Oxidative Medicine and Cellular Longevity
Volume 2015 (2015), Article ID 189863, 8 pages
http://dx.doi.org/10.1155/2015/189863

Review Article

Cardiopulmonary Bypass and Oxidative Stress

Mustafa Zakkar, Gustavo Guida, M-Saadeh Suleiman, and Gianni D. Angelini

Bristol Royal Infirmary, Level 7, Upper Maudlin Street, Bristol BS2 8HW, UK

Received 29 December 2014; Accepted 19 January 2015

Academic Editor: Giuseppe Cirillo

Copyright © 2015 Mustafa Zakkar et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

The development of the cardiopulmonary bypass (CPB) revolutionized cardiac surgery and contributed immensely to improved patients outcomes. CPB is associated with the activation of different coagulation, proinflammatory, survival cascades and altered redox state. Haemolysis, ischaemia, and perfusion injury and neutrophils activation during CPB play a pivotal role in oxidative stress and the associated activation of proinflammatory and proapoptotic signalling pathways which can affect the function and recovery of multiple organs such as the myocardium, lungs, and kidneys and influence clinical outcomes. The administration of agents with antioxidant properties during surgery either intravenously or in the cardioplegia solution may reduce ROS burst and oxidative stress during CPB. Alternatively, the use of modified circuits such as minibypass can modify both proinflammatory responses and oxidative stress.

1. Introduction

The development of the cardiopulmonary bypass (CPB) revolutionized cardiac surgery and contributed immensely to improved patients outcomes [1, 2].

It is accepted that CPB exposes patients to a complex set of nonphysiological conditions during which organs are subjected to severe functional alterations. CPB is associated with the activation of different coagulation, proinflammatory, survival cascades and altered redox state [3–5] (Figure 1). Despite significant refinements over the years, oxidative stress and inflammation remain major concerns when using CPB [6, 7].

Figure 1: Schematic overview of inflammatory and oxidative stress response during cardiopulmonary bypass.

2. Reactive Oxygen Species

Free radicals are molecules with unpaired electrons making them highly reactive. They can be derived from oxygen, nitrogen, or sulfur molecules. Free radicals derived from oxygen are usually called reactive oxygen species (ROS) [8, 9]. The main forms of cardiac ROS are superoxide (), hydrogen peroxide (H₂O₂), hydroxyl radicals (•OH), and peroxynitrite (ONOO⁻). Although hydrogen peroxide is not a free radical it is considered a ROS due to its highly reactive nature.

ROS can be formed as a natural byproduct of normal metabolism of oxygen as aerobic metabolism results in the production of ROS in the mitochondria during ATP formation. Nonetheless, cells are normally able to shield themselves against ROS through different defense mechanisms that include enzymatic and free radical scavenging activities to neutralize these radicals resulting in a balance (redox state) between ROS production and cells ability to detoxify ROS or to repair any subsequent damage. During periods of stress, however, ROS levels can increase drastically leading to substantial damage to many cellular molecules such as lipids, proteins, and DNA [8–10].

Redox signalling occurs as a response to changes in the levels of ROS and the mitochondria appear to be of pivotal importance for this signalling due to its role in metabolism, the continuous flux of and oxygen sensing. Redox signalling is involved in multiple processes such as homoeostasis, stress response pathways, and cardiac remodeling and fibrosis [8, 10–12].

3. Oxidative Stress, Inflammation, and Cardiopulmonary Bypass

The presence of atherosclerotic coronary artery disease requiring intervention is associated with evidence of oxidative stress and inflammation prior to surgery which can be markedly accentuated during CPB [13]. Furthermore, patients undergoing cardiac surgery tend to have other coexisting morbidities such as diabetes and renal and lung diseases which are associated with abnormal redox state and oxidative stress.

CPB initiates multiple processes that impact both cellular and noncellular contents of blood. The repeated passage of blood through the nonendothelialised extracorporeal circuit triggers the activation of polymorphonuclear leukocytes (mainly neutrophils) which are believed to be a prime source of ROS during cardiac surgery. Activation of neutrophils during CPB is evident by the loss of L-selectin and the upregulation of CD11b/CD18 (Mac-1) [14–17] (Figure 2).

Figure 2: Main triggers of inflammatory response during cardiopulmonary bypass.

During CPB, ischaemic injury occurs when the blood supply to tissue is suboptimal and accompanied by cellular adenosine triphosphate depletion due to its degradation by hypoxanthine [7, 18]. Hypoxanthine is normally oxidized by the enzyme xanthine dehydrogenase to xanthine using nicotinamide adenine dinucleotide (NAD) in a reaction converting NAD to nicotinamide adenine dinucleotide hydrogenase (NADH), conversely; xanthine dehydrogenase is converted to xanthine oxidase during periods of ischaemia. Furthermore, anaerobic metabolism results in the production of lactic acid and altered cellular homeostasis with the loss of ion gradients across cell membranes [7, 16–19]. Reperfusion after a period of ischaemia plays a pivotal role in oxidative stress by initiating a series of biochemical events that result in the generation of excessive amount of ROS. Reduction of oxygen leads to the production of the superoxide anion, which is able to penetrate through cell membranes where it is converted into other more toxic oxygen species. Therefore, the dismutase reaction (catalyzed by superoxide dismutase) leads to the conversion of the superoxide anion into hydrogen peroxide. This can lead to the production of hypochlorous acid by the action of MPO, or through interaction with iron salts, in the Haber-Weiss reaction to generate the highly toxic hydroxyl radical. The toxicity of the hydroxyl radical results from its ability to take electrons from a wide range of molecules, leading to the formation of a new radical that can continue the reaction [16, 17, 19].

ROS can modulate signalling proteins activity by nitrosylation, carbonylation, disulphide bond formation, and glutathionylation triggering the activation of proinflammatory and proapoptotic signalling pathways such as MAPK and NF-B.

