- Email: [email protected]
315: The Impact of HLA-G Polymorphism on Acute Rejection in Pediatric Heart Transplant Recipients
S106
The Journal of Heart and Lung Transplantation, Vol 29, No 2S, February 2010
mean pulmonary artery pressure (MPAP) associated with increased pulmonary vascular resistance (PVR) and left and right filling pressure. There was no change in heart rate, mean arterial pressure (MAP), or cardiac output, except in one animal in which severe acute PHT precipitated cardiac arrest. There were no changes in PLA or CON animals over the corresponding period.[figure1]From 90 mins post-BD (i.e. 30 mins after T3) there was an increase in MAP in T3 animals; there was a smaller increase in PLA animals, such that by 360 mins they trended towards lower MAP (77.8⫾3.4 vs 91.7⫾5.7, p⫽0.063). In contrast MAP declined in CON animals; by 360 mins they were significantly hypotensive compared with T3 and PLA animals (43.0⫾5.7 p⬍0.003 vs T3 and PLA). There were no differences in heart rate, MPAP or filling pressures.
Conclusions: T3 loading dose causes acute PHT in brain dead pigs due to increased PVR. Methylprednisolone is an important element of HR in achieving haemodynamic stability. The need for a T3 loading dose in HR protocols should be revisited. 314 Myocardial Protection in Heart Transplantation Using Blood Cardioplegia: 12 Years Outcome of a Prospective Randomized Trial A. Forni, G. Faggian, G.B. Luciani, B. Chiominto, F. Patelli, V. Giambruno, A. Mazzucco. University Hospital of Verona, Verona, Italy. Purpose: Early outcome heart transplantation (HTX) using blood cardioplegia showed lower prevalence of right heart failure, arrhytmias and myocardial ischemia. In order to define its long term impact, 12 years (y.) outcome of a prospective randomized patients (pts.) cohort was reviewed. Methods and Materials: Pts. enrolled either to crystalloid (27 pts.), group1,G1 or to blood cardioplegia (20 pts.) group 2, G2. did not show in preoperative evaluation statistically significant difference neither in terms of sex (G1, male 89% vs. G2 male 90%, p.0.9), nor of age (G1 m.age 54⫾ 11y. vs. 55⫾ 7y, p.0.9,) nor of HTX indication (Dilated cardiomyiopathy: G1 65% vs. G2 65%, p.v. 0.8), nor of transpulmonary gradient ⬎ 5 Woods Units (G1 25% vs. G2 28% p.0.6). Among donors difference was not significant neither for age (G1: 32⫾11 y. vs. 31⫾13), nor for cause of death, (vascular, G1: 33% vs. 40%, p.v. 0.5) nor for marginal criteria classification (G1: 15% vs. G2:45% p: 0.2. Pts. were follow-up from 152 to 137 mos. (m.142 ⫾ 32 mos.). Chronic rejection (CR) surveillance was based on annual coronary angiography. Results: Twelve y. survival was 77 ⫾12 in G1 vs. 59 ⫾ 7 in G2, p.0.7. Causes of death were CR in 14 pts. (7 G1 and 7 G2), lymphoma in 2 pts. (1 G1, 1 G2), pulmonary adenocarcinoma in 2 pts. (1 G1, 1 G2,and freedom from neoplasia: G1 84%⫾7 in G1 vs. 74% 12 in G2).Twelve y. freedom from CR was 56% ⫾8 in G1 vs, 65%⫾12 in G2.Mean revascularization procedures (PTCA)number/pt was 2,7 ⫾ 0.5 in G1 vs. 1,9 ⫾0.1 in G2, p.n.s.. Single vessel occurence was: G1 49%⫾11 vs. G2: 58%, while, while multiple vessels occurence was: G1, 45% vs. G2, 36%. Interval between diagnosis of CR and death was 18⫾0,9 mos. in G1 vs. 22⫾1.7 in G2. Blood cardioplegia containing high potassium concentration didn’t lead to severe endothelium damage. Conclusions: Blood cardioplegia is safe and effective both in the short and
in the long term. Occurrence of CR, extent of coronary arteries lesions and PTCA number was higher in crystalloid but not statistically significant. 