Molecular pathways activation in coronary artery bypass surgery: which role for pump avoidance?

Parolari, Alessandro; Poggio, Paolo; Myasoedova, Veronika; Songia, Paola; Pilozzi, Alberto; Alamanni, Francesco; Tremoli, Elena

Journal of Cardiovascular Medicine: January 2016 - Volume 17 - Issue 1 - p 54–61
doi: 10.2459/JCM.0000000000000293
Cardiac surgery

In this study, we review current knowledge regarding molecular pathways activation and their possible mechanisms in the perioperative period of coronary artery bypass surgery (CABG). We also highlight the role of off-pump CABG as a possible way to better understand these biological changes.

We show that, after both on-pump and off-pump CABG, there is a marked and protracted activation of several molecular pathways indicating increased inflammatory status, haemostasis activation, as well as increased oxidative stress and unfavourable endothelial milieu. These changes persist for days and even weeks after surgery. Interestingly, a relatively limited number of these pathways show a more pronounced activation in case of cardiopulmonary bypass use, and these markers are mainly associated with oxidative stress activation; on the contrary, the vast majority of the pathways has a similar course both in on and off-pump procedures. Surgical stress accounts for more protracted and marked molecular pathway perturbations overall, being the effect of cardiopulmonary, if any, limited to the very early hours after surgery. The near future of the translational research in coronary bypass surgery is to develop therapeutic strategies aimed at reducing this response, that is largely unrelated to cardiopulmonary bypass use, in order to reduce perioperative complications and to speed up patients’ recovery.

aUniversità degli Studi di Milano, Dipartimento di Scienze Biomediche per la Salute

bUnità Operativa di Cardiochirurgia e Ricerca Traslazionale, San Donato IRCCS, San Donato Milanese

cUnit for the Study of Aortic, Valvular and Coronary Pathologies, Centro Cardiologico Monzino IRCCS

dCentro Cardiologico Monzino IRCCS

eUniversità degli Studi di Milano, Dipartimento di Scienze Farmacologiche e Biomolecolari, Milan, Italy

Correspondence to Alessandro Parolari, MD, PhD, Dipartimento di Scienze Cardiovascolari, Università degli Studi di Milano, Centro Cardiologico - Fondazione Monzino IRCCS, Via Parea 4, 20138 Milan, Italy Tel: +39 02 580021; fax: +39 02 580002750; e-mail:

Received 17 October, 2014

Revised 4 March, 2015

Accepted 5 April, 2015

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The treatment of coronary artery disease by coronary artery bypass surgery (CABG) is undoubtedly a landmark in the fields of cardiovascular disease. Introduced in the late sixties, CABG still guarantees the best early, mid-term and long-term results in terms of survival and of event-free survival; therefore, it is not only the treatment of choice in case of severe coronary disease, left main trunk disease and reduced cardiac function,1,21,2 but also in case of diabetes3,43,4 and in the majority of patients affected by two and three-vessel disease.5,65,6 Notwithstanding a constant worsening of the severity of clinical features of patients undergoing CABG, the early results of this procedure have been not even stable but improving over the years with low perioperative mortality rates (from 2.4% in 2000 to 1.9% in 2009), and relatively low complication rates (risk reduction of 26.4% for stroke, 9.2% for reoperative for bleeding and 32.9% in the incidence of sternal wound).7,87,8 Over the years, the biological effects of CABG have been intensively investigated, and several studies have shown that this intervention is associated with the activation of different molecular pathways and cellular components, leading to a persisting systemic inflammatory response associated with the activation of the haemostatic systems, of endothelium and of oxidative metabolism.9,109,10 It is well known that the peak incidence of cardiovascular adverse events such as cardiac death, myocardial infarction, stroke, graft occlusion and need for additional revascularization procedures corresponds to the burst of activation of these pathways occurring much more frequently in the early days, weeks and months after surgery.11,1211,12 And a possible explanation of this increased incidence of clinical complication could lay in the upsurge of biomarkers occurring in the perioperative period and in the early follow-up of CABG.13

In this study, we review the accumulating knowledge regarding molecular pathways activation and their possible mechanisms, with a special emphasis on the role of cardiopulmonary bypass (CPB) on these perturbations.