Superoxide radicals () are generated rapidly in EC by the NADPH oxidase complex in response to TNFR [20]. Application of antioxidants to EC or the overexpression of HO-1 can inhibit the induction of E-Selectin and VCAM-1 whereas ICAM-1 is relatively refractory [21, 22]. MAPK activities are tightly regulated by redox. Antioxidants shorten the kinetics of MAPK activation following treatment with TNFα, suggesting that endogenous ROS are essential for prolonged MAPK activity and the underlying mechanism may involve suppression of negative regulators of MAPK by ROS [23]. For example, in resting cells, thioredoxin suppresses MAPK signalling pathways by interacting with the N-terminal portion of ASK1 to inhibit its catalytic activity [24]. This interaction is disrupted by ROS which alters the structure of thioredoxin by triggering the formation of intramolecular disulphides. Thus the prolonged activation of MAPK in response to proinflammatory signalling relies on disruption of thioredoxin-ASK1 interaction by ROS [24].

Activation of NF-B under oxidative stress has been reported in a number of inflammatory conditions [25–27]. Oxidative stress-induced LDAs and their GS-conjugates play a major role in the mediation of NF-B-induced inflammatory signals via PLC/PKC/IKK/MAPK pathways. Furthermore, ROS can act as toxic messengers that activate NF-B and affect the cellular functions of growth factors, cytokines, and other molecules [28, 29].

CPB and ischaemia and reperfusion injury during surgery can cause substantial myocardial stress leading to the generation of proinflammatory mediators and ROS resulting in damage to proteins, lipids, and DNA which impact on postoperative cardiac functional and outcomes [13].

Ischaemia leads to reduction in mitochondria energy production due to the lack of oxygen and nutrients. This is followed by fall in ATP, decrease in intracellular pH, and a rise in intracellular concentrations of Na⁺ and Ca²⁺ [7, 18] Furthermore, cardiac myocytes exposed to ischaemia react by producing proinflammatory cytokines and the consequent activation of leukocyte adhesion cascade allowing neutrophils to accumulate in the myocardium, adhere to the myocytes, and release ROS and other proteolytic enzymes. Moreover, reperfusion can lead to irreversible myocardial damage due to mitochondrial dysfunction driven by cytosolic Ca²⁺ loading and generation of ROS [7, 30, 31]. ROS can also stimulate the opening of the mitochondrial permeability transition pore (mPTP) leading to further ROS production and generating a positive feedback loop of ROS formation and mPTP opening [32–35]. The opening of mPTP can also result in mitochondrial swelling, mitochondrial membrane damage, and cell death via either apoptosis or necrosis [35, 36].

CPB exposes RBCs to abnormal settings resulting in integrity and function alteration. Shear stress forces generated by the CPB pump cause mechanical damage to the RBCs and induce ionic pump changes at the cell surface and an abnormal accumulation of intracellular cations [37–39]. This reduces RBC deformability which is important for maintaining normal microcirculation by making them more rigid and fragile. Furthermore, and as a consequence of membrane distortion, RBC become vulnerable to the membrane attack complex (MAC) generated from the activation of complement, leading to haemoglobin leak, thus substantially increasing the concentration of free Hb which can act as a peroxidase in the presence of H₂O₂ [37, 39–41].

Blood transfusion during or postsurgery is associated with increased oxidative stress due to the use of stored blood which has decreased antioxidant properties. Blood storage will lead to changes in erythrocytes (storage defect) which include depletion of adenosine triphosphate and 2,3-diphosphoglycerate, alterations in nitric oxide-mediated functions, and increased lipid peroxidation [42, 43]. Moreover; erythrocyte membrane changes make them less deformable and more fragile with an increased tendency toward progressive haemolysis leading to the accumulation of free haemoglobin and iron in the circulation which are redox active and prooxidant as discussed previously.

Increased ROS production and, more specifically, increased superoxide anion production derived from the atrial nicotinamide adenine dinucleotide phosphate oxidase are independently associated with a higher risk of POAF supporting an association between ROS in human atrium and POAF [44, 45]. Furthermore, atrial tissue from patients in whom POAF developed displayed an upregulation of mitochondrial MnSOD activity and an increased sensitivity of mPTP opening [45, 46].

It is recognised that cardiac surgery using CPB is associated with a wide spectrum of acute lung injury which can manifest in its most severe form as acute respiratory distress syndrome (ARDS). ARDS is rare after surgery; however it can have significant impact on morbidity and mortality. It has been thought that complement and neutrophils activation alongside red blood cell damage and reoxygenation injury in lung tissue are responsible for altering the redox status towards oxidative stress conditions. Bronchoalveolar lavage and plasma analysis of patients with ARDS after cardiac surgery has shown evidence of severe oxidative stress including the presence of high levels of chlorotyrosine, nitrotyrosine, and orthotyrosine [47–49].

Acute kidney injury (AKI) as a complication of cardiac surgery using CPB can be triggered by many elements including ischaemia and reperfusion injury, altered blood flow patterns, haemolysis, and blood transfusion [50, 51]. Haemolysis associated with increased levels of free haemoglobin in conjunction with increased levels of plasma myoglobin has been shown to be independent predictors of AKI after CPB due to their prooxidant properties. Ischaemia and reperfusion injury with the associated depletion of energy in renal epithelial cells causes mitochondrial dysfunction, the release of ROS, and the activation of proinflammatory signalling pathways (MAPK and NF-B) that can cause disruption of the cytoskeleton and lead to cell tubular damage [52–55]. Furthermore, these events taking place in the kidney will result in active neutrophil sequestration to renal tissue and more ROS generation [53, 55].

4. Intervention to Reduce Oxidative Stress during CPB

4.1. Antioxidant Supplements

The effects of ROS are counteracted under physiological conditions by antioxidants which are molecules that are capable of neutralizing free radicals by accepting or donating electron(s) thereby eliminating the unpaired condition of the radical. The antioxidant molecules may directly react with the reactive radicals and destroy them, while they may become new free radicals which are less active, longer-lived, and less dangerous than those radicals they have neutralized. They may be neutralized by other antioxidants or other mechanisms to terminate their radical status.

