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Ann Thorac Surg 1996;62:915-922
© 1996 The Society of Thoracic Surgeons

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Current Review

Endothelial Cell Injury in Cardiovascular Surgery

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

	Abstract

Top Footnotes Abstract Introduction Normal Vascular Form and... Vasomotor Dysfunction Coagulation Neutrophil-Endothelial Cell... Intimal Hyperplastic Response to... Chronic Endothelial Cell Injury Conclusion References

 
In the last decade the endothelium has been shown to play a major role in regulating membrane permeability, lipid transport, vasomotor tone, coagulation, inflammation, and vascular wall structure. These critical endothelial cell functions are extremely sensitive to injury in the form of hypoxia, exposure to cytokines, endotoxin, cholesterol, nicotine, surgical manipulation, or hemodynamic shear stress. In response to injury endothelial cells become activated, tipping the balance of endothelial-derived factors to disrupt barrier function, and enhance vasoconstriction, coagulation, leukocyte adhesion, and smooth muscle cell proliferation. Although these responses likely exist as protective mechanisms, if the stimuli are severe the responses may become excessive, resulting in damaged tissue, impaired organ function, and an abnormal fibroproliferative response. Recent discoveries in the field of vascular biology have led to an expanded understanding of many of the complications of cardiovascular operations. Because of the wide impact endothelial cell dysfunction has on patients with cardiovascular disease, issues pertaining to endothelial biology are in the forefront of research that will affect the current and future practice of cardiothoracic surgery.

	Introduction

Top Footnotes Abstract Introduction Normal Vascular Form and... Vasomotor Dysfunction Coagulation Neutrophil-Endothelial Cell... Intimal Hyperplastic Response to... Chronic Endothelial Cell Injury Conclusion References

 
The importance of the vascular endothelium in almost all aspects of cardiovascular surgery has become increasingly recognized [1]. Although the vascular endothelium has long been considered simply a nonthrombogenic barrier serving to separate the blood from the body's tissues, the ability to culture and directly study human endothelial cells has led to an explosion of information concluding that the endothelium actively participates in maintaining normal cardiovascular homeostasis. The role of the vascular endothelium is especially prominent in regulating membrane permeability, lipid transport, vasomotor tone, coagulation, fibrinolysis, inflammation and in sustaining or altering vascular wall structure (Fig 1). This is done by tightly regulating the expression of endothelial-derived biologically active agents, in the form of either surface proteins or locally secreted soluble factors, that exert opposing effects to either increase or decrease the degree of vasoconstriction, promote or prevent coagulation, enhance or impede platelet and leukocyte adhesion, or alter the shape of the arterial wall through the release of growth factors and extracellular matrix [2–6].

View larger version (42K): [in this window] [in a new window]   Fig 1.. Acute and chronic endothelial cell injury results in changes that promote leukocyte adherence, transendothelial cell migration, coagulation, increased vascular tone, and fibroproliferation.

	Normal Vascular Form and Function

Top Footnotes Abstract Introduction Normal Vascular Form and... Vasomotor Dysfunction Coagulation Neutrophil-Endothelial Cell... Intimal Hyperplastic Response to... Chronic Endothelial Cell Injury Conclusion References

 
Normal vascular function is a dynamic process resulting from the interaction of the layers of the vessel wall and the passing elements in the blood. The vessel wall is made up of three distinct layers: the adventitia, the media, and the intima. The adventitia and media compose the structural backbone of the vessel wall and are important in vascular wall remodeling. The intima is lined with the endothelium, which is situated on a basement membrane and subendothelial matrix. Although it consists of a thin and seemingly inert layer, the endothelium has profound influences on the form of the vessel wall and the function of the entire cardiovascular system. Although comprising only 1% of the body's net mass, the endothelium has a surface area of approximately 5,000 m² [9]. Because of its strategic position between the blood and interstitial tissues the endothelium is in a unique position to regulate both intravascular and extravascular events. Perhaps the best-known endothelial cell function is in providing a permeability barrier through which there is exchange and active transport of substances into the arterial wall. Exchange of substances across the capillary barrier occurs through nonspecific and ligand-directed transcytosis as well as passively between cells [9]. When this is disrupted, such as seen after diffuse inflammatory states, there is increased fluid loss across this barrier resulting in interstitial edema and impaired end-organ function.

