The Role of Immunomodulation in Vein Graft Remodeling and Failure

Baganha, Fabiana; Jong, Alwin de; Jukema, J. Wouter; Quax, Paul H.A.; Vries, Margreet R. de

doi:10.1007/s12265-020-10001-y

Cited by 15 publications

(15 citation statements)

References 101 publications

(132 reference statements)

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“…Histopathological studies and experimental vein graft models have shown that the inflammatory components of the innate immune system are present in all stages of vein graft adaptation (21). Crucial for a long-term good vein graft patency is the proper amount of vascular remodeling.…”

Section: Discussionmentioning

confidence: 99%

“…A certain degree of inflammation is beneficial in the process of remodeling (22). Inflammatory cytokines and growth factors excreted by leukocytes invading the vessel wall contribute to the reendothelialization of the, during the surgery, damaged endothelium and activate smooth muscle cell migration and activation (1,21,22). This inflammatory trigger needs to dampen after the initial period to drive the remodeling process toward the positive outward remodeling.…”

Section: Discussionmentioning

confidence: 99%

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Interfering in the ALK1 Pathway Results in Macrophage-Driven Outward Remodeling of Murine Vein Grafts

Jong

Sier

Peters

et al. 2022

Front. Cardiovasc. Med.

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AimsVein grafts are frequently used to bypass coronary artery occlusions. Unfortunately, vein graft disease (VGD) causes impaired patency rates. ALK1 mediates signaling by TGF-β via TGFβR2 or BMP9/10 via BMPR2, which is an important pathway in fibrotic, inflammatory, and angiogenic processes in vascular diseases. The role of the TGF-β pathway in VGD is previously reported, however, the contribution of ALK1 signaling is not known. Therefore, we investigated ALK1 signaling in VGD in a mouse model for vein graft disease using either genetic or pharmacological inhibition of the Alk1 signaling.Methods and ResultsMale ALK1 heterozygous (ALK1+/−), control C57BL/6, as well as hypercholesterolemic ApoE3*Leiden mice, underwent vein graft surgery. Histologic analyses of ALK1+/− vein grafts demonstrated increased outward remodeling and macrophage accumulation after 28 days. In hypercholesterolemic ApoE3*Leiden mice receiving weekly ALK1-Fc injections, ultrasound imaging showed 3-fold increased outward remodeling compared to controls treated with control-Fc, which was confirmed histologically. Moreover, ALK1-Fc treatment reduced collagen and smooth muscle cell accumulation, increased macrophages by 1.5-fold, and resulted in more plaque dissections. No difference was observed in intraplaque neovessel density. Flow cytometric analysis showed increased systemic levels of Ly6CHigh monocytes in ALK1-Fc treated mice, supported by in vitro increased MCP-1 and IL-6 production of LPS-stimulated and ALK1-Fc-treated murine monocytes and macrophages.ConclusionReduced ALK1 signaling in VGD promotes outward remodeling, increases macrophage influx, and promotes an unstable plaque phenotype.Translational PerspectiveVein graft disease (VGD) severely hampers patency rates of vein grafts, necessitating research of key disease-driving pathways like TGF-β. The three-dimensional nature of VGD together with the multitude of disease driving factors ask for a comprehensive approach. Here, we combined in vivo ultrasound imaging, histological analyses, and conventional in vitro analyses, identifying the ambiguous role of reduced ALK1 signaling in vein graft disease. Reduced ALK1 signaling promotes outward remodeling, increases macrophage influx, and promotes an unstable plaque phenotype in murine vein grafts. Characterization of in vivo vascular remodeling over time is imperative to monitor VGD development and identify new therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Interfering in the ALK1 Pathway Results in Macrophage-Driven Outward Remodeling of Murine Vein Grafts

Jong

Sier

Peters

et al. 2022

Front. Cardiovasc. Med.

