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Ann Thorac Surg 1996;62:1868-1875
© 1996 The Society of Thoracic Surgeons

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Current Review

Endothelial Cell Injury in Cardiovascular Surgery: Ischemia-Reperfusion

Division of Cardiothoracic Surgery, University of Washington, Seattle, Washington

	Abstract

Top Footnotes Abstract Introduction Ischemia-Reperfusion Injury Hypoxic Endothelial Cell... Leukocyte-Endothelial Cell... Neutrophil-Mediated Injury The No-Reflow Phenomenon Potential Therapy References

 
Myocardial ischemia and reperfusion is a common occurrence in cardiovascular surgery patients. Acute ischemia results in a spectrum of derangements, which range from transient reversible stunning of the myocardium to severe irreversible abnormalities such as infarction. Many of these abnormalities are accentuated upon reperfusion with oxygenated blood. Recently, the endothelium has been shown to play a key role in the injury suffered after ischemia and reperfusion. When rendered hypoxic and then reoxygenated, endothelial cells become activated to express proinflammatory properties that include the induction of leukocyte-adhesion molecules, procoagulant factors and vasoconstrictive agents that increase vasomotor tone. These changes may contribute to the no-reflow phenomenon by promoting endothelial edema, neutrophil and platelet plugging, microthrombosis, and enhanced vasomotor tone. An increased understanding of the role that hypoxic endothelial cell activation plays in myocardial dysfunction after ischemia/reperfusion may allow therapies to be designed to further attenuate this response.

O lente, lente currite noctis equi!

The stars move still, time runs, the clock will strike,

The Devil will come, and Faustus must be damned.

O' I'll leap up to my God! Who pulls me down?

See, see where Christ's blood streams,

In the firmament!

Marlowe, Doctor Faustus, V, iii.

	Introduction

Top Footnotes Abstract Introduction Ischemia-Reperfusion Injury Hypoxic Endothelial Cell... Leukocyte-Endothelial Cell... Neutrophil-Mediated Injury The No-Reflow Phenomenon Potential Therapy References

 
Modern cardiac surgery is predicated on a Faustian bargain: Advanced surgical techniques are now used routinely to restore normal blood flow through and to the heart. For such extraordinary procedures to be performed, the patient in return must endure severe stresses that result from cardiopulmonary bypass (CPB) and reperfusion of the heart after variable periods of ischemia. Indeed, many of the complications associated with cardiovascular operations can often be attributed to these two events. During and after extracorporeal circulation, several abnormalities develop, which include a diffuse capillary fluid leak with increased fluid requirements, acute lung injury requiring mechanical ventilation, acute renal insufficiency, neuropsychiatric dysfunction, a decrease in hepatic synthetic capacity, and disturbances in coagulation. In addition to the systemic effects of CPB, the heart may be ischemic preoperatively and is always made ischemic during the aortic cross-clamp period. When subsequently reperfused with blood, the myocardium is often markedly impaired by what is now recognized as a distinct pathologic process, referred to as "ischemia/reperfusion injury." This myocardial mechanical dysfunction can result in a prolonged need for pharmacologic or mechanical circulatory support. Despite the use of cardioprotective techniques, such as cardioplegia and hypothermia, there is still a significant degree of cardiac dysfunction encountered intraoperatively and postoperatively, particularly in the increasing number of patients who have sustained significant physiologic deterioration before the operation. The resulting morbidity leads to longer hospital stays and, therefore, escalating costs.

