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Selenium and Cardiovascular Surgery: An Overview Fengwei Guo, Nadejda Monsefi, Anton Moritz and Andres Beiras-Fernandez* Department of Thoracic and Cardiovascular Surgery, Johann-Wolfgang-Goethe University Hospital, Frankfurt/Main, Germany Abstract: Selenium is an essential nutritional element to mammalians necessary for the active function of different oxidant enzymes, as glutathione peroxidase (GPx), thioredoxin reductases (TrxR), and iodothyronine deiodinases (IDD). The anti-oxidative effect of selenium is pivotal for the human physiology. Oxidative stress is associated with various diseases, such as cardiovascular disease, diabetes mellitus or cancer, and is also associated with the majority of surgical procedures. Particularly, the use of cardiopulmonary bypass for open cardiac surgery with aortic clamping is always related to oxidative stress due to ischemia and reperfusion. Whereas myocardial protection with different temperatures and cardioplegic solutions has become more efficient, reperfusion is often followed by the activation of an injurious oxidative cascade. The pathogenesis of ischemia/reperfusion injury depends on many factors, among them, reactive nitrogen species (RNS) and reactive oxygen species (ROS) are considered as initiators of the injury. ROS formed during oxidative stress can initiate lipid peroxidation, oxidize proteins to inactive states and cause DNA strand breaks. ROS production is physiologically controlled by free radical scavengers such as GPx and TrxR, and superoxide dismutase systems. GPx and TrxR are seleno-cysteine dependent enzymes, and their activity is known to be related to selenium availability. Furthermore, selenium has been reported to regulate gene expression of these selenoproteins as a cofactor and there is some evidence that selenium supplementation can attenuate the oxidative stress and decrease the complications after cardiac surgery. However, other clinical studies failed to demonstrate an association between selenium deficiency and cardiovascular outcomes. The aim of our review is to summarize the experimental and clinical evidence of preoperative selenium supplementation and therapy after cardiac surgery, focusing on the pathophysiology of oxidative stress and the clinical usage of selenium.
Keywords: Selenium, ischemia-reperfusion, surgery. INTRODUCTION Selenium (Se) is an essential trace element for human beings, and plays a key role in the anti-oxidant defense through its incorporation as a co-factor into selenoproteins such as glutathione peroxidase (GPx), thioredoxin reductases (TrxR), and iodothyronine deiodinases (IDD) [1]. These selenoproteins are involved in redox reactions which play a crucial role in the homeostatic balance. Many experimental studies have demonstrated the protective effects of Se during oxidative stress. Moreover, low plasmatic levels of Se are associated with an increased mortality in the presence of various entities, such as cancer, inflammation, myocardial infarction or cardiovascular disease, sepsis, and complications after surgery, among others [2]. Cardiac surgery with cardiopulmonary-bypass provokes a systemic inflammatory response and is always related to the onset of a variable period of ischemia and following reperfusion. The impact of the oxidative stress on the occurrence of multi-organ dysfunction after surgery and its contribution to perioperative mortality has been described before [3]. However, the pathogenesis of this reperfusion reaction is not completely understood, and there is considerable evidence implicating reactive nitrogen species (RNS) and reactive oxygen species (ROS) [4]. GPx and *Address correspondence to this author at the Department of Thoracic and Cardiovascular Surgery, Johann Wolfgang Goethe University Hospital, Frankfurt am Main, Germany; Tel: + 49-69-6301-6354; Fax: + 49-69-6301-5849; E-mail:
