidence of TCAD in this study makes it difficult to identify risk factors in the multivariable analysis. This study did not address the impact of medical therapies such as statins, calcium channel blockers, or type of immunosuppression on the development of TCAD. This would require a multicenter prospective study. CONCLUSIONS The incidence of TCAD in children is smaller than that in adults but increases significantly with recipient and donor age. Rejection may be a risk factor. Although graft loss was infrequent, the presence of moderate or severe TCAD was associated with poor prognosis. Prospective studies that assess the impact of different medical therapies, as well as continued follow-up of this cohort, will be necessary to follow the impact of TCAD in children. REFERENCES 1. Boucek MM, Edwards LB, Keck BM, et al. The Registry of the International Society for Heart and Lung Transplantation: Fifth Official Pediatric Report—2001 to 2002. J Heart Lung Transplant 2002;21:827– 40. 2. Pahl E, Zales VR, Fricker FJ, Addonizio LJ. Posttransplant coronary artery disease in children. A multicenter national survey. Circulation 1994;90:56 – 60. 3. Luyt CE, Drobinski G, Dorent R, et al. Prognosis of moderate coronary artery lesions in heart transplant patients. J Heart Lung Transplant 2003;22:130 – 6. 4. Johnson MR. Transplant coronary disease: nonimmunologic risk factors. J Heart Lung Transplant 1992;11:S124 –32.
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5. Costanzo-Nordin MR. Cardiac allograft vasculopathy: relationship with acute cellular rejection and histocompatibility. J Heart Lung Transplant 1992;11:S90 –103. 6. Costanzo MR, Naftel DC, Pritzker MR, et al. Heart transplant coronary artery disease detected by coronary angiography: a multiinstitutional study of preoperative donor and recipient risk factors. Cardiac Transplant Research Database. J Heart Lung Transplant 1998;17: 744 –53. 7. Kobashigawa JA. Postoperative management following heart transplantation. Transplant Proc 1999;31:2038 – 46. 8. Michaels PJ, Espejo ML, Kobashigawa J, et al. Humoral rejection in cardiac transplantation: risk factors, hemodynamic consequences and relationship to transplant coronary artery disease. J Heart Lung Transplant 2003;22:58 – 69. 9. Addonizio LJ. Current status of cardiac transplantation in children. Curr Opin Pediatr 1996;8:520 – 6. 10. Uretsky BF, Murali S, Reddy PS, et al. Development of coronary artery disease in cardiac transplant patients receiving immunosuppressive therapy with cyclosporine and prednisone. Circulation 1987;76:827–34. 11. Pahl E, Naftel DC, Canter CE, Frazier EA, Kirklin JK, Morrow WR. Death after rejection with severe hemodynamic compromise in pediatric heart transplant recipients: a multi-institutional study. J Heart Lung Transplant 2001;20:279 – 87. 12. Valantine HA. Role of CMV in transplant coronary artery disease and survival after heart transplantation. Transpl Infect Dis 1999;1(Suppl 1):25–30. 13. Kobashigawa JA, Katznelson S, Laks H, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1995;333:621–7. 14. Gao SZ, Alderman EL, Schroeder JS, Silverman JF, Hunt SA. Accelerated coronary vascular disease in the heart transplant patient: coronary arteriographic findings. J Am Coll Cardiol 1988;12:334 – 40. 15. Tuzcu EM, Schoenhagen P, Starling RC, et al. Impact of everolimus on allograft vasculopathy the SDZ RAD/Heart Intravascular Ultrasound Study. J Heart Lung Transplant 2002;21:68. 16. Michler RE, Edwards NM, Hsu D, et al. Pediatric retransplantation. J Heart Lung Transplant 1993;12(6 Pt 2): S319 –27. 17. Razzouk AJ, Chinnock RE, Dearani JA, et al. Cardiac retransplantation for graft vasculopathy in children: should we continue to do it? Arch Surg 1998;133:881–5. 18. Aranda JM Jr, Hill J. Cardiac transplant vasculopathy. Chest 2000;118:1792– 800. 19. Halle AA III, DiSciascio G, Massin EK, et al. Coronary angioplasty, atherectomy and bypass surgery in cardiac transplant recipients. J Am Coll Cardiol 1995;26:120 – 8. 20. Kuhn MA, Jutzy KR, Deming DD, et al. The medium-term findings in coronary arteries by intravascular ultrasound in infants and children after heart transplantation. J Am Coll Cardiol 2000;36:250 – 4. 21. Dent CL, Canter CE, Hirsch R, Balzer DT. Transplant coronary artery disease in pediatric heart transplant recipients. J Heart Lung Transplant 2000;19:240 – 8.