In addition to regulating barrier function, the endothelium plays a major role in regulating the structure of the vessel in response to changes in the local environment. The endothelium manufactures and secretes growth factors as well as growth inhibitors that regulate vascular wall structure. Through the manufacture and secretion of growth and regulatory molecules such as platelet-derived growth factor, basic fibroblast growth factor, insulin-like growth factor, and interleukin-1 (IL-1), endothelial cells regulate the maintenance of the basement membrane collagen and proteoglycans upon which they rest [10]. Removal of the endothelium leads to proliferative response by the underlying smooth muscle cells, suggesting that factors released by the functional endothelium are usually responsible for inhibiting uncontrolled smooth muscle cell proliferation. Important growth inhibitors produced by the endothelium include heparin and heparin sulfates and transforming growth factor B [2]. Study of the inciting stimuli and inhibitors of this process is a particularly fertile area of vascular biologic research because of the implications this has on long-term vessel function in various disease states.

In addition to the normal functions of the endothelium and vessel wall there are a variety of pathologic conditions common to cardiovascular surgery patients that result from impaired vascular function. These pathologic conditions, such as acute vasospasm, thrombosis and fibrinolysis, neutrophil adhesion, and fibroproliferation, have several common features but for the most part are considered separately.

	Vasomotor Dysfunction

Top Footnotes Abstract Introduction Normal Vascular Form and... Vasomotor Dysfunction Coagulation Neutrophil-Endothelial Cell... Intimal Hyperplastic Response to... Chronic Endothelial Cell Injury Conclusion References

 
The endothelium produces substances that act locally and remotely to influence the degree of vascular tone. These include constitutively expressed relaxant factors such as nitric oxide (NO), prostacyclin, and adenosine, all of which work together to promote vascular patency by dilating vessels and preventing thrombosis. Additionally, the endothelium produces factors that promote increased vascular tone, such as endothelin, leukotrienes, and angiotensin II. Most patients with end-stage coronary artery disease referred for coronary artery bypass grafting have a preexisting impairment of vasomotor control. For example, the capacity of endothelial cells to produce relaxant factors decreases with advanced age, diabetes mellitus, hypertension, chronic nicotine use, hypercholesterolemia, and atherosclerosis, suggesting a direct link between the ability to synthesize prostacyclin, NO, and adenosine in the vessel wall and vulnerability to episodes of thrombosis, hypertension, and atherogenesis [11]. The intraoperative and postoperative milieu may contribute additionally to vasomotor dysfunction. In response to injury, such as cardiopulmonary bypass (CPB), ischemia-reperfusion injury, or direct manipulation, endothelial cells not only lose their ability to promote vasodilatation, they produce potent vasoconstrictor substances, such as endothelin, thromboxane A₂, and angiotensin II [12]. Specific injurious stimuli that induce vasoconstriction via the loss of these substances include stretch, hypoxia, high potassium level, cytokines, and arachidonic acid metabolites. Endothelial cell injury secondary to hypoxia and exposure to cytokines causes the production of superoxide radicals, which exert a profound effect on increasing vascular tone by inactivating NO. Experiments with cultured endothelial cells demonstrate a fourfold to eightfold increase in the release of endothelin in response to low oxygen tension [13]. The kidney is about ten times more sensitive to the effects of endothelin than other end organs, suggesting that endothelial cell injury may play a role in the development of renal failure in acute injury states. Alterations in vascular reactivity have multiple deleterious effects on acute perioperative cardiac function as well. Increased vascular reactivity can predispose to coronary spasm, spasm of the internal mammary conduit, or microcirculatory no-reflow leading to acute myocardial ischemia [14, 15]. Efforts to replace NO, prostacyclin, or adenosine during ischemia/reperfusion seem to have cytoprotective effect [16].