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TrxR are seleno-cysteine dependent anti-oxidant enzymes, and their activity is known to be dependent upon selenium availability. Furthermore, selenium has been reported to regulate gene expression of these selenoproteins as a cofactor and there is some evidence that selenium supplementation can attenuate the oxidative stress and decrease postoperative complications after cardiac surgery [5]. This review focuses on the antioxidant properties of selenium applied to the pathophysiology of ischemia and reperfusion after cardiac surgery, its relationship with other electrolytes homeostasis, as well as on its safety and therapeutical profile. ELECTROLYTE BALANCE AND OXIDATIVE STRESS Electrolyte balance is extremely important for the maintenance of physiologic reactions, as electrolytes regulate many aspects of the cellular stability, internal environment, and metabolism [6]. The electrolyte disbalance is related to metabolic complications in many collectives, especially in critically-ill patients, such as burn, trauma, sepsis, and acute myocardial infarction patients [6]. The acute stressor states are associated with a homeostatic activation of the hypothalamic-pituitary-adrenal axis (HPA). The elevation of circulating catecholamines, cortisol and aldosterone, and electrolyte disbalance in critically-ill patients is particularly important in the context of cardiovascular disease, as small variations can provoke dramatic changes in the myocardial function. For example: hyperadrenergic state, elicited in response to an acute © 2012 Bentham Science Publishers
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stressor, causes intracellular Ca2+ overloading and induction of oxidative stress, which, in cardiac myocytes and mitochondria, leads to the destruction of these organelles and necrotic cell death [7]. Hypokalemia, hypocalcaemia, hypomagnesaemia have been reported as triggers of prolonged repolarization, causing atrial and ventricular arrhythmia, myocardial death, and increased formation of fibrous tissue [6]. Potassium plays a crucial role in the cell homeostasis as its large gradient is the basis for almost the whole cellular activity. Under hypokalemia, the former gradient becomes larger, and the cellular capacity of diffusion increases. Na+-K+ ATPase activation through catecholamines can further stimulate hypokalemia, with an increase of the repolarization time and thus an increased vulnerability to atrial or ventricular arrhythmias. It has also been observed that hypokalemia is often related to hypocalcaemia and hypomagnesaemia. Hypomagnesaemia of moderate to marked severity is also associated with the appearance of atrial and ventricular arrhythmias. Furthermore, it modulates inflammatory cytokines, such as IFN-r, TNF-a, IL-1, and IL-6 [8]. Se and Zinc are wellknown essential trace elements with potent antioxidant effects. They are also an important cofactor of selenoproteins (GPx and TrxR) and superoxide dismutase (SOD). Furthermore, a dyshomeostasis of trace elements, Zn2+ and Se2+, is also seen in critically-ill patients. Adverse consequences of Zn2+and Se2+ deficiency are related to impaired metalloenzyme-based antioxidant defenses, immunity and tissue repair [6]. Besides, age is a risk factor for dyshomeostasis. Elderly are more at risk of a lowered Se status than young patients, in particular, patients above 80 years [9]. A description of every pathophysiological pathway is beyond the scope of this review. A recent published review covers the issue of oxidative stress at length, including its involvement in several conditions unrelated to cardiovascular surgery [10]. ISCHEMIA-REPERFUSION Ischemia-reperfusion injury (IR/I) is a complex pathophysiological process as the balance of supply/demand of blood plays a pivotal role in normal tissue. Ischemia induces a decrease in cellular oxidative phosphorylation, resulting in a failure to resynthesize energy-rich phosphates, including adenosine 5'-triphosphate (ATP) and phosphocreatine. Reperfusion is the second phase in which the tissue obtains enough blood due to restoration of blood flow. Unfortunately, restored blood flow during the reperfusion may result in tissue damage, even cell death, through cellular and humoral activation. IR/I can be observed in different clinical settings, including warm IR/I (myocardial infarction, cardiac surgery with cardiopulmonary bypass), and cold IR/I (transplantation surgery). Former studies have shown that different mechanisms in IR/I had to be considered, among others reactions with reactive oxygen species, calcium overload, and activation of neutrophils. ROS result in damage to proteins, lipids, DNA and sequent outcomes, cell necrosis, apoptosis, and inflammation induced by activation of innate and adaptive immune responses complement [11]. ROS activation of transcriptional factor NF-kB pathways increases the expression of adhesion molecule genes, cytokine and