Like the multiple organ dysfunction seen after CPB, ischemia-reperfusion injury is a manifestation of an acute inflammatory response initiated by overlapping cascades of inflammatory mediators expressed at a local and systemic level [1, 2]. It is now established that human endothelial cells are altered substantially during exposure to inflammatory mediators and hypoxia. The development of an altered endothelial cell phenotype, referred to as "endothelial cell activation," includes the expression of activities that initiate and amplify inflammation and coagulation. Furthermore, endothelial cells can be stimulated to release substances that profoundly affect vascular tone during the course of an inflammatory response [3]. Endothelial cell activation can be differentiated into two types. In one type, in response to the abrupt restoration of blood flow to ischemic tissues, stimuli, such as reactive oxygen species and activated complement fragments, induce within seconds to minutes the transient expression of preformed proteins stored within the endothelium that promote leukocyte-endothelial cell interactions and coagulation. Alternatively, in response to tumor necrosis factor, interleukin-1, and interleukin-6, transcriptional activation of several genes is initiated in endothelial cells, and translation of specific transcripts into protein products on the endothelial surface is completed over the course of several hours. These proteins include leukocyte adhesion molecules that mediate recruitment of neutrophils to sites of inflammation early in the course of an activation reaction, and tissue factor that initiates the intravascular formation of thrombin [4]. Thus depending on the nature of the inflammatory stimulus, endothelial cells either transiently deploy preformed defenses or acquire over time a defensive phenotype. In both cases leukocyte activation and coagulation are promoted. Recent evidence suggests that the ischemia reperfusion injury suffered by the heart during cardiovascular operations results from varying degrees of both of these mechanisms.

	Ischemia-Reperfusion Injury

Top Footnotes Abstract Introduction Ischemia-Reperfusion Injury Hypoxic Endothelial Cell... Leukocyte-Endothelial Cell... Neutrophil-Mediated Injury The No-Reflow Phenomenon Potential Therapy References

 
Oxygen is critical to myocardial cell aerobic metabolism and maintenance of high-energy stores for normal myocardial function. Acute ischemia results in a spectrum of derangements, which range from transient reversible stunning of the myocardium, manifested as arrhythmias and postischemic myocardial dysfunction, to severe irreversible abnormalities such as infarction [5]. These detrimental effects can be regional, for example, after acute coronary occlusion, or global, as seen after a cardiac operation. Myocardial stunning, or postischemic dysfunction, is the myocardial dysfunction that persists after reperfusion despite the absence of irreversible damage [5]. Areas of infarction are often surrounded by a secondary zone of "at-risk" ischemic myocardium that, although stunned, may recover by cessation of the ischemic insult. After myocardial infarction, it is these areas of at-risk myocardium that benefit from therapeutic efforts to restore perfusion.

Early clinical experience with CPB revealed a syndrome of postischemic myocardial dysfunction that resulted in a low, but in many cases recoverable cardiac output. Timely reperfusion of ischemic myocardium should lead to the correction of the deleterious effects of ischemia, yet the restoration of flow to ischemic myocardium is associated with prolonged and at times profound mechanical abnormalities, which resolve slowly over a period of hours to days [5, 6]. Reintroduction of oxygen to previously hypoxic myocardium can result in a sudden increase in irreversible tissue injury initially referred to as the "oxygen paradox" phenomenon [7]. Exacerbation of injury to ischemic tissue after restoration of blood flow is now termed "ischemia-reperfusion injury."

Ischemia-reperfusion injury may be encountered after an apparent acute myocardial infarction with early reperfusion (secondary to percutaneous transluminal coronary angioplasty or thrombolytics), and CPB with ischemic cardiac arrest. The volume of borderline myocardium surrounding an infarct zone may be enlarged or reduced depending on the degree of injury sustained on reperfusion. Also, ischemia-reperfusion injury is a critical determinant of early graft function after heart and lung transplantation [8, 9]. Although regional ischemia-reperfusion injuries can be readily demonstrated in individual organs, systemic whole-body ischemia-reperfusion injury after shock and fluid resuscitation is more difficult to characterize. Whole-body ischemia-reperfusion injury, however, is one of the most common manifestations of this particular pathophysiologic mechanism. Therefore, the apparent importance of ischemia-reperfusion injury in cardiothoracic surgery has stimulated detailed investigations of the cellular and molecular mechanisms responsible for this syndrome.