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22. Costello JM, Wax DF, Binns HJ, Backer CL, Mavroudis C, Pahl E. A comparison of intravascular ultrasound with coronary angiography for evaluation of transplant coronary disease in pediatric heart transplant recipients. J Heart Lung Transplant 2003;22:44 –9. 23. Sechtem U. Do heart transplant recipients need annual coronary angiography? Eur Heart J 2001;22:895–7. 24. Smart FW, Ballantyne CM, Cocanougher B, et al. Insensitivity of noninvasive tests to detect coronary artery vasculopathy after heart transplant. Am J Cardiol 1991;67: 243–7. 25. Pahl E, Crawford SE, Swenson JM, et al. Dobutamine stress echocardiography: experience in pediatric heart transplant recipients. J Heart Lung Transplant 1999;18: 725–32. 26. Larsen RL, Applegate PM, Dyar DA. Dobutamine stress echocardiography for assessing coronary artery disease after transplantation in children. J Am Coll Cardiol 1998; 32:515–20. 27. Rickenbacher PR, Kemna MS, Pinto FJ, Hunt SA. Coronary artery intimal thickening in the transplanted heart. An in vivo intracoronary ultrasound study of immunologic and metabolic risk factors. Transplantation 1996;61:46 –53.
APPENDIX Appendix A Pediatric Heart Transplant Study, Participating Institutions 1. Arkansas Children’s Hospital, Little Rock, Arkansas, W. Robert Morrow, MD 2. Children’s Hospital, Boston, Massachusetts, Elizabeth D. Blume, MD 3. Cleveland Clinic Foundation, Cleveland, Ohio, Maryann R. K. Chrisant, MD 4. Children’s Hospital Medical Center, Cincinnati, Ohio, Robert Spicer, MD 5. Cardinal Glennon Children’s Hospital, St. Louis, Missouri, Ian Balfour, MD 6. Children’s Hospital of Michigan, Detroit, Michigan, Tajinder P. Singh, MD
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7. Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, Steve Webber, MD 8. Children’s Memorial Hospital, Chicago, Illinois, Elfriede Pahl, MD 9. Columbia University/Babies Hospital, New York, New York, Linda J. Addonizio, MD 10. Egleston Children’s Hospital, Atlanta, Georgia, Kirk R. Kanter, MD 11. University of Florida/Shands Hospital, Jay Fricker, MD 12. Hospital for Sick Children, Toronto, Ontario, Lori West, MD 13. Loma Linda University Medical Center, Loma Linda, California, Richard E. Chinnock, MD 14. Primary Children’s Medical Center, Salt Lake City, Utah, Robert Shaddy, MD 15. St. Louis Children’s Hospital, St. Louis, Missouri, Charles E. Canter, MD 16. Stanford University Medical Center, Palo Alto, California, Daniel Bernstein, MD 17. University of Alabama at Birmingham, Birmingham, Alabama, James K. Kirklin, MD 18. University of Colorado/The Children’s Hospital, Denver, Colorado, Bill Pietra, MD 19. University of Iowa Hospitals and Clinics, Iowa City, Iowa, R. Erik Edens, MD 20. University of South Florida/All Children’s Hospital, St. Petersburg, Florida, Robert Boucek, MD
Appendix B Multivariate Analysis for Development of Angiographic Coronary Disease–Variables Examined 1. 2. 3. 4. 5. 6. 7.
Recipient demographics Donor variables Clinical variables Rejection history Surgical variables Recipient/donor mismatch variables Institution