Related Experiment Video
Updated: May 28, 2026
Pre-clinical Model of Cardiac Donation after Circulatory Death
Published on: August 2, 2019
Circulating Mitochondrial DNA Aggravates Post-Ischemic Functional and Metabolic Recovery in an Isolated Rat Heart
Maria Nieves Sanz1,2, Maria Arnold1,2, Adrian Segiser1,2
1Department of Cardiac Surgery, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland.
Abstract:
During donation after circulatory death (DCD), circulating levels of mitochondrial damage-associated molecular patterns (mtDAMPs) may increase, thereby exposing donor hearts to mtDAMPs prior to procurement and during machine perfusion. Mitochondrial DNA (mtDNA) is a pro-inflammatory mtDAMP that may stimulate several intracellular cascades including that of toll-like receptor 9 (TLR9). We administered mtDNA or ODN2088 (TLR9 antagonist) to hearts at reperfusion onset using an isolated rat heart model of DCD transplantation to investigate their effects. Four experimental groups were compared: (1) no ischemia; (2) ischemia; (3) ischemia + mtDNA; (4) ischemia + ODN2088. During reperfusion, cardiac power in ischemic hearts was significantly reduced compared to non-ischemic hearts (p < 0.01), and was further decreased with mtDNA (p < 0.05), but remained unchanged with ODN2088. Reduced ventricular recovery in mtDNA-treated hearts likely resulted from lower recovery of oxidative metabolism, demonstrated by reduced oxygen efficiency (p < 0.05) and a strong tendency for increased cytochrome c release (p < 0.06),indicating mitochondrial dysfunction and disruption, respectively. ODN2088 phosphorylated IκBα (NF-κB inhibitor alpha) and appeared to decrease cardiomyocyte death compared to ischemic hearts. Given the detrimental effects of circulating mtDNA on cardiac functional and metabolic recovery, circulating mtDAMPs, and particularly mtDNA, are of clinical relevance as potential therapeutic targets for optimizing graft quality and post-transplant outcomes.
Insights
Mitochondrial DNA (mtDNA) worsens heart function after circulatory death (DCD) donation. Blocking toll-like receptor 9 (TLR9) with ODN2088 may protect the donor heart, improving transplant outcomes.
Area of Science:
- Cardiovascular Research
- Transplantation Immunology
- Mitochondrial Biology
Background:
- Donation after circulatory death (DCD) involves potential damage to donor organs from circulating mitochondrial damage-associated molecular patterns (mtDAMPs).
- Mitochondrial DNA (mtDNA), a pro-inflammatory mtDAMP, can activate toll-like receptor 9 (TLR9), potentially impairing graft quality.
Purpose of the Study:
- To investigate the impact of administering mtDNA or a TLR9 antagonist (ODN2088) on isolated rat hearts in a DCD transplantation model.
- To assess the effects of mtDNA and ODN2088 on cardiac function, metabolic recovery, and cell death during reperfusion.
Main Methods:
- Utilized an isolated rat heart model simulating DCD transplantation.
- Compared four groups: no ischemia, ischemia, ischemia + mtDNA, and ischemia + ODN2088.
- Administered mtDNA or ODN2088 at reperfusion onset and analyzed cardiac power, oxygen efficiency, and cytochrome c release.
Main Results:
- Ischemic hearts showed reduced cardiac power, further decreased by mtDNA administration.
- mtDNA treatment led to impaired recovery of oxidative metabolism, evidenced by reduced oxygen efficiency and increased cytochrome c release, indicating mitochondrial dysfunction.
- ODN2088 treatment did not alter cardiac power but appeared to reduce cardiomyocyte death and modulate NF-κB signaling.
Conclusions:
- Circulating mtDNA has detrimental effects on cardiac functional and metabolic recovery post-DCD.
- mtDAMPs, particularly mtDNA, are clinically relevant targets for improving donor graft quality and post-transplant outcomes.
- TLR9 antagonism may offer a therapeutic strategy to mitigate mtDNA-induced damage in DCD donor hearts.
