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LONG-TERM SURVIVAL AFTER CARDIAC TRANSPLANTATION: PAST, PRESENT AND FUTURE
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.
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Canadian Journal of Cardiology Volume 31 2015
The group 1 (survival 20 years) included younger patients (3811 vs 488 years, p¼0.001), more females (28% vs 8%, p¼0.001) and a lower prevalence of ischemic heart disease (42% vs 65%, p¼0.001) compared to group 2 (survival <20 years). Patients in group 3 (transplanted between 2010 and 2015), a mirror of our current population, were older (5212 vs 3811 years, p¼0.001), sicker (hospitalization rate at transplantation 48% vs 20%, p¼0.001) and transplanted with organs from older donors (4215 vs 2911 years, p¼0.001) compared to group 1 (survival 20 years). CONCLUSION: Long-term survival (20 years) was observed in almost 30% of patients transplanted during the first decade of our experience. This excellent outcome will be difficult to achieve in the current era when considering our present population of older and sicker patients, transplanted with organs from older donors. RESULTS:
however, triglycerides were continually consumed by loaded hearts and secreted by unloaded heats (Figure 1). CONCLUSION: EVHP in a loaded state improves the preservation of myocardial function. Uncoupling of fatty acid oxidation may contribute to the decline in myocardial function observed in unloaded hearts; however, further research is required to elucidate the mechanism underlying these observations. These results highlight the need for an EVHP device capable of preserving the donor heart in a physiologic working mode.
Trainee Research Award Finalist e Basic Science 381 EX VIVO PERFUSION IN A LOADED STATE IMPROVES THE PRESERVATION OF DONOR HEART FUNCTION CW White, S Shan, S Hatami, V Gurtu, A Kinnaird, N Matsumura, N Aboelnazar, JR Dyck, GD Lopaschuk, E Michelakis, DH Freed, J Nagendran Edmonton, Alberta BACKGROUND:
Ex vivo heart perfusion (EVHP) has been proposed as a means improving heart preservation and expanding the donor pool. Current clinical EVHP protocols involve preservation in an unloaded and non-working state; however, the impact of this approach on the preservation of donor heart function is unknown. We sought to determine if myocardial load during EVHP impacts the preservation of donor heart function. METHODS: Donor porcine hearts were perfused ex vivo in a beating state for 12 hours. Loaded hearts (N¼4) were perfused in a working mode (left atrial pressure¼6 mmHg, heart rate¼100 beats/minute) for the entire EVHP interval. Unloaded hearts (N¼4) were briefly transitioned into a working mode at hours 1 (T1), 5 (T5), and 11 (T11) for metabolic and functional assessments, but were otherwise perfused in a resting mode (left atrial pressure¼0 mmHg). RESULTS: Myocardial function (T11 cardiac index (mL/minute/gram): loaded¼6.91.0 vs. unloaded¼2.01.2, p¼0.02) and mechanical efficiency (T11: loaded¼111 vs. unloaded¼21 %, p<0.01) were better preserved in loaded hearts. Myocardial injury (T11 troponin I (ng/mL): loaded¼11.60.4 vs. unloaded¼12.10.3, p¼0.39) and edema formation (% weight gain: loaded¼148 vs. unloaded¼243 %, p¼0.15) did not account for these differences. Free fatty acids were rapidly depleted in both groups;
Trainee Research Award Finalist e Clinical Science 382 SINGLE CENTER COMPARATIVE ANALYSIS OF HEARTMATE II AND HEARTWARE HVAD CONTINUOUS FLOW DEVICES H Nazzari, J Bashir, K Tauh, S Virani, M Davis, B Munt, A Kaan, A Ignaszewski, A Cheung, M Toma Vancouver, British Columbia BACKGROUND:
Left Ventricular assist devices (LVAD) have revolutionized the treatment of patients with end-stage heart failure as a bridge-to-transplantation (BTT), bridge-to-candidacy (BTC), and destination therapy (DT). Continuous flow devices are now widely used and have the benefit of improved technology, durability and outcomes. Limited data is available comparing the outcomes in the newer generation LVADs. We examined the outcomes of two new generations LVADs: the HeartMate II (HMII) and HeartWare ventricular assist device (HVAD). METHODS: We conducted a single center review of 108 patients implanted with either the HMII or HVAD between
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.
