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Ann Thorac Surg 1996;62:1222-1228
© 1996 The Society of Thoracic Surgeons

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Current Review

Endothelial Cell Injury in Cardiovascular Surgery: The Pathophysiology of Vasomotor Dysfunction

Divisions of Cardiothoracic Surgery, Departments of Surgery of Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts, and the University of Washington, Seattle, Washington

Accepted for publication May 16, 1996.

	Abstract

Top Footnotes Abstract Introduction Resting Vasomotor Tone Coronary and Graft Reactivity... Microcirculatory Vasomotor... Systemic Vasomotor Alteration Clinical Effects and Therapeutic... Acknowledgments References

 
Impaired vasomotor function has been suggested as playing a role in the pathophysiology of hypertension, diabetes, hypercholesterolemia, and atherosclerosis, all of which are common in cardiovascular surgery patients. In addition to chronic vasomotor dysfunction, alterations in vasomotor tone can result in acute arterial spasm, microcirculatory ischemia, and wide variations in systemic blood pressure. Changes in the health of the vascular endothelium may also impact the late patency of coronary artery bypass grafts, the progression of atherosclerosis in the native coronary circulation, and the long-term success of cardiac transplants. In the resting state the endothelium produces several substances that promote vascular relaxation and inhibition of platelet function, thus assuring the unhindered flow of blood through the capillaries. In response to injury, the endothelium loses some capacity to relax and also releases powerful vasoconstrictive agents. Attempting to understand the contributions that these substances play in the vasomotor dysfunction seen after cardiothoracic surgery is an area of active investigation.

	Introduction

Top Footnotes Abstract Introduction Resting Vasomotor Tone Coronary and Graft Reactivity... Microcirculatory Vasomotor... Systemic Vasomotor Alteration Clinical Effects and Therapeutic... Acknowledgments References

 
Since the first report of the endothelium modulating vasomotor tone, endothelial dysfunction has been found to occur in a variety of cardiovascular disease states. Impaired vasomotor function has been suggested as playing a role in the pathophysiology of hypertension, diabetes, hypercholesterolemia, and atherosclerosis, all of which are common in cardiovascular surgery patients [1]. In addition to chronic vasomotor dysfunction, alterations in vasomotor tone can affect the acute care of the cardiac patient. Cardiothoracic surgeons and cardiologists are familiar with the concept of coronary artery spasm after coronary artery bypass grafting, during reperfusion through a previously occluded artery, or the microcirculatory no-reflow phenomenon that sometimes follows cardioplegic arrest. Changes in the health of the vascular endothelium may not only have implications concerning the short-term clinical course of patients undergoing coronary artery bypass grafting, but may affect the late patency of coronary artery bypass grafts, the progression of atherosclerosis in the native coronary circulation, and the long-term success of cardiac transplants [2–4]. The possible mechanisms of these clinical entities have only recently been understood and the ubiquitous nature of altered vasomotor function realized.

Recent discoveries in the field of vascular biology have led to an improved understanding of how endothelial dysfunction affects cardiovascular disease. Since the first description of an essential role for the endothelium in mediating relaxation responses to acetylcholine in mammalian arteries by Furchogott and Zawadzki [5], the study of blood vessel modulation by the endothelium has dramatically and continuously increased. Yet, many of the same questions that were posed before to Furchogott and Zawadski's discovery remain unanswered: What is the role of the endothelium in modulating the vasomotor state of arteries under experimental (basic science or catheterization laboratory) conditions?, and What are the clinical implications in unstable angina, stroke, mesenteric vascular insufficiency, and other diseases related to impaired organ perfusion? Of more importance, What can the clinician do to change the natural history of these illnesses by modulating the health of the vascular endothelium? Without addressing these questions and applying advancing scientific knowledge to the clinical realm, investigation of endothelium and vascular pathophysiology consists of a quest for interesting but largely irrelevant scientific trivia.

