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Abstract

Coronary artery bypass grafting remains the treatment of choice for a large cohort of patients with significant coronary disease. Despite the increased use of arterial grafts, the long saphenous vein remains the most commonly used conduit. Long-term graft patency continues to be the Achilles heel of saphenous vein grafts. This is due to the development of intimal hyperplasia, a chronic inflammatory disease that results in the narrowing and occlusion of a significant number of vein grafts. Research models for intimal hyperplasia are essential for a better understanding of pathophysiological processes of this condition. Large animal models resemble human anatomical structures and have been used as a surrogate to study disease development and prevention over the years. In this paper, we systematically review all published studies that utilized large animal models of vein graft disease with a focus on the type of model and any therapeutic intervention, specifically the use of external stents/mesh.

Keywords

intimal hyperplasia vein grafts disease (coronary artery bypass graft) CABG porcine large animals

Introduction

The long saphenous vein (LSV) is the most commonly used conduit in cardiac surgery; however, its use is complicated by an increased risk of late stenosis or occlusion due to the development of intimal hyperplasia (IH) and accelerated atherosclerosis.^1,2 IH is a chronic inflammatory process characterized by an activation and subsequent switching of the vascular smooth muscle cells (VSMCs) from a quiescent state to a synthetic proliferative and its migration to the intimal layer.² The development of IH is a complex process that is not fully understood. Many small and large animal models were developed over the years to study the pathophysiology of IH and/or to try and modify it using different therapeutics. In this review, we systematically look at the studies that utilized large animals in the field of IH and vein grafts disease and the therapeutics used with especial focus on the external stents/mesh which are external scaffolds that are made of different materials which can make then stiff around the vessel of just soft material that just wrap the graft with some of them able to be loaded with different therapeutic agents and can be placed around the veins during surgery which made them an interesting venue to explore by cardiac surgeons, considering the ability to place them on vein during surgery without significantly affecting the flow or length of surgery.

Methods

A systematic review was performed using methods described in Cochrane Handbook for Systematic Reviews of Interventions.³ A protocol was registered prospectively on International Prospective Register of Systematic Reviews (PROSPERO) (CRD42021262342). The study adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

The aim of the review was to systematically review studies of vein grafts IH using large animals with detailed description of the different models of grafting and any therapeutic methods used.

Search strategy

Three reviewers (FO, LM, and SL) independently performed each step of the literature search. Electronic searches were conducted using the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE without date or language restriction from inception to the end of December 2020. A full description of the search terms is listed in the Supplementary Materials. In addition, the reference lists of all retrieved articles were manually searched for further relevant studies not previously identified. Each reviewer independently screened the title and abstract to first identify relevant articles. Next, the full text of each article was independently screened. After each stage, agreement on included studies was reached through discussion.

Study Eligibility

The inclusion criteria were 1. Any in vivo large animal studies investigating the development or modification of IH in vein grafts in any large animal model.

Exclusion Criteria included the following: (1) studies that did not look at IH and focused on other parameters such as flow pattern studies or acute thrombosis, (2) small animal studies, (3) animal studies that were designed to look at IH in the setting of arterio-venous fistula, (4) studies that used synthetic tissue or focused on tissue engineering, (5) transplant-related diseases, (6) studies looking at venous patch grafts, (7) ex vivo studies using large animal tissue, (8) arterial graft models, and (9) abstracts.

Data Extraction

A standardized form was developed to extract data from the included studies for assessment of study quality and evidence synthesis. This form was tabulated using Microsoft Excel 2016 (Microsoft, Redmond, Washington). Data extraction first considered data from figures, tables, and graphs (using digital ruler software where appropriate), followed by data extraction from the main text. Data extracted to the standardized form was categorized under the following headings: author, title, year, journal, research aims and objectives, subjects examined, cell type examined, sequencing method, research methodology, and key findings. Data extraction was performed by three authors (FO, MZ, and LM), and any discrepancies were resolved by discussion.

Bias and Quality Assessment

Quality was assessed using the ARRIVE Essential 10 guidelines checklist.⁴ For assessment of the risk of bias, a modified version of this tool specific for animal intervention studies, SYRCLE, was utilized.⁵ Following data extraction, the authors (FO, LM, and SL) performed quality and risk of bias assessment. Any discrepancies were resolved by discussion between all authors.

Data Synthesis

A narrative synthesis of all included studies was performed, with all relevant data tabulated where appropriate. For all outcomes, data was extracted in text format or as mean +/− standard deviation for numerical values. Where applicable, continuous variables were summarized with standardized mean difference, and dichotomous data was summarized with risk and odd ratios. Where relevant data was missing, authors were contacted (where possible); otherwise, data was presented as described in the article or supplementary data. Given the anticipated diversity of outcome measures, limited scope for statistical analysis was expected and as such, meta-analysis was not undertaken.

Results

A flow diagram showing the results of the searches is shown in Figure 1. Initial search identified 3049 records, which was reduced to 2841 after the removal of duplicate. Of these, 2100 were excluded as it did not report the outcome of interest, and 601 were not relevant. The remaining 140 records were re-assessed, and 86 papers were finally included. An additional 13 papers were identified from the reference’s searches, and 99 were finally included in this review. The studies included were over a span of more than 30 years (1985–2020) and included three species (dogs in 55 studies, porcine in 39 studies, and sheep in 5 studies).

Figure 1.

Flow diagram of study selection.

Dog models

Fifty-five papers were identified to use a dog model of IH and are summarized in Table 1.^6–60

Table 1.

Summary of studies using the dog model of vein grafts IH.

