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.

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.

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.

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.

Distinct Differences on Neointima Formation in Immunodeficient and Humanized Mice after Carotid or Femoral Arterial Injury.

Percutaneous coronary intervention is widely adopted to treat patients with coronary artery disease. However, restenosis remains an unsolved clinical problem after vascular interventions. The role of the systemic and local immune response in the development of restenosis is not fully understood. Hence, the aim of the current study was to investigate the role of the human immune system on subsequent neointima formation elicited by vascular injury in a humanized mouse model. Immunodeficient NOD.Cg-PrkdcscidIL2rgtm1Wjl(NSG) mice were reconstituted with human (h)PBMCs immediately after both carotid wire and femoral cuff injury were induced in order to identify how differences in the severity of injury influenced endothelial regeneration, neointima formation, and homing of human inflammatory and progenitor cells. In contrast to non-reconstituted mice, hPBMC reconstitution reduced neointima formation after femoral cuff injury whereas hPBMCs promoted neointima formation after carotid wire injury 4 weeks after induction of injury. Neointimal endothelium and smooth muscle cells in the injured arteries were of mouse origin. Our results indicate that the immune system may differentially respond to arterial injury depending on the severity of injury, which may also be influenced by the intrinsic properties of the arteries themselves, resulting in either minimal or aggravated neointima formation.

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.

Medication management of cardiac allograft vasculopathy after heart transplantation.

Cardiac allograft vasculopathy (CAV) is a common complication following heart transplantation (HT), resulting in diminished graft survival. The preferred strategy for preventing CAV is optimal medical management; however, for patients who develop CAV, delaying disease progression through effective medication management is equally important. A review of the literature regarding medication management of CAV was conducted via a search of the MEDLINE database. Studies were included if they were published in English, conducted in humans ≥ 18 years of age or older, and used noninvestigational medications. Immunosuppressive medications such as the antiproliferative mycophenolate, the calcineurin inhibitor tacrolimus, and the proliferation signal inhibitors sirolimus and everolimus have been shown to prevent the development of CAV. Certain cardiovascular medications, such as HMG-CoA reductase inhibitors (statins), gemfibrozil, calcium channel blockers, and angiotensin-converting enzyme inhibitors, have also demonstrated efficacy in preventing this disease process. Prevention of CAV has also been observed with prophylaxis against cytomegalovirus infection and antioxidant medications. Despite being commonly used in HT patients, neither antiplatelet agents nor glycemic control have proved effective at preventing CAV. Only sirolimus has been shown to arrest the progress of existing CAV.

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.

Anti-platelet factor 4/heparin antibodies in patients with impaired graft function after liver transplantation.

BACKGROUND: Heparin, the standard perioperative anticoagulant for the prevention of graft vessel thrombosis in patients undergoing liver transplantation (LT), binds to the chemokine platelet factor 4 (PF4). Antibodies that are formed against the resulting PF4/heparin complexes can induce heparin-induced thrombocytopenia. LT is a clinical situation that allows the study of T-cell dependency of immune responses because T-cell function is largely suppressed pharmacologically in these patients to prevent graft rejection. OBJECTIVES: To investigate the immune response against PF4/heparin complexes in patients undergoing LT. PATIENTS AND METHODS: In this prospective cohort study, 38 consecutive patients undergoing LT were systematically screened for anti-PF4/heparin antibodies (enzyme immunoassay and heparin-induced platelet aggregation assay), platelet count, liver function, and engraftment. RESULTS: At baseline, 5 (13%) of 38 patients tested positive for anti-PF4/heparin IgG (non-platelet-activating) antibodies. By day 20, an additional 5 (15%) of 33 patients seroconverted for immunoglobulin G (two platelet-activating) antibodies. No patient developed clinical heparin-induced thrombocytopenia. Two of six patients with graft function failure had anti-PF4/heparin IgG antibodies at the time of graft function failure. Graft liver biopsy samples from these patients showed thrombotic occlusions of the microcirculation. CONCLUSIONS: Anti-PF4/heparin IgG antibodies are generated despite strong pharmacologic suppression of T cells, indicating that T cells likely have a limited role in the immune response to PF4/heparin complexes in humans.

The impact of non-HLA antibodies directed against endothelin-1 type A receptors (ETAR) on early renal transplant outcomes.

