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Ann Thorac Surg 2004;78:1312-1318
© 2004 The Society of Thoracic Surgeons

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Original article: cardiovascular

Intimal Hyperplasia and Expression of Transforming Growth Factor-ß1 in Saphenous Veins and Internal Mammary Arteries Before Coronary Artery Surgery

^a Department of Cardiac Surgery, University Hospital Ulm, Ulm, Germany
^b Division of Nephrology, University Hospital Ulm, Ulm, Germany
^c Department of Cardiology, University Hospital Ulm, Ulm, Germany
^d Department of Cardiology, University Hospital Maastricht, Maastricht, the Netherlands

Accepted for publication February 18, 2004.

^* Address reprint requests to Dr Stracke, Division of Nephrology, University Hospital of Ulm, Robert-Koch Str 8, 89081 Ulm, Germany
sylvia.stracke{at}medizin.uni-ulm.de

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
BACKGROUND: The development of fibromuscular intimal hyperplasia and subsequent graft failure remains an urgent problem in cardiac surgery. Transforming growth factor-ß1 (TGF-ß1) is involved in the pathogenesis of arteriosclerosis through induction of extracellular matrix proteins. We tested the hypothesis that intimal hyperplasia is already present in human saphenous veins and left internal mammary arteries before coronary artery bypass surgery and is associated with an increased expression of TGF-ß1.

METHODS: Forty-six segments of saphenous veins and 27 of left internal mammary arteries were collected from 50 patients undergoing coronary artery bypass surgery. Morphometric analysis was performed by microscopic computer analysis. Immunohistochemistry was performed with antibodies directed against TGF-ß1, its latent binding protein (LTBP-1) and its type 2 receptor (RII).

RESULTS: The incidence of intimal hyperplasia was significantly higher in saphenous veins (67.4%) than in mammary arteries (29.6%; p < 0.05). Saphenous veins and mammary arteries with intimal hyperplasia expressed more TGF-ß1 (endothelial and intimal layers) and LTBP-1 (intimal and medial layers) when compared with corresponding vessels without hyperplasia (both groups p < 0.05). Endothelial and intimal RII expression was significantly higher in saphenous veins with intimal hyperplasia as compared with saphenous veins without hyperplasia (p < 0.05). Transforming growth factor-ß1 staining in the intima correlated with the presence of an intimal hyperplasia in saphenous veins ( = 0.317) and mammary arteries ( = 0.428).

CONCLUSIONS: Local TGF-ß1 expression is associated with the presence of intimal hyperplasia in the examined vessels. Preexisting intimal hyperplasia is more prevalent and serious in saphenous veins than in left internal mammary arteries, giving further explanation to the superior long-term results of left internal mammary grafts.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Coronary artery bypass graft disease represents an important and unresolved medical problem and leads to a significant economic burden. Over a 10-year period, only 50% of human saphenous vein (HSV) grafts remain patent [1]. The additional use of the internal mammary artery (IMA) has resulted in better clinical long-term results [2] because of its superior late patency, which is reported as high as 90% over a 10-year period [3, 4].

In HSV grafts, fibromuscular intimal hyperplasia develops within 1 year after coronary artery bypass grafting (CABG) and represents a precursor to arteriosclerosis, leading subsequently to graft thrombosis and occlusion [5–7]. Intimal hyperplasia is characterized by the migration and proliferation of vascular smooth muscle cells with concomitant deposition of extracellular matrix and also appears to be the cause of late occlusion in IMA grafts [4, 8].

Several in vitro studies have successfully linked transforming growth factor-ß1 (TGF-ß1) to the development of intimal hyperplasia by deposition of extracellular matrix [9–11]. Transforming growth factor-ß1 is produced by vascular endothelial cells, vascular smooth muscle cells, and inflammatory cells. It seems to enhance intimal thickening in both arteries and veins. In an artery injury model, this effect could experimentally be provoked by administration of TGF-ß1 [10] and suppressed by the use of a neutralizing antiserum against TGF-ß1 [12]. Recently, we described TGF-ß1 overexpression in the intimal hyperplasia of stenosed venous hemodialysis fistulas [13].

