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Higher Intensity Statin Therapy Reduces Clinical Endpoints after Heart Transplantation Independent of Lipid Levels
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The Journal of Heart and Lung Transplantation, Vol 38, No 4S, April 2019
Laboratory, University of Helsinki, Helsinki, Finland; and the 2Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland. Purpose: Numerous studies have shown that statin therapy initiated early after heart transplantation has beneficial effects on the development of cardiac allograft vasculopathy. Recently, we were able to show in a randomized clinical trial that simvastatin treatment of brain-dead donors conditions the heart transplant to withstand ischemia-reperfusion injury and to reduce the need for rejection treatments early after transplantation. In this study, we analyzed myocardial gene expression profiles in cardiac allografts after donor simvastatin treatment. Methods: 84 heart transplant donors received 80 mg of simvastatin via nasogastric tube (n=42), or no treatment (n=42) in a prospective, doubleblinded randomized controlled trial. Transmural Tru-Cut biopsies were taken from the apex of left ventricle of the donor heart immediately before reperfusion and 1 hour after reperfusion. 20 heart biopsies from donors without treatment and 20 heart biopsies from donors with simvastatin treatment will be analyzed with RNA sequencing. Results: The preliminary analysis of RNA sequencing data from myocardial biopsies revealed altogether 137 significantly differentially expressed genes in all pairwise comparisons. The overall biological functions of these genes were related to gene ontology terms such as response to toxic substance, leukocyte migration, neutrophil mediated immunity, response to lipopolysaccharide, and response to oxidative stress. At the KEGG pathway level, our results indicated alterations in IL-17, TNF, MAPK and the AGE-RAGE signaling pathways. Conclusion: We have shown in previous studies that donor simvastatin treatment induces protective effects against IRI in heart transplant recipients. In this study, we were able to detect significantly differentially expressed genes related to effects of simvastatin treatment. In order to single out genes that show beneficial effects of simvastatin treatment, further analysis will be conducted by exploring gene expression changes in specific biological functional categories, such as interleukin signaling and neutrophil degranulation. The complete analysis will be presented at the ISHLT 2019 congress. 163 Higher Intensity Statin Therapy Reduces Clinical Endpoints after Heart Transplantation Independent of Lipid Levels J.R. Golbus,1 S. Adie,1 S. Hanigan,1 M. Dorsch,1 B. Rooks,2 K.D. Aaronson,1 and M.C. Konerman.1 1Internal Medicine, University of Michigan, Ann Arbor, MI; and the 2University of Michigan, Ann Arbor, MI. Purpose: Coronary artery disease is a leading cause of morbidity and mortality after heart transplantation (HT), resulting from cardiovascular risk factors and those associated with a proinflammatory state. Statins reduce incidence of post-HT cardiac allograft vasculopathy (CAV); it is unknown whether they act through their lipid-lowering effects or through alternative mechanisms. Methods: We performed a retrospective study of 347 adults who underwent HT from 2006 to 2018. Patients not on statin therapy were excluded. Statin intensity was defined at 1-year post-HT as low versus moderate/high (mod/h) based on ACC guidelines. CAV was defined as coronary revascularization, ISHLT grade 2/3 CAV, or flow reserve < 2.0 on PET imaging. Our primary endpoint was the composite of time to coronary revascularization, heart failure hospitalization, and death. Secondary endpoints included time to significant rejection and CAV. Cox proportional hazards model was used to evaluate longitudinal lipid exposure and outcomes, adjusted for statin intensity. Results: 282 patients were included in the analysis; 191 (67.7%) were on low, 81 (28.7%) on mod, and 10 (3.5%) on h-intensity statin therapy. On multivariable analysis adjusting for clinical covariates, mod/h intensity statin therapy was associated with a significant reduction in the primary outcome (HR 0.52, 95% CI 0.40-0.68, p <0.001; Figure). Mod/h-intensity statin therapy was associated with a reduction in clinically-significant rejection (HR 0.53, 95% CI 0.38-0.73, p<0.001; n=246) after adjustment for clinical covariates and immunosuppression levels. Similarly, mod/h intensity statin therapy was associated with a reduction in CAV after adjustment for clinical covariates (HR 0.47, 95% CI 0.34-0.65,p<0.001; n=203). Lipids were not associated with the primary endpoint.
