Ex vivo Heart Perfusion with Cyclosporine Inhibits Ischemia Reperfusion Injury and Promotes Post Transplantation Myocardial Function in a Murine Model
Presented During:
Monday, May 4, 2026: 9:00AM - 4:00PM
McCormick Place Lakeside Center
Posted Room Name:
Exhibit Hall, Poster Area
Abstract No:
P0131
Submission Type:
C. Walton Lillehei Resident Forum
Authors:
Jason Breithaupt (1), Jack Zakrzewski (1), Benjamin Borg (1), Nicolas Drysdale (1), James Jaggers (2), Matthew Stone (2)
Institutions:
(1) University of Colorado, Anschutz Medical Center, Aurora, CO, (2) Children's Hospital of Colorado, Aurora, CO
Submitting Author:
Jason Breithaupt
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University of Colorado, Anschutz Medical Center
University of Colorado, Anschutz Medical Center
Co-Author(s):
Jack Zakrzewski
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University of Colorado, Anschutz Medical Center
University of Colorado, Anschutz Medical Center
Benjamin Borg
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University of Colorado, Anschutz Medical Center
University of Colorado, Anschutz Medical Center
Nicolas Drysdale
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University of Colorado, Anschutz Medical Center
University of Colorado, Anschutz Medical Center
*James Jaggers
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Children's Hospital of Colorado
Children's Hospital of Colorado
Matthew Stone
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Children's Hospital of Colorado
Children's Hospital of Colorado
Presenting Author:
Jason Breithaupt
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Abstract:
Objective
Success of cardiac transplant is limited by ischemia reperfusion injury (IRI) and resultant primary graft dysfunction (PGD). Ex vivo heart perfusion (EVHP) is a novel preservation strategy that may enable the delivery of targeted therapies to the donor allograft during preservation. Further, our group has adopted EVHP to identifty mitochondrial viability and function as a principal determinant of post-transplant graft function. Cyclosporine (CsA) has been successfully adopted in transplantation as a calcineurin inhibitor for immunosuppression with more recent investigations promoting its efficacy as an inhibitor of the mitochondrial permeability transition pore (mPTP). mPTP opening is a critical step in IRI leading to mitochondrial dysfunction, rupture, and ultimately cellular apoptosis. Herein, we test the hypothesis that EVHP with CsA will improve post-transplantation graft function in a heterotopic transplant model.
Methods
Wild-type C57BL/6 murine hearts were explanted and stratified by 90-minute preservation method: EVHP with acellular, krebs-henseleit (KH) buffer (Group 1) and EVHP with KH buffer + 100 ng/ml CsA (Group 2). Hearts were heterotopically transplanted onto the cervical vessels of recipient mice for 120-minutes of reperfusion prior to assessment of left ventricular function by echocardiography and IRI by immunohistochemistry staining for the macrophage marker f4/80.
Results
Following heterotopic transplantation, Group 2 hearts demonstrated higher levels of fractional shortening (21.71% ± 8.76%, 1.60/2.01 mm vs. 10.04% ± 4.67%, 1.90/2.09 mm, p=0.015) compared to group 1 hearts (Figure 1a). Further, Group 2 hearts were found to have lower numbers of macrophages (32.86 ± 5.98 f4/80 + cell/hpf vs. 43.38 ± 7.56 f4/80 + cell/hpf, p=0.016) compared to group 1 hearts (Figure 1b). Together these findings demonstrate improved graft function and decreased IRI afforded by EVHP with CsA compared to hypothermic, acellular buffer alone, further validating the importance of mitochondrial function and viability on post-transplantation graft function.
Conclusion
CsA attenuates IRI in transplanted murine hearts as demonstrated by improvements in fractional shortening (myocardial function) and decreased macrophage infiltration. These findings support adoption of CsA within EVHP pre-clinical trials to define the optimal strategy to decrease IRI and improve post-transplantation allograft function.
Success of cardiac transplant is limited by ischemia reperfusion injury (IRI) and resultant primary graft dysfunction (PGD). Ex vivo heart perfusion (EVHP) is a novel preservation strategy that may enable the delivery of targeted therapies to the donor allograft during preservation. Further, our group has adopted EVHP to identifty mitochondrial viability and function as a principal determinant of post-transplant graft function. Cyclosporine (CsA) has been successfully adopted in transplantation as a calcineurin inhibitor for immunosuppression with more recent investigations promoting its efficacy as an inhibitor of the mitochondrial permeability transition pore (mPTP). mPTP opening is a critical step in IRI leading to mitochondrial dysfunction, rupture, and ultimately cellular apoptosis. Herein, we test the hypothesis that EVHP with CsA will improve post-transplantation graft function in a heterotopic transplant model.
Methods
Wild-type C57BL/6 murine hearts were explanted and stratified by 90-minute preservation method: EVHP with acellular, krebs-henseleit (KH) buffer (Group 1) and EVHP with KH buffer + 100 ng/ml CsA (Group 2). Hearts were heterotopically transplanted onto the cervical vessels of recipient mice for 120-minutes of reperfusion prior to assessment of left ventricular function by echocardiography and IRI by immunohistochemistry staining for the macrophage marker f4/80.
Results
Following heterotopic transplantation, Group 2 hearts demonstrated higher levels of fractional shortening (21.71% ± 8.76%, 1.60/2.01 mm vs. 10.04% ± 4.67%, 1.90/2.09 mm, p=0.015) compared to group 1 hearts (Figure 1a). Further, Group 2 hearts were found to have lower numbers of macrophages (32.86 ± 5.98 f4/80 + cell/hpf vs. 43.38 ± 7.56 f4/80 + cell/hpf, p=0.016) compared to group 1 hearts (Figure 1b). Together these findings demonstrate improved graft function and decreased IRI afforded by EVHP with CsA compared to hypothermic, acellular buffer alone, further validating the importance of mitochondrial function and viability on post-transplantation graft function.
Conclusion
CsA attenuates IRI in transplanted murine hearts as demonstrated by improvements in fractional shortening (myocardial function) and decreased macrophage infiltration. These findings support adoption of CsA within EVHP pre-clinical trials to define the optimal strategy to decrease IRI and improve post-transplantation allograft function.
Category:
Adult Cardiac
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