Transforming growth factor-ß is a family of regulatory proteins (TGF-ß 1 to 3) that exhibit their effects by binding to cell-surface receptors. Three distinct receptors (type 1, 2, and 3) have been identified in a variety of cells including vascular smooth muscle cells. The type 1 and type 2 TGF-ß receptors are serine threonin kinases and are responsible for signal transmission [14]. Transforming growth factor-ß is released as an inactive high-molecular weight mass complex. The large latent complex of TGF-ß1 from human platelets has been purified and characterized. This complex contains three components: the mature TGF-ß1, the latency-associated peptide and the latent TGF-ß1 binding protein (LTBP) [15]. Latent TGF-ß1 binding protein-1 has been suggested to play a role as an extracellular fibrillar structure in the storage of TGF-ß1 as a large latent TGF-ß1-complex. Transforming growth factor-ß1 is stored in its latent form in the extracellular matrix and is released by proteases cleaving LTBP-1, subsequently localized to the cell surface by either latency-associated peptide or LTBP-1, and activated by cell-associated plasmin [16].

Many studies address the problem of arteriosclerosis in IMA and HSV bypass grafts after CABG. In contrast, we tested the hypothesis that intimal hyperplasia as the first pathogenic mechanism of early graft-arteriosclerosis is already present in HSV and IMA at the time of operation and that in areas of intimal hyperplasia an increased growth factor expression can be found. We therefore compared the incidence of intimal hyperplasia in HSV and IMA in a group of patients in whom both vessels were harvested for CABG. Comparative histopathology and morphometric analysis were carried out. Immunohistochemistry was performed to assess the expression of TGF-ß1, its binding protein LTBP-1, and the type 2 TGF-ß receptor (RII).

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Patients
From August to November 2000, 50 consecutive patients who underwent CABG were included in a prospective study. Informed consent was obtained from all patients. There were 38 male (76%) and 12 female patients (24%). The mean age at operation was 65.1 ± 7.9 years (range, 48 to 79). The vessels diseased ranged from 1 to 3 arteries, including 9 main-stem stenoses. All patients underwent myocardial revascularization with the use of HSV or IMA grafts, or both.

Harvesting of HSV and IMA
Forty-six HSV and 27 IMA segments were collected from 50 patients. There were 20 paired HSV and IMA vessel segments from 20 patients. A segment (approximately 1 to 2 cm) of the distal ends of HSV and IMA grafts were obtained immediately after surgical harvesting and collected in cold Bretschneider cardioplegic solution containing sodium heparin, 4 IU/mL. Tissue specimens were transported at 4°C to the laboratory and immediately snap frozen in cold isopentane cooled by liquid nitrogen and stored at –80°C until processed for immunohistochemistry.

Histologic and Morphometric Analysis
In all, 73 vessels were suitable for histologic and morphometric analysis. Multiple transverse specimens of the vessels were cryosectioned at 5 µm and stained with hemalaun. The specimens were examined by two independent viewers (SS, JL) blinded to the clinical data and origin of the vessels. The HSV and IMA vessel segments were recorded as normal if there was no cellular or stromal tissue between the endothelium and the internal elastic lamina. The HSV and IMA segments were recorded as having various degrees of intimal hyperplasia when the vessels showed fibrous tissue or intimal cells between the endothelium and the internal elastic lamina. The morphometric measurements of the vessels were analyzed with a Nikon microscope and a color image analysis system (Digital image analyzer, software from Bilany Consultants GmbH). Each measurement was performed three times in a blinded fashion as previously described [17]. In this study, two standardized indices [18] were used to evaluate the degree of intimal thickening and arteriosclerosis: (1) intimal thickness index (ITI) = intimal area/medial area, and (2) intima-to-media ratio (IMR) = width of intima at maximal intimal thickness/width of media at maximal intima thickness.

Antibodies
Antihuman–latency-associated peptide (TGF-ß1) and antihuman–TGF-ß-type 2 receptor (RII) were purchased from R&D Systems (Wiesbaden, Germany). Antihuman–LTBP-1 as well as all secondary antibodies and blocking sera were purchased from Santa Cruz (Heidelberg, Germany).

Immunohistochemistry
The vascular segments were cryosectioned into 5-µm slices, fixed in ice-cold 100% acetone for 10 minutes, air dried, and stored at –80°C. Immunohistochemical staining was performed using the ABC method with various primary antibodies as previously reported by our group [13]. The stained sections were evaluated by two of the authors independently (SS, JL). Photomicrographs were taken with a light microscope (Axiophot; Zeiss, Oberkochen, Germany). A semiquantitative scheme was applied as described earlier [13] to evaluate tissue sections referring to the intensity of the immunostaining, as follows: 0 = no staining, 1 = weak staining, 2 = moderate staining, 3 = strong staining.

