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Ann Thorac Surg 2002;73:1002-1008
© 2002 The Society of Thoracic Surgeons

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Review

The endothelium in clinical cardiac transplantation

^a The Cardiothoracic Transplant Unit, Papworth Hospital, Cambridge, United Kingdom

* Address reprint requests to Mr Large, Papworth Hospital, Papworth Everard Cambridge CB3 8RE, United Kingdom
e-mail: stephenrlarge{at}hotmail.com

	Abstract

Top Abstract Introduction Surgical physiology of the... Transplantation pathophysiology Treatments and future areas Conclusion Acknowledgments References

 
Cardiac transplantation is the most successful therapy for refractory heart failure, but clinical transplantation is still confronted with the problems of acute rejection and acute pump failure. The limiting factor in achieving prolonged survival remains cardiac allograft vasculopathy. In recent years it has become apparent that from brain death onward, the cardiac endothelium plays a key role in these acute and chronic events. Brain death is associated with an inflammatory response that primes the endothelium for cumulative injury during the subsequent stages of ischemic cold storage, reperfusion and allorecognition. As a structural and functional interface, the endothelium is the site at which inflammatory cells move from the bloodstream through the vessel wall into the parenchyma. The endothelium interacts with the complement system, the coagulation and inflammatory cascades, circulating leukocytes, the immune system, the smooth muscle in the vessel wall, and the surrounding matrix and cardiomyocytes. A better understanding of its many roles may lead to expansion of our therapeutic possibilities and better outcomes overall. This article reviews the possible roles of the endothelium in relation to cardiac transplantation, and discusses the diagnostic and therapeutic modalities that are available to date.

	Introduction

Top Abstract Introduction Surgical physiology of the... Transplantation pathophysiology Treatments and future areas Conclusion Acknowledgments References

 
For decades the endothelium was viewed as a semipermeable membrane, separating the lumen from the smooth muscle of the vessels or from the interstitium. In recent years the picture has changed. Cardiac surgery involves a daily interaction with the coronary endothelium but transplantation is one of the areas in which the complexity of the endothelium is perhaps best illustrated. Seen simply as a monolayer, it is the membrane separating the transplanted organ from the recipient. This review aims to summarize the current laboratory and clinical experience on the role of the endothelium in cardiac transplantation. A synopsis of generic functions is initially presented, followed by a summary of diagnostic and experimental methods. Finally, the endothelial changes are described in chronological order from the moment of brain death onward to transplantation and chronic vasculopathy. The key message is the following: early events result in endothelial priming and increased susceptibility to cumulative injury, involving the whole allograft. Myocardial and endothelial preservation should become inseparable notions.

	Surgical physiology of the endothelium

Top Abstract Introduction Surgical physiology of the... Transplantation pathophysiology Treatments and future areas Conclusion Acknowledgments References

 
The endothelium is a monolayer organ covering an immense area of several square meters [1]. It responds to a variety of physical and humoral stimuli with a large repertoire of molecules expressed and secreted. Physiologically, it is equipped to take part in vasoregulation, inflammation, immune interaction, coagulation, fibrinolysis, and angiogenesis. In addition to its generic functions, the endothelium has a heterogeneous phenotype and embraces organ-specific roles [2, 3]. In the coronary circulation it has adapted to supplying oxygen and energy substrates to this most metabolically active tissue [4]. The coronary circulation is frequently involved by arteriosclerosis and there is increasing evidence that endothelial dysfunction represents an early event that initiates the disease process [5]. This is of interest to all those involved in transplantation as the main limiting factor for long-term survival is chronic vasculopathy, which resembles arteriosclerosis [6].