Year	Author	Model details	Poor runoff	Maximum time frame	Number of samples	Aim of study	Conclusion	Adenovirus	Drug	Decoy	Other	Knockout model	Hypercholesterolemic model	Diabetic model
1985	Landymore⁷	Jugular–femoral artery	No	6 weeks	14	Determine if this cod liver oil would prevent IH	Cod liver oil could be usedto prevent IH	0	Cod liver oil	0	0	0	0	0
1985	Donovan¹⁰	Different veins to arteries	No	7 weeks	9	Compare valveless nonreversed veins to standard vein use	Valveless nonreversed veins are better to use for grafting	0	0	0	Valveless non reversed	0	0	0
1986	Landymore⁶	Jugular–femoral artery	No	6 weeks	38	To determine the effects of cod liver oil and a combination of cod liver oil and dipyridamole on vein grafts	A combination of cod liver oil and dipyridamole is more effective than cod liver oil alone in reducing canine vein-graft intimal hyperplasia	0	Liver oil and dipyridamole combination	0	0	0	0	0
1986	Landymore⁸	Jugular–femoral artery	No	6 weeks	24	Determine if this cod liver oil would prevent IH	Cod liver oil was more effective than aspirin-dipyridamole	0	Aspirin/dipyridamole and liver oil	0	0	0	0	0
1986	Endean¹¹	Jugular–femoral artery	No	6 weeks	25	Examine the effect of an orally active thromboxane (TXA2) synthetase inhibitor (TSI) on vein grafts	TSI treatment may improve early vein graft patency during the transient period of endothelial injury	0	Thromboxane (TXA2) synthetase inhibitor	0	0	0	0	0
1986	Bush¹²	Jugular–carotid	No	12 weeks	75	Establish whether preservation of the endothelium before arterialization is a critical factor in the development of late functional and morphologic abnormalities of autogenous vein grafts	Early after surgery, vein grafts develop functional and morphologic abnormalities consistent with injury. Morphologic healing of the endothelial monolayer progressed slowly back to normal but will not match that of the pre-surgery vein nor that of normal host arteries	0	0	0	Reverse/in situ	0	0	0
1987	Cambria¹³	Jugular–carotid and femoral vein–femoral artery	No	14 weeks	33	A comparative study of experimental reversed and in situ vein grafts	Functioning human INS vein grafts are less compliant than suspected on the basis of prior ex vivo and clinical studies of RV saphenous vein grafts	0	0	0	Compare two methods	0	0	0
1987	Cahill¹⁴	Femoral vein–artery	No	12 weeks	4	Study changes in vein grafts	Canine venoarterial autologous grafts undergo biochemical arterialization which appears to be an incomplete one	0	0	0	0	0	0	0
1987	Karlson¹⁵	Saphenous vein–femoral artery	No	6 months	15	Study the use of previously grafted veins as a conduit for regrafting	Operations using undiseased portions of old vein grafts should be considered a viable option in repeat coronary revascularization for early stenoses	0	0	0	Regrafting old veins	0	0	0
1987	Adcock¹⁶	Jugular–carotid	No	10 days	18	Study the role of preservation of EC on vein grafts	EC preservation with improved harvesting techniques inhibits thrombosis and limits wall thickening and also that macrophages may play a protective role by promoting endothelial proliferation	0	0	0	Denudation of EC versus standard	0	0	0
1987	Morinaga¹⁷	Femoral vein–artery	Yes	8 months	—	To investigate the influence of hemodynamic conditions on intimal thickening of arterially transplanted autologous vein grafts	Intimal thickening was only observed under conditions of abnormal flow (poor run-off). Implantation of diseased vessels under normal flow conditions results in the regression of intimal thickening. Thickened intima comprised proliferation of transformed smooth muscle cells with a marked increase in the mitochondria, the rough endoplasmic reticulum, and an abundant fibrous matrix, whereas with the regressed thickness of the intima, the smooth muscle cells were spindle-shaped with distinct myofibrillae	0	0	0	0	0	0	0
1987	Miller¹⁸	Femoral vein–artery	No	6 weeks	Nonumber	Determine whether grafting of veins into the arterial circulation would alter the endothelium-dependent responses of the veins	EC of venous grafts can initiate changes in tone of the smooth muscle	0	0	0	0	0	0	0
1988	Cahill¹⁹	Jugular–carotid	No	3 months	25	Assess the effects of EPA on vein graft intimal thickening, platelet and vascular prostaglandin metabolism, lipid and lipoprotein receptor metabolism, and hematologic parameters	Dietary supplementation with marine omega-3 fatty acids reduced the extent and magnitude of accelerated vein graft intimal thickening induced by hypercholesterolemia	0	Omega-3 fatty acids (chiefly, eicosapentanoic acid [EPA] and docosahexanoic acid [DHA])	0	0	0	Yes	0
1988	Kuroki²⁰	Femoral vein–artery	Yes	6 months	—	Etiology of IH in poor run-off	Abnormal flow conditions enhance the permeation into immaturely repaired intimal tissues which can result in the proliferation of SMC	0	0	0	0	0	0	0
1989	Sarris²²	Femoral vein–carotid	No	3 months	48	Investigate the mechanisms involved in the protective role of fish oil in vein grafts	The effect of fish oil can be related to in vivo inhibition of platelet-mitogen growth factor release	0	Fish oil	0	0	0	Yes	0
1989	Landymore⁹	Jugular–femoral artery	No	6 weeks	15	Study the effects of low-dose cod liver oil on intimal hyperplasia of vein grafts	Small doses of fish oil will reduce intimal proliferation in autologous vein grafts by a mechanism other than their known effects on prostanoid metabolism	0	Liver oil	0	0	0	0	0
1990	Fann²¹	Femoral vein–carotid	No	12 weeks	13	Assess the reversibility of functional and morphological changes of arterialized vein segments by returning them to the venous circulation	Changes associated with arterialization such as adrenergic sensitivity, maximum tension to 5-HT, medial thickening and intimal hyperplasia can revert toward venous values when veins are replaced in the venous environment but no changes noted in luminal PGI2	0	0	0	0	0	0	0
1991	Yukizane²⁴	Femoral vein–artery	Yes	21 days	23	Study the effects of platelets on the development of IH	Intimal thickening in vein grafts correlates well with the enhanced platelet adherence on the intima of the vein grafts in an early period after implantation	0	0	0	0	0	0	0
1991	Eguchi²³	Femoral vein–artery	Yes	4 weeks	—	Study the role of the endothelial lining in occurrence and development of intimal thickening in vein grafts	Intimal thickening was induced by an accelerated permeability in the presence of abnormal flow conditions until full re-endothelialization after the implantation	0	0	0	0	0	0	0
1992	Shrestha²⁵	Femoral vein–artery	Yes	3 months	—	Study intimal hyperplasia of arterially implanted autovein bypass grafts and their distal end-to-side anastomoses	Intimal hyperplasiaat the distal anastomosis in autovein bypass grafting differed from those of the implanted autovein graft itself; the former being related to excessive proliferation of fibroblasts and collagen fibers while the latter displayed an active proliferation of smooth muscle cells	0	—	0	0	0	0	0
1993	Hirko²⁶	Jugular vein interpositioned bilaterally into each of the paired carotid and femoral arteries	No	6 weeks	72	Evaluate the efficacy of three drugs (cilazapril, cyclosporine, and aspirin) in modulating the progression of IH	Aspirin and cyclosporine in can reduce IH	0	Aspirin, cilazapril, and cyclosporine	0	0	0	0	0
1993	Ishii²⁷	Saphenous vein–fem artery	No	6 weeks	—	Examine the natural course of endothelium-dependent and -independent responses in reversed autogenous vein grafts during regeneration and tissue repair processes	The endothelium-dependent responses to ADP and calcium ionophore A23187 were constantly maintained, but there was a selective loss of acetylcholine-mediated relaxation in vein grafts in the early postoperative stage, a time when the intima is not thickened	0	0	0	0	0	0	0
1994	Segers²⁸	Femoropopliteal saphenous vein	No	6 months	6	Compare in situ to reversed veins	No significant difference between in situ and reversed noted in relation to intima-to-media ratio. The preservation of adventitia and vasa vasorum had no biologic effect on the development of the same intimal changes in the midsection of reversed and in situ vein grafts	0	0	0	Reverse/in situ	0	0	0
1995	Rohn²⁹	Jugular–carotid	No	3 months	18	Effect of ibuprofen on IH	No significant difference noted in the development of IH with the use of ibuprofen	0	Ibuprofen	0	0	0	0	0
1995	Komori³⁰	Femoral vein– artery	No	6 weeks	12	Examine the effect of purified eicosapentanoic acid (EPA) on IH	EPA enhances the release of endothelium-derived relaxing factor in vein grafts and can reduce IH	0	Eicosapentanoic acid (EPA)	0	0	0	0	0
1995	Odashiro³¹	Jugular–carotid	No	4 weeks	15	Determine whether the endothelium-dependent responses differed between in situ and reversed vein grafts	EC derived relaxing factors in the in situ vein graft can be preserved; thus, adventitial dissection in the in situ vein graft should be minimized to preserve EC function	0	0	0	Reverse/in situ	0	0	0
1996	Funahashi³²	Femoral vein–artery	Yes	5 weeks	8	Determine the role of lumbar sympathectomy on the modulation of EC-derived relaxing factor	Lumbar sympathectomy does not alter EC function in terms of EDRF, although mean blood flow of the denervated femoral arteries and vein grafts was significantly higher than that of the innervated femoral artery and vein grafts. These results suggest that continuous vasodilation following sympathectomy may be a more potent factor with respect to regulation of vascular tonus than physiologic regulation of EDRF	0	0	0	Lumbar sympathectomy	0	0	0
1997	Mawatari³³	Femoral vein–artery	Yes	4 weeks	No number	Evaluate the efficacy of antiplatelet agent, 4-cyano-5, 5-bis [methoxyphenyl]-4-pentenoic acid (E5510) on IH	E5510 reduced IH under distal poor runoff conditions by reducing the degree of smooth muscle cell proliferation	0	Antiplatelet agent, 4-cyano-5, 5-bis [methoxyphenyl]-4-pentenoic acid (E5510) group and aspirin group	0	0	0	0	0