Statistical Analysis
To compare the incidence of intimal hyperplasia in HSV and IMA grafts, as well as to compare the expression of peptides between different vessels, statistical calculations were peformed on both the morphometric and the semiquantitative immunostaining data using the SPSS system applying the Kruskal-Wallis test (² approximation), Mann-Whitney U test, and Holm's adjustment. The nonparametric Spearman correlational analysis between rank-ordered raw numbers was used to assess the correlational pattern between TGF-ß1 staining intensity and the indices of intimal hyperplasia. Results were considered significant with a probability level of p less than 0.05 and are given as median (first quartile; third quartile).

	Results

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Histopathology
Among 46 HSV vessel segments examined, various degrees of preexisting intimal hyperplasia were detected in 31 grafts (67.4%; Fig 1A). In other 15 HSV segments (32.6%), no preexisting intimal hyperplasia was detected (Fig 1B). Among 27 IMA vessel segments examined, there were 8 grafts (29.6%) with mild to moderate intimal hyperplasia (Fig 1C), and another 19 grafts (67.4%) without (Fig 1D). The incidence of intimal hyperplasia was significantly higher in HSV grafts than in IMA grafts (p < 0.05; Fig 2). The pathologic changes that occurred in IMA grafts tended to be focal, while the pathologic changes in HSV grafts were more often concentric lesions. In 20 patients, we collected paired HSV and IMA segments from the same patient. Parallel to the whole group, intimal hyperplasia was detected in 13 (65%) of HSV segments and 6 (30%) of corresponding IMA segments (p < 0.05).

View larger version (127K): [in this window] [in a new window]   Fig 1. (A) Human saphenous vein (HSV) with a circumferential intimal hyperplasia and an increased staining for transforming growth factor-ß1 (TGF-ß1) in the endothelial, intimal, and medial layer (original magnification x5; inset x20). (B) A normal native HSV without any tissue between the endothelium and the internal elastic membrane. Transforming growth factor-ß1 staining in the medial layer is stronger than in the normal native internal mammary artery ([IMA] original magnification x5; inset x20). (C) Internal mammary artery with a focal intimal hyperplasia and an increased staining for TGF-ß1 in the endothelial, intimal, and medial layer (original magnification x5; inset x20). (D) Normal IMA with no stromal or cellular tissue between the endothelium and the internal elastic membrane. Staining for TGF-ß1 is weak (original magnification x5; inset x20).

View larger version (19K): [in this window] [in a new window]   Fig 2. The incidence of intimal hyperplasia (IH) was significantly higher in native human saphenous vein (HSV) compared with native internal mammary artery (IMA).

Expression of TGF-ß Type II Receptor in HSV and IMA Grafts
The expression of RII was found to be significantly higher in endothelial and intimal layers in diseased HSV when compared with normal HSV (p < 0.05; Table 3). The expression of RII was significantly higher in the media and the vasa vasorum in IMA with intimal hyperplasia when compared with IMA without intimal hyperplasia (p < 0.05). The expression of RII was also significantly higher in endothelial and intimal layers in HSV with intimal hyperplasia when compared with IMA with intimal hyperplasia (p < 0.05). The expression of RII was higher in all layers, except adventitia in HSV without intimal hyperplasia, than in IMA without intimal hyperplasia (p < 0.05). Human saphenous veins have an overall higher expression level of the TGF-ß RII than internal mammary arteries.

Correlational Analysis Between Indices of Intimal Hyperplasia and TGF-ß1 Expression in HSV and IMA Grafts
We evaluated the correlation between the indices of intimal hyperplasia and the local expression of TGF-ß1, LTBP-1, and RII in all vessel layers using Spearman correlational analysis. The intimal TGF-ß1 expression correlated with the presence of an intimal hyperplasia in HSV and IMA: in HSV grafts, the TGF-ß1 staining intensity in the intima weakly correlated with the ITI ( = 0.317, p < 0.05), but not with the IMR. In IMA grafts, TGF-ß1 staining intensity in the intima correlated with both the IMR ( = 0.536, p < 0.05) and ITI ( = 0.428, p < 0.05). There were no other correlations of peptide expression with the indices of intimal hyperplasia.

	Comment

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
In this communication, we have shown that intimal hyperplasia is present before CABG in two of the most frequently used bypass graft vessels, HSV and IMA. The incidence of intimal hyperplasia was significantly higher in native HSV (67.4%) compared with native IMA (29.6%). In areas of intimal hyperplasia, an increased expression of the proatherogenic growth factor TGF-ß1, its latent binding protein LTBP-1 and its type 2 receptor RII was seen. The expression of intimal TGF-ß1 correlated with the indices of intimal hyperplasia, ITI and IMR.

