Anti-phosphorylcholine IgM, an Anti-inflammatory Mediator, Predicts Peripheral Vein Graft Failure: A Prospective Observational Study.

OBJECTIVES: One third of infrainguinal vein bypasses may fail within the first 1.5 years. Pro- and anti-inflammatory mechanisms are thought to be involved in these graft stenoses and occlusions. In previous studies, low levels of anti-phosphorylcholine IgM (anti-PC IgM, an innate anti-inflammatory IgM) have been associated with increased cardiovascular events. In this study, the peri-operative dynamics of anti-PC IgM levels were established during leg bypass surgery, and associations assessed between anti-PC IgM levels and primary graft patency. DESIGN AND METHODS: This was a prospective, observational cohort study of infrainguinal autogenous vein bypass for peripheral arterial occlusive disease involving four university affiliated hospitals. Plasma cytokine and anti-PC IgM levels were measured pre- and post-operatively. The outcome of interest was loss of primary graft patency because of occlusion or intervention for graft stenosis. RESULTS: One hundred and forty-two consecutive patients were enrolled: mean age 66 (46-91); 91% white race and male; 72.5% critical limb ischaemia (Fontaine III or IV). Median pre-operative anti-PC IgM levels were 49 units/mL (IQR 32.3-107.7, mean 89.8 + 101 sd). During follow up of an average of 1.8 years (1 month-7.4 years), 50 (35.2%) grafts lost primary patency. Pre-operative levels of interleukin 6 or C-reactive protein did not predict graft failure. Patients with pre-operative anti-PC IgM values in the lowest quartile had a twofold increased risk of graft failure (multivariable Cox proportional hazard, p = .03, HR 2.11, 95% CI 1.09-4.07), even after accounting for the other significant factors of conduit diameter, distal anastomosis, smoking, and the severity of leg ischaemia. CONCLUSIONS: Low levels of anti-PC IgM are associated with vein bypass graft failure. This biological mediator may be a useful marker to identify patients at higher risk, and offers the potential for novel, directed therapies for vascular inflammation and its consequences.

Re-evaluation of glomerulitis using occlusion criteria based on the Banff 2013 revision: a retrospective study.

The presence of occlusion/near-occlusion of glomerular capillaries was recently added to the existing definition of glomerulitis (g). We retrospectively re-evaluated 135 renal allograft biopsies regarding g to ensure no antibody-damaged grafts were missed. Previous and revised g scores (pg and rg, respectively) were compared for clinicopathologic correlations. The g score did not change in 100 (74.1%) biopsies. Thirty-five (25.9%) biopsies were changed to a lower score. Sensitivity and specificity of pg and rg for the presence of donor-specific antibodies (DSA) were 76% vs. 58% and 70% vs. 79%, respectively. Pg score indicated graft loss with 65% sensitivity and 63% specificity, whereas rg showed 46% sensitivity and 71% specificity. Area under the curve (AUC) values in ROC analysis for DSA and graft loss were as follows: pg, 0.773; rg, 0.693; and pg, 0.635; rg, 0.577, respectively. A comparison of the two AUC values revealed a significant difference between pg and rg only for DSA (P = 0.0076). Pg and post-transplant time of biopsy independently predicted graft loss, whereas rg did not. In conclusion, revised g scores showed lesser sensitivity but higher specificity for DSA and graft loss. Recent definition of g missed antibody-mediated rejection in few cases, and it was not an independent predictor for graft loss.

Cryopreserved Arterial Allografts and ABO and Rhesus Compatibility.

BACKGROUND: Arterial cryopreserved allografts are conduit of choice for arterial bypass in case of infection. They are sometimes submitted to accelerated degeneration: stenosis, thrombosis, or aneurysmal evolution. We hypothesized that ABO group and Rhesus compatibility could play a role in arterial cryopreserved allograft complications. METHODS: Patients who benefit from allograft bypass from 2006 to 2011 were retrospectively compared, regarding ABO or rhesus compatibility and irregular agglutinins. RESULTS: Seventy-two patients were included. Regarding ABO mismatch, there was no difference in terms of death (51% vs. 43%, P = 0.820), thrombosis (25% vs. 32%, P = 0.78), rupture (9% vs. 0%, P = 0.247), stenosis (3% vs. 12%, P = 0.331), aneurysmal degeneration (16% vs. 12%, P = 1), and 5 years of secondary patency rate (34% vs. 39%, P = 0.141). There was also no difference regarding Rhesus mismatch. CONCLUSIONS: Allograft degeneration does not seem to be related to ABO mismatch. This degeneration could be related to another way of immunogenicity, particularly Human Leukocyte Antigen mismatch, and needs further exploration.