The use of additive antioxidants such as propofol, L-arginine, and N-acetyl-cysteine (NAC) during CPB as intravenous infusion or mixed with cardioplegia can be an appropriate strategy to counteract the impact of ROS.

Propofol (2,6-diisopropylphenol) is a commonly used agent in cardiac surgery for both induction and maintenance of anaesthesia. The phenolic hydroxyl group included in Propofol’s structure is similar to vitamin E which is known to be a natural antioxidant. Multiple in vitro and in vivo studies have demonstrated significant antioxidant effects of propofol [56–58]. It has been reported to inhibit lipid peroxidation to protect cells against oxidative stress and to increase the antioxidant capacity of plasma in humans [59]. Propofol can react with peroxynitrite, leading to the formation of a propofol-derived phenoxyl radical and it therefore can act as a peroxynitrite scavenger. Furthermore, propofol can protect against peroxynitrite-mediated cytotoxicity, DNA ladderization, and apoptosis [59–61]. Moreover propofol administrated intravenously can attenuate the activation of NF-B [62] which has a pivotal role in oxidative stress and inflammatory responses activated during ischemia/reperfusion.

Animal studies demonstrated that propofol increases the antioxidant capacity of the liver, kidney, heart, and lung by decreasing t-BHP-induced TBARS formation in an ischaemia and reperfusion model [56–58, 63]. During CPB, RBC antioxidant capacity as measured by MDA production is enhanced and maintained with the administration of intravenous propofol. Furthermore, the administration of a large dose of propofol during CPB attenuates postoperative myocardial cellular damage in patients undergoing CABG [64]. We have previously demonstrated in an animal model that propofol protects isolated perfused rat hearts from ischaemia/reperfusion injury through the preservation of mitochondrial function during reperfusion by inhibiting mitochondrial permeability transition pore opening [65]. Moreover, in another animal study, we demonstrated that propofol infusion during CPB attenuated the changes in myocardial tissue levels of adenine nucleotides, lactate, and amino acids during ischaemia and reduced cardiac troponin I release on reperfusion [66]. Furthermore, the permeability transition in mitochondria isolated from hearts treated with propofol was less sensitive to [Ca²⁺] than control mitochondria. The result of a randomised trial designed to address the effect of adding propofol to cardioplegia solution in patients undergoing cardiac surgery will report shortly [67].

L-Arginine is an amino acid that can play an important role in immune function and vascular homeostasis as a precursor for the synthesis of nitric oxide (NO). It is recognised that cardiac surgical patients have arginine/nitric oxide pathway impairment evident by increased levels of nitric oxide inhibitor asymmetric dimethylarginine [68, 69]. The use of oral L-arginine supplements in patients undergoing heart transplant resulted in reduced vascular endothelial cells dysfunction and decreased serum H₂O₂ production suggesting an increase in bioavailability of NO [70]. Such changes were translated clinically by improved exercise capacity of postsurgery [71]. When L-arginine was added to cardioplegia solutions in patients undergoing CABG, it was associated with higher Myocardial O₂ uptake and reduced malondialdehyde (MDA) extraction [72, 73]. In patients with impaired LV function, L-arginine cardioplegia decreases biochemical markers of myocardial damage and oxidative stress and resulted in increased superoxide dismutase activity [74].

NAC is another effective scavenger of free radicals with neutrophil aggregation inhibitory properties. When NAC is used as intravenous infusion during CABG surgery, it was noted that luminol, H₂O₂, HOCl-, and lucigenin levels were significantly lower than the control group. Furthermore, tumour necrosis factor-alpha levels were significantly decreased as a result of NAC administration [75, 76]. Moreover, MDA levels were significantly lower in the NAC enriched group during the reperfusion period [75]. When adding NAC to cardioplegia solution, it was noted that it can significantly reduce serum MDA, glutathione, catalase, SOD, glutathione peroxidase, and glutathione reductase [77–79].

Levosimendan is a calcium sensitizer that enhances myocardial contractility without increasing myocardial oxygen. Its function involves the activation of mitochondria ATP-sensitive potassium (mito-KATP) channels and production of eNOS-dependent NO through Akt and MAPK [80, 81].

KATP channels belong to the ATP-binding cassette transporter superfamily. Two KATP channel subtypes coexist in the myocardium, with one subtype located in the sarcolemma (sarc-KATP) membrane and the other in the inner membrane of the mito-KATP [82]. Under homeostatic conditions KATP channels are closed. However, under conditions of ischemia/reperfusion, KATP channels are activated allowing a net influx of K⁺ ions into the matrix and preventing Ca²⁺ accumulation in the matrix, thus blunting the opening of mPTP and its deleterious effects (as discussed above). Furthermore, the activation of mito-KATP can protect cells from damage induced by ROS and reduce cell apoptosis [83–86]. Clinical studies in patients undergoing cardiac surgery showed that Levosimendan significantly enhanced primary weaning from CPB compared with placebo in patients undergoing CABG. Moreover, the need for additional inotropic or mechanical therapy was decreased especially in patients with blunted ventricular function [87–90]. Furthermore, a meta-analysis which was of randomised studies including 529 patients in 5 trials suggested that Levosimendan might reduce renal injury in adult patients undergoing cardiac surgery [91].

Recent years have witnessed the use of mitochondrial targeted antioxidants such as Mitoquinone mesylate (MitoQ). MitoQ is made up of a lipophilic triphenylphosphonium (TPP) cation covalently attached to a ubiquinone antioxidant moiety. The positive charge on the TPP cation means that it is rapidly and extensively taken up by mitochondria due to the large membrane potential across the mitochondrial inner membrane. Within mitochondria, the ubiquinone moiety of MitoQ is rapidly reduced by complex II of the mitochondrial respiratory chain to the active antioxidant ubiquinol form and, after detoxifying a ROS, it is converted to the ubiquinone form which is then rapidly recycled back to the active antioxidant [92, 93].

