Genetic Therapy for Vein Bypass Graft Disease: Current Perspectives

Vascular ◽  
2004 ◽  
Vol 12 (4) ◽  
pp. 213-217
Author(s):  
Hector F. Simosa ◽  
Michael S. Conte
Keyword(s):  
Vein Graft ◽  
Graft Failure ◽  
Bypass Graft ◽  
Graft Patency ◽  
The United States ◽  
Secondary Patency ◽  
Matrix Remodeling ◽  
Peripheral Ischemia ◽  
Genetic Interventions ◽  
Vein Graft Failure

Although continued progress in endovascular technology holds promise for less invasive approaches to arterial diseases, surgical bypass grafting remains the mainstay of therapy for patients with advanced coronary and peripheral ischemia. In the United States, nearly 400,000 coronary and 100,000 lower extremity bypass procedures are performed annually. The autogenous vein, particularly the greater saphenous vein, has proven to be a durable and versatile arterial substitute, with secondary patency rates at 5 years of 70 to 80% in the extremity.1 However, vein graft failure is a common occurrence that incurs significant morbidity and mortality, and, to date, pharmacologic approaches to prolong vein graft patency have produced limited results. Dramatic advances in genetics, coupled with a rapidly expanding knowledge of the molecular basis of vascular diseases, have set the stage for genetic interventions. The attraction of a genetic approach to vein graft failure is based on the notion that the tissue at risk is readily accessible to the clinician prior to the onset of the pathologic process and the premise that genetic reprogramming of cells in the wall of the vein can lead to an improved healing response. Although the pathophysiology of vein graft failure is incompletely understood, numerous relevant molecular targets have been elucidated. Interventions designed to influence cell proliferation, thrombosis, inflammation, and matrix remodeling at the genetic level have been described, and many have been tested in animal models. Both gene delivery and gene blockade strategies have been investigated, with the latter now reaching the stage of advanced clinical trials.

scholarly journals Torsion Does Not Affect Early Vein Graft Patency in the Rat Femoral Artery Model

2018 ◽  
Vol 35 (04) ◽  
pp. 299-305
Author(s):  
Amro Harb ◽  
Maxwell Levi ◽  
Akio Kozato ◽  
Yelena Akelina ◽  
Robert Strauch
Keyword(s):  
Vein Graft ◽  
Graft Failure ◽  
Blood Flow Rate ◽  
Graft Patency ◽  
Sprague Dawley ◽  
Rat Models ◽  
Vein Grafts ◽  
Sprague Dawley Rats ◽  
Training Courses ◽  
Vein Graft Failure

Background Torsion of vein grafts is a commonly cited reason for graft failure in clinical setting. Many microsurgery training courses have incorporated vein graft procedures in their curricula, and vein graft torsion is a common technical error made by the surgeons in these courses. To improve our understanding of the clinical reproducibility of practicing vein graft procedures in microsurgery training courses, this study aims to determine if torsion can lead to early vein graft failure in nonsurvival surgery rat models. Methods Sprague-Dawley rats were divided into five cohorts with five rats per cohort for a total of 25 rats. Cohorts were labeled based on degree of vein graft torsion (0, 45, 90, 135, and 180 degrees). Torsion was created in the vein grafts at the distal arterial end by mismatching sutures placed between the proximal end of the vein graft and the distal arterial end. Vein graft patency was then verified 2 and 24 hours postoperation. Results All vein grafts were patent 2 and 24 hours postoperation. At 2 hours, the average blood flow rate measurements for 0, 45, 90, 135, and 180 degrees of torsion were 0.37 ± 0.02, 0.38 ± 0.04, 0.34 ± 0.01, 0.33 ± 0.01, and 0.29 ± 0.02 mL/min, respectively. At 24 hours, they were 0.94 ± 0.07, 1.03 ± 0.15, 1.26 ± 0.22, 1.41 ± 0.11, and 0.89 ± 0.15 mL/min, respectively. Conclusion Torsion of up to 180 degrees does not affect early vein graft patency in rat models. To improve the clinical reproducibility of practicing vein graft procedures in rat models, we suggest that microsurgery instructors assess vein graft torsion prior to clamp release, as vessel torsion does not seem to affect graft patency once the clamps are removed.

scholarly journals Systems Approach to Discovery of Therapeutic Targets for Vein Graft Disease PPARα Pivotally Regulates Metabolism, Activation, and Heterogeneity of Macrophages and Lesion Development