1997	Mawatari³⁴	Femoral vein–artery	No	4 weeks	No number	Compare the effects of vasoconstrictor substances such as 5-hydroxytryptamine (5-HT) and endothelin on the smooth muscle in vein grafts	5-HT produced significantly larger contraction vein grafts than in control veins. In veins with adventitial dissection alone and vein-to-vein grafts, 5-HT produced small contractions which were comparable to those in control vein. This contraction response to 5-HT in may be due to an increased responsiveness of the 5-HT1 receptor caused by grafting into the arterial circulation	0	0	0	0	0	0	0
1997	Komori³⁵	Femoral vein–artery	Yes	6 weeks	10	To assess the effects of changes in shear stress on endothelium-dependent responses	Dysfunction of the endothelium under conditions of abnormal flow may accelerate intimal thickening of the vein graft and result in late graft failure	0	0	0	0	0	0	0
1997	Rhee³⁶	Femoral vein–artery	No	6 weeks	—	Determine the role of nitric oxide in mediating EC-dependent responses in in situ vein grafts	In situ vein grafts exhibit two unique properties which are unlike unoperated arteries or veins including¹ alpha2-adrenergic receptors may be coupled to the release of contractile EC-derived factors associated with production of nitric oxide and² nitric oxide may be released by the smooth muscle in response to purinergic stimulation	0	0	0	0	0	0	0
1998	Matsumoto³⁷	Femoral vein–artery	Yes	4 weeks	32	Investigate the role of in vivo gene transfer of endothelial cell NO synthase (ecNOS) on IH	Intimal thickness after implantation was significantly reduced by ecNOS gene transfer	Nuclear-targeted lac zgene, bovine ecNOS cDNA, or control vector plasmid encapsulated in the hemagglutinating virus of Japan-liposomes	0	0	0	0	0	0
1999	Tamaki³⁸	Femoral vein–artery	Yes	13 months	—	Examine the microscopic features and distribution of collagens in vein grafts	The increase in types IV and V collagen, particularly in the deep layer of the hyperplastic intima which is due to development of numerous vasa vasora in that area	0	0	0	0	—	—	—
2000	Ulus³⁹	Jugular–femoral artery	No	6 weeks	12	To evaluate the efficacy of single-dose pre-insertion gamma radiation of vein grafts in the prevention of IH	Single-dose external pre-insertion gamma radiation of vein grafts reduced the amount of IH	0	0	0	Single-dose external pre-insertion gamma radiation	0	0	0
2001	Komori⁴⁰	Femoral vein–artery	Yes	4 weeks	20	The efficacy of ONO-1608 (liposomal formulation of prostaglandin E 1 prodrug) evaluated on IH	Of ONO-1608 in reducing the degree of IH by inhibiting PDGF-stimulated proliferation of the smooth muscle cell	0	ONO-1608	0	0	0	0	0
2001	Takai⁴¹	Jugular–carotid	No	4 weeks	10	Investigate the effect of NK3201 (chymase inhibitor) on vein grafts	Oral administration of a NK3201, appears useful for preventing vascular proliferation due to the reduction of chymase activity	0	Novel chymase inhibitor, NK3201	0	0	0	0	0
2002	Akasaka⁴²	Femoral vein–artery	No	3 weeks	18	To investigate the uptake of lipoprostaglandin E (1) (LPGE(1)) by ECs and SMCs and the effects of the LPGE(1) on re-endothelialization of vein grafts	Daily administration of LPGE(1) resulted in significant enhancement of vein graft re-endothelialization. LPGE(1) was absorbed by the SMC, whereas the EC showed no uptake; therefore, the enhancement is probably due to a paracrine effect of SMC	0	Lipo-prostaglandin E−1	0	0	0	0	0
2002	Shintani⁴³	End to side saphenous vein between LAD and aorta	No	4 weeks	10	Investigate the role of transfection of NF-κB decoy into the vein graft wall suppresses neointimal hyperplasia and the differentiation of medial smooth muscle cells	Intraoperative transfection of the NFκB decoy into the vein graft wall for attenuation of IH by suppressing SMC differentiation and proliferation	0	0	cis element decoy oligodeoxynucleotide of NF-κB (N-FκB decoy)	0	0	0	0
2003	Kim⁴⁴	Femoropopliteal saphenous vein	No	8 weeks	8	To identify differentially expressed mRNA by method using an mRNA differential display	Several genes identified with osme of them had already had their function and sequence identified whereas some of them have yet to be identified	0	0	0	0	0	0	0
2004	Petrofski⁴⁵	End to side saphenous vein between LAD and aorta	No	13 weeks	10	Characterize a canine model of aortocoronary saphenous vein graft intimal hyperplasia and to demonstrate that ex vivo gene delivery is possible in these grafts using adenoviral vector	Adenoviral-treated saphenous vein grafts demonstrated positive transgene expression either by X-gal staining (beta-galactosidase) or northern analysis (beta-adrenergic receptor kinase carboxyl terminus)	Recombinant adenovirus containing beta-galactosidase (n = 2) or the beta-adrenergic receptor kinase carboxyl terminus	0	0	0	0	0	0
2004	Saunders⁴⁶	Jugular–carotid	No	4 weeks	29	Characterize mitogen-activated protein kinase activation in veingrafts	Vein graft arterialization induces bimodal activation of extracellular-signal regulated kinase and p38; however, in contrast with what is described in arterial injury, it does not induce c-jun N-terminal kinase activation	0	0	0	0	0	0	0
2004	Kalish⁴⁷	Cephalic vein–femoral artery interposition graft	No	4 weeks	18	Identify temporal gene expression in vein grafts versus control veins through microarray analysis	49 genes were consistently upregulated and 31 genes were consistently downregulated in the animals at different times	0	0	0	0	0	0	0
2006	Cho⁴⁸	Jugular–femoral artery	No	16 weeks	8	Evaluate the effect of the AP-1 decoy on IH	AP-1 decoy using HVJ-liposomes effectively prevented IH	0	0	AP-1 decoy	0	0	0	0
2006	Pintucci⁴⁹	Jugular-carotid	No	4 days	9	Investigate the effects of topical inhibition of ERK-1/2 MAPK activation on vascular cell proliferation and apoptosis, and on the inflammatory response in vein grafts	This treatment abolished arterialization-induced ERK-1/2 activation, decreased medial cell proliferation and increased apoptosis. Additionally, there was inhibition of vein graft infiltration by myeloperoxidase-positive inflammatory cells. Topical ex vivo administration of MAPK inhibitors can provide a pharmacological tool to prevent or reduce IH	0	Topical inhibition of ERK-1/2 MAPK	0	0	0	0	0
2006	Gulkarov⁵⁰	Jugular-carotid	No	4 weeks	—	Investigate the mechanisms of CRP up-regulation in arterialized vein grafts	CRP levels are increased invein grafts peaking 24 h after grafting. However, no significant production of CRP was detected in the grafts. Therefore, increased CRP levels within grafts appear to originate mostly from CRP diffusion from the systemic circulation	0	0	0	0	0	0	0
2007	Kawatsu⁵¹	Femoral vein–artery	No	4 weeks	25	Investigate the role of rapamycin-eluting biodegradable poly L-lactic acid and epsilon-caprolactone copolymer (PLA-CL) film applied externally on vein grafts	Rapamycin-eluting biodegradable PLA-CL film applied externally can inhibit neointimal hyperplasia of arterial and vein grafts in a canine model. Inhibition of neointimal growth was associated with reduced cell proliferation, as evidenced by proliferating cell nuclear antigen immunostaining and diminished alpha-actin positive vascular smooth muscle cells	0	0	0	Rapamycin-eluting biodegradable poly L-lactic acid and epsilon-caprolactone copolymer (PLA-CL)	0	0	0
2007	Kuma⁵²	Femoral vein-artery	Yes	4 weeks	14	Investigated the effect of E4177 (AngII AT1 receptors antagonist) on vein grafts	Inhibiting AngII can modulate vein grafts disease as AngII has the potential to promote growth of SMC and suggest that this growth promotion may be mediated by enlargement of the cell surface area. The effect of AngII was associated with an increase in the expression level of platelet-derived growth factor (PDGF)	0	Novel AngII inhibitor E4177	0	0	0	0	0
2007	Monahan⁵³	Cephalic vein–femoral artery interposition graft	No	4 weeks	12	Study CDH11 expression in vein grafts and characterize its role in vascular remodeling	CDH11 is up-regulated in SMC in vivo as part of the response to injury. Inhibition of CDH11 decreases SMC migration and proliferation	0	0	0	0	0	0	0
2007	Tatewaki⁵⁴	Jugular-carotid	No	4 weeks	24	Study the role of local anti-MCP-1 therapy on vein grafts	Denovirus-mediated gene transfer significantly attenuated inflammation and proliferation and neointimal formation but did not affect endothelial regeneration process	Denoviral gene transfer of 7ND (N-terminal deletion mutant of the MCP-1 gene)	0	0	0	0	0	0
2007	Zou⁵⁵	Femoral vein- artery	No	4 weeks	30	Define the size of an external stent appropriate for a particular graft by comparing vein grafts with different sizes of external stents	External stents can reduce intimal hyperplasia of vein grafts. Stents of different diameters (4,6 and 8 mm) exert the similar effect on prevention of IH	0	0	0	External stents	0	0	0
2009	Saito⁵⁶	Femoral vein- artery	No	2 weeks	20	Study the role of intracoronary radiation therapy vein grafts	Irradiation can inhibit anastomotic stenosis by targeting the adventitia and reducing cells migration to neointima	0	0	0	External irradiation of the anastomotic sites	0	0	0
2009	Kudo⁵⁷	Jugular-carotid	No	4 weeks	12	Investigate the role of cilostazol (cyclic adenosine monophosphate (cAMP) phosphodiesterase inhibitor) on vein grafts	Cilostazol suppressed the development of IH which may be associated with the modulation of cell proliferation and apoptosis	0	cilostazol	0	0	0	0	0
2010	Zhou⁵⁹	Jugular-carotid	No	4 weeks	32	Investigate if postoperative insulin medication prevents the autologous vein graft from IH	Postoperative insulin use inhibited cell proliferation, reduced intimal/medial thickness, upregulated endothelial nitric oxide synthase, and [alpha]-smooth muscle actin expression. Additionally, it may protect vein grafts possibly through the phosphatidylinositol-3 kinase/Akt signaling pathway	0	Insulin (post op)	0	0	0	0	0
2013	Liu⁵⁸	Femoral vein–artery	No	8 weeks	20	To investigate theeffects of batroxobin on vein grafts	These findings suggested that BX could inhibit intimal hyperplasia through suppressing cell proliferation activity	0	Batroxobin	0	0	0	0	0
2016	Sato⁶⁰	Femoral vein–artery	No	52 weeks	24	Study the role of a novel biodegradable external mesh stent on vein grafts	The biodegradable P (LA/CL) external mesh stent improved vein graft patency and prevented vein graft dilatation and intimal hyperplasia associated with suppressed neointimal layer cellular proliferating activity	0	0	0	Biodegradable external mesh stent	0	0	0