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Inflammatory and haemostatic pathways

Several studies have shown over time that CABG elicits a complex pro-thrombotic and pro-inflammatory response that peaks, depending on the biomarkers that are considered, in a time frame spanning from the end of CPB and from protamine administration to the early hours thereafter. The activation of plasmatic (contact system, intrinsic coagulation, extrinsic coagulation, complement, and fibrinolytic systems) and cellular (platelets, neutrophils, monocytes, endothelial cells and lymphocytes) blood components recognize two different moments and mechanisms: the contact of blood with the surgical wound (e.g. the pericardium); and the contact of blood with foreign nonendothelialized surfaces of CPB circuit or of cell saver device.

Now it is well known that the contact of blood with the surgical wound is the most important contributor to the initial activation of the haemostatic system14,1514,15 and this activation, ultimately, leads to thrombin generation (Fig. 1). In detail, cellular tissue factor and soluble plasma tissue factor (together with a phospholipid cofactor provided by monocytes, platelets or microparticles) activate the factor VII pathway to generate the factor VIIa/tissue factor complex. Then, this complex activates both factors IX and X.15 Even if initiated via an extrinsic pathway, the activation of factor X is then mainly carried on by the intrinsic coagulation system that progressively takes over becoming the main source of factor Xa.16 This pathway, which was for a long time believed to be the only and the principal activator of the haemostatic system,17 is also activated by the contact of blood with foreign surfaces of the CPB circuit16 or of the cell saver devices18 (Fig. 2). In fact, the contact of the blood with the foreign surfaces of CPB triggers the activation of contact system, consisting of factor XII, prekallikrein, high molecular weight kininogen and factor IX, indeed causing an early burst of complement activation and of complement-related anaphylatoxins generation.19 Moreover, a second complement burst (still debated20) is expected to occur at the time of aortic crossclamp removal,21 and a third one at the time of protamine administration.22 All these events stimulate neutrophils, monocytes and endothelial cells to release pro-inflammatory and anti-inflammatory cytokines, thus promoting and further potentiating the cell-induced inflammation.

Finally, as the link between inflammation and coagulation is bidirectional, the activation of coagulation can increase the inflammatory reaction itself and vice versa. In detail, it is known that factor Xa, thrombin and fibrin may elicit directly a pro-inflammatory activity stimulating the synthesis of interleukin (IL)-6 and of IL-8 in endothelial cells and monocytes,23 whereas activated tissue factor may, per se, increase the circulating levels of these two cytokines.24 Moreover, coagulation proteases may bind to protease-activated receptors (PARs) that are situated in several blood and vessel wall cells. In particular, whereas PAR-3 and PAR-4 are merely thrombin receptors, PAR-1 is also a receptor for tissue factor complex and for factor Xa, and this may further enhance cytokine release. Finally, fibrinogen or fibrin can further affect the production and release of cytokines by monocytes and endothelial cells, probably acting directly on the Toll-like receptor-4 (i.e. the receptor of endotoxin).25

Concerning the crosstalk between haemostasis activation and anti-inflammatory pathways, it has been suggested that antithrombin III has important anti-inflammatory effects that are partly exerted by thrombin activity inhibition, and in part by direct anti-inflammatory properties not related to its antithrombin activity,26 but a recent clinical trial failed to prove its anti-inflammatory effects.27 Antithrombin can also prevent binding of neutrophils and platelets to the endothelium28,2928,29 and it can induce the release of prostacyclin from endothelium itself.30 Moreover, it is well known that the protein C pathway also plays a major role in modulating inflammation and potentially decreasing endothelial cell apoptosis in response to inflammatory cytokines and ischemia.31 Fink et al.32 recently demonstrated a direct binding of monocyte receptor Mac-1 to the endothelial protein C receptor in human cells in dynamic and in static conditions. These findings suggest a prominent role of this pathway in the crosstalk between coagulation and inflammation at the cellular level. Moreover, it indicates new potential targets for the modulation of both these responses during pathological states, such as sepsis or even systemic inflammatory reaction to CPB and surgical trauma.

Interestingly, two clinical trials (DECS and SIRS) have analysed steroids as prophylactic therapy; they demonstrated a nonsignificant effect in the former and surprisingly a greater risk of heart attacks after steroids administration in the latter.33 The results of these trials could indicate that systemic inflammation inhibition, after cardiac surgery, is not beneficial and even more could cause harm to patients.

