Antti I Nykänen1,2,3, Emil J Holmström1,3, Raimo Tuuminen1,3, Rainer Krebs1,3, Kishor Dhaygude1,3, Matti Kankainen3,4,5, Janne J Jokinen6,7, Jyri Lommi, Ilkka Helanterä8, Anne Räisänen-Sokolowski9, Simo O Syrjälä1,2,3, Karl B Lemström1,2,3. 1. Transplantation Laboratory (A.I.N., E.J.H., R.T., R.K., K.D., S.O.S., K.B.L.), University of Helsinki and Helsinki University Hospital, Finland. 2. Department of Cardiothoracic Surgery (A.I.N., S.O.S., K.B.L.), University of Helsinki and Helsinki University Hospital, Finland. 3. Translational Immunology Program Research Programs Unit (A.I.N., E.J.H., R.T., R.K., K.D., M.K., S.O.S., K.B.L.), University of Helsinki and Helsinki University Hospital, Finland. 4. Medical and Clinical Genetics (M.K.), University of Helsinki and Helsinki University Hospital, Finland. 5. Institute for Molecular Medicine Finland, University of Helsinki (M.K.). 6. Department of Cardiology (J.L.), University of Helsinki and Helsinki University Hospital, Finland. 7. Päijät-Häme Central Hospital, Department of Surgery, Lahti, Finland (J.J.J.). 8. Transplantation and Liver Surgery (I.H.), University of Helsinki and Helsinki University Hospital, Finland. 9. Pathology (A.R.-S.), University of Helsinki and Helsinki University Hospital, Finland.
Abstract
BACKGROUND: Ischemia-reperfusion injury may compromise the short-term and long-term prognosis after heart transplantation. Experimental studies show that simvastatin administered to the organ donor is vasculoprotective and inhibits cardiac allograft ischemia-reperfusion injury. METHODS:Eighty-four multiorgan donors were randomly assigned to receive 80 mg of simvastatin (42 donors) via nasogastric tube after declaration of brain death and upon acceptance as a cardiac donor, or to receive no simvastatin (42 donors). The primary efficacy end point was postoperative plasma troponin T and I levels during the first 24 hours after heart transplantation. Secondary end points included postoperative hemodynamics, inflammation, allograft function, rejections and rejection treatments, and mortality. Results:Organ donor simvastatin treatment significantly reduced the heart recipient plasma levels of troponin T by 34% (14 900 ± 12 100 ng/L to 9800 ± 7900 ng/L, P=0.047), and troponin I by 40% (171 000± 151000 ng/L to 103 000 ± 109 000 ng/L, P=0.023) at 6 hours after reperfusion, the levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide) by 36% (32 800 ± 24 300 ng/L to 20 900 ± 15 900 ng/L; P=0.011) at 1 week, and the number of rejection treatments with hemodynamic compromise by 53% within the first 30 days (P=0.046). Donor simvastatin treatment did not affect donor lipid levels but was associated with a specific transplant myocardial biopsy gene expression profile, and a decrease in recipient postoperative plasma levels of CXCL10 (C-X-C motif chemokine 10), interleukin-1α, placental growth factor, and platelet-derived growth factor-BB. Postoperative hemodynamics, biopsy-proven acute rejections, and mortality were similar. No adverse effects were seen in recipients receiving noncardiac solid organ transplants from simvastatin-treated donors. CONCLUSIONS:Donor simvastatin treatment reduces biomarkers of myocardial injury after heart transplantation, and-also considering its documented general safety profile-may be used as a novel, safe, and inexpensive adjunct therapy in multiorgan donation. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01160978.
RCT Entities:
BACKGROUND:Ischemia-reperfusion injury may compromise the short-term and long-term prognosis after heart transplantation. Experimental studies show that simvastatin administered to the organ donor is vasculoprotective and inhibits cardiac allograft ischemia-reperfusion injury. METHODS: Eighty-four multiorgan donors were randomly assigned to receive 80 mg of simvastatin (42 donors) via nasogastric tube after declaration of brain death and upon acceptance as a cardiac donor, or to receive no simvastatin (42 donors). The primary efficacy end point was postoperative plasma troponin T and I levels during the first 24 hours after heart transplantation. Secondary end points included postoperative hemodynamics, inflammation, allograft function, rejections and rejection treatments, and mortality. Results: Organ donorsimvastatin treatment significantly reduced the heart recipient plasma levels of troponin T by 34% (14 900 ± 12 100 ng/L to 9800 ± 7900 ng/L, P=0.047), and troponin I by 40% (171 000 ± 151 000 ng/L to 103 000 ± 109 000 ng/L, P=0.023) at 6 hours after reperfusion, the levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide) by 36% (32 800 ± 24 300 ng/L to 20 900 ± 15 900 ng/L; P=0.011) at 1 week, and the number of rejection treatments with hemodynamic compromise by 53% within the first 30 days (P=0.046). Donorsimvastatin treatment did not affect donorlipid levels but was associated with a specific transplant myocardial biopsy gene expression profile, and a decrease in recipient postoperative plasma levels of CXCL10 (C-X-C motif chemokine 10), interleukin-1α, placental growth factor, and platelet-derived growth factor-BB. Postoperative hemodynamics, biopsy-proven acute rejections, and mortality were similar. No adverse effects were seen in recipients receiving noncardiac solid organ transplants from simvastatin-treated donors. CONCLUSIONS:Donorsimvastatin treatment reduces biomarkers of myocardial injury after heart transplantation, and-also considering its documented general safety profile-may be used as a novel, safe, and inexpensive adjunct therapy in multiorgan donation. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01160978.
Authors: Isabela R Zanetti; Michelle Burgin; Liqiang Zhang; Steve T Yeh; Sriram Ambadapadi; Jacquelyn Kilbourne; Jordan R Yaron; Kenneth M Lowe; Juliane Daggett-Vondras; David Fonseca; Ryan Boyd; Dara Wakefield; William Clapp; Efrem Lim; Hao Chen; Alexandra Lucas Journal: Pathogens Date: 2022-05-16
Authors: Jessica R Golbus; Sarah Adie; Matheos Yosef; Venkatesh L Murthy; Keith D Aaronson; Matthew C Konerman Journal: ESC Heart Fail Date: 2020-06-24