Abstract
Background: The saphenous vein (SV) is used as an essential conduit in coronary artery bypass grafting (CABG), but the long-term patency of SV grafts is a crucial issue. The use of the novel “no-touch” technique of harvesting the SV together with its surrounding tissue has been reported to result in good long-term graft patency of SV grafts. We recently showed that perivascular adipose tissue (PVAT) surrounding the SV (SV-PVAT) had lower levels of metaflammation and consecutive adipose tissue remodeling than did PVAT surrounding the coronary artery. However, the difference between SV-PVAT and subcutaneous adipose tissue (SCAT) remains unclear.
Methods and Results: Fat pads were sampled from 55 patients (38 men, 17 women; mean [±SD] age 71±8 years) with coronary artery disease who underwent elective CABG. Adipocyte size was significantly larger in SV-PVAT than SCAT. The extent of fibrosis was smaller in SV-PVAT than SCAT. There were no significant differences between SCAT and SV-PVAT in macrophage infiltration area, quantified by antibodies for CD68, CD11c, and CD206, or in gene expression levels of metaflammation-related markers. Expression patterns of adipocyte developmental and pattern-forming genes differed between SCAT and SV-PVAT.
Conclusions: The properties of SV-PVAT are close to, but not the same as, those of SCAT, possibly resulting from inherent differences in adipocytes. SV-PVAT has healthy expansion with less fibrosis in fat than SCAT.
The internal thoracic artery (ITA), saphenous vein (SV), radial artery, and right gastroepiploic artery are widely used as conduits in coronary artery bypass grafting (CABG).1 The ITA, a vessel resistant to atherosclerosis, is most commonly used as the gold standard graft material for CABG because of its excellent long-term patency.1 With the spread of percutaneous coronary intervention, the indication for CABG in recent years has been limited to severe coronary artery disease with multivessel disease. Therefore, vessels other than the ITA for grafts are frequently required. After the first report on the use of the SV for CABG in 1969,2 the SV graft remains the most commonly used conduit for CABG because it is located in a superficial position that makes it easily accessible.3 Furthermore, the SV can be used for multiple grafts because of its length. However, the long-term patency of the SV harvested using the conventional technique is a crucial issue.4 It has been reported that the long-term patency of conventional SV grafts is 50–61% over 10 years.5–7
Perivascular adipose tissue (PVAT) has been reported to be associated with the regulation of vascular tone and structure via adipose-derived factors that affect vascular remodeling and contribute to the protection or progression of atherosclerotic vascular disease.8 It has also been shown that metabolically driven chronic inflammation, called metaflammation, in PVAT is a causal factor for the development of arteriosclerosis.9 We previously proposed that PVAT surrounding the ITA is protected from metaflammation and consecutive adipose tissue remodeling and contributes to the decreased atherosclerotic plaque burden in the ITA, resulting in long-term patency of the ITA graft in CABG.10
As the second choice after the ITA, attention has recently been paid to the no-touch SV graft as well as the radial artery.11,12 The use of the novel “no-touch” technique of harvesting the SV together with its surrounding tissue has been reported to result in good long-term patency of SV grafts.12–14 The long-term patency of no-touch SV grafts at 16 years was comparable to that of ITA grafts.13 We previously showed that the anti-atherosclerotic phenotype of PVAT surrounding the SV (SV-PVAT) may be involved in this good patency.15
Conversely, subcutaneous adipose tissue (SCAT) has been shown to be less prone to metaflammation in white adipose tissue than in visceral adipose tissue.16 Because the SV is located on the surface of the lower limbs, it is possible that SV-PVAT has the same profile as SCAT. However, no study has compared the phenotypes of SV-PVAT and SCAT. Therefore, in the present study we investigated whether SV-PVAT and SCAT have distinct phenotypes in terms of histology, gene expression, and functional relevance to vascular remodeling in patients with coronary artery disease who have undergone elective CABG.
Methods
Study Patients
Patients diagnosed with coronary artery disease who underwent elective CABG surgery were consecutively recruited from Sapporo Medical University Hospital and the affiliated Hokkaido Ohno Memorial Hospital, Sapporo Central Hospital, Sapporo City General Hospital, Teine Keijinkai Hospital, and Otaru City General Hospital from March 2018 through March 2020. Patients treated with hemodialysis and those who underwent CABG without using the SV were excluded. Some of the recruited patients had been investigated in a previous study about SV-PVAT but not SCAT.15
The present study conformed to the principles outlined in the Declaration of Helsinki and was performed with the approval of the Ethics Committee of Sapporo Medical University (Reference no. 312-34). Written informed consent was received from all study participants.