	Resting Vasomotor Tone

Top Footnotes Abstract Introduction Resting Vasomotor Tone Coronary and Graft Reactivity... Microcirculatory Vasomotor... Systemic Vasomotor Alteration Clinical Effects and Therapeutic... Acknowledgments References

 
Vasomotor tone results from the complex interaction of the circulating substances, the components of vascular wall, the surrounding parenchymal tissue, and neuronal influences. The influence of the various properties of vascular tissue ranging from passive factors due to the connective tissue content of blood vessels, the tone of vascular smooth muscle due to neuro and myogenic mechanisms, and modulation of the vascular smooth muscle by the endothelium contribute to the ultimate vasomotor state. When one or more of these mechanisms is altered or if the circulating concentration of vasoactive substances (eg, during platelet, macrophage, or neutrophil activation) is increased, vasomotor tone may substantially change (Fig 1). Further complicating the analysis of vasomotor tone are metabolic, autoregulatory, and extravascular compressive forces and other nonvascular influences on the blood vessel.

View larger version (28K): [in this window] [in a new window]   Fig 1. . Common determinants of endothelial-derived vasomotor tone.

Like many physiologic systems, there is a degree of redundancy in the vasorelaxant functions of the endothelium. In addition to NO, the endothelium constitutively produces the eicosanoid prostacyclin, which has a similar function as NO. Although both NO and prostacyclin promote smooth muscle relaxation, the fundamental difference between NO and prostacyclin is that prostacyclin acts only to inhibit activated platelets and therefore, has no effect on platelet adhesion. In contrast, NO inhibits both adhesion and aggregation of activated platelets [12]. In addition, the endothelium produces the purine nucleoside adenosine. Like NO and prostacyclin, adenosine mediates smooth muscle cell relaxation and inhibits platelet and neutrophil aggregation. Adenosine has several other beneficial effects, such as the inhibition of the release of norepinephrine from sympathetic nerve endings, dilation of resistance vessels resulting in improved tissue perfusion, and the inhibition of calcium entry into cardiomyocytes, an event associated with ischemia reperfusion injury. These beneficial effects are rapidly lost when the endothelium is injured, for example, after ischemia reperfusion [13]. Drugs that potentiate the effect of adenosine, such as acadesine, can have profound cardioprotective effects demonstrating the pleuripotent role that this compound plays [14].

In the past decade it was demonstrated that the endothelium could mediate not only rapid relaxation but also rapid contraction [15]. Endothelial-derived contracting factors have since been demonstrated to occur as a result of endothelial injury, in the form of high luminal pressure or hypoxia [16]. In 1988 Yanagisawa and colleagues [17] and Davies and Hagen [18] reported the discovery of the polypeptide endothelin, which has since been characterized as a family of vasoactive peptides (ET-1, ET-2, ET-3). Because of its potent smooth muscle-constricting effects it has been implicated in a variety of vascular diseases, including pulmonary hypertension, acute renal failure, and the myocardial injury suffered after cardiovascular operation [19]. Endothelin is the most potent pressor substance yet discovered and its action is long lived [20]. The endothelium also plays a role in the powerful renin-angiotensin system. When hypoperfused, the kidneys produce renin. Renin catalyzes the formation of angiotensin I. Endothelial cells produce the angiotensin-converting enzyme, which is responsible for the powerful vasoconstrictor angiotensin II. In addition, the endothelium can produce other potent vasoconstricting substances such as histamine, thromboxane A₂, and other cyclooxygenase-dependent contracting factors [13].

Thus, under resting conditions, the endothelium produces a variety of substances that influence the degree of vascular tone. Under physiologic conditions, endothelium-derived relaxing factors most likely dominate [13]. Many of the premorbid features and perioperative conditions required to perform cardiac operations upset the balance of relaxation and contraction. The combination of hypercontractility of vascular smooth muscle and endothelial dysfunction makes the likelihood of postoperative vascular spasm or microvascular contraction an attractive mechanism for reduced postoperative myocardial perfusion and subsequent reduced cardiac function. An appreciation of the various roles that these substances have in controlling vascular tone has significant implications if we are to have an effect on the natural history of vasomotor dysfunction in our patients suffering from acute vasospasm, microvascular no-reflow, as well as the long-term implications this has on graft patency and function.

