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Item does not contain fulltext BACKGROUND: Ischemic myocardial damage accompanying coronary artery bypass graft surgery remains a clinical challenge. We investigated whether xenon anesthesia could limit myocardial damage in coronary artery bypass graft surgery patients, as has been reported for animal ischemia models. METHODS: In 17 university hospitals in France, Germany, Italy, and The Netherlands, low-risk elective, on-pump coronary artery bypass graft surgery patients were randomized to receive xenon, sevoflurane, or propofol-based total intravenous anesthesia for anesthesia maintenance. The primary outcome was the cardiac troponin I concentration in the blood 24 h postsurgery. The noninferiority margin for the mean difference in cardiac troponin I release between the xenon and sevoflurane groups was less than 0.15 ng/ml. Secondary outcomes were the safety and feasibility of xenon anesthesia. RESULTS: The first patient included at each center received xenon anesthesia for practical reasons. For all other patients, anesthesia maintenance was randomized (intention-to-treat: n = 492; per-protocol/without major protocol deviation: n = 446). Median 24-h postoperative cardiac troponin I concentrations (ng/ml [interquartile range]) were 1.14 [0.76 to 2.10] with xenon, 1.30 [0.78 to 2.67] with sevoflurane, and 1.48 [0.94 to 2.78] with total intravenous anesthesia [per-protocol]). The mean difference in cardiac troponin I release between xenon and sevoflurane was -0.09 ng/ml (95% CI, -0.30 to 0.11; per-protocol: P = 0.02). Postoperative cardiac troponin I release was significantly less with xenon than with total intravenous anesthesia (intention-to-treat: P = 0.05; per-protocol: P = 0.02). Perioperative variables and postoperative outcomes were comparable across all groups, with no safety concerns. CONCLUSIONS: In postoperative cardiac troponin I release, xenon was noninferior to sevoflurane in low-risk, on-pump coronary artery bypass graft surgery patients. Only with xenon was cardiac troponin I release less than with total intravenous anesthesia. Xenon anesthesia appeared safe and feasible.

Acute myocardial infarction (AMI or heart attack), in which myocardial damage is primarily the result of ischemia-reperfusion (I/R) injury, remains the leading cause of morbidity and mortality worldwide. This thesis aims to explore therapeutic strategies for acute myocardial I/R injury and reveal the mechanisms underlying I/R injury. We first evaluated several promising cardioprotective compounds in an in vivo model employing clinically relevant anesthesia, showing that only nicotinamide riboside (NR; NAD precursor) reduced I/R injury in presence of clinic therapies. We then showed in the isolated heart that NR’s protection is through activation of glycolysis. Next, knowing that oxidative stress is a major initial triggers for I/R injury, a recently developed clinically-applicable antioxidant compound (KH176m) was examined and shown higher efficacy of cardioprotection than the classic antioxidant N-(2-mercaptopropionyl)-glycine. However, antioxidant protection was mostly shown for short, but not long, ischemia. Additionally, we examined the NOD-like receptors X1 (NLRX1), an anti-inflammatory mitochondrial innate immune receptor which was shown to protect against severe ischemia. By deep-diving into the mechanisms, NLRX1 was proven to be a novel constituent of the mitochondrial permeability transition pore (mPTP), regulate mitochondrial function, and indirectly contribute to cardioprotection by facilitating reperfusion injury salvage kinase (RISK) pathway activation. After 70 years of searching for the molecular identity of the mPTP, NLRX1 is a strong candidate to finally fill that knowledge gap. In conclusion, this thesis addresses several strategies for acute cardiac I/R injury and unravelling the underlying protecting mechanisms improves our understanding of the crucial pathological processes of I/R injury.

In recent years, cardiovascular research has focused on investigating approaches to protect the heart against the severe consequences of ischemia/reperfusion (I/R) injury occurring after myocardial infarction and revascularization. Numerous pharmacological strategies have shown beneficial effects on cardioprotection in different animal species. Employing substances as pharmacological conditioning strategies that are already clinically approved and used in patients, for instance volatile anesthetics, opioids or α2-adrenoreceptor agonists, seems encouraging. However, definite translation of these strategies from experimental studies into the clinical setting improving patient outcome, remains incomplete. The question lingers whether certain substances, conditioning strategies or combination of approaches targeting different mechanisms, can be successful in conferring cardioprotection in patients. The present thesis focuses on cardioprotective strategies before (preconditioning) and after (postconditioning) myocardial ischemia by different pharmacological agents, investigating their underlying mechanisms in healthy and diseased hearts. Studies included in this thesis demonstrate that Ramelteon-induced preconditioning is mediated via protein kinase B / protein kinase G (Akt/PKG) pathways which trigger activation of mitochondrial large-conductance calcium-sensitive potassium (mBKCa) channels. This activation in turn leads to reactive oxygen species (ROS) release and inhibition of mitochondrial permeability transition pore (mPTP) opening. Further, our research shows that a combination of conditioning stimuli and substances, in specific Sildenafil and Milrinone, in sub-protective concentrations leads to a reduction of cardiac damage after I/R injury. Finally, it is demonstrated that Dexmedetomidine induces early and late postconditioning via activation of different mitochondrial potassium (mK+) channels and that postconditioning with Dexmedetomidine is fully abolished under acute hyperglycemia.

