HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Verrier, E. D. Articles by Morgan, E. N. Search for Related Content PubMed PubMed Citation Articles by Verrier, E. D. Articles by Morgan, E. N.

Ann Thorac Surg 1998;66:S17-S19
© 1998 The Society of Thoracic Surgeons

Endothelial response to cardiopulmonary bypass surgery

^a Division of Cardiothoracic Surgery, Department of Surgery, University of Washington, Seattle, Washington, USA

Address reprint requests to Dr Verrier, Cardiothoracic Surgery, University of Washington, 1959 NE Pacific St, Box 356310, Seattle, WA 98195

Presented at "Risk Management in CABG: Significant Surgical Considerations," New Orleans, LA, Jan 24, 1998.

	Abstract

Top Abstract Introduction Normal vascular form and... Vascular tone and vasospasm Coagulation and fibrinolysis Neutrophil-endothelial... Intimal hyperplasia and chronic... Treatment goals for endothelial... Conclusion References

 
Background. The vascular endothelium has been shown to actively participate in maintaining normal cardiovascular homeostasis by influencing the regulation of membrane permeability, lipid transport, vasomotor tone, coagulation, fibrinolysis, and inflammation. Endothelial cells are very responsive to a wide range of local and systemic stimuli that occur during cardiopulmonary bypass (CPB) operation. Major pathologic conditions result from impaired vascular function secondary to CPB, including vasospasm, coagulopathy, and widespread neutrophil adhesion secondary to a systemic inflammatory response. Additionally, more chronic responses to endothelial cell injury include the development of intimal hyperplasia and arteriosclerosis, both of which limit the long-term success of coronary artery bypass grafting.

Methods. Because of the increasingly recognized role of the endothelium in the maintenance of normal cardiovascular function, this article will review the normal structure and function of the endothelium, as well as the major pathologic conditions that result in response to CPB.

Results. Potential treatments to counteract endothelial cell dysfunction secondary to CPB are under active investigation. Strategies may be directed toward blocking single cytokines, integrins, or adhesion molecules involved in endothelial dysfunction or, alternatively, toward targeting a molecular event that governs the expression of these proinflammatory, procoagulant, and vasoactive genes. In our laboratory, we have used both strategies to study the pathologic response to CPB. We blocked neutrophil adhesion in subhuman primates with a monoclonal antibody. Alternatively, we targeted the transcriptional activation of multiple genes involved in the endothelial cell’s response to CPB.

Conclusions. Although both therapies help elucidate the multiple, redundant pathways involved in the pathologic response to CPB, it is through molecular biology that we are beginning to understand the mechanics of transcriptional control and translational expression that occurs in the endothelial cell in response to CPB. This knowledge will allow the development of therapies that inhibit not a single cytokine or adhesion molecule, but rather an array of substances that result in the endothelial cell’s pathologic response to CPB.

	Introduction

Top Abstract Introduction Normal vascular form and... Vascular tone and vasospasm Coagulation and fibrinolysis Neutrophil-endothelial... Intimal hyperplasia and chronic... Treatment goals for endothelial... Conclusion References

 
During the last decade, the vascular endothelium has been shown to actively participate in maintaining normal cardiovascular homeostasis. This biologic structure is no longer considered an inert barrier separating the blood from the body’s tissues. Extensive research has revealed that the endothelium plays a major role in regulating membrane permeability, lipid transport, vasomotor tone, coagulation, fibrinolysis, and inflammation [1–6]. This regulation is achieved by the expression of endothelial-derived surface proteins or secretion of biologically active soluble factors.

Endothelial cells are extremely sensitive to insults that occur during cardiopulmonary bypass (CPB). These insults include hypoxia, which occurs when the heart is arrested to allow surgical procedures in a bloodless, motionless field. Also, the endothelium is frequently exposed to inflammatory stimuli such as cytokines and endotoxin, as well as to physical injury in the form of surgical manipulation or hemodynamic shear stress. All of these insults cause endothelial cells to rapidly alter their phenotype, a response termed endothelial cell activation. This response leads to disruption of barrier function, enhanced vasoconstriction, abnormal coagulation, leukocyte adhesion, and smooth muscle proliferation [7, 8]. Teleologically, these changes serve protective purposes; however, in the case of CPB, when the stimuli are severe, this same response is excessive, resulting in damaged tissue, impaired organ function, and an abnormal fibroproliferative response.