	Hypoxic Endothelial Cell Activation

Top Footnotes Abstract Introduction Ischemia-Reperfusion Injury Hypoxic Endothelial Cell... Leukocyte-Endothelial Cell... Neutrophil-Mediated Injury The No-Reflow Phenomenon Potential Therapy References

 
In the early 1980s, Pober's group introduced the concept of endothelial activation, which they defined as a quantitative change in the surface properties of the endothelium that cumulatively allow endothelial cells to perform new functions [10]. Endothelial cell activation allows endothelial cells to localize inflammation to sites of injury or infection. Under normal circumstances, the human vascular endothelium repels neutrophils in the circulation. In response to tissue injury, such as occurs with ischemia, neutrophils accumulate and subsequently remove necrotic material, followed by healing and scar formation. In the context of ischemia-reperfusion, endothelial cells appear to be activated to express proinflammatory properties that include the induction of leukocyte-adhesion molecules [11, 12]. This is evident during myocardial infarction, with complete coronary occlusion. In this setting neutrophil accumulation on the activated endothelium is seen within 3 to 6 hours and peaks by 2 days after vessel occlusion [13]. When the tissue is reperfused before infarction there is a more rapid accumulation of neutrophils with initiation of neutrophil infiltration in 3 minutes and a peak in 2 to 3 hours [14–16]. The more pronounced the degree of ischemia, the more severe the accumulation of neutrophils [17]. Once the neutrophils adhere, they are activated to release oxygen-derived free radicals, which contribute to a positive feedback loop by further activating the host inflammatory response to injury. These neutrophils subsequently transmigrate through the endothelium and confer much of the damage associated with ischemia-reperfusion injury [18, 19].

Although the response of human endothelium to cytokines released by macrophages in sepsis or after shock is well-known, comparatively little is known about the mechanism of hypoxia-induced endothelial activation. Shreeniwas and associates [20] demonstrated the adherence of leukocytes to cultured monolayers of human endothelial cells was increased when the endothelial cells were rendered anoxic. Anoxia-induced adhesion was prevented by the addition of cycloheximide to the cultures, suggesting that endothelial cell-dependent leukocyte adherence in an anoxic environment required new protein synthesis. The intracellular adhesion molecule (ICAM) was subsequently shown to be up-regulated during conditions of hypoxia. Leukocyte adhesion to anoxic endothelial cells was also prevented by addition of a monoclonal antibody directed against the cytokine interleukin-1a, suggesting that this cytokine is released by endothelial cells in an anoxic environment and, in an autocrine fashion, contributes to the anoxia-induced adhesion of leukocytes to endothelial cells [20](Fig 1). In addition to known adhesion molecules, such as E-selectin and ICAM, there may be another class of adherence molecules that arise in hypoxic cells. For example, Ginis and colleagues [21] recently characterized a novel adherence molecule that appears to be specific to hypoxic endothelial cells and underlying muscle. Once the neutrophils are adherent, hypoxic endothelial cells release agents that facilitate leukocyte-mediated injury, such as interleukin-8 (IL-8). Interleukin-8 is a member of the chemokine class of cytokines, which are important activators of leukocytes. High levels of IL-8 can be demonstrated in patients during acute myocardial infarction and in patients undergoing CPB [22, 23]. Interleukin-8 also appears to be a particularly important for endothelial cell-neutrophil interactions in an ischemic environment. When endothelial cells are activated under hypoxic conditions, IL-8 is released, which can feed back to increase the adhesiveness of endothelial cells for neutrophils [24]. Once the neutrophils are adherent to the endothelium, IL-8 is particularly important in the regulation of transendothelial neutrophil migration [25]. In addition, IL-8 has an important stimulating effect on activating neutrophils to release their toxic products. Collectively these experiments suggest that hypoxia and reoxygentation alone (without necrosis) can induce neutrophil-endothelial cell interactions, perhaps through interleukin-1– and IL-8–dependent mechanisms.

View larger version (15K): [in this window] [in a new window]   Fig 1. . Hypoxic endothelial cell activation. Hypoxia stimulates Weibel-Palade bodies to release P-selectin and activates NF-B. NF-B is translocated to the nucleus, where it promotes the transcription of E-selectin, intracellular adhesion molecule (ICAM), Tissue factor, interleukin-8 (IL-8) and interleukin-1 (IL-1). Interleukin-1 feeds back to promote more endothelial cell activation through the activation of NF-B.