Patients suffering from type 2 diabetes mellitus have at least twice as much chance to develop heart failure. A new class of anti-diabetic drug, named sodium/glucose cotransporter 2 inhibitors (SGLT2i’s), can reduce the risk of hospitalization for heart failure, an outcome that could not be attained by general cardiovascular risk factors reduction. This thesis provides insight that off-target and direct cardiac and endothelial actions of SGLT2i's may, at least partly, elicit the beneficial drug effects that could ultimately reduce the risk of heart failure. These mechanisms include changes in the cellular ion homeostasis, metabolism and inflammation and are to some extent modulated by the inhibition of the Na+/H+-exchanger. Our data show that SGLT2i's lower Na+/H+-exchanger activity and cytoplasmatic sodium levels in isolated cardiomyocytes and endothelial cells. In isolated hearts, SGLT2i empagliflozin caused 1) acute vasodilation in the healthy condition, 2) delayed the contracture onset during ischemia and 3) lowered lactate and increased α-ketoglutarate levels in the type 2 diabetic condition. Improved endothelial function, i.e. lower oxidative stress formation and increased nitric oxide bioavailability, during inflammation was observed with empagliflozin and dapagliflozin administration. Finally, this thesis shows that cytokine release during inflammation is dampened by canagliflozin through the reduction of hexokinase 2. In conclusion, SGLT2i’s provoke direct cardiac and endothelial effects that are to some extent modulated by inhibition of the Na+/H+-exchanger.

This thesis explores two promising forms of conditioning for organ protection against ischaemia and reperfusion injury: remote ischaemia and helium inhalation. We evaluated whether these methods of conditioning could be translated into clinical practice; and what the possible underlying mechanism is. We reviewed the results of 23 different randomised clinical trials on remote ischaemic conditioning and although this reduced cardiac injury, there was no improvement in clinical outcome. In a randomised controlled trial in cardiac surgery patients we found no effect of remote ischaemic conditioning on the molecular markers ERK-1, ERK-2, STAT3 or STAT5 in myocardial tissue. Nor did we see a reduction in myocardial injury as measured by troponin T release after surgery. This was the case in patients with or without diabetes mellitus. We demonstrated that helium conditioning prevents endothelial dysfunction in healthy volunteers after forearm ischaemia. This was not mediated by eNOS and we found no effect on the level of circulating cytokines or microparticles. In cardiac surgery patients however, we did not see an effect of helium pre- or postconditioning on ERK-1, ERK-2, p-38 mitogen-activated protein kinase or protein kinase C-epsilon activation. Nor did conditioning with helium reduce troponin T release after surgery. We demonstrated that helium can safely be administered to patients admitted to the intensive care unit after cardiac arrest and this allowed for a reduction in respiratory rate and minute volume ventilation. Despite promising early results, neither form of conditioning protected against ischaemia and reperfusion injury in patients in a clinically relevant setting.

The general aim of this thesis was to study the effects of hexokinase II (HKII) on cardiac ischemia/reperfusion (I/R) injury and metabolism. In cancer cells, increased binding of both HKI and HKII have been associated with the increased survival rate of these cells. In previous studies it has been observed that binding of HKII to the mitochondria (mtHKII) protects the heart and skeletal muscle against I/R injury. This thesis focused on elucidating the cellular mechanisms by which mtHKII protects the heart against I/R injury. We focused on the effect of a reduction in mtHKII on cardiac metabolism, oxygen consumption, reactive oxygen species and the correlation between HKII and cyclophilin D (CypD). In addition, this thesis studied whether cardioprotection by remote ischemic preconditioning (RIPC) and metformin treatment in cardiac surgical patients is associated with increased amounts of mtHKII. Taken together, this thesis shows that 1) low doses (200 nM) of the special peptide TAT-HKII can be used to study effects of mtHKII reduction in the heart, 2) a reduction in mtHKII turns non-injurious I/R into injurious I/R and is accompanied by increased reactive oxygen species (ROS) production at reperfusion, and increased energetics at baseline, 3) the cardioprotective effect of CypD deletion might, at least partly, be caused by increased mtHK activity, 4) an acute, but not chronic, decrease in mtHKII affects cardiac metabolism 5) glucose-only is insufficient substrate for the Langendorff perfused mouse heart, and 6) metformin treatment and RIPC in the absence of propofol are not cardioprotective in coronary artery bypass graft (CABG) surgery under the conditions used in this thesis.

The aims of this thesis were to investigate whether helium induces preconditioning in humans, and to elucidate the mechanisms behind this possible protection. First, we collected data regarding organ protective effects of noble gases in general, and of helium in particular (chapters 1-3). In chapter 4 we demonstrated that helium inhalation in healthy volunteers had no negative side effects on the innate human immune system and the ability to respond to pathogens in vitro. After that, we showed that helium induces preconditioning in humans and protects against postischemic endothelial damage following forearm ischemia-reperfusion in healthy volunteers. (chapter 5). In chapter 6 we conducted a clinical trial, including 125 patients undergoing coronary artery bypass graft surgery, investigating whether helium affects signal transduction kinases (P38 mitogen-activated protein kinase, extracellular signal–regulated kinase-1/2, protein kinase C-ε or heat shock protein-27) or postoperative troponin release. The second aim of this thesis was to elucidate the mechanisms behind helium conditioning, which we investigated in cultured endothelial cells in vitro. In chapter 7 we demonstrate prolonged helium exposure (30 minutes) in endothelial cells surprisingly aggravated oxidative stress induced cell damage, increasing cell death. In chapter 9 we showed exposure to helium (20 minutes) increased cortical localization of F-actin fibers and decreases permeability via caveolin-1. Focusing on the possible effect of caveolin in the buoyant fraction (supernatant or plasma), we investigated whether plasma from healthy volunteers undergoing helium or ischemic conditioning protected endothelial cells against hypoxia in vitro (chapter 8 and 10).