Cu-bearing steel reduce inflammation after stent implantation.

Copper (Cu)-bearing stainless steel with release of Cu2+ ions is a novel material for coronary stents that could reduce the in-stent restenosis after the stent implantation. The inflammation has been recently recognized as an important factor to smooth muscle cells proliferation, thrombosis, and hence the restenosis post-angioplasty. The objective of this study is to further investigate the effect and relevant mechanism of Cu-bearing stainless steel (316L-Cu SS) on the inflammation reaction after stent implantation. The results demonstrated that, compared with commercial coronary stent material (316L SS), 316L-Cu SS could inhibit the inflammation caused by endothelial dysfunction through blockading the inflammatory factors (TNF-α, IL-1ß, 6, 8), which would then reduce the recruitment and infiltration of leukocytes, rather than have direct effect on leukocytes. This finding further explained the reduction effect of 316L-Cu SS on in-stent restenosis from a novel view.

Anti-inflammatory and anti-proliferative effects of CBS3830 in arterialized vein grafts in rats.

OBJECTIVE: To investigated whether CBS3830, a highly selectively inhibitor of p38MAPK, could ameliorate inflammation and intimal hyperplasia in arterialized vein grafts (AVGs). METHODS: Sixty male Sprague-Dawley rats underwent a reversed right jugular vein to common carotid artery interposition graft and were randomly treatment with vehicle (control) or single-dose (3 mg/kg, preoperative) or double-dose (3 mg/kg, preoperative and 4 d postoperative) CBS3830. Twenty rats underwent sham operation. The levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) were determined by ELISA. Vein grafts were analyzed by intimal/medial morphometry, proliferating cell nuclear antigen (PCNA) expression, and p38MAPK phosphorylation. RESULTS: TNF-α, IL-1ß, and IL-6 gradually increased then slowly decreased in AVG rats. However, at 4 d and 7 d, TNF-α levels decreased by 37.5% and 29.5% (p = 0.003, 0.05, respectively) in the single-dose CBS3830 group, and by 37.6% and 32.5%, respectively (both p = 0.003) in the double-dose group compared with those of control. IL-1ß levels significantly reduced at 4 d and 14 d in both dosage groups. IL-6 levels significantly reduced at 7 d in both groups. Intima and medial thickening were significantly reduced in both dosage treated groups at 7, 14, and 28 d (all p = 0.000) compared to the controls. Further study showed CBS3830 inhibited p38MAPK phosphorylation and decreased PCNA expression. CONCLUSIONS: CBS3830 significantly decreases inflammation and intimal hyperplasia in AVGs.

[Immunological aspects of formation of restenoses after endothelial lesions].

The article deals with an analysis of the literature data concerning immunological mechanisms of the formation of restenoses after damage of the arterial wall, considering the participants of the early and late phases of inflammatory response initiated by endothelial damage. Also given is characteristics of the process of formation on the neointima, followed by description of the role of intercellular adhesion molecules in initiation and maintaining of the processes of acute and chronic inflammation.

Low levels of a natural IgM antibody are associated with vein graft stenosis and failure.

BACKGROUND: All humans have natural, protective antibodies directed against phosphorylcholine (PC) epitopes, a common inflammatory danger signal appearing at sites of cell injury, oxidative stress, and on bacterial capsules. In large human cohorts, low levels of anti-PC IgM were associated with a significantly increased risk of stroke or myocardial infarction. However, it is not known if these antibodies protect against the premature closure of arterial reconstructions. METHODS: A prospective, observational study of patients undergoing elective, infrainguinal, autogenous vein bypasses for atherosclerotic occlusive disease of the legs was conducted. Clinical data were recorded prospectively, and preoperative levels of anti-PC IgM measured with the CVDefine kit from Athera Biotechnologies (Solna, Sweden). The principal clinical end point was the loss of primary patency (loss of graft flow, or any intervention for stenosis). Patients were followed regularly by duplex ultrasound at 1, 3, 6, 12, 18 months, and yearly thereafter. RESULTS: Fifty-six patients were studied, for an average of 1.3 years. Indications for surgery were claudication (33.9%), ischemic rest pain (17.9%), and ischemia with ulceration or gangrene (48.2%). Seventeen (30.4%) patients experienced loss of primary patency (10 graft occlusions, seven surgical or endovascular revisions of graft stenoses). Kaplan-Meier survival analysis showed that the quartile of patients with the lowest anti-PC IgM levels had significantly worse primary graft patency (log-rank test, P = .0085). Uni- and multivariate Cox proportional hazards analysis revealed that the preoperative anti-PC IgM level was an important predictor of graft failure. Patients with IgM values in the lowest quartile had a 3.6-fold increased risk of graft failure (95% confidence interval: 1.1-12.1), even after accounting for other significant clinical or technical factors such as indication for surgery, site of distal anastomosis, or vein graft diameter. CONCLUSIONS: A naturally occurring IgM antibody directed against the proinflammatory epitope PC may be protective against vein graft stenosis and failure, through anti-inflammatory mechanisms. Measurement of this antibody may be a useful prognostic indicator, although larger studies of more diverse populations will be needed to confirm these results. The biological actions of anti-PC IgM suggest it may be useful in developing immunotherapies to improve bypass longevity.

Soluble epoxide hydrolase expression in a porcine model of arteriovenous graft stenosis and anti-inflammatory effects of a soluble epoxide hydrolase inhibitor.

Synthetic arteriovenous (AV) grafts, placed between an artery and vein, are used for hemodialysis but often fail due to stenosis, typically at the vein-graft anastomosis. This study recorded T lymphocyte and macrophage accumulation at the vein-graft anastomosis, suggesting a role for inflammation in stenosis development. Epoxyeicosatrienoic acids (EETs), products of cytochrome P-450 epoxidation of arachidonic acid, have vasculoprotective and anti-inflammatory effects including inhibition of platelet activation, cell migration, and adhesion. EETs are hydrolyzed by soluble epoxide hydrolase (sEH) to less active diols. The effects of a specific inhibitor of sEH (sEHI) on cytokine release from human monocytes and mouse bone marrow-derived macrophages (BMMΦ) from wild-type (WT) and sEH knockout (KO) animals were investigated. Expression of sEH protein increased over time at the anastomosis as evaluated by immunohistochemistry. Pre-exposure of adherent human monocytes to sEHI (5 µM) significantly inhibited lipopolysaccharide-induced release of monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor-α and enhanced the EET-to-diol ratio. Release of MCP-1 from WT BMMΦ was significantly inhibited but release from sEH KO BMMΦ was not attenuated indicating the specificity of the sEHI. In contrast, sEHI did not inhibit the release of macrophage inflammatory protein-1 or interleukin-6. Nuclear translocation of NF-κB, as assessed by immunocytochemical staining, was not decreased with sEHI in monocytes, but the phosphorylation of JNK was completely abrogated, suggesting this pathway is the target of sEHI effects in monocytes. These results suggest that sEHI may be useful for inhibition of inflammation and subsequently stenosis in AV grafts.

Circulating inflammatory cells are associated with vein graft stenosis.

OBJECTIVE: Infrainguinal autogenous vein grafts are especially prone to narrowing and failure, and both inflammatory and thrombotic pathways are implicated. Platelets and monocytes are the key thrombo-inflammatory cells that arrive first at sites of vascular injury. These cells have potent interactions that recruit and activate one another, propagating thrombotic and inflammatory responses within the vessel wall. We therefore hypothesized that elevated levels of platelet-monocyte aggregates (PMA) might be associated with stenosis, and could possibly discriminate between patients with or without vein graft stenosis. METHODS: Thirty-six vascular surgery patients were studied, in a stable quiescent period after infrainguinal autogenous vein graft bypasses for occlusive disease. Eighteen patients had hemodynamically significant graft stenoses confirmed by imaging, and 18 were free from stenosis. The level of PMA in whole blood was quantified after blood draw using two-color flow cytometry. Three measurements were made per sample: the basal, in-vivo level of aggregates (baseline PMA); the predisposition to spontaneously generate PMA (spontaneous PMA); and PMA generation by the addition of exogenous thrombin receptor-activating peptide (stimulated PMA). The baseline, in-vivo level of PMA was estimated by immediate flow analysis. The predisposition to spontaneously generate PMA was measured after in vitro incubation. Responsiveness to thrombin stimulation of the blood was quantified by the in vitro dose response to an exogenous thrombin receptor-activating peptide (sfllrn). RESULTS: Baseline PMA levels were similar in patients with vein graft stenosis vs nonstenosis (14.8% ± 3.2 vs 10.1% ± 1.5, respectively, mean ± SEM). However, patients with stenosis showed higher spontaneous PMA levels (58.5% ± 4.5 vs 28.3% ± 4.3; P < .001) and higher stimulated PMA levels (P < .001; analysis of variance). Covariables of smoking, diabetes, statin, or antithrombotic therapy could not account for these differences. CONCLUSIONS: Platelet-monocyte reactivity may play a role in the development of vein graft stenoses. Those with/without stenosis differed primarily in their threshold, or predisposition to form aggregates (spontaneous PMA), while their basal circulating levels of PMA (baseline PMA) were similar. These measurements may unmask pathologic differences in thrombo-inflammatory responsiveness that are not apparent in basal measurements. Understanding the causes and mechanisms leading to abnormal platelet-monocyte responses may improve approaches to predicting or preventing vein graft stenosis.

[Predictors of coronary adverse events in patients with acute coronary syndrome with ST segment elevation treated with percutaneous coronary interventions with stenting].

OBJECTIVE: The aim of this 12 months observational study was to investigate risk factors of major adverse coronary events, such as death or Q wave myocardial infarction due to stent thrombosis or in stent restenosis. MATERIAL AND METHODS: One hundred fifty four patients with ST segment elevation acute coronary syndrome were treated with percutaneous coronary intervention (PCI) and with implantation of metal stent. TIMI and CADILLAC scores were used for evaluation of initial risk. Blood levels of cytokines and sP selectin were measured on day 1 before PCI and on day 10 of hospitalization. RESULTS: We proved that CADILLAC score was applicable for evaluation of prognosis in patients with acute coronary syndrome and ST segment elevation treated with coronary stenting. High levels of tumor necrosis factor during first 24 hours of acute coronary syndrome and interleikin 8 on day 10 after PCI were found to be risk factors of major adverse coronary events during subsequent 12 months. High sP selectin level on day 10 predicted stent thrombosis during long term follow up.

Systemic inflammatory response to renal artery percutaneous angioplasty with stent placement and the risk for restenosis: a pilot study.

PURPOSE: Time changes in plasma concentrations of six different cytokines were investigated to evaluate the inflammatory response to renal artery stent placement. MATERIALS AND METHODS: A total of 22 patients (17 men; mean age, 66 years +/- 13) with ostial renal artery stenosis and poorly controlled hypertension treated with stent placement were studied. Blood samples were collected at baseline and at 24 hours and 6 months after the intervention. Plasma concentrations of (i) tumor necrosis factor-alpha, (ii) interleukin-6 (IL-6), (iii) monocyte chemoattractant protein-1, (iv) intercellular adhesion molecule-1, (v) vascular cell adhesion molecule-1, and (vi) regulated upon activatin normal T-cell expressed presumed secreted were measured. Restenosis diagnosed with imaging follow-up at 6 months was recorded. Plasma concentrations of the aforementioned cytokines were compared between patients with and without restenosis. RESULTS: IL-6 concentration increased significantly 24 hours after stent placement (8.3 pg/mL +/- 1.24 vs. 2.76 pg/mL +/- 1.27 at baseline) and returned to baseline levels (2.6 pg/mL +/- 1.77) at 6-month follow-up (P < .0001). No significant changes occurred in the concentrations of any other cytokines at the three time points. Baseline and 6-month concentrations of IL-6 were significantly higher in patients with restenosis than in those without restenosis (8.13 pg/mL +/- 4 vs 0.75 pg/mL +/- 0.47 [P < .005] and 9.55 pg/mL +/- 6.5 vs 0.42 pg/mL +/- 0.35 [P < .02], respectively). CONCLUSIONS: Renal artery angioplasty with stent placement induces an inflammatory response, as evidenced by increased IL-6 production. Additionally, IL-6 seems to identify patients prone to develop restenosis; therefore, it might be used as an early predictor of restenosis after renal angioplasty with stent placement. However, larger studies are required to confirm IL-6 as a potential predictor of restenosis.

Incomplete cellular depopulation may explain the high failure rate of bovine ureteric grafts.

BACKGROUND: The aim was to assess the results of a decellularized bovine ureter graft (SynerGraft) for complex venous access. METHODS: Bovine ureter conduits were implanted in patients with a failed fistula or access graft in whom native vessels were unsuitable as conduits. Graft histories were obtained from all patients who had undergone this procedure at one institution. Failed grafts were explanted and subjected to histological examination. A sample of fresh bovine ureter was immunostained for galactose (alpha1 --> 3) galactose (alpha-Gal). RESULTS: Nine patients with a median age of 46 (range 25-70) years underwent complex venous access surgery between August 2004 and November 2006 using a SynerGraft. Graft types included loop superficial femoral artery to stump of long saphenous vein (four patients), loop brachial artery to vein (two), brachial artery to axillary vein (two) and left axillary artery to innominate vein (one). Three grafts developed aneurysmal dilatation and two thrombosed. Histological assessment of the explanted bovine ureters revealed acute and chronic transmural inflammation. Immunostaining of fresh bovine ureter suggested residual cells and the xenoantigen alpha-Gal. CONCLUSION: Graft failure with aneurysmal dilatation and thrombosis in complex arteriovenous conduits using bovine ureter may be due to residual xenoantigens.

Quilty in biopsy is associated with poor prognosis after heart transplantation.

We tested if Quilty (endocardial infiltration of lymphocytes) in routinely processed endomyocardial biopsy is associated with poor outcome after heart transplantation (HTx). Biopsies (n=9829) harvested within the first post-transplant year from 938 patients (778 men, mean age 49 years) were evaluated for Quilty and acute cellular rejection (according to the International Society for Heart and Lung Transplantation, ISHLT, classification). Transplant vasculopathy was evaluated by coronary angiography, and severe stenosis was found in 19% of patients. Survival was tested by Kaplan-Meier and Cox regression analyses for all-cause mortality and major cardiac events (lethal acute cellular rejection, graft loss or myocardial infarction). We found 1840 (19%) Quilty-positive biopsies in 487 Quilty-positive patients (52%). Quilty was more prevalent in women (p=0.038) and younger men (p=0.001), and was correlated with ISHLT grade 1R (OR 1.45, 95% CI 1.36-1.55; p<0.001) and ISHLT grade 2R (OR 2.48, 95% CI 2.21-3.41; p<0.001). Quilty in any biopsy was associated with a higher all-cause mortality (log rank p=0.045) due to a higher risk for major cardiac event (p=0.0001). Multivariate regression analysis showed Quilty (RR 1.69, 95%CI 1.05-2.73) and transplant vasculopathy (RR 2.78, 95%CI 1.68-4.61) as risk factors for major cardiac events and treated hyperlipidemia as lowering the risk for major cardiac events (RR 0.47, 95%CI 0.28-0.77). Quilty is associated with graft loss and poor outcome post HTx. Index biopsy during the first post-transplant year is a useful tool to identify patients at risk and is recommended during routine post-transplant management.

C. sinensis ablates allograft vasculopathy when used as an adjuvant therapy with cyclosporin A.

Immunosuppressive treatments are available to suppress acute cardiac rejection; however, no viable treatment exists for long-term cardiac graft failure. Moreover, extended use of calcineurin inhibitor immunosuppressants, the mainstay of the current therapeutic for cardiac transplantation, leads to significant associated pathologies such as nephrotoxicity and increased risk of cardiac disease. For the last ten years alternatives to calcineurin inhibitors, or adjuvant therapies designed to complement their activities, have been explored. In tandem with this development, there has been considerable interest in Traditional Chinese Medicines (TCM) as sources for novel therapeutics. Our study examines the ability of the TCM Cordyceps sinensis to reduce acute and chronic rejection associated with cardiac transplantation. The objectives of this study were to first determine if oral delivery of the extract could reduce acute rejection in a rat heterotopic heart model of transplantation. The second objective was to determine, in vitro, if a sterile, aqueous extract of C. sinensis could decrease CD8+ T cell activity. The third objective was to determine if oral delivery of the extract could ablate allograft vasculopathy in a mouse abdominal aortic transplant model. We found that oral delivery of the extract demonstrated a reduction in acute rejection when used in conjunction with a sub-therapeutic dose of Cyclosporine. Further, we found, using a mixed lymphocyte reaction, that the extract was able to significantly reduce CD8+ T cell activity. Finally, we demonstrate that oral delivery of the extract, used with a therapeutic dose of Cyclosporine to suppress acute rejection, ablates allograft vasculopathy.

Association of anticardiolipin antibodies levels with instent restenosis in patients with coronary artery disease.

Present study was conducted to evaluate the association of IgG anticardiolipin antibodies with instent restenosis in patients having undergone percutaneous intervention with bare metal or drug eluting stents. Coronary artery disease patients with stent placement at least 6 months prior were screened for eligibility. 26 satisfied the inclusion/exclusion criteria. 10 patients with symptoms of restenosis, confirmed on check angiography served as cases and 16 without symptoms of restenosis served as control. Unpaired t- test was applied to ascertain the significance of any difference between control and study groups. Antibody levels were estimated on ELISA reader. The mean (+/- SD) anticardiolipin antibodies levels in cases and controls were 11.8 +/- 5.1 GPL/U/ml and 14.3 +/- 10.2 GPL/U/ml, respectively. The difference was not statistically significant (P > 0.05). In conclusion, we did not observe any significant correlation between the level of IgG aCL and instent restenosis.

Arteriovenous fistula outcomes in human immunodeficiency virus-positive patients.

Arteriovenous fistula (AVF) remodeling is an active area of research in vascular biology given the high rates of primary failure, complications, and cost burden for the health-care system. Comorbidities such as diabetes and different types of vascular disease are known to influence AVFs outcomes. However, little is known about the effects of immunosuppression, particularly human immunodeficiency virus (HIV) infection, on AVF primary failure and patency. This retrospective study assessed the impact of HIV infection and T-cell counts on AVF outcomes. Using a retrospective cohort of 495 patients, we compared the risk of AVF primary failure and primary unassisted patency on HIV-positive and nonimmunocompromised individuals using logistic regressions and Cox proportional hazard models. Within the HIV-infected subset (n = 43), we analyzed the association between immunological parameters such as T-cell counts and primary failure. Positive predictors of primary failure were HIV infection [odds ratio (OR) = 3.09, P = 0.002] and history of a previous AVF (OR = 2.18, P = 0.003). However, there was no difference in primary unassisted patency between HIV-positive and negative individuals after excluding primary failure cases. There was no association between T-cell subset counts and AVF outcomes. Our results indicate that HIV-positive individuals have a higher risk of AVF primary failure than nonimmunocompromised patients. However, this increased susceptibility is not explained by the degree of immunosuppression.

Direct and indirect effects of alloantibodies link neointimal and medial remodeling in graft arteriosclerosis.

OBJECTIVE: Chronic vascular rejection, the main cause of allograft failure, is characterized by the destruction of smooth muscle cells (SMCs) in the media concomitantly with the proliferation of SMCs in the adjacent neointima. We hypothesized that alloantibodies might be responsible for these 2 opposite but coordinated events. METHODS AND RESULTS: We used the rat aortic interposition model of chronic vascular rejection. During the rejection process, a neointima composed of proliferating SMCs from the recipient developed, whereas the SMCs in the media, all of donor origin, underwent apoptosis. Alloantibody deposition was detected only in the media. Using in vitro cultures experiments, we observed that alloantibody binding to donor SMCs exerts (1) a rapid upregulation of the transcription of growth factors genes, followed by (2) the induction of apoptosis after 24 hours. The transient production of growth factors by donor SMCs in response to the binding of alloantibodies induced the proliferation of recipient SMCs in culture supernatant transfer experiments. Additional data suggest that among the repertoire of alloantibodies, those directed against major histocompatibility complex I might carry the remodeling effect. CONCLUSIONS: Our data suggest that during chronic vascular rejection, alloantibody binding to donor medial SMCs is a crucial event that links neointimal and medial remodeling.