Collection of Fat Pads
Fat pads of SV-PVAT from the area of the lower thigh SV and SCAT from beneath the skin of the upper abdomen near the sternum were collected during surgery before anticoagulation and establishment of extracorporeal circulation. SV-PVAT was collected using a conventional method, but not an endoscopic method, after harvesting the SV. Samples were divided into 2 parts: the first specimen was stored in formalin and embedded in paraffin for histological staining and the second was frozen in liquid nitrogen for mRNA isolation and real-time polymerase chain reaction (PCR).
Histological Analysis
Samples of fat pads were fixed in 10% formalin solution, dehydrated, and embedded in paraffin. Serial 5-μm sections were prepared, mounted onto glass slides, deparaffinized, and rehydrated through degraded ethanol. Tissues were stained with hematoxylin-eosin (HE) and Masson’s trichrome reagents. Immunohistochemical 3,3′-diaminobenzidine staining using mouse anti-cluster of differentiation (CD) 68 (Dako, Santa Clara, CA, USA), rabbit anti-CD11c (Abcam, Cambridge, UK), and mouse anti-CD206 (Abnova, Taipei, Taiwan) antibodies was performed as described previously.10,15 Control experiments were performed by omitting the primary antibodies or by adding goat anti-mouse or goat anti-rabbit immunoglobulins (Dako) as control primary antibodies.
Quantitative Image Analysis
Images were captured with a microscope (BZ-X700; Keyence, Osaka, Japan). Image analyses were performed using ImageJ and Fiji software. The cross-sectional area of an adipocyte in HE-stained sections was determined by calculating the mean area of 100 randomly selected adipocytes per optical field at a magnification of ×200. The results were averaged and are expressed as adipocyte size (μm2). After checking areas of HE-stained sections to avoid non-specific fibrosis staining in the adventitia, sections were chosen to stain the fibrosis area inside, but not at the edge, of adipose tissues from 32 consecutive patients for whom sections in a set of 2 parts of adipose tissue were all adequate. Fibrosis was assessed in Masson’s trichrome-stained tissue sections by quantifying the blue area (representing collagen) relative to the total tissue area at a magnification of ×100. Furthermore, macrophage infiltration in tissue sections was assessed by quantifying the area stained by anti-CD68, anti-CD11c, or anti-CD206 antibodies relative to the total tissue area at a magnification of ×200. For each quantitative analysis of fibrosis and macrophage infiltration, 3 randomly selected optical fields were examined per adipose tissue depot, and the results were averaged. The positive area is presented as a percentage of the total area. All measurements were performed in a double-blind manner by 2 different researchers. Intraclass correlation coefficients of intra- and interobserver variability for adipocyte size and area of fibrosis were >0.99.
Quantitative Real-Time PCR
Total RNA was isolated from samples using the miRNeasy Micro Kit (QIAGEN, Hilden, Germany) and the RNase-Free DNase Set (QIAGEN). The amount and quality of isolated RNA were determined spectrophotometrically using NanoDrop (Thermo Fisher Scientific, Waltham, MA, USA), and 500 ng total RNA was reverse transcribed by using the high-capacity cDNA archive Reverse Transcription Kit (Applied Biosystems, Foster City, CA, USA). Quantitative real-time PCR analysis was performed using SYBR green in the real-time PCR system (Applied Biosystems, Warrington, UK). The thermal cycling program was 10 min at 95℃ for enzyme activation, followed by 40 cycles of denaturation for 15 s at 95℃, 30 s of annealing at 58℃, and 30 s of extension at 72℃. The primers used in the present study are listed in Supplementary Table. To normalize expression data, 18s rRNA was used as an internal control gene. Results are presented as the relative expression of each target gene in each patient, with expression in SCAT set at 1.