Different models were designed to study the development of IH. This included using femoral vein–femoral artery interposition in 23 studies (in situ or reversed),^{14,17,18,20,23–25,30,32–38,40,42,51,52,55,56,58,60} jugular vein–carotid artery interposition grafts in 12 studies,^{12,16,19,29,31,41,46,49,50,54,57,59} jugular vein–femoral artery interposition graft in 7 studies,^{6–9,11,39,48} cephalic vein–femoral artery interposition graft in 2 studies,^47,53 femoral vein–carotid interposition in 2 studies,^21,22 saphenous vein–femoral artery interposition model in 2 studies,^15,27 Jugular vein to both the carotid and femoral arteries in 1 study,¹³ jugular vein to carotid artery and femoral vein to femoral artery in 1 study (in situ or reversed),²⁶ and 1 study used different types of venous and arterial interposition models.¹⁰ The saphenous vein end to side between the LAD and aorta was used in 2 studies,^43,45 and 2 studies utilized a femoropopliteal-saphenous vein end to the side model.^28,44

The dog model additionally included the step of developing a poor run off model in 12 studies, all using the femoral vein–femoral artery model.^{17,20,23–25,32,33,37,38,40,52} This model was originally described by Morinaga et al.¹⁷ where all tributary arteries distal to the saphenous artery in the posterior limb are ligated and severed, except for a superior branch of the posterior femoral artery. Thus, a condition of poor runoff is created. Four weeks after the first surgical procedure, when the collateral vessels seem to be fully developed, the femoral artery and vein are exposed, and a segment of femoral vein is interpositioned into the femoral artery.

None of these were a diabetic model with 2 papers reporting the use of hypercholestolemic dogs.^19,22

Nineteen of these studies used a drug as an intervention to modulate IH which included a wide range of medications such as liver oil, ibuprofen, rapamycin, and selective inflammatory inhibitors.^{6–9,11,19,22,26,29,30,33,40–42,49,52,57–59} Other treatment modalities included the use of antisense oligomers, decoys, adenovirus, radiation, different storage or harvest methods, and external stents including biodegradable and drug eluting stents. Few studies looked at the difference between in situ and reversed veins which were of no clinical value in CABG; however, these studies highlighted an important role for EC preservation in the modulation of IH.^12,28,31

One study looked at the role of using an in-house developed rapamycin-eluting biodegradable PLA-CL film applied externally in a femoral vein to femoral artery interposition and femoral artery to femoral artery model where three concentrations of rapamycin were used. In the vein graft models, the ratio of intimal area was significantly decreased only in the high concentration group compared with control at 4 weeks, while all concentrations were able to suppress IH in the arterial grafting model. The inhibition of neointimal growth was associated with reduced cell proliferation, as evidenced by proliferating cell nuclear antigen immunostaining and diminished alpha-actin positive vascular smooth muscle cells.⁵¹

Using different sizes of expanded polytetrafluoroethylene (ePTFE) as external stents (4, 6, and 8 mm) in a model of femoral vein to femoral artery interposition grafts, Zou et al. showed that stents with different size can exert similar effect on the prevention of IH at 4 weeks after surgery.⁵⁵ A biodegradable PLA-CL mesh external stent (8 mm) was compared to a nonabsorbable stent and no stent control in a femoral vein to femoral artery interposition grafts model. At 12 months, the endoluminal circumferential and the vein graft length was significantly smaller in the PLA-CL and nonabsorbable groups than that in the control group. Similarly, the mean intimal–medial thickness was less in PLA-CL and nonabsorbable stent groups compared to the control group. Interestingly, all grafts that had the biodegradable stent were patented compared to the nonabsorbable and control groups.⁶⁰

Porcine model

Thirty-nine papers were identified to use a porcine model of IH and are summarized in Table 2.^61–99

Table 2.