MitoQ has been used in a wide range of animal studies and demonstrated efficacy in preventing mitochondrial oxidative damage in the heart, liver, kidney, and brain [92, 94–97]. Furthermore, MitoQ has been shown to be protective against liver damage in hepatitis C patients [98]. The combination of strong evidence indicating a pivotal role of mitochondrial damage in CPB related oxidative stress and data from animal studies showing that MitoQ prevents such damage in the heart provides a compelling case for evaluating the effectiveness of MitoQ in protecting the myocardium as an additive to cardioplegia solution during cardiac surgery to counteract the effect of CPB.

4.2. Mini-CPB

The impact of surface contact activation, air-fluid interface, and cell damage by cardiotomy suction associated with conventional bypass on the activation of proinflammatory and survival cascades has led to the development of minimised cardiopulmonary bypass circuit (mini-CPB). The design is a closed CPB system characterised by reduced surface area and thus priming volume, elimination of cardiotomy suction, and prevention of air-blood contact. The use of mini-CPB is associated with delayed or reduced secretion of different proinflammatory cytokines, attenuated complement activation, and blunted leukocytes activation compared to conventional circuit [99, 100].

The utilization of mini-CPB is associated with significant reduction in red blood cell damage (as measured by free Hb), activation of coagulation cascades, and blunted fibrinolytic and proinflammatory activities. Furthermore, serum concentration of MDA and allantoin/urate ratio as markers of oxidative stress tend to be reduced in patients undergoing surgery using mini-CPB when compared to conventional circuit [101, 102].

5. Conclusions

Cardiopulmonary bypass, although not perfect, remains an essential part of cardiac surgery. The utilization of CPB is associated with the production of ROS and oxidative stress.

Haemolysis, ischaemia, and perfusion injury and neutrophils activation during CPB play a pivotal role in oxidative stress and the associated activation of proinflammatory and proapoptotic signalling pathways which can affect the function and recovery of multiple organs such as the myocardium, lungs, and kidneys and influence clinical outcomes.

The administration of agents with antioxidant properties during surgery either intravenously or in the cardioplegia solution may reduce ROS burst and oxidative stress during CPB. Alternatively, the use of modified circuits such as minibypass can modify both proinflammatory responses and oxidative stress. More in-depth research and adequately powered randomised clinical studies with strict CPB protocols are still required.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgment

This research was supported by the National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol.

References

L. H. Edmunds, “Cardiopulmonary bypass after 50 years,” The New England Journal of Medicine, vol. 351, no. 16, pp. 1603–1606, 2004.

R. C. Daly, J. A. Dearani, C. G. A. McGregor et al., “Fifty years of open heart surgery at the Mayo Clinic,” Mayo Clinic Proceedings, vol. 80, no. 5, pp. 636–640, 2005.

C. Baufreton, J.-J. Corbeau, and F. Pinaud, “Inflammatory response and haematological disorders in cardiac surgery: toward a more physiological cardiopulmonary bypass,” Annales Francaises d'Anesthesie et de Reanimation, vol. 25, no. 5, pp. 510–520, 2006.

A. Dabbous, C. Kassas, and A. Baraka, “The inflammatory response after cardiac surgery,” Middle East Journal of Anesthesiology, vol. 17, no. 2, pp. 233–254, 2003.

J. K. Kirklin and D. C. McGiffin, “Early complications following cardiac surgery,” Cardiovascular Clinics, vol. 17, no. 3, pp. 321–343, 1987.

C. S. H. Ng and S. Wan, “Limiting inflammatory response to cardiopulmonary bypass: pharmaceutical strategies,” Current Opinion in Pharmacology, vol. 12, no. 2, pp. 155–159, 2012.

M.-S. Suleiman, K. Zacharowski, and G. D. Angelini, “Inflammatory response and cardioprotection during open-heart surgery: the importance of anaesthetics,” British Journal of Pharmacology, vol. 153, no. 1, pp. 21–33, 2008.

R. K. Gupta, A. K. Patel, N. Shah, A. K. Chaudhary, U. K. Jha, and U. C. Yadav, “Oxidative stress and antioxidants in disease and cancer: a review,” Asian Pacific Journal of Cancer Prevention, vol. 15, pp. 4405–4409, 2014.

M. Barzegar Amiri Olia, C. H. Schiesser, and M. K. Taylor, “New reagents for detecting free radicals and oxidative stress,” Organic & Biomolecular Chemistry, vol. 45, no. 40, 2014.

G. Noctor, C. Lelarge-Trouverie, and A. Mhamdi, “The metabolomics of oxidative stress,” Phytochemistry, 2014.

A. Nabeebaccus, M. Zhang, and A. M. Shah, “NADPH oxidases and cardiac remodelling,” Heart Failure Reviews, vol. 16, no. 1, pp. 5–12, 2011.

Y. H. Zhang, C. Z. Jin, J. H. Jang, and Y. Wang, “Molecular mechanisms of neuronal nitric oxide synthase in cardiac function and pathophysiology,” The Journal of Physiology, vol. 592, pp. 3189–3200, 2014.

T. A. Pearson, G. A. Mensah, R. W. Alexander et al., “Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the centers for disease control and prevention and the American Heart Association,” Circulation, vol. 107, no. 3, pp. 499–511, 2003.

D. Royston, “The inflammatory response and extracorporeal circulation,” Journal of Cardiothoracic and Vascular Anesthesia, vol. 11, no. 3, pp. 341–354, 1997.

J. H. Levy and K. A. Tanaka, “Inflammatory response to cardiopulmonary bypass,” The Annals of Thoracic Surgery, vol. 75, no. 2, pp. S715–S720, 2003.