315 The Impact of HLA-G Polymorphism on Acute Rejection in Pediatric Heart Transplant Recipients A. Zeevi,1 M. Brooks,1 D. Girnita,1 R. Ferrell,1 R. Chinnock,2 C. Canter,3 L. Addonizio,4 D. Bernstein,5 J. Kirklin,6 D. Naftel,6 S. Webber.1 1University of Pittsburgh, Pittsburgh, PA; 2Loma Linda University, Loma Linda, CA; 3Washington University, St. Louis, MO; 4 Columbia University, New York, NY; 5Stanford University, Palo Alto, CA; 6University of Alabama Birmingham, Birmimgham, AL. Purpose: Acute rejection remains a leading cause of death after pediatric heart transplantation (PHTx) and recipient black race and age at transplantation have been shown to be major risk factors. We previously demonstrated that the combination of IL-6 High/VEGF High and IL-10 Low genetic polymorphisms was associated with increased risk of rejection independent of race and age. IL-10 has been shown to enhance the expression of HLA-G, the non-classical HLA class Ib gene, involved in immune modulation. Differences in the pattern of alternative splicing of HLA-G mRNA transcripts have been associated with HLA-G polymorphisms (GP), especially a 14bp deletion/insertion polymorphism in the 3’ un-translated region of the HLA-G gene. Aim: To determine the frequency of HLA-G genotype (14bp⫺/14bp⫺ or DD; 14bp⫺/14bp⫹ or DI; 14bp⫹/14bp⫹or II) in a large cohort of PHTx recipients and to explore associations with acute rejection profiles while controlling for other variables known to influence acute rejection (i.e. race, age and cytokine GP). Methods and Materials: 414 PHTx recipients at six centers followed within the Pediatric Heart Transplant were analyzed for the14bp polymorphism of exon 8 in the 3’-untranslated region of HLA-G. First year rejection episodes and repeat rejection were analyzed by genotype, controlling for potential confounders. Results: Mean follow-up for the cohort was 5.25 years. The frequency of HLA-G genotype was 34% DD, 48.6% DI and 17.4% II. PHTx carriers of HLA-G II genotype experienced an increased frequency of rejection in the first year post-Tx (mean⫾ SD: II group 1.38⫾1.28 vs DD group 1.03⫾1.13 and ID group 0.98⫹1.15) (p⫽0.0425). The hazard ratio for second rejection event was 1.69 (p⫽0.016) (controlling for race, age and IL-10 genotype) for II genotype compared to DD. Conclusions: Our data provide support for the hypothesis that HLA-G may have a protective effect and lower expression (HLA-G II genotype) is associated with increased frequency of rejection. The protective effect of HLA-G genotype was independent from the IL-10 High genotype. 316 Minimal (A1) Acute Rejection Episodes are Independent Risk Factors for the Development of Bronchiolitis Obliterans Syndrome in Pediatric Lung Transplant Recipients O. Elidemir,1 N.P. Varghese,1 E.O. Smith,1 G.B. Mallory,1 E.D. McKenzie,2 J.S. Heinle,2 D.L. Morales,2 M.G. Schecter.1 1Baylor College of Medicine, Houston, TX; 2Baylor College of Medicine, Houston, TX. Purpose: Bronchiolitis obliterans (BO) is the principal cause of long-term morbidity and mortality in lung transplant recipients. While the exact etiology of BO and its clinical correlate, bronchiolitis obliterans syndrome (BOS), is unknown, an association with minimal (A1) rejection has been recently reported in the adult transplant literature. However, this has never been documented in pediatric lung transplant recipients. Thus, in this study we evaluated A1 acute rejection episodes as an independent risk factor for the development of BOS in pediatric lung transplant recipients. Methods and Materials: We performed a retrospective chart review of lung transplant recipients at Texas Childrens Hospital transplanted between October 2002 and July 2007. Ordinary multiple logistic regression analysis was used to assess the number of A1 rejection episodes as a risk factor for BOS while controlling for sex and age. Results: Total of 68 pediatric lung transplant recipients were identified; 42
The Journal of Heart and Lung Transplantation, Vol 29, No 2S, February 2010
mean pulmonary artery pressure (MPAP) associated with increased pulmonary vascular resistance (PVR) and left and right filling pressure. There was no change in heart rate, mean arterial pressure (MAP), or cardiac output, except in one animal in which severe acute PHT precipitated cardiac arrest. There were no changes in PLA or CON animals over the corresponding period.[figure1]From 90 mins post-BD (i.e. 30 mins after T3) there was an increase in MAP in T3 animals; there was a smaller increase in PLA animals, such that by 360 mins they trended towards lower MAP (77.8⫾3.4 vs 91.7⫾5.7, p⫽0.063). In contrast MAP declined in CON animals; by 360 mins they were significantly hypotensive compared with T3 and PLA animals (43.0⫾5.7 p⬍0.003 vs T3 and PLA). There were no differences in heart rate, MPAP or filling pressures.
