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Ann Thorac Surg 2001;72:S2245-S2252
© 2001 The Society of Thoracic Surgeons
a Department of Surgery, VA Boston Healthcare System, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
* Address reprint requests to Dr Thatte, Surgical Service (112), VA Boston Healthcare System, 1400 VFW Parkway, West Roxbury, MA 02132, USA
e-mail: hemant_thatte{at}hms.harvard.edu
Presented at Monitoring and Improving Patient Safety During and Following Cardiac Surgery, San Diego, CA, May 5, 2001.
Abstract
Prevention of intraoperative injury to the vascular endothelium is of primary importance in maintaining viability and patency of the aorto-coronary saphenous vein graft. Surgical manipulation, ischemia, storage conditions, and distension before anastomosis can abnormally alter the antithrombogenic property of the endothelium leading to vasospasms, thrombogenesis, occlusive intimal hyperplasia, and stenosis. Endothelial injury can also form an initiation site for the formation of later-stage atheromas and graft failure. A multifactorial strategy aimed at prevention of endothelial injury and graft failure should include improved surgical techniques, optimal preservation conditions, avoidance of nonphysiologic distension pressures, and use of specific pharmacologic agents as the primary form of intervention. The successful application of this strategy, and the development of newer and more efficacious strategies that may impact on long-term graft patency, can now be aided by assessment of the structural and functional integrity of bypass conduits using multiphoton imaging techniques.
The vascular endothelium is a hemocompatibile monolayer of mesenchymal cells forming a barrier between the circulating blood and etxravascular space, and is known to be a complex modulator of a variety of biological systems [1, 2]. The preservation of endothelial cell viability is vital for inhibiting early pathologic changes and the long-term patency of vascular grafts [1–7]. Restenosis of venous bypass grafts can occur as a healing and remodeling response to the initial tissue injury in a poorly regulated process. Despite the widespread use and superior patency of the internal mammary artery (IMA), the saphenous vein continues to be the most commonly used conduit for coronary artery bypass graft (CABG) and peripheral arterial surgery. The pathologic changes leading ultimately to vein graft occlusion and loss in vasomotor function are well documented [1–7]. Endothelial damage appears to be a major cause of graft failure. This injury may occur at the time of harvest, due to blunt surgical trauma and stretch [1, 4, 6], or to ischemia and superoxide free radical generation during prolonged ex vivo preservation, storage conditions, and distension or pressurization before anastomosis. Endothelial trauma is also caused by exposure to arterial circulation pressure and oxygenated blood [1, 8] graft insertion [9, 10], turbulent blood flow or local stasis from slow boundary layer flow [10].
This review elucidates the potential causes and adverse effects of intraoperative injury to the endothelium of an aorto-coronary bypass conduit, and underscores the relationships between intraoperative endothelial injury and the pathogenesis of early and late graft failure. It also introduces a novel method employing multiphoton fluorescent imaging for the intraopertaive assessment of aorto-coronary bypass graft endothelial function.
Pathogenesis of endothelial dysfunction in aorto-coronary bypass conduits
Stage 1: thrombogenesis
Venous graft failure within 1 month after CABG surgery is thought to occur as a result of thrombogenesis [1–9, 11]. Early pathologic changes observed in autogenous saphenous vein grafts implanted as arterial autografts include acute thrombosis, denudation of endothelium, platelet and fibrin accumulation, cellular intimal subendothelial infiltrates, myointimal proliferation, smooth muscle necrosis, and inflammation [1–9].