Conclusion: Moderate/high intensity statin therapy is associated with a significant delay in time to rejection, CAV, and clinical outcomes after HT.
164 Everolimus in the Prevention of Calcineurin-Inhibitor-Induced Left Ventricular Hypertrophy in Heart Transplantation (RAD-TAC Study) C. Anthony, M. Imran, S. Emmanuel, J. Iliff, E. Kotlyar, K. Muthiah, A.M. Keogh, C.S. Hayward, P.S. Macdonald and A. Jabbour. Heart and Lung Transplant, St Vincent's Hospital Sydney, Sydney, Australia. Purpose: To determine whether low-dose everolimus in combination with low-dose tacrolimus compared to full-dose tacrolimus without everolimus safely attenuates left ventricular hypertrophy after heart transplantation Methods: In this prospective study, orthotopic heart transplant (OHT) transplant recipients were randomized at 12 weeks post-transplant to a combination of everolimus, tacrolimus (low dose), mycophenolate and prednisolone (RAD-TAC group) OR tacrolimus (normal dose) mycophenolate and prednisolone (TAC group). Left ventricular mass (LVM), mass index (LVMi), function and fibrosis markers (T1 mapping) were assessed by Cardiac MRI (CMR) at baseline and at 52 weeks post-transplant Results: Forty patients were randomized. Patient characteristics, including LVMi, age and gender were evenly matched between groups at baseline. Patients in the RAD-TAC group had significantly lower tacrolimus levels (5.5 (1.5) ug/L vs. 8. 3 (3.1) ug/L, mean (SD); p=0.03). The mean everolimus level was 6.8 (1.8) ug/L. LV Mass in the RAD-TAC group significantly reduced over the 40-week study period; in contrast, LV Mass in the TAC group increased (LV Mass change -11.1g (18.3) vs. +0.4g (6.3); p=0.001, LVMi change -6.1g/m2 (8.8) vs.+1.4g/m2 (5.8); p=0.001). Interstitial fibrosis (by CMR T1 mapping) in the RAD-TAC group significantly reduced over the 40-week period; in contrast, interstitial fibrosis in the TAC group increased (fibrosis change -31 (51) ms vs. +33 (-94) ms; p=0.002). No significant differences were observed in measures of myocardial function, significant rejection episodes, hypertension (systolic BP 131 (9.2) mmHg vs. 132 (8.5) mmHg; p=0.51) or serious adverse events between groups Conclusion: Low-dose everolimus in combination with low-dose tacrolimus compared to full-dose tacrolimus safely attenuates left ventricular hypertrophy after heart transplantation. The reduction in CMR-determined fibrosis also provides insights into a potential mechanistic role of everolimus in the pathophysiology of cardiac hypertrophy after transplantation. 165 Gut Microbial Diversity, Inflammation and Oxidative Stress is Associated with Tacrolimus Dosing Requirements Early after Heart Transplant D.L. Jennings,1 B. Bohn Damasceno Ferreira,2 A. Zuver,2 O. Drew,3 M. Gaine,3 E. Royzman,3 J. Hupf,3 M. Farr,3 F. Latif,3 S. Restaino,3 A.R. Garan,3 H. Takayama,4 K. Takeda,4 Y. Naka,4 P.C. Colombo,3 R. Demmer,5 and M. Yuzefpolskaya.3 1Pharmacy, NewYork-Presbyterian Hospital, New York, NY; 2Public Health, Columbia University, New York, NY; 3Medical Cardiology, Columbia University, New York, NY; 4 Cardiothoracic Surgery, Columbia University, New York, NY; and the 5 Public Health, University of Minnesota, Minneapolis, MN.