Conclusions: T3 loading dose causes acute PHT in brain dead pigs due to increased PVR. Methylprednisolone is an important element of HR in achieving haemodynamic stability. The need for a T3 loading dose in HR protocols should be revisited. 314 Myocardial Protection in Heart Transplantation Using Blood Cardioplegia: 12 Years Outcome of a Prospective Randomized Trial A. Forni, G. Faggian, G.B. Luciani, B. Chiominto, F. Patelli, V. Giambruno, A. Mazzucco. University Hospital of Verona, Verona, Italy. Purpose: Early outcome heart transplantation (HTX) using blood cardioplegia showed lower prevalence of right heart failure, arrhytmias and myocardial ischemia. In order to define its long term impact, 12 years (y.) outcome of a prospective randomized patients (pts.) cohort was reviewed. Methods and Materials: Pts. enrolled either to crystalloid (27 pts.), group1,G1 or to blood cardioplegia (20 pts.) group 2, G2. did not show in preoperative evaluation statistically significant difference neither in terms of sex (G1, male 89% vs. G2 male 90%, p.0.9), nor of age (G1 m.age 54⫾ 11y. vs. 55⫾ 7y, p.0.9,) nor of HTX indication (Dilated cardiomyiopathy: G1 65% vs. G2 65%, p.v. 0.8), nor of transpulmonary gradient ⬎ 5 Woods Units (G1 25% vs. G2 28% p.0.6). Among donors difference was not significant neither for age (G1: 32⫾11 y. vs. 31⫾13), nor for cause of death, (vascular, G1: 33% vs. 40%, p.v. 0.5) nor for marginal criteria classification (G1: 15% vs. G2:45% p: 0.2. Pts. were follow-up from 152 to 137 mos. (m.142 ⫾ 32 mos.). Chronic rejection (CR) surveillance was based on annual coronary angiography. Results: Twelve y. survival was 77 ⫾12 in G1 vs. 59 ⫾ 7 in G2, p.0.7. Causes of death were CR in 14 pts. (7 G1 and 7 G2), lymphoma in 2 pts. (1 G1, 1 G2), pulmonary adenocarcinoma in 2 pts. (1 G1, 1 G2,and freedom from neoplasia: G1 84%⫾7 in G1 vs. 74% 12 in G2).Twelve y. freedom from CR was 56% ⫾8 in G1 vs, 65%⫾12 in G2.Mean revascularization procedures (PTCA)number/pt was 2,7 ⫾ 0.5 in G1 vs. 1,9 ⫾0.1 in G2, p.n.s.. Single vessel occurence was: G1 49%⫾11 vs. G2: 58%, while, while multiple vessels occurence was: G1, 45% vs. G2, 36%. Interval between diagnosis of CR and death was 18⫾0,9 mos. in G1 vs. 22⫾1.7 in G2. Blood cardioplegia containing high potassium concentration didn’t lead to severe endothelium damage. Conclusions: Blood cardioplegia is safe and effective both in the short and
in the long term. Occurrence of CR, extent of coronary arteries lesions and PTCA number was higher in crystalloid but not statistically significant. 315 The Impact of HLA-G Polymorphism on Acute Rejection in Pediatric Heart Transplant Recipients A. Zeevi,1 M. Brooks,1 D. Girnita,1 R. Ferrell,1 R. Chinnock,2 C. Canter,3 L. Addonizio,4 D. Bernstein,5 J. Kirklin,6 D. Naftel,6 S. Webber.1 1University of Pittsburgh, Pittsburgh, PA; 2Loma Linda University, Loma Linda, CA; 3Washington University, St. Louis, MO; 4 Columbia University, New York, NY; 5Stanford University, Palo Alto, CA; 6University of Alabama Birmingham, Birmimgham, AL. Purpose: Acute rejection remains a leading cause of death after pediatric heart transplantation (PHTx) and recipient black race and age at transplantation have been shown to be major risk factors. We previously