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Updated: Nov 4, 2025
Author Spotlight: Enhancing Donor Heart Preservation Through Isolated Rat Heart Perfusion Studies
Published on: October 4, 2024
The Effect of Increasing Donor Age on Myocardial Ischemic Tolerance in a Rodent Model of Donation After Circulatory
Jeanette E Villanueva1,2, Hong C Chew1, Ling Gao1
1Physiology and Transplantation, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.
Insights
Donor heart age impacts recovery after circulatory death. Pharmacologic supplementation aids younger donor hearts but not older ones, due to age-related mitochondrial decline.
Area of Science:
- Cardiology
- Transplantation Biology
- Gerontology
Background:
- Donation after circulatory death (DCD) hearts face warm ischemic time (WIT) injury.
- Older donor hearts are more vulnerable to WIT, impacting transplant outcomes.
- Understanding age-related injury mechanisms is crucial for improving DCD heart utilization.
Purpose of the Study:
- Investigate the combined effects of donor age and pharmacologic supplementation on DCD heart recovery.
- Assess how aging affects cardiac mitochondrial function and oxidative capacity.
- Determine the efficacy of GTN/EPO/Z supplementation in mitigating age-related DCD heart injury.
Main Methods:
- Wistar rats of varying ages (12, 18, 24 months) underwent DCD with a 20-min WIT.
- Hearts were preserved and perfused using a Langendorff system with or without GTN/EPO/Z supplementation.
- Cardiac function (aortic flow, cardiac output) and cell damage (LDH) were measured.
- Mitochondrial respiratory capacity was assessed in native heart tissue.
Main Results:
- Older DCD hearts (18, 24 months) showed significantly reduced functional recovery compared to younger hearts.
- GTN/EPO/Z supplementation improved recovery in 18-month-old hearts but not 24-month-old hearts.
- 24-month-old hearts exhibited impaired mitochondrial respiration at multiple complexes.
Conclusions:
- Increasing donor age reduces ischemic tolerance in DCD hearts.
- Pharmacologic supplementation enhances DCD heart recovery in younger to middle-aged donors (up to 18 months).
- Age-related decline in mitochondrial function likely limits the benefits of supplementation in older donor hearts.
Abstract:
Hearts from older donors or procured via donation after circulatory death (DCD) can alleviate transplant waitlist; however, these hearts are particularly vulnerable to injury caused by warm ischemic times (WITs) inherent to DCD. This study investigates how the combination of increasing donor age and pharmacologic supplementation affects the ischemic tolerance and functional recovery of DCD hearts and how age impacts cardiac mitochondrial respiratory capacity and oxidative phosphorylation.
Methods:
Wistar rats (12-, 18-, and 24-mo-old) were subjected to DCD with 20-min fixed WIT. Hearts were procured, instrumented onto a Langendorff perfusion circuit, flushed with Celsior preservation solution with or without supplementation (glyceryl trinitrate [GTN]/erythropoietin [EPO]/zoniporide [Z]) and perfused (Krebs-Henseleit buffer, 37°C Langendorff 30-min, working 30-min). Cardiac functional recovery of aortic flow (AF), coronary flow (CF), cardiac output (CO), and lactate dehydrogenase release were measured. Native heart tissue (3-, 12-, and 24-mo) were assessed for mitochondrial respiratory capacity.
Results:
Unsupplemented 18- and 24-month DCD hearts showed a 6-fold decrease in AF recovery relative to unsupplemented 12-month DCD hearts. GTN/EPO/Z supplementation significantly increased AF and CO recovery of 18-month DCD hearts to levels comparable to supplemented 12-month hearts; however, GTN/EPO/Z did not improve 24-month DCD heart recovery. Compared to 12-month heart tissue, 24-month hearts exhibited significantly impaired mitochondrial oxygen flux at complex I, II, and uncoupled maximal respiration stage.
Conclusions:
Reduced ischemic tolerance after DCD was associated with increasing age. Pharmacologic supplementation improves functional recovery of rat DCD hearts but only up to age 18 months, possibly attributed to a decline in mitochondrial respiratory capacity with increasing age.
