Developing cardioprotective therapies against ischemia-reperfusion injury in preclinical models mimicking the clinical condition

This study explores the multifaceted interactions between metabolic, pharmacological, and hemodynamic factors in the context of cardioprotection during IRI. The metabolic state of the heart plays a critical role in determining IRI severity and the potential for cardioprotection. Increases in glycolysis and glucose metabolism generally provides protection. The strongest known cardioprotective intervention, ischemic preconditioning, only protect when glucose is present, supporting that glucose metabolism is essential for cardioprotection. Insulin negates the benefits of other interventions including NR and malonate, probably because of maximal activation of glycolysis by insulin. NR and malonate cannot further activate glycolysis in these conditions and therefore lose its protection. In addition, cardioprotective potential is affected by interactions of perioperative medications. Fentanyl already activates the RISK pathway, such that protective agents working through activation of the RISK pathway lose its protection. The benzodiazepine midazolam inhibits caspases and mPTP opening and propofol inhibits cardiac glucose uptake and reduce ROS such that in the presence of these agents protective interventions working through these mechanism will also have diminished potential to protect. Furthermore, the study highlights the impact of the balloon usage on coronary flow dynamics in isolated heart models of IRI, demonstrating that the beneficial effects of interventions such as hydralazine can be reversed to detrimental outcomes with a disturbed cardiac vasculature. Overall, the thesis emphasizes the need for research reporting on specific conditions when interventions actually do not protect anymore, before embarking on clinical trials that are doomed to failed because of poor characterization of these none-working conditions.