In addition to all haemostasis pathways that are involved in whole-body reactions, it is interesting to note that also platelets can play a definite role both in molecular pathways activation and in the induction of inflammation. In fact, parallel to haemostasis activation, platelets are activated via several different mechanisms, among them contact with nonendothelialized surfaces, interaction with fibrinogen bound to CPB circuit, thrombin (via PAR-1) and plasmin (via PAR-4); this ultimately leads to reduced numbers of circulating platelets, perioperative platelet dysfunction and the release in the bloodstream of several platelet-associated biomarkers: p-selectin,34 beta-thromboglobulin, platelet factor-435 and granule membrane protein-140. These changes, however, occur for a very limited time span starting from the initiation of CPB and usually return to baseline soon after the end of surgery itself, and this, theoretically, substantially limits possible implications of these markers as predictors of an unfavourable outcome. On the contrary, the effect of coronary bypass surgery on platelet function is not limited to these early hours; it is in fact well documented that, soon after surgery, the responsiveness of newly formed platelets to antiplatelet drugs, especially aspirin, can be substantially impaired and this impairment can last for several weeks thereafter; this phenomenon, called aspirin resistance, has been reviewed in depth elsewhere. It is really noteworthy that the occurrence of this phenomenon that has been described and studied only in recent years is almost coincident with the very early peak of coronary bypass graft failures that usually occurs within 1–2 months after surgery. In addition, although platelets are commonly thought to be mainly involved in haemostasis and wound repair after vascular injury,36 there is growing evidence suggesting their role in inflammation induction. In detail, platelets release a broad range of inflammatory mediators that support endothelial cell activation, leukocyte adhesion and transmigration, monocyte maturation and elaboration of cytokines and reactive oxygen species (ROS).37

Finally, almost simultaneously to haemostatic pathways activation, there is an increase of fibrinolysis, the process that controls blood clotting and avoids excessive and indiscriminate dissemination of the coagulation cascade (Fig. 3). This phenomenon mainly occurs because thrombin induces endothelial cells to produce and release tissue plasminogen activator (t-PA), which, in turn, binds to fibrin and plasminogen. The binding of plasminogen to fibrin significantly increases the rate of plasminogen-induced plasmin production. Plasmin then cleaves fibrin and generates several fibrin degradation products. Among them, D-dimer is the smallest but due to its high concentration, it is the easiest fibrin degradation product assayable in plasma. Another contribution to fibrinolysis activation comes from inflammatory pathways that increase gene expression and protein synthesis of plasminogen activator inhibitor-1 (PAI-1) in adipose tissue. Release of PAI-1 in circulating blood, during CPB, further potentiates fibrinolysis itself.38

However, the simultaneous activation of pro-inflammatory and anti-inflammatory pathways, as well as the stimulation of procoagulant and anticoagulant pathways and of fibrinolysis, does not fade away once surgery is completed. Rather, it persists at least from several days to several weeks after the intervention. In fact, thrombin generation markers, namely thrombin–antithrombin complexes and pro-thrombin factor F1.2, increase during surgery and remain higher than baseline from 139 to 4 weeks after surgery;40,4140,41 this is also paralleled by a persistent increase of fibrinolysis marker D-dimer, whose increases may extend up to 2 months after surgery.39 This upsurge of haemostasis activation can be, at least in part, explained by a concurrent increase in plasma tissue factor that can be higher than baseline for at least 4 days after surgery.34,3934,39 Moreover, fibrinogen, the final protein of clotting and an inflammation marker, is elevated up to 8–15 days after surgery.39,4239,42 Other inflammatory markers that are persistently increased in the days following CABG are C-reactive protein (CRP),42 IL-2 receptor (IL-2R),43 IL-6,42 IL-8,42,4342,43 neutrophil elastase42 and procalcitonin44 that remain higher than baseline from several days to several weeks after surgery.