Summary of studies using porcine model of vein grafts IH.

Year	Author	Model details	Maximum time frame	Number of samples	Aim of study	Conclusion	Adenovirus	Drug	Decoy	Other	Knockout model	Hypercholesterolemic model	Diabetic model
1990	Angelini⁶¹	Saphenous vein-carotid artery interposition	5 weeks	No number	Study the effect of distension of vein grafts	The data show that distention leads to medial and endothelial damage and that this is associated with increased platelet and leukocyte adhesion and with reduced early patency	0	0	0	0	0	0	0
1992	Angelini⁶²	Saphenous vein–carotid artery interposition	4 weeks	—	Investigate the time-course changes in medial and intimal size, cell number, cell density, endothelial morphology and cholesterol concentration in vein grafts	Three processes contribute to medial and intimal thickening which are an initial phase of rapid smooth muscle cell proliferation followed by migration, hypertrophy, and synthesis of extracellular matrix and a late phase of slower smooth muscle cell proliferation. The late phase occurs despite regeneration of a morphologically intact endothelium and in the absence of progressive cholesterol accumulation	0	0	0	0	0	0	0
1993	Violaris⁷⁸	Saphenous vein–carotid artery interposition	4 weeks	—	Study the effect of reducing wall stress with an external porous polytetrafluoroethylene stent (4 mm)	4-mm external stenting reduces medial enlargement and hyperplasia but increases encroachment of the intima into the lumen thus is unlikely to be of benefit in reducing IH	0	0	0	External stent	0	0	0
1994	Chen⁸²	Jugular vein to carotid artery interposition graft	3 DAYS	No number	To determine whether direct adenovirus-mediated transfer of genes encoding inhibitory proteins may prevent or slow progression of vein graft disease	Ex vivo gene transfer before vein grafting is feasible	Recombinant adenoviruses containing the cDNA for the marker gene lacZ (Ad.CMVlacZ) or soluble vascular cell adhesion molecule (sVCAM) (Ad.CB-sVCAM)	0	0	0	0	0	0
1996	Izzat⁷¹	Saphenous vein–carotid artery interposition	4 weeks	30	Investigate the influence of different external stent sizes on graft wall dimensions and cell proliferation	Neointimal thickness was significantly reduced by 6-mm and 8-mm stents but not by 5-mm stents. Thus, oversized stents give profound suppression of intimal thickening, obviating the need for precise size matching with the graft and greatly simplifying the surgical procedure	0	0	0	External stents	0	0	0
1996	Angelini⁶³	Saphenous vein-carotid artery interposition	4 weeks	9	Study the use of unrestricted external stent on IH	Cell proliferation was also greatly reduced by stenting in the neointimal and medial layers	0	0	0	External stent	0	0	0
1996	Jeremy⁷⁵	Saphenous vein-carotid artery interposition	4 weeks	—	Measure the synthesis of PGI2 and LTB4 in vein grafts	PGI2 release markedly diminish in vein grafts while LTB4 release is significantly enhanced which can contribute to the development of vein grafts disease by affecting smooth muscle cells	0	0	0	0	0	0	—
1997	Jeremy⁷⁴	Saphenous vein-carotid artery interposition	4 weeks	—	Investigate the prostacyclin-cAMP and nitric oxide-cGMP axes in vein grafts	Adenylyl and guanylyl cyclase activity are down-regulated in vein grafts, which may contribute to the development of intimal and medial thickening. Nitric oxide release and endothelial nitric oxide synthase content are up-regulated in vein grafts, which is indicative of an adaptation to the arterial conditions of shear stress and pulsatile pressure	0	0	0	0	0	0	0
1998	Dashwood⁶⁸	Saphenous vein-carotid artery interposition	4 weeks	3	Study the regional distribution of endothelin-1 (ET-1) and its receptor subtypes (ETA and ETB) in vein grafts	ETA receptors may play a role in vein graft thickening at the medial and neointimal vascular smooth-muscle cell level, whereas ETB receptors may play a role in microangiogenesis	0	0	0	0	0	0	0
1998	Dashwood⁶⁹	Saphenous vein-carotid artery interposition	4 weeks	9	Investigate the distribution of ET-1 and ET-1 receptor subtypes (ET A and ET B) in porcine vein grafts	ET A receptors may play a role in vein graft thickening at the medial and neointimal VSMC level, whereas ET B receptors may play a role in microangiogenesis. The higher levels of ET A receptors in the tunica media of ungrafted saphenous vein relative to the carotid artery and vein graft may also render this conduit susceptible to neointima formation	0	0	0	0	0	0	0
1998	Mannion⁸³	Saphenous vein-carotid artery interposition	3 days	36	Examine whether vein responses to grafting could be modified by the intraoperative application of c-myc antisense oligomers	c-myc antisense was associated with a significant attenuation of macrophage infiltration, a concentration-dependent decrease in tissue edema and the attenuated loss of smooth muscle cells suggesting a potential protective role for c-myc antisense	0	0	0	c-myc antisense oligomers	0	0	0
1998	Mehta⁷⁶	Saphenous vein-carotid artery interposition	6 months	6	Compared morphological changes and PDGF expression in stented vein grafts	External stenting is associated with reduced medial thickening, neointima formation, and cell proliferation which was associated with a significant reduction in PDGF expression	0	0	0	External stent	0	0	0
1998	Jeremy⁷³	Saphenous vein-carotid artery interposition	4 weeks	16	Investigated the impact of external stent on factors known to inhibit vascular smooth muscle cell proliferation: Prostacyclin (PGI2), nitric oxide (NO), cAMP and cGMP formation in different regions of stented and unstented porcine vein grafts	There is a role for PGI2 and NO in promoting microangiogenesis in the adventitia of stented vein grafts which may in turn minimize graft hypoxia, an established contributory factor to neointima formation	0	0	0	External stent	0	0	0
1999	Zurbrügg⁸⁴	Saphenous vein–carotid artery interposition	4 weeks	5	Investigate the role of phynox mesh tubing (a wrought cobalt-chromium-nickel-molybdenum-iron alloy) on vein grafts disease	External support of vein grafts reduces intimal and medial layer proliferation	0	0	0	External stent/	0	0	0
2000	Dashwood⁶⁷	Saphenous vein-carotid artery interposition	6 months	No number	Investigate neural distribution in vein grafts as well as the localization of immunoreactive ET-1 and its receptors	Neural reorganization in vein grafts and indicate that ET-1 content and binding may play a role in the process of IH	0	0	0	0	0	0	0
2001	George⁷⁰	Saphenous vein–carotid artery interposition	4 weeks	10	Investigate the effect of external macro-porous (polyester) and micro-porous (polytetrafluorethylene) stents of equal diameter on IH and the expression of PDGF receptors	Porosity is crucial to the efficacy of external stents in reducing neointima formation in porcine vein grafts. Decreases in PDGF expression and cell proliferation accompany the reduction in neointima formation. In addition, macro-porous stents allow adventitial microvessels to connect with the vasculature outside the stent, thereby potentially improving oxygenation	0	0	0	External stent	0	0	0