Shear stress from the bloodstream is constantly "sensed" by the endothelium. The physiologic vasoregulators responsible for this are nitric oxide (NO), endothelin, angiotensin II, and prostacyclin [2, 7, 8]. Nitric oxide is made by three isoforms of NO synthase (nNOS, neuronal; eNOS, endothelial; iNOS, inducible) and diffuses isotropically through cell membranes [9]. This property of NO makes cause and effect studies particularly difficult. Its vasodilatory effects are mediated through multiple pathways by cyclic guanosine monophosphate (GMP), interaction with redox-sensitive potassium channels, and inhibition of endothelin [8]. Endothelin, a powerful vasoconstrictor originating in the endothelium, acts not so much as a circulating hormone but in an auto/paracrine fashion [10]. Cardiac NO and endothelin are known to interact with inflammatory effectors [6, 11]. In addition there is compelling evidence that perturbation of NO homeostasis, particularly through redox signaling pathways, is capable of initiating arteriosclerosis [5, 11].

The endothelium performs many of its functions by surface adhesion molecules, the distribution and roles of which have become better understood. Selectins, integrins, and members of the immunoglobulin superfamily are expressed on platelets, leukocytes, endothelia, and subendothelial matrix. Coupling of a ligand to its receptor is rarely sufficient to initiate a certain cell program, similar to T cells, which require two or more signals to become activated [12]. Adhesion molecules interact "promiscuously" with a range of ligands and a phenomenon such as leukocyte extravasation or apoptosis depends on a whole repertoire of membrane and subcellular events [13]. When the mechanism of leukocyte rolling, adhesion, and particularly tissue extravasation is completely characterized, it will be possible to interfere with diapedesis at different checkpoints [14].

The interaction between the complement system and the endothelium is bidirectional. The normal endothelium is able to inactivate complement through a range of mechanisms [1]. On the other hand, activated complement products are able to bind to the endothelium through specific receptors and subsequently promote vasoregulation, inflammation, and coagulation, all of which are intimately related processes. The endothelium is physiologically an anticoagulant surface with the contribution of the antithrombin III and the thrombomodulin-protein C-protein S systems [15]. Endothelial dysfunction is associated with varying degrees of antithrombin III and thrombomodulin downregulation. Thrombin is a pleiotropic agent with actions far exceeding the enzymatic serine protease function [16–20]. It has mitogenic and proinflammatory properties mediated by transmembrane signaling through protease-activated receptors, four types being described to date [19]. The endothelium is capable of expressing different protease-activated receptors [19]. Protease-activated receptor-2 expression for instance has recently been shown to be protective against ischemia-reperfusion (IR) injury in the rat myocardium [20]. The platelets, no longer seen as "innocent bystanders," exhibit chemotactic and mitogenic properties [16]. Platelet-endothelial cell adhesion molecule (PECAM-1) (CD31), normally expressed on all endothelia, facilitates interaction with activated platelets [17]. The endothelium is also an immunologic interface: its antigen-presenting properties and the capacity for apoptosis induction in leukocytes are highly relevant to transplantation (discussed later) [12, 21].

Noxious stimuli generally elicit a two-stage endothelial response. Initially constitutive molecules (eg, intercellular adhesion molecule-2 [ICAM-2]) or other proteins that can be mobilized readily from underneath the cell membrane (eg, P-selectin stored in the Weibel-Palade bodies) are involved. This phase (also called type 1 activation) does not involve de novo protein synthesis, as opposed to the second phase (type 2 activation), which is transcription dependent and takes place after 4 hours or more [22]. The mechanism of endothelial activation in cardiopulmonary bypass and in IR has been described elsewhere [23–27]. We shall focus next on issues particular to transplantation.

Before proceeding to discuss research findings, it is important to summarize the experimental and clinical methods of studying the endothelium (Table 1) and the expression of the more important cell adhesion molecules in the normal human heart (Table 2). Extrapolation of experimental research to clinical practice requires a cautious and methodical approach. Here is just one example. As opposed to the coronary microcirculation of humans, rodents (and also the human umbilical vein) do not express major histocompatibility complex class II constitutively on the endothelium [12]. This feature may make it easier to suppress rejection in rodent experiments.

