Graft Lesions Research Articles

Targeted delivery of IL-21 neutralizing nanotherapeutics to lymph nodes and kidney allografts attenuates B cell alloimmunity.

Targeted delivery of IL-21 neutralizing nanotherapeutics to lymph nodes and kidney allografts attenuates B cell alloimmunity.

Role of Embolic Protection in Percutaneous Coronary Intervention Without Saphenous Venous Graft Lesions in ST-Segment-Elevation Myocardial Infarction: A Systematic Review and Meta-Analysis: Erratum.

Role of Embolic Protection in Percutaneous Coronary Intervention Without Saphenous Venous Graft Lesions in ST-Segment-Elevation Myocardial Infarction: A Systematic Review and Meta-Analysis: Erratum.

Osteoclast-like multinucleated giant cells reinforce polycaprolactone grafts.

Successful application of advanced engineered materials in osteoplasty requires a biological understanding of the recipient reaction. The immune system acts like a double-edged sword by maintaining targeted tissue and rejecting grafts. Nevertheless, even for promising graft materials such as polycaprolactone, insights on contact with immune cells have been restricted due to lacking quantitative assays. Here, we show that polycaprolactone graft sites after cranioplasty are dominated by an immature type of multinucleated giant cells, probably derived from transmigrating peripheral monocytes. The cells interact with the polycaprolactone through extensive pseudopodia formation and localized polymer dissolution. Dynamic mechanical analysis revealed osteoclast-like cells, derived in vitro from primary human monocytes, reinforce polycaprolactone by depositing a CD18 integrin-rich attachment matrix. Our findings give a new perspective on immune cells' beneficial and detrimental functions in graft lesions, guiding therapy with better graft designs.

Role of Embolic Protection in Percutaneous Coronary Intervention Without Saphenous Venous Graft Lesions in ST-Segment-Elevation Myocardial Infarction: A Systematic Review and Meta-Analysis.

Embolic protection devices (EPDs) are catheter-based devices that can be used to capture atherosclerotic remnants released during percutaneous coronary intervention (PCI). We aim to study the efficacy and safety of EPDs in PCIs without saphenous vein grafts (SVGs) in ST-segment-elevation myocardial infarction (MI). Three electronic databases of MEDLINE, Web of Science, and Embase were searched from inception to April 10, 2024, to identify relevant randomized controlled trials that compared outcomes of patients subjected to EPD during PCI with a control group where EPDs were not utilized. The primary outcome was 30-day all-cause mortality. Secondary outcomes were major adverse cardiovascular and cerebrovascular events at 30 days, post-PCI thrombolysis in MI grade 3 flow attainment, ST-segment resolution at 90 minutes post-procedure, and postprocedure angiographically detectable signs of distal embolization. The effect estimates of outcomes were assessed using risk ratio (RR) with a 95% confidence interval (CI). Random-effects meta-analysis was conducted using the restricted maximum likelihood method, given that the interstudy variance was inevitable. We included 3 randomized controlled trials enrolling 741 patients (age, 61.6 ± 12.15 years; 22% females) undergoing PCI without SVG lesions. As opposed to the control group, the use of EPD did not yield a significant effect on all-cause mortality [RR, 0.76 (95% CI, 0.31-1.86); I 2 = 0%], major adverse cardiovascular and cerebrovascular events [RR, 0.66 (95% CI, 0.34-1.27); I 2 = 0%], post-PCI thrombolysis in MI 3 flow [RR, 1.18 (95% CI, 0.86-1.62); I 2 = 77%], and ST-segment resolution at 90 minutes post-procedure [RR, 1.05 (95% CI, 0.90-1.22); I 2 = 0%]. However, EPD significantly decreased angiographically detectable signs of distal embolization [RR, 0.60 (95% CI, 0.36-0.99); I 2 = 0%]. EPD significantly reduced angiographically detectable signs of distal embolization in PCI without SVG lesions in ST-segment-elevation MI though there were no clinical signs of improved flow or mortality. Further trials are necessary to thoroughly evaluate the potential benefits and requirements of EPD usage in such procedures.

