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Cardiovascular Mortality Among Heart Transplant Recipients With Asymptomatic Antibody-Mediated or Stable Mixed Cellular and Antibody-Mediated Rejection
Cardiovascular Mortality Among Heart Transplant Recipients With Asymptomatic Antibody-Mediated or Stable Mixed Cellular and Antibody-Mediated Rejection Abdallah G. Kfoury, MD,a,b M. Elizabeth H. Hammond, MD,a,b,c,d Gregory L. Snow, PhD,a Stavros G. Drakos, MD,a,b,c Josef Stehlik, MD,b,c,d Patrick W. Fisher, DO, PhD,a,b Bruce B. Reid, MD,a,b Melanie D. Everitt, MD,b,e Feras M. Bader, MD,b,c and Dale G. Renlund, MDa,b,c Background: Little has been reported on the clinical significance of asymptomatic antibody-mediated rejection (AMR) alone or mixed rejection (MR), defined as concurrent cellular rejection (CR) and AMR in heart transplantation. In this study, we examined whether a differential impact on cardiovascular mortality (CVM) existed when comparing asymptomatic AMR, to stable MR or CR. Methods: The Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program pathology database of all heart transplant recipients between 1985 and 2004 was queried. Patients were classified as cellular, antibody-mediated, or mixed rejectors based on their predominant pattern of rejection type in the first three months post-transplant. Kaplan-Meier survival curves were fit to each of the three groups and analyses were adjusted for age at the time of transplant, gender, and underlying primary cardiac disease. Results: Eight hundred and sixty nine heart transplant recipients qualified for analysis. Over the study period, patients with asymptomatic AMR or stable MR patterns had significantly worse CVM when compared to patients with stable CR pattern (AMR, 21.2%; MR, 18.0%; CR, 12.6%; AMR vs. CR, p ⫽ 0.009; MR vs. CR, p ⫽ 0.001). In contrast, CVM was comparable in patients with asymptomatic AMR or stable MR patterns (p ⫽ 0.9). Conclusions: Asymptomatic or subclinical AMR and MR are clinically relevant, should be recognized, and deserve consideration for therapeutic intervention in hopes of avoiding adverse outcomes. J Heart Lung Transplant 2009;28:781– 4. Copyright © 2009 by the International Society for Heart and Lung Transplantation.
Heart transplantation is a standard lifesaving therapy for select patients with end-stage heart failure.1 Acute cardiac allograft rejection remains a leading cause of morbidity early after transplantation. Cellular rejection (CR) has been well explored and continues to be the customary end point in clinical trials. The recently updated International Society for Heart and Lung Transplantation (ISHLT) guidelines for heart rejection recognized and defined antibody-
From the aIntermountain Medical Center and Intermountain Healthcare, bUtah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, cUniversity of Utah School of Medicine, dGeorge E. Wahlen Veterans Affairs Medical Center, and ePrimary Children’s Medical Center, and Salt Lake City, Utah. Submitted January 13, 2009; revised March 26, 2009; accepted April 29, 2009. Reprint requests: A.G. Kfoury, MD, FACC, Heart Failure Prevention and Treatment Program, Intermountain Medical Center, 5121 S Cottonwood St, Murray, UT 84107. Telephone: 801-507-4637. Fax: 801-507-4811. E-mail: [email protected] Copyright © 2009 by the International Society for Heart and Lung Transplantation. 1053-2498/09/$–see front matter. doi:10.1016/ j.healun.2009.04.035
mediated rejection (AMR), but only when clinically manifest. Routine screening for asymptomatic AMR was therefore not recommended by the consensus group report. Also, although briefly acknowledged, the clinical significance of concurrent CM and AMR, or mixed rejection (MR) remains obscure.2,3 Clinical outcomes after transplantation have historically been linked to singular episodes of allograft rejection rather than to their repetitive patterns. In contrast, we have additionally grouped heart transplant recipients as cellular, mixed, or antibody-mediated rejectors based on their predominant rejection type pattern in the first 12 weeks after transplantation. This prospective classification strategy, based on early histologic and immunofluorescence evaluation, has proven reliable for prognostication and formed the basis of 5 outcome studies, all showing a similar detrimental effect of AMR on outcomes.4 – 8 In these studies, the diagnosis of AMR was based strictly on pathologic examination of myocardial tissue, and clinically apparent AMR accounted for only approximately 6% of end points. Still, little has been reported on the effect of asymptomatic AMR alone on clinical outcomes. 781
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Kfoury et al.