	Coronary and Graft Reactivity and Patency

Top Footnotes Abstract Introduction Resting Vasomotor Tone Coronary and Graft Reactivity... Microcirculatory Vasomotor... Systemic Vasomotor Alteration Clinical Effects and Therapeutic... Acknowledgments References

 
Whereas the primary site of regulation of myocardial perfusion resides in the coronary microcirculation, acute spasm of the internal mammary artery or saphenous vein grafts may significantly disrupt perfusion to the subtended myocardium, and cause sudden cardiac decompensation. The local loss of NO and other relaxant factors and the release of contracting factors may precipitate coronary spasm [13]. When the endothelium is damaged and microthrombi form, platelets are another important source of vasoconstrictive substances that contribute to spasm [21]. Coronary artery spasm during the early hours after coronary bypass grafting is often unrecognized and may lead to the rapid deterioration in cardiac function with concomitant signs of myocardial ischemia. Retrospective studies have estimated that coronary artery spasm occurs in approximately 1% to 3% of patients undergoing coronary bypass grafting [22, 23]. Lockerman and colleagues [24] found transient ST segment elevations occur during Holter monitoring in 8% of patients in the first 12 hours after coronary bypass grafting. Thus, it is likely that vascular spasm or contraction in the coronary bed is not an "all or none" phenomenon, but is a continuum ranging from clinically insignificant reductions in coronary flow to circulatory collapse and death.

The propensity to spasm of the various bypass vessels as grafts is likely related to the different biologic properties of the blood vessel wall and the degree of injury incurred upon harvest and implantation [2]. The degree of bypass graft injury is important because it can be related to early graft spasm or to the remote development of intimal hyperplasia, limiting long-term graft patency [25]. Recently, several investigators [26–28] have examined the vascular reactivity of the common conduits used in coronary bypass grafting. The responses of the different arterial grafts to contractile and vasodilator substances may be heterogeneous making consideration of this differential reactivity important when assessing the need and choice of inotropic and vasoactive drugs [26, 27]. Pearson and colleagues [4] demonstrated that the left internal mammary artery produced more NO than the right internal mammary artery. In contrast they found relatively poor basal release of NO by human saphenous veins in most patients, and absent NO production in many other patients [29]. Although the arterial grafts produces the most NO and other vasorelaxant substances this can easily be lost with endothelial injury, which can occur during harvest and the construction of the anastomosis. When this occurs, focal vasospasm can result in impaired myocardial oxygen delivery.

In addition to early postoperative vasospasm, the determinants of vasomotor dysfunction can have an impact on the long-term success of the bypass grafts as well. It is widely recognized that different bypass conduits have different long-term patency and it is increasingly appreciated that the vascular endothelium plays an integral role in influencing these outcomes. Saphenous and upper arm veins are used as bypass conduits because of their availability; however, studies have shown that occlusion occurs frequently and longevity is limited. Arterialization of vein grafts results in a shear response by submitting them to abnormal mechanical stress that results in endothelial injury [25]. In contrast to the saphenous vein, the internal mammary requires less handling with harvest, storage, and implantation. Therefore, there is less potential for endothelial cell injury. The internal mammary arteries have been shown to have superior long-term patency, especially when grafted to the left anterior descending artery [30]. Because NO induces vasodilatation and inhibits platelet adhesion and atherosclerosis, some investigators have postulated that the increased release of NO by internal mammary artery grafts contributes to the superior results with this conduit in bypass grafting in comparison to saphenous vein grafts [4].

	Microcirculatory Vasomotor Dysfunction

Top Footnotes Abstract Introduction Resting Vasomotor Tone Coronary and Graft Reactivity... Microcirculatory Vasomotor... Systemic Vasomotor Alteration Clinical Effects and Therapeutic... Acknowledgments References

 
The microcirculation in the coronary vascular bed provides the primary control over organ perfusion [31]. Whereas large conduit arteries may be involved in pathologic processes, especially during vasospastic, embolic, or thrombotic occlusion, the microcirculation is more important in regulating perfusion to the various vascular beds. Not only is the microcirculation important because it is the primary site of regulation of end-organ perfusion, but it is significant that its response to neurohumoral substances, such as serotonin and norepinephrine, is often different in magnitude or opposite to that observed in large vessels [32, 33]. Thus, the study of microvascular changes may be more physiologically relevant than alterations in larger arteries. Furthermore, specific microvascular responses need to be considered when administering vasoactive drugs, as many preconceived ideas concerning vascular responses have often been inaccurately based on the responses of large arteries or on in vivo studies complicated by extravascular influences.

