Ann Thorac Surg 2000;69:1183-1187
© 2000 The Society of Thoracic Surgeons
ORIGINAL ARTICLES: CARDIOVASCULAR
Functional assessment of disease-free saphenous vein grafts at redo coronary artery bypass grafting
Thomas V. Bilfinger, MDa,
James A. Vosswinkel, MDa,
Christos M. Rialas, MSa,
Irvin B. Krukenkamp, MDa,
George B. Stefano, PhDa
a Division of Cardiothoracic Surgery, Department of Surgery, University Hospital and Medical Center, State University of New York at Stony Brook, Stony Brook, New York, USA
Address reprint requests to Dr Bilfinger, Division of Cardiothoracic Surgery, Department of Surgery, HSC T-19 080, University Hospital and Medical Center, Stony Brook, NY 11794-8191
e-mail: bifinge{at}surg.som.sunysb.edu
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Abstract
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Background. Reoperations for coronary artery bypass grafting are on the rise. The general rule of replacing all saphenous vein grafts (SVGs) older than 5 years of age at the time of reoperation has recently been challenged on clinical grounds. This study provides functional data of endothelial behavior in long-term vein grafts.
Methods. Previously placed SVGs were removed at the time of redo operations. Nitric oxide (NO) measurements in real time were carried out before and after stimulation with morphine. The measurements were compared to the angiographic appearance of the grafts obtained prior to operation. Grafts were categorized into 3 groups: disease-free, moderately diseased, and severely diseased.
Results. Sixteen grafts were analyzed. Five were angiographically disease-free, 4 had moderate, and 7 severe disease. In the disease-free group, peak NO production after 10-6 mol/L morphine stimulation was 35 mol/L, equivalent to the production of native saphenous vein. The severely diseased group did not demonstrate an increase in NO production, and the moderately diseased group produced a small rise in production.
Conclusions. Measurement of NO release of old SVGs, when angiographically pristine, equals that of native saphenous vein. These findings support the recent clinical observations that long-term angiographically disease-free vein grafts are biologically privileged.
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Introduction
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Redo operations for coronary artery bypass grafting (CABG) constitutes a part of the practice of every cardiothoracic surgeon. In large institutions, between 9% and 16% of coronary revascularizations have been reported as redo procedures, with this number on the rise [1, 2]. Most of these operations are performed on partially or completely occluded saphenous vein grafts (SVGs). Saphenous vein graft conduits have a closure rate of 15% to 19% by 1 year, and more than 50% by the 12th postoperative year [3–5]. Controversy exists about the replacement of old vein grafts at the time of redo operations. Routine replacement of all SVGs which are beyond 5 years of age at the time of reoperation, despite their angiographic appearance [6], has been an accepted practice at many institutions. A recent observational study has questioned this rule from a clinical standpoint. No disadvantage in terms of operative survival, angina relief, incidence of late myocardial infarction, cardiac readmission, or long-term survival was noted in patients who did not have original vein graft conduits replaced at redo operation [7].
Normal graft function requires an intact endothelium and presumably intact functioning of vasomotor regulation. Many ligands are involved in this regulatory process, but a key function is fulfilled by a small signal molecule, nitric oxide (NO). It acts in an autoregulatory capacity and is released by the endothelial cells in a paracrine fashion [8]. It is designed to keep the vessel adapted to produce optimal flow conditions for the vascular bed. Abnormalities in endothelium-dependent vasomotion are detectable in many vascular disease states. These abnormalities in smooth muscle cell reactivity are thought to result from abnormal endothelial NO homeostasis [9]. In addition to vasomotion, endothelium-derived NO appears to have a natural vasoprotective or antiatherogenic role in disease pathogenesis [8].
The present study was designed to look at graft function, correlating angiographic data with endothelial function, in an attempt to evaluate preexisting SVG conduits on a physiologic basis.
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Material and methods
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Based on the literature, the customary practice at our institution has been to replace all SVGs older than 5 years, in patients requiring redo CABG operations. Coronary arteriography has been performed in all patients before redo CABG. Based on the angiogram, grafts were classified into 3 categories: disease-free, defined as grafts having a completely patent lumen without any anastomotic or luminal irregularities (Fig 1A); moderately diseased, defined as luminal irregularities or stenoses not exceeding 50% of the diameter and being segmental in length (Fig 1B); and severely diseased, defined as disease encompassing the entire length of the graft of any degree or stenoses in excess of 50% (Fig 1C).
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Fig 1. Angiographic examples of saphenous vein grafts at redo coronary artery bypass grafting. (A) Disease-free (top), (B) moderate luminal irregularities (middle), (C) severe luminal obstructions (bottom).
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The native coronary arteries as well as the previous bypass grafts were evaluated. Redo CABG was carried out in a standard fashion using a midline sternotomy and cardiopulmonary bypass. Blood cardioplegia was used in all cases to arrest the heart. During the conduct of the operation, an old coronary artery graft was excised. They were all vein grafts. Diabetic patients were excluded, as well as patients with other systemic illnesses. All experiments involving the use of human tissue were approved by the institutional review board for human experimentation (renewed February 1998).
