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Updated: Oct 31, 2025
Pre-clinical Model of Cardiac Donation after Circulatory Death
Published on: August 2, 2019
Pre-ischemic Lactate Levels Affect Post-ischemic Recovery in an Isolated Rat Heart Model of Donation After
Maria Arnold1,2, Adrian Segiser1,2, Selianne Graf1,2
1Department of Cardiovascular Surgery, Inselspital, Bern University Hospital, Bern, Switzerland.
Insights
Pre-ischemic lactate levels in donation after circulatory death (DCD) hearts impair recovery. Inhibiting mitochondrial calcium uptake during reperfusion improves outcomes, suggesting a therapeutic target for DCD hearts.
Area of Science:
- Cardiology
- Organ Transplantation
- Physiology
Background:
- Donation after circulatory death (DCD) offers a potential solution to donor heart shortages.
- DCD hearts face both warm ischemia and a damaging pre-ischemic phase.
- Pre-ischemic conditions, including lactate levels, may impact post-transplant heart function.
Purpose of the Study:
- To investigate the impact of DCD-relevant pre-ischemic lactate levels on isolated rat heart recovery.
- To determine if lactate affects post-ischemic functional and mitochondrial recovery.
- To explore the role of mitochondrial calcium uptake in DCD heart reperfusion injury.
Main Methods:
- Isolated working rat hearts underwent global ischemia and reperfusion.
- Hearts were perfused with varying pre-ischemic lactate concentrations (0 mM, 0.5 mM, 1 mM).
- A subset received a mitochondrial calcium uniporter inhibitor (Ru360) during reperfusion.
Main Results:
- Physiologic lactate (0.5 mM) improved post-ischemic left ventricular work compared to no lactate or 1 mM lactate.
- Higher lactate levels (1 mM) correlated with decreased function, increased cellular/mitochondrial damage, and higher calcium content.
- Mitochondrial calcium uptake inhibition (Ru360) partially restored function and reduced damage in high-lactate hearts.
Conclusions:
- DCD-relevant pre-ischemic lactate levels negatively affect heart recovery post-ischemia.
- Mitochondrial calcium overload is implicated in DCD heart reperfusion injury.
- Inhibiting mitochondrial calcium uptake presents a potential therapeutic strategy for DCD heart preservation.
Abstract:
Introduction: Donation after circulatory death (DCD) could substantially improve donor heart availability. In DCD, the heart is not only exposed to a period of warm ischemia, but also to a damaging pre-ischemic phase. We hypothesized that the DCD-relevant pre-ischemic lactate levels negatively affect the post-ischemic functional and mitochondrial recovery in an isolated rat heart model of DCD. Methods: Isolated, working rat hearts underwent 28.5' of global ischemia and 60' of reperfusion. Prior to ischemia, hearts were perfused with one of three pre-ischemic lactate levels: no lactate (0 Lac), physiologic lactate (0.5 mM; 0.5 Lac), or DCD-relevant lactate (1 mM; 1 Lac). In a fourth group, an inhibitor of the mitochondrial calcium uniporter was added in reperfusion to 1 Lac hearts (1 Lac + Ru360). Results: During reperfusion, left ventricular work (heart rate-developed pressure product) was significantly greater in 0.5 Lac hearts compared to 0 Lac or 1 Lac. In 1 vs. 0.5 Lac hearts, in parallel with a decreased function, cellular and mitochondrial damage was greater, tissue calcium content tended to increase, while oxidative stress damage tended to decrease. The addition of Ru360 to 1 Lac hearts partially abrogated the negative effects of the DCD-relevant pre-ischemic lactate levels (greater post-ischemic left ventricular work and less cytochrome c release in 1 Lac+Ru360 vs. 1 Lac). Conclusion: DCD-relevant levels of pre-ischemic lactate (1 mM) reduce contractile, cellular, and mitochondrial recovery during reperfusion compared to physiologic lactate levels. Inhibition of mitochondrial calcium uptake during early reperfusion improves the post-ischemic recovery of 1 Lac hearts, indicating calcium overload as a potential therapeutic reperfusion target for DCD hearts.