	Leukocyte-Endothelial Cell Interactions

Top Footnotes Abstract Introduction Ischemia-Reperfusion Injury Hypoxic Endothelial Cell... Leukocyte-Endothelial Cell... Neutrophil-Mediated Injury The No-Reflow Phenomenon Potential Therapy References

View larger version (24K): [in this window] [in a new window]   Fig 2. . Neutrophil adhesion is a multistep process that involves initial contact between the neutrophil and members of the selectin family of adhesion molecules (P-selectin, E-selectin) expressed on the activated endothelium. These low-affinity bonds result in rolling and slowing of the leukocytes. As this occurs the neutrophil becomes activated and a firm bond occurs between integrins on the leukocyte surface (ie, CD 11/18) and adhesion molecules on the endothelium (ie, intracellular adhesion molecule-1, vascular cell adhesion molecule, platelet-endothelial cell adhesion molecule). (LPS = lipopolysaccharide.)

The relative role of the different adherence molecules in the ischemic injury suffered by the heart after cardioplegic arrest in the clinical setting is unknown. Ischemic cardiac arrest in the operating room is not a pure form of ischemia and reperfusion as seen experimentally because of the protective effects of hypothermia and cardioplegic solutions. Furthermore, there are a number of inflammatory mediators circulating as a result of the CPB circuit that likely influence the degree of endothelial cell activation on reperfusion. Recently studies by Burns and associates [31] and Kilbridge and colleagues [32] demonstrated the induction of P-selectin, E-selectin, and ICAM on the endothelium in myocardial biopsy specimens taken during ischemic arrest in hearts of infants undergoing complex cardiac repairs. Although further studies are needed, these clinical observations, as well those described by Pinsky and colleagues [30], provide a necessary link in recognizing the importance of the activated endothelium in the injury suffered after a cardiovascular operation.

	Neutrophil-Mediated Injury

Top Footnotes Abstract Introduction Ischemia-Reperfusion Injury Hypoxic Endothelial Cell... Leukocyte-Endothelial Cell... Neutrophil-Mediated Injury The No-Reflow Phenomenon Potential Therapy References

 
Although the molecular signals that activate endothelial cells are initiated during the ischemic period, it is not until reperfusion that neutrophil-mediated damage occurs. Upon adherence and transendothelial cell migration, neutrophils become activated to cause a tremendous amount of nonspecific damage. Histologically neutrophil-mediated reperfusion injury is characterized by an abrupt release of intracellular constituents due to the sudden rupture of cell membranes resulting in the unique phenomenon of contraction band formation [7, 33]. This histologic picture is partially mediated by activated neutrophils that generate highly reactive, oxygen-derived free radicals, which contribute to the disruption of these cellular membranes. Oxygen-derived free radicals are cytotoxic due to the capacity of these molecules to react with and damage endothelial cells and myocyte membrane lipids and nucleic acids, resulting in cellular dysfunction, edema, and cell death [34]. Oxygen-derived free radicals also produce damage by reacting with polyunsaturated fatty acids, resulting in the formation of lipid peroxides and hydroperoxides, which in turn inhibit many membrane-bound enzyme systems, damaging the sarcolemma and thereby causing disruption of cellular integrity [35]. This contributes to intracellular calcium overload and myocardial excitation-contraction uncoupling at the cellular level, recognized as the mechanical syndrome of stunning at the clinical level. Furthermore, free radicals may induce significant functional alterations in endothelial cells that promote and extend the inflammatory reaction. In particular, free radicals stimulate platelet-activating factor release from the endothelium, which in turn can further activate cells of the growing neutrophil infiltrate in an amplifying feedback loop [36]. Activated neutrophils may release several proteolytic enzymes that may destroy viable myocardium as well as supporting extracellular matrix. Increased levels of neutrophil-derived proteolytic enzymes have been demonstrated in ischemic myocardium, including elastases, b-glucosaminidases, b-glucuronidases, and myeloperoxidases, all of which break down the barrier function of the endothelium, leading to swelling and impaired cardiomyocyte function [37].