The forms of endothelial cell dysfunction may be classified as chronic or acute. Hypertension, smooth muscle proliferation, intimal hyperplasia, and arteriosclerosis are important examples of chronic abnormalities in endothelial cell function affecting the long-term success of coronary artery bypass grafting. The acute response of endothelial cells to CPB results in systemic inflammation, coagulation abnormalities, and vasomotor changes that may all be critically important to perioperative outcome. Discussed here are the normal structure and function of the endothelium and vessel wall, as well as the major pathologic conditions resulting from impaired vascular function that are of importance to the practicing cardiothoracic surgeon.

	Normal vascular form and function

Top Abstract Introduction Normal vascular form and... Vascular tone and vasospasm Coagulation and fibrinolysis Neutrophil-endothelial... Intimal hyperplasia and chronic... Treatment goals for endothelial... Conclusion References

 
The endothelium is a fascinating organ. Because of its strategic location between blood and interstitial tissues, the endothelium is in a unique position to regulate both intravascular and extravascular events. Endothelial cells provide a permeability barrier through which exchange of substances occurs by both nonspecific and ligand-directed transcytosis [9]. In addition to regulating barrier function, the endothelium promotes structural changes of the vessel in response to changes in the local environment. These phenomena are accomplished through maintenance of a delicate balance between growth factors and growth inhibitors that are produced by endothelial cells.

When subjected to cellular stress (either oxidative or infectious), the endothelial cell undergoes a phenotypic change recognized as endothelial cell activation. This activation consists of an immediate and a delayed response. The immediate response deploys inflammatory mediators that are stored in cytoplasmic vacuoles termed Weibel-Palade bodies. The delayed response involves transcriptional activation of several genes and new protein expression on the endothelial cell surface during the course of several hours. On a local basis, these phenomena act to isolate and neutralize infection and injury. When endothelial cell activation occurs on a more diffuse basis, as occurs in the inflammatory response to CPB, the end result may be end-organ damage and dysfunction. Discussed here will be the pathologic sequelae secondary to widespread endothelial cell activation in response to CPB.

	Vascular tone and vasospasm

Top Abstract Introduction Normal vascular form and... Vascular tone and vasospasm Coagulation and fibrinolysis Neutrophil-endothelial... Intimal hyperplasia and chronic... Treatment goals for endothelial... Conclusion References

 
Vascular tone is maintained by the production of substances that exert opposing effects, either locally or remotely, to increase or decrease the degree of vasoconstriction. Relaxant factors such as nitric oxide, prostacyclin, and adenosine are balanced against the factors that promote increased vascular tone, such as endothelin, leukotrienes, and angiotensin II [10]. Many patients undergoing coronary artery bypass graft operations have preexisting conditions that predispose to increased vascular tone. In addition, a number of stimuli encountered during the intraoperative and postoperative periods, for example, CPB, surgical manipulation, and ischemia-reperfusion, result in activation of endothelial cells. The balance is tipped toward vasoconstriction by the loss of the ability to promote vasodilation and increased production of potent constrictor substances. This increased vascular reactivity can predispose to native coronary artery or grafted vessel spasm or to microcirculation no-reflow. The net result is increased myocardial injury.

	Coagulation and fibrinolysis

Top Abstract Introduction Normal vascular form and... Vascular tone and vasospasm Coagulation and fibrinolysis Neutrophil-endothelial... Intimal hyperplasia and chronic... Treatment goals for endothelial... Conclusion References

 
The vascular endothelium has multiple mechanisms to provide an anticoagulant surface. Antithrombotic mechanisms include (1) secretion of vasoactive substances such as prostaglandin I₂ and adenosine to maintain vasodilation and prevent platelet adhesion and aggregation; (2) endothelial surface expression of heparin like substances to potentiate the action of antithrombin III, thereby preventing fibrin formation; (3) the constitutive expression of tissue plasminogen activator to catalyze plasmin generation and lysis of local fibrin clot formation; and (4) the expression of thrombomodulin, which actively prevents coagulation by binding protein C, also resulting in the inhibition of factors V and VIII [11].

