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HUMAN LEUKOCYTE ANTIGEN-G POLYMORPHISMS ARE PREDICTORS OF POST-TRANSPLANT CARDIAC ALLOGRAFT VASCULOPATHY
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Canadian Cardiovascular Society (CCS) Oral MAN VS MACHINE: TRANSPLANT AND VAD’S Sunday, October 25, 2015 377 INSIGHTS FROM A QUÉBEC FIELD EVALUATION OF LEFT VENTRICULAR ASSIST DEVICE THERAPY COMPARED WITH THE INTERMACS REGISTRY: CAN SMALL STILL BE BEAUTIFUL? A Ducharme, E Charbonneau, R Cecere, M Carrier, N Giannetti, M Sénéchal, LJ Lambert, G Sas, C Sanscartier, L Azzi, P Bogaty Montréal, Québec BACKGROUND:
The left ventricular assist device (LVAD) is now an accepted therapy for patients with terminal heart failure, even if they are not candidates for cardiac transplantation. Recent reports have suggested that favorable outcomes are directly related to the per-centre volume of LVAD implantation. We examined the characteristics and clinical outcomes of our province-wide field evaluation and compared them with the large US INTERMACS registry. METHODS: Patient data were collected by the clinical teams in Québec’s 3 adult implantation centres. All LVAD patients from 2010-14 were included for long-term outcomes but comparisons with INTERMACS are only available for 2014. RESULTS: 83 Québec patients were implanted with a Heartmate-II LVAD over the 5-year period with an annual centre volume ranging from 0-11. Age and sex distribution were similar in Québec and INTERMACS patients. Québec patients were more likely to be listed for transplant (40.7% vs 28.7% in INTERMACS) and fewer implants were performed for destination therapy (11.1% vs 35.7% for INTERMACS; p¼ 0.004), but acuity and disease severity using INTERMACS profiles were similar (11.1%, 25.9%, 44.4% and 18.5% vs. 17.7%, 37.8%, 27% and 13% for Profiles 1-4, for Québec and INTERMACS patients, respectively; p¼0.7). Background: therapies were similar, including both ACE and mineralocorticoid inhibitors, beta-blockers, amiodarone, and defibrillators/resynchronization therapy. Renal dysfunction appeared slightly more severe in Québec patients (BUN: 37.123.7 mg/dL vs. 30.319.2 mg/dL; creatinine: 1.50.6 mg/dL vs. 1.40.8 mg/dL; p¼0.06 and p¼0.2, respectively). While more INTERMACS patients had a left ventricular ejection fraction <20% (65.1% vs. 44.4% for Québec patients, p¼0.02), severe mitral regurgitation was more often present in Québec patients (48.1% vs. 20.9% in INTERMACS, p¼0.02). Peak Vo2 was severely and similarly depressed in both groups (13.64.1 vs. 14.86.8 mL/Kg/min, p¼0.3). Mean length-of-stay after implant tended to be longer for Québec patients (3431 vs. 2522 days, p¼0.06). NYHA class improved similarly from 3.2 at baseline to 1.5 at 6 months. Long-term survival for Québec patients was 94% (1 month), 84% (12 months), 81% (24 months) and 70% (36 months), comparing favorably with INTERMACS.