Taken together, these data suggest that, apart from early activation, there is an ongoing and protracted activation of several haemostatic and inflammatory molecular mechanisms. Current protocols of management of patients undergoing CABG do not control the activation of these pathways, which are persisting over time after surgery, and could potentially represent a major target for therapeutic strategies aimed at reducing possible or concomitant causes of perioperative and postoperative major adverse events (e.g. aspirin resistance) (Fig. 4). Of note, a substantial part of these pathways is not affected by CPB use10 or by techniques aimed at reducing the trauma due to the CPB itself. These data, which will be reviewed in deep in one of the chapters ahead, shed important light on surgical trauma itself, that is almost the parallel of the term we have previously used when describing the phases of coagulation activation as ‘contact of blood with the surgical wound’.

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Oxidative stress and endothelial function

Oxidative stress results from the imbalance between the generation of ROS and the capability of tissues and cells to steadily detox them, and this can lead to organ damage and dysfunction. Indeed, enhanced production or attenuated degradation of ROS affect endothelial and vascular function and may contribute to atherosclerosis, coronary artery disease, diabetes and heart failure development and progression. It has been shown that cardiovascular risk factors can promote an imbalance between endogenous oxidants and antioxidants resulting in oxidative stress, impaired nitric oxide pathway function and, eventually, vascular dysfunction.45,4645,46 Previous studies have addressed the problem of oxidative stress in atherosclerosis and in coronary artery disease, suggesting that oxidative stress might even be considered as a unifying mechanism for many cardiovascular risk factors, and that a vicious circle between oxidative stress and inflammation can occur in the diseased arterial wall, causing loss of antioxidant protection and cell death.47 For the aforementioned reasons, the production and release of ROS are nowadays considered to be potential contributors to the incidence of peri-operative or postoperative complications occurring after CABG. In fact, a ROS increment during CABG surgery can overwhelm local antioxidant defense mechanisms and cause damage and dysfunction of macromolecules, cells and tissues.48

Recent studies have shown that, in patients affected by coronary artery disease requiring surgical revascularization, oxidative stress markers pattern indicates an increased pro-oxidant state and reduced antioxidant defenses already at baseline with respect to healthy controls,49 even if matched for cardiovascular risk factors with the CABG patient population.50 Apart from preoperative levels, several studies have then shown an upsurge of oxidative response during the intraoperative period and during the very early hours after surgery with increases in several pro-oxidant markers such as urinary isoprostanes,51 plasma35,51,5235,51,5235,51,52 and urinary malondialdheide,53 urinary xanthines,53 plasma lipid hydroperoxides,54 protein carbonyls,54,5554,55 nitrotyrosine,54 glutathione peroxidase and superoxide dismutase. Conversely, antioxidant substances such as tocopherols56,5756,57 and reduced glutathione49,5649,56 are diminished in the perioperative period, with an imbalance in sharp favour of oxidation as reflected by decreases in plasma total antioxidant status.51,5651,56 Unfortunately, none of the previously cited studies extended the observation of the patients beyond the early perioperative period (usually 24 h after surgery).To the best of our knowledge, the only article with observation times reaching 1 week postoperatively has shown that myeloperoxidase levels are increased up to the second postoperative days, whereas asymmetric dimethylarginine, an indicator of the perturbed nitric oxide pathway, is decreased on the first postoperative day returning to baseline the day after.58 Unfortunately, the limited numbers of patients enrolled in this study, together with the fact that only the two aforementioned markers were assessed, does not allow the drawing of meaningful conclusions about the behaviour of oxidative stress markers beyond the first 24 h after surgery.

On the contrary, only few data are available about the impact of different therapeutic approaches on oxidative stress balance. Interestingly, a recent study showed a beneficial effect of aspirin treatment, which was found to be associated with lower isoprostane levels after CABG.59