The Journal of Heart and Lung Transplantation, Vol 38, No 4S, April 2019
Laboratory, University of Helsinki, Helsinki, Finland; and the 2Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland. Purpose: Numerous studies have shown that statin therapy initiated early after heart transplantation has beneficial effects on the development of cardiac allograft vasculopathy. Recently, we were able to show in a randomized clinical trial that simvastatin treatment of brain-dead donors conditions the heart transplant to withstand ischemia-reperfusion injury and to reduce the need for rejection treatments early after transplantation. In this study, we analyzed myocardial gene expression profiles in cardiac allografts after donor simvastatin treatment. Methods: 84 heart transplant donors received 80 mg of simvastatin via nasogastric tube (n=42), or no treatment (n=42) in a prospective, doubleblinded randomized controlled trial. Transmural Tru-Cut biopsies were taken from the apex of left ventricle of the donor heart immediately before reperfusion and 1 hour after reperfusion. 20 heart biopsies from donors without treatment and 20 heart biopsies from donors with simvastatin treatment will be analyzed with RNA sequencing. Results: The preliminary analysis of RNA sequencing data from myocardial biopsies revealed altogether 137 significantly differentially expressed genes in all pairwise comparisons. The overall biological functions of these genes were related to gene ontology terms such as response to toxic substance, leukocyte migration, neutrophil mediated immunity, response to lipopolysaccharide, and response to oxidative stress. At the KEGG pathway level, our results indicated alterations in IL-17, TNF, MAPK and the AGE-RAGE signaling pathways. Conclusion: We have shown in previous studies that donor simvastatin treatment induces protective effects against IRI in heart transplant recipients. In this study, we were able to detect significantly differentially expressed genes related to effects of simvastatin treatment. In order to single out genes that show beneficial effects of simvastatin treatment, further analysis will be conducted by exploring gene expression changes in specific biological functional categories, such as interleukin signaling and neutrophil degranulation. The complete analysis will be presented at the ISHLT 2019 congress. 163 Higher Intensity Statin Therapy Reduces Clinical Endpoints after Heart Transplantation Independent of Lipid Levels J.R. Golbus,1 S. Adie,1 S. Hanigan,1 M. Dorsch,1 B. Rooks,2 K.D. Aaronson,1 and M.C. Konerman.1 1Internal Medicine, University of Michigan, Ann Arbor, MI; and the 2University of Michigan, Ann Arbor, MI. Purpose: Coronary artery disease is a leading cause of morbidity and mortality after heart transplantation (HT), resulting from cardiovascular risk factors and those associated with a proinflammatory state. Statins reduce incidence of post-HT cardiac allograft vasculopathy (CAV); it is unknown whether they act through their lipid-lowering effects or through alternative mechanisms. Methods: We performed a retrospective study of 347 adults who underwent HT from 2006 to 2018. Patients not on statin therapy were excluded. Statin intensity was defined at 1-year post-HT as low versus moderate/high (mod/h) based on ACC guidelines. CAV was defined as coronary revascularization, ISHLT grade 2/3 CAV, or flow reserve < 2.0 on PET imaging. Our primary endpoint was the composite of time to coronary revascularization, heart failure hospitalization, and death. Secondary endpoints included time to significant rejection and CAV. Cox proportional hazards model was used to evaluate longitudinal lipid exposure and outcomes, adjusted for statin intensity. Results: 282 patients were included in the analysis; 191 (67.7%) were on low, 81 (28.7%) on mod, and 10 (3.5%) on h-intensity statin therapy. On multivariable analysis adjusting for clinical covariates, mod/h intensity statin therapy was associated with a significant reduction in the primary outcome (HR 0.52, 95% CI 0.40-0.68, p <0.001; Figure). Mod/h-intensity statin therapy was associated with a reduction in clinically-significant rejection (HR 0.53, 95% CI 0.38-0.73, p<0.001; n=246) after adjustment for clinical covariates and immunosuppression levels. Similarly, mod/h intensity statin therapy was associated with a reduction in CAV after adjustment for clinical covariates (HR 0.47, 95% CI 0.34-0.65,p<0.001; n=203). Lipids were not associated with the primary endpoint.