Y. Haga, N. Hatori, H. Yoshizu, E. Okuda, Y. Uriuda, and S. Tanaka, “Granulocyte superoxide anion and elastase release during cardiopulmonary bypass,” Artificial Organs, vol. 17, no. 10, pp. 837–842, 1993.

K. Kawahito, E. Kobayashi, M. Ohmori et al., “Enhanced responsiveness of circulatory neutrophils after cardiopulmonary bypass: increased aggregability and superoxide producing capacity,” Artificial Organs, vol. 24, no. 1, pp. 37–42, 2000.

M.-S. Suleiman, A. P. Halestrap, and E. J. Griffiths, “Mitochondria: a target for myocardial protection,” Pharmacology and Therapeutics, vol. 89, no. 1, pp. 29–46, 2001.

D. Gadaleta, A. L. Fahey, M. Verma et al., “Neutrophil leukotriene generation increases after cardiopulmonary bypass,” The Journal of Thoracic and Cardiovascular Surgery, vol. 108, no. 4, pp. 642–647, 1994.

J.-M. Li, A. M. Mullen, S. Yun et al., “Essential role of the NADPH oxidase subunit p47phox in endothelial cell superoxide production in response to phorbol ester and tumor necrosis factor-α,” Circulation Research, vol. 90, no. 2, pp. 143–150, 2002.

N. Marui, M. K. Offermann, R. Swerlick et al., “Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells,” The Journal of Clinical Investigation, vol. 92, no. 4, pp. 1866–1874, 1993.

M. P. Soares, M. P. Seldon, I. P. Gregoire et al., “Heme oxygenase-1 modulates the expression of adhesion molecules associated with endothelial cell activation,” Journal of Immunology, vol. 172, no. 6, pp. 3553–3563, 2004.

H. Kamata, S.-I. Honda, S. Maeda, L. Chang, H. Hirata, and M. Karin, “Reactive oxygen species promote TNFα-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases,” Cell, vol. 120, no. 5, pp. 649–661, 2005.

M. Saitoh, H. Nishitoh, M. Fujii et al., “Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1,” The EMBO Journal, vol. 17, no. 9, pp. 2596–2606, 1998.

M. Grossmann, Y. Nakamura, R. Grumont, and S. Gerondakis, “New insights into the roles of ReL/NF-κB transcription factors in immune function, hemopoiesis and human disease,” The International Journal of Biochemistry and Cell Biology, vol. 31, no. 10, pp. 1209–1219, 1999.

K. van der Heiden, S. Cuhlmann, L. A. Luong, M. Zakkar, and P. C. Evans, “Role of nuclear factor kappaB in cardiovascular health and disease,” Clinical Science, vol. 118, no. 10, pp. 593–605, 2010.

P. J. Barnes and M. Karin, “Nuclear factor-κB—a pivotal transcription factor in chronic inflammatory diseases,” The New England Journal of Medicine, vol. 336, no. 15, pp. 1066–1071, 1997.

U. C. S. Yadav and K. V. Ramana, “Regulation of NF-κB-induced inflammatory signaling by lipid peroxidation-derived aldehydes,” Oxidative Medicine and Cellular Longevity, vol. 2013, Article ID 690545, 11 pages, 2013.

N. Chaudhari, P. Talwar, A. Parimisetty, C. Lefebvre d'Hellencourt, and P. Ravanan, “A molecular web: endoplasmic reticulum stress, inflammation, and oxidative stress,” Frontiers in Cellular Neuroscience, vol. 8, article 213, 2014.

M.-S. Suleiman, M. Hancock, R. Shukla, C. Rajakaruna, and G. D. Angelini, “Cardioplegic strategies to protect the hypertrophic heart during cardiac surgery,” Perfusion, vol. 26, supplement 1, pp. 48–56, 2011.

M. Wang, L. Baker, B. M. Tsai, K. K. Meldrum, and D. R. Meldrum, “Sex differences in the myocardial inflammatory response to ischemia-reperfusion injury,” The American Journal of Physiology—Endocrinology and Metabolism, vol. 288, no. 2, pp. E321–E326, 2005.

C. P. Connern and A. P. Halestrap, “Recruitment of mitochondrial cyclophilin to the mitochondrial inner membrane under conditions of oxidative stress that enhance the opening of a calcium-sensitive non-specific channel,” The Biochemical Journal, vol. 302, part 2, pp. 321–324, 1994.

D. B. Zorov, C. R. Filburn, L.-O. Klotz, J. L. Zweier, and S. J. Sollott, “Reactive oxygen species (ROS)-induced ROS release: a new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes,” The Journal of Experimental Medicine, vol. 192, no. 7, pp. 1001–1014, 2000.

P. Pasdois, J. E. Parker, E. J. Griffiths, and A. P. Halestrap, “The role of oxidized cytochrome in regulating mitochondrial reactive oxygen species production and its perturbation in ischaemia,” The Biochemical Journal, vol. 436, no. 2, pp. 493–505, 2011.

A. P. Halestrap, S. J. Clarke, and S. A. Javadov, “Mitochondrial permeability transition pore opening during myocardial reperfusion—a target for cardioprotection,” Cardiovascular Research, vol. 61, no. 3, pp. 372–385, 2004.

H. M. Honda, P. Korge, and J. N. Weiss, “Mitochondria and ischemia/reperfusion injury,” Annals of the New York Academy of Sciences, vol. 1047, pp. 248–258, 2005.

J. F. Hoffman, “Cation transport and structure of the red-cell plasma membrane,” Circulation, vol. 26, pp. 1202–1213, 1962.