The reperfusion of ischemic myocardium is associated with impaired contractility, termed stunning. The stunned myocardium can have severe flow defects, presumably due to ischemic impairment of intrinsic vasorelaxation. Because various techniques of myocardial protection can have profound effects on microcirculatory flow it is of interest to review current studies that attempt to dissect out these mechanisms. Recently, the effect of hyperkalemic cardioplegia on endothelial function has been studied in detail. Crystalloid cardioplegia has a significant detrimental impact on endothelium-dependent relaxation and presumably other indices of endothelial function. Not only is the function of the endothelium impaired by hyperkalemic crystalloid cardioplegia, but the function of the vascular smooth muscle can also be altered, as manifested by impaired ß-adrenergic and cyclic AMP-mediated relaxation and reduced myogenic contraction. These alterations in vascular reactivity may predispose to coronary spasm or other manifestations of vascular dysfunction such as microcirculatory no-reflow. Hyperkalemic cardioplegia has been determined to cause acute changes in cell viability and vascular reactivity as well. Carpentier and colleagues [34] examined the cytotoxicity of various hyperkalemic solutions on cells in culture and found that the viability of human endothelial cells and fibroblasts was markedly reduced after several hours of incubation in a hyperkalemic crystalloid solution. They found that the addition of blood to the solution significantly improved the indices of cell viability. Subsequent studies have confirmed that hyperkalemia alters endothelial morphology and impairs endothelium-dependent relaxation of both large epicardial coronary arteries of arterioles [35–38]. Hiratzka and co-workers [39] examined the effects of CPB and cold hyperkalemic cardioplegic solution on coronary flow velocity and hyperemic responses in patients and dogs. In the first hour after initiation of reperfusion, a blunting of the hyperemic response was observed after brief periods of coronary occlusion. During these same periods, baseline coronary perfusion was increased while coronary resistance was reduced, likely due to metabolic influences. This study clearly demonstrated, for the first time, the vascular effects of hyperkalemic cardioplegia in the clinical setting, and is consistent with other studies that have examined in vitro vascular responses. After a period of ischemic arrest using cold crystalloid cardioplegia, endothelium-dependent relaxation is moderately impaired and vascular smooth muscle contractile responses are reduced [40, 41]. This may result in the maintenance of vessels in a relatively fixed, dilated state. After prolonged reperfusion, responses to contractile substances, such as thromboxane, endothelin, and serotonin recover, whereas the impairment in endothelium-dependent relaxation progresses. The extent of impairment may be related to the duration of exposure and the degree of hyperkalemia in the cardioplegic solution and the pressure and other conditions under which the solution is delivered [42].

Neutrophil adherence to the vascular endothelium can affect the degree of vasomotor tone. Leukocytes have been implicated in causing or contributing to myocardial and endothelial damage after either cold cardioplegia or warm myocardial ischemia [43, 44]. Focal leukocyte–endothelial adherence has been observed on transmission electron microscopy after cardioplegia and reperfusion [41]. Kawata and colleagues [43] showed improved recovery of myocardial function and perfusion when leukocyte-depleted blood was used to reperfuse isolated lamb hearts after cardioplegic arrest. Activated leukocytes may cause endothelial dysfunction through inflammatory mechanisms or may generate oxygen-derived free radicals. Recent studies have demonstrated that inhibition of oxygen-derived free radicals has a beneficial effect on endothelium-dependent relaxation in the coronary circulation after hyperkalemic cardioplegia [41]. Oxygen-derived free radicals may be generated after ischemia or cardioplegia by several mechanisms. These include the conversion of xanthine dehydrogenase to xanthine oxidase, activation of cyclooxygenase, mitochondrial respiration, and catecholamine auto-oxidation. Oxygen-derived free radicals may produce direct injury to endothelial cells. Furthermore, they may reduce indirectly the potency of endothelium-derived NO through enhanced breakdown of the NO radical.