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chemokine genes so that there is an increased release of adhesion molecules, cytokines and chemokines in the tissue [12]. Increased amounts of neutrophils, monocytes and T cells from the periphery migrate to the ischemic zone causing tissue injury and being another potential source of ROS [13]. The beneficial effect of selenium on this setting may be related to the reduction of ROS, thus decrease of the inflammatory and endothelial reactions. Other effects of IR/I include vascular leakage and no reflow phenomenon [11]. In clinical conditions of myocardial ischemia, reperfusion is often associated with some specific deleterious effects brought about by oxidative stress upon reflow, such as lifethreatening ventricular arrhythmias and persistent contractile dysfunction (myocardial stunning) [14]. These mechanisms are carried out synergistically at the same tissue and also exacerbate the damage in addition to increase clinical mortality and morbidity [13]. OXIDATION/REDOX: THE ROLE OF ANTIOXIDANTS ATP (adenosine 5'-triphosphate) is a direct energy source for the cell. Cardiac tissue has high oxygen consumption due to ATP needs, so that a constant and adequate oxygen supply is needed [15]. The role of oxygen in the heart goes well beyond its role in energy production and remains complex. On one hand, oxygen or some oxygen derived compounds, ROS and nitrogen-derived compounds, reactive nitrogen species (RNS) can participate as helpful molecules in cell signaling processes in cardiomyocytes [16]; On the other hand, they can also exert deleterious effects, contributing to the pathogenesis of cardiac dysfunction and inducing irreversible myocardial tissue damage or cell death [16]. Besides, oxidative stress is also involved in various cardiovascular diseases, including atherosclerosis, hypertension, and in the aging process. Oxidative stress is defined as an excessive ROS production, overwhelming the counterbalancing ability of endogenous anti-oxidants. Under uncontrolled oxidative stress, the ROS-induced damages cellular structure such as lipids, proteins membranes and mitochondria [14]. Some antioxidant enzymes stress are glutathione peroxidase (GPx), thioredoxin reductase (TrxR), catalase (CAT), and superoxide dismutase (SOD) in which selenium is a cofactor. Some other anti-oxidants are ascorbic acid (vitamin C), alpha-tocopherol (vitamin E), -carotene, glutathione, coenzyme Q10, lipoic acid and urate [17]. GPx plays a crucial role in protecting the tissues against oxidative stress by means of catalyzing the reduction of a variety of hydroperoxides, being also capable to neutralize ROS and RNS, so that increasing GPx-1 activity might lower the risk of cardiovascular events [18]. SOD can dismutate superoxide anions into hydrogen peroxide (H2O2), the sequential outcome is that H2O2 is decomposited into water and oxygen by catalase preventing the damage of the cell. GPx requires selenium and SOD rely on Cu and Zn for normal function respectively [18]. Decreasing serum selenium level in patients aggravates certainly quantity and function of these antioxidant enzymes, further injuring cells and tissues by excessive ROS. The effects of ascorbic acid are, among others, the clearance of free radicals and the reduction of hydrogen peroxide. Alpha-tocopherol can transfer a hydrogen atom with a single electron to free radicals, thus
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removing the radicals before they can interact with the cell membrane proteins or generate lipid peroxidation. In the cell, coenzyme Q10 presents its highest concentrations in the mitochondria, and it is also an integral component of the mitochondrial respiratory chain transferring electrons and generating energy production. In addition, it is also a fat soluble antioxidant. CoQ10 has recently been shown to have gene regulatory functions involving energy production in the cell [17]. SELENIUM: EXPERIMENTAL EVIDENCE The increasing antioxidative effects and mechanisms of selenium have been demonstrated in different experimental investigations. In a male senescent rat’s model, Tanguy found that high-selenium diet considerably limits the sensitivity of senescent rat hearts to ischemia and reperfusion. It is well-known that selenium status decreases with age in humans, so that selenium supply could improve the prognosis of cardiovascular diseases in old patients [19]. In another rat model treated with high-Se diet (1.50mg/kg) and low-Se diet (0.05mg/kg), Tanguy found that infarct size and cardiac passive compliance were increased in the low-Se group compared with the high-selenium diet group, and cardiac remodeling (thinning index and expansion index) was increased in low-Se hearts. Simultaneously, these adverse effects on cardiac remodeling were accompanied by an increase