In-vitro assays of polymer-coated stents eluting platelet glycoprotein IIb/IIIa receptor monoclonal antibody.

The monoclonal antibody (mAb) to the platelet glycoprotein (GP) IIb/IIIa receptor has potent antiplatelet and antithrombotic characteristics shown to reduce thrombus-related major complications after coronary angioplasty. This mAb can be incorporated in drug-eluting stents capable of releasing single or multiple bioactive agents into the bloodstream and surrounding tissues. Stents eluting the monoclonal mouse anti-human platelet glycoprotein IIb/IIIa antibody SZ-262 were tested for their effectiveness in improving the blood compatibility and the antithrombotic characteristics by immunofluorescence and scanning electron microscopy (SEM). The SEM results convincingly demonstrated that the surface of the mAb eluting-stents was completely free of platelet uptake without any sign of cellular debris or proteinaceous deposits, compared with controls. The deformation index of platelets on the L-polylactic acid (L-PLA) coated stents were higher than bare Nitinol intravascular stents, as shown by SEM images. Monoclonal antibody to the platelet GP IIb/IIIa receptor, when eluting from L-PLA polymer-coated stents, effectively inhibits platelet aggregation in the stent microenvironment, thus demonstrating a potential capacity of reducing thrombosis, improving blood flow and arterial patency rates, and inhibiting cyclic blood flow variations. These results highlight the possibility of such monoclonal antibody-eluting stents to reduce or possibly eliminate thrombosis and in-stent restenosis.

Coronary restenotic reduction of drug-eluting stenting may be due to its anti-inflammatory effects.

The development of coronary stent has revolutionized the field of interventional cardiology by reducing the incidence of restenosis after balloon angioplasty. However, the stent has still associated with a serious complication, namely, in-stent restenosis. Although, restenosis following coronary stenting has long been attributed to neointimal proliferation, thrombosis, and negative remodeling, the inflammation may be a trigger for those vascular reactions following coronary stenting. Both experimental and clinical studies have demonstrated a marked activation of local and systemic inflammatory response following stent implantation, suggesting that inflammation may play an important role in determining in-stent restenosis via neointimal proliferation. The key role of inflammation in vascular healing and in-stent retsenosis has also been increasingly well understood. Recently, drug-eluting stents (DESs) have been shown to decrease in-stent restenosis in a large number of clinical studies. In addition to their anti-proliferative activity, DESs have been considered to possess an anti-inflammatory property, especially for sirolimus-eluting stent compared with bare metal stent. Moreover, the benefit of the anti-inflammatory therapy during the peri-procedural period and long-term follow-up by means of drug administration is also dependent on the inflammatory status during percutaneous coronary intervention. Measurement of cytokine and acute phase proteins, such as C-reactive protein, therefore, may be important to identify high-risk subjects and develop specific treatment tailored to the individual patients with stent restenosis. Thus, therapeutic approach should be further directed toward increasing local resistance to proliferative inflammatory stimuli by means of anti-proliferative, locally delivered drugs and reducing the magnitude and persistence of systemic inflammation.

Tissue-engineered vascular grafts for congenital cardiac disease: Clinical experience and current status.

Congenital heart disease is a leading cause of death in the newborn period, and man-made grafts currently used for reconstruction are associated with multiple complications. Tissue engineering can provide an alternative source of vascular tissue in congenital cardiac surgery. Clinical trials have been successful overall, but the most frequent complication is graft stenosis. Recent studies in animal models have indicated the important role of the recipient׳s immune response in neotissue formation, and that modulating the immune response can reduce the incidence of stenosis.