Ann Thorac Surg 2000;70:1338-1344
© 2000 The Society of Thoracic Surgeons
Original articles: cardiovascular
Histology and morphology of 59 internal thoracic artery grafts and their distal anastomoses
Matadial Ojha, PhDa,c,
Richard L. Leask, MASca,
K. Wayne Johnston, MDa,c,
Tirone E. David, MDc,
Jagdish Butany, MDb
a Institute of Biomedical Engineering, University of Toronto, Canada
b Department of Pathology, The Toronto Hosital and University of Toronto, Toronto, Ontario, Canada
c Department of Surgery, The Toronto General Hospital and University of Toronto, Toronto, Ontario, Canada
Address reprint requests to Dr Butany, Department of Pathology, The Toronoto General Hospital, 200 Elizabeth St, E4-316, Toronto, Ontario, Canada M5G 2C4
e-mail: jagdish.butany{at}uhn.on.ca
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Abstract
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Background. The left internal thoracic artery (LITA) is accepted as a superior graft for the left coronary system because of its better long-term patency rate than saphenous grafts. The postsurgical histomorphometric changes at the distal anastomsis of LITA grafts are not well documented.
Methods. The cellular changes within the intima of 59 LITA grafts were analyzed by light microscopy.
Results. Grafts implanted 1 week or less (n = 34) showed no postsurgical tissue proliferation. Of the 7 grafts implanted 1 to 8 weeks, only the suture sites exhibited intimal thickening (6 of 7 grafts, 0.08 ± 0.07 mm). The remaining grafts (n = 18), aged 2 months to 10 years, showed significant intimal thickening at the suture sites (0.39 ± 0.17 mm) and on the hood (0.29 ± 0.25 mm), with variable thickening on the floor (10 of 18 left anterior descending coronary arteries, 0.11 ± 0.12 mm). The graft body showed insignificant intimal changes (10 of 18, 0.03 ± 0.04 mm), with mild focal atherosclerotic lesions in 2 of 18 late LITA grafts.
Conclusions. Left internal thoracic artery grafts develop fibromuscular intimal hyperplasia primarily around the anastomotosis. The response on the hood appears to be a hemodynamic response, secondary to that of the suture sites.
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Introduction
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The left internal thoracic artery (LITA) is used routinely as a bypass graft to restore blood flow to the left anterior descending coronary artery (LAD). Over a 10-year period, the patency rate for LITA grafts is reported as high as 90% versus 50% for saphenous vein grafts (SVGs) [1, 2], resulting in better patient survival with the use of an LITA graft [3].
Early LITA graft failure is attributed to technical errors and distal anastomosis [1, 4]. Fibromuscular intimal hyperplasia (IH) appears to be the cause of late occlusion of LITA grafts [5], in contrast to vein grafts, in which the degree of fibromuscular intimal thickening (IT) appears to reach a plateau at 1 year with subsequent failure from the progression of fibrous plaque and thrombosis [6]. Angiographic evaluation indicates that narrowing of LITA grafts develops at the distal anastomosis [1]. A small study (four grafts) by van Son and colleagues [7] showed that the degree of IT decreases from the proximal to the distal segments within the body of LITA grafts. Other studies have shown LITA grafts to rarely develop atherosclerosis (< 5%) [8, 9].
There are few additional data available on the presence and progression of intimal proliferation within LITA grafts and none regarding changes at the distal anastomoses, even though angiographic data suggest that this is the site of late LITA graft stenosis [1, 4]. This retrospective study of the body and distal anastomosis of LITA grafts was undertaken to document, in detail, the histomorphologic changes that occur at these sites and to compare the data with our previous study on aortocoronary SVGs [6]. This information provides insight into the long-term patency and success of LITA grafts and demonstrates the nature and detailed localization of changes at the distal anastomosis.
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Material and methods
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The LITA used as a bypass graft to the LAD and its distal anastomosis were excised from 49 hearts at autopsy and 10 at transplantation (recipient hearts) at The Toronto General Hospital (n = 48) and The Ottawa Civic Hospital (n = 11) over a 4-year period. After detailed gross examination, the hearts were fixed in 10% phosphate-buffered formalin. The fixed vessels were excised and decalcified as necessary.