2002	Angelini⁶⁴	Saphenous vein-carotid artery interposition	3 months	7	To determine the effects of supporting grafts with oversized, highly porous polyester stents in hypercholesterolemic pigs	External stenting with polyester favorably influences both neointima formation and early atherosclerosis and decreases the expression of VCAM-1	0	0	0	External stenting with polyester	0	Yes(high fat diet)	0
2002	Dashwood⁶⁶	Saphenous vein-carotid artery interposition	6 months	16	To determine the effect of external stenting on the innervation of porcine vein grafts	Neural reorganization plays a role in vein-graft failure and external stenting can prevent this reorganization	0	0	0	External stent	0	0	0
2003	Bartels⁸⁵	Jugular veins to carotid artery end-to-side t	4 weeks	23	To determine the value of prophylactic brachytherapy on vein graft disease	Prophylactic gamma radiation of does not prevent vein graft disease in a hypercholesterolemic porcine model	0	0	0	Prophylactic brachytherapy	0	Yes	0
2004	Jeremy⁷²	Saphenous vein-carotid artery interposition	4 weeks	8	Study the effect of external macro-porous biodegradable (polyglactin) sheaths on vein grafts	A nonrestrictive, biodegradable (polyglactin), external sheath reduces medial and intimal thickening possibly through inflammatory cell-mediated angiogenesis	0	0	0	External stents	0	0	0
2004	Wan⁸⁶	Saphenous vein-carotid artery interposition	3 months	13	Investigate the role of p53 overexpression on vein graft	Induction of SMC apoptosis by transient p53 overexpression positively influenced vein graft remodeling	Ad-overexpressed the proapoptotic gene p53	0	0	0	0	0	0
2004	Vijayan⁷⁷	Saphenous vein-carotid artery interposition	6 months	12	Investigate the effect of a biodegradable external stent on porcine vein graft thickening	Biodegradable external stents therefore have potential advantages over permanent stent material in clinical application	0	0	0	External stents	0	0	0
2004	Wan⁸¹	Saphenous vein-carotid artery interposition	4 weeks	40	Study the effect of administration of the endothelin 1(A) receptor antagonist BSF 302146 on vein grafts	The administration of BSF 302146 reduces graft thickening and promotes positive remodeling through an endothelin 1(A)-mediated effect on vascular smooth muscle cell replication	0	Endothelin 1(A) receptor antagonist	0	0	0	0	0
2005	Akowuah⁸⁹	Saphenous vein-carotid artery interposition	4 weeks	23	To investigate ex vivo gene transfer of TIMP-3 plasmid using microbubble-enhanced ultrasound on IH	Nonviral TIMP-3 plasmid delivery by USE achieves significant biological effects. The total vessel area were significantly greater in the TIMP-3 group compared to untransfected	0	0	0	U/S mediated TIMP-3 plasmid	0	0	0
2006	Wan⁸⁷	Saphenous vein-carotid artery interposition	4 months	8	Study the role of perivenous application of fibrin glue on vein grafts	Perivenous application of fibrin glue enhances graft thickening and as such does not constitute a strategy for preventing late vein graft failure	0	0	0	Fibrin glue	0	0	0
2007	Wan⁸⁰	Saphenous vein-carotid artery interposition	4 weeks	16	Examine the effect of the copperchelator penicillamine on saphenous vein grafts	The administration of penicillamine reduces vein graft thickening and promotes positive remodeling through negation of copper-induced cell proliferation	0	Penicillamine	0	0	0	0	0
2007	Wan⁷⁹	Saphenous vein-carotid artery interposition	4 weeks	64	Study the effect of administration ofthe aspirin-nitric oxide adduct, NCX 4016, compared with aspirin alone and the nitric oxide donor, morpholinosydnonimine alone on vein grafts	NCX 4016 inhibited neointimal thickness and area. Aspirin alone and morpholinosydnonimine alone were less effective in inhibiting neointimal thickness and neointimal area	0	Aspirin-nitric oxide adduct	0	0	0	0	0
2008	Kritz ⁹⁰	Saphenous vein-carotid artery interposition	4 weeks	No number	Assess the potential therapeutic effects of ad-nogo-B delivery to injured vessels in vivo	Gene delivery of Nogo-B exerts a positive effect on vascular injury-inducedremodeling and reduces IH	Ad-Nogo-B	0	0	0	0	0	0
2008	Popov⁹¹	Mammary vein- LAD end to side	4 weeks	6	Study the use internal mammary veins as a model for IH	The model is suitable to investigate the pathophysiology of aortocoronary vein graft intimal hyperplasia as well as therapeutic approaches	0	0	0	0	0	0	0
2010	Rajathurai⁹²	Saphenous vein-carotid artery interposition	12 weeks	56	Investigate the short- and long-term effects of periadventitial application of a sustained-release formulation of rapamycin vein grafts	Local toxicity and poor long-term efficacy limits the clinical applicability of locally applied, sustained rapamycin release in vein graft disease	0	Rapamycin	0	0	0	0	0
2010	Bloor⁶⁵	Saphenous vein-carotid artery interposition	4 weeks	No number	Study the effect of folic acid administration on vein grafts ina model of diabetes	Folic acid administration reduces neointimal thickening, augments vasa vasorum neoformation and reduces oxidative stress	0	Folic acid	0	0	0	0	Yes
2011	Jevon⁹³	Jugular veinto carotid artery interposition graft	4 weeks	8	Determine the source of neointimal cells	The majority of neointimal SMC in the IH seen after interposition vein grafting derive from the engrafted local vessel wall	0	0	0	0	0	0	0
2011	Ji⁹⁴	Saphenous vein to femoral artery interposition graft	4 weeks	24	Evaluate short-term effects of self-designed double-layer autologous saphenous vein graft on restraining excessive distension of vein graft and alleviating IH	The self-designed double-layer autologous saphenous vein graft restrains early excessive distension of vein graft and alleviates early IH	0	0	0	Double layered vein	0	0	0
2012	Kang⁸⁸	Saphenous vein-carotid artery interposition	3 months	30	Assess the performance of OPN following vein grafting	Early induction of OPN in vein grafts may contribute to the subsequent increase in MMP activities as well as vascular smooth muscle cell proliferation	0	0	0	0	0	0	0
2012	Thim⁹⁵	Jugular veinto carotid artery interposition graft	14 weeks	10	Develop a large animal model for the study of pathogenesis and treatment of vein graft disease	This finding suggests that oversized vein grafts may have detrimental effects on patient outcome	0	0	0	0	0	Hypercholesterolemic minipigs	0
2013	McDonald⁹⁹	Saphenous vein-carotid arteryinterposition	4 weeks	—	Identify microRNAs (miRNAs) that are dysregulated during neointimal formation and determine their pathophysiological relevance following miRNA manipulation	—	—	—	—	—	—	—	—
2016	Goldstone⁹⁶	Saphenous vein-carotid artery interposition	4 weeks	5	Investigate the role of photochemical tissue passivation (PTP) treatment of vein grafts	PTP decreases SMC proliferation and migration thereby reducing IH	0	0	0	Photochemical tissue passivation (PTP) treatment	0	0	0
2019	Pinel⁹⁷	Saphenous vein-carotid artery interposition	4 weeks	No number	Conduct a detailed analysis of both guide and passenger miRNA expression in vascular cells in vitro and vein grafts	miRNA passenger strands are predominantly dysregulated in response to vascular injury	0	0	0	0	0	0	0
2020	Garoffolo⁹⁸	Saphenous vein-carotid artery interposition	4 weeks	No number	Address the role of mechanical forces in the activation of maladaptive vein bypass remodeling	Matricellular mechanism is involved in the human vein arterialization process controlled by alterations in tissue mechanics	0	0	0	0	0	0	0