Endothelial cells are known to be important mediators in regulating platelet anticoagulant as well as procoagulant processes and fibrinolytic functions. These properties of the endothelium facilitate circulation of blood; they also facilitate blood clotting and thrombogenesis following endothelial injury [6–11]. Damage to the endothelium or denudation of endothelial cells activates the intrinsic pathway of the coagulation cascade due to the exposure of basement membrane collagens, as shown in Figure 1 [1, 11]. Endothelial injury and inflammatory cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and complement fragment 5a also activate the extrinsic coagulation processes by the induction of tissue factor that is constitutively expressed on the endothelial cells and the exposed subendothelial matrix [1, 4, 6, 11]. Both pathways activate clotting factor X, which converts prothrombin to thrombin and which, in turn, converts soluble fibrinogen to an insoluble meshwork of fibrin that is deposited on the damaged endothelium. Fibrin meshwork then traps blood cells, forming the thrombus [11]. Similarly, impaired secretion of prostacycline (PGI2), nitric oxide, adenosine, and tissue plasminogen activator (tPA) by the damaged endothelial cells leads to platelet activation, recruitment, and aggregation, and deposition of fibrin on the damaged luminal surface. Aggregation of platelets, recruitment of monocytes and neutrophils, trapping of red blood cells, and fibrin meshwork lead to thrombus formation and embolism, as shown in Figure 1 [1–4, 6, 7, 9, 11]. This process is further accelerated by the interaction of platelets (mediated through Gp Ib and Gp IIb/IIIa complex, and CD41/CD61, 
IIbß3 integrins) with high concentration of endothelium-derived von Willebrand factor, fibrinogen, and fibronectin deposited in the extracellular matrix [1, 4, 6, 11]. Further, activity of endothelial cell membrane-bound thrombomodulin is attenuated by loss of or damage to the endothelial cells. Thrombomodulins are known to exert antithrombotic effects by cleaving clotting factors VIIIa and Va by forming a complex with its cofactor protein S, thrombin, and the circulating anticoagulant protein C [4, 6, 11, 12].
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Stage 2: intimal hyperplasia
The 1-year patency of the saphenous vein graft is low relative to the that of the IMA, the occlusion rate in the saphenous vein being of 15% to 26% in the first year [1, 6, 7, 9]. Venous graft failures between 1 month and 1 year after CABG surgery are thought to occur as a result of intimal hyperplasia [1, 4, 6, 9]. Proliferation of smooth muscle cells and intimal hyperplasia is generally not observed with a normal endothelium in intact saphenous veins. However, nearly all arterialized vein grafts demonstrate a significant decrease in lumen size due to intimal thickening within 4 to 6 weeks after implantation [6, 10, 14]. Even though the decrease in lumen size may not contribute to stenosis in these early stages, the intimal hyperplasia is responsible nevertheless for the decrease in lumen size and forms the nucleation site for the later development of graft atheromas. Irrespective of whether they are arterial or vein grafts, neointimal hyperplasia in injured vessels demonstrate similar pathogenic sequelae. Injury or denudation of the endothelium stimulates the proliferation of smooth muscle, leading to the formation of thickened intima (Fig 1). This hyperplastic reaction is attributed to the release of various cytokines and growth factors such as platelet-derived growth factor (PDGF), basic fibrobalst growth factor (bFGF), platelet-derived endothelial cell growth factor (PD-ECGF), agiogenesis factor, and transforming growth factor ß (TGF-ß), by the activated platelets, injured endothelial cells, and injured smooth muscle cells in the intima and media [1, 4, 6]. In response to these growth factors and cytokines, smooth muscle cells in the media initially proliferate and then migrate to the intima, where they continue to undergo hyperplasia. Subsequent synthesis and deposition of extracellular matrix by activated smooth muscle cells, formation of neoendothelium over a layer of platelets, and fibrin adhering to the basement membrane result in a progressive increase in intimal fibrosis that eventually leads to obstruction of the lumen and to failure of the graft (Fig 1).
The considerable amount of endothelial damage observed in vein grafts before anastomosis and during the process of arterialization leads to greater secretion of growth factors and cytokines and, consequently, to an increase in intimal smooth muscle cell proliferation, stenosis, and failure of saphenous vein grafts. In contrast, internal mammary artery grafts, free of endothelial damage and already acclimated to the arterial environment, develop significantly less intimal hyperplasia and demonstrate greater long-term patency after aorto-coronary bypass surgery [1, 6, 9, 10]. Unlike arterial grafts, the "ischemia-reperfusion" cycle encountered by venous grafts may be an additional mechanism of injury and intimal hyperplasia in these conduits. Injury sustained by the endothelial cells not only results in a decrease in prostacyclin, nitric oxide, and adenosine synthesis, but also leads to the formation of superoxide radicals that directly promote smooth muscle cell proliferation [1, 4, 6]. This decrease in nitric oxide production is further compounded by the destruction of released nitric oxide by the superoxides, thus decreasing the endothelium dependent vasomotor function of the vein graft.