Statistical Analysis
Numeric variables are expressed as the mean±SEM for quantitative real-time PCR data, as the mean±SD for normally distributed data, and as the median with interquartile range for skewed variables. Paired t-tests were used to detect significant differences in data between SV-PVAT and SCAT. P<0.05 was considered statistically significant. All data were analyzed using JMP Pro 16.0.0 for Macintosh (SAS Institute, Cary, NC, USA).
Results
Baseline Characteristics of Study Patients
The baseline characteristics of the 55 patients recruited to the study (38 men, 17 women) who underwent elective CABG surgery using the SVG are presented in Table 1. The age and body mass index of the recruited patients were 71±8 years and 23.3±4.8 kg/m2, respectively. Among the study cohort, 8 (14.5%) and 35 (63.6%) patients were current and former smokers, respectively. Most patients (92.8%) were diagnosed with multivessel coronary artery disease. There were 25 (45.4%), 44 (80.0%), 48 (87.2%), and 10 (18.1%) patients with diabetes, hypertension, dyslipidemia, and myocardial infarction, respectively. The left ventricular ejection fraction assessed by echocardiography was 56±12%. Data of laboratory measurements are presented in Table 2.
Table 1. Characteristics of Patients Recruited to the Study
| No. patients |
55 |
| Men (n) |
38 |
| Women (n) |
17 |
| Age (years) |
71±8 |
| Body mass index (kg/m2) |
23.3±4.8 |
| Waist circumference (cm) |
85.4±8.3 |
| Systolic blood pressure (mmHg) |
129±16 |
| Diastolic blood pressure (mmHg) |
67±14 |
| Pulse rate (beats/min) |
70±9 |
| Smoking habit |
| Current smoker |
8 (14.5) |
| Former smoker |
35 (63.6) |
| Never smoked |
12 (21.8) |
| Drinking habit |
23 (41.8) |
| Coronary artery disease |
| 1-vessel disease |
4 (7.2) |
| 2-vessel disease |
17 (30.9) |
| 3-vessel disease |
34 (61.8) |
| Complications |
| Diabetes |
25 (45.4) |
| Hypertension |
44 (80.0) |
| Dyslipidemia |
48 (87.2) |
| Myocardial infarction |
10 (18.1) |
| Medications |
| Oral antidiabetic drugs |
19 (34.5) |
| Insulin |
4 (7.2) |
| ACEI or ARB |
24 (43.6) |
| β-blocker |
28 (50.9) |
| Statin |
43 (78.1) |
| Antiplatelet drug |
42 (76.3) |
| Anticoagulant drug |
2 (3.6) |
| Echocardiography |
| LVEF (%) |
56±12 |
Unless indicated otherwise, data are presented as n (%) or mean±SD. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; LVEF, left ventricular ejection fraction.
Table 2. Laboratory Measurements
| Hemoglobin (g/dL) |
11.3±2.1 |
| AST (IU/L) |
24 [18–34] |
| ALT (IU/L) |
20 [11–36] |
| γGTP (IU/L) |
27 [17–42] |
| Blood urea nitrogen (mg/dL) |
17 [14–25] |
| Creatinine (mg/dL) |
0.97 [0.81–1.49] |
| eGFR (mL/min/1.73 m2) |
49.3±23.3 |
| Uric acid (mg/dL) |
6.1±4.3 |
| Total cholesterol (mg/dL) |
141±43 |
| LDL-C (mg/dL) |
80±31 |
| HDL-C (mg/dL) |
42±10 |
| Triglycerides (mg/dL) |
94 [64–124] |
| Fasting glucose (mg/dL) |
106 [93–130] |
| Insulin (μU/mL) |
5.2 [2.8–9.8] |
| HOMA-IR |
1.24 [0.67–3.31] |
| HbA1c (%) |
5.9±1.3 |
| hsCRP (mg/dL) |
0.14 [0.05–0.29] |
| NT-proBNP (pg/mL) |
318 [108–1,264] |
Data are presented as the mean±SD or median [interquartile range]. ALT, alanine transaminase; AST, aspartate transaminase; eGFR, estimated glomerular filtration rate; γGTP, γ-glutamyl transpeptidase; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; hsCRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; NT-proBNP, N-terminal pro B-type natriuretic peptide.
Representative images of HE staining for SCAT and SV-PVAT are shown in Figure 1A. Adipocyte size was significantly larger in SV-PVAT than in SCAT (Figure 1B). A crown-like structure, which is composed of macrophages surrounding dead or dying adipocytes,17 was not observed in either SCAT or SV-PVAT.