Circulation ◽  
2021 ◽  
Author(s):  
Julius L. Decano ◽  
Sasha A. Singh ◽  
Cauê Gasparotto Bueno ◽  
Lang Ho Lee ◽  
Arda Halu ◽  
...  
Keyword(s):  
Single Cell ◽  
Vein Graft ◽  
Graft Failure ◽  
Systems Approach ◽  
Therapeutic Targets ◽  
Sphingolipid Metabolism ◽  
Peroxisome Proliferator ◽  
Matrix Remodeling ◽  
Lesion Development ◽  
Vein Graft Failure

Background: Vein graft failure remains a common clinical challenge. We applied a systems approach in mouse experiments to discovering therapeutic targets for vein graft failure. Methods: Global proteomics and high-dimensional clustering on multiple vein graft tissues were used to identify potential pathogenic mechanisms. The peroxisome proliferator-activated receptors (PPARs) pathway served as an example to substantiate our discovery platform. In vivo mouse experiments with macrophage-targeted PPARα siRNA and the novel, selective activator pemafibrate demonstrate the role of PPARα in the development and inflammation of vein graft lesions. In vitro experiments further included metabolomic profiling, qPCR, flow cytometry, metabolic assays, and single-cell RNA-sequencing on primary human and mouse macrophages. Results: We identified changes in the vein graft proteome associated with immune responses, lipid metabolism regulated by the PPARs, fatty acid metabolism, matrix remodeling, and hematopoietic cell mobilization. PPARα agonism by pemafibrate retarded the development and inflammation of vein graft lesions in mice, while gene silencing worsened plaque formation. Pemafibrate also suppressed arteriovenous fistula lesion development. Metabolomics/lipidomics, functional metabolic assays, and single-cell analysis of cultured human macrophages revealed that PPARα modulates macrophage glycolysis, citrate metabolism, mitochondrial membrane sphingolipid metabolism, and heterogeneity. Conclusions: This study explored potential drivers of vein graft inflammation and identified PPARα as a novel potential pharmacologic treatment for this unmet medical need.

Harvesting conduits

2021 ◽  
pp. 291-294
Author(s):  
Alice Wang ◽  
Peter K. Smith
Keyword(s):  
Vein Graft ◽  
Graft Failure ◽  
Saphenous Vein Graft ◽  
Artery Bypass ◽  
The United States ◽  
First Year ◽  
Clinical Consequence ◽  
Bypass Grafting ◽  
Repeat Revascularization ◽  
Vein Graft Failure

The saphenous vein graft (SVG) remains the most commonly used conduit for circumflex, right coronary, and diagonal coronary grafts and is used in approximately 90% of patients undergoing coronary artery bypass grafting in the United States. Vein graft failure, however, remains a persistent disadvantage of the SVG compared to arterial conduits. Up to 15% of SVGs occlude within the first year and up to half are occluded by 10 years. Vein graft failure has serious clinical consequence as studies have found SVG occlusion to be associated with the need for repeat revascularization, myocardial infarction, and death. Consequently, much research has been dedicated to identifying causes of increased rates of vein graft failure, particularly whether the method of harvest affects SVG patency.

Growth and Remodeling of Vein Graft in an Arterial Environment: Parameter Estimation and Sensitivity Analysis

2013 ◽  
Author(s):  
Abhay B. Ramachandra ◽  
Sethuraman Sankaran ◽  
Jay D. Humphrey ◽  
Alison L. Marsden
Keyword(s):  
Vein Graft ◽  
Graft Failure ◽  
Computational Models ◽  
Bypass Graft ◽  
Coronary Bypass ◽  
Active Role ◽  
Underlying Mechanism ◽  
The United States ◽  
Arterial System ◽  
Growth And Remodeling

In coronary artery disease, surgical revascularization using venous bypass grafts is performed to relieve symptoms and prolong life. Coronary bypass graft surgery is performed on approximately 500,000 people every year in the United States, with graft failure rates as high as 50% within 5 years. When a vein graft is implanted in the arterial system it adapts to the high flow rate and high pressure of the arterial environment by changing composition and geometry. Hemodynamics is known to play an active role in growth and remodeling of blood vessels but the complete underlying mechanism of vein graft failure is not well understood. Experiments required to understand this phenomenon can be resource and time intensive. In order to augment the existing knowledge and to guide design and interpretation of experiments that are needed to refine our understanding of vein graft growth and remodeling, computational models of vascular growth and remodeling are used to describe and predict the response of vein grafts to changes in hemodynamic loads. Computational models of growth and remodeling have numerous parameters, and even the inputs from experiments have uncertainties associated with them. There is therefore a need for a systematic approach to estimate the parameters included in growth and remodeling models and to evaluate sensitivity of the quantities of interest to parametric variations.