The Journal of Heart and Lung Transplantation August 2009
This study evaluates cardiovascular mortality among heart transplant recipients with asymptomatic AMR, stable CR, and stable MR patterns.
cant. Analyses were adjusted for age at time of transplant, gender, and underlying primary cardiac disease. The Institutional Review Board approved this study.
METHODS Patient Population Eligible patients underwent transplantation within the Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program from 1985 through 2004. Cardiovascular mortality was defined as death resulting from acute myocardial infarction, cardiac allograft vasculopathy, sudden cardiac death, heart failure and cardiogenic shock, primary allograft failure, and pulmonary embolism. Redo heart transplantation was also considered a cardiovascular mortality end point. To focus on asymptomatic AMR and stable MR or CR, the analysis excluded patients who died from acute rejection, regardless of type, and patients presenting with hemodynamic compromise, defined as left ventricular ejection fraction of ⬍ 0.4, symptoms or signs of heart failure, or the need for intravenous inotropic therapy. The definition of stable rejection did not exclude treated patients who were otherwise clinically stable. Asymptomatic AMR was uniformly left untreated, and treated AMR was always accompanied by hemodynamic compromise.
RESULTS Patients Characteristics From 1985 through 2004, 869 patients were transplanted in the U.T.A.H. Cardiac Transplant Program and qualified for the study. Complete records were available for analysis in 822 patients. Of them, 35 patients underwent redo transplantation. The study excluded 12 patients who presented with acute rejection and hemodynamic compromise and 9 patients who never rejected. According to our definition of rejection patterns, 118 patients were classified as antibody-mediated rejectors, 193 as mixed rejectors, and 490 as cellular rejectors. Their average age was 46.6 ⫾ 15.5 years and 83% were male. Prevailing indications for heart transplantation included advanced ischemic (48%), idiopathic dilated (37%) and valvular (5%) cardiomyopathy, and congenital heart disease (5%). Induction and maintenance immunosuppression protocols were standardized across all participating institutions. The data comprised 22,325 endomyocardial biopsy specimens performed on the study population during the 19-year follow-up period.
Data Source and Rejection Pattern Definitions Our pathology data registry of endomyocardial biopsies performed on the study population was queried. Surveillance for AMR was routinely done on all biopsy specimens in the first 8 to 12 weeks after transplantation by histologic and immunofluorescence evaluation, using antibodies directed against IgG and IgM, C3d, C4d, C1q, HLA-DR, and fibrin. Histologic and immunopathologic findings were recorded independently in the pathology database. AMR was diagnosed in endomyocardial biopsies exhibiting complement and immunoglobulin deposits on frozen section, as well as histologic changes of endothelial activation and vascular adherence of macrophages, with or without edema or hemorrhage. CR was diagnosed and graded based on standardized ISHLT criteria for cardiac rejection. Patients were grouped according to their predominant rejection pattern in the first 12 weeks after transplantation.9 Cellular rejectors had ⬍ 3 episodes suggestive of AMR, antibody-mediated rejectors had ⱖ 3 episodes of AMR, and mixed rejectors included patients with ⱖ 3 episodes of concurrent CR and AMR.
Cardiovascular Mortality by Stable Rejection Pattern With an average follow-up of 91 months, (range, 0 –238 months), cardiovascular mortality occurred in 12.6% of cellular rejectors, 21.2% of antibody-mediated rejectors, and 18.0% of mixed rejectors. Figure 1 shows the actuarial survival curves for each rejection pattern group over 19 years. Survival was significantly worse in asymptomatic
Statistical Analysis Kaplan-Meier survival curves were fit to each of the 3 groups. The pairwise differences in the curves were tested using the log-rank or Mantel-Haenszel test. A value of p ⱕ 0.05 was considered statistically signifi-
Figure 1. Kaplan-Meier survival curves by rejection pattern. CR, cellular rejection; MR, mixed rejection; AMR, antibody-mediated rejection.
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cardiovascular mortality risk compared with CR. Others have also shown a higher incidence of cardiac allograft vasculopathy associated with asymptomatic AMR.11 MR is likely identified and reported by local pathologists on a regular basis, but its implications on clinical practice remain to be fully elucidated. This study contributes two essential new observations: 1. stable MR is at least as common as asymptomatic AMR; and 2. compared with stable CR, MR confers an increased cardiovascular mortality risk, even when asymptomatic or in stable patients.