Canadian Journal of Cardiology Volume 31 2015 CONCLUSION:
Québec patients were similar to INTERMACS registry patients in terms of disease severity and clinical characteristics but were more often listed for transplant at the time of implant and less likely to receive LVAD as destination therapy. Despite relatively small and variable annual volumes per Québec center, these results suggest this costly technology can provide excellent survival in carefully selected patients. Trainee Research Award Finalist e Clinical Science 378 HUMAN LEUKOCYTE ANTIGEN-G POLYMORPHISMS ARE PREDICTORS OF POST-TRANSPLANT CARDIAC ALLOGRAFT VASCULOPATHY J Lazarte, L Goldraich, C Manlhiot, H Kawajiri, A Ghashghai, L Grosman-Rimon, H Ross, V Rao, DH Delgado
Toronto, Ontario BACKGROUND:
Human Leukocyte Antigen (HLA)-G is a natural immune regulator protein that has been shown to inhibit smooth muscle cell proliferation in vitro and overall potentially promote vasculature protection against cardiac allograft vasculopathy (CAV). Single polymorphism nucleotides (SNPs) throughout the gene influence the expression of HLA-G. The association between HLA-G SNPs in heart transplant recipients or donors and CAV remains unclear. OBJECTIVE: To determinee association of multiple HLA-G SNPs from both recipient and donor with the diagnosis of CAV post heart transplant. METHODS: Retrospective cohort in which 251 adult heart transplant recipients and 196 matching donors were evaluated for various HLA-G SNPs. The recipients were screened for CAV according to institutional protocol. Coronary angiographies were graded according to the International Society for Heart and Lung Transplantation classification and severe CAV was defined as 2/3 categories. DNA was genotyped for SNPs 5’ URR 201, 3’ UTR 3196, 3187, 3142 and 14bp INDEL using the Sequenom MassARRAY Platform. The association of genotypes and diagnosis of severe CAV were evaluated in parametric hazard regression model. RESULTS: General characteristics: recipient age 4812 years, 69% males and donor age 3514 years. Of those, 20 (8%) recipients were diagnosed with severe CAV over a median follow-up of 6 years. Proportions of major (CC)/minor (TT) genotypes for SNP 201 were 25%/24% for recipients and 26%/ 22% for donors, respectively. For SNP 3142, proportions of major (CC)/minor (GG) genotypes were 34%/ 17% for recipients and 23%/22% for donors, respectively. In multivariable analysis adjusting for donor age, donor cause of death and pre-transplant creatinine, the presence of donor SNP 201 (CC vs TT/TC) was associated with increased risk of development of severe CAV (HR 5.29; CI 1.70-16.20; p¼ 0.004) (Figure 1). Matching between recipient and donor
Abstracts
genotypes at SNP 201 was also associated with increased risk (HR 7.50; CI 2.50-22.39; p< 0.001). Furthermore, donor SNP 3142 (GG vs CG/CC) was associated with increased risk of severe CAV (HR 10.05; CI 1.40-71.65; p< 0.02). CONCLUSION: Donor HLA-G SNPs 3142/201 and recipient/ donor genotype matching for SNP 201 were independent risk factors for the diagnosis of severe CAV. This is the first investigation to identify an association between HLA-G SNPs and CAV. This association suggests that differences in HLA-G expression constitute a pathogenic pathway to be explored for potential enhancement of diagnostic, preventive and therapeutic strategies for CAV.
Trainee Research Award Finalist e Basic Science 379 THERAPEUTIC EFFECT OF VEGF INHIBITION IN CARDIAC ALLOGRAFT VASCULOPATHY S Chatur, B Wong, J Carthy, BM McManus Vancouver, British Columbia BACKGROUND:
Cardiac allograft vasculopathy (CAV) affects approximately 70% of heart transplants and represents the greatest limitation for long term survival. This expression of chronic rejection is characterized by a widespread and concentric thickening of the donor heart macrovessels which increases over time, eventually resulting in tissue ischemia and ultimately graft failure. Vascular endothelial growth factor (VEGF) has been shown to be endogenously over expressed within both human and animal model heart allografts. Significant host bone marrow-derived stem cell migration to the allograft has been previously demonstrated, contributing new endothelial cells to micro vessels. It is thought that VEGF induced graft neo-angiogenesis and inflammation may be central mechanisms involved in the pathogenesis of CAV. OBJECTIVE: To investigate the therapeutic effect of the inhibition of VEGF expression in CAV. METHODS/RESULTS: Female 129J donor hearts were heterotopically transplanted into C57/B16 males and maintained on