S202
Canadian Journal of Cardiology Volume 31 2015
The group 1 (survival 20 years) included younger patients (3811 vs 488 years, p¼0.001), more females (28% vs 8%, p¼0.001) and a lower prevalence of ischemic heart disease (42% vs 65%, p¼0.001) compared to group 2 (survival <20 years). Patients in group 3 (transplanted between 2010 and 2015), a mirror of our current population, were older (5212 vs 3811 years, p¼0.001), sicker (hospitalization rate at transplantation 48% vs 20%, p¼0.001) and transplanted with organs from older donors (4215 vs 2911 years, p¼0.001) compared to group 1 (survival 20 years). CONCLUSION: Long-term survival (20 years) was observed in almost 30% of patients transplanted during the first decade of our experience. This excellent outcome will be difficult to achieve in the current era when considering our present population of older and sicker patients, transplanted with organs from older donors. RESULTS:
however, triglycerides were continually consumed by loaded hearts and secreted by unloaded heats (Figure 1). CONCLUSION: EVHP in a loaded state improves the preservation of myocardial function. Uncoupling of fatty acid oxidation may contribute to the decline in myocardial function observed in unloaded hearts; however, further research is required to elucidate the mechanism underlying these observations. These results highlight the need for an EVHP device capable of preserving the donor heart in a physiologic working mode.
Trainee Research Award Finalist e Basic Science 381 EX VIVO PERFUSION IN A LOADED STATE IMPROVES THE PRESERVATION OF DONOR HEART FUNCTION CW White, S Shan, S Hatami, V Gurtu, A Kinnaird, N Matsumura, N Aboelnazar, JR Dyck, GD Lopaschuk, E Michelakis, DH Freed, J Nagendran Edmonton, Alberta BACKGROUND:
Ex vivo heart perfusion (EVHP) has been proposed as a means improving heart preservation and expanding the donor pool. Current clinical EVHP protocols involve preservation in an unloaded and non-working state; however, the impact of this approach on the preservation of donor heart function is unknown. We sought to determine if myocardial load during EVHP impacts the preservation of donor heart function. METHODS: Donor porcine hearts were perfused ex vivo in a beating state for 12 hours. Loaded hearts (N¼4) were perfused in a working mode (left atrial pressure¼6 mmHg, heart rate¼100 beats/minute) for the entire EVHP interval. Unloaded hearts (N¼4) were briefly transitioned into a working mode at hours 1 (T1), 5 (T5), and 11 (T11) for metabolic and functional assessments, but were otherwise perfused in a resting mode (left atrial pressure¼0 mmHg). RESULTS: Myocardial function (T11 cardiac index (mL/minute/gram): loaded¼6.91.0 vs. unloaded¼2.01.2, p¼0.02) and mechanical efficiency (T11: loaded¼111 vs. unloaded¼21 %, p<0.01) were better preserved in loaded hearts. Myocardial injury (T11 troponin I (ng/mL): loaded¼11.60.4 vs. unloaded¼12.10.3, p¼0.39) and edema formation (% weight gain: loaded¼148 vs. unloaded¼243 %, p¼0.15) did not account for these differences. Free fatty acids were rapidly depleted in both groups;
Trainee Research Award Finalist e Clinical Science 382 SINGLE CENTER COMPARATIVE ANALYSIS OF HEARTMATE II AND HEARTWARE HVAD CONTINUOUS FLOW DEVICES H Nazzari, J Bashir, K Tauh, S Virani, M Davis, B Munt, A Kaan, A Ignaszewski, A Cheung, M Toma Vancouver, British Columbia BACKGROUND:
Left Ventricular assist devices (LVAD) have revolutionized the treatment of patients with end-stage heart failure as a bridge-to-transplantation (BTT), bridge-to-candidacy (BTC), and destination therapy (DT). Continuous flow devices are now widely used and have the benefit of improved technology, durability and outcomes. Limited data is available comparing the outcomes in the newer generation LVADs. We examined the outcomes of two new generations LVADs: the HeartMate II (HMII) and HeartWare ventricular assist device (HVAD). METHODS: We conducted a single center review of 108 patients implanted with either the HMII or HVAD between