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“…We present the results of early reperfusion, suggesting that overactivity of the inflammatory system following off-pump procedures can predispose patients for graft endothelium injury as proinflammatory cytokines are released. The role of immunomodulation in vein graft failure in humans was reviewed by Baganha et al [ 64 ]. Immune cells in long-term intimal hyperplasia and accelerated atherosclerosis were presented on experimental and clinical basis.…”

Section: Discussionmentioning

confidence: 99%

The Prognostic Significance of Neutrophil to Lymphocyte Ratio (NLR), Monocyte to Lymphocyte Ratio (MLR) and Platelet to Lymphocyte Ratio (PLR) on Long-Term Survival in Off-Pump Coronary Artery Bypass Grafting (OPCAB) Procedures

Urbanowicz

Olasińska-Wiśniewska

Michalak

et al. 2021

Biology

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Background: Cardiovascular diseases, apart from commonly known risk factors, are related to inflammation. There are several simple novel markers proposed to present the relation between inflammatory reactions activation and atherosclerotic changes. They are easily available from whole blood count and include neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), and platelets to lymphocyte ratio (PLR). The RDW results were excluded from the analysis. Method and results: The study based on retrospective single-centre analysis of 682 consecutive patients (131 (19%) females and 551 (81%) males) with median age of 66 years (60–71) who underwent off-pump coronary artery bypass grafting (OPCAB) procedure. During the median 5.3 +/− 1.9 years follow-up, there was a 87% cumulative survival rate. The laboratory parameters including preoperative MLR > 0.2 (HR 2.46, 95% CI 1.33–4.55, p = 0.004) and postoperative NLR > 3.5 (HR 1.75, 95% CI 1.09–2.79, p = 0.019) were found significant for long-term mortality prediction in multivariable analysis. Conclusion: Hematological indices NLR and MLR can be regarded as significant predictors of all-cause long-term mortality after OPCAB revascularization. Multivariable analysis revealed preoperative values of MLR > 0.2 and postoperative values of NLR > 3.5 as simple, reliable factors which may be applied into clinical practice for meticulous postoperative monitoring of patients in higher risk of worse prognosis.

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“…Accumulating evidence suggests that the immune system plays a critical part in tissue maintenance and repair beyond its traditional role of distinguishing self from non-self and eradicating pathogens (31). In recent years, the immune system has been recognized as an important contributor to a number of cardiovascular diseases, including hypertension, atherosclerosis, and the vasculitides (15,16,(18)(19)(20)32). While the intact vascular endothelium is not immunologically reactive, if the blood vessels become damaged, further vascular injury may occur through a variety of innate and adaptive immune mechanisms (33,34).…”

Section: Discussionmentioning

confidence: 99%

Arteriovenous Fistula Nonmaturation: What’s the Immune System Got to Do with It?

2021

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Background Arteriovenous fistula (AVF) non-maturation is a persistent problem, particularly among female and Black patients. Increasingly, the immune system has been recognized as an important contributor to vascular disease, but few studies have examined immune factors relative to AVF maturation outcomes. This study evaluated the association of serum panel reactive antibodies (PRA), a measure of immune system reactivity assessed in patients undergoing kidney transplant evaluation, with AVF non-maturation. Methods We identified 132 patients at our institution who underwent surgical AVF placement between 2010-2019 and had PRA testing within one year of AVF creation. Multivariable logistic regression was used to determine the association of patient demographic and clinical factors, class I and class II PRA levels, and preoperative arterial and venous diameters with AVF maturation outcomes. Results AVF non-maturation was more likely in females than males (44% vs 20%, p=0.003) and in Black than white patients (40% vs 13%, p=0.001). Class II PRA was higher in females than males (12% ± 23% vs 4% ± 13%, p=0.02). In the multivariable model, AVF non-maturation was associated with class II PRA (adjusted odds ratio [aOR] 1.34 per 10% increase; 95% confidence interval [CI], 1.04 to 1.82, p=0.02) and Black race (aOR 3.34; 95% CI, 1.02 to 10.89, p=0.03), but not with patient sex or preoperative arterial or venous diameters. Conclusions The association of elevated class II PRA with AVF non-maturation suggests that the immune system may play a role in AVF maturation outcomes, especially among female patients.

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The Role of Immunomodulation in Vein Graft Remodeling and Failure

Cited by 15 publications

References 101 publications

Interfering in the ALK1 Pathway Results in Macrophage-Driven Outward Remodeling of Murine Vein Grafts

Interfering in the ALK1 Pathway Results in Macrophage-Driven Outward Remodeling of Murine Vein Grafts

The Prognostic Significance of Neutrophil to Lymphocyte Ratio (NLR), Monocyte to Lymphocyte Ratio (MLR) and Platelet to Lymphocyte Ratio (PLR) on Long-Term Survival in Off-Pump Coronary Artery Bypass Grafting (OPCAB) Procedures

Arteriovenous Fistula Nonmaturation: What’s the Immune System Got to Do with It?

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