Five to ten tissue blocks were processed for light microscopy from each LITA graft, and reviewed. One complete cross section of the anastomosis and up to five cross sections from the body of the graft were selected for analysis. Care was taken to obtain segments of the graft body which showed tissue cut at right angles to the long axis of the LITA and, at the anastomosis, at right angles to the host artery (Fig 1). The sections were stained with hematoxylin and eosin, a combined Verhoff elastic-Masson trichrome stain, or Movat pentachrome stain. Some sections were also stained immunohistochemically with antibodies (Dako Diagnostics, Mississauga, Ontario, Canada) to factor VIII and smooth muscle actin to identify endothelial and smooth muscle cells (SMC), respectively.
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Fig 1. (A) The distal anastomosis and the central anastomotic cross section. (B) A central anastomotic cross section indicating the anastomotic measurement sites (hood, sutures, and floor). The hood (the section of the internal thoracic artery) is on the top and the floor (the section of the left anterior descending coronary artery [LAD]) is at the bottom. The inner black line (arrows in all relevant figures) is the internal elastic lamina and is seen on both the left internal thoracic artery (LITA) and the native coronary artery. Significant intimal thickening is seen on the hood and the suture sites (S).
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There was one in situ LITA graft per heart and one to four SVGs. Thirty-four LITA grafts had been in place 1 week or less and showed no noticeable postsurgical intimal changes. Clinical data for the 25 LITA grafts in situ for more than 1 week are shown in Tables 1 and 2. Seven of these cases were classified as early, in situ for 1 to 6 weeks (Table 1), and the remaining 18 were classified as late grafts, in situ 2 months to 10 years (Table 2).
The Leica QMC500 morphometric package and a DMRB photomicroscope (Leica, Toronto, Ontario) were used to measure postsurgical IT in the graft and around the LITA/LAD anastomosis. In the body of the graft, the thickness at each site was taken as the average of 15 equally spaced measurements around the circumference of the artery. At the distal anastomosis an intact central section between the heel and toe junctions was analyzed (Fig 1A), and the thickness was obtained at the locations around the anastomosis (Fig 1B). Measurements were made at the midpoint on the hood of the LITA graft, the two suture sites, and the midpoint of the floor or arterial wall. For each of these sites, seven points were digitized and the averaged value was recorded.
For the LAD, only the postsurgical IT was measured. The preexisting IT was identified by the presence of dense collagen, focal calcification, foam cells, cholesterol clefts, necrotic debris, and a usually evident line of demarcation between the old and recent IT.
Morphometric data are presented as mean ± 1 standard deviation. For hypothesis-based testing, no assumption was made about the distribution of the data. When comparing the same site at different time periods or graft type, a nonparametric t test was employed. A Kruskal-Wallis test was used for the late case data to evaluate deviation of the thickness for all sites, with a post-Dunn’s multiple comparison test to compare between the individual sits. A value of p less than 0.05 was considered significant. All statistical calculations were performed with GraphPad Prism Software (GraphPad Software, Inc, San Diego, CA).
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Results
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Grafts in situ 1 week or less
LITA grafts, in situ 1 week or less (n = 34), showed no visible neointimal thickening or change. The intimal cells were not always apparent and, when present, were only a few cell layers thick. A distinct wavy internal elastic lamina separated the intima from the media for grafts of all ages (Figs 2A, 2B). The media consisted of layers of elastic laminae separated by SMCs and variable amounts of collagen. Few discontinuities were evident in the SMCs or the elastic lamellae of the media. The adventitia was comprised of elastic tissue interspersed in densely packed collagen rings around the external elastic lamina. At the suture sites, no postsurgical thickening was evident. A variable (usually thin) rim of thrombus was seen around the suture sites and consistently around exposed sutures.
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Fig 2. Sections of an early and late left internal thoracic artery (LITA) graft body (A, B), anastomostic suture sites (S) (C, D), hood of the anastomosis (E, F), and floor of the host left anterior descending coronary artery (LAD) (G, H). The early sample (case 7) was in situ for 2 weeks whereas, the late sample (case 18) was in situ for more than 6 years. Arrows indicate the internal elastic lamina; arrow- heads show suture site neointima. (Movat pentachrome stain.)
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Early grafts
The most notable change in the seven grafts in situ 12 days to 2 months was the development of IH at the suture sites (Fig 2C). Suture site IH, evident in 6 of 7 (86%) grafts, consisted of SMC, collagen, and elastic tissue. The earliest sign of IT occurred in the "cleft" between the two vessels (the microscopic notch on the intimal surface created by the anastomosis of the two vessels). This loose cellular mass with an endothelial cell lining bridged the gap between the two vessels (Fig 2C). The degree of IT increased around exposed sutures. Limited postsurgical thickening was present on the hood of the anastomosis in 2 of 7 (29%) and on the floor of the LAD in 1 of 7 (14%) (Figs 2E, 2G). This growth was predominantly cellular, stained positively with SMC actin, consistent with a myogenic origin. Overall, thickening in the graft body (2 of 7, 29%), hood, and floor of the anastomosis was insignificant but highly variable. Only the suture sites displayed consistent IT.