R. I. Weed, “Membrane structure and its relation to haemolysis,” Clinics in Haematology, vol. 4, pp. 3–28, 1975.

A. M. Morariu, Y. J. Gu, R. C. G. G. Huet, W. A. Siemons, G. Rakhorst, and W. V. Oeveren, “Red blood cell aggregation during cardiopulmonary bypass: a pathogenic cofactor in endothelial cell activation?” European Journal of Cardio-Thoracic Surgery, vol. 26, no. 5, pp. 939–946, 2004.

S. Saraf, D. Wellsted, S. Sharma, and D. A. Gorog, “Shear-induced global thrombosis test of native blood: pivotal role of ADP allows monitoring of P2Y12 antagonist therapy,” Thrombosis Research, vol. 124, no. 4, pp. 447–451, 2009.

O. K. Baskurt and H. J. Meiselman, “Blood rheology and hemodynamics,” Seminars in Thrombosis and Hemostasis, vol. 29, no. 5, pp. 435–450, 2003.

H. Relevy, A. Koshkaryev, N. Manny, S. Yedgar, and G. Barshtein, “Blood banking-induced alteration of red blood cell flow properties,” Transfusion, vol. 48, no. 1, pp. 136–146, 2008.

K. Karkouti, “Transfusion and risk of acute kidney injury in cardiac surgery,” British Journal of Anaesthesia, vol. 109, no. 1, supplement, pp. i29–i38, 2012.

Y. M. Kim, H. Kattach, C. Ratnatunga, R. Pillai, K. M. Channon, and B. Casadei, “Association of atrial nicotinamide adenine dinucleotide phosphate oxidase activity with the development of atrial fibrillation after cardiac surgery,” Journal of the American College of Cardiology, vol. 51, no. 1, pp. 68–74, 2008.

D. Montaigne, X. Marechal, P. Lefebvre et al., “Mitochondrial dysfunction as an arrhythmogenic substrate: a translational proof-of-concept study in patients with metabolic syndrome in whom post-operative atrial fibrillation develops,” Journal of the American College of Cardiology, vol. 62, no. 16, pp. 1466–1473, 2013.

R. Nowicki, J. Saczko, J. Kulbacka et al., “The estimation of oxidative stress markers and apoptosis in right atrium auricles cardiomyocytes of patients undergoing surgical heart revascularisation with the use of warm blood cardioplegia,” Folia Histochemica et Cytobiologica, vol. 48, no. 2, pp. 202–207, 2010.

M. E. Callister, A. Burke-Gaffney, G. J. Quinlan et al., “Extracellular thioredoxin levels are increased in patients with acute lung injury,” Thorax, vol. 61, no. 6, pp. 521–527, 2006.

N. J. Lamb, J. M. C. Gutteridge, C. Baker, T. W. Evans, and G. J. Quinlan, “Oxidative damage to proteins of bronchoalveolar lavage fluid in patients with acute respiratory distress syndrome: evidence for neutrophil-mediated hydroxylation, nitration, and chlorination,” Critical Care Medicine, vol. 27, no. 9, pp. 1738–1744, 1999.

G. J. Quinlan, N. J. Lamb, T. W. Evans, and J. M. C. Gutteridge, “Plasma fatty acid changes and increased lipid peroxidation in patients with adult respiratory distress syndrome,” Critical Care Medicine, vol. 24, no. 2, pp. 241–246, 1996.

M. T. Ghorbel, N. N. Patel, M. Sheikh, G. D. Angelini, M. Caputo, and G. J. Murphy, “Changes in renal medulla gene expression in a pre-clinical model of post cardiopulmonary bypass acute kidney injury,” BMC Genomics, vol. 15, no. 1, article 916, 2014.

S. Romagnoli and Z. Ricci, “Postoperative acute kidney injury,” Minerva Anestesiologica, 2014.

J. V. Bonventre and A. Zuk, “Ischemic acute renal failure: an inflammatory disease?” Kidney International, vol. 66, no. 2, pp. 480–485, 2004.

E. Ozbek, “Induction of oxidative stress in kidney,” International Journal of Nephrology, vol. 2012, Article ID 465897, 9 pages, 2012.

H. Mao, N. Katz, W. Ariyanon et al., “Cardiac surgery-associated acute kidney injury,” CardioRenal Medicine, vol. 3, no. 3, pp. 178–199, 2013.

P. Devarajan, “Update on mechanisms of ischemic acute kidney injury,” Journal of the American Society of Nephrology, vol. 17, no. 6, pp. 1503–1520, 2006.

Y.-C. Li, P. Ridefelt, L. Wiklund, and G. Bjerneroth, “Propofol induces a lowering of free cytosolic calcium in myocardial cells,” Acta Anaesthesiologica Scandinavica, vol. 41, no. 5, pp. 633–638, 1997.

N. Kokita and A. Hara, “Propofol attenuates hydrogen peroxide-induced mechanical and metabolic derangements in the isolated rat heart,” Anesthesiology, vol. 84, no. 1, pp. 117–127, 1996.

N. Kokita, A. Hara, Y. Abiko, J. Arakawa, H. Hashizume, and A. Namiki, “Propofol improves functional and metabolic recovery in ischemic reperfused isolated rat hearts,” Anesthesia and Analgesia, vol. 86, no. 2, pp. 252–258, 1998.

P. G. Murphy, D. S. Myers, M. J. Davies, N. R. Webster, and J. G. Jones, “The antioxidant potential of propofol (2,6-diisopropylphenol),” British Journal of Anaesthesia, vol. 68, no. 6, pp. 613–618, 1992.

O. Eriksson, P. Pollesello, and N.-E. L. Saris, “Inhibition of lipid peroxidation in isolated rat liver mitochondria by the general anaesthetic propofol,” Biochemical Pharmacology, vol. 44, no. 2, pp. 391–393, 1992.

T. R. Green, I. S. R. Bennett, and V. M. Nelson, “Specificity and properties of propofol as an antioxidant free radical scavenger,” Toxicology and Applied Pharmacology, vol. 129, no. 1, pp. 163–169, 1994.