The addition of blood to a crystalloid cardioplegic solution has a beneficial effect on endothelium-dependent relaxation during ischemic arrest [40]. The mechanism of this ameliorating effect is uncertain but may be due to one of several factors. Blood is a potent inhibitor of oxygen-derived free radicals that may be released upon initiation of reperfusion. Second, the soluble O₂ from the oxygenated blood may provide a small additional amount of oxygen to the cells reducing the amount of ischemia. Crystalloid cardioplegia has been reported to cause changes in the morphology of endothelial cells in some studies and these morphologic changes are reduced when blood is added to the cardioplegic solution [37]. Although the addition of blood to a crystalloid cardioplegic solution has clearly been found to be beneficial in the laboratory when examining isolated vascular and myocardial tissue or a whole animal model, the benefit is not as clear when examining the clinical outcome of nonacutely ischemic patients after cardiac operation [45]. Whether the use of continuous warm blood cardioplegia has an impact on endothelial function or coronary vascular reactivity remains to be determined.

After periods of ischemia or cardioplegia, the regulation of coronary blood flow is determined by metabolic and myogenic mechanisms, although the endothelium may contribute due to the flow-mediated release of NO [46, 47]. Metabolic control is mediated by the local release of vasoactive substances, whereas myogenic mechanisms are based more on the intrinsic property of vascular smooth muscles [48]. Cardioplegic arrest decreases myogenic-induced contraction as well as the intrinsic tone of coronary arterioles. Because the vascular smooth muscle is the effector of endothelial-mediated responses, the effect of cardioplegia on the function of the smooth muscle deserves some attention. Prolonged hyperkalemia causes depolarization and contraction of vascular smooth muscle through the influx of calcium ions into the smooth muscle cytosol. This may lead to the accumulation of calcium within the cell and subsequent impairment of calcium-mediated contractile and relaxation mechanisms [49]. Although endothelium-dependent relaxations are altered after hyperkalemic cardioplegia, endothelium-independent relaxation of vessels to sodium nitroprusside and other cyclic GMP-mediated vasodilators seems to be less susceptible to alteration [38, 40–42, 50] However, other endothelium-independent smooth muscle mechanisms, such as ß-adrenergic and other cyclic AMP-mediated vascular smooth muscle responses in the coronary circulation, have been found to be impaired by hyperkalemic cardioplegia [51]. After a period of post-cardioplegia reperfusion, these responses were substantially recovered, but ß-adrenergic receptors were uncoupled from second-messenger mechanisms. Catecholamine-induced desensitization of ß-adrenoreceptors may be responsible for this alteration in signal transduction of the coronary ß-adrenergic system. Cardiopulmonary bypass is associated with increased circulating levels of catecholamines, which may contribute to hypertension after cardiac operation [52, 53]. In addition, the ß-adrenergic function could be affected by changes in membrane structure and function of vascular smooth muscle due to cardioplegia and reperfusion-induced injury. It is conceivable that hyperkalemia and hypothermic arrest might interfere with intracellular relaxation pathway by alterations in intracellular calcium mobilization into the sarcoplasmic reticulum or extracellular compartment.

	Systemic Vasomotor Alteration

Top Footnotes Abstract Introduction Resting Vasomotor Tone Coronary and Graft Reactivity... Microcirculatory Vasomotor... Systemic Vasomotor Alteration Clinical Effects and Therapeutic... Acknowledgments References

 
Wide variations in systemic blood pressure are common in patients recovering from CPB. Systemic hypotension occurs frequently in patients during and after extracorporeal circulation. Thus, systemic hypotension after CPB may result from a generalized defect in the intrinsic control of the vascular smooth muscle. The cause of this alteration in intrinsic tone may be related to increased circulating levels of tumor necrosis factor and other cytokines released during CPB and increased basal release of endothelium-derived NO [48, 54]. Although increased blood flow is generally considered to be a beneficial process, maintenance of organ perfusion could be compromised by the concomitant systemic hypotension. Furthermore, autoregulation, an important modulator of organ perfusion between the extremes in blood pressure, may be abnormal after CPB. The administration of peripheral vasoconstrictor substances such as phenylephrine or norepinephrine to maintain systemic vascular resistance may have a detrimental action on the mesenteric and renal perfusion due to differential sensitivities of vessels to these vasoactive substances. Although the systemic circulation may have reduced vasomotor tone after termination of CPB, the pulmonary and other vascular beds may manifest increased vasomotor tone [55].

