Treatment with inhaled medical gases to improve myocardial and neurological outcome after cardiac arrest

<b>Introduction</b> Heart and brain protection exerted by argon (Ar) ventilation after cardiac arrest and cardiopulmonary resuscitation (CA/CPR) was demonstrated in preclinical animal models. The aim of this thesis is to provide new pathophysiological insights of Ar treatment after CA/CPR. This thesis will:<br> 1. Investigate mechanisms of heart and brain protection induced by Ar after CA/CPR, focusing on the alterations in mitochondrial integrity and function. <br> 2. Investigate the association of inhaled Ar treatment with a novel protective intervention, i.e. hydrogen (H₂) on brain and myocardial injury.<br><br> <b>Methods</b> For the first aim, a reliable experimental model of CA/CPR in rats was used. For the second aim, a preclinical model of CA/CPR in pigs was employed. <br> Neurological and myocardial function together with histological damage to the heart and brain were assessed using scales, imaging (echocardiography and magnetic resonance) and immunohistochemistry approaches. Tissue protein expression levels of mitochondrial integrity mediators were assessed by Western Blot analyses. The identification of mitochondrial ultrastructure parameters was investigated by transmission electron microscopy in rodents.<br><br> <b>Results</b> CA/CPR in rats induced neurological and cardiac impairment together with alterations in mitochondrial morphology and integrity, making this model suitable to monitor the efficacy of inhaled Ar intervention. In this model, ventilation with Ar conferred cardioprotective effects by mitochondrial protection by the activation of mitochondrial biogenesis and mitophagy processes. <br> In pigs, the inhalatory mixture of 68% Ar +2% H₂ in oxygen reduced both neuronal degeneration and neuroinflammation after CA.<br><br> <b>Conclusion</b> Alterations in mitochondrial integrity and function are strongly implicated in myocardial and brain injury after CA/CPR; myocardial and neurological protection exerted by Ar treatment seems to be related to this mitochondrial protection. The combined use of Ar and H₂ may offer a promising, cost-effective intervention to reduce post-CA brain injury by leveraging the distinct protective mechanisms each gas provides concurrently.