Copyright © 2007, European Society of Cardiology
Oxidative stress injury during cardiac surgery: How important is it?
Cardiac Surgical Research, The Rayne Institute (King's College London), Guy's and St Thomas' NHS Foundation Trust, St Thomas' Hospital, London SE1 7EH, UK
* Tel.: +44 20 7188 0958; fax: +44 20 7188 3902. Email address: david.chambers{at}kcl.ac.uk david.chambers{at}gstt.nhs.uk
Received 5 January 2007; accepted 9 January 2007
See article by Milei et al. [11] (pages 710–719) in this issue.
The concept that the reintroduction of oxygen to the ischaemic myocardium causes significant injury has long been known [1], and it is now well-established [2] that oxidative stress is one of the major initiators of myocardial injury during ischaemia and reperfusion. Cardiac surgery for coronary artery bypass generally involves cardiopulmonary bypass with cardioplegic arrest and elective global ischaemia of the heart. It would appear to represent the ideal situation to evaluate the potential injury induced by oxidative stress during ischaemia and subsequent reperfusion, since in this clinical situation (and unusually for most ischaemic conditions) the time of onset and the duration of ischaemia are known as is the time and conditions of reperfusion, and all are under the control of the operating surgeon. This means that studies in patients undergoing surgery are able to be controlled in a similar manner to that of experimental studies involving animal models. In experimental studies on isolated rat hearts, ischaemia and reperfusion are known to generate oxygen-derived free radicals; the use of electron-spin-resonance techniques has allowed the direct detection of reactive oxygen species produced when ischaemic myocardium is reperfused [3] and has also shown that this production can be prevented by various antioxidant or scavenger agents [4]. A large number of experimental studies that simulate this surgical ischaemia and reperfusion have shown that various antioxidant agents can ameliorate the detrimental effects of oxidative stress resulting from ischaemia and reperfusion and lead to improved post-ischaemic function, either when the agents are provided as a pretreatment before the elective ischaemia, or as additives to the cardioplegic solution [5,6]. Short periods of regional ischaemia induces myocardial stunning, and this has also been shown to be attenuated by antioxidant administration immediately (1 min) before reperfusion but ineffective when infused 1 min after the onset of reperfusion [7]. Cardiac surgery also induces myocardial stunning (seen as transient cardiac dysfunction) in the initial few hours after reperfusion [8] and it might be expected that this myocardial stunning should also be ameliorated by antioxidants.
Thus, many studies have suggested that oxidative stress, induced during cardiac surgery, could be a suitable target for improved post-ischaemic recovery. There are, however, important differences between studies involving animal models and the clinical situation in humans. In comparison to most experimental studies that use hearts from healthy animals, hearts of patients requiring coronary artery surgery will have significant underlying disease (ischaemic heart disease) which may make the myocardium more tolerant to injury (possibly arising from some endogenous adaptive phenomenon such as preconditioning). In addition, it has been suggested that the anaesthetics used during cardiac surgery may induce a preconditioning protection per se [9,10]. Another important difference between experimental and clinical conditions is the degree of ischaemic injury imposed when the agents are tested. Thus, in experimental animal studies, an ischaemic injury is induced that will allow the beneficial or detrimental effects of the drugs under investigation to be determined. This cannot (ethically) occur in the clinical situation, and all clinical studies have to be conducted under the restriction that the safety of the patient is paramount. This makes detection of any effect difficult without the requirement for large numbers of patients to detect small differences. It also raises the possibility that the conditions that apply in the experimental situation and are amenable to beneficial intervention of the drug under investigation, may not (in the clinical situation) be sufficiently severe to show clinical benefit (despite the underlying injury mechanism being present and detectable).
This is the argument put forward by Milei and coworkers [11] in their study published in this issue of Cardiovascular Research concerning the importance of oxidative stress during cardiac surgery. The study investigates markers of oxidative stress in a small number of low risk patients (24 in total) undergoing coronary artery bypass surgery. Measurements were made of blood glutathione release (as a marker of oxidant production), myocardial antioxidant (vitamin E and ubiquinol) and lipid peroxidation (TBARS) levels, as well as ultrastructural assessment of tissue injury (from myocardial biopsies) and evaluation of post-ischaemic haemodynamic function and clinical outcome. The results show that there was evidence of increased glutathione release in the initial 20 min of reperfusion, and a decrease in tissue antioxidant levels of ubiquinol (but not vitamin E), and minimal increase in tissue lipid peroxidation or any ultrastructural damage. In addition, there was full recovery of functional parameters; although no data is provided for the initial few hours after reperfusion, it is stated that haemodynamic recovery is normal after a few hours, which implies that some myocardial stunning did occur.
The concept of oxidative stress influencing post-operative outcome in patients undergoing coronary artery bypass surgery remains a controversial issue. There have been many recent studies in this area and the results have been inconclusive, although most are in agreement with the work of Milei et al. N-acetylcysteine (NAC) has been examined as an anti-inflammatory and antioxidant agent and has been shown either to have no effect on biochemical markers of injury such as CK-MB, troponin T, and creatinine levels [12] or to attenuate myocardial oxidative stress (measured as lipid peroxidation and peroxynitrite-mediated injury) [13]. In both of these studies, however, there was no effect of NAC on haemodynamic or clinical outcomes. Supplementation of patients with the antioxidant vitamin E before surgery has also been investigated [14] and shown to exert no protective effect as measured by clinical outcome or when lipid peroxidation and other biochemical markers were measured. Oxidative stress (measured by lipid peroxidation) has been compared in patients undergoing coronary artery surgery with or without cardiopulmonary bypass (on-pump or off-pump) and shown to be less in the off-pump group; however, glutathione levels decreased and catalase activity increased to similar values between groups [15]. These results are not surprising since it would be envisaged that the ischaemia and reperfusion involved in on-pump surgery would induce an oxidative stress. What is surprising, however, is the relatively little difference between them, and this may support the contention of Milei and colleagues that the oxidative stress induced is relatively benign. It is interesting to note that, in all these studies, the patients were at low risk with good ventricular function; it is probably not surprising, therefore, that these patients had minimal increases in oxidative stress.
Determination of whether oxidative stress exerts a significant influence on the outcome of patients undergoing cardiac surgery probably necessitates conducting studies in high risk patients with low ejection fraction and poor myocardial function in whom myocardial protection by conventional cardioplegia may be less efficacious; these patients may have an increased oxidative stress induced by less tolerance to ischaemia and hence be more amenable to antioxidant treatment. Unfortunately, most clinical studies tend to be conducted only in a small number of low risk patients that makes detection of significant clinical outcome differences difficult.
The study by Milei and colleagues [11] is important as it increases the evidence that, for the majority of low risk patients undergoing coronary artery bypass surgery, oxidative stress remains a constant underlying factor that will be unlikely to significantly influence clinical outcome as long as meticulous myocardial protection is provided and the ischaemic duration is kept as short as possible. Anything outside these limits, however, may benefit from intervention to attenuate oxidative stress.
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