Dilation of the vein conduits in the arterial circuit due to pressure differences leads to an increase in vein diameter and, thus, to a decrease in blood velocity and shear stress [6, 10]. This results in an increased production of shear-regulated potent mitogens such as PDGF, bFGF, and endothelin-1, simultaneously decreasing the production of growth inhibitors such as nitric oxide and transforming growth factor ß, thus shifting the equilibrium in favor of smooth muscle cell proliferation and intimal hyperplasia and further contributing to graft failure [1, 4, 6]. Unlike the saphenous vein, the IMA is not explanted; does not require ex vivo storage; and undergoes minimal processing and handling before implantation. As such, it offers less potential for endothelial injury [5].
Stage 3: arteriosclerosis
Attrition of veinous grafts and recurrence of ischemic symptoms beyond 1 year after CABG surgery is attributed to atherosclerotic changes. Chronic injury to the endothelium and the smooth muscle cells leads to ongoing recruitment of platelets, neutrophils, monocytes, macrophages, and lymphocytes at the site of injury and to resultant inflammation (Fig 1). Endothelial cell damage occurring at the time of saphenous vein grafting can be the principal event triggering both the development of late atherosclerotic changes and their subsequent adverse effects on cellular structure, endothelial function, and vasoreactivity [1, 5]. Endothelial cell growth and proliferation is contact-regulated [4]. These cells try to reestablish contact by stretching out and proliferating in the wounded region. However, because of chronic injury and loss in function, endothelial cells loose their capacity to replicate, leading to areas of subendothelial exposure. This allows the adhesion of platelets and inflammatory cells in these regions, which become activated and induce the smooth muscle cells to proliferate and to cover the denuded region, as shown in Figure 1 [4].
Nitric oxide, prostacyclin, and adenosine, apart from their vasorelaxation function, are also potent antiadhesive mediators that prevent neutrophil–endothelial adhesion under normal physiologic condition [4]. However, sublethal damage to the endothelial cells can not only cause the loss of these antiadhesive effector molecules, but can also cause induction and upregulation of leukocyte adhesion molecules on the endothelial cells; the latter attract neutrophils, monocytes, and macrophages to these areas (Fig 1). The activation of adherent leukocytes leads to the release of oxygen-derived free radicals, proteases, and cytokines such as TNF, IL-1, IL-6, and IL-8 and to further recruitment of inflammatory cells; these in turn perpetuate disruption of the subendothelium and induce smooth muscle cell proliferation [4, 6]. Temporally, atherosclerotic plaques develop by the transformation of lipid-filled macrophages into foam cells and encapsulation of proliferating smooth muscle cells [4, 6]. Atherosclerotic plaques progress by the accumulation of alternate layers of foam cells, smooth muscle cells, and necrotic debris, as shown in Figure 1 [4]. Vein graft atheromas, in contrast to native vessel atheromas, are found to be diffuse, concentric, and friable, with poorly developed fibrous cap and without calcification [6]. The plaques continue to grow and to encroach into the lumen, thereby impeding blood flow. In later stages, they may recruit thrombii or may rupture, leading to stenosis, graft failure, and myocardial infarction. In contrast to vein grafts, IMA grafts can resist the formation of atheromas [6]. Internal mammary artery conduits, therefore, tend to be superior in comparison to saphenous vein grafts because of the low incidence of thrombogenesis, intimal hyperplasia, and arteriosclerosis observed in these grafts. Also, IMA grafts are not explanted; therefore, sympathetic and parasympathetic control of IMA grafts may also play an important role in maintaining the patency of these conduits. In follow-up reports of patients evaluated 5 to 12 years after CABG surgery, the patencies confirmed by angiography were 95% for IMA versus 55% for saphenous vein grafts [1, 6]. These differences were more apparent when both conduits were used in the same patient [1].