Parallel to haemostasis and inflammation activation, and simultaneous to oxidative stress perturbations, endothelial activation and damage have been documented to occur perioperatively. This activation recognizes several different mechanisms, among them ischemia/reperfusion injury, hypothermia, mechanical forces exerting on endothelium during coronary surgery and endothelial damage due to cardioplegic solutions (when these are used). These mechanisms have been described in detail elsewhere.60 It follows that several markers of endothelial activation and damage increase during and after CABG. As for some oxidative stress markers, in patients affected by coronary artery disease listed for CABG, some of endothelial activation markers are already increased before surgery with respect to healthy controls, and, among them, there are circulating endothelial cells.61 This cell population is a subtype of circulating bone marrow derived cells that have the potential to proliferate and differentiate into mature endothelial cells at virtually any site in the body. Circulating endothelial cells are also a specific and sensitive marker of endothelial activation and damage in a variety of vascular disorders and are increased preoperatively as compared with healthy controls. Apart from that, CABG elicits a substantial increase not only of circulating endothelial cells up to 24 h after surgery61,6261,62 but also of circulating endothelial progenitor cells,63 a potential new biomarker that could help predict cardiovascular events independently from traditional and emerging risk factors64 and of endothelial progenitor cell-colony forming units.65 In addition, CABG causes impaired viability and function of circulating endothelial cells and increased capability of the serum of patients undergoing this procedure to induce apoptotic changes in primary cultures of human umbilical vein endothelial cells.62 All these data are the proof of concept that an unfavourable environment for endothelium develops during and shortly after CABG and that the reversal of such an environment potentially constitutes a major goal in a near future to improve the results of this surgery, and a targeted therapy in this setting is eagerly a waited. The fact that changes in some of these markers occur not only in CABG but also in different adult cardiac surgical procedures, such as valves,65 suggests that these modulations may not be specific for CABG but more generally diffuse in adult patients undergoing heart surgery.

In addition, several other markers indicating endothelial activation and unfavourable endothelial environment [vascular endothelial growth factor,66–6866–6866–68 soluble vascular endothelial growth factor receptor-1,69 soluble vascular cell adhesion molecule-1 (VCAM),41,70,7141,70,7141,70,71 intracellular adhesion molecule-1,70 monocyte chemo-attractant protein-167 and von Willebrand factor (vWF)]41,7241,72 are substantially increased in the CABG perioperative period. Although most of these markers usually increase early after surgery and persist for a maximum of 48 h thereafter, vWF increases 1–2 days after surgery and remains high at least for a week after surgery.41,7241,72 In addition, some authors described that VCAM-1 is increased in the early hours (but not immediately as many other markers) after surgery and for a maximum of 24–48 h,70,7170,71 whereas others could document late increases 30 days after CABG.41 The fact that some endothelial cell markers (VCAM and vWF) increase and remain higher than baseline levels later after surgery suggests that a persistently unfavourable milieu for endothelium may ensue and persist for several weeks after surgery. This deserves further investigation as a potentially new target for promoting a better endothelial protection and function in the early weeks after CABG.

In summary, currently available data indicate that, during and after surgery, there is a wide and somehow protracted activation of oxidative pathways and endothelial cell impairment and damage. If we consider that there is a concomitant activation of molecular mechanisms associated with haemostasis and inflammation, it is now clear that the derangements associated with CABG are really substantial and the possible modulation could have an important impact on early and long-term outcomes. One of the easiest ways to do that could be, at least theoretically, the avoidance of the pump, which will be addressed in the next chapter.

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Cardiopulmonary bypass use vs. cardiopulmonary bypass avoidance: molecular pathways activation

CPB has been for a long time considered to be the major contributor to the activation of molecular pathways that occur during cardiac surgical procedures. However, it is well known that a substantial degree of molecular pathways activation such as inflammatory, haemostatic and oxidative stress changes occur in other surgical disciplines associated with opening of the thorax but that do not foresee CPB use such as thoracic surgery,73,7473,74 or in many other surgical disciplines that are not even associated with the chest such as in open75 or endovascular76 treatment of abdominal aortic aneurysms; interestingly, this also occurs in surgical interventions that do not primarily involve the vascular tree such as general surgery procedures.77,7877,78 Moreover, this activation occurs even in general surgery procedures that are performed with a less invasive laparoscopic approach,79,8079,80 or in minor surgery such as in hernia repairs.81 Finally, the activation of several molecular pathways has also been demonstrated in several different other disciplines such as orthopaedic surgery82 and even in neurosurgery.83 This is the proof of concept that surgery per se is enough to elicit a complex whole-body response whose molecular mechanisms are not necessarily associated with CPB use, but to surgical trauma itself or to the contact of blood with structures outside the endothelialized vascular tree. The advent in the mid-nineties of the possibility to perform the most common procedure, namely CABG, without the use of CPB has provided the researchers and investigators with a totally unique possibility to discriminate what is the real contribution of CPB itself and of surgical trauma to the perturbations of the molecular pathways that were already well documented at that time, and the chance to improve the knowledge regarding the role of biological perturbations in the occurrence of unfavourable events and of complications after coronary surgery. The results of the first 10-year of research in the role of CPB use on the occurrence of molecular pathways derangements have been previously reviewed,10 and it could be easily demonstrated that, without any reasonable doubt, CPB is responsible for the activation of a relatively limited part of the pathways associated with inflammation, haemostasis, oxidative stress and cell damage for the very early perioperative period, namely for the time frame spanning from surgery to the early hours thereafter. However, surgical trauma gives a substantial contribution not only to the pathways that are not affected by CPB but also it prolongs the activation of the different pathways initially stimulated from CPB use for a time period beginning few hours after surgery, when the contribution of the heart-lung machine is no more present, and lasting, for some markers, up to several weeks after surgery. Taken together, previous and current evidence on this topic suggests a potential advantage, on the molecular standpoint, of coronary bypass surgery performed without CPB use that is limited to the early hours after surgery.