	Transplantation pathophysiology

Top Abstract Introduction Surgical physiology of the... Transplantation pathophysiology Treatments and future areas Conclusion Acknowledgments References

Ischemia
It is claimed that discussion of ischemia without reperfusion is of academic interest only. Nevertheless, it is useful to separate the extent of these phenomena in the experimental setting to be able to understand their independent contribution to injury. Pinsky and colleagues [33] elegantly showed how hypoxia alone is sufficient to induce exocytosis of the Weibel-Palade bodies, with expression of von Willebrand factor and P-selectin on to the cell membrane in a time-dependent fashion. They also demonstrated the key role of P-selectin in neutrophil recruitment in a rat isograft model of cardiac transplantation. P-selectin null hearts transplanted into wild-type recipients had marked reduction in neutrophil infiltration and increased graft survival compared with wild-type control transplants. Hypoxia alone, if severe and prolonged, produces a significant alteration in endothelial permeability [34]. Hypoxia may downregulate basal VCAM-1 and ICAM-1 [35], but the combination of hypoxia and inflammatory stimuli is able to enhance ICAM-1 expression [36, 37].

During ischemia the cell switches to anaerobic metabolism and the energy stores are used for vital cell functions. Hypothermia is an effective strategy to reduce metabolism overall but the duration of cold storage is, of necessity, finite. Adenosine triphosphate depletion after prolonged ischemia, like in the more extensively studied cardiomyocytes, will directly affect the ATP-dependent pumps and lead to alteration of ionic and osmotic gradients across the cell membrane. Catabolism of high-energy phosphates produces hypoxanthine that, upon reperfusion, is one of the most powerful generators of oxygen radicals [38]. The fate of the cell on reperfusion depends on the extent of ischemia and the capacity of physiologic scavengers. Lesser degrees of ischemia, in combination with reperfusion, will create a highly reactive endothelial phenotype.

Reperfusion
The redox state of the vasculature influences gene expression in an adaptive fashion [39]. Oxygen radicals represent more than noxious stimuli or effectors of bacterial killing in phagocytic blood cells. At lower levels, commonly referred to as oxidative stress, they may function as second messengers in intricate mechanisms of signal transduction and transcription control. Nuclear factor-B (NF-B) and activator protein-1 are the most extensively studied redox-sensitive transcription factors. It is unlikely that oxygen radicals directly activate the transcription factors. The probability is that activation takes place through protein phosphorylation pathways. The NF-B regulates a multitude of cytoprotective genes and, due to its central position, might be ideally suited to therapeutic inhibition [24, 40]. Some of the convergent pathways of IR injury are mentioned below.

Collard and colleagues [41] showed in a human umbilical vein endothelial cell preparation that prolonged hypoxia produces NF-B translocation to the nucleus, which further increases during reoxygenation. In addition it appears that the ensuing protein synthesis leads to a neo-epitope expression in the membrane followed by iC3b complement deposition and activation through the classic pathway. The activation of complement in IR is multifactorial, especially in transplantation, but far from innocuous [1, 27].

Neutrophils are the main bloodstream mediators of IR, and their recruitment is greatly facilitated by phenotypic changes in the ischemic tissues. The ischemic myocardium is able to secrete a variety of leukotactic substances, including tumor necrosis factor- (TNF-), interleukin-8 (IL-8), IL-6, platelet-activating factor, complement, and leukotrienes [26, 42]. IR can rapidly induce selectin ligand expression on to the surface of cardiomyocytes and cultured endothelial cells [43]. ICAM-1 is unaffected by hypoxia in the coronary endothelium, but reoxygenation produces marked upregulation through a NF-B-mediated pathway. Nitric oxide is able to reduce reoxygenation-specific ICAM-1 expression, probably by diminishing oxidative stress [44]. The same group of Kupatt and colleagues [42], using NF-B decoy oligonucleotides, were then able to block ICAM-1 upregulation and neutrophil adhesion to rodent coronary endothelium. Feeley and associates [40] used the same method of NF-B inhibition in a transplant experiment and demonstrated reduced endothelial adhesiveness and a decrease in acute and chronic allograft rejection. In a murine cardiac isograft model, which avoids allorecognition bias, the positive feedback loop established between ICAM-1 and IL-1 after reperfusion may be pivotal to primary graft failure [45]. Jaakkola and colleagues [46] recently performed a study on ischemic and reperfused human myocardium showing the distribution of salient CAMs and their role in leukocyte binding.