To evaluate safety of the adsorption hemofiltration technique for treatment of septic shock in severe burn patients

Objectives: Evaluating the safety of continuous hemofiltration using an adsorbent membrane to treat septic shock in severe burns patients. Subjects and methods: The study describes 55 episodes of septic shock in 38 severe burn patients (16 - 60 years old) treated at the Intensive Care Unit, Le Huu Trac National Burn Hospital from January 2023 to June 2024. Results: The total number of filters used was 247, of which 8 filters had frozen membranes (3.2%), the average life of the filter was 15.87 hours. There were no cases of systolic blood pressure falling below 90 mmHg when entering the filter. During continuous veno-venous hemodiafiltration (CVVHDF): Body temperature was always within allowable limits; there were no differences in blood potassium levels, blood protein and albumin concentration, and hypocoagulation disorders at all time points (p > 0.05); blood sodium concentration decreased significantly to normal limits (p < 0.01). There was no difference in hypocoagulation status between time points (p > 0.05). There was 1 case of bleeding at the dialysis catheter fixation site (1.82%) and 2 cases of bleeding at the skin graft lesion requiring hemostatic treatment (3.62%). Conclusion: There were no differences in blood potassium levels, blood protein and albumin concentration, and hypocoagulation disorders at all time points.

Drug-Coated Balloons in Autologous Vein Peripheral-Distal Bypass Graft Maintenance: Advancements and Potential Impact.

Initial surgical revascularization has a recognized primary role in patients with critical limb-threatening ischemia with a high-quality great saphenous vein for conduit. However, approximately one-third of lower extremity vein grafts develop lesions threatening graft patency. Traditional treatments have limitations, highlighting the need for innovative solutions. The advantage of drug-coated balloons (DCBs) in treating native femoropopliteal occlusive disease is well established for its anti-restenotic features. This study evaluates the use of DCBs in maintaining the patency of autologous vein infrainguinal bypass grafts. This retrospective multicenter cohort study included consecutive patients who underwent DCB angioplasty of infrainguinal bypass vein graft stenoses from January 2010 to December 2022 in 4 tertiary Vascular Surgery referral Centers. The primary endpoints were assisted primary patency rate, amputation, and death. All endpoints were assessed at baseline, at 1, 3, and 6 months, and every 6 months after the procedure. Follow-up was mainly performed via duplex ultrasound, by hand of an experienced independent operator. In total, 296 patients received an endovascular procedure for primary patency loss of a pre-existing infrainguinal saphenous vein bypass graft. Of these, 86 cases (29%) were treated with a paclitaxel-coated balloon. The mean age of patients was 72 (67-75) years, most being males (62%, n=53). The median time from the primary revascularization to reintervention with DCB was 2.58 (95% confidence interval [CI]: 2.31-3.10) years. The DCB angioplasty involved the proximal anastomosis in 20%, the graft in 51%, the distal anastomosis in 33%, and the outflow region in 28% of cases. During a median follow-up of 5 years (3.93-7.01), a 69% assisted primary patency rate was recorded. Limb salvage was achieved in 100% of cases at 1 year and in 90% of cases at 3 years. Only 6 cases of major amputation were recorded in a median follow-up time of 10 years. Overall survival reached 84% at 5 years, calculated on a median follow-up of 9.4 (95% CI: 8.7-10.1) years. Results suggest that DCBs may have a transformative impact on vascular care, reducing the need for repeated reinterventions, and thus improving the quality of life for patients with peripheral bypass grafts. This study proposes a groundbreaking shift in the management of lower extremity vein graft lesions. By demonstrating the efficacy of drug-coated balloons (DCBs) in maintaining patency of infrainguinal vein bypass grafts, it offers clinicians a novel strategy to address a significant clinical challenge. Unlike traditional treatments with their limitations, DCBs present a promising alternative, potentially reducing the burden of repeated reinterventions. This innovation signifies a tangible improvement in patient outcomes, promising enhanced limb salvage rates and overall survival, thereby revolutionizing vascular care and enhancing the quality of life for individuals with peripheral bypass grafts.