In recent years, some articles have shed more light on this topic adding further evidence in favour of the previous hypotheses, confirming that, during and in the early hours after surgery, even if some biomarkers show a less pronounced stimulation after off-pump coronary artery bypass (OPCAB), there are several markers that seem to be unaffected by CPB use, and these are involved in inflammatory pathways such as IL-6,42,43,58,7042,43,58,7042,43,58,7042,43,58,70 and CRP,42,7042,70 in haemostatic pathways such as plasma,34 monocyte-bound34 and platelet-bound tissue factor,34 vWF41 and soluble fibrin,72 or to both such as fibrinogen.42 On the contrary, several recent articles have underscored that patients undergoing OPCAB show a more preserved platelet function overall, and that this aspect may put patients submitted to this technique at a higher risk for thrombotic events;84 the role of the pump on the occurrence of perioperative aspirin resistance is nowadays still controversial, as there is not only evidence in favour of a reduced occurrence of this phenomenon with OPCAB but also evidence suggesting similar rates of that after CABG or OPCAB.84

Finally, once the early perioperative period is over, even the time course of the markers that are sensibly different in on-pump and off-pump CABG becomes similar, and the return to baseline may occur several days or weeks after surgery, depending on the kinetics of the marker itself.34,39,41,4234,39,41,4234,39,41,4234,39,41,42 This is the proof of concept that this protracted activation over days and weeks recognizes a different causative model than CPB, and that surgical trauma can be the only reasonable explanation for that. Concerning oxidative stress and cell damage, it is noteworthy to see how current evidence, although mainly limited to 24–48 postoperative hours, has shown, on the contrary, that off-pump techniques are associated with lower oxidative stress49,51,52,55–5749,51,52,55–5749,51,52,55–5749,51,52,55–5749,51,52,55–5749,51,52,55–57 as well as substantially reduced endothelial damage.62,63,67,70,7162,63,67,70,7162,63,67,70,7162,63,67,70,7162,63,67,70,71 Taken together, previous and current evidence on this topic suggests reduced oxidative stress as a potential advantage, on the molecular standpoint, of coronary bypass surgery performed without CPB use; on the contrary, the improved preservation of platelet function in OPCAB may theoretically increase the risk of thrombotic events.

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After coronary bypass surgery, performed either with or without CPB use, there is a marked and protracted activation of several molecular pathways indicating increased inflammatory status, haemostasis activation, as well as increased oxidative stress and unfavourable endothelial milieu. These changes may persist for days and even weeks after surgery, some of these pathways showing a much more pronounced activation in case of CPB use, many being not affected by the heart-lung machine. Avoidance of CPB use can help reducing molecular pathways activation only in a limited way, and future researches should address much more extensively the molecular mechanisms underlying the vast pro-thrombotic and pro-inflammatory activation rather than elimination of the pump itself, as it is now well know that the much more pronounced and prolonged activation of the majority of biological pathways occurs irrespectively from the use or nonuse of CPB.

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biomarkers; cardiopulmonary bypass; coronary artery bypass; outcomes

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