Mark J Kearns1, Sally D Miller, Anson Cheung, Jamil Bashir, Stephanie Wong, Michael A Seidman, John H Boyd. 1. 1 UBC Centre for Heart Lung Innovation at St. Paul's Hospital, Vancouver, British Columbia, Canada. 2 Division of Cardiovascular Surgery, St. Paul's Hospital, Vancouver, British Columbia, Canada. 3 Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada. 4 Department of Critical Care Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Abstract
BACKGROUND: Organ donation after circulatory death (DCD) is increasingly being used as a means of addressing the organ supply/demand mismatch in solid organ transplantation. There is reluctance to use DCD hearts, due to an inability to precisely identify hearts that have suffered irreversible injury. We investigated novel biomarkers and clinically relevant endpoints across a spectrum of warm ischemic times, before and during ex vivo heart perfusion (EVHP), to identify features associated with a nonviable cardiac phenotype. METHODS: Donor rats sustained a hypoxic cardiac arrest, followed by variable acirculatory standoff periods (DCD groups). Left ventricular function, histochemical injury, and differences in left ventricular gene expression were studied before, and during, EVHP. RESULTS: As warm ischemic time exposure increased in DCD groups, fewer hearts were functional during EVHP, and ventricular function was increasingly impaired. Histochemical assessment identified severely injured hearts during EVHP. A novel gene expression signature identified severely injured hearts during EVHP (upregulation of c-Jun, 3.19 (2.84-3.60); P = 0.0014; HMOX-1, 3.87 (2.72-5.50); P = 0.0037; and Hsp90, 7.66 (6.32-9.27); P < 0.0001 in DCD20), and may be useful in identifying high-risk hearts at the point of harvest (Hsp90). CONCLUSIONS: We demonstrate that our preclinical model recapitulates the cardio-respiratory decompensation observed in humans, and that EVHP appears necessary to unmask distinguishing features of severely injured DCD hearts. Furthermore, we outline a clinically relevant multimodal approach to assessing candidate DCD hearts. Novel mRNA signatures correlated with elevations in cardiac Troponin-I in severely injured hearts during EVHP, and may also detect injury at the point of harvest.
BACKGROUND: Organ donation after circulatory death (DCD) is increasingly being used as a means of addressing the organ supply/demand mismatch in solid organ transplantation. There is reluctance to use DCD hearts, due to an inability to precisely identify hearts that have suffered irreversible injury. We investigated novel biomarkers and clinically relevant endpoints across a spectrum of warm ischemic times, before and during ex vivo heart perfusion (EVHP), to identify features associated with a nonviable cardiac phenotype. METHODS:Donorrats sustained a hypoxic cardiac arrest, followed by variable acirculatory standoff periods (DCD groups). Left ventricular function, histochemical injury, and differences in left ventricular gene expression were studied before, and during, EVHP. RESULTS: As warm ischemic time exposure increased in DCD groups, fewer hearts were functional during EVHP, and ventricular function was increasingly impaired. Histochemical assessment identified severely injured hearts during EVHP. A novel gene expression signature identified severely injured hearts during EVHP (upregulation of c-Jun, 3.19 (2.84-3.60); P = 0.0014; HMOX-1, 3.87 (2.72-5.50); P = 0.0037; and Hsp90, 7.66 (6.32-9.27); P < 0.0001 in DCD20), and may be useful in identifying high-risk hearts at the point of harvest (Hsp90). CONCLUSIONS: We demonstrate that our preclinical model recapitulates the cardio-respiratory decompensation observed in humans, and that EVHP appears necessary to unmask distinguishing features of severely injured DCD hearts. Furthermore, we outline a clinically relevant multimodal approach to assessing candidate DCD hearts. Novel mRNA signatures correlated with elevations in cardiac Troponin-I in severely injured hearts during EVHP, and may also detect injury at the point of harvest.
Authors: Martina Bona; Rahel K Wyss; Maria Arnold; Natalia Méndez-Carmona; Maria N Sanz; Dominik Günsch; Lucio Barile; Thierry P Carrel; Sarah L Longnus Journal: J Am Heart Assoc Date: 2021-01-30 Impact factor: 5.501
Authors: Jeanette E Villanueva; Hong C Chew; Ling Gao; Aoife Doyle; Sarah E Scheuer; Mark Hicks; Andrew Jabbour; Kumud K Dhital; Peter S Macdonald Journal: Transplant Direct Date: 2021-05-18
Authors: Michael Mengel; Alexandre Loupy; Mark Haas; Candice Roufosse; Maarten Naesens; Enver Akalin; Marian C Clahsen-van Groningen; Jessy Dagobert; Anthony J Demetris; Jean-Paul Duong van Huyen; Juliette Gueguen; Fadi Issa; Blaise Robin; Ivy Rosales; Jan H Von der Thüsen; Alberto Sanchez-Fueyo; Rex N Smith; Kathryn Wood; Benjamin Adam; Robert B Colvin Journal: Am J Transplant Date: 2020-06-27 Impact factor: 9.369