There were no significant differences in gene expression levels of adipocyte differentiation-related molecules, including peroxisome proliferator-activated receptor γ (PPARG; Figure 1C), adiponectin (Figure 1D), and fatty acid-binding protein 4 (FABP4; Figure 1E), between SCAT and SV-PVAT.
Fibrosis in Fat Pats
Representative images of Masson’s trichrome staining for SCAT and SV-PVAT are shown in Figure 1F. Adequate samples for fibrosis area were available for 32 of the 55 patients, and baseline clinical characteristics of this subgroup of patients were similar to those of the entire study cohort (data not shown). The fibrosis area inside, but not at the edge, of SV-PVAT was smaller than that of SCAT (Figure 1G).
The gene expression levels of transforming growth factor-β (TGF-β), a fibrosis-related molecule, were comparable in SCAT and SV-PVAT (Figure 1H). However, SV-PVAT had significantly lower gene expression levels of macrophage-inducible C-type lectin (MINCLE), a regulator of fibrosis in adipose tissue,18,19 than did SCAT (Figure 1I).
Macrophage Infiltration and Metaflammation in Fat Pats
Representative images of immunohistological staining for CD68, a marker of macrophages, CD11c, a marker of M1 macrophages, and CD206, a marker of M2 macrophages, in SCAT and SV-PVAT are shown in Figure 2A–C. There was no significant difference in the macrophage infiltration area quantified by antibodies for CD68 (Figure 2D), CD11c (Figure 2E), or CD206 (Figure 2F) between SCAT and SV-PVAT. The ratio of CD11c-positive/CD206-positive macrophages (M1/M2) in SCAT and SV-PVAT was comparable (Figure 2G).
There was no significant difference in gene expression levels of metaflammation-related molecules, including monocyte chemoattractant protein-1 (MCP1), interleukin-1β (IL1B), interleukin-6 (IL6) and tumor necrosis factor-α (TNFA), between SCAT and SV-PVAT (Figure 2H).
Adipocyte Developmental and Pattern-Forming Genes in Fat Pads
To further address phenotypic differences between adipose tissues, gene expression levels of adipocyte developmental and pattern-forming genes, including engrailed homeobox 1 (EN1), empty spiracles homeobox 2 (EMX2), and homeobox A5 (HOXA5), were investigated as shown in previous studies.10,15,20–22 Gene expression levels of EN1 in SCAT and SV-PVAT were comparable (Figure 3A). However, EMX2 expression was significantly higher (Figure 3B) and HOXA5 expression level was significantly lower (Figure 3C) in SV-PVAT than in SCAT. Expression patterns of adipocyte developmental and pattern-forming genes, EMX2 and HOXA5, were different between SCAT and SV-PVAT.
Discussion
The present study showed that SV-PVAT had larger-sized adipocytes, a smaller extent of fibrosis, and decreased gene expression level of MINCLE, a fibrosis-related marker, than SCAT, although there was no significant difference in macrophage infiltration or metaflammation between SCAT and SV-PVAT. Expression patterns of adipocyte developmental and pattern-forming genes differed between SCAT and SV-PVAT, indicating that the phenotypes may result from inherent differences in adipocytes. SV-PVAT seems to have healthy expansion with less fibrosis in adipose tissue than SCAT, which may contribute, at least in part, to the good long-term patency of grafting when the no-touch technique is used to harvest the SV.