Thirty-three studies used the saphenous vein–carotid interposition graft model,^{61–81,86–90,92,96–99} 3 papers used the jugular vein–carotid artery interposition as a model^82,93,95 and end to side in 1 study.⁸⁵ The saphenous vein was used as a self-designed double-layer autologous graft to femoral artery in 1 study⁹⁴ and the mammary vein to the LAD end to side in 1 study.⁹¹

There were no poor run-off models. Three studies used a hypercholestolemic model which was high fat diet induced or hypercholestolemic minipigs^64,85,95 and 1 diabetic model.⁶⁵

The most common intervention used in this model was external stents, which was of different material or sizes. This model was driven by the Bristol Heart institute since the early 1990s. Violaris et al. ⁷⁸ used this model to investigate the role of using a 4 mm external porous polytetrafluoroethylene stent. At 4 weeks, all grafts showed an increase in external size, but this was restricted by stenting. Furthermore, there was an increase in the cross-sectional area of the tunica media and tunica intima; however, stented grafts showed less enlargement of the media but greater enlargement of the intima. Thus, wall size was, therefore, similar in stented and unstented grafts. The group concluded that the use of 4-mm external stents is unlikely to benefit as the final luminal size is thought to be of paramount importance in maintaining long-term patency. The group revisited the use of different sizes of stents when Izzat et al. ⁷¹ used a VP1200 polyester Locknit tube externally supported with helically wound polypropylene stent sizes (5-mm, 6-mm, and 8-mm diameter). At 4 weeks after grafting, total wall thickness was decreased in all stented grafts compared to unstented grafts. However, neointimal thickness was only reduced when using 6-mm and 8-mm stents but not by 5-mm stents. The concern raised by the group previously in term of intimal encroachment of the intima into the lumen was significantly reduced when using the 6- or 8-mm stents versus unstented grafts. Both neointimal and medial cell proliferation were significantly reduced by all three stents compared with unstented grafts, which was further supported by Angelini et al. ⁶³

Using 8 mm external stents, Mehta et al.⁷⁶ compared morphological changes and PDGF expression in stented grafts and contralateral unstented grafts in the same pigs, 6 months after graft implantation, and demonstrated that reduced medial thickening, neointima formation, and cell proliferation were sustained in externally stented grafts, and these effects were associated with a significant reduction in PDGF expression. Jeremy et al. ⁷³ using the 6-mm grafts further investigated the mechanisms involved in the modulation of IH by external stents and showed an essential role for PGI2 and NO in promoting microangiogenesis in the adventitia of stented vein grafts, which may in turn minimize graft hypoxia which is an established contributory factor to neointima formation.

These results encouraged the use of other types of external stents material such as a compliant Phynox mesh tubing (a wrought cobalt–chromium–nickel–molybdenum–iron Alloy) which similarly showed significant reduction of IH in stented grafts.⁸⁴ George et al.⁷⁰ used two different stent materials contra-laterally in the same pigs. One comprised an 8-mm diameter macroporous polyester velour tube and the other an 8-mm diameter microporous PTFE tube. One month after surgery, macroporous stents significantly reduced neointimal and medial thickening compared with microporous stents. Macroporous stents significantly reduced the percentage of cells expressing PDGF and PCNA compared with microporous stents. Adventitial microvessel formation occurred across macroporous stents but was markedly suppressed by microporous stents. This data clearly demonstrated the importance of porosity in external stents in reducing neointima.

To further understand the mechanisms involved in regulating IH by external stents, Angelini et al.⁶⁴ used the 8-mm-polyester locknit velour tube externally with polypropylene in pigs fed on a high-fat diet and only animals that achieved a plasma cholesterol level of at least 8 mmol/L were included in the study to maximize the stimulus for graft cholesterol accumulation. Further plasma cholesterol determinations were carried out in these pigs at the time of graft harvest. The group noted that stenting reduced graft cholesterol concentration significantly. Furthermore, foam cells were observed in unstented grafts but not in stented grafts. Moreover, vascular cell adhesion molecule 1 was strongly expressed in intimal and medial cells in unstented compared to stented grafts. More understanding of the mechanisms involved in modulating IH came from Dashwood et al.^66,67 using the 8-mm stents showed that neural reorganization plays a role in vein graft failure, possibly through the local release of mitogens; the prevention of this reorganization contributes to the inhibitory effect of the external stent on neointima formation.

Another study by Jeremy et al.⁷² used external placement of polyglactin (Vicryl) sheaths (8 mm in diameter) and showed that these polyglactin sheaths significantly reduced intimal thickness, medial thickness, and the percentage of proliferating cells compared with unsheathed controls after 4 weeks. Interestingly, there was a pronounced accumulation of macrophages, giant cells, EC, and microvessels within and surrounding the biodegradable sheath compared with controls, suggesting that this stents may reduce medial and intimal thickening through inflammatory cell–mediated angiogenesis. When looking at the long-term effect of such a stent, Vijayan et al.⁷⁷ showed a persistent reduction in neointimal thickening at 6 months even after the degradation of the stent itself, confirming the important potential role of using a biodegradable external stent as a novel approach to ameliorating the problem of intimal hyperplasia that plagues these grafts.

Five studies used drugs including orally administered medications including penicillamine, endothelin 1(A) receptor antagonist BSF 302,146, aspirin-nitric oxide adduct, or folic acid and showed promising results by reducing vein graft thickening and promotes positive remodeling.^65,80,81 Adenovirus transfer was used in a small amount of studies and included Ad overexpressed in the proapoptotic gene p53, Nogo-B, or soluble vascular cell adhesion molecule (sVCAM) (Ad.CB-sVCAM) with promising results .^82,86,90

Other modulation methods included the use of fibrin glue, prophylactic brachytherapy, photochemical tissue passivation (PTP) treatment, ultrasound-mediated tissue inhibitor of metalloproteinase (TIMP-3) plasmid, periadventitial rapamycin-eluting microbeads, and using the vein as a double layer to restrain excessive distension, ^{83,85,87,89,92,94,96} all with encouraging results during the time of study except for the periadventitial rapamycin-eluting microbeads as the initial effect of rapamycin was not sustained, and there was no therapeutic benefit evident in 12-week grafts .⁹²

Sheep model

Five papers were identified that used a sheep model and are summarized in Table 3.^100–104

Table 3.

Summary of studies using porcine model of vein grafts IH.