BACKGROUND: Non-HLA antibodies (Abs) targeting vascular receptors are considered to have an influence on renal transplant injury. Anti-endothelin-1 type A receptor (anti-ETAR) antibodies were associated with cellular and antibody-mediated rejection and early onset of vasculopathy in heart transplant patients but their role in renal transplantation remains unclear. The aim of our study was to assess the incidence and importance of anti-ETAR antibodies and their impact on renal transplant during the first year observation. METHODS: We evaluated the presence of anti-ETAR antibodies in 116 consecutive renal transplant recipients in pre- and post-transplant screening (before and in 1st, 3rd, 6th, 12th month after transplantation). Additionally, we assessed the presence of anti-HLA antibodies. Anti-ETAR antibodies were assayed by ELISA. The diagnosis of acute rejection was based on the Banff criteria. RESULTS: Anti-ETAR antibodies were observed in 55 (47.4%) of the analyzed recipients before transplantation. The function of renal transplant was significantly worse in the anti-ETAR(+) group compared to the anti-ETAR(-) group during the first post-transplant year. One month after transplantation the serum creatinine in anti-ETAR (+) patients (pts) was 1.86±0.8mg/dl and 1.51±0.5 in anti-ETAR(-) pts (p=0.009). Twelve months after transplantation the difference between the groups was still observed 1.70±0.7 vs. 1.40±0.4 (p=0.04). Biopsy proven acute rejection was recognized in 8/55 (14.5%) in ETAR(+) and 9/61 (14.8%) in ETAR(-) patients but cases with mild to severe intimal arteritis (v1-v3) were more often observed in patients with the presence of anti-ETAR Abs 4/55 (7.2%) comparing with 1/61 (1.6%) in anti-ETAR(-) patients. The anti-ETAR antibody levels varied at different measurement intervals during the one-year follow-up. CONCLUSIONS: The presence of anti-ETAR antibodies is associated with a worse renal transplant function during the first 12months after transplantation. Including anti-ETAR antibodies in the diagnostics of renal transplant recipient immune status should be considered to provide comprehensive assessment of humoral alloimmunity.

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.

Anti-PF4/heparin antibodies and venous graft occlusion in postcoronary artery bypass surgery patients randomized to postoperative unfractionated heparin or fondaparinux thromboprophylaxis.

BACKGROUND: Anti-PF4/heparin antibodies are frequently generated after coronary artery bypass grafting (CABG) surgery, with platelet-activating IgG implicated in heparin-induced thrombocytopenia (HIT). It is controversial whether non-platelet-activating antibodies are associated with thrombosis. OBJECTIVES: To determine in post-CABG patients whether thromboprophylaxis using fondaparinux vs. unfractionated heparin (UFH) reduces the frequency of anti-PF4/heparin antibodies, and whether anti-PF4/heparin antibodies are associated with early graft occlusion. METHODS/PATIENTS: In a pre-planned secondary analysis of a randomized control trial (RCT) comparing fondaparinux vs. UFH thromboprophylaxis post-CABG, we determined the frequency of anti-PF4/heparin antibody formation by solid-phase enzyme-immunoassay (EIA) and of platelet-activating antibodies by serotonin-release assay (SRA); the SRA and fluid-phase EIA were used to assess fondaparinux cross-reactivity. We also examined whether anti-PF4/heparin antibodies were associated with early arterial or venous graft occlusion (6-week CT angiography). RESULTS: We found no significant difference in the frequency of antibody formation between patients who received fondaparinux vs. UFH (65.3% vs. 46.0%; P = 0.069), and no significant fondaparinux cross-reactivity. Venous graft occlusion(s) occurred in 6/26 patients who formed 'strong' IgG antibodies (≥ 1.0 optical density [OD] units and ≥ 2× baseline) vs. 3/66 who did not (P = 0.0139). In both unadjusted and adjusted analyses, strong postoperative (but not pre-operative) anti-PF4/heparin IgG responses were associated with a markedly increased risk of early venous (but not arterial) graft occlusion (adjusted OR, 9.25 [95% CI, 1.73, 49.43]; P = 0.0093); notably, none of the three SRA-positive patients developed a venous graft occlusion. CONCLUSIONS: Fondaparinux vs. UFH thromboprophylaxis postCABG does not reduce anti-PF4/heparin antibody formation. Non-platelet-activating anti-PF4/heparin IgG antibodies generated post operatively are associated with early venous graft occlusion.

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.

Inhibitory effects of calcitonin gene-related peptides on experimental vein graft disease.

BACKGROUND: Vein graft disease is a chronic inflammatory disease and limits the long-term clinical outcome of coronary revascularization. Because calcitonin gene-related peptide (CGRP) inhibits macrophage infiltration and inflammatory mediators, we hypothesized that transfected CGRP gene would inhibit macrophage infiltration and expression of inflammatory mediators in vein graft disease. METHODS: Autologous rabbit jugular vein grafts were incubated ex vivo in a solution of mosaic adeno-associated virus vectors containing CGRP gene (AAV2/1.CGRP) or Escherichia coli B-galactosidase gene (LacZ) or a saline solution and then interposed in the carotid artery. Expression of CGRP gene was identified by reverse transcription-polymerase chain reaction, and E. coli LacZ gene expression was identified by X-gal staining. Intima to media ratios were evaluated at postoperative 4 weeks. Macrophages were identified with CD68 antibody by immunocytochemistry. Inflammatory mediators were measured with real-time polymerase chain reaction. RESULTS: The CGRP and LacZ gene expression were positive at postoperative 4 weeks. The intima to media ratio was significantly inhibited in the AAV2/1.CGRP group. Macrophage infiltration and expression of inflammatory mediators including monocyte chemoattractant protein-1, tumor necrosis factor-alpha, inducible nitric oxide synthase, and matrix metalloproteinase-9 were also significantly inhibited in the AAV2/1.CGRP group. CONCLUSIONS: Transfection of AAV2/1.CGRP inhibited inflammatory mediator expression, macrophage infiltration, and neointimal hyperplasia in experimental vein graft disease.