P131. Ex vivo Heart Perfusion with Cyclosporine Inhibits Ischemia Reperfusion Injury and Promotes Post Transplantation Myocardial Function in a Murine Model
Presented During: Adult Cardiac Poster Session II
Denver, CO
United States - Contact Me
I am a general surgery resident at the University of Colorado, and I hope to become a cardiac surgeon and translational investigator in my field. I am inspired to create new, and innovative treatment options to improve the care of cardiac surgical patients through research. In pursuit of this goal I completed a Sarnoff Cardiovascular Research Fellowship at Duke University and medical school at the University of Miami.
Monday, May 4, 2026: 9:00 AM - 4:00 PM
McCormick Place Lakeside Center
Room: Exhibit Hall, Poster Area
Description
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.
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
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.
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
Presentation Duration
There is no formal presentation for posters. Your poster will be on display on your assigned day from 9:00AM - 4:00PM
View Submission
Category
Adult Cardiac