Figure 2. Modes of cardiovascular death by cellular (CR, grey bars), mixed (MR, white bars) or antibody-mediated rejection (AMR, black bars) pattern. CAV, cardiac allograft vasculopathy; HF, heart failure; AMI, acute myocardial infarction; HTx, heart transplantation; SCD, sudden cardiac death; PE, pulmonary embolism.
antibody-mediated rejectors (p ⫽ 0.009) and stable mixed rejectors (p ⫽ 0.001) compared with cellular rejectors. Of interest, there was no significant difference in cardiovascular mortality between stable MRs and asymptomatic antibody-mediated rejectors (p ⫽ 0.9). Also, it appears that the separation in survival between groups started early in the post-transplant course. A breakdown of the modes of cardiovascular death by rejection pattern is detailed in Figure 2. Cardiac allograft vasculopathy and heart failure accounted for most of the deaths, regardless of the rejection pattern. This was followed by sudden cardiac death and unexplained allograft dysfunction. DISCUSSION The long-overdue recognition of cardiac AMR by the ISHLT in 2005 has resulted in a heightened interest in the topic in recent years. This has been manifest as more abstracts and didactic sessions on AMR at annual scientific meetings as well as a recent spike in related peer-reviewed publications. Yet, much remains to be answered before a standardized surveillance approach and effective treatments for AMR can be tested and implemented. The lack of non-selective screening for cardiac AMR in the absence of clinical manifestation has made it difficult to assess its true incidence. Our 23-year experience of routine early screening for AMR suggests that it, albeit mostly asymptomatic, may be more prevalent than commonly perceived.10 Also supported by the current ISHLT guidelines, has been the general inclination to discount AMR unless clinically apparent. In contrast, our study findings indicate that asymptomatic or sub-clinical AMR is associated with an increased
The cardiovascular mortality risk is statistically similar to the one associated with asymptomatic AMR. Still unanswered is which of the cellular or antibody-mediated determinants of MR comes first, or whether MR truly reflects two different but simultaneous immunologic processes rather than one. For the field to advance, the prevailing paradigm in our approach to AMR needs to evolve with the growth of our knowledge base. Specifically, asymptomatic AMR, and probably MR, should be recognized as clinically relevant; surveillance for AMR needs to increase in the early posttransplant period; a resolution should be made on which of the myocardial deposits (eg, complement, fibrin) are the most pertinent; and a consensus AMR severity scale should be developed as is the case in CR.12 Acknowledging asymptomatic AMR by eliminating defining clinical parameters would, rightfully so, make the diagnosis of AMR a strict pathologic one. It would be difficult to design and carry treatment trials in AMR in the absence of a more global and uniform approach and better understanding. To that end, updating the current ISHLT diagnostic criteria for AMR is a good initial step. REFERENCES 1. Taylor DO, Edwards LB, Boucek MM, et al. Registry of the International Society for Heart and Lung Transplantation: twentyfourth official adult heart transplant report--2007. J Heart Lung Transplant 2007;26:769 – 81. 2. Stewart S, Winters G, Fishbein M, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant 2005; 24:1710 –20. 3. Reed EF, Demetris AJ, Hammond E, et al. International Society for Heart and Lung Transplantation. Acute antibody-mediated rejection of cardiac transplants. J Heart Lung Transplant 2006;25: 153–9. 4. Hammond MEH, Yowell RL, Nunoda S, et al. Vascular (humoral) rejection in heart transplantation: pathologic observations and clinical implications. J Heart Lung Transplant 1989;8:430 – 43. 5. Ensley RD, Hammond EH, Renlund DG, et al. Clinical manifestations of vascular rejection in cardiac transplantation. Transplant Proc 1991;23:1130 –2. 6. Olsen SL, Wagoner LE, Hammond EH, et al. Vascular rejection in cardiac transplantation: clinical correlation, treatment options and
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future considerations. J Heart Lung Transplant 1993;12(suppl): S135– 42. 7. Ma H, Hammond EH, Taylor DO, et al. The repetitive histologic pattern of vascular cardiac allograft rejection. Increased incidence associated with longer exposure to prophylactic murine monoclonal anti-CD3 antibody (OKT3). Transplantation 1996; 62:205–10. 8. Taylor DO, Yowell RL, Kfoury AG, Hammond EH, Renlund DG. Allograft coronary artery disease: clinical correlation with circulating anti HLA antibodies and the immunohistopathologic pattern of vascular rejection. J Heart Lung Transplant 2000;19:518 –21. 9. Kfoury AG, Stehlik J, Renlund DG, et al. The impact of repetitive episodes of antibody-mediated or cellular rejection
The Journal of Heart and Lung Transplantation August 2009
on cardiovascular mortality in cardiac transplant recipients: defining rejection patterns. J Heart Lung Transplant 2006; 25:1277– 82. 10. Kfoury AG, Hammond EH, Snow GL, et al. Early screening for antibody-mediated rejection in heart transplant recipients. J Heart Lung Transplant 2007;26:1264 –9. 11. Patel JK, Lai C, Fishbein MC, et al. Asymptomatic humoral rejection after heart transplantation: does it require therapy? J Heart Lung Transplant 2006;25:S109. 12. Kfoury AG, Renlund DG, Snow GL, et al. A clinical correlation study of severity of antibody-mediated rejection and cardiovascular mortality in heart transplantation. J Heart Lung Transplant 2009;28:51–7.