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Western diet in the presence or absence soluble VEGF receptor 1 (sVEGFR1). At 21 days post transplantation, significant reductions in both the average grade of luminal narrowing (P<0.05) and the percentage of vessels affected (P<0.005) were observed in sVEGFR-1treated transplants. Administration of sVEGR1 also significantly (P<0.05) reduced average wet heart weight as compared to vehicle controls while mean ventricular cross-sectional area remained similar. Bone marrow (BM) was subsequently harvested from male C57/B16 mice. The effect of VEGF inhibition on bone marrow mediated micro-vascular outgrowth and endothelial cell migration and proliferation were assessed using in vitro assays of aortic ring angiogenesis, wound healing and proliferation, respectively. Compared to non-treated controls, treatment of aortic rings with sVEGFR1 significantly (P<0.05) reduced bone-marrow mediated microvascular outgrowth length and area. Treatment of Human Coronary Artery Endothelial Cells (HCAEC) with sVEGR1 significantly (p<0.05) reduced bone marrow mediated endothelial cell migration and proliferation. CONCLUSION: These results indicate that VEGF inhibition via administration of sVEGR1 may reduce the severity and incidence of CAV through reduced myocardial edema and neo-angiogenesis. We provide in vitro evidence for the role of VEGF signaling in BM mediated microvascular outgrowth, and endothelial cell migration and proliferation, supporting the function of the VEGF inhibition strategy. Strong evidence that manipulation of the VEGF signaling axis within the allograft ameliorates CAV prognosis could pave the road for a novel approach to CAV treatment and prevention. CIHR 380 LONG-TERM SURVIVAL AFTER CARDIAC TRANSPLANTATION: PAST, PRESENT AND FUTURE N Vistarini, A Nguyen, LP Perrault, D Bouchard, R Cartier, P Demers, M Pellerin, Y Lamarche, I El-Hamamsy, M Carrier Montréal, Québec BACKGROUND:
The aim of this study was to evaluate the heart transplant experience of the Montréal Heart Institute, focusing on long-term survival (greater than or equal to 20 years), and to compare the transplant experience of the first decade with our recent and current practice. METHODS: From April 1983 through April 2015, 425 consecutive patients underwent heart transplantation at the Montréal Heart Institute. Patients who survived 20 years (group 1, n¼46) and transplanted between April 1983 and April 1995, were compared to patients who died within 20 years after surgery (group 2, n¼110). In order to compare the transplant experience of the first decades with our current practice, we evaluated our recent 5 years experience (group 3, n¼54), focusing on differences in terms of donors and recipients characteristics. Patients who received heart retransplantation were not excluded from the study.
Canadian Cardiovascular Society (CCS) Oral MAN VS MACHINE: TRANSPLANT AND VAD’S Sunday, October 25, 2015 377 INSIGHTS FROM A QUÉBEC FIELD EVALUATION OF LEFT VENTRICULAR ASSIST DEVICE THERAPY COMPARED WITH THE INTERMACS REGISTRY: CAN SMALL STILL BE BEAUTIFUL? A Ducharme, E Charbonneau, R Cecere, M Carrier, N Giannetti, M Sénéchal, LJ Lambert, G Sas, C Sanscartier, L Azzi, P Bogaty Montréal, Québec BACKGROUND:
The left ventricular assist device (LVAD) is now an accepted therapy for patients with terminal heart failure, even if they are not candidates for cardiac transplantation. Recent reports have suggested that favorable outcomes are directly related to the per-centre volume of LVAD implantation. We examined the characteristics and clinical outcomes of our province-wide field evaluation and compared them with the large US INTERMACS registry. METHODS: Patient data were collected by the clinical teams in Québec’s 3 adult implantation centres. All LVAD patients from 2010-14 were included for long-term outcomes but comparisons with INTERMACS are only available for 2014. RESULTS: 83 Québec patients were implanted with a Heartmate-II LVAD over the 5-year period with an annual centre volume ranging from 0-11. Age and sex distribution were similar in Québec and INTERMACS patients. Québec patients were more likely to be listed for transplant (40.7% vs 28.7% in INTERMACS) and fewer implants were performed for destination therapy (11.1% vs 35.7% for INTERMACS; p¼ 0.004), but acuity and disease severity using INTERMACS profiles were similar (11.1%, 25.9%, 44.4% and 18.5% vs. 17.7%, 37.8%, 27% and 13% for Profiles 1-4, for Québec and INTERMACS patients, respectively; p¼0.7). Background: therapies were similar, including both ACE and mineralocorticoid inhibitors, beta-blockers, amiodarone, and defibrillators/resynchronization therapy. Renal dysfunction appeared slightly more severe in Québec patients (BUN: 37.123.7 mg/dL vs. 30.319.2 mg/dL; creatinine: 1.50.6 mg/dL vs. 1.40.8 mg/dL; p¼0.06 and p¼0.2, respectively). While more INTERMACS patients had a left ventricular ejection fraction <20% (65.1% vs. 44.4% for Québec patients, p¼0.02), severe mitral regurgitation was more often present in Québec patients (48.1% vs. 20.9% in INTERMACS, p¼0.02). Peak Vo2 was severely and similarly depressed in both groups (13.64.1 vs. 14.86.8 mL/Kg/min, p¼0.3). Mean length-of-stay after implant tended to be longer for Québec patients (3431 vs. 2522 days, p¼0.06). NYHA class improved similarly from 3.2 at baseline to 1.5 at 6 months. Long-term survival for Québec patients was 94% (1 month), 84% (12 months), 81% (24 months) and 70% (36 months), comparing favorably with INTERMACS.