Previously we have shown that a µ-opiate receptor-like material is present in saphenous vein endothelium [10]. Morphine, upon acting on this receptor, has been shown to stimulate NO release [11, 12]. At the time of operation, old SVGs were resected. The vein segments were placed in a balanced electrolyte solution (Plasmalyte and 5000 units heparin/500 cc) (Baxter, Northbrook, IL) and transported on ice (4° C) to the laboratory. There the vessel was cut open. Endothelial release of NO and NO exposure to a standard protocol of drugs were measured. Results were expressed relative to the basal constitutive level of NO production. Nitric oxide released from the endothelium was measured directly using a NO-specific amperometric probe with a tip diameter of 200 µm (World Precision Instruments, Sarasota, FL) as described elsewhere [12].
Briefly, the vessel segments, endothelial side up, were suspended in 2 mL phosphate buffer solution. The probe was positioned by a micromanipulator (Zeiss Eppendorf, Erlangen, Germany), attached to the stage of an inverted microscope, 15 µm above the cell surface (Nikon Diaphot, Melville, NY). The system was calibrated daily using different concentrations of a nitrosothiol donor S-nitrosyl-N-acetyl-DL-penicillamine (SNAP; Sigma, St. Louis, MO) to reproducibly standardize the system. S-acetyl-DL-penicillamine was used as a negative control. Nitric oxide gas in solution was measured in real time with the DUO 18 computer data acquisition system (World Precision Instruments). The probe was allowed to equilibrate for 40 minutes in cell-free incubation medium before being transferred to vials containing the tissue for another 20 minutes for calibration. Manipulation and handling of the tissue was performed only with glass instruments. Each experiment was repeated 4 times, and the mean NO values were graphed. Furthermore, to avoid measuring artifactual drift by the probe, controls for each experiment were performed on the tissue obtained from the same vessel and patient.
All NO measurements were performed in a blinded fashion, without being aware of the angiographic data.
One and two-tailed Student’s t tests were used because each experiment served as its own control. A p value of less than 0.05 was considered significant. The experimental values were transferred to SigmaPlot and SigmaStat (Jandel, Corte Madera, CA) for graphic representation and evaluation.
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Results
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Sixteen patients in whom redo CABG was performed were available for evaluation. Of these patients, 2 were women and 14 were men. The mean age was 73.9 ± 10.03 years, (minimum, 60 years of age; maximum, 86 years of age). The time interval between the first CABG and the redo operation was 11.28 ± 6.70 years (minimum, 1.5 years; maximum, 20 years). The mean ejection fraction in this patient population was 40.56% ± 13.10% (range, 20% to 60%).
The vein segments were categorized according to the criteria described above. Five grafts were deemed angiographically disease-free, 4 grafts fell into the moderately diseased group by angiographic criteria, and 7 grafts were placed into the severely diseased group. The ability of the endothelium of these grafts to release NO was different (Fig 2). Nitric oxide release in response to stimulation with 10-6 mol/L morphine [11, 12] was statistically significant in angiographically disease-free grafts compared with that of the other two groups. In the moderately diseased group a rise was still observed, while in the severely diseased group essentially no response to stimulation was observed. The amount of NO released in the aging grafts in the angiographically disease-free group is equivalent to the amount of NO release observed in fresh saphenous vein when stimulated with the same amount of morphine (Fig 3).
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Fig 3. Comparison of morphine stimulated nitric oxide production. (A) Fresh saphenous vein (top), (B) 12-year-old angiographically disease-free vein graft (bottom).
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Because of the anecdotal observation of long-term pristine grafts, an attempt was made to correlate angiographic graft appearance with graft age. The groups are too small for meaningful statistics, but 3 out of 5 pristine grafts were older than 10 years, while 3 out of 7 grafts in the severely diseased category were 10 years old or older.
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Comment
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There is a paucity of information available concerning the handling of disease-free SVGs at the time of redo CABG. Yet, the practical application of this controversy is a fundamental question. In 1986, Marshall and colleagues [6] made their recommendation that all vein grafts older than 5 years should be replaced at the time of redo operation, despite their angiographic appearance. This has become the rule in many cardiac surgical practices. The rationale for this recommendation, at that time, was two-fold. First, there was the experience of 2 patients who had closure of original SVG conduits 2 years after having no major angiographic abnormalities detected in the same grafts at the time of redo operation. Second, there was evidence with 16 patients that angiography underestimated pathological disease in SVGs. Subsequently, Grondin [13] wrote an editorial with a more conservative view. Based on his own long-term follow-up data, which included angiography, he noted that although in general graft disease afflicts 75% of grafts during the first decade, there is a subgroup of patients who have pristine-looking grafts at recatheterization after 5 years, and often after 10 years. His view on the replacement of angiographically normal grafts after 5 years by another vein segment was, "probably not". Lytle [14], after studying a large number of patients, concluded that either early symptomatic vein graft stenoses or late asymptomatic graft stenoses, which are multiple, in the left anterior descending distribution, or affect large areas of myocardium, warrant surgical intervention. Despite this extensive review, no recommendations pertaining to angiographically disease-free grafts at reoperation were made. Recently, Mehta and colleagues [7] have shown clinical evidence that nonreplacement of disease-free SVGs at the time of redo revascularization, 0.5 to 18 years (mean, 9.25 years) after the initial operation, confers no clinical disadvantages and possibly advantages. Factors including operative outcome, angina relief, incidence of late myocardial infarction, and long-term survival were evaluated.