Several inflammatory cytokines released by infiltrating leukocytes in reperfused myocardium have the potential to significantly modulate the inflammatory response. For example, transforming growth factor is released from neutrophils and through direct transcriptional activation of the plasminogen activator inhibitor-1 genes in endothelial cells produces increased levels of the inhibitors of fibrinolysis, resulting in persistence of microvascular thrombi. Recently, IL-8, another powerful neutrophil chemoattractant of the chemokine class of inflammatory cytokines produced by hypoxic endothelial cells and leukocytes, has been associated with myocardial ischemia during cardiopulmonary bypass [22, 23, 24, 38]. Locally elevated concentrations of IL-8 may be an essential signal during initiation of the inflammatory response, contributing to the amplification of the neutrophil-mediated injury pattern.

	The No-Reflow Phenomenon

Top Footnotes Abstract Introduction Ischemia-Reperfusion Injury Hypoxic Endothelial Cell... Leukocyte-Endothelial Cell... Neutrophil-Mediated Injury The No-Reflow Phenomenon Potential Therapy References

 
In early studies of ischemia and reperfusion Kloner and colleagues observed that a dye marker injected after myocardial reperfusion failed to penetrate some reperfused areas. They termed this the "no-reflow phenomenon," defined as "the inability to perfuse previously ischemic myocardium, even when blood flow has been restored to the large arteries supplying the tissue." [17] Hypoxic endothelial cell activation may contribute to the no-reflow phenomenon by several mechanisms (Fig 3). The primary feature of the no-reflow phenomenon appears to be capillary plugging by neutrophils adherent to the activated endothelium and to each other [17]. Proteolytic digestion of endothelial basement membranes by migrating neutrophils has been suggested as a mechanism leading to endothelial cell swelling, detachment, increased vascular permeability, and microvascular obstruction by detached cells and cellular debris [39, 40]. Observations in our laboratory and others suggest that hypoxia promotes a procoagulant response in endothelial cells that could exacerbate ischemia by promoting intravascular microthrombosis [41, 42]. Recently, Golino and colleagues [43] demonstrated that blocking the procoagulant response with a monoclonal antibody to tissue factor preserved myocardial blood flow after reperfusion. Microvascular vasoconstriction may contribute as well. The endothelium normally modulates vascular tone by promoting vasodilatation. Endothelial cells release prostaglandin I₂, adenosine, and nitric oxide, which all act on underlying smooth muscle cells, causing relaxation and vasodilatation. After ischemia-reperfusion injury, the vasodilatory influence of the endothelium may be lost through down-regulation or inactivation of prostaglandin I₂, adenosine, and nitric oxide release, allowing unopposed vasoconstriction to occur that worsens the ischemic insult [44–46]. This may occur in part because oxygen-derived free radicals, which are released by hypoxic endothelial cells and adherent neutrophils, are potent inhibitors of nitric oxide. Furthermore, hypoxia followed by reoxygenation results in a 198% increase in endothelial cell release of endothelin-1, the most powerful vasoconstrictor yet identified [47]. During an inflammatory reaction, lipoxygenase products such as leukotriene B4 released from activated neutrophils in combination with endothelial cell-derived thromboxane A2 have the capacity to cause vasoconstriction. Thus acute hypoxic endothelial cell injury may result in endothelial edema, neutrophil and platelet plugging, microthrombosis, and enhanced vasoconstriction, all of which can work in concert to contribute to the impaired perfusion that is sometimes seen despite what appears to be adequate restoration of blood flow.

View larger version (65K): [in this window] [in a new window]   Fig 3. . The no-reflow phenomenon. Hypoxia results in activation of the endothelial cell layer that promotes leukocyte adhesion and degranulation, endothelial swelling, platelet activation, micothrombosis, and increased vasomotor tone. This contributes to impaired microcirculatory flow, despite what appears to be adequate perfusion through the large epicardial arteries. Adherent neutrophils infiltrate the underlying myocardium and promote lipid peroxidation, enzymatic degradation of membranes, calcium overload, and excitation contraction uncoupling. Collectively these events result in impaired myocardial function.