	Coagulation

Top Footnotes Abstract Introduction Normal Vascular Form and... Vasomotor Dysfunction Coagulation Neutrophil-Endothelial Cell... Intimal Hyperplastic Response to... Chronic Endothelial Cell Injury Conclusion References

 
Given its location between the circulating blood and the interstitial tissues, the vascular endothelium must be an anticoagulant surface under basal conditions [4]. To keep blood in the fluid state the endothelium possesses multiple mechanisms to prevent coagulation. First, the endothelial cell is one of the only cells that does not constitutively express tissue factor, the surface protein responsible for activation of the extrinsic pathway of coagulation. Most other cells, especially in the subendothelial and intimal layers, constitutively express tissue factor, constituting an important mechanism in promoting the formation of clot at sites of injury [17]. The second endothelial-derived anticoagulant mechanism is the constant local secretion of soluble vasoactive substances such as NO, prostacyclin, and adenosine, which maintain vasodilatation and prevent platelet aggregation and adhesion. An additional mechanism is the endothelial surface expression of heparin, which binds to thrombin, reducing cleavage of fibrinogen to fibrin. If any clot is formed, the constitutive endothelial cell expression of tissue-plasminogen activator catalyzes the conversion of plasminogen to plasmin, which promotes local lysis of fibrin clot [4]. The final natural antithrombotic mechanism involves thrombomodulin. Thrombomodulin is a membrane-bound protein expressed on the surface of endothelial cells. Thrombin forms a 1:1 complex with thrombin, which activates protein C to form activated protein C. In the presence of its cofactor protein S, the thrombomodulin-thrombin-activated protein C complex inhibits coagulation by cleaving factors VIIIa and Va.

Although there are likely many causes of abnormal coagulation associated with heart operations, changes in the intravascular milieu during CPB promote profound alterations in the coagulation status of the endothelium. These changes have an impact on the propensity to bleed or to thrombose after a cardiovascular operation. Immediately after the initiation of bypass there is a rapid increase in the circulating levels of tissue-plasminogen activator [18]. Tissue-plasminogen activator, which is stored and released by endothelial cells, catalyzes the formation of plasmin from plasminogen, which acts directly to lyse clots. Release of tissue-plasminogen activator combined with hemodilution, platelet dysfunction, and heprinization lead to difficulties in blood clotting in some CPB patients [19]. In addition to its dynamic functions in preventing coagulation, the endothelium actively promotes coagulation in response to injury, either locally or remotely. Endothelial cell activation by inflammatory cytokines results in the transcription of the tissue factor gene, with appearance of tissue factor on the endothelial cell surfaces within 2 hours [20–26]. Experimental observations demonstrate that inflammatory mediators widely circulating in cardiac surgery patients, such as tumor necrosis factor, IL-1, and complement fragment 5a, induce the expression of tissue factor on endothelial cells in culture may explain why there is an extensive activation of the extrinsic pathway of coagulation in CPB patients [21, 27]. Diffuse tissue factor expression likely results in a depletion of circulating coagulation factors, which occurs after uncontrolled coagulation is triggered [28]. When this occurs diffusely, obstructing fibrin deposits accumulate in the microvascular circulation and platelets are consumed when they become trapped in fibrin mesh [19,28–30]. Postoperatively, when tissue-plasminogen activator levels decrease and coagulation factors have recovered, the pendulum is tilted from a state of consumption and fibrinolysis toward a tendency to clot [18]. Efforts to characterize the events that result in tissue-plasminogen activator release and tissue factor expression after inflammation may allow the development of techniques to modulate and thereby prevent some of the coagulation disturbances that sometimes complicate cardiothoracic operations.