Since the time of the recommendation by Marshall and colleagues [6], major advances have been made in basic vascular biology. It is now known that the endothelium is responsible for initiating many of the changes observed in SVGs. The endothelium regulates relaxing and vasoconstrictive properties, as well as anti and procoagulation [15]. In addition, the endothelium serves a significant immune function [15]. Damage to the endothelium effects all of these properties, and may occur at 3 time points: immediate, early, and late.
Initially, endothelial damage can occur during harvesting from direct mechanical trauma, overdistention, exposure to solutions of low-oncotic pressure, or from prolonged exposure to hypothermia [16]. Additional factors occur with the institution of cardiopulmonary bypass with activation of leukocytes and platelets, leading to a cascade of neural, immune, and inflammatory changes. At this early stage, the principal underlying mechanism is graft thrombosis. Not surprisingly, SVG occlusion, with or without symptoms, occurs within the first month after bypass operation in 7% to 10% of cases [3, 4].
Intimal hyperplasia, defined as the accumulation of smooth muscle cells and extracellular matrix in the intimal compartment, is the major disease process in venous grafts between 1 month and 1 year [17]. This process, in itself, can cause significant stenosis, as well as predispose for development of graft atheroma. Hyperplastic changes can progress and may exert an adverse affect for up to 5 years postoperatively [7]. Many years of vascular research have not yet yielded a satisfactory explanation for this phenomenon. Theories of ischemic injury, occurring at the time of harvest or at a later stage from loss of vasa vasorum, and the effects of flow velocity and shear-stress have been proposed [17]. Suffice to say, the endothelium plays a key role in regulating intimal growth, and a chronic injury situation with efforts of repair leading to deranged autoregulatory processes is involved.
Lastly, progression of the atherosclerotic process generally affects the SVG. Necropsy studies have found evidence of atheromatous plaques as early as 1 year after CABG [18], but hemodynamically important stenoses, which result in recurrent symptoms, rarely occur before 3 years after grafting [17]. Fitzgibbon and colleagues [5] have reported an incidence of significant atherosclerotic angiographic changes (irregularity of > 50% of the estimated intimal surface) of 22% at 5 years and 43% at 10 years in patent grafts. Physiologic and biochemical factors, which include intimal hyperplasia, have been implicated in this accelerated process.
Endothelial derived NO is produced by 1 of 3 isozymes known as the NO synthases, and is specifically restricted to the endothelium. Decreased NO production is detectable in vascular disease states, such as intimal hyperplasia [19] and atherosclerosis [20]. Nitric oxide is evoked from the endothelium by opiate alkaloids through the µ3 receptor [11, 12]. Through this mechanism, it is possible to assess an aspect of the physiologic functioning of SVGs. Mehta and colleagues [7] proposed from clinical outcomes that angiographically pristine grafts observed at long-term follow-up may be considered biologically privileged. These grafts were capable of overcoming each of the above-mentioned patency pitfalls and have been selected out from the native population. Our data supports this theory. Saphenous vein grafts, which were classified in angiographic excellent condition, exhibited an equivalent amount of NO release as native saphenous vein, while grafts that were deemed to be heavily diseased by angiographic criteria essentially showed no response to stimulation. Angiographic criteria for evaluating disease, atherosclerosis, and intimal hyperplasia, coincided with physiologic findings relating to disease evaluation. Therefore, grafts that have no angiographic disease at long-term follow-up provide the same physiologic function in terms of endothelial NO release as native saphenous vein, despite previous harvesting, arterial anastomosis, and long-term arterial flow dynamics. For these reasons, we believe that pristine grafts, though aged, have an equal to better chance of continued patency compared to new SVG conduits. This observation does not explain why in a patient with a pristine vein graft, the neighboring graft, presumably harvested from the same leg under the same conditions, fares worse.
In conclusion, routine replacement of SVG conduits which are beyond 5 years of age at the time of redo CABG despite angiographic findings is a common practice at many institutions. The original evidence for this dictum was based on angiography underestimating pathologic evaluation of vascular disease. Recent evidence has shown no clinical disadvantages, and even advantages, of not replacing angiographically pristine grafts at long-term follow-up [7]. Measurement of endothelium-derived NO supports these clinical findings, and current modes of angiography appears to be accurate for disease evaluation. In our opinion, SVG conduits with no evidence of disease at long-term follow-up are biologically privileged, and should not be definitively replaced.
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Accepted for publication October 18, 1999.
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Abstract
Introduction
) disease-free, (
) moderate disease, (•) severe disease.