Autogenous Femoral Vein for Secondary Repair of Subclavian Arteries: A Salvage Solution for Complex Clinical Scenarios.

BACKGROUND: Endovascular stent and prosthetic graft placement are commonplace techniques for correction of subclavian artery (SCA) lesions. However, when initial surgical repair of the SCA becomes complicated by subsequent infection or thrombosis of the repair site, stents and prosthetic grafts are no longer suitable for secondary repair due to the risk of recurrent failure and limited longevity. Autogenous tissue is more resistant to infection and has improved long-term patency, and thus may be a better option for secondary reconstruction in these complex clinical scenarios. The most commonly used autogenous conduit for SCA reconstruction is the great saphenous vein; however, the significant size mismatch makes this unsuitable in many circumstances. The autogenous femoral vein is a promising alternative conduit for SCA repair. Here we present 3 successful cases of its use as a salvage technique following iatrogenic complications of prior surgical repair. METHODS: From 2015 to 2019, 3 patients underwent harvest of the femoral vein for use in SCA repair, with 2 carotid-axillary bypasses and 1 carotid-subclavian bypass. Indications included a mycotic pseudoaneurysm secondary to an infected SCA stent, an SCA avulsion secondary to an infected carotid-subclavian bypass graft, and an occluded SCA stent in a young patient. Postoperative graft patency was monitored via clinical resolution of symptoms and maintenance of perfusion, intact pulses, and arterial duplex or computed tomography (CT) scan. RESULTS: All these patients had a good outcome following their procedures. Each had intact radial pulses immediately postoperatively and maintained normal perfusion to the upper extremity for the duration of follow-up, with bypass patency confirmed via CT scan or arterial duplex. The SCA repair also allowed for salvage of the upper extremity and symptomatic relief in all patients. None of the patients developed deep vein thrombosis in the donor extremity, and neither of the infected patients developed recurrent infection of the repair site. CONCLUSIONS: The success of these cases demonstrates that the autogenous femoral vein is an effective and safe option for SCA reconstruction. It is particularly useful for secondary salvage when prior surgical repair via standard techniques is complicated by infection or thrombosis, and when target vessel size precludes the use of the great saphenous vein. This is an excellent choice of conduit that vascular surgeons should consider for use in complex SCA repairs.

Adsorption-based immobilization of Caldicellulosiruptor saccharolyticus cellobiose 2-epimerase on Bacillus subtilis spores.

Nonrecombinant spore was examined as a novel immobilization support to adsorb enzymes. Caldicellulosiruptor saccharolyticus cellobiose 2-epimerase (CsCE), efficiently producing lactulose using lactose as a single substrate, was immobilized on Bacillus subtilis spores via adsorption. The immobilization process was optimized, and the properties of immobilized CsCE and the interactions between the enzyme and spores were also investigated. Under the optimized conditions (pH 4.5, temperature 4 °C, reaction time 2 H, and initial enzyme concentration 2.4 mg/mL), the maximum adsorbed amount of CsCE was 1.47 mg/10(11) spores, and the enzyme activity recovery was 79.4%. The spore-immobilized CsCE presented a higher pH and thermal stability than a free enzyme. Total desorption of the immobilized enzyme was only achieved by treatment with 1.0 M NaCl at pH 1.0, indicating a strong adsorption between CsCE and B. subtilis spores. Efficient binding may require a potent combination of electrostatic and hydrophobic interactions between spores and an enzyme. The immobilized CsCE was applied to produce 395 g/L lactulose after 4 H. Moreover, the spores could be regenerated and the spore-immobilized enzyme showed good reusability as it retained approximately 70% of its initial activity after eight recycles.

Thinking inside the graft: applications of optical coherence tomography in coronary artery bypass grafting.

Recent advances in catheter-based optical coherence tomography (OCT) have provided the necessary resolution and acquisition speed for high-quality intravascular imaging. Complications associated with clearing blood from the vessel of a living patient have prevented its wider acceptance. We identify a surgical application that takes advantage of the vascular imaging powers of OCT but that circumvents the difficulties. Coronary artery bypass grafting (CABG) is the most commonly performed major surgery in America. A critical determinant of its outcome has been postulated to be injury to the conduit vessel incurred during the harvesting procedure or pathology preexistent in the harvested vessel. As a test of feasibility, intravascular OCT imaging is obtained from the radial arteries (RAs) and/or saphenous veins (SVs) of 35 patients scheduled for CABG. Pathologies detected by OCT are compared to registered histological sections obtained from discarded segments of each graft. OCT reliably detects atherosclerotic lesions in the RAs and discerns plaque morphology as fibrous, fibrocalcific, or fibroatheromatous. OCT is also used to assess intimal trauma and residual thrombi related to endoscopic harvest and the quality of the distal anastomosis. We demonstrate the feasibility of OCT imaging as an intraoperative tool to select conduit vessels for CABG.

PIK3CA Mutations Contribute to Acquired Cetuximab Resistance in Patients with Metastatic Colorectal Cancer.

Purpose: Mutations in KRAS are considered to be the main drivers of acquired resistance to epidermal growth factor receptor (EGFR) blockade in patients with metastatic colorectal cancer (mCRC). However, the potential role of other genes downstream of the EGFR signaling pathway in conferring acquired resistance has not been extensively investigated.Experimental Design: Using circulating tumor DNA (ctDNA) from patients with mCRC and with acquired cetuximab resistance, we developed a targeted amplicon ultra-deep sequencing method to screen for low-abundance somatic mutations in a panel of genes that encode components of the EGFR signaling pathway. Mutations with significantly increased variant frequencies upon disease progression were selected by using quartile analysis. The functional consequences of the identified mutations were validated in cultured cells.Results: We analyzed 32 patients with acquired cetuximab resistance in a development cohort. Of them, seven (22%) carried five novel PIK3CA mutations, whereas eight (25%) carried previously reported KRAS mutations. Functional studies showed that novel PIK3CA mutations (all in exon 19; p.K944N, p.F930S, p.V955G, p.V955I, and p.K966E) promote cell viability in the presence of cetuximab. Only one novel PIK3CA mutation (p.K944N) was verified in one of the 27 patients with acquired resistance in a validation cohort, simultaneous KRAS and PIK3CA hotspot mutations were detected in two patients. Among the above 59 acquired resistance patients, those with PIK3CA or RAS mutations detected in ctDNA showed a pronounced decrease in progression-free survival than patients with no mutation.Conclusions: The PIK3CA mutations may potentially contribute to acquired cetuximab resistance in patients with mCRC. Clin Cancer Res; 23(16); 4602-16. ©2017 AACR.

Platelet function tests predict bleeding and thrombotic events after off-pump coronary bypass grafting.

OBJECTIVE: A balanced coagulation system after cardiac surgery minimizes bleeding and thrombotic events. However, the best method to monitor this balance has not been established. We used a series of tests of coagