Vein Graft Thrombosis Research Articles

ОДНОЭТАПНАЯ КОРРЕКЦИЯ ПОСЛЕДСТВИЙ ПОВРЕЖДЕНИЯ ЛОКТЕВОГО НЕРВА

Objective: : To enhance the outcomes of surgical treatment for chronic ulnar nerve injuries by performing one-stage correction. Methods: From 2015 to 2023, 11 patients with chronic ulnar neurovascular bundle (NVB) injuries underwent one-stage reconstruction to restore hand function. The operations were performed on 8 men and 3 women aged 16 to 23. The duration of treatment for patients from the time of injury varied from 1.2 years to 5 years Results: In cases where there was a diastasis between the neural ends of no more than 3 cm in the upper third of the forearm due to nerve damage, restoration of the nerve with epineural suture was performed in 2 patients, while in two other cases with more significant gaps of 3.5 and 5 cm, epineural repair was carried out after anterior transposition of the nerve trunk. In one case of nerve damage in the middle third of the forearm, epineural sutures were applied to a 2.5 cm gap. Among 6 patients with damage to the ulnar NVB in the lower third of the forearm, 4 received epineural restoration of the ulnar nerve, and autologous neuroplasty was performed in gaps exceeding 3 cm in 2 patients. In cases of damage to the ulnar artery, 3 patients received autologous vein grafting, while in 3 other cases, there were no indications for vascular reconstruction. No infectious or inflammatory complications were observed in the immediate postoperative period, and there were no cases of thrombosis of autologous vein grafts of the ulnar artery. After evaluating all patients for 6 months to 2 years, it was found that 9 cases showed favorable and satisfactory long-term functional outcomes, while 2 cases exhibited unsatisfactory results. Conclusion: Restoring hand function after damage to the ulnar nerve is greatly influenced by the location, extent, and type of the damage, as well as the choice of an appropriate reconstruction method. Breaking the procedure into multiple stages can prolong patient recovery and negatively impact treatment outcomes. Conversely, performing the operation in a single stage within a relatively short timeframe can restore hand function and significantly reduce overall treatment and rehabilitation time Keywords: Ulnar nerve, neurovascular bundle, injury, tendon-muscular transfer, epineural suture

Outcomes of Ligation without Revascularization in Pseudoaneurysms of Peripheral Arteries in Intravenous Drug Users

Management of pseudoaneurysms in intravenous drug users is complex and challenging due to an associated infection and unavailability of autologous vein grafts. Here we observe the outcomes of ligation and local debridement as a primary modality of treatment in this subset of patients with pseudoaneurysms. This is a descriptive cross sectional study of 15 patients over a period of 4 years who presented with pseudoaneurysm of peripheral artery from intravenous drug use. In this study, we describe the presentations and management outcomes in 15 patients with peripheral arterial pseudoaneurysmfrom IV drug use. The most common site involved was common femoral artery among 12 (80%) patients followed by superficial femoral artery among 8 (13.3%) patients and external iliac artery in 1 (6.7%) patient. Twelve (80%) patients were having signs of infection. All patients underwent surgical intervention which comprised of excision of pseudoaneurysm and ligation of artery without revascularization among 12 (80%) patients and with revascularization with autologous venous graft among 3 (20%) patients. There was no mortality or a major bleeding requiring re-exploration. None of the patients developed limb ischemia necessitating amputation.One patient with femoral artery ligation without revascularization at one year of follow up is having claudication on brisk walking.There was one saphenous vein graft thrombosis in immediate postoperative period. With the use of ligation without revascularization technique, there was no mortality or major bleeding requiring re-exploration. None of the patients developed limb ischemia necessitating amputation so this treatment modality seems promising in treatment of pseudoaneurysms in intravenous drug users.

Combat vascular injury: Influence of mechanism of injury on outcome

BackgroundHaemorrhage is the leading cause of death on the battlefield. Seventy percent of injuries are due to explosive mechanisms. Anecdotally, these patients have had poorer outcomes when compared to those with penetrating mechanisms of injury (MOI). We wished to test the hypothesis that outcomes following vascular reconstruction were worse in blast-injured than non blast-injured patients. MethodsRetrospective cohort study. British and American combat casualties with arterial injuries sustained in Iraq or Afghanistan (2003–2014) were identified from the UK Joint Theatre Trauma Registry (JTTR). Eligibility included explosive or penetrating MOI, with follow-up to UK hospital discharge, or death. Outcomes were mortality, amputation, graft thrombosis, haemorrhage, and infection. Statistical analysis was performed using Pearson Chi-Square test, t-tests, ANOVA or non-parametric equivalent, and survival analyses. ResultsOne hundred and fifteen patients were included, 80 injured by explosive and 35 by penetrating mechanisms. Evacuation time, ISS, number of arterial injuries, age and gender were comparable between groups. Seventy percent of arterial injuries resulted from an explosive MOI. The explosive injuries group received more blood products (p = 0.008) and suffered more regions injured (p < 0.0001). Early surgical interventions in both were ligation (n = 36, 31%), vein graft (n = 33, 29%) and shunting (n = 9, 8%). Mortality (n = 12, 10%) was similar between groups. Differences in limb salvage rates following explosive (n = 17, 53%) vs penetrating (n = 13, 76.47%) mechanisms approached statistical significance (p = 0.056). Nine (28%) vein grafted patients developed complications. No evidence of a difference in the incidence of vein graft thrombosis was found when comparing explosive with non-explosive cohorts (p = 0.154). ConclusionsThe recorded numbers of vein grafts following combat arterial trauma in are small in the JTTR. No statistically-significant differences in complications, including vein graft thrombosis, were found between cohorts injured by explosive and non-explosive mechanisms.

Apixaban for the treatment of saphenous vein graft thrombosis presenting as unstable angina: a case report

BackgroundSaphenous vein graft thrombosis can present as unstable angina. However, percutaneous coronary intervention for saphenous vein graft lesions poses a high risk of slow flow related to the procedure. Here we present the utilization of the novel oral anticoagulant, apixaban, in the treatment of unstable angina with extensive saphenous vein graft thrombus, leading to considerable thrombus resolution and eliminating the need of percutaneous coronary intervention.Case presentationA 72-year-old man with 3-vessel coronary artery bypass graft surgery using a saphenous vein graft and a left internal mammary artery, performed 25 years earlier, presented at our hospital with recurrent chest tightness. The echocardiography showed regional hypokinesis of the post-lateral wall with moderate left ventricular dysfunction, which had not been previously confirmed. Coronary angiography showed obstruction of the saphenous vein graft with a large thrombus burden. The left internal mammary artery was patent and other natives were the same as they had been 3 years ago. He was diagnosed with unstable angina due to acute saphenous vein graft thrombosis. Instead of percutaneous coronary intervention, he was treated with apixaban 5 mg twice a day. The angiography 3 weeks after starting apixaban showed considerable resolution of the thrombus and opening of the saphenous vein graft.ConclusionsApixaban could become a viable treatment option for acute saphenous vein graft thrombosis.

Intraoperative saphenous vein graft thrombosis during off-pump coronary artery bypass surgery using argatroban as an anticoagulation in a hemodialysis patient with suspected heparin-allergy

Intraoperative saphenous vein graft thrombosis during off-pump coronary artery bypass surgery using argatroban as an anticoagulation in a hemodialysis patient with suspected heparin-allergy

Risk Factors for Nonplatelet Thromboxane Generation After Coronary Artery Bypass Graft Surgery.

BackgroundPersistent thromboxane (TX) generation while receiving aspirin therapy is associated with an increased risk of cardiovascular events. The Reduction in Graft Occlusion Rates (RIGOR) study found that aspirin‐insensitive TXA 2 generation, indicated by elevated urine 11‐dehydro‐TXB 2 (UTXB 2) 6 months after coronary artery bypass graft surgery, was a potent risk factor for vein graft thrombosis and originated predominantly from nonplatelet sources. Our goal was to identify risks factors for nonplatelet TXA 2 generation.Methods and ResultsMultivariable modeling was performed by using clinical and laboratory variables obtained from 260 RIGOR subjects with verified aspirin‐mediated inhibition of platelet TXA 2 generation. The strongest variable associated with UTXB 2 6 months after surgery, accounting for 47.2% of the modeled effect, was urine 8‐iso‐prostaglandin (PG)F 2α, an arachidonic acid metabolite generated nonenzymatically by oxidative stress (standardized coefficient 0.442, P<0.001). Age, sex, race, lipid therapy, creatinine, left ventricular ejection fraction, and aspirin dose were also significantly associated with UTXB 2 (P<0.03), although they accounted for only 4.8% to 10.2% of the modeled effect. Urine 8‐iso‐PGF 2α correlated with risk of vein graft occlusion (odds ratio 1.67, P=0.001) but was not independent of UTXB 2. In vitro studies revealed that endothelial cells generate TXA 2 in response to oxidative stress and direct exposure to 8‐iso‐PGF 2α.ConclusionsOxidative stress–induced formation of 8‐iso‐PGF 2α is strongly associated with nonplatelet thromboxane formation and early vein graft thrombosis after coronary artery bypass graft surgery. The endothelium is potentially an important source of oxidative stress–induced thromboxane generation. These findings suggest therapies that reduce oxidative stress could be useful in reducing cardiovascular risks associated with aspirin‐insensitive thromboxane generation.

Successful Treatment of Acute Vein Graft Thrombosis Precipitated by Delayed Sepsis and Duodenocaval Fistulization

[...]with increasing recognition that adoption of a liberal visceral en bloc resection may achieve greater local control in retroperitoneal sarcomas and that adjuvant radiotherapy may provide additional benefit,2 surgeons are adopting a radical approach toward tumor resection involving the right upper abdominal viscera, which may have contributed to the observation of duodenocaval fistula formation.3, 4 An astute clinical acumen is essential in being able to make an early diagnosis and institute appropriate operative treatment.

C‐reactive protein induces expression of tissue factor and plasminogen activator inhibitor‐1 and promotes fibrin accumulation in vein grafts

C-reactive protein (CRP) promotes tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) expression invitro, and an elevated plasma CRP concentration is associated with an increased risk of vein graft (VG) thrombosis after coronary artery bypass surgery. However, little is known about the effects of CRP on VG TF and PAI-1 expression invivo, or on VG thrombosis. We studied transgenic (Tg) mice expressing human CRP in a VG model to explore invivo cause-and-effect relationships between CRP and TF, PAI-1, and VG thrombosis. Vein segments from wild-type (WT) and CRP-Tg donors were transplanted into carotid arteries of WT and CRP-Tg recipients. VGs were analyzed 1-4weeks later. Human CRP accumulated in VGs during the first 4weeks after surgery, but appeared to originate exclusively from systemic sources, rather than local production. Human CRP significantly increased TF gene expression, protein concentration and activity in VGs. Human CRP also increased PAI-1 concentrations in VGs, although only in vascular endothelial cells. Human CRP stimulated macrophage migration, invasion into VGs, and TF expression. Fibrin deposition was significantly greater in VGs of CRP-Tg mice than in WT controls. CRP accumulates in VGs early after surgery, originating from systemic sources rather than local synthesis. Human CRP promotes TF and PAI-1 expression in VGs, although with different expression patterns. Human CRP stimulates macrophage invasion and fibrin deposition within VGs. These results suggest that CRP induces pathologic changes in VGs that contribute to early VG occlusion.

Who might benefit from early aspirin after coronary artery surgery?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether early administration of aspirin might optimize vein graft patency. More than 250 papers were found using the reported search, of which 4 new papers in addition to the previous 7 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Early postoperative aspirin administered within 6 h following coronary artery bypass grafting (CABG) has been shown to be optimal for prevention of vein graft occlusion. Early aspirin has significant benefit in reducing vein graft occlusion, mortality, myocardial infarction, stroke, renal failure and bowel infarction. The efficacy of early postoperative aspirin on vein graft patency diminishes the later it is administered. It has optimal benefit at 6 h, some benefit at 24 h and no benefit after 48 h post CABG. ACC/AHA, EACTS and ACCP have issued guidelines recommending administration of early aspirin or an alternative (clopidogrel, ticlopidine and indobufen) at 6 h or soon after bleeding has settled as the standard of care for optimization of vein graft patency. The ACCP guideline has also suggested that optimal prevention of cardiovascular complication should have higher value than prevention of postoperative bleeding. Several randomized, controlled studies, including a meta-analysis, have shown that early administration of aspirin following CABG is not associated with increased blood loss or transfusion requirement. Postoperative bleeding has been identified as a significant reason for non administration of early aspirin in a prospective study. It is essential to define/quantify the postoperative blood loss that precludes administration of early aspirin. This will enhance prompt administration in some cases and guide judgement, especially in patients with high-risk factors for vein graft thrombosis. Administration at 6 h is the optimal time to give aspirin as long as bleeding has settled.

Factors associated with primary vein graft occlusion in a multicenter trial with mandated ultrasound surveillance

Even in the setting of duplex ultrasound (DUS) surveillance, a significant number of lower extremity vein bypass grafts (LEVBGs) become occluded as a first event. We sought to identify factors that may contribute to these primary occlusions. This was a retrospective analysis of the Project of Ex Vivo Graft Engineering via Transfection III (PREVENT III) multicenter randomized clinical trial, in which 1404 patients with critical limb ischemia (CLI) underwent LEVBG with 1-year follow-up. Subjects were to undergo DUS at regular intervals (1, 3, 6, and 12 months), with reintervention based on prespecified DUS criteria. Patients who had nontechnical graft occlusion as the initial graft-related event were identified, and multivariate analysis was used to determine factors associated with primary graft occlusion. Primary vein graft occlusion occurred in 200 subjects and accounted for 36% of all primary patency events and 64% of all graft occlusions in the trial. Primary occlusion events were evenly distributed throughout the first postoperative year. Rates of recurrent CLI, loss of secondary patency, and major amputation in those with primary occlusion were 55%, 79%, and 22% respectively as compared to 18%, 10%, and 10% for subjects without primary occlusion (P < .001). On multivariate analysis, African-American race (subdistribution hazard ratio [SHR], 1.50; 95% confidence interval [CI], 1.06-2.12), a graft diameter <3 mm (SHR, 2.31; 95% CI, 1.33-4.01), and nonadherence with ultrasound surveillance (SHR, 1.58; 95% CI, 1.10-2.27) were independently associated with primary graft occlusion. Of the 123 subjects who received their last scheduled surveillance DUS prior to a primary occlusion event, 39 had a critical ultrasound abnormality identified but failed to undergo graft revision, while 84 had no critical ultrasound abnormality identified. Among these 84 subjects, female gender (SHR, 1.65; 95% CI, 1.07-2.54), and graft diameter <3 mm (SHR, 2.12; 95% CI, 1.03-4.37) were independent factors associated with unheralded graft occlusion. Among patients undergoing LEVBG for CLI, almost half of primary patency events are occlusions even in the setting of a DUS surveillance protocol. African Americans, patients with smaller-diameter grafts, and those who are nonadherent with surveillance ultrasound are at increased risk. Failure to intervene on critical findings, and lack of sensitivity of DUS threshold criteria to predict thrombosis, are also important contributors. These findings suggest that prevention of vein graft thrombosis requires further improvements in risk stratification, surveillance, and the timing of reinterventions.

Differential 1‐year clinical outcomes for ST‐segment elevation myocardial infarction related to stent thrombosis or saphenous vein graft thrombosis

Thrombosis of stents and of saphenous vein grafts (SVG) remains a severe complication of either revascularization techniques that often are present as ST elevation myocardial infarction (STEMI). The aim of this longitudinal cohort study was to compare the 1-year clinical outcomes among STEMI patients requiring primary PCI due to stent thrombosis and graft occlusion presenting with STEMI. We prospectively collected data on all patients undergoing primary PCI at the Montreal Heart Institute between April 1, 2007 and March 30, 2008. Study patients were grouped according to the etiology of the STEMI: stent thrombosis, graft thrombosis, or atherosclerosis-related STEMIs (control group). The primary combined end-point, major adverse cardiac events (MACE), was defined as death, myocardial infarction, and target vessel revascularization within 12 months as primary end point. Of the 489 STEMI patients included in the study, 23 were due to stent thrombosis, 22 to graft thrombosis, and 444 in the control group. Stent and graft thromboses were associated with a higher MACE rates, 26.1 and 22.7%, respectively, compared to the control group, 9.3% (P = 0.004). Moreover, only stent thrombosis was associated with an increased risk of MACE (HR 2.57, confidence interval 95% 1.08-6.08. Patients with stent thrombosis present with higher rate of reinfarction while graft thrombosis is associated with an increase in 1-year cardiac mortality. Using multivariate analysis, higher MACE rates were associated with stent thrombosis as compared to graft thrombosis.

Factors Associated With Primary Vein Graft Thrombosis in a Multicenter Trial With Mandated Ultrasound Surveillance

The benefits of preventing lower extremity vein bypass graft (LEVBG) occlusion through duplex ultrasound (DUS) surveillance and timely reintervention are established. However, even in the setting of surveillance, a significant number of LEVBG become occluded as a first event. We sought to identify factors that may contribute to these primary occlusions using a multicenter clinical trial database. This was a retrospective analysis of the PREVENT III cohort of 1404 patients with critical limb ischemia who underwent LEVBG. Participants were followed up with DUS at regular intervals (1, 3, 6, 9, and 12 months), with reintervention based on prespecified DUS criteria. Patients who had graft occlusion as the initial graft-related event were identified, and technical failures (adjudicated) were excluded. Multivariate analysis was used to identify predictors of primary graft occlusion. Primary graft occlusion occurred in 200 participants (14%), accounting for 34% of all initial graft-related events. Primary occlusion events were distributed throughout the postoperative year. Rates of recurrent critical limb ischemia, loss of secondary patency, and major amputation in those with primary occlusion were 55%, 79%, and 22%, respectively, compared with 18%, 10%, and 10% for the remaining cohort (P < .001). On univariate analysis (hazard ratio [HR] [95% confidence interval]), African American race (1.4 [1.01-1.9]), use of anticoagulants (1.54 [1.2-2]), use of alternative/spliced vein conduit (1.44 [1.1-1.97]) and graft diameter <3 mm (1.97 [1.2-3.3]) were associated with increased risk of primary occlusion. On multivariate analysis (HR [95% confidence interval]) graft diameter <3 mm (1.8 [1.1-3]) and use of anticoagulants (1.4 [1.04-1.89]) were independent predictors. In 110 individuals, DUS had revealed no critical threshold abnormalities prior to the thrombosis. On multivariate analysis, graft diameter <3 mm (2.3 [1.2-4.7]) was the sole independent predictor of these unheralded occlusions. Approximately one-third of primary vein graft events are occlusions even in the setting of DUS surveillance. Smaller diameter grafts are at increased risk. These findings suggest that prevention of vein graft thrombosis requires further improvements in risk stratification, surveillance, and antithrombotic therapies.

Effect of assay specificity on the association of urine 11‐dehydro thromboxane B2 determination with cardiovascular risk

Elevated urine 11-dehydro TXB(2), an indicator of persistent thromboxane generation in aspirin-treated patients, correlates with adverse cardiovascular outcome and has recently been identified as an independent risk factor for vein graft thrombosis after cardiac bypass surgery in the Reduction in Graft Occlusion Rates (RIGOR) study. The polyclonal antibody-based ELISA used to measure 11-dehydro TXB(2) in these previous studies is no longer clinically available and has been supplanted by a Food and Drug Administration (FDA)-cleared second-generation monoclonal antibody-based ELISA. To compare the laboratory and clinical performance of the first- and second-generation assays in a well-defined study population. 11-dehydro TXB(2) was quantified in 451 urine samples from 229 Reduction in Graft Occlusion Rates (RIGOR) subjects using both ELISA. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and spiking studies were used to investigate discordant assay results. The association of 11-dehydro TXB(2) to clinical outcome was assessed for each assay using multivariate modeling. Median 11-dehydro TXB(2) levels were higher by monoclonal antibody- compared with polyclonal antibody-based ELISA (856 vs. 399 pg mg(-1) creatinine, P < 0.000001), with the latter providing values similar to UPLC-MS/MS. This discrepancy was predominantly as a result of cross-reactivity of the monoclonal antibody with 11-dehydro-2,3-dinor TXB(2), a thromboxane metabolite present in a similar concentration but with a poor direct correlation with 11-dehydro TXB(2). In contrast to the first-generation ELISA, 11-dehydro TXB(2) measured by the monoclonal antibody-based ELISA failed to associate with the risk of vein graft occlusion. Quantification of urine 11-dehydro TXB(2) by monoclonal antibody-based ELISA was confounded by interference from 11-dehydro-2,3-dinor TXB(2) which reduced the accuracy and clinical utility of this second-generation assay.

Animal models for studying vein graft failure and therapeutic interventions

Vein grafts have been extensively used to bypass blockages in arteries, but are themselves subject to early closure by thrombosis or later obstruction by vein graft disease (neointimal hyperplasia and remodelling). Animal models are a crucial means of testing potential therapeutic and surgical interventions to prevent graft stenosis and occlusion. This review outlines many of the animal models of vein grafting. Recent studies include targeted gene therapy to prevent acute vein graft thrombosis and the use of folic acid to limit graft failure in diabetic pigs.

Use of microvena snare catheter in non-ST elevation myocardial infarction due to saphenous vein graft occlusive thrombi

A 75-year-old man presented with acute coronary syndrome; he had a saphenous vein graft thrombosis. Percutaneous coronary intervention of bypass graft vessels is more challenging due to a higher incidence of periprocedural distal micro-emobilization and myocardial infarction. Current guidelines for percutaneous coronary intervention advocate the use of distal embolic protection devices, especially in patients with large thrombus burden, undergoing percutaneous intervention for vein graft disease. This patient was treated by manual aspiration of graft thrombus using a microvena catheter and successful clot removal was achieved. There are yet no best available therapeutic options for patients undergoing percutaneous coronary intervention of saphenous vein graft lesions.

03 Varicose and non-varicose veins are able to activate the hypoxia-inducible factor pathway when exposed to hypoxia

IntroductionHypoxia has been postulated to contribute to various venous pathology including varicose veins (VV) and vein graft thrombosis or stenosis. Hypoxia-inducible factors (HIF) are nuclear transcriptional factors regulating transcription of...

Vasoprotection by heme oxygenase-1: interactions with soluble guanylate cyclase

Background Heme oxygenase-1 (HO-1) is a highly inducible enzyme that metabolizes heme to generate equimolar amounts of carbon monoxide (CO), biliverdin, and ferrous iron. Subsequently, biliverdin is metabolized to the potent antioxidant bilirubin by biliverdin reductase. Compelling experimental evidence indicates that HO-1 and its end products protect against the development of vascular dysfunction in animal models atherosclerosis, postangioplasty restenosis, vein graft stenosis, thrombosis, myocardial infarction, and hypertension.

Sutureless anastomoses: the main goal for a calcified aorta?

We read with great interest the article written by Dohmen et al. published in the EJCTS January 2011 [1]. The authors reported on their experience with the PAS-Port automated proximal aortic connector device (ACD) in 17 patients with heavily calcified aorta during coronary bypass surgery grafting (CABG). The early graft patency in every patient was proven by computed tomography (CT) scan after 30 days. To avoid aortic manipulation, every CABG procedure was performed in off-pump beating-heart technique, though two patients had to convert to cardiopulmonary bypass (CPB) in case of ventricular fibrillation and hemodynamic instability. These two patients suffered from prolonged reversible neurological deficits (PRIND) and another one from longlasting postoperative delirium. With respect to the older patient population, every heart surgeon is familiar with the problem of severe calcified aorta not only during CABG procedure. As described in the article, there are many different strategies in the literature to cope with this problem during CABG surgery, such as off-pump aortic ‘non-touch technique’ using tor y-arterial grafts to the internal thoracic arteries [2]. The use of ACDs in this special patient population, as stated in the article, is not new. Though many technical problems, for example, proper alignment of the vein graft and early graft thrombosis, were seen in the initial phase after using ACDs, the results are not worse than hand-sutured anastomoses. However, midterm results remain poor and led to abandonment of ACDs in the routine use. Long-term follow-up for ACD patients is hardly

Effects of Aspirin Responsiveness and Platelet Reactivity on Early Vein Graft Thrombosis After Coronary Artery Bypass Graft Surgery

The purpose of this study was to determine if an incomplete response to or inadequate antiplatelet effect of aspirin, or both, contribute to saphenous vein graft (SVG) occlusion after coronary artery bypass graft (CABG) surgery. Thrombosis is the predominant cause of early SVG occlusion. Aspirin, which inhibits cyclooxygenase-1 activity and thromboxane generation in platelets, reduces early SVG occlusion by one-half. Aspirin responsiveness and platelet reactivity were characterized 3 days and 6 months after coronary artery bypass graft surgery in 229 subjects receiving aspirin monotherapy by platelet aggregation to arachidonic acid, adenosine diphosphate, collagen and epinephrine, Platelet Function Analyzer-100 (Siemens Healthcare Diagnostics, Newark, Delaware) closure time (CT) using collagen/epinephrine agonist cartridge and collagen/adenosine diphosphate (CADP) agonist cartridge, VerifyNow Aspirin assay (Accumetrics, Inc., San Diego, California), and urine levels of 11-dehydro-thromboxane B(2) (UTXB(2)). SVG patency was determined 6 months after surgery by computed tomography coronary angiography. Inhibited arachidonic acid-induced platelet aggregation, indicative of aspirin-mediated cyclooxygenase-1 suppression, occurred in 95% and >99% of subjects 3 days and 6 months after surgery, respectively. Despite this, 73% and 31% of subjects at these times had elevated UTXB(2). Among tested parameters, only UTXB(2) and CADP CT measured 6 months after surgery correlated with outcome. By multivariate analysis, CADP CT of ≤88 s (odds ratio: 2.85, p = 0.006), target vessel diameter of ≤1.5 mm (odds ratio: 2.38, p = 0.01), and UTXB(2) of ≥450 pg/mg creatinine (odds ratio: 2.59, p = 0.015) correlated with SVG occlusion. CADP CT and UTXB(2) in combination further identified subjects at particularly high and low risk for SVG occlusion. Aspirin-insensitive thromboxane generation measured by UTXB(2) and shear-dependent platelet hyper-reactivity measured by Platelet Function Analyzer-100 CADP CT are novel independent risk factors for early SVG thrombosis after coronary artery bypass graft surgery.

Targeting Heme Oxygenase-1 in Vascular Disease

Heme oxygenase-1 (HO-1) metabolizes heme to generate carbon monoxide (CO), biliverdin, and iron. Biliverdin is subsequently metabolized to bilirubin by biliverdin reductase. HO-1 has recently emerged as a promising therapeutic target in the treatment of vascular disease. Pharmacological induction or gene transfer of HO-1 ameliorates vascular dysfunction in animal models of atherosclerosis, post-angioplasty restenosis, vein graft stenosis, thrombosis, myocardial infarction, and hypertension, while inhibition of HO-1 activity or gene deletion exacerbates these disorders. The vasoprotection afforded by HO-1 is largely attributable to its end products: CO and the bile pigments, biliverdin and bilirubin. These end products exert potent anti-inflammatory, antioxidant, anti-apoptotic, and anti-thrombotic actions. In addition, CO and bile pigments act to preserve vascular homeostasis at sites of arterial injury by influencing the proliferation, migration, and adhesion of vascular smooth muscle cells, endothelial cells, endothelial progenitor cells, or leukocytes. Several strategies are currently being developed to target HO-1 in vascular disease. Pharmacological induction of HO-1 by heme derivatives, dietary antioxidants, or currently available drugs, is a promising near-term approach, while HO-1 gene delivery is a long-term therapeutic goal. Direct administration of CO via inhalation or through the use of CO-releasing molecules and/or CO-sensitizing agents provides an attractive alternative approach in targeting HO-1. Furthermore, delivery of bile pigments, either alone or in combination with CO, presents another avenue for protecting against vascular disease. Since HO-1 and its products are potentially toxic, a major challenge will be to devise clinically effective therapeutic modalities that target HO-1 without causing any adverse effects.