Measuremnt of endothelial function
The intraoperative preservation of harvested saphenous veins before performance of coronary artery bypass grafting is a factor in the protection of the endothelial cells. Short-term preservation of free vascular grafts is a daily routine in coronary operations, in which 1 to 2 hours may elapse between harvesting and reperfusion. This interval may affect both the structure and function of the graft, depending upon the composition of the storage solution, the storage temperature, or the duration of ischemia before reimplantation [1, 4]. Because endothelial damage appears to be a major cause of graft failure, defining the time and nature of this injury is of prime importance. Currently available assays define vascular damage by measuring vasomotor function, including primarily static vascular cell culture, ring studies of sectioned vascular tissues in an organ bath, and animal models in which relaxation of precontracted tissues is measured [5, 15]. Collectively these techniques are limited by the lack of concomitant in situ assessment of the viability of the endothelium. Furthermore, they do not allow for simultaneous visualization of the structural integrity of endothelial and smooth muscle cells. They also do not allow the real-time measurement of the function of these cells in the form of calcium signaling or nitric oxide generation.
Until very recently, the intracellular events transpiring within endothelial cells in intact living vessels could not be evaluated directly because of the inability of conventional fluorescence microscopy to image deep into thick tissues. Although, tissue culture models of endothelial cells have been widely explored, these experimental models may provide only limited insight into the mechanisms that operate in tissues in situ. However, with the recent development of multiphoton fluorescence microscopy [16], these limitations have been overcome by allowing deeper penetration into the tissues using imaging technology through the use of the infrared region of the electromagnetic spectrum as an excitation source [16–18]. Therefore, optical sectioning and construction of three-dimensional images has become possible without physically dissecting the sample. Localization of multiphoton excitation to a limited volume at the focal plane minimizes photo-damage and out-of-plane fluorescence, thereby generating high-contrast, well-resolved images from deep within the tissues [16–18]. Multiphoton microscopy has been used in the three-dimensional functional imaging of diverse tissues such as cornea [19], human skin [18], mammalian kidney and brain [11], cardiac myocyte [20], and mammalian embryo [21]. We have successfully applied this imaging technology in real time to assess the structure and physiologic function of explanted, living, intact human saphenous veins preserved in the course of cardiac surgery [22, 23]. The next section of this article reviews the methodology and the lessons learned to date from this investigation.
Application of multiphoton microscopy to intraoperative assessment of endothelial function in whole aorto-coronary bypass conduits
Structural assessment
The structural and functional viability of vessel endothelium is measured with a fluorescence-based, super-vitality, live–dead assay [24]. This assay measures the structural integrity of cells by allowing the membrane-permeable calcein AM ester dye to enter the cell and be transformed by the cellular esterases to produce green fluorescence in living cells, thus providing a measure of enzyme activity and cell viability. In contrast, the membrane impermeable ethidium homodimer enters compromised cells and intercalates with nucleic acids, giving red fluorescence in dead or damaged cells, demonstrating altered structural integrity of the cells. The high affinity for DNA and low membrane permeability of ethidium homodimer makes it an ideal indicator of dead cells [22–24]. This combination of calcein and ethidium homodimer has been applied as a viability assay in brain, sperm, and corneal tissue [24]. Calcein, alone, has been used as a marker of cell viability in cultured human saphenous vein endothelial cells [25]. The application of this two-color viability assay to the cells of whole segments of human saphenous vein has recently been reported [22, 23].
To estimate the penetration depth required to visualize the lumen and the endothelial cell layer in whole saphenous vein, vein segments freshly obtained from the operating room are divided into two pieces and cannulated. Both pieces are then labeled with calcein and ethidium homodimer dyes by way of the lumenal region. Using multiphoton microscopy we are able to image successfully deep into the saphenous vein, as shown in Figure 2 [22, 23]. The lumen, endothelial cell layer, and smooth muscle layer of the intimal region are identified at a depth of 
150 µm in these preparations. The endothelial and subsequent smooth muscle cell layers are clearly visible surrounding the lumen; the viability of these cell layers is indicated by the robust green cellular fluorescence (Fig 2A). The fluorescent signal of media and the adventitia was less intense, probably reflecting the short time of incubation with the fluorescent dyes, which must diffuse from the vein lumen to label the outer layers of the vessel. In one piece the endothelial cells in the lumen are intentionally damaged by short exposure to the detergent Triton-X100. As expected, considerable cell death, indicated by presence of red fluorescence, is observed in the clearly identifiable endothelial region of the lumen in the detergent-treated vein piece (Fig 2B). By using these protocols we consistently resolve the vein lumen up to a depth of 300 µm for structural and functional investigations [22, 23].