In the conventional SV harvesting technique, the vein is exposed by a longitudinal leg incision and PVAT is stripped off.1 The conduit is removed from the leg after dissection and is manually distended with saline using a syringe to prevent spasm.1 Conversely, in the no-touch technique, the SV is exposed by a longitudinal incision and is then isolated together with a pedicle of surrounding tissue.23 It has been reported that the no-touch SV graft has better long-term patency than the conventional SV graft in CABG.13,14 There are several possible reasons for the improvement in patency. First, the endothelium of SV grafts remains relatively undamaged because of the avoidance of high-pressure dilation to prevent spasm.24 Second, because the no-touch SV graft is harvested together with a pedicle of surrounding tissue including the vasa vasorum, which comprises a microvessel network of the vascular wall, and it remains intact with normal endothelial and vascular smooth muscle cell morphology.25 Third, PVAT provides beneficial effects of so-called adipocyte-derived relaxing factors.9 Furthermore, we recently showed that SV-PVAT had low levels of metaflammation and consecutive adipose tissue remodeling, specifically augmented immune cell infiltration, induction of proinflammatory cytokines, and increased fibrosis, compared with PVAT surrounding the coronary artery.15
Adipose tissue has traditionally been thought to play a major role as a cushion.26 In the present study, we showed that SV-PVAT has healthy expansion with less fibrosis in adipose tissue than SCAT, suggesting that SV-PVAT has a higher cushioning property than SCAT. As a possible role of PVAT in the no-touch SV graft, the surrounding tissue may provide physical protection from graft kinking and squeezing due to heartbeat. It has been shown that that external metallic support for preventing kinking in the conventional SV graft improves graft patency in CABG,27 possibly due to laminar blood flow in the SV graft and a reduction in intima thickening.28 Furthermore, it has been reported that the retained perivascular tissue of no-touch SV grafts protects against surgical- and distension-induced damage and preserves endothelial nitric oxide synthase and nitric oxide synthase activity.24 The tissue surrounding the SV may act as a cushion and protect the endothelium against high-pressure distension in no-touch SV grafts. Therefore, the cushioning property of PVAT affects the physical protection of SV grafts not only from the outside, but also from the inside intima.
It has been reported that the transplantation of healthy SCAT around the artery markedly attenuated neointima hyperplasia and suppressed vascular remodeling in mice after endovascular injury.8 Both SV-PVAT15 and PVAT surrounding the ITA as well as SCAT10 have been shown to have an anti-inflammatory phenotype compared with PAVT surrounding the coronary artery, contributing to positive effects on vascular remodeling and excellent patency of grafts using the ITA and no-touch SV in CABG. It has also been shown that SCAT has less metaflammation16 and that adipocytes in SCAT can be larger by healthy expansion than those in visceral adipose tissue.29 Because the SV is superficially located on the lower limb, it is possible that SV-PVAT has the same properties as SCAT. However, adipocyte size was larger in SV-PVAT than SCAT, and the extent of fibrosis was significantly smaller and the expression of MINCLE, a fibrosis-related molecule, was significantly lower in SV-PVAT than in SCAT. Furthermore, expression patterns of adipocyte developmental and pattern-forming genes EMX2 and HOXA5 were found to differ between SCAT and SV-PVAT in the present study, suggesting that they are distinct adipose tissues with different and unique characteristics.
Fibrosis in adipose tissue limits the expandability of adipocytes during the development of obesity, leading to ectopic fat accumulation in the liver and skeletal muscle.30 It has been reported that adipose tissue fibrosis is negatively correlated with adipocyte size in human adipose tissue.31 It has been reported that MINCLE is mainly localized to proinflammatory M1 macrophages in crown-like structures of adipose tissue18 and that it promotes the development of interstitial fibrosis.19 In the present study, SV-PVAT had a significantly smaller extent of fibrosis, significantly lower MINCLE expression, and a larger adipocyte size than SCAT, although there was no significant difference in macrophage infiltration between SCAT and SV-PVAT. Healthy adipose tissue expansion,30 which is achieved in an anti-inflammatory state through enlargement of pre-existing adipocytes by lipid accumulation as adipocyte hypertrophy, may occur more in SV-PVAT than in SCAT.
The present study has some limitations. First, because only Japanese patients were recruited in the present study, it is unclear whether the findings can be generalized to other ethnicities. Second, the number of patients was small, and there would have been selection bias of patients. However, the clinical profile of the patients enrolled in this study did not deviate from the average profiles of patients registered in the Japan Cardiovascular Surgery Database (JCVSD). Third, the subcutaneous fat pads used in the present study were taken from beneath the skin of the upper abdomen near the sternum but not near the SV. Fourth, the gene expression of molecules was mainly investigated because of the small amount of fat pads in the present study. The protein expression of molecules needs to be investigated in the future. Finally, the recruited patients had several diseases, including diabetes, hypertension, and dyslipidemia, and had been treated with several drugs. Pretreatment with several drugs may have affected the extent of metaflammation and fibrosis in adipose tissue.