scholarly journals Antithrombotic treatment after coronary artery bypass graft surgery: systematic review and network meta-analysis

BMJ ◽  
2019 ◽  
pp. l5476 ◽  
Author(s):  
Karla Solo ◽  
Shahar Lavi ◽  
Conrad Kabali ◽  
Glenn N Levine ◽  
Alexander Kulik ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Saphenous Vein ◽  
Vein Graft ◽  
Graft Failure ◽  
Saphenous Vein Graft ◽  
Meta Analysis ◽  
Artery Bypass ◽  
Bypass Graft ◽  
Artery Bypass Graft ◽  
Vein Graft Failure

Abstract Objective To assess the effects of different oral antithrombotic drugs that prevent saphenous vein graft failure in patients undergoing coronary artery bypass graft surgery. Design Systematic review and network meta-analysis. Data sources Medline, Embase, Web of Science, CINAHL, and the Cochrane Library from inception to 25 January 2019. Eligibility criteria for selecting studies Randomised controlled trials of participants (aged ≥18) who received oral antithrombotic drugs (antiplatelets or anticoagulants) to prevent saphenous vein graft failure after coronary artery bypass graft surgery. Main outcome measures The primary efficacy endpoint was saphenous vein graft failure and the primary safety endpoint was major bleeding. Secondary endpoints were myocardial infarction and death. Results This review identified 3266 citations, and 21 articles that related to 20 randomised controlled trials were included in the network meta-analysis. These 20 trials comprised 4803 participants and investigated nine different interventions (eight active and one placebo). Moderate certainty evidence supports the use of dual antiplatelet therapy with either aspirin plus ticagrelor (odds ratio 0.50, 95% confidence interval 0.31 to 0.79, number needed to treat 10) or aspirin plus clopidogrel (0.60, 0.42 to 0.86, 19) to reduce saphenous vein graft failure when compared with aspirin monotherapy. The study found no strong evidence of differences in major bleeding, myocardial infarction, and death among different antithrombotic therapies. The possibility of intransitivity could not be ruled out; however, between-trial heterogeneity and incoherence were low in all included analyses. Sensitivity analysis using per graft data did not change the effect estimates. Conclusions The results of this network meta-analysis suggest an important absolute benefit of adding ticagrelor or clopidogrel to aspirin to prevent saphenous vein graft failure after coronary artery bypass graft surgery. Dual antiplatelet therapy after surgery should be tailored to the patient by balancing the safety and efficacy profile of the drug intervention against important patient outcomes. Study registration PROSPERO registration number CRD42017065678.

Preventing treatment failures in coronary artery disease: what can we learn from the biology of in-stent restenosis, vein graft failure, and internal thoracic arteries?

2019 ◽  
Vol 116 (3) ◽  
pp. 505-519 ◽  
Author(s):  
Cristiano Spadaccio ◽  
Charalambos Antoniades ◽  
Antonio Nenna ◽  
Calvin Chung ◽  
Ricardo Will ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Vein Graft ◽  
Graft Failure ◽  
Bypass Graft ◽  
Stent Restenosis ◽  
Artery Disease ◽  
Vein Graft Failure ◽  
In Stent Restenosis

Abstract Coronary artery disease (CAD) remains one of the most important causes of morbidity and mortality worldwide, and the availability of percutaneous or surgical revascularization procedures significantly improves survival. However, both strategies are daunted by complications which limit long-term effectiveness. In-stent restenosis (ISR) is a major drawback for intracoronary stenting, while graft failure is the limiting factor for coronary artery bypass graft surgery (CABG), especially using veins. Conversely, internal thoracic artery (ITA) is known to maintain long-term patency in CABG. Understanding the biology and pathophysiology of ISR and vein graft failure (VGF) and mechanisms behind ITA resistance to failure is crucial to combat these complications in CAD treatment. This review intends to provide an overview of the biological mechanisms underlying stent and VGF and of the potential therapeutic strategy to prevent these complications. Interestingly, despite being different modalities of revascularization, mechanisms of failure of stent and saphenous vein grafts are very similar from the biological standpoint.

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