Canadian Journal of Cardiology Volume 31 2015 CONCLUSION:
Québec patients were similar to INTERMACS registry patients in terms of disease severity and clinical characteristics but were more often listed for transplant at the time of implant and less likely to receive LVAD as destination therapy. Despite relatively small and variable annual volumes per Québec center, these results suggest this costly technology can provide excellent survival in carefully selected patients. Trainee Research Award Finalist e Clinical Science 378 HUMAN LEUKOCYTE ANTIGEN-G POLYMORPHISMS ARE PREDICTORS OF POST-TRANSPLANT CARDIAC ALLOGRAFT VASCULOPATHY J Lazarte, L Goldraich, C Manlhiot, H Kawajiri, A Ghashghai, L Grosman-Rimon, H Ross, V Rao, DH Delgado
Toronto, Ontario BACKGROUND:
Human Leukocyte Antigen (HLA)-G is a natural immune regulator protein that has been shown to inhibit smooth muscle cell proliferation in vitro and overall potentially promote vasculature protection against cardiac allograft vasculopathy (CAV). Single polymorphism nucleotides (SNPs) throughout the gene influence the expression of HLA-G. The association between HLA-G SNPs in heart transplant recipients or donors and CAV remains unclear. OBJECTIVE: To determinee association of multiple HLA-G SNPs from both recipient and donor with the diagnosis of CAV post heart transplant. METHODS: Retrospective cohort in which 251 adult heart transplant recipients and 196 matching donors were evaluated for various HLA-G SNPs. The recipients were screened for CAV according to institutional protocol. Coronary angiographies were graded according to the International Society for Heart and Lung Transplantation classification and severe CAV was defined as 2/3 categories. DNA was genotyped for SNPs 5’ URR 201, 3’ UTR 3196, 3187, 3142 and 14bp INDEL using the Sequenom MassARRAY Platform. The association of genotypes and diagnosis of severe CAV were evaluated in parametric hazard regression model. RESULTS: General characteristics: recipient age 4812 years, 69% males and donor age 3514 years. Of those, 20 (8%) recipients were diagnosed with severe CAV over a median follow-up of 6 years. Proportions of major (CC)/minor (TT) genotypes for SNP 201 were 25%/24% for recipients and 26%/ 22% for donors, respectively. For SNP 3142, proportions of major (CC)/minor (GG) genotypes were 34%/ 17% for recipients and 23%/22% for donors, respectively. In multivariable analysis adjusting for donor age, donor cause of death and pre-transplant creatinine, the presence of donor SNP 201 (CC vs TT/TC) was associated with increased risk of development of severe CAV (HR 5.29; CI 1.70-16.20; p¼ 0.004) (Figure 1). Matching between recipient and donor
Abstracts
genotypes at SNP 201 was also associated with increased risk (HR 7.50; CI 2.50-22.39; p< 0.001). Furthermore, donor SNP 3142 (GG vs CG/CC) was associated with increased risk of severe CAV (HR 10.05; CI 1.40-71.65; p< 0.02). CONCLUSION: Donor HLA-G SNPs 3142/201 and recipient/ donor genotype matching for SNP 201 were independent risk factors for the diagnosis of severe CAV. This is the first investigation to identify an association between HLA-G SNPs and CAV. This association suggests that differences in HLA-G expression constitute a pathogenic pathway to be explored for potential enhancement of diagnostic, preventive and therapeutic strategies for CAV.