Conclusion: Moderate/high intensity statin therapy is associated with a significant delay in time to rejection, CAV, and clinical outcomes after HT.
164 Everolimus in the Prevention of Calcineurin-Inhibitor-Induced Left Ventricular Hypertrophy in Heart Transplantation (RAD-TAC Study) C. Anthony, M. Imran, S. Emmanuel, J. Iliff, E. Kotlyar, K. Muthiah, A.M. Keogh, C.S. Hayward, P.S. Macdonald and A. Jabbour. Heart and Lung Transplant, St Vincent's Hospital Sydney, Sydney, Australia. Purpose: To determine whether low-dose everolimus in combination with low-dose tacrolimus compared to full-dose tacrolimus without everolimus safely attenuates left ventricular hypertrophy after heart transplantation Methods: In this prospective study, orthotopic heart transplant (OHT) transplant recipients were randomized at 12 weeks post-transplant to a combination of everolimus, tacrolimus (low dose), mycophenolate and prednisolone (RAD-TAC group) OR tacrolimus (normal dose) mycophenolate and prednisolone (TAC group). Left ventricular mass (LVM), mass index (LVMi), function and fibrosis markers (T1 mapping) were assessed by Cardiac MRI (CMR) at baseline and at 52 weeks post-transplant Results: Forty patients were randomized. Patient characteristics, including LVMi, age and gender were evenly matched between groups at baseline. Patients in the RAD-TAC group had significantly lower tacrolimus levels (5.5 (1.5) ug/L vs. 8. 3 (3.1) ug/L, mean (SD); p=0.03). The mean everolimus level was 6.8 (1.8) ug/L. LV Mass in the RAD-TAC group significantly reduced over the 40-week study period; in contrast, LV Mass in the TAC group increased (LV Mass change -11.1g (18.3) vs. +0.4g (6.3); p=0.001, LVMi change -6.1g/m2 (8.8) vs.+1.4g/m2 (5.8); p=0.001). Interstitial fibrosis (by CMR T1 mapping) in the RAD-TAC group significantly reduced over the 40-week period; in contrast, interstitial fibrosis in the TAC group increased (fibrosis change -31 (51) ms vs. +33 (-94) ms; p=0.002). No significant differences were observed in measures of myocardial function, significant rejection episodes, hypertension (systolic BP 131 (9.2) mmHg vs. 132 (8.5) mmHg; p=0.51) or serious adverse events between groups Conclusion: Low-dose everolimus in combination with low-dose tacrolimus compared to full-dose tacrolimus safely attenuates left ventricular hypertrophy after heart transplantation. The reduction in CMR-determined fibrosis also provides insights into a potential mechanistic role of everolimus in the pathophysiology of cardiac hypertrophy after transplantation. 165 Gut Microbial Diversity, Inflammation and Oxidative Stress is Associated with Tacrolimus Dosing Requirements Early after Heart Transplant D.L. Jennings,1 B. Bohn Damasceno Ferreira,2 A. Zuver,2 O. Drew,3 M. Gaine,3 E. Royzman,3 J. Hupf,3 M. Farr,3 F. Latif,3 S. Restaino,3 A.R. Garan,3 H. Takayama,4 K. Takeda,4 Y. Naka,4 P.C. Colombo,3 R. Demmer,5 and M. Yuzefpolskaya.3 1Pharmacy, NewYork-Presbyterian Hospital, New York, NY; 2Public Health, Columbia University, New York, NY; 3Medical Cardiology, Columbia University, New York, NY; 4 Cardiothoracic Surgery, Columbia University, New York, NY; and the 5 Public Health, University of Minnesota, Minneapolis, MN.