Heart transplantation is a standard lifesaving therapy for select patients with end-stage heart failure.1 Acute cardiac allograft rejection remains a leading cause of morbidity early after transplantation. Cellular rejection (CR) has been well explored and continues to be the customary end point in clinical trials. The recently updated International Society for Heart and Lung Transplantation (ISHLT) guidelines for heart rejection recognized and defined antibody-
From the aIntermountain Medical Center and Intermountain Healthcare, bUtah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, cUniversity of Utah School of Medicine, dGeorge E. Wahlen Veterans Affairs Medical Center, and ePrimary Children’s Medical Center, and Salt Lake City, Utah. Submitted January 13, 2009; revised March 26, 2009; accepted April 29, 2009. Reprint requests: A.G. Kfoury, MD, FACC, Heart Failure Prevention and Treatment Program, Intermountain Medical Center, 5121 S Cottonwood St, Murray, UT 84107. Telephone: 801-507-4637. Fax: 801-507-4811. E-mail: [email protected] Copyright © 2009 by the International Society for Heart and Lung Transplantation. 1053-2498/09/$–see front matter. doi:10.1016/ j.healun.2009.04.035
mediated rejection (AMR), but only when clinically manifest. Routine screening for asymptomatic AMR was therefore not recommended by the consensus group report. Also, although briefly acknowledged, the clinical significance of concurrent CM and AMR, or mixed rejection (MR) remains obscure.2,3 Clinical outcomes after transplantation have historically been linked to singular episodes of allograft rejection rather than to their repetitive patterns. In contrast, we have additionally grouped heart transplant recipients as cellular, mixed, or antibody-mediated rejectors based on their predominant rejection type pattern in the first 12 weeks after transplantation. This prospective classification strategy, based on early histologic and immunofluorescence evaluation, has proven reliable for prognostication and formed the basis of 5 outcome studies, all showing a similar detrimental effect of AMR on outcomes.4 – 8 In these studies, the diagnosis of AMR was based strictly on pathologic examination of myocardial tissue, and clinically apparent AMR accounted for only approximately 6% of end points. Still, little has been reported on the effect of asymptomatic AMR alone on clinical outcomes. 781
782
Kfoury et al.
The Journal of Heart and Lung Transplantation August 2009
This study evaluates cardiovascular mortality among heart transplant recipients with asymptomatic AMR, stable CR, and stable MR patterns.
cant. Analyses were adjusted for age at time of transplant, gender, and underlying primary cardiac disease. The Institutional Review Board approved this study.
METHODS Patient Population Eligible patients underwent transplantation within the Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program from 1985 through 2004. Cardiovascular mortality was defined as death resulting from acute myocardial infarction, cardiac allograft vasculopathy, sudden cardiac death, heart failure and cardiogenic shock, primary allograft failure, and pulmonary embolism. Redo heart transplantation was also considered a cardiovascular mortality end point. To focus on asymptomatic AMR and stable MR or CR, the analysis excluded patients who died from acute rejection, regardless of type, and patients presenting with hemodynamic compromise, defined as left ventricular ejection fraction of ⬍ 0.4, symptoms or signs of heart failure, or the need for intravenous inotropic therapy. The definition of stable rejection did not exclude treated patients who were otherwise clinically stable. Asymptomatic AMR was uniformly left untreated, and treated AMR was always accompanied by hemodynamic compromise.