Conclusions
Properties of SV-PVAT are close to, but not the same as, those of SCAT, possibly resulting from inherent differences in adipocytes. SV-PVAT has healthy expansion with less fibrosis in adipose tissue than SCAT. The phenotype of SV-PVAT may contribute, at least in part, to the good long-term patency of grafting when the no-touch technique is used to harvest the SV.
Sources of Funding
T. Mikami was supported by a grant from the Japan Surgical Society Young Researcher Award. M.F. was supported by grants from the Japan Society for the Promotion of Science (20K08913, 22K08313) and Takeda Medical Research Foundation.
IRB Information
This study was approved by the Ethics Committee of Sapporo Medical University (Reference no. 312-34).
Supplementary Files
Please find supplementary file(s);
https://doi.org/10.1253/circj.CJ-22-0740
References
- 1.
Kitamura S. Physiological and metabolic effects of grafts in coronary artery bypass surgery. Circ J 2011; 75: 766–772.
- 2.
Favaloro RG. Saphenous vein graft in the surgical treatment of coronary artery disease: Operative technique. J Thorac Cardiovasc Surg 1969; 58: 178–185.
- 3.
Schwann TA, Habib RH, Wallace A, Shahian DM, O’Brien S, Jacobs JP, et al. Operative outcomes of multiple-arterial versus single-arterial coronary bypass grafting. Ann Thorac Surg 2018; 105: 1109–1119.
- 4.
Caliskan E, de Souza DR, Boning A, Liakopoulos OJ, Choi YH, Pepper J, et al. Saphenous vein grafts in contemporary coronary artery bypass graft surgery. Nat Rev Cardiol 2020; 17: 155–169.
- 5.
Fitzgibbon GM, Kafka HP, Leach AJ, Keon WJ, Hooper GD, Burton JR. Coronary bypass graft fate and patient outcome: Angiographic follow-up of 5,065 grafts related to survival and reoperation in 1,388 patients during 25 years. J Am Coll Cardiol 1996; 28: 616–626.
- 6.
Goldman S, Zadina K, Moritz T, Ovitt T, Sethi G, Copeland JG, et al. Long-term patency of saphenous vein and left internal mammary artery grafts after coronary artery bypass surgery: Results from a Department of Veterans Affairs Cooperative Study. J Am Coll Cardiol 2004; 44: 2149–2156.
- 7.
Sabik JF 3rd, Lytle BW, Blackstone EH, Houghtaling PL, Cosgrove DM. Comparison of saphenous vein and internal thoracic artery graft patency by coronary system. Ann Thorac Surg 2005; 79: 544–551; discussion 544–551.
- 8.
Takaoka M, Nagata D, Kihara S, Shimomura I, Kimura Y, Tabata Y, et al. Periadventitial adipose tissue plays a critical role in vascular remodeling. Circ Res 2009; 105: 906–911.
- 9.
Fernandez-Alfonso MS, Gil-Ortega M, Aranguez I, Souza D, Dreifaldt M, Somoza B, et al. Role of PVAT in coronary atherosclerosis and vein graft patency: Friend or foe? Br J Pharmacol 2017; 174: 3561–3572.
- 10.
Numaguchi R, Furuhashi M, Matsumoto M, Sato H, Yanase Y, Kuroda Y, et al. Differential phenotypes in perivascular adipose tissue surrounding the internal thoracic artery and diseased coronary artery. J Am Heart Assoc 2019; 8: e011147.
- 11.
Gaudino M, Hameed I, Robinson NB, Ruan Y, Rahouma M, Naik A, et al. Angiographic patency of coronary artery bypass conduits: A network meta-analysis of randomized trials. J Am Heart Assoc 2021; 10: e019206.
- 12.
Furuhashi M, Mikami T, Kawaharada N, Dashwood MR. Saphenous vein harvesting: Meta-analysis, metaflammation, and adipose tissue remodeling. J Card Surg 2021; 36: 4832–4833.
- 13.
Samano N, Geijer H, Liden M, Fremes S, Bodin L, Souza D. The no-touch saphenous vein for coronary artery bypass grafting maintains a patency, after 16 years, comparable to the left internal thoracic artery: A randomized trial. J Thorac Cardiovasc Surg 2015; 150: 880–888.