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The production of nitric oxide in intact saphenous vein was measured directly in real time by using a nitric oxide–specific, membrane-permeable diacetate form of fluorescent diaminofluorescein dye (DAF-2DA). This dye is cleaved by the endothelial esterases in living cells and is converted to its membrane-impermeable form, DAF-2. This DAF-2 dye, in the presence of molecular oxygen, combines with intracellularly generated nitric oxide to yield the brightly fluorescent triazolofluorescein derivative [27]. Temporal change in intracellular fluorescence is imaged and quantitated using multiphoton microscopy. Nitric oxide assays are performed under conditions that are encountered after the intraoperative harvesting and the short-term, ex vivo storage of the saphenous vein [22, 23]. To study endothelial function, vein segments harvested in course of cardiac surgery are loaded with DAF-2DA. Lumenal eNOS is functionally activated with bradykinin and the endothelial layers are identified by XYZ scanning. Figure 3 demonstrates a 2.5- to 3-fold increase in fluorescence in the endothelial region of the saphenous vein after bradykinin treatment. This increase in fluorescence, which is directly related to endothelial cell functionality, is quantitated by temporal integration of per pixel change in fluorescence in specific regions of the endothelium.
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Effect of distension on human saphenous vein
Distension of vein grafts before anastomosis is a common practice in CABG surgery. This process allows the surgeon to check for the patency of the graft as well as for leakage. However, pressurization of the vessel above physiologic pressures with saline solutions causes a considerable amount of damage to the endothelium, intima, and media of the vessel [1]. By using calcein-ethidium homodimer assays and multiphoton microscopy we were able to observe the detrimental effects of distension on vessel structure. The convoluted viable endothelial regions of the freshly excised saphenous vein, identified by the green, living cell fluorescence (Fig 6A), were denuded and structurally damaged due to distension before anastomosis, apparent from the considerable amount of red fluorescence observed in the intima and media (Fig 6B). In contrast to a distended saphenous vein (>180 mm Hg pressure), a robust green fluorescence is observed in the endothelial region of IMA before anastomosis (Fig 6C), as the latter is not normally subjected to distension. It is interesting to note the differential arrangement of the convoluted endothelium in saphenous vein (Fig 6A) versus the flow-directed, linearly arranged endothelium in the IMA (Fig 6C).
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Endothelial dysfunction is the primary determinant in the interrelated pathogenesis of thrombosis, intimal hyperplasia, and arteriosclerosis in aorto-coronary saphenous vein graft failure. The plethora of risk factors that can cause endothelial abnormalities and graft failure include (but are not restricted to) surgical trauma, ischemia, storage conditions, distension, and arterialization of venous grafts. Inherent deficiencies of the vein as a bypass conduit, structural and functional damage to the endothelium, and exposure of vein conduit to high oxygen tension and arterial pressure amplify the pathologic effects of risk factors. The compendium of these factors causes endothelial damage before transposition of the vein graft into the aorto-coronary circuit, and thus affects the long-term outcome of the saphenous vein graft. Multiphoton imaging can be successfully applied to elucidate the metabolic changes that take place during intraoperative storage of saphenous veins. This methodology can be used as a model to examine the effects of various storage conditions, agonists, antagonists, and other mediators of vein function. Intraoperative studies in which the endothelial structure and function were assessed by multiphoton microscopy have demonstrated marked endothelial dysfunction and loss of endothelial viability with current storage conditions and distension. These adverse effects, which might account for long-term graft failure, can be partly ameliorated by the use of the new preservative solution GALA and by avoiding distension of the aorto-coronary bypass conduits.
Acknowledgments
We thank Vaidya (Dr.) Ajit S. Kolatkar for sharing his knowledge of blood circulation and useful discussions. HST acknowledges Aditi Thatte for her encouragement and support. The editorial assistance of Mrs. Nancy Healey is greatly appreciated.
References
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