Late grafts
Intimal thickening was present in 10 of 18 (56%) LITA grafts in situ 2 months or longer. The intima consisted of SMCs dispersed in a loose matrix of collagen and elastic fibers. Two grafts showed small focal infiltrates of lipid in the intima. Overall, the intimal thickness of these late grafts (0.03 ± 0.04 mm) was not significantly different from that seen in the early cases (p = 0.62). However, there was a distinct qualitative and structural difference, with the early IT being cellular and loose in appearance and the late cases showing mainly collagen, elastic, and some cellularity close to the lumen. The IT at the central section of the floor was similarly highly variable (0.11 ± 0.12 mm), with only 10 of 18 anastomoses exhibiting any significant neointima, similar to the early cases (p = 0.082). Identifying the luminal edge of preexisting plaques on the floor of the LAD was at times difficult, especially with older grafts as seen in Figure 2H. In this case, the floor shows old fibrous intima, which is more yellow in hue, with superimposed postsurgical IT.
The suture sites and hood developed a significant intimal "cushion" that became more collagen rich and less cellular with age (Figs 2C, D). The late case suture site (Fig 2D) displays an old healed anastomotic site 6 years postsurgical procedure (case 18). Mature collagen is evident in the intima at the suture site and along the LAD. On the LITA side, away from the suture site, more SMCs are evident in the intima (purple color). At the hood, a significant intimal mass of collagen and SMC is seen, with increased cellularity near the lumen (Fig 2F). The mean suture site thickness (0.39 ± 0.17 mm) was greater than the mean thickness on the hood (0.29 ± 0.25 mm), though statistically indistinguishable (p > 0.05). The hood and suture site displayed consistent IT in all samples (16 of 18 and 18 of 18 samples, respectively, with measurable IT), whereas the floor and graft exhibited a large variability in neointimal thickness (10 of 18 for both sites). The greatest increase in thickness between the early and late grafts occurred on the hood (14.5 times greater than the early thickness).
Late grafts: SVG versus LITA
Our previous study summarized the morphology of SVG aortocoronary distal anastomosis [6] and showed that the hood of the SVG is the site of greatest IT, with approximately two thirds of this thickness seen at the suture site and one third in the graft body [6]. Figure 3 shows sections of an SVG graft anastomosed to the obtuse marginal coronary artery and a LITA graft to the LAD from the same heart harvested 5.6 years postsurgical procedure. A distinct difference is seen in both the media and intima of the two graft bodies (Figs 3A, B). Less collagen and more elastin and smooth muscle were apparent in the LITA grafts. The venous graft body develops a diffuse IT that is about three times greater than that of the LITA graft body. Neointimal thickening at the suture sites (Figs 3C, D) led to a smooth transition from the graft to the native artery with no apparent hump or indentation. The hood (Figs 3E, F) shows a similar composition to that seen in the graft body, and the floor in both cases (Figs 3G, H) shows old plaque with superimposed postsurgical thickening.
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Fig 3. Sections of an old sapheous vein graft (SVG) and left internal thoracic artery (LITA) graft taken from the graft body (A, B), suture site (S) (C, D), hood (E, F) and floor (G, H). Both grafts were removed from the same patient, 5.6 years after bypass operation (late case 7). Arrows indicate the internal elastic lamina; arrowheads show suture site neointima. (LAD = left anterior descending coronary artery;OM = obtuse marginal coronary artery.) (Elastic trichrome stain.)
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Overall, significantly more intimal thickness developed at all sites in the SVGs compared with the LITA grafts, as shown in Figure 4 (graft p < 0.001, hood p = 0.0027, suture p = 0.033, and floor p = 0.012). In addition, intimal thickness at all sites of the SVGs and anastomoses was far less variable than in the LITA grafts.
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Fig 4. Comparison of left internal thoracic artery (LITA) (n = 18) and saphenous vein graft (SVG) (n = 16) [6] intimal thickening. The error bars represent 1 standard deviation.
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Comment
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Left internal thoracic artery grafts to the left coronary system are a routine part of planned coronary artery bypass grafting (CABG) owing to their excellent long-term patency. This superior patency is reflected in the increased survival statistics of CABG patients who have had a LITA graft [3]. Several previous studies have evaluated the morphology and histology of LITA graft bodies both before and after implant and compared them wit aortocoronary SVGs [4, 5].