TCT-754 Native Coronary Artery Instead of Saphenous Vein Graft Intervention for Treatment of Significant Saphenous Vein Graft Lesions (NASA Registry)

TCT-754 Native Coronary Artery Instead of Saphenous Vein Graft Intervention for Treatment of Significant Saphenous Vein Graft Lesions (NASA Registry)

TCT-757 Plaque Morphology According to Optical Coherence Tomography in Patients Undergoing Percutaneous Coronary Intervention for Saphenous Vein Graft Lesions in Acute Coronary Syndrome

TCT-757 Plaque Morphology According to Optical Coherence Tomography in Patients Undergoing Percutaneous Coronary Intervention for Saphenous Vein Graft Lesions in Acute Coronary Syndrome

Impact of aging on peribiliary glands in ischemia-reperfusion injury.

The detailed mechanisms underlying the development of ischemia-type biliary lesions (ITBLs) in aged donor grafts remain unclear. In the present study we aimed to investigate the impact of aging on the response of the peribiliary gland (PBG) to ischemia-reperfusion injury (IRI) and its temporal changes. Experiments were performed using a 90-min partial warm liver ischemia model in male Wistar rats of two age groups: young (7-8 weeks old) and old (52-60 weeks old). Liver tissues were obtained 24, 72, and 168 h after IRI. Histopathological and immunohistochemical assessments of the perihilar bile duct (PHBD), including the PBG, distal to the clip-clamped site were performed. Young rats showed little change in the bile duct tissues after IRI. However, old rats showed an increased PBG volume in the PHBD and marked PBG cell proliferation 24 h after IRI. Bile duct wall thickening with narrowing of the lumen peaked 72 h after IRI. Mucus production and oxidative stress in the PBG were significantly higher in old than in young rats after IRI. These findings showed a trend toward improvement 168 h after IRI. Age-dependent differences in the response of the PBG to IRI may be related to differences in ITBL frequency.

Therapeutic inhibition of biomechanically-activated YAP-TAZ signaling prevents vein graft atherosclerosis

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Rembrandt Institute for Cardiovascular Sciences Background Venous bypass grafts may have limited patency due to excessive intimal hyperplasia and accelerated atherosclerosis. YAP-TAZ signaling regulates cellular responses to biomechanical cues, such as disturbed flow or vessel distention as seen in vein grafts. YAP activation leads to inflammation and angiogenesis, which both contribute to vein graft atherosclerosis. Inhibition of YAP-TAZ attenuates naive atherogenesis, but its potential to inhibit intraplaque angiogenesis and reduce vein graft atherosclerosis has not been explored. Methods Saphenous vein progenitor cells (SVPs) were subjected to mechanical strain in vitro to assess YAP activation. IHC to assess YAP-expression was performed on vein grafts from pigs as well as ex vivo cultured human saphenous veins. Furthermore, YAP-IHC was performed on murine vein grafts from hypercholesterolemic ApoE3*Leiden mice harvested at early, mid- and late-stage disease timepoints to assess optimal treatment window. In a separate experiment, mice (n=11-13/group) underwent bypass surgery and were treated with the FDA-approved YAP-TAZ inhibitor Verteporfin (50 mg/kg) or vehicle 3 times/week from day 10 until sacrifice (day 28). Ultrasound was used to longitudinally quantify vascular remodeling. Vein grafts were harvested and processed for morphometric and compositional analysis. Results Mechanical strain induced activation of YAP and its downstream targets (Ctgf, Cyr61) in SVPs, which was inhibited by Verteporfin (confirmed by WB, IP and qPCR). Moreover, YAP was abundantly expressed in pig vein graft lesions, whilst Verteporfin blocked YAP expression in ex vivo cultured human saphenous veins after exposure to disturbed flow. In addition, YAP was increasingly expressed during vein graft lesion development in mice, reaching its peak around day 14, which coincides with the initiation of intraplaque angiogenesis. Furthermore, YAP was predominantly expressed in luminal and adventitial endothelial cells. Analysis of ultrasound demonstrated that Verteporfin prevented vein graft thickening in mice over time. End-point histology revealed that the intima/media ratio was significantly decreased by Verteporfin treatment (37%, p=0.001). Intraplaque angiogenesis was also reduced (34%, p=0.002), whilst neovessel maturation was improved upon verteporfin treatment. The vessel wall ACTA2 content was reduced (42%, p=0.023), whilst collagen was not altered between both groups, indicating that Verteporfin diminished the fibroproliferative response without affecting vessel wall stability. Conclusion Verteporfin inhibited YAP-TAZ activation induced by mechanical strain in vitro (SVPs) as well as ex vivo (cultured human saphenous veins). In vivo, Verteporfin treatment resulted in a significant decrease of vein graft atherosclerosis and intraplaque angiogenesis. Therefore, therapeutic targeting of YAP-TAZ using Verteporfin might be a new candidate to improve vein graft patency.

Lenti-viral overexpression of RhoGEF Trio reduces CD8 T cell extravasation into atherosclerotic vein graft lesions in mice

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Rembrandt Institute for Cardiovascular Sciences Background In advanced atherosclerotic plaques, such as vein graft lesions, neovessels grow into the hypoxic plaque. This intraplaque angiogenic neovessels lack proper endothelial cell-cell junctions and are therefore susceptible to extravasation of leukocytes, which results in inflammation and atherosclerosis. T cells are the largest leukocyte subset found in atherosclerotic plaques and are key drivers of inflammation and plaque progression. RhoGEF Trio improves endothelial barrier function by strengthening endothelial cell-cell junctions in vitro, but its effect on T cell transmigration and its therapeutic potential to impede atherogenesis remains unknown. Methods ApoE3*Leiden mice (n=10/group) underwent bypass surgery in which a donor caval vein was interpositioned into the arterial circulation at the site of the right common carotid artery. Immediately post-operatively, a pluronic gel containing either GFP-Lentivirus (LV) (control) or Trio-GFP-LV (Trio) was locally applied around the vein graft to induce local overexpression of Trio. At post-op day 28, vein grafts were harvested and processed for morphometric and compositional analysis of the atherosclerotic lesions. Additionally, CD4 and CD8 T cells were isolated from healthy human donors and used in vitro to assess the role of Trio on trans-endothelial migration over in vitro-cultured HUVECs. Results At post-op day 28, both luminal and neovessel endothelial cells were GFP positive indicating successful transfection. CD8 T cell infiltration into the atherosclerotic plaque was reduced in the Trio group (45%, p=0.0426), whilst plaque size and the number of neovessels were unaffected. Mechanistically, we observed that adherence of CD8, but not CD4 T cells to the endothelial monolayer was reduced in vitro upon transfection with Trio-LV. This resulted in a decrease in the absolute number of transmigrated CD8 T cells (56%, p=0.0197), whilst the number of transmigrated CD4 T cells was unaffected. Interestingly, CD8 T cells exhibited no difference trans-/paracellular diapedesis, whilst for CD4 T cells Trio overexpression induced transcellular, rather than paracellular, transmigration. Conclusions LV transfection of vein grafts by local application of a pluronic gel holds promise a therapeutic strategy to improve bypass surgery outcomes. LV transfection with RhoGEF Trio did reduce CD8 T cell transmigration (in vivo and in vitro), but not CD4 T cell transmigration (in vitro) into the atherosclerotic plaque, whilst plaque size was not affected. Ongoing investigations focus on the effect of Trio on micro-vascular leakage as well as infiltration of other immune cells into the plaque.

Arthroscopic Measurements Predict Knee Chondral Lesion Size More Accurately Than Magnetic Resonance Imaging, and Mechanism of Injury Influences Ability of Either Technique to Predict Graft Size

Arthroscopic Measurements Predict Knee Chondral Lesion Size More Accurately Than Magnetic Resonance Imaging, and Mechanism of Injury Influences Ability of Either Technique to Predict Graft Size

Endovascular correction of lesions of coronary arteries and coronary artery bypass grafts in patients with coronary artery disease with recurrent ischemia after surgical myocardial revascularization

Despite the modern optimal drug therapy and various surgical methods, coronary artery disease is currently one of the most significant problems of medicine. The risk of recurrent myocardial ischemia increases in long-term period after coronary artery bypass surgery, especially in patients with diffuse coronary lesions. The main factors of such results are progression of atherosclerosis and dysfunction of coronary artery grafts. Repeated myocardial revascularization through percutaneous coronary intervention is the safest and optimal option. However, there is currently no unambiguous and generally accepted opinion about endovascular treatment of such patients with diffuse coronary lesions. Objective. To estimate the efficacy and safety of endovascular correction of coronary artery and bypass graft lesions in patients with coronary artery disease, diffuse coronary artery lesions and myocardial ischemia recurrence after coronary artery bypass surgery. Material and methods. The study included 106 patients with recurrent myocardial ischemia after coronary artery bypass surgery who underwent treatment in 2013—2020. Coronary artery stenting was performed in the 1st group (55 (51.9%) patients), and graft stenting was carried out in the 2nd group (51 (48.1%) patients). Clinical and angiographic characteristics were similar. The endpoints were mortality, restenosis after endovascular correction, myocardial infarction and MACE after 1 and 12 months. Results. In the 1st group, lesion length and number of implanted stents were significantly greater: 25.7 [20.9; 31.6] and 18.8 [17.2; 22.1] mm p=0.023; 121 and 71 stents, respectively. Transradial access was more common in the 1st group (24 (43.6%) and 9 (17.6%), respectively, p=0.004). In long–term period, mortality and restenosis rate were slightly higher in the 2nd group (4 (7.3%) and 6 (11.8%) deaths, p=0.434; 7 (10.8%) and 9 (16.7%) cases of restenosis, respectively, p=0.352). The MACE rate was similar (11 (20.0%) and 15 (29.4%) cases, respectively, p=0.265). Conclusion. Stenting of native coronary arteries in patients with coronary artery disease, diffuse coronary lesions and recurrent myocardial ischemia after coronary artery bypass surgery demonstrates a tendency to better results within 1 and 12 months regarding restenosis, myocardial infarction rate and mortality compared to stenting of coronary artery bypass grafts.

Myeloid PHD2 Conditional Knockout Improves Intraplaque Angiogenesis and Vascular Remodeling in a Murine Model of Venous Bypass Grafting.

Intraplaque angiogenesis occurs in response to atherosclerotic plaque hypoxia, which is driven mainly by highly metabolically active macrophages. Improving plaque oxygenation by increasing macrophage hypoxic signaling, thus stimulating intraplaque angiogenesis, could restore cellular function and neovessel maturation, and decrease plaque formation. Prolyl hydroxylases (PHDs) regulate cellular responses to hypoxia. We therefore aimed to elucidate the role of myeloid PHD2, the dominant PHD isoform, on intraplaque angiogenesis in a murine model for venous bypass grafting. Myeloid PHD2 conditional knockout (PHD2cko) and PHD2 wild type mice on an Ldlr-/- background underwent vein graft surgery (n=11-15/group) by interpositioning donor caval veins into the carotid artery of genotype-matched mice. At postoperative day 28, vein grafts were harvested for morphometric and compositional analysis, and blood was collected for flow cytometry. Myeloid PHD2cko induced and improved intraplaque angiogenesis by improving neovessel maturation, which reduced intraplaque hemorrhage. Intima/media ratio was decreased in myeloid PHD2cko vein grafts. In addition, PHD2 deficiency prevented dissection of vein grafts and resulted in an increase in vessel wall collagen content. Moreover, the macrophage proinflammatory phenotype in the vein graft wall was attenuated in myeloid PHD2cko mice. Invitro cultured PHD2cko bone marrow-derived macrophages exhibited an increased proangiogenic phenotype compared with control. Myeloid PHD2cko reduces vein graft disease and ameliorates vein graft lesion stability by improving intraplaque angiogenesis.

Plaque Morphology by Optical Coherence Tomography in Patients Undergoing Percutaneous Coronary Intervention for Saphenous Vein Graft Lesions: A Prospective Observational Pilot study

Plaque Morphology by Optical Coherence Tomography in Patients Undergoing Percutaneous Coronary Intervention for Saphenous Vein Graft Lesions: A Prospective Observational Pilot study

Host CD34+ cells are replacing donor endothelium of transplanted heart

Host CD34+ cells are replacing donor endothelium of transplanted heart

Short-term outcomes of drug-coated balloon versus drug-eluting stent for de novo saphenous vein graft lesions in coronary heart disease.

As a device for percutaneous coronary intervention, drug-coated balloon (DCB) is widely used to treat in-stent restenosis. However, data regarding the use of DCB in treating de novo saphenous vein graft (SVG) lesions are limited. This study aimed to explore the outcomes of using the DCB in the treatment of de novo SVG lesions of coronary heart disease (CHD). This retrospective and observational study analyzed CHD patients with de novo SVG lesions treated with DCB or the new-generation drug-eluting stent (DES) between January 2018 and December 2020. Restenosis was the primary endpoint, whereas target lesion revascularization (TLR), major adverse cardiac events, restenosis, cardiac death, target vessel revascularization, and myocardial infarction were the secondary outcomes. We enrolled 31 and 23 patients treated with DCB and DES, respectively. The baseline clinical data, lesion characteristics, and procedural characteristics were similar between the two groups. Twenty-eight (90.3%) patients in the DCB group and 21 (91.3%) in the DES group completed follow-up angiography after 1 year. The quantitative coronary angiography measurements at angiographic follow-up showing late lumen loss were -0.07 ± 0.95 mm for the DCB group and 0.86 ± 0.71 mm for the DES group (P = 0.039), and the rates of restenosis were 13.3% and 21.7% for the DCB and DES groups, respectively (P = 0.470). No significant differences were observed in the rates of MACE (16.7% vs. 26.1%, P = 0.402) and TLR (13.3% vs. 4.3%, P = 0.374) during clinical follow-up. Our findings suggest that when pre-dilatation was successful, DCB might be safe and effective in treating de novo SVG lesions.

Meet the First Authors.

Meet the First Authors.

Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Promotes Macrophage Activation via LDL Receptor-Independent Mechanisms.

Activated macrophages contribute to the pathogenesis of vascular disease. Vein graft failure is a major clinical problem with limited therapeutic options. PCSK9 (proprotein convertase subtilisin/kexin 9) increases low-density lipoprotein (LDL)-cholesterol levels via LDL receptor (LDLR) degradation. The role of PCSK9 in macrophage activation and vein graft failure is largely unknown, especially through LDLR-independent mechanisms. This study aimed to explore a novel mechanism of macrophage activation and vein graft disease induced by circulating PCSK9 in an LDLR-independent fashion. We used Ldlr-/- mice to examine the LDLR-independent roles of circulating PCSK9 in experimental vein grafts. Adeno-associated virus (AAV) vector encoding a gain-of-function mutant of PCSK9 (rAAV8/D377Y-mPCSK9) induced hepatic PCSK9 overproduction. To explore novel inflammatory targets of PCSK9, we used systems biology in Ldlr-/- mouse macrophages. In Ldlr-/- mice, AAV-PCSK9 increased circulating PCSK9, but did not change serum cholesterol and triglyceride levels. AAV-PCSK9 promoted vein graft lesion development when compared with control AAV. In vivo molecular imaging revealed that AAV-PCSK9 increased macrophage accumulation and matrix metalloproteinase activity associated with decreased fibrillar collagen, a molecular determinant of atherosclerotic plaque stability. AAV-PCSK9 induced mRNA expression of the pro-inflammatory mediators IL-1β (interleukin-1 beta), TNFα (tumor necrosis factor alpha), and MCP-1 (monocyte chemoattractant protein-1) in peritoneal macrophages underpinned by an in vitro analysis of Ldlr-/- mouse macrophages stimulated with endotoxin-free recombinant PCSK9. A combination of unbiased global transcriptomics and new network-based hyperedge entanglement prediction analysis identified the NF-κB (nuclear factor-kappa B) signaling molecules, lectin-like oxidized LOX-1 (LDL receptor-1), and SDC4 (syndecan-4) as potential PCSK9 targets mediating pro-inflammatory responses in macrophages. Circulating PCSK9 induces macrophage activation and vein graft lesion development via LDLR-independent mechanisms. PCSK9 may be a potential target for pharmacologic treatment for this unmet medical need.

When Intracoronary Anatomy is Superior to Physiology.

Physiologic assessment has become an essential tool to guide revascularization decisions due to the multiple limitations of angiographic and anatomic measures of physiologic significance. However, in certain cases the apparent physiologic measurement may not accurately reflect the severity of coronary disease compared with anatomical measurements. This article will review how anatomy trumps physiology in cases of acute coronary syndromes, left main disease, saphenous vein graft lesions, and myocardial bridging, and how to overcome the limitations of physiologic measurement in these clinical situations.