目标体温管理通过抑制铁死亡改善心肺复苏后心肌功能障碍的机制研究

心肺复苏后心肌I/R损伤导致的复苏后心肌功能障碍（PRMD）是CA患者的主要死因之一，目标体温管理（TTM）对PRMD有确切保护作用，但具体机制尚未明确。基于铁死亡在I/R损伤发生机制中的作用，结合本课题组前期研究结果，提出“复苏后心肌细胞铁自噬被过度激活，进一步发生铁死亡，造成线粒体损伤和PRMD，TTM通过抑制铁死亡减轻心肌I/R损伤”的理论假设。为此，本研究拟通过建立大鼠CPR模型，采用TTM方法进行干预，利用原代心肌细胞模拟I/R损伤及亚低温干预，在细胞和分子水平上证实CPR后心肌细胞中核受体共激活因子4介导的铁自噬被过度激活，诱发铁死亡和线粒体损伤，造成PRMD，并探讨TTM对PRMD的保护机制是否通过激活Nrf2/FPN1途径减轻线粒体铁超载，进一步抑制心肌细胞铁死亡。这将丰富PRMD的发生发展机制及TTM临床实用依据，具有重要临床价值和科学意义。

Post-resuscitation myocardial dysfunction (PRMD) caused by myocardial ischemia/reperfusion (I/R) injury is a prevailing cause of death. Target temperature management (TTM) has a definite protective effect on PRMD, but its pathogenesis is still open to discussion. Based on the role of ferroptosis in the mechanism of I/R injury and our previous study, we hypothesized that ferritinophagy is excessively activated, which further leads to ferroptosis, resulting in mitochondrial damage and PRMD, and TTM attenuates myocardial I/R injury by inhibiting ferroptosis. The aim of the study is to verify that ferritinophagy mediated by NCOA4 is excessively activated after resuscitation, inducing ferroptosis, mitochondrial damage and PRMD in a rat model of CPR and I/R injury cell model of primary cardiomyocytes with TTM intervention.We will further explore whether TTM protects PRMD by activating Nrf2/FPN1 pathway to reduce mitochondrial iron overload and inhibit ferroptosis. It will enrich the mechanisms of myocardial I/R injury after resuscitation and TTM, which has important clinical value and great significance.