However, no study has focused on the histomorphometry of the distal anastomosis of LITA grafts, which is often reported in clinical studies as the location of early LITA graft failure [4]. Angiographic studies have also shown narrowing at the distal anastomosis of venous and arterial grafts, in situ 6 months or more, to be a cause of graft failure [1].
In this study, we found that fibromuscular IT developed mainly around suture sites, followed by the hood and the floor of the LAD. This pattern of intense suture and hood thickening is similar to that seen in aortocoronary SVGs [6], however, the SVGs showed diffuse thickening throughout the grafts, a feature that was insignificant in the LITA grafts. Intimal thickening on the hood has not been reported in previous LITA coronary bypass studies or in studies focusing on the anastomotic region of peripheral bypass grafts.
Graft body
Left internal thoracic artery grafts in situ 2 months or more showed small but variable intimal thicknesss, similar to that seen in early LITA grafts. It is unclear why LITA grafts show relatively low levels of IT and atherosclerosis [8, 9]. Intrinsic factors such as an ability to enlarge over time and increased vasoactivity could protect LITA grafts [10]. Similarly, the LITA elastic medial structure [11], its increased lymphatic drainage, and the presence of vasovasorum and bed runoff [8, 12] are believed to help limit intimal accumulation. These grafts are also reported to produce more prostacyclin and nitric oxide and possess fewer basic fibroblast growth factor receptors than do SVGs [10, 13, 14], which may also inherently limit hyperplasia.
Less manipulation and trauma during surgical preparation and the necessity of SVGs to adapt to arterial hemodynamics likely favor the LITA graft [15]. Although both conduits are placed in the coronary circulation, their flow dynamics differ significantly. Peak flow occurs during diastole in the distal sections of the LITA and in systole in the proximal regions, whereas flow in the SVG occurs predominately in diastole along the length of the conduit [16]. This phase-dependent flow pattern together with discrepancy in graft diameter and compliance will alter the tangential stress within the graft. Also, the larger diameter of the SVG under similar flow rates will result in a lower basal wall shear rate, possibly favoring IT [17].
Anastomosis
The first visible cellular response to coronary artery bypass grafts appears at the suture sites within 2 weeks of operation, with the presence of neovasculature and cellular intimal proliferation being regarded as a response to surgical trauma or wound healing. This cellular response appears to start at the graft/artery interface with the neointima bridging the gap between the graft and native artery. Further stimulus is likely provided by protein synthesis and the release of growth factors and autacoids [18] promoted by localized tensile stress concentrations from compliance mismatch at the suture sites [19].
Unlike the body of the LITA graft, the hood develops significant IH. It is unlikely that this proliferation is driven by an intrinsic change along the graft, as van Son and coworkers [7] have shown the distal region of LITA grafts to have the least IT. Trauma to the hood during operation and dissection of the pedicle at the distal anastomosis may induce a cellular response [20]. The reaction at the hood, however, was slower than the response seen at the suture sites, suggesting that surgical trauma is not the only cause of IH at the hood. Hood thickening may be a continuation of the suture site hyperplasia; however, in SVGs the hood revealed the greatest degree of IT, suggesting an active IH response rather than a simple progression of suture line thickening. Increased tensile stress because of compliance mismatch and heart vessel motion may produce a proliferative environment. The curvature at the hood and expansion through the anastomosis could induce unusual shear stress patterns (both temporally and spatially) that promote IH as reported elsewhere [21].
Conclusions
The LITA is widely accepted as a superior graft for the coronary artery system because of its increased long-term patency and associated high survival rate. The lack of LITA graft body IT is undoubtedly linked to the success of these conduits. We found that the distal anastomosis develops significantly more IT than the graft body. The suture site response to the surgical procedure begins early and develops the most IT. The reason for the increased thickening seen along the hood of the anastomosis is unclear, but we suggest a unique hemodynamic feature of vascular end-to-side anastomoses. In time, progression of IT at the anastomosis could lead to late LITA graft failure. Further understanding of the genesis of distal anastomotic IT may improve the long-term results of arterial and saphenous vein coronary bypass grafts.
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Acknowledgments
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Financial support from the Heart and Stroke Foundation of Ontario (grant NA-3476 MO, Jagdish Butany), the R. Fraser Elliot Chair in Vascular Surgery (K. Wayne Johnston), and the Natural Sciences and Engineering Research Council of Canada (Richard L. Leask) is gratefully acknowledged.
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Accepted for publication May 13, 2000.
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Abstract
Introduction