S. Zhao, L.-J. Xie, J.-X. Zhang, and L.-F. Li, “Effects of propofol on the activation of nuclear factor-kappaB and cardiomyocytes apoptosis during myocardial ischemia/reperfusion injury in rats,” Zhongguo Ying Yong Sheng Li Xue Za Zhi, vol. 26, no. 3, pp. 291–295, 2010.

T. D. Runzer, D. M. Ansley, D. V. Godin, and G. K. Chambers, “Tissue antioxidant capacity during anesthesia: propofol enhances in vivo red cell and tissue antioxidant capacity in a rat model,” Anesthesia & Analgesia, vol. 94, no. 1, pp. 89–93, 2002.

Z. Xia, Z. Huang, and D. M. Ansley, “Large-dose propofol during cardiopulmonary bypass decreases biochemical markers of myocardial injury in coronary surgery patients: a comparison with isoflurane,” Anesthesia and Analgesia, vol. 103, no. 3, pp. 527–532, 2006.

S. A. Javadov, K. H. H. Lim, P. M. Kerr, M.-S. Suleiman, G. D. Angelini, and A. P. Halestrap, “Protection of hearts from reperfusion injury by propofol is associated with inhibition of the mitochondrial permeability transition,” Cardiovascular Research, vol. 45, no. 2, pp. 360–369, 2000.

K. H. H. Lim, A. P. Halestrap, G. D. Angelini, and M.-S. Suleiman, “Propofol is cardioprotective in a clinically relevant model of normothermic blood cardioplegic arrest and cardiopulmonary bypass,” Experimental Biology and Medicine, vol. 230, no. 6, pp. 413–420, 2005.

Z. E. Plummer, S. Baos, C. A. Rogers et al., “The effects of propofol cardioplegia on blood and myocardial biomarkers of stress and injury in patients with isolated coronary artery bypass grafting or aortic valve replacement using cardiopulmonary bypass: protocol for a single-center randomized controlled trial,” JMIR Research Protocols, vol. 3, no. 3, article e35, 2014.

V. Cavalca, E. Tremoli, B. Porro et al., “Oxidative stress and nitric oxide pathway in adult patients who are candidates for cardiac surgery: patterns and differences,” Interactive CardioVascular and Thoracic Surgery, vol. 17, no. 6, pp. 923–930, 2013.

I. Karu, G. Taal, K. Zilmer, C. Pruunsild, J. Starkopf, and M. Zilmer, “Inflammatory/oxidative stress during the first week after different types of cardiac surgery,” Scandinavian Cardiovascular Journal, vol. 44, no. 2, pp. 119–124, 2010.

D. S. Lim, S. J. Mooradian, C. S. Goldberg et al., “Effect of oral L-arginine on oxidant stress, endothelial dysfunction, and systemic arterial pressure in young cardiac transplant recipients,” The American Journal of Cardiology, vol. 94, no. 6, pp. 828–831, 2004.

S. Doutreleau, O. Rouyer, P. Di Marco et al., “L-Arginine supplementation improves exercise capacity after a heart transplant,” The American Journal of Clinical Nutrition, vol. 91, no. 5, pp. 1261–1267, 2010.

U. Kiziltepe, B. Tunçtan, Z. B. Eyileten et al., “Efficiency of L-arginine enriched cardioplegia and non-cardioplegic reperfusion in ischemic hearts,” International Journal of Cardiology, vol. 97, no. 1, pp. 93–100, 2004.

M. Carrier, L. P. Perrault, A. Fortier, D. Bouchard, and M. Pellerin, “L-arginine supplemented nondiluted blood cardioplegia: a clinical trial,” Journal of Cardiovascular Surgery, vol. 51, no. 2, pp. 283–287, 2010.

D. T. Andrews, J. Sutherland, P. Dawson, A. G. Royse, and C. F. Royse, “L-arginine cardioplegia reduces oxidative stress and preserves diastolic function in patients with low ejection fraction undergoing coronary artery surgery,” Anaesthesia and Intensive Care, vol. 40, no. 1, pp. 99–106, 2012.

G. Orhan, N. Yapici, M. Yuksel et al., “Effects of N-acetylcysteine on myocardial ischemia-reperfusion injury in bypass surgery,” Heart and Vessels, vol. 21, no. 1, pp. 42–47, 2006.

O. Peker, T. Peker, D. Erdogan et al., “Effects of intravenous N-acetylcysteine on periprocedural myocardial injury after on-pump coronary artery by-pass grafting,” The Journal of Cardiovascular Surgery, vol. 49, no. 4, pp. 527–531, 2008.

A. Prabhu, D. I. Sujatha, N. Kanagarajan, M. A. Vijayalakshmi, and B. Ninan, “Effect of N-acetylcysteine in attenuating ischemic reperfusion injury in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass,” Annals of Vascular Surgery, vol. 23, no. 5, pp. 645–651, 2009.

A. J. Rodrigues, P. R. B. Évora, S. Bassetto et al., “Blood cardioplegia with N-acetylcysteine may reduce coronary endothelial activation and myocardial oxidative stress,” The Heart Surgery Forum, vol. 12, no. 1, pp. E44–E48, 2009.

A. Vento, A. Nemlander, J. Aittomäki, J. Salo, J. Karhunen, and O. J. Rämö, “N-acetylcysteine as an additive to crystalloid cardioplegia increased oxidative stress capacity in CABG patients,” Scandinavian Cardiovascular Journal, vol. 37, no. 6, pp. 349–355, 2003.

E. Grossini, C. Molinari, P. P. Caimmi, F. Uberti, and G. Vacca, “Levosimendan induces NO production through p38 MAPK, ERK and Akt in porcine coronary endothelial cells: role for mitochondrial KATP channel,” British Journal of Pharmacology, vol. 156, no. 2, pp. 250–261, 2009.