	Clinical Effects and Therapeutic Options

Top Footnotes Abstract Introduction Resting Vasomotor Tone Coronary and Graft Reactivity... Microcirculatory Vasomotor... Systemic Vasomotor Alteration Clinical Effects and Therapeutic... Acknowledgments References

 
Clinical manifestations of endothelial and smooth muscle dysfunction in the coronary circulation remain ill-defined, and the most appropriate method to correct these abnormalities remains unknown. Reduced cardiac function after cardiac operations using cardioplegia may be largely due to primary myocardial dysfunction. However, impaired or altered vasomotion may play an important role. Clinical assessment is of prime importance and cardiac tamponade, acute graft occlusion, and other technical and clinical factors need to be ruled out before making the diagnosis of acute coronary spasm. If vasospasm occurs after bypass, immediate treatment may be critical. Infusion of vasodilators, such as nitroglycerin and nitroprusside, have been reported to reduce coronary spasm of the grafts or in the recipient vasculature [56]. These agents work in part as NO donors [9]. Nifedipine and other calcium channel blockers may have a theoretical advantage over nitroglycerin as these drugs relax coronary microvessels, whereas nitroglycerin has minimal effects on the coronary microcirculation [57, 58]. Antiinflammatory agents may help preserve endothelial cell function as well. The addition of blood or of oxygen-derived free radical scavengers to a cardioplegic solutions has been shown, at least theoretically, to preserve endothelium-dependent relaxation. In addition, aspirin and other cyclooxygenase inhibitors have been found to improve short-term coronary bypass graft patency after operation [59]. It is interesting to speculate that this may be in part due to maintenance of graft flow due to prevention of microvascular constriction in the early postoperative period, as well as to prevention of platelet aggregation and thrombus formation. Indeed, blockade of cyclooxygenase has been found to lessen the contractile response of vessels to serotonin after cold cardioplegia and reperfusion [40]. Because of the central role that NO plays in maintaining normal vascular function, there are a variety of substrate and gene-oriented therapies being evaluated with the goal of enhancing basal NO secretion [9].

Because most patients obviously do not experience the untoward effects of altered vasomotor tone, it is likely that myogenic, adrenergic, and other smooth muscle mechanisms compensate for the endothelial dysfunction. Learning why some patients have clinical manifestations of ubiquitous experimental findings is one of the challenges that lies ahead. Future studies will undoubtedly better define the complex role of the endothelium in modulating vascular tone under normal and pathologic conditions. Yet the critical question remains how this actually modulates the clinical course and outcome of patients. Nevertheless, it is likely that a better understanding of the interaction of the endothelium with the vascular smooth muscle and extravascular factors may lead to improved care of patients manifesting signs of impaired vasomotor tone.

	Acknowledgments

Top Footnotes Abstract Introduction Resting Vasomotor Tone Coronary and Graft Reactivity... Microcirculatory Vasomotor... Systemic Vasomotor Alteration Clinical Effects and Therapeutic... Acknowledgments References

 
This study was supported by a National Heart, Lung and Blood Institute grant HL46716 and American Heart Association (Massachusetts Affiliate) grant-in-aid 13–501–912.

	Footnotes

Top Footnotes Abstract Introduction Resting Vasomotor Tone Coronary and Graft Reactivity... Microcirculatory Vasomotor... Systemic Vasomotor Alteration Clinical Effects and Therapeutic... Acknowledgments References

 
Address reprint requests to Dr Sellke, Division of Cardiothoracic Surgery, Beth Israel Hospital, Dana 905, 330 Brookline Ave, Boston, MA 02215.

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Top Footnotes Abstract Introduction Resting Vasomotor Tone Coronary and Graft Reactivity... Microcirculatory Vasomotor... Systemic Vasomotor Alteration Clinical Effects and Therapeutic... Acknowledgments References

 

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