	Neutrophil–Endothelial Cell Interaction

Top Footnotes Abstract Introduction Normal Vascular Form and... Vasomotor Dysfunction Coagulation Neutrophil-Endothelial Cell... Intimal Hyperplastic Response to... Chronic Endothelial Cell Injury Conclusion References

 
Recruitment of neutrophils from the blood stream to extravascular sites of injury is a critical event in host defense against bacterial infection and in the repair of damaged tissue [31]. This process probably evolved teleologically to be a localized process, beneficial in fighting an inoculation of bacteria. When the signals are diffuse, as they are after shock, sepsis, or CPB, there may be multiorgan endothelial activation resulting in widespread surface expression of neutrophil adherence molecules. Because of the potential magnitude of the body's host defenses, the endothelium possesses several endogenous antiadhesive properties that prevent the inadvertent adherence of neutrophils to the endothelium. In the unactivated cell, the endothelium does not possess the neutrophil adherence molecules needed to mediate adhesion. Nitric oxide is a potent antiadhesive mediator that prevents neutrophil/endothelial cell adhesion under basal conditions. The importance of NO in preventing leukocyte adhesion under normal physiologic conditions has been demonstrated by investigators when N^G-monomethyl-L arginine was used to block NO production, resulting in a 15-fold increase in neutrophil adhesion [32]. Prostacyclin and adenosine have similar adhesive inhibitory effects [33].

Although the normal endothelium actively produces substances that repel passing leukocytes, injury to the endothelium results in expression of leukocyte adhesion molecules, which allow the endothelium to localize neutrophils to areas of injury [34]. In examining this phenomenon at the cellular level, Bevilacqua and colleagues [35] noted that endothelial cells in culture produced surface proteins that caused leukocyte adhesion in response to tumor necrosis factor or IL-1. These proteins, which are not usually present in the resting state but are easily inducible when the cells are activated, have since been characterized as the leukocyte adhesion molecules. Although the exact mechanisms of how these processes begin and end are unknown, it appears that the process of endothelial cell activation is self limited because many of the same agonists that activate endothelial cells also induce the manufacture of inhibitory factors, such as the inhibitory factor-B, that feedback to turn off this response [36].

The Whole-Body Inflammatory Response to Cardiopulmonary Bypass
Systemically endothelial cell–neutrophil adhesion is most evident in the whole-body inflammatory response that results from the release of complement degradation products and cytokines after blood exposure to the artificial conduits of the CPB circuit. Proinflammatory endothelial cell changes promote widespread leukosequestration, which results when leukocytes adhere to capillary beds in the kidneys, liver, brain, extremities, and, most noticeably, the heart and lungs. The complement activation byproduct complement fragment 5a mediates the early phase of inflammation that initiates expression of neutrophil adhesion molecules on the surface of activated endothelial cells after CPB [37]. Cytokines, released from ischemically injured endothelial cells and tissue-fixed macrophages in the heart, in the lungs, and throughout the body, mediate the next phase of neutrophil adherence over the ensuing hours [38]. This results from the cytokine response to CPB, evident by increasing levels of tumor necrosis factor, IL-1, IL-6, IL-8, and oxygen-derived free radicals, which are likely released by damaged endothelial cells, neutrophils, and macrophages [39–43]. Recently, adherence molecules (E-selectin, intracellular adhesion molecule, P-selectin) have been demonstrated in skeletal muscle biopsy specimens taken during the course of CPB, providing direct evidence that in vitro endothelial cell culture observations correlate as expected in the clinical setting [37, 44].