A. Hönisch, N. Theuring, B. Ebner, C. Wagner, R. H. Strasser, and C. Weinbrenner, “Postconditioning with levosimendan reduces the infarct size involving the PI3K pathway and KATP-channel activation but is independent of PDE-III inhibition,” Basic Research in Cardiology, vol. 105, no. 2, pp. 155–167, 2010.

J. D. McCully and S. Levitsky, “The mitochondrial KATP channel and cardioprotection,” The Annals of Thoracic Surgery, vol. 75, no. 2, pp. S667–S673, 2003.

K. D. Garlid and P. Paucek, “Mitochondrial potassium transport: The K⁺ cycle,” Biochimica et Biophysica Acta, vol. 1606, no. 1–3, pp. 23–41, 2003.

A. P. Halestrap, “The regulation of the oxidation of fatty acids and other substrates in rat heart mitochondria by changes in the matrix volume induced by osmotic strength, valinomycin and Ca²⁺,” The Biochemical Journal, vol. 244, no. 1, pp. 159–164, 1987.

T. Miura, Y. Liu, M. Goto et al., “Mitochondrial ATP-sensitive K⁺ channels play a role in cardioprotection by Na⁺-H⁺ exchange inhibition against ischemia/reperfusion injury,” Journal of the American College of Cardiology, vol. 37, no. 3, pp. 957–963, 2001.

S.-X. Shao, L. Zhang, H.-X. Chen et al., “Diazoxide pretreatment enhances L6 skeletal myoblast survival and inhibits apoptosis induced by hydrogen peroxide,” Anatomical Record, vol. 295, no. 4, pp. 632–640, 2012.

H. I. Eriksson, J. R. Jalonen, L. O. Heikkinen et al., “Levosimendan facilitates weaning from cardiopulmonary bypass in patients undergoing coronary artery bypass grafting with impaired left ventricular function,” Annals of Thoracic Surgery, vol. 87, no. 2, pp. 448–454, 2009.

L. Tritapepe, V. de Santis, D. Vitale et al., “Levosimendan pre-treatment improves outcomes in patients undergoing coronary artery bypass graft surgery,” British Journal of Anaesthesia, vol. 102, no. 2, pp. 198–204, 2009.

A. Akgul, L. Mavioglu, S. F. Katircioglu, M. Pac, and A. Cobanoglu, “Levosimendan for weaning from cardiopulmonary bypass after coronary artery bypass grafting,” Heart Lung and Circulation, vol. 15, no. 5, pp. 320–324, 2006.

S. G. De Hert, S. Lorsomradee, H. vanden Eede, S. Cromheecke, and P. J. Van der Linden, “A randomized trial evaluating different modalities of levosimendan administration in cardiac surgery patients with myocardial dysfunction,” Journal of Cardiothoracic and Vascular Anesthesia, vol. 22, pp. 699–705, 2008.

Z.-Z. Niu, S.-M. Wu, W.-Y. Sun, W.-M. Hou, and Y.-F. Chi, “Perioperative levosimendan therapy is associated with a lower incidence of acute kidney injury after cardiac surgery: a meta-analysis,” Journal of Cardiovascular Pharmacology, vol. 63, no. 2, pp. 107–112, 2014.

M. P. Murphy and R. A. J. Smith, “Targeting antioxidants to mitochondria by conjugation to lipophilic cations,” Annual Review of Pharmacology and Toxicology, vol. 47, pp. 629–656, 2007.

R. A. J. Smith, R. C. Hartley, and M. P. Murphy, “Mitochondria-targeted small molecule therapeutics and probes,” Antioxidants and Redox Signaling, vol. 15, no. 12, pp. 3021–3038, 2011.

R. A. J. Smith and M. P. Murphy, “Animal and human studies with the mitochondria-targeted antioxidant MitoQ,” Annals of the New York Academy of Sciences, vol. 1201, pp. 96–103, 2010.

D. Graham, N. N. Huynh, C. A. Hamilton et al., “Mitochondria-targeted antioxidant mitoq10 improves endothelial function and attenuates cardiac hypertrophy,” Hypertension, vol. 54, no. 2, pp. 322–328, 2009.

V. J. Adlam, J. C. Harrison, C. M. Porteous et al., “Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury,” The FASEB Journal, vol. 19, no. 9, pp. 1088–1095, 2005.

G. S. Supinski, M. P. Murphy, and L. A. Callahan, “MitoQ administration prevents endotoxin-induced cardiac dysfunction,” American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 297, no. 4, pp. R1095–R1102, 2009.

E. J. Gane, F. Weilert, D. W. Orr et al., “The mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients,” Liver International, vol. 30, no. 7, pp. 1019–1026, 2010.

H. A. Vohra, R. Whistance, A. Modi, and S. K. Ohri, “The inflammatory response to miniaturised extracorporeal circulation: a review of the literature,” Mediators of Inflammation, vol. 2009, Article ID 707042, 7 pages, 2009.

B. Kiaii, S. Fox, S. A. Swinamer et al., “The early inflammatory response in a mini-cardiopulmonary bypass system: a prospective randomized study,” Innovations, vol. 7, no. 1, pp. 23–32, 2012.

W. B. Gerritsen, W.-J. P. van Boven, D. S. Boss, F. J. Haas, E. P. van Dongen, and L. P. Aarts, “Malondialdehyde in plasma, a biomarker of global oxidative stress during mini-CABG compared to on- and off-pump CABG surgery: a pilot study,” Interactive Cardiovascular and Thoracic Surgery, vol. 5, no. 1, pp. 27–31, 2006.

W.-J. van Boven, W. B. Gerritsen, F. G. Waanders, F. J. Haas, and L. P. Aarts, “Mini extracorporeal circuit for coronary artery bypass grafting: initial clinical and biochemical results: a comparison with conventional and off-pump coronary artery bypass grafts concerning global oxidative stress and alveolar function,” Perfusion, vol. 19, no. 4, pp. 239–246, 2004.