Intimal hyperplasia as a pathogenic feature has been described in arterial and venous bypass conduits after CABG, in homograft transplanted organs [8, 19], and in veins used as arteriovenous fistulas [13]. In a recent study, prebypass vein quality of 85 HSV was assessed for lower extremity revascularization [20]. In accordance with our results, intimal hyperplasia as a prebypass morphologic change occurred in about 80% of HSV. In other studies, mild to moderate intimal hyperplasia of the IMA at the time of operation was detected to a variable degree ranging between 22.5% [21] and 68.7% [18] whereas severe arteriosclerosis was rarely observed. From our morphologic findings in paired matches, it is further evident that these pathologic changes are more prevalent and serious in HSV grafts than in IMA grafts in the same patient. The preexisting intimal hyperplasia in IMA and HSV as well as the observed increased growth factor expression in the same patients are an indicator for the systemic nature of arteriosclerosis that affects not only arteries but also veins.

The relation between the extent of the intimal hyperplasia at the time of operation and the development of graft arteriosclerosis after CABG remains to be elucidated. So far, studies in stenosed and occluded arterial and venous bypass grafts demonstrate that intimal hyperplasia represents an accelerated stage of graft disease, leading subsequently to stenosis [4, 8, 13, 19]. Recently, a correlation between the extent of preexisting intimal thickness of HSV and smooth muscle cell proliferative activity with development of intimal hyperplasia has been shown in an in vitro tissue culture system [22]. We have now demonstrated that intimal hyperplasia as an initial step in the pathogenesis of coronary graft disease already starts in the native HSV and IMA vessels.

Until now, studies investigating the involvement of growth factors in coronary graft disease have mainly been performed in occluded or stenosed bypass vessels, either in animal studies [23], by in vitro tissue culture [24, 25], or in postmortem specimens [4]. These studies show intimal hyperplasia in a high percentage in the diseased graft vessels and also an increased expression of locally active growth factors as platelet-derived growth factor, basic fibroblast growth factor, or TGF-ß1 [26, 27]. We now could demonstrate that already at the time of operation, an increased expression of TGF-ß1 in areas of intimal hyperplasia is present in vivo, suggesting a role of TGF-ß1 in the development of intimal hyperplasia in the in situ HSV and IMA. Our findings oppose the view that increased growth factor expression may simply be the result of arterialization of a vein.

Furthermore, in a rat animal model, TGF-ß gene transcription was upregulated in arterialized vein grafts between 1 and 4 hours, with prominent mRNA expression from 1 day to 2 weeks [28, 29]. An upregulation of TGF-ß mRNA has also been found in vein bypass atherectomy specimens with prominent extracellular matrix deposition [30]. Increased flow and shear stress also mediate the release of TGF-ß1 in rabbit arteries [9]. Overexpression of TGF-ß1 could be demonstrated by us previously in venous stenoses of hemodialysis fistulas [13]. We conclude that graft vessels with preexisting intimal hyperplasia are already in a chronic adaptive state of remodeling and are possibly more susceptible to develop accelerated graft arteriosclerosis secondary to a further upregulation of TGF-ß1 release after surgery.

Patients needing CABG most likely suffer from generalized arteriosclerosis affecting both arteries and veins. Human saphenous veins are more severely and more often diseased than IMAs. In areas of intimal hyperplasia, the expression of the proatherogenic growth factor TGF-ß1, its binding protein LTBP-1 and RII are all significantly increased, thus possibly leading to overt and irreversible deposition of extracellular matrix. This process may even be aggravated after arterialization, as may be suspected from studies in occluded bypass grafts [4, 30]. However, we are aware that the development of graft stenosis is a multifactorial process involving many other cytokines such as, for example, vascular endothelial growth factor, stimulating an increased release of nitric oxide in IMAs [31]. Especially the fact that IMA endothelial cells release more nitric oxide than HSV endothelium gives further explanation to the differences between IMA and HSV long-term results [32].

Our data provide additional and independent evidence for the superiority of the IMA as the conduit of choice for the routine bypass operation. For patients needing multivessel bypass, it is recommended to carefully choose the vein graft using any available method. For future therapeutic strategies, it might be helpful to develop principles directed against overexpression of TGF-ß1 that can be applied locally within the grafted vessels.

	Acknowledgments

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
The authors thank Rosa Herzog for skillful technical assistance. The work of Dr Waltenberger was supported by a Heisenberg Career Development Scholarship from the German Research Council DFG (Wa 734/5–1).

	References

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Reinhard Friedl Jun Li Bernd Schumacher Andreas Hannekum Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Friedl, R. Articles by Stracke, S. Search for Related Content PubMed PubMed Citation Articles by Friedl, R. Articles by Stracke, S. Related Collections Coronary disease