RESULTS Patients Characteristics From 1985 through 2004, 869 patients were transplanted in the U.T.A.H. Cardiac Transplant Program and qualified for the study. Complete records were available for analysis in 822 patients. Of them, 35 patients underwent redo transplantation. The study excluded 12 patients who presented with acute rejection and hemodynamic compromise and 9 patients who never rejected. According to our definition of rejection patterns, 118 patients were classified as antibody-mediated rejectors, 193 as mixed rejectors, and 490 as cellular rejectors. Their average age was 46.6 ⫾ 15.5 years and 83% were male. Prevailing indications for heart transplantation included advanced ischemic (48%), idiopathic dilated (37%) and valvular (5%) cardiomyopathy, and congenital heart disease (5%). Induction and maintenance immunosuppression protocols were standardized across all participating institutions. The data comprised 22,325 endomyocardial biopsy specimens performed on the study population during the 19-year follow-up period.
Data Source and Rejection Pattern Definitions Our pathology data registry of endomyocardial biopsies performed on the study population was queried. Surveillance for AMR was routinely done on all biopsy specimens in the first 8 to 12 weeks after transplantation by histologic and immunofluorescence evaluation, using antibodies directed against IgG and IgM, C3d, C4d, C1q, HLA-DR, and fibrin. Histologic and immunopathologic findings were recorded independently in the pathology database. AMR was diagnosed in endomyocardial biopsies exhibiting complement and immunoglobulin deposits on frozen section, as well as histologic changes of endothelial activation and vascular adherence of macrophages, with or without edema or hemorrhage. CR was diagnosed and graded based on standardized ISHLT criteria for cardiac rejection. Patients were grouped according to their predominant rejection pattern in the first 12 weeks after transplantation.9 Cellular rejectors had ⬍ 3 episodes suggestive of AMR, antibody-mediated rejectors had ⱖ 3 episodes of AMR, and mixed rejectors included patients with ⱖ 3 episodes of concurrent CR and AMR.
Cardiovascular Mortality by Stable Rejection Pattern With an average follow-up of 91 months, (range, 0 –238 months), cardiovascular mortality occurred in 12.6% of cellular rejectors, 21.2% of antibody-mediated rejectors, and 18.0% of mixed rejectors. Figure 1 shows the actuarial survival curves for each rejection pattern group over 19 years. Survival was significantly worse in asymptomatic
Statistical Analysis Kaplan-Meier survival curves were fit to each of the 3 groups. The pairwise differences in the curves were tested using the log-rank or Mantel-Haenszel test. A value of p ⱕ 0.05 was considered statistically signifi-
Figure 1. Kaplan-Meier survival curves by rejection pattern. CR, cellular rejection; MR, mixed rejection; AMR, antibody-mediated rejection.
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cardiovascular mortality risk compared with CR. Others have also shown a higher incidence of cardiac allograft vasculopathy associated with asymptomatic AMR.11 MR is likely identified and reported by local pathologists on a regular basis, but its implications on clinical practice remain to be fully elucidated. This study contributes two essential new observations: 1. stable MR is at least as common as asymptomatic AMR; and 2. compared with stable CR, MR confers an increased cardiovascular mortality risk, even when asymptomatic or in stable patients.
Figure 2. Modes of cardiovascular death by cellular (CR, grey bars), mixed (MR, white bars) or antibody-mediated rejection (AMR, black bars) pattern. CAV, cardiac allograft vasculopathy; HF, heart failure; AMI, acute myocardial infarction; HTx, heart transplantation; SCD, sudden cardiac death; PE, pulmonary embolism.
