Targeted temperature management alleviates post-resuscitation myocardial dysfunction by inhibiting ferroptosis

Area of Science:

• Cardiology
• Biochemistry
• Cell Biology

Background:

• Targeted temperature management (TTM) is crucial for cardiac arrest survivors to prevent post-resuscitation myocardial dysfunction (PRMD).
• The optimal temperature for TTM and its underlying mechanisms in mitigating myocardial ischemia/reperfusion (I/R) injury remain debated.
• Myocardial I/R injury involves complex cellular processes including oxidative stress and iron dysregulation.

Purpose of the Study:

• To investigate the efficacy of TTM at different temperatures (33°C vs. 36°C) in mitigating PRMD.
• To elucidate the molecular mechanisms by which TTM and Deferoxamine (DFO) protect against myocardial injury.
• To explore the role of iron homeostasis, ferroptosis, and Nrf2 activation in TTM's protective effects.

Main Methods:

• In vivo rat model of cardiac arrest (CA), cardiopulmonary resuscitation (CPR), and TTM.
• In vitro cell models to study myocardial I/R injury.
• Assessment of hemodynamic function, myocardial damage, mitochondrial function, oxidative stress markers, lipid peroxidation, and iron levels.
• Analysis of ferritinophagy, ferroptosis, and Nrf2 pathway activation.

Main Results:

• TTM at 33°C significantly improved post-resuscitation hemodynamics and myocardial function compared to 36°C in rats.
• Both 33°C TTM and DFO treatment reduced myocardial and mitochondrial damage, oxidative stress, lipid peroxidation, and iron overload.
• Hypothermia and DFO suppressed ferritinophagy and ferroptosis, correlating with enhanced nuclear translocation and activation of Nrf2.
• Nrf2 activation led to inhibited ferritinophagy and increased iron export, suggesting a key role in cytoprotection.

Conclusions:

• TTM at 33°C is more effective than 36°C in alleviating PRMD and reducing myocardial damage by inhibiting ferroptosis.
• The protective effects of 33°C TTM and DFO are mediated by Nrf2 activation and improved iron homeostasis.
• DFO exerts protective effects through iron chelation and activation of the Nrf2 signaling pathway, offering a potential therapeutic strategy for PRMD.