in cardiac TNF-alpha expression, a decreased activity of antioxidant seleno-enzymes and an increase in connexin-43 dephosphorylation, all these changes enhancing the fibrous remodelling of the heart, thus reducing the myocardial contractility [20]. In an experimental model of burn injury, Sandre et al. in 2006 showed that plasma Se concentration and GPx activity were lower in animals with a selenium-depleted diet; Se-supplementation after burn injury was able to improve the Se concentration and GPx activity; however, it couldn’t counteract the present oxidative stress damage. The author suggested that combined antioxidant administration may be necessary to counteract burn-induced oxidative stress [21]. Ostadalova reported that Se supplementation elevated the serum concentration of Se, and increased ischemic tolerance and the sensitivity to the inotropic effect of isoproterenol, thus protecting isolated rat heart during ischemia and reperfusion [22]; in addition, the fact that heart rate, contractile force and heart work were significantly higher after reperfusion with enriched-selenium solution was also demonstrated in an isolated pig heart model [23]. Venardos et al. showed that selenium supplementation increased the endogenous activity of thioredoxin reductase and GPx and resulted in improved recovery of cardiac function post ischemia reperfusion in an experimental model, and that endogenous activity of GPx and TrxR strongly depends on an adequate supply of selenium [24]. Additionally, selenium supplementation induced a significant reduction of the severity of reperfusionarrhythmias and limited the incidence of both ventricular tachycardia and irreversible ventricular fibrillation in a rat model [25]. In other studies, selenium deficiency decreased the activity of GPx, recovery of cardiac function and altered the myocardial ventricular ultrastructure after reperfusion when compared to controls. The authors conclude that selenium plays a crucial role in antioxidative processes determining the susceptibility of the heart to ischemia and
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reperfusion [26]. Wang et al. showed that chemical modifications of selenium, such as methylselenic acid (MSeA) and methylselenocysteine (MSeC) were also efficacious in a murine model [27]. SELENIUM: DEFICIENCY/TOXICITY There are big differences among the plasma selenium level worldwide, as the main source for human being, the dietary selenium, depends on the soil selenium level. Adequate selenium intake is required for optimal activity of key antioxidant enzymes. Indeed, selenium dietary intake of millions of people worldwide is below 55 mg/day, the recommended dietary intake by most scientific committees, which optimizes the activity of glutathione peroxidase [28, 29]. The populations with deficient selenium intake are when combined with acute illness - more vulnerable to oxidative stress. Se deficiency and Se toxicity have been observed in animals and people, and Se poisoning or selenosis is very rare. Livestock fed on plants with high selenium concentration were shown to develop a subacute form of selenosis, called blind staggers or chronic selenosis called alkali disease [30]. Some endemic chronic selenosis happens in Chinese people. Health consequences observed in affected persons included nail deformation, hair loss and skin lesions [30]. Selenium compounds can also be considered ‘pro-oxidative’, as the pro-oxidative effect of selenium may become toxic to humans due to increase oxidative stress and leads to glutathione depletion and increased cell death. However, Heyland reported that supplementation with 800 g of selenium (in combination with other antioxidants) was safe [31]. The consequences of the deficiency of selenium in different nutritional, immunological and oncological clinical situations have been also recently described [32-34]. The toxicity of selenium is clearly dose dependent and varies depending on the type of selenium compound administered [35] In a meta-analysis in 2005, Heyland et al. suggested that Selenium supplementation (alone and in combination with other antioxidants) could be associated with a reduction in mortality [Risk Ratio (RR) 0.59, 95% confidence intervals (CI) 0.32. 1.08, p=0.09] whereas nonselenium antioxidants had no effect on mortality (RR 0.73, 95% CI 0.41, 1.29, p=0.3); however, the studies regarding higher dosing strategies of selenium (more than 500 g/day) showed a tendency towards a decrease in mortality [RR 0.52, 95% CI 0.24-1.14, P=0.10], whereas studies that used a lower dose(
