Introduction:
Solid evidence support that cyclophilin D (CypD), which promotes the lethal opening of the mitochondrial permeability transition pore (mPTP), is involved in the pathogenesis of ischemia-reperfusion injury, including after cardiac arrest (CA). However, a recent trial (CYRUS study) showed that cyclosporine A, the reference mPTP inhibitor (via its binding to CypD), failed to limit the severity of the post-CA syndrome, raising the question of whether CypD is a viable target for protection in CA. Therefore, we aimed to reassess the role of CypD in CA resuscitation using CypD knockout mice.
Hypothesis:
We hypothesized that CypD is a target of interest for CA treatment.
Methods:
Wild type (WT) or CypD knockout (CypD
-/-
) mice underwent 5 minutes of asphyxia-induced CA followed by cardiopulmonary resuscitation. Additional mice were treated with therapeutic hypothermia (32-34°C) as the gold standard intervention to confer protection after CA. In a first set of experiments, animals were euthanized after 2 hours of reperfusion for biochemical and mitochondrial assays. In a second set of experiments, animals were observed for up to 7 days for survival and neurological status.
Results:
All animals underwent similar durations of asphyxia before CA. Rate of ROSC was significantly higher in CypD
-/-
group (with a shorter cardiac massage duration) compared to WT group (p<0.05). CA-induced myocardial dysfunction and increase in plasma levels of troponin were both attenuated by CypD deletion (p<0.05 versus WT) without additional benefits of hypothermia. CypD
-/-
mice exhibited significantly less brain damage than WT. CypD deletion prevented both CA-induced mPTP opening and respiration impairment in isolated brain mitochondria (p<0.05 versus WT). Short-term survival (24 hours) was significantly higher in CypD
-/-
than WT mice (p<0.05). Only therapeutic hypothermia significantly improved both short-term and neurological intact survival at day 7 after CA compared to WT (p<0.05).
Conclusions:
Our results suggest that CypD remains a potential major target to improve resuscitability and early but not long-term outcomes. Supplementary interventions, such as therapeutic hypothermia, are needed to enhance long-term recovery.
Short Term Safety and Pharmacokinetics of the Selective NOS Inhibitor 2-Iminobiotin in Asphyxiated Neonates during Therapeutic Hypothermia: Protocol for the 2-STEP Study