- 14.
Tian M, Wang X, Sun H, Feng W, Song Y, Lu F, et al. No-touch versus conventional vein harvesting techniques at 12 months after coronary artery bypass grafting surgery: Multicenter randomized, controlled trial. Circulation 2021; 144: 1120–1129.
- 15.
Mikami T, Furuhashi M, Sakai A, Numaguchi R, Harada R, Naraoka S, et al. Antiatherosclerotic phenotype of perivascular adipose tissue surrounding the saphenous vein in coronary artery bypass grafting. J Am Heart Assoc 2021; 10: e018905.
- 16.
Rittig K, Dolderer JH, Balletshofer B, Machann J, Schick F, Meile T, et al. The secretion pattern of perivascular fat cells is different from that of subcutaneous and visceral fat cells. Diabetologia 2012; 55: 1514–1525.
- 17.
Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 2005; 46: 2347–2355.
- 18.
Ichioka M, Suganami T, Tsuda N, Shirakawa I, Hirata Y, Satoh-Asahara N, et al. Increased expression of macrophage-inducible C-type lectin in adipose tissue of obese mice and humans. Diabetes 2011; 60: 819–826.
- 19.
Tanaka M, Ikeda K, Suganami T, Komiya C, Ochi K, Shirakawa I, et al. Macrophage-inducible C-type lectin underlies obesity-induced adipose tissue fibrosis. Nat Commun 2014; 5: 4982.
- 20.
Gesta S, Bluher M, Yamamoto Y, Norris AW, Berndt J, Kralisch S, et al. Evidence for a role of developmental genes in the origin of obesity and body fat distribution. Proc Natl Acad Sci USA 2006; 103: 6676–6681.
- 21.
Tchkonia T, Lenburg M, Thomou T, Giorgadze N, Frampton G, Pirtskhalava T, et al. Identification of depot-specific human fat cell progenitors through distinct expression profiles and developmental gene patterns. Am J Physiol Endocrinol Metab 2007; 292: E298–E307.
- 22.
Chatterjee TK, Stoll LL, Denning GM, Harrelson A, Blomkalns AL, Idelman G, et al. Proinflammatory phenotype of perivascular adipocytes: Influence of high-fat feeding. Circ Res 2009; 104: 541–549.
- 23.
Souza D. A new no-touch preparation technique: Technical notes. Scand J Thorac Cardiovasc Surg 1996; 30: 41–44.
- 24.
Dashwood MR, Savage K, Tsui JC, Dooley A, Shaw SG, Fernandez Alfonso MS, et al. Retaining perivascular tissue of human saphenous vein grafts protects against surgical and distension-induced damage and preserves endothelial nitric oxide synthase and nitric oxide synthase activity. J Thorac Cardiovasc Surg 2009; 138: 334–340.
- 25.
Dreifaldt M, Souza DS, Loesch A, Muddle JR, Karlsson MG, Filbey D, et al. The “no-touch” harvesting technique for vein grafts in coronary artery bypass surgery preserves an intact vasa vasorum. J Thorac Cardiovasc Surg 2011; 141: 145–150.
- 26.
Rosen ED, Spiegelman BM. What we talk about when we talk about fat. Cell 2014; 156: 20–44.
- 27.
Goldstein DJ. Device profile of the VEST for external support of SVG coronary artery bypass grafting: Historical development, current status, and future directions. Expert Rev Med Devices 2021; 18: 921–931.
- 28.
Chiu JJ, Chien S. Effects of disturbed flow on vascular endothelium: Pathophysiological basis and clinical perspectives. Physiol Rev 2011; 91: 327–387.
- 29.
Vishvanath L, Gupta RK. Contribution of adipogenesis to healthy adipose tissue expansion in obesity. J Clin Invest 2019; 129: 4022–4031.
- 30.
Kusminski CM, Bickel PE, Scherer PE. Targeting adipose tissue in the treatment of obesity-associated diabetes. Nat Rev Drug Discov 2016; 15: 639–660.
- 31.
Divoux A, Tordjman J, Lacasa D, Veyrie N, Hugol D, Aissat A, et al. Fibrosis in human adipose tissue: Composition, distribution, and link with lipid metabolism and fat mass loss. Diabetes 2010; 59: 2817–2825.