Year	Author	Model details	Maximum time frame	Number of samples	Aim of study	Conclusion	Other
1986	Barra¹⁰¹	Jugular vein to carotid artery interposition	4 months	14	Evaluate the role of constrictive mesh for vein graft	The distention and subsequent damage of the vein graft may be minimized by use of a constrictive mesh	External stent
2002	Krejca¹⁰³	Jugular vein to carotid artery interposition	12 weeks	21	Investigate if sheathing of the vein graft with pressure-resistant tubing might prolong vein graft patency	The external vein graft support with mesh tubing reduces intimal and medial layer thickening and cell proliferation in composite vein grafts transplanted in the arterial position	External stent
2007	Klesius¹⁰⁴	Femoral vein to carotid arteryinterposition	6 months	12	Investigate the use of different external stents in vein grafts	Both in the short and long terms, the new polyester stent led to significantly higher reduction of neointimal hyperplasia and luminal encroachment compared to the native vessel. It proved superior to PTFE stenting, while the biocompound material failed to prove efficacy	External stent
2010	Krejca¹⁰²	Radial vein to carotid artery interposition	12 weeks	12	Assess whether a stented vein graft has an impact on VEGF-A and VEGFR-1expression compared with non-stented vein grafts	External stenting of the vein graft decreases VEGF-A expression and induces significant down-regulation of VEGFR-1 in the intima and media after the re-endothelialization	External stent
2015	El-Kurdi¹⁰⁰	Saphenous vein to femoral artery end to side	52 weeks	23	A surgical model in sheep intended to study IH development in vein grafts	Bilateral SVGs implanted onto the femoral arteries of sheep produced, controlled and consistent angiographic and histomorphometric results for which direct correlations could be made	0

The models included the jugular vein to carotid artery interposition model in 2 studies,^101,103 radial vein to carotid artery in 1 study,¹⁰² the femoral vein to carotid artery in 1 study,¹⁰⁴ and 1 saphenous vein to femoral artery as the end to side mode.¹⁰⁰

None of these studies was designed as a poor run-off, and none of them was a diabetic or hypercholesteremic model.

These studies were designed to study the role of using an external mesh/stent to modulate IH except for the saphenous vein model¹⁰⁰ that was a descriptive study of a new model of vein graft disease.

Barra et al. compared the impact of using a constrictive mesh tube to no mesh and suggested that 4 months after surgery, the use of mesh was associated with more normal endothelium and moderate and regular intimal thickening.¹⁰¹

Similarly, Krejca et al.¹⁰² used a newly designed 4-mm polyester fiber (torlen/dacron). The mean intimal wall thickness was assessed at different times (up to 12 weeks) and was consistently significantly less than the control graft weeks with a smooth endothelial layer with intact nuclei and when looking at the potential mechanisms involved in the protective effect of this new stent, it was noted that it can be related to the downregulation of VEGF-A.

Klesius et al.¹⁰⁴ compared the short-term impact (4 weeks) of using three different stents chosen based on ex vivo work performed by the group and included a newly designed polyester stent, microporous PTFE stent grafts, and metallic biocompound stents. In addition, the group investigated the long-term (6 months) effect of using the polyester stent in a femoral vein to the carotid interposition model and concluded that the new macroporous polyester stent led to significantly higher reduction of neointimal hyperplasia and luminal encroachment compared to the native vessel. It proved superior to PTFE stenting, while the biocompound material failed to prove its efficacy.

Risk of Bias and quality assessment

Risk of bias using the modified SYRCLE is presented in Figure 2. There was no sufficient information regarding sequence generation or random housing. All the other fields showed that the risk of bias was low or unclear with some minor concern of high risk of bias regarding baseline characteristics in 3 studies,^9,13,101 selective reporting in 3 studies,^9,13,60 incomplete outcome data in 1 study,⁶⁰ and other sources of bias in 3 studies ^9,52,92

Figure 2.

Risk of bias assessment.

Quality assessment using the ARRIVE Essential 10 is presented in Figure 3. Overall, all studies clearly presented information regarding inclusion/exclusion criteria, outcome measures, statistical methods, experimental animals, and procedures and results. There was no clear data regarding randomization, and 23 studies did not report clear number of animals used.^{17,18,20,23,25,27,33,34,36,38,50,60–62,65,67,74,75,78,82,90,97,98}

Figure 3.

ARRIVE quality assessment.

Discussion

Saphenous vein graft IH remains a major problem for patients undergoing CABG, despite many years of research. It is accepted that IH is a chronic inflammatory disease that is associated with the proliferation and migration of SMC from the media to the intima coupled with MMP changes.^1,2 However, there remain significant gaps in our understanding of the complex processes that take place when a vein is implanted into arterial circulation. While cellular models can be used and undoubtedly yield useful data,^105–107 the comparatively simplistic nature of these systems makes insights gained from such models limited when it comes to translation. Considering unfeasibility of studying vein grafts disease temporal progression and mechanisms in the human body directly, different small and large animal models were developed as a surrogate. Large animal models complement small animal studies with the added value of longer lifespan, better size match, and the fact that they are genetically more closely related to humans.

The most common two large animals used are the dog and porcine model. Most of the studies attempted a simplistic vein interposition grafting of a segment of vein to arterial circulation which although useful does not truly represent the end to side anastomosis in the human body. Very limited work been carried out using an end to side model between a vein and a coronary artery in large animals, and this can be related to the difficulty of carrying out such a procedure and recovering these large animals for a prolonged period. In addition, it is important to remember that there are different genetic differences that exist among these animal groups and humans and that genetic regulation and interplay can differ.¹⁰⁸ However, it seems that the canine, porcine, and sheep immune system shares many similarities to that of the human system, making them a very appealing model to study inflammatory responses.^109–111 Moreover, in pigs, intravenous or intralymphatic cannulations can be performed and blood or lymph samples taken for several days without the stress effect that is present in restrained rodents or sheep, for example.¹¹⁰

Despite such limitation, the use of large animal models has been instrumental in improving our understanding of the disease progression as their size is a particular advantage for physiological models such as cardiovascular diseases. They are also outbred and, therefore, representative of population diversity. Furthermore, it allowed the use of different therapeutic interventions to modulate the inflammatory processes or suppress SMC activity to try to modulate IH.

Over the years, many encouraging results from animal studies failed to translate into human with the exception of very few such as the early work by Weglarz et al. in a study that aimed to assess plaque formation in saphenous vein grafts (SVGs) covered by an external Dacron stent in comparison with the classical technique which showed inferior results when using the external stents.¹¹² More encouraging results were reported in the VEST trials and others which showed that external stenting mitigates saphenous vein graft remodeling and significantly reduces diffuse intimal hyperplasia and the development of lumen irregularities after coronary artery bypass surgery.^113–116

The selection of the most appropriate model is not an easy task and need to take into account the disease studied, available funding, and most importantly the 3 Rs (replacement, reduction, and refinement).¹¹⁷ The 3 Rs concept should be essential when considering the use of animals especially in the current era where alternative ex vivo perfusion systems and different bioreactors are available. These are capable of mimicking some of the complex hemodynamic conditions related to vein grafting and allow the administration of different treatments or sampling the vein graft at different time points, thus allowing for at least partial replacement and reduction by focusing the research at specific time points, resulting in the reduction of animals required.¹¹⁸

Supplemental Material

sj-pdf-1-prf-10.1177_02676591221091200 – Supplemental material for Large animal model of vein grafts intimal hyperplasia: A systematic review

Supplemental material, sj-pdf-1-prf-10.1177_02676591221091200 for Large animal model of vein grafts intimal hyperplasia: A systematic review by Oluwatomini Fashina, Riccardo G Abbasciano, Liam W McQueen, Shameem Ladak, Sarah J George, Sadeeh Suleiman, Prakash P Punjabi, Gianni D Angelini and Mustafa Zakkar in Perfusion

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Supplemental Material

Supplemental material for this article is available online.

ORCID iDs

Liam W McQueen

Prakash P Punjabi

Gianni D Angelini

Mustafa Zakkar

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