	Potential Therapy

Top Footnotes Abstract Introduction Ischemia-Reperfusion Injury Hypoxic Endothelial Cell... Leukocyte-Endothelial Cell... Neutrophil-Mediated Injury The No-Reflow Phenomenon Potential Therapy References

Although hypothermia appears to be protective when the heart is cold, this protection is rapidly lost upon rewarming, prompting efforts to discern novel therapeutic interventions that can be used in the interval between rewarming and recovery from the inflammatory insult. Adhesion molecule blockade has been found to attenuate ischemia-reperfusion injury in a variety of in vivo models. Investigators have used monoclonal antibodies, peptides, or small molecules such as oligosaccharides that either bind the adhesion molecule directly and interfere with the molecule binding to its ligand or interfere with intracellular signaling, resulting in a decrease in expression or activation of adhesion molecules. For example, in myocardial ischemia-reperfusion models, monoclonal antibodies to P-, E-, and L-selectins, CD11a, CD11b, CD18, and ICAM-1 have been found to reduce injury [9, 18, 19, 51–55]. Leumedins, amino acids that inhibit the surface expression of CD11b/CD18, have also been found to attenuate myocardial ischemia-reperfusion injury [11]. Sialyl Lewis x, an oligosaccharide that is the neutrophil ligand for E- and P-selectin, has also been found to reduce myocardial ischemia-reperfusion injury [55]. Ma and colleagues [52, 55] examined the effect of L-selectin blockade in a feline myocardial ischemia-reperfusion model by transiently ligating the left anterior descending artery. After 1.5 hours of ischemia, the ligature was removed and the heart allowed to reperfuse for 6 hours. Ten minutes before reperfusion, they administered either a blocking L-selectin monoclonal antibody or a nonbinding control antibody. They found that treatment with the blocking L-selectin monoclonal antibody significantly reduced myocardial necrosis, expressed as percentage of area at risk, from 32% in the nonbinding control antibody group to 14% in the L-selectin monoclonal antibody group. These findings correlated with the amount of myeloperoxidase in the myocardium, an enzyme found in neutrophils used as a marker of neutrophil accumulation in tissue [52, 55]. In a similar study, Weyrich and colleagues [51] examined the role of P-selectin in myocardial ischemia-reperfusion injury, in which the left anterior descending artery is transiently ligated to produce ischemia. Treatment with either a blocking or nonblocking monoclonal antibody to P-selectin was administered 10 minutes before reperfusion. They found that treatment with blocking P-selectin monoclonal antibody significantly reduced myocardial necrosis, expressed as percentage of area at risk, compared with the nonblocking P-selectin antibody by 58%. They concluded that P-selectin blockade reduces myocardial ischemia-reperfusion injury and that P-selectin plays an important role in neutrophil-endothelial cell interactions that result in ischemia-reperfusion injury [51].

Although antiadhesion molecule therapy is beneficial experimentally, its ability to prevent ischemia reperfusion injury is far from complete. Currently there is a great deal of interest in developing gene-directed therapy techniques to alter the course of diseases where gene expression plays a role. Future therapies may be directed at specific gene products or signal transduction pathways so endothelial cell activation can be attenuated more specifically. Dissecting the mechanisms of the genetic control of endothelial cell activation proteins may prove to be a more specific and direct approach to therapies for ischemia-reperfusion injury. The advantage of using this technique to treat the ischemia-reperfusion that follows a cardiovascular operation is that the effects need only to be temporary, lasting from the interval between rewarming and when the body clears the circulating inflammatory mediators, usually around 24 hours. Furthermore, the recognition that the endothelial cell activation that contributes to both the myocardial dysfunction that follows ischemia/reperfusion and the whole-body inflammatory response that results from CPB arise from similar pathophysiologic mechanisms may allow therapies to be designed to preserve endothelial cell function on a much broader scale.

	Footnotes

Top Footnotes Abstract Introduction Ischemia-Reperfusion Injury Hypoxic Endothelial Cell... Leukocyte-Endothelial Cell... Neutrophil-Mediated Injury The No-Reflow Phenomenon Potential Therapy References

 
Address reprint requests to Dr Verrier, Division of Cardiothoracic Surgery, University of Washington, 1959 Pacific St NE, Box 356310, Seattle WA 98195 (e-mail: verriere{at}ctd.surgery.washington.edu).

	References

Top Footnotes Abstract Introduction Ischemia-Reperfusion Injury Hypoxic Endothelial Cell... Leukocyte-Endothelial Cell... Neutrophil-Mediated Injury The No-Reflow Phenomenon Potential Therapy References

 

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