demonstrated that the combination of IL-6 High/VEGF High and IL-10 Low genetic polymorphisms was associated with increased risk of rejection independent of race and age. IL-10 has been shown to enhance the expression of HLA-G, the non-classical HLA class Ib gene, involved in immune modulation. Differences in the pattern of alternative splicing of HLA-G mRNA transcripts have been associated with HLA-G polymorphisms (GP), especially a 14bp deletion/insertion polymorphism in the 3’ un-translated region of the HLA-G gene. Aim: To determine the frequency of HLA-G genotype (14bp⫺/14bp⫺ or DD; 14bp⫺/14bp⫹ or DI; 14bp⫹/14bp⫹or II) in a large cohort of PHTx recipients and to explore associations with acute rejection profiles while controlling for other variables known to influence acute rejection (i.e. race, age and cytokine GP). Methods and Materials: 414 PHTx recipients at six centers followed within the Pediatric Heart Transplant were analyzed for the14bp polymorphism of exon 8 in the 3’-untranslated region of HLA-G. First year rejection episodes and repeat rejection were analyzed by genotype, controlling for potential confounders. Results: Mean follow-up for the cohort was 5.25 years. The frequency of HLA-G genotype was 34% DD, 48.6% DI and 17.4% II. PHTx carriers of HLA-G II genotype experienced an increased frequency of rejection in the first year post-Tx (mean⫾ SD: II group 1.38⫾1.28 vs DD group 1.03⫾1.13 and ID group 0.98⫹1.15) (p⫽0.0425). The hazard ratio for second rejection event was 1.69 (p⫽0.016) (controlling for race, age and IL-10 genotype) for II genotype compared to DD. Conclusions: Our data provide support for the hypothesis that HLA-G may have a protective effect and lower expression (HLA-G II genotype) is associated with increased frequency of rejection. The protective effect of HLA-G genotype was independent from the IL-10 High genotype. 316 Minimal (A1) Acute Rejection Episodes are Independent Risk Factors for the Development of Bronchiolitis Obliterans Syndrome in Pediatric Lung Transplant Recipients O. Elidemir,1 N.P. Varghese,1 E.O. Smith,1 G.B. Mallory,1 E.D. McKenzie,2 J.S. Heinle,2 D.L. Morales,2 M.G. Schecter.1 1Baylor College of Medicine, Houston, TX; 2Baylor College of Medicine, Houston, TX. Purpose: Bronchiolitis obliterans (BO) is the principal cause of long-term morbidity and mortality in lung transplant recipients. While the exact etiology of BO and its clinical correlate, bronchiolitis obliterans syndrome (BOS), is unknown, an association with minimal (A1) rejection has been recently reported in the adult transplant literature. However, this has never been documented in pediatric lung transplant recipients. Thus, in this study we evaluated A1 acute rejection episodes as an independent risk factor for the development of BOS in pediatric lung transplant recipients. Methods and Materials: We performed a retrospective chart review of lung transplant recipients at Texas Childrens Hospital transplanted between October 2002 and July 2007. Ordinary multiple logistic regression analysis was used to assess the number of A1 rejection episodes as a risk factor for BOS while controlling for sex and age. Results: Total of 68 pediatric lung transplant recipients were identified; 42