Endothelial cell activation that occurs in response to CPB shifts the endothelial anticoagulant phenotype to a procoagulant phenotype by increasing the expression of tissue factor on the endothelial surface. Tissue factor binds to factor VIIa, which initiates the critical conversion of factor X to factor Xa, leading to the generation of thrombin. Diffuse tissue factor expression, therefore, likely results in widespread fibrin deposition in the microvasculature. In concert with increased expression of tissue factor, thrombomodulin is downregulated to enhance the procoagulant phenotype. Alternatively, increased release of tissue plasminogen activator may lead to difficulties in clotting in some patients.

	Neutrophil–endothelial interaction

Top Abstract Introduction Normal vascular form and... Vascular tone and vasospasm Coagulation and fibrinolysis Neutrophil-endothelial... Intimal hyperplasia and chronic... Treatment goals for endothelial... Conclusion References

 
In addition to altering vasomotor tone and coagulation, endothelial cell activation also includes the expression of surface proteins that promote leukocyte–endothelial cell interactions. This process includes the initial tethering of circulating leukocytes through the endothelial cell’s immediate release of P-selectin. It is followed by the firm, high-affinity bond between the adhesion molecules expressed on the surface of the activated endothelium and the integrin expressed on the neutrophil’s surface. Subsequent infiltration of the neutrophil into the perivascular tissue results in the release of oxygen-derived free radicals, proteases, and elastases, leading to nonspecific cellular damage [12]. On a local basis, this process, although destructive, is protective. On a systemic basis, as occurs in CPB, end-organ damage occurs because of neutrophil adhesion throughout entire vascular beds.

	Intimal hyperplasia and chronic endothelial cell injury

Top Abstract Introduction Normal vascular form and... Vascular tone and vasospasm Coagulation and fibrinolysis Neutrophil-endothelial... Intimal hyperplasia and chronic... Treatment goals for endothelial... Conclusion References

 
The long-term success of arterial graft operation may be limited by intimal hyperplasia. This is a reparative process at the site of vessel injury; however, if the injury is excessive, exaggerated proliferation of the neointima will occur, the natural anticoagulant properties will be lost, and luminal narrowing, restricted blood flow, and thrombosis may result.

Chronic endothelial cell injury from sources such as nicotine, hypertension, diabetes, and hypercholesterolemia can lead to an arteriosclerotic response. Neutrophils, lymphocytes, platelets, and macrophages adhere and migrate into the subendothelium. Activation of these inflammatory cells and further damage to the subendothelium attract smooth muscle cells. Atheromatous plaques begin as fatty streaks consisting of lipid-filled macrophages or foam cells and progress to fibrous plaques as the proliferating smooth muscle cells are encompassed. Blood flow is compromised as intrusion into the lumen of the artery occurs; in late lesions, the plaques are prone to rupture, leading to acute myocardial infarction and sudden death.

	Treatment goals for endothelial cell activation in cardiovascular surgery

Top Abstract Introduction Normal vascular form and... Vascular tone and vasospasm Coagulation and fibrinolysis Neutrophil-endothelial... Intimal hyperplasia and chronic... Treatment goals for endothelial... Conclusion References

 
During cardiac operations and, in particular, as a result of CPB, endothelial cells become activated, and normally protective responses become excessive, often leading to disrupted barrier function, enhanced vasoconstriction, coagulation, leukocyte adhesion, and smooth muscle proliferation.

Today there are several new directions and potential treatments to counteract endothelial cell activation resulting from cardiac operations. Ideally, any treatment used will be short-term and reversible. Additionally, it should not compromise the patient’s ability to fight infection. Strategies to achieve this goal may involve blocking the expression of single inflammatory mediators or adhesion molecules expressed as a result of endothelial cell activation, or alternatively, targeting a critical molecular control point involved in endothelial cell activation (Fig 1).