Cardiopulmonary bypass and reperfusion with nonautologous blood are the two other factors adding to the complexity of the IR phenomenon in cardiac transplantation. In the inflammatory responses associated with cardiopulmonary bypass, complement activation and circulating cytokines are instrumental to subsequent cell-cell interactions and tissue extravasation [23]. Because of the sequence of events described so far it is conceivable, although not demonstrated, that the reperfused donor heart has a higher inflammatory load than native hearts in conventional cardiac surgery.

Allorecognition and acute rejection
All the microvascular and small vessel endothelial cells constitutively express major histocompatibility complex class II antigens [12], further upregulated by IR along with major histocompatibility complex class I [47]. The work of Rose [12] actually demonstrated that endothelial cells are able to cause allostimulation of T cells, which is strongly suggestive of their antigen-presenting abilities. The dendritic cells are the main antigen presenters in T-cell allorecognition and their activation may take place in the donor even before organ procurement [28, 47]. Land [47] reviewed the processes of stimulation, costimulation, and adhesion that underlie direct allorecognition and acute rejection. Recipient T cells and donor dendritic cells are normally separated by the endothelial monolayer. The endothelium, however, is far from inert after IR and has the ability to specifically interact with T lymphocytes by VCAM-1 or Fas ligand [21, 48]. Fas (CD95/APO-1) is a "death receptor" expressed on most cell types, including leukocytes. On the other hand, Fas ligand, a member of the type II membrane proteins like TNF-, is restricted in its expression to immune privileged sites (eg, eye, testis) and the endothelium. The Fas-Fas ligand system has a physiologic role in lymphocyte apoptosis by limiting antigen-activated lymphocyte extravasation. This function diminishes in TNF-mediated inflammation [21]. Modulation of the Fas ligand in target transplant tissue has so far led to conflicting results but will undoubtedly receive increasing attention [49, 50]. How acute rejection and episodes of infection, particularly with cytomegalovirus, subsequently lead to repeated endothelial cell activation has been well described and is beyond the scope of this review [27, 51].

Protective mechanisms
It is now relevant to mention some of the defense mechanisms mounted in response to this cumulative injury. A complex intracellular dialogue decides upon life or death of the individual cell. The bcl family of genes is involved in cytoprotection both through their antiapoptotic properties but also by downregulation of proinflammatory genes through NF-B inhibition [52]. Heat shock proteins are another group of "molecular chaperones," the induction of which is associated with enhanced mechanical and endothelial function after cardiac ischemia. Amrani and colleagues [53] showed that the coronary endothelium is the main site of 70-kD heat shock protein induction in the rat heart. The heme oxygenases are proteins involved in reducing oxidative stress, with induction of heme oxygenase-1 having protective effects in terms of reduced leukocyte adhesion in vitro [54].

Given the extent of the insult, what are the functional consequences for the transplanted heart? In the immediate postoperative period they can range from subclinical to lethal as a result of acute allograft failure or rejection. Acute pump failure is not necessarily a consequence of energy store depletion and it has been recognized in an unpredictable fashion even in association with domino donation or short ischemic times. A no reflow phenomenon in the microcirculation has long been implicated in an the pathogenesis of the syndrome [38]. In a series of animal experiments, Murphy’s group [55] demonstrated how the right ventricular microvasculature is affected more than in the left ventricle by the sequence of cold storage and reperfusion. Indeed, in clinical practice postoperative right ventricular dysfunction is still relatively common. The key to preventing it might be better preservation of the endothelium. We have analyzed elsewhere different preservation experiments and clinical strategies, few of which provide for the endothelium (Stoica SC, Satchithananda DK, Dunning J, Large SRL, unpublished). No preservation solution or method has emerged as superior so far [56, 57] and, with equal short-term outcomes, their efficacy should also be judged against the ability to prevent CAV.