Ischemia/Reperfusion Injury
The systemic inflammatory response may have a particularly deleterious effect on the heart, where an additional insult occurs from myocardial ischemia during cardiac arrest [45, 46]. Myocardial ischemia, present in many patients preoperatively and as a result of cardioplegic arrest during CPB, activates the vascular endothelium to recruit neutrophils that accentuate injury upon reperfusion with oxygenated blood [47]. Mallory [48] first described the infiltration of leukocytes after acute coronary occlusion in autopsy specimens. This pattern of insult, know as ischemia-reperfusion injury, has since been reproduced experimentally in numerous studies that have shown that when ischemic tissue is reperfused with oxygenated blood, neutrophils accumulate rapidly in the infarcted tissue [49, 50]. Once neutrophils adhere to the hypoxically injured endothelium, leukocyte-mediated impairment appears to result from the release of a variety of substances such as oxygen-derived free radicals, thromboxanes, leukotrienes, elastases, and proteases that disrupt cellular membranes and impair myocardial function [51].

The cellular and molecular mechanisms of the neutrophil-endothelial cell adhesion in ischemia/reperfusion injury are increasingly understood. Recently Shreeniwas and colleagues [52] demonstrated the induction of neutrophil adherence molecules on the surface of endothelial cells rendered hypoxic and then reoxygenated in culture. Interestingly, neutrophils do not adhere to the hypoxically injured endothelium until cells are reoxygenated, emphasizing the importance of reoxygenation in this syndrome. Evidence supporting the importance of neutrophil adherence molecules in ischemia/reperfusion injury is provided by studies using monoclonal antibodies against adherence molecules which block many of the deleterious effects of reperfusion of ischemic tissue [53–57]. New insights into the mechanisms of ischemia-reperfusion injury stemming from the study of cultured endothelial cells rendered hypoxic are rapidly appearing in the literature, some of which may lead to novel therapeutic options in the not too distant future.

Organ Preservation
Another area in cardiothoracic surgery where endothelial cell–neutrophil adherence may play a role is the field of thoracic transplantation. Having worked out many of the technical and immunologic features of heart transplantation, Shumway and colleagues recognized that effective preservation of the allograft would be a salient feature of clinical transplantation [58]. Their pioneering work demonstrated that the heart would tolerate anoxia for up to an hour if cooled, establishing topical hypothermia as the mainstay of cardiac preservation for the last three decades. This approach, first demonstrated in the laboratory and later in the operating room, has led to markedly reduced mortality during intracardiac operations and has allowed distant organ procurement to expand the available donor pool for both heart and lung transplantation [59]. Despite the benefits of hypothermia, early graft function is still severely limited by ischemia-reperfusion injury. This is especially evident as ischemic times approach 6 hours. In these circumstances impaired myocardial function can lead to an increased dependence on inotropic or mechanical circulatory support. Although efforts to improve organ preservation solutions have traditionally been directed at substrate repletion, recent attention has been focused on the injured endothelium as a potential source of dysfunction after cardiac preservation. Bando and colleagues [60, 61] depleted leukocytes by mechanical filtration in both donor and recipient, which they found improved the ischemic tolerance of thoracic grafts beyond that provided by donor core cooling alone. This provided evidence that ischemic endothelial cell activation is important in recruiting neutrophils to the graft endothelium. Byrne and colleagues [55, 62] found that adding antiadhesive monoclonal antibodies to University of Wisconsin solution markedly improved their ability to prevent ischemia reperfusion injury, allowing them to prolong the ischemic interval to 15 hours in a cardiac transplant model. Improved understanding of the mechanisms of hypoxic endothelial injury, especially in cells that are hypothermic, may allow further studies to be designed to improve the ability to preserve heart and lung grafts before transplantation.