antibody-mediated rejectors (p ⫽ 0.009) and stable mixed rejectors (p ⫽ 0.001) compared with cellular rejectors. Of interest, there was no significant difference in cardiovascular mortality between stable MRs and asymptomatic antibody-mediated rejectors (p ⫽ 0.9). Also, it appears that the separation in survival between groups started early in the post-transplant course. A breakdown of the modes of cardiovascular death by rejection pattern is detailed in Figure 2. Cardiac allograft vasculopathy and heart failure accounted for most of the deaths, regardless of the rejection pattern. This was followed by sudden cardiac death and unexplained allograft dysfunction. DISCUSSION The long-overdue recognition of cardiac AMR by the ISHLT in 2005 has resulted in a heightened interest in the topic in recent years. This has been manifest as more abstracts and didactic sessions on AMR at annual scientific meetings as well as a recent spike in related peer-reviewed publications. Yet, much remains to be answered before a standardized surveillance approach and effective treatments for AMR can be tested and implemented. The lack of non-selective screening for cardiac AMR in the absence of clinical manifestation has made it difficult to assess its true incidence. Our 23-year experience of routine early screening for AMR suggests that it, albeit mostly asymptomatic, may be more prevalent than commonly perceived.10 Also supported by the current ISHLT guidelines, has been the general inclination to discount AMR unless clinically apparent. In contrast, our study findings indicate that asymptomatic or sub-clinical AMR is associated with an increased
The cardiovascular mortality risk is statistically similar to the one associated with asymptomatic AMR. Still unanswered is which of the cellular or antibody-mediated determinants of MR comes first, or whether MR truly reflects two different but simultaneous immunologic processes rather than one. For the field to advance, the prevailing paradigm in our approach to AMR needs to evolve with the growth of our knowledge base. Specifically, asymptomatic AMR, and probably MR, should be recognized as clinically relevant; surveillance for AMR needs to increase in the early posttransplant period; a resolution should be made on which of the myocardial deposits (eg, complement, fibrin) are the most pertinent; and a consensus AMR severity scale should be developed as is the case in CR.12 Acknowledging asymptomatic AMR by eliminating defining clinical parameters would, rightfully so, make the diagnosis of AMR a strict pathologic one. It would be difficult to design and carry treatment trials in AMR in the absence of a more global and uniform approach and better understanding. To that end, updating the current ISHLT diagnostic criteria for AMR is a good initial step. REFERENCES 1. Taylor DO, Edwards LB, Boucek MM, et al. Registry of the International Society for Heart and Lung Transplantation: twentyfourth official adult heart transplant report--2007. J Heart Lung Transplant 2007;26:769 – 81. 2. Stewart S, Winters G, Fishbein M, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant 2005; 24:1710 –20. 3. Reed EF, Demetris AJ, Hammond E, et al. International Society for Heart and Lung Transplantation. Acute antibody-mediated rejection of cardiac transplants. J Heart Lung Transplant 2006;25: 153–9. 4. Hammond MEH, Yowell RL, Nunoda S, et al. Vascular (humoral) rejection in heart transplantation: pathologic observations and clinical implications. J Heart Lung Transplant 1989;8:430 – 43. 5. Ensley RD, Hammond EH, Renlund DG, et al. Clinical manifestations of vascular rejection in cardiac transplantation. Transplant Proc 1991;23:1130 –2. 6. Olsen SL, Wagoner LE, Hammond EH, et al. Vascular rejection in cardiac transplantation: clinical correlation, treatment options and
784
Kfoury et al.
future considerations. J Heart Lung Transplant 1993;12(suppl): S135– 42. 7. Ma H, Hammond EH, Taylor DO, et al. The repetitive histologic pattern of vascular cardiac allograft rejection. Increased incidence associated with longer exposure to prophylactic murine monoclonal anti-CD3 antibody (OKT3). Transplantation 1996; 62:205–10. 8. Taylor DO, Yowell RL, Kfoury AG, Hammond EH, Renlund DG. Allograft coronary artery disease: clinical correlation with circulating anti HLA antibodies and the immunohistopathologic pattern of vascular rejection. J Heart Lung Transplant 2000;19:518 –21. 9. Kfoury AG, Stehlik J, Renlund DG, et al. The impact of repetitive episodes of antibody-mediated or cellular rejection
The Journal of Heart and Lung Transplantation August 2009
on cardiovascular mortality in cardiac transplant recipients: defining rejection patterns. J Heart Lung Transplant 2006; 25:1277– 82. 10. Kfoury AG, Hammond EH, Snow GL, et al. Early screening for antibody-mediated rejection in heart transplant recipients. J Heart Lung Transplant 2007;26:1264 –9. 11. Patel JK, Lai C, Fishbein MC, et al. Asymptomatic humoral rejection after heart transplantation: does it require therapy? J Heart Lung Transplant 2006;25:S109. 12. Kfoury AG, Renlund DG, Snow GL, et al. A clinical correlation study of severity of antibody-mediated rejection and cardiovascular mortality in heart transplantation. J Heart Lung Transplant 2009;28:51–7.