View larger version (19K): [in this window] [in a new window]   Fig 1. Schematic of endothelial cell activation. Asterisks show potential points of pharmacologic intervention in the prevention of endothelial cell-dependent systemic inflammatory response syndrome associated with cardiopulmonary bypass. (TNF = tumor necrosis factor; VCAM = vascular cell adhesion molecule; NF-kB = nuclear factor kB.)

In addition to focusing on neutrophil blockade, we are now directing our attention toward more proximal molecular events that govern the expression of proinflammatory, procoagulant, and vasoactive genes involved in endothelial cell activation. Specifically, we have focused on the activation of the nuclear transcription factor NF-kB. This transcription factor is a proximal point of convergence for the molecular mechanisms involved in endothelial cell activation. By pharmacologic inhibition of this one cellular protein, reduced expression of the wide array of genes involved in this systemic inflammatory response may result.

	Conclusion

Top Abstract Introduction Normal vascular form and... Vascular tone and vasospasm Coagulation and fibrinolysis Neutrophil-endothelial... Intimal hyperplasia and chronic... Treatment goals for endothelial... Conclusion References

 
Endothelial cell activation occurs commonly in the cardiovascular surgery patient, affecting both acute and chronic events. Local and systemic inflammatory responses are in turn mediated throughout the body by the endothelium, thereby affecting each end organ, and in particular, the heart. Molecular biologists are having an impact on cardiovascular surgery today by establishing a link between specific genes and injury patterns in these patients, by characterizing important regulatory pathways responsible for the expression of these genes, and by evaluating therapies to inhibit these pathways.

	References

Top Abstract Introduction Normal vascular form and... Vascular tone and vasospasm Coagulation and fibrinolysis Neutrophil-endothelial... Intimal hyperplasia and chronic... Treatment goals for endothelial... Conclusion References

 

1. Verrier E.D. The vascular endothelium: friend or foe?. Ann Thorac Surg 1993;55:818-819.[Medline]
2. Luscher T.F., Tanner F.C., Tschudi M.R., Noll G. Endothelial dysfunction in coronary artery disease. Annu Rev Med 1993;44:395-418.[Medline]
3. Lefer A.M., Lefer D.J. Pharmacology of the endothelium in ischemia-reperfusion and circulatory shock. Annu Rev Pharmacol Toxicol 1993;33:71-90.[Medline]
4. Crossman D.C., Tuddenham E.D.G. Procoagulant functions of the endothelium. In: Warren J.B., ed. The endothelium: an introduction to current research. New York: Wiley-Liss, 1990:119-128.
5. Schwartzm S.M., deBlois D., O’Brien E.R. The intima: soil for atherosclerosis and restenosis. Circ Res 1995;77:445-465.[Free Full Text]
6. Harlan J.M. Leukocyte–endothelial interactions. Blood 1985;65:513-525.[Free Full Text]
7. Ross R. Cell biology of atherosclerosis. Annu Rev Physiol 1995;57:791-804.[Medline]
8. Pober J.S., Cotran R.S. Cytokines and endothelial cell biology. Physiol Rev 1990;70:427-451.[Free Full Text]
9. Davies M.G., Hagen P.O. The vascular endothelium: a new horizon. Ann Surg 1993;218:593-609.[Medline]
10. Luscher T. Endothelium-derived vasoactive factors and regulation of vascular tone in human blood vessels. Lung 1990;168(Suppl):27-34.
11. Boyle E.M., Jr, Verrier E.D., Spiess B.D. Endothelial cell injury in cardiovascular surgery: the procoagulant response. Ann Thorac Surg 1996;62:1549-1557.[Abstract/Free Full Text]
12. Boyle E.M., Pohlman T.H., Cornejo C.J., Verrier E.D. Endothelial cell injury in cardiovascular surgery: ischemia-reperfusion injury. Ann Thorac Surg 1996;62:1868-1875.[Abstract/Free Full Text]

This article has been cited by other articles:

				Y F Cheung, X Ou, and S J Wong Central and peripheral arterial stiffness in patients after surgical repair of tetralogy of Fallot: implications for aortic root dilatation Heart, December 1, 2006; 92(12): 1827 - 1830. [Abstract] [Full Text] [PDF]