	Intimal Hyperplastic Response to Endothelial Cell Injury

Top Footnotes Abstract Introduction Normal Vascular Form and... Vasomotor Dysfunction Coagulation Neutrophil-Endothelial Cell... Intimal Hyperplastic Response to... Chronic Endothelial Cell Injury Conclusion References

 
Long-term success of coronary artery bypass grafting is limited by the development of intimal hyperplasia at the sites of vessel injury. All forms of arterial reconstruction cause some form of endothelial cell injury. Graft harvest and handling as well as the construction of the anastomosis are common causes of vessel damage in cardiovascular surgery patients. The intimal response to injury is characterized by a subendothelial fibroproliferation and the formation of a neointima [5]. This intimal hyperplastic response is part of the reparative process that takes place in all arteries after injury [5, 63]. This response is important because neointimal formation occurs in all arteries secondary to a variety of injuries including direct trauma, construction of an anastomosis, dilation with a balloon catheter, or transplant rejection. In some instances, however, injury is excessive, which causes an exaggerated proliferation of the neointima and the loss of inhibitory natural anticoagulants, resulting in a reduction in luminal narrowing, restricted blood flow, and in some cases thrombosis [63].

Intensive study of this process has led to an improved understanding of the pathogenesis of intimal hyperplasia. It appears that there are three phases of intimal response to arterial injury. The first consists of medial smooth muscle proliferation and begins within 24 hours of injury to endothelium. Once the endothelium is stripped away, platelets adhere to the vessel wall, spread, and degranulate. Mitogens released from activated, adherent platelets, such as platelet-derived growth factor, stimulate smooth muscles to migrate into the intima [64]. When endothelial and smooth muscle cells are injured, other mitogens such as basic fibroblast growth factor are liberated, which stimulate a proliferative smooth muscle response in the media [64]. After 3 to 14 days of proliferation in the media, migration of smooth muscles from the media to the intima begins, which forms the neointima. Once the neointima is formed, these smooth muscle cells rapidly proliferate to form a thick layer, which can eventually obstruct the lumen.

	Chronic Endothelial Cell Injury

Top Footnotes Abstract Introduction Normal Vascular Form and... Vasomotor Dysfunction Coagulation Neutrophil-Endothelial Cell... Intimal Hyperplastic Response to... Chronic Endothelial Cell Injury Conclusion References

 
Atherosclerosis is the principal cause of death in the western world and the main indication for patient referral to cardiothoracic surgeons. In 1973 Ross and Glomset [65] proposed that atherosclerosis resulted from an endothelial cell response to chronic injury that leads to neutrophil, lymphocyte, platelet, and macrophage adhesion and migration into the subendothelium. Subsequently these cells orchestrate the molecular and cellular events that lead to progressive reductions in arterial lumenal size. Common sources of chronic endothelial cell injury include nicotine, hypertension, diabetes, and hypercholesterolemia, all of which are independent risk factors for the development of atherosclerosis. Furthermore, chronic transplant rejection is associated with an widespread endothelial cell insult that leads to an accelerated form of diffuse atherosclerois. Investigators have shown that these forms of endothelial cell injury funnel down to several mechanisms that lead to increased vessel wall mass. These common mechanisms result from the damaging effects of platelet, neutrophil, lymphocyte, and monocyte adhesion to the injured endothelial cell layer.

Endothelial cells are unique in that they grow as a strict monolayer and halt proliferation in response to contact inhibition [7]. When they are injured they attempt to proliferate and stretch into the wound to reestablish contact [7]. In models of chronic injury, it is hypothesized that endothelial cells lose their capacity to replicate, resulting in an area of chronic subendothelial exposure, which allows neutrophils, lymphocytes, platelets, and macrophages to adhere and smooth muscle cells to proliferate to cover the denuded area [10]. Experimental observations have confirmed that these inflammatory cells become activated, causing them to release agents that attract smooth muscle cells. Disruption of the endothelium may be particularly marked at areas such as branches and bifurcation, where advanced proliferative lesions are often found [66]. High levels of glucose, as seen in diabetics, can impair endothelial cell replication and accelerate cell death of endothelial cells in culture [67]. Chronic forms of endothelial cell injury can result in the prolonged expression of leukocyte adhesion molecules that attract neutrophils to the area. The presence of leukocytes in the vessel wall can lead to the release of oxygen-derived free radicals, proteases, and cytokines that further disrupt the subendothelium and cause smooth muscle cell proliferation. In atherosclerosis there is evidence of reduced NO in response to acetylcholine [68]. This may contribute to vascular spasm with increased shear stress, loss of the antimitogenic effects of NO that help reduce smooth muscle cell proliferation, increased platelet adherence, and thrombosis. The mechanism of reduced NO production in atherosclerosis is still under investigation but may depend in part on the direct effects of oxidized low-density lipoproteins [69].

With time these inflammatory cells accumulate in response to chronic endothelial cell injury. Atherosclerotic plaques develop grossly, beginning as fatty streaks, which consists of lipid-filled macrophages, or foam cells [7]. These fatty streaks progress to fibrous plaques as a dense capsule encompasses the proliferating smooth muscle cells. Progression of atherosclerotic lesions is thus marked by the accumulation of alternating layers of smooth muscle cells and lipid-laden macrophages [10]. The migrating and proliferating foam cells and smooth muscle cells intrude into the lumen of the artery and compromise blood flow [7]. In late lesions the layers of fibrous tissue and smooth muscle cells cover a core of lipid and necrotic debris [10]. These plaques are prone to rupture, which leads to occlusive platelet thrombi, acute myocardial infarction, and sudden death [7].

	Conclusion

Top Footnotes Abstract Introduction Normal Vascular Form and... Vasomotor Dysfunction Coagulation Neutrophil-Endothelial Cell... Intimal Hyperplastic Response to... Chronic Endothelial Cell Injury Conclusion References

 
Various forms of endothelial cell injury occur commonly and can alter the course of the cardiovascular surgery patient both acutely and chronically, locally and systemically. Because of the wide impact of endothelial cell dysfunction in patients with cardiovascular disease, issues pertaining to endothelial biology are in the forefront of research that will have an effect on the current and future practice of cardiothoracic surgery. Recent discoveries in the field of vascular biology have allowed an expanded understanding of the pathogenesis of many of the acute and chronic complications of patients referred for cardiovascular operations as well as novel opportunities for therapeutic intervention. Understanding the endothelial cell responses to injury is therefore central to appreciating the role that dysfunction plays in the preoperative, operative, and postoperative course of nearly all cardiovascular surgery patients.

This review was intended to be a brief introduction to the major topics of vascular biology that are of importance to the practicing cardiothoracic surgeon. The roles of the endothelium in regulating vascular tone, coagulation, leukocyte adhesion, and smooth muscle proliferation were singled out because of the critical elements these host defenses play in the recovery or demise of our patients. Although all are related by the common thread of the endothelial cell response to injury, the study of vasomotor tone, coagulation, inflammation, and the fibroproliferative response have evolved into specialty areas of research expertise, which are more fairly considered in greater detail on their own. In the reviews that follow we have assembled the current literature that details the importance of endothelial cell injury in cardiovascular surgery in each of these major categories of endothelial cell biology. The authors have focused their analysis on the impact endothelial injury has on the preoperative, operative, and postoperative course of cardiothoracic surgery patients. We hope that these reviews will serve as a detailed reference point for cardiothoracic surgeons as they evaluate the ever-accumulating research and new therapies that stem from the study of the endothelium in response to cardiothoracic operations.

	Footnotes

Top Footnotes Abstract Introduction Normal Vascular Form and... Vasomotor Dysfunction Coagulation Neutrophil-Endothelial Cell... Intimal Hyperplastic Response to... Chronic Endothelial Cell Injury Conclusion References

 
Address reprint requests to Dr Verrier, Division of Cardiothoracic Surgery, Department of Surgery, University of Washington, 1059 Pacific Ave NE, Box 356310, Seattle, WA 98195 (E-mail: verriere{at}ctd.surgery.washington.edu).

	References

Top Footnotes Abstract Introduction Normal Vascular Form and... Vasomotor Dysfunction Coagulation Neutrophil-Endothelial Cell... Intimal Hyperplastic Response to... Chronic Endothelial Cell Injury Conclusion References

 

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