Chronic rejection
For a detailed discussion of immune and alloantigen independent risk factors see the reviews by Weis and von Scheidt [6] and Häyry [58]. As expected, the endothelium is kept in a chronic state of low key inflammation and mediates proliferative events that take place in the surrounding smooth muscle and matrix. Andreassen and colleagues [59] showed that serum levels of TNF-, P-selectin, and VCAM-1 were persistently elevated in patients followed up for up to 2 years after transplantation. Most of the proinflammatory genes already mentioned are expressed in CAV, including evidence of Fas-mediated cytotoxicity [58, 60, 61]. In a rat model of accelerated CAV, Koskinen and Lemström [60] showed that P-selectin and VCAM-1 are significantly upregulated during acute and chronic rejection. A unifying view is now emerging according to which the perioperative phase, the acute and the chronic rejection represent a continuum of events [47, 62]. It is based in turn on a novel approach to the immune response, which is not primarily triggered by recognition of nonself but by danger and tissue destruction in a wider sense. In an attempt to separate the immune factors, Wang and associates [63] used a murine model of transplantation and demonstrated that IR injury is on its own sufficient to induce CAV in isografts and that CAV was greatly accelerated in an allograft milieu. Furthermore, cyclic adenosine monophosphate pulse therapy during preservation was able to inhibit CAV, but the mechanism remains unknown. Interestingly, acute and chronic rejection also depend on the cytokine and growth factor genotypes, a good example being the reduced incidence of CAV in donor or recipients who are low producers of transforming growth factor-ß [64, 65]. The recipient may also influence the degree of allograft loss by production of antiendothelial and anti-human leukocyte antigen (HLA) antibodies, although the precise mechanism is not yet deciphered [12, 66–68]. Very probably, the individual genotype affects all phases of peritransplant endothelial cell activation and more studies in this area are expected.

Early endothelial dysfunction appears to be transitory in terms of vasomotion [69], but is predictive of development of CAV at 1 year postoperatively [70]. As a result many efforts are directed toward the enhanced inflammatory state posttransplant and toward predicting CAV before it is clinically apparent [10, 59, 71, 72]. Weis and colleagues [10] established a relationship between endothelial vasomotion and perturbation of endothelin physiology early after transplantation. Another study from the same group in Munich showed that 26% of their patients had microvascular endothelial dysfunction within 1 month of transplantation and postulated that abnormalities in the NO synthesis pathways and increased levels of circulating cytokines might be partly responsible [71]. To date it is unclear whether iNOS has a protective or a causative role in the development of CAV [9]. Other tissue or serum markers of CAV have been investigated. For example, a coagulant phenotype in the allograft microvasculature is predictive of CAV [72]. The therapeutic options in CAV are very limited and the outcome is universally fatal [6]. Therefore, prevention and slowing down the progression of disease appear as the best strategies. In this sense, lipid-lowering agents are known for their direct antioxidative effect on the endothelium and are routinely given after transplantation [59].

	Treatments and future areas

Top Abstract Introduction Surgical physiology of the... Transplantation pathophysiology Treatments and future areas Conclusion Acknowledgments References

 
Myocardial protection intraoperatively and immunosuppressive therapy after the operation have solely been unable to generate excellent long-term outcomes for cardiac transplantation. In the injury sequence to the allograft the endothelium holds a pivotal position and should be one of the main targets for intervention (Table 3). The literature abounds with studies in which a given intervention is made in one particular transplant phase in an experimental or clinical set-up. We are now faced with the challenge to transform this body of knowledge into a comprehensive strategy of preservation.

	Conclusion

Top Abstract Introduction Surgical physiology of the... Transplantation pathophysiology Treatments and future areas Conclusion Acknowledgments References

	Acknowledgments

Top Abstract Introduction Surgical physiology of the... Transplantation pathophysiology Treatments and future areas Conclusion Acknowledgments References

 
Serban C. Stoica is supported by a research grant from the Garfield Weston Foundation.

	References

Top Abstract Introduction Surgical physiology of the... Transplantation pathophysiology Treatments and future areas Conclusion Acknowledgments References

 

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