				M. Chello, C. Goffredo, G. Patti, D. Candura, R. Melfi, S. Mastrobuoni, G. Di Sciascio, and E. Covino Effects of atorvastatin on arterial endothelial function in coronary bypass surgery Eur. J. Cardiothorac. Surg., December 1, 2005; 28(6): 805 - 810. [Abstract] [Full Text] [PDF]

				F. Onorati, L. Cristodoro, P. Mastroroberto, A. di Virgilio, A. Esposito, M. Bilotta, and A. Renzulli Should We Discontinue Intraaortic Balloon During Cardioplegic Arrest? Splanchnic Function Results of a Prospective Randomized Trial Ann. Thorac. Surg., December 1, 2005; 80(6): 2221 - 2228. [Abstract] [Full Text] [PDF]

				A. M. Morariu, Y. J. Gu, R. C.G. G. Huet, W. A. Siemons, G. Rakhorst, and W. v. Oeveren Red blood cell aggregation during cardiopulmonary bypass: a pathogenic cofactor in endothelial cell activation? Eur. J. Cardiothorac. Surg., November 1, 2004; 26(5): 939 - 946. [Abstract] [Full Text] [PDF]

				M. Yada, A. Shimamoto, C. R. Hampton, A. J. Chong, H. Takayama, C. L. Rothnie, D. J. Spring, H. Shimpo, I. Yada, T. H. Pohlman, et al. FR167653 diminishes infarct size in a murine model of myocardial ischemia-reperfusion injury J. Thorac. Cardiovasc. Surg., October 1, 2004; 128(4): 588 - 594. [Abstract] [Full Text] [PDF]

				F. Doguet, P.-Y. Litzler, F. Tamion, V. Richard, M.-F. Hellot, C. Thuillez, A. Tabley, F. Bouchart, and J. P. Bessou Changes in mesenteric vascular reactivity and inflammatory response after cardiopulmonary bypass in a rat model Ann. Thorac. Surg., June 1, 2004; 77(6): 2130 - 2137. [Abstract] [Full Text] [PDF]

				B. Wei, Y. Liu, Q. Wang, C. Yu, C. Long, Y. Chang, and Y. Ruan Lung perfusion with protective solution relieves lung injury in corrections of Tetralogy of Fallot Ann. Thorac. Surg., March 1, 2004; 77(3): 918 - 924. [Abstract] [Full Text] [PDF]

				A. J. Chong, T. H. Pohlman, C. R. Hampton, A. Shimamoto, N. Mackman, and E. D. Verrier Tissue factor and thrombin mediate myocardial ischemia-reperfusion injury Ann. Thorac. Surg., February 1, 2003; 75(2): S649 - 655. [Abstract] [Full Text] [PDF]

				C. Bianchi, E. G. Araujo, K. Sato, and F. W. Sellke Biochemical and Structural Evidence for Pig Myocardium Adherens Junction Disruption by Cardiopulmonary Bypass Circulation, September 18, 2001; 104 (2009): I-319 - I-324. [Abstract] [Full Text] [PDF]

				K. Kottke-Marchant and S. Sapatnekar Hemostatic Abnormalities in Cardiopulmonary Bypass: Pathophysiologic and Transfusion Considerations Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2001; 5(3): 187 - 206. [Abstract] [PDF]

				E. G. Araujo, C. Bianchi, K. Sato, R. Faro, X. A. Li, and F. W. Sellke Inactivation of the MEK/ERK pathway in the myocardium during cardiopulmonary bypass J. Thorac. Cardiovasc. Surg., April 1, 2001; 121(4): 773 - 781. [Abstract] [Full Text] [PDF]

				C Jaggy, M Lachat, B Leskosek, G Zund, and M Turina Affinity pump system: a new peristaltic blood pump for cardiopulmonary bypass Perfusion, January 1, 2000; 15(1): 77 - 83. [Abstract] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Verrier, E. D. Articles by Morgan, E. N. Search for Related Content PubMed PubMed Citation Articles by Verrier, E. D. Articles by Morgan, E. N.