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Human Leukocyte Antigen-G Polymorphisms as Predictors of Early Cardiac Allograft Vasculopathy
Abstracts S99 with bx within pAMR1i or pAMR2 types (p= 0.265). CVM was significantly worse for those pts with 1 or more pAMR3 bx (HR= 10.7) Conclusion: Complement negative AMR confers the same increased risk of CVM as complement positive AMR - pAMR1i and pAMR2. Complement negative AMR appears to a rare but real variant of AMR. Such AMR could result from deposition of non-complement binding antibodies, endothelial specific processes like infection or inflammation or due to complement testing inaccuracy.
Bx and Pt Characteristics Categories Never pAMR (pAMR0) but testing done Complement negative AMR (pAMR1h only), > 0 bx/pt Any AMR (pAMRi,2,3), > 0 bx/pt; mixed rejection included
No of Bx
No of Pts
724 514
152 73
13096
836
“Mild” MR [1R/pAMR 1(H+) and 1R/pAMR 1(I+)] was by far the most common occurrence (1170 out of 2184, 54%). When the CR score increased in severity, the AMR score tended to follow (pAMR 2 and pAMR 3 most frequent within 2R and 3R respectively). Interestingly, this was not the case with the vascular (pAMR) score as mild CR still prevailed regardless of AMR severity. Conclusion: Our observations suggest that in MR, cellular mechanisms are more likely to entrain a stepwise humoral response whereas the course of AMR is more likely to proceed independently. This favors “the sum of two” hypothesis for MR but with some unequal interplay, yet to be elucidated, between CR and AMR.
2( 51)
2( 50) Mixed Cellular and Antibody-Mediated Rejection in Heart Transplantation: A Distinct Entity or Simply the Sum of Two? A. Kfoury , D. Miller, G. Snow, K. Afshar, J. Stehlik, D. Budge, W. Caine, S. McKellar, M. Everitt, R. Alharethi, J. Fang, S. Drakos, E. Gilbert, E. Hammond. UTAH Cardiac Transplant Program, Murray, UT. Purpose: Mixed rejection (MR) of the cardiac allograft is limited to rare case reports and a brief acknowledgment in the updated 2013 ISHLT working formulation for the standardization of antibody-mediated rejection nomenclature. A fundamental question remains whether MR is a separate entity with unique pathologic characteristics or just cellular rejection (CR) and antibody-mediated rejection (AMR) occurring concomitantly. Methods: The UTAH Cardiac Transplant Program (UCTP) pathology database was queried for all endomyocardial biopsies (EMBs) on heart transplant recipients between 1985 and 2014. Acute rejection was strictly defined by pathologic criteria without consideration of clinical significance. Only EMBs with reported both CR and AMR scores were included. EMBs with mismatched “old” versus “new” cellular rejection nomenclatures (for ex, 1A and 3R) and those with incomplete information (for ex, missing the biopsy date) were excluded. Since we have diagnosed AMR for over 25 years, UCTP AMR scores predating standardization were converted to their equivalent ISHLT pAMR scores. Results: 28,484 EMBs from 1207 patients qualified for analyses. The overall incidence of MR was 7.7%. The prevalence of each of the 12 possible permutations of CR (1R to 3R) and AMR (pAMR 1 to pAMR 3) scores consistent with MR are detailed in the table below.