Trainee Research Award Finalist e Basic Science 379 THERAPEUTIC EFFECT OF VEGF INHIBITION IN CARDIAC ALLOGRAFT VASCULOPATHY S Chatur, B Wong, J Carthy, BM McManus Vancouver, British Columbia BACKGROUND:
Cardiac allograft vasculopathy (CAV) affects approximately 70% of heart transplants and represents the greatest limitation for long term survival. This expression of chronic rejection is characterized by a widespread and concentric thickening of the donor heart macrovessels which increases over time, eventually resulting in tissue ischemia and ultimately graft failure. Vascular endothelial growth factor (VEGF) has been shown to be endogenously over expressed within both human and animal model heart allografts. Significant host bone marrow-derived stem cell migration to the allograft has been previously demonstrated, contributing new endothelial cells to micro vessels. It is thought that VEGF induced graft neo-angiogenesis and inflammation may be central mechanisms involved in the pathogenesis of CAV. OBJECTIVE: To investigate the therapeutic effect of the inhibition of VEGF expression in CAV. METHODS/RESULTS: Female 129J donor hearts were heterotopically transplanted into C57/B16 males and maintained on
S201
Western diet in the presence or absence soluble VEGF receptor 1 (sVEGFR1). At 21 days post transplantation, significant reductions in both the average grade of luminal narrowing (P<0.05) and the percentage of vessels affected (P<0.005) were observed in sVEGFR-1treated transplants. Administration of sVEGR1 also significantly (P<0.05) reduced average wet heart weight as compared to vehicle controls while mean ventricular cross-sectional area remained similar. Bone marrow (BM) was subsequently harvested from male C57/B16 mice. The effect of VEGF inhibition on bone marrow mediated micro-vascular outgrowth and endothelial cell migration and proliferation were assessed using in vitro assays of aortic ring angiogenesis, wound healing and proliferation, respectively. Compared to non-treated controls, treatment of aortic rings with sVEGFR1 significantly (P<0.05) reduced bone-marrow mediated microvascular outgrowth length and area. Treatment of Human Coronary Artery Endothelial Cells (HCAEC) with sVEGR1 significantly (p<0.05) reduced bone marrow mediated endothelial cell migration and proliferation. CONCLUSION: These results indicate that VEGF inhibition via administration of sVEGR1 may reduce the severity and incidence of CAV through reduced myocardial edema and neo-angiogenesis. We provide in vitro evidence for the role of VEGF signaling in BM mediated microvascular outgrowth, and endothelial cell migration and proliferation, supporting the function of the VEGF inhibition strategy. Strong evidence that manipulation of the VEGF signaling axis within the allograft ameliorates CAV prognosis could pave the road for a novel approach to CAV treatment and prevention. CIHR 380 LONG-TERM SURVIVAL AFTER CARDIAC TRANSPLANTATION: PAST, PRESENT AND FUTURE N Vistarini, A Nguyen, LP Perrault, D Bouchard, R Cartier, P Demers, M Pellerin, Y Lamarche, I El-Hamamsy, M Carrier Montréal, Québec BACKGROUND:
The aim of this study was to evaluate the heart transplant experience of the Montréal Heart Institute, focusing on long-term survival (greater than or equal to 20 years), and to compare the transplant experience of the first decade with our recent and current practice. METHODS: From April 1983 through April 2015, 425 consecutive patients underwent heart transplantation at the Montréal Heart Institute. Patients who survived 20 years (group 1, n¼46) and transplanted between April 1983 and April 1995, were compared to patients who died within 20 years after surgery (group 2, n¼110). In order to compare the transplant experience of the first decades with our current practice, we evaluated our recent 5 years experience (group 3, n¼54), focusing on differences in terms of donors and recipients characteristics. Patients who received heart retransplantation were not excluded from the study.