Human Leukocyte Antigen-G Polymorphisms as Predictors of Early Cardiac Allograft Vasculopathy J. Lazarte ,1 L. Goldraich,2 H. Kawajiri,3 A. Ghashghai,1 L. GrosmanRimon,3 L. Tumiati,3 V. Rao,3 D. Delgado.2 1Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 2Cardiology, Toronto General Hospital, Toronto, ON, Canada; 3Cardiovascular Surgery, Toronto General Hospital, Toronto, ON, Canada. Purpose: The Human Leukocyte Antigen (HLA)-G, a non-classical class 1b protein from the major histocompatibility complex (MHC), promotes an inhibitory response in natural killer cells, cytotoxic T-lymphocytes, macrophages and mononuclear cells. High serum levels of HLA-G are associated with lower rates of rejection and better graft outcomes in heart transplant recipients. The association between HLA-G polymorphisms and cardiac allograft vasculopathy (CAV) remains unclear. Objective: to determine the association between HLA-G single nucleotide polymorphisms (SNPs) and early CAV. Methods: Consecutive adult heart transplant recipients who had 1-year coronary angiogram at 1-year post-transplant were evaluated for the presence of HLA-G SNPs. CAV was classified according to ISHLT criteria. Each patient’s DNA was collected and genotyped for 14bp INDEL and 3’ UTR +3196. The ancestral genotyped was compared against the heterozygous and mutant genotype combined. For SNP +3196, the GG genotype was compared to the GC and CC and for SNP 14bp DEL genotype vs. INSDEL and INS genotype. Prevalence of CAV at 1 year was compared between patients with and without ancestral genotypes for each SNP. The association between SNPs and CAV at 1 year was examined by logistic regression model adjusted for recipient gender and donor age. Results: We prospectively enrolled 103 heart transplant patients (recipient age 47±12 years; 38% female; donor age 36.15±14.8 years). Of those, 32 (31%) were diagnosed with CAV at 1-year post transplant. There was a significant association between presence of CAV and the 14bp and +3196 SNP frequencies (p = 0.046 and p = 0.013). On multivariable analysis adjusting for recipient age at transplant and donor age, SNP +3196 (CC/GC) was associated with increase protection (0.27, CI 0.09-0.75, p= 0.012). On the other hand, SNP 14bp (INS/INSDEL) trended towards increase risk (2.47, CI 0.91- 6.73 and p= 0.076). Conclusion: The +3196 CC/GC genotype was significantly associated with a reduction in early CAV after heart transplantation after adjusting for donor and recipient age. GG genotype is a predictive variable for increase risk of early CAV (OR = 3.84). In addition, there is a borderline association between SNP 14bp and INS/INSDEL genotype and increase risk of early CAV (OR = 2.47). 2( 52) Influence of Angiotensin-Type1-Receptor Antibodies in Chronic Vascular Injury on Heart Transplant Patients L. Borgese ,1 L. Potena,2 E. Resciniti,1 S. Capelli,3 A. Bontadini,3 S. Iannelli,3 F. Fruet,3 M. Sabatino,1 F. Scardino,1 M. Masetti,1 P. Prestinenzi,1 V. Manfredini,1 C. Rapezzi,2 F. Grigioni.1 1University of Bologna, Bologna, Italy; 2Cardiovascular Department, S.Orsola-Malpighi
Bx and Pt Characteristics Categories Never pAMR (pAMR0) but testing done Complement negative AMR (pAMR1h only), > 0 bx/pt Any AMR (pAMRi,2,3), > 0 bx/pt; mixed rejection included
No of Bx
No of Pts
724 514
152 73
13096
836
“Mild” MR [1R/pAMR 1(H+) and 1R/pAMR 1(I+)] was by far the most common occurrence (1170 out of 2184, 54%). When the CR score increased in severity, the AMR score tended to follow (pAMR 2 and pAMR 3 most frequent within 2R and 3R respectively). Interestingly, this was not the case with the vascular (pAMR) score as mild CR still prevailed regardless of AMR severity. Conclusion: Our observations suggest that in MR, cellular mechanisms are more likely to entrain a stepwise humoral response whereas the course of AMR is more likely to proceed independently. This favors “the sum of two” hypothesis for MR but with some unequal interplay, yet to be elucidated, between CR and AMR.
2( 51)
2( 50) Mixed Cellular and Antibody-Mediated Rejection in Heart Transplantation: A Distinct Entity or Simply the Sum of Two? A. Kfoury , D. Miller, G. Snow, K. Afshar, J. Stehlik, D. Budge, W. Caine, S. McKellar, M. Everitt, R. Alharethi, J. Fang, S. Drakos, E. Gilbert, E. Hammond. UTAH Cardiac Transplant Program, Murray, UT. Purpose: Mixed rejection (MR) of the cardiac allograft is limited to rare case reports and a brief acknowledgment in the updated 2013 ISHLT working formulation for the standardization of antibody-mediated rejection nomenclature. A fundamental question remains whether MR is a separate entity with unique pathologic characteristics or just cellular rejection (CR) and antibody-mediated rejection (AMR) occurring concomitantly. Methods: The UTAH Cardiac Transplant Program (UCTP) pathology database was queried for all endomyocardial biopsies (EMBs) on heart transplant recipients between 1985 and 2014. Acute rejection was strictly defined by pathologic criteria without consideration of clinical significance. Only EMBs with reported both CR and AMR scores were included. EMBs with mismatched “old” versus “new” cellular rejection nomenclatures (for ex, 1A and 3R) and those with incomplete information (for ex, missing the biopsy date) were excluded. Since we have diagnosed AMR for over 25 years, UCTP AMR scores predating standardization were converted to their equivalent ISHLT pAMR scores. Results: 28,484 EMBs from 1207 patients qualified for analyses. The overall incidence of MR was 7.7%. The prevalence of each of the 12 possible permutations of CR (1R to 3R) and AMR (pAMR 1 to pAMR 3) scores consistent with MR are detailed in the table below.
Human Leukocyte Antigen-G Polymorphisms as Predictors of Early Cardiac Allograft Vasculopathy J. Lazarte ,1 L. Goldraich,2 H. Kawajiri,3 A. Ghashghai,1 L. GrosmanRimon,3 L. Tumiati,3 V. Rao,3 D. Delgado.2 1Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 2Cardiology, Toronto General Hospital, Toronto, ON, Canada; 3Cardiovascular Surgery, Toronto General Hospital, Toronto, ON, Canada. Purpose: The Human Leukocyte Antigen (HLA)-G, a non-classical class 1b protein from the major histocompatibility complex (MHC), promotes an inhibitory response in natural killer cells, cytotoxic T-lymphocytes, macrophages and mononuclear cells. High serum levels of HLA-G are associated with lower rates of rejection and better graft outcomes in heart transplant recipients. The association between HLA-G polymorphisms and cardiac allograft vasculopathy (CAV) remains unclear. Objective: to determine the association between HLA-G single nucleotide polymorphisms (SNPs) and early CAV. Methods: Consecutive adult heart transplant recipients who had 1-year coronary angiogram at 1-year post-transplant were evaluated for the presence of HLA-G SNPs. CAV was classified according to ISHLT criteria. Each patient’s DNA was collected and genotyped for 14bp INDEL and 3’ UTR +3196. The ancestral genotyped was compared against the heterozygous and mutant genotype combined. For SNP +3196, the GG genotype was compared to the GC and CC and for SNP 14bp DEL genotype vs. INSDEL and INS genotype. Prevalence of CAV at 1 year was compared between patients with and without ancestral genotypes for each SNP. The association between SNPs and CAV at 1 year was examined by logistic regression model adjusted for recipient gender and donor age. Results: We prospectively enrolled 103 heart transplant patients (recipient age 47±12 years; 38% female; donor age 36.15±14.8 years). Of those, 32 (31%) were diagnosed with CAV at 1-year post transplant. There was a significant association between presence of CAV and the 14bp and +3196 SNP frequencies (p = 0.046 and p = 0.013). On multivariable analysis adjusting for recipient age at transplant and donor age, SNP +3196 (CC/GC) was associated with increase protection (0.27, CI 0.09-0.75, p= 0.012). On the other hand, SNP 14bp (INS/INSDEL) trended towards increase risk (2.47, CI 0.91- 6.73 and p= 0.076). Conclusion: The +3196 CC/GC genotype was significantly associated with a reduction in early CAV after heart transplantation after adjusting for donor and recipient age. GG genotype is a predictive variable for increase risk of early CAV (OR = 3.84). In addition, there is a borderline association between SNP 14bp and INS/INSDEL genotype and increase risk of early CAV (OR = 2.47). 2( 52) Influence of Angiotensin-Type1-Receptor Antibodies in Chronic Vascular Injury on Heart Transplant Patients L. Borgese ,1 L. Potena,2 E. Resciniti,1 S. Capelli,3 A. Bontadini,3 S. Iannelli,3 F. Fruet,3 M. Sabatino,1 F. Scardino,1 M. Masetti,1 P. Prestinenzi,1 V. Manfredini,1 C. Rapezzi,2 F. Grigioni.1 1University of Bologna, Bologna, Italy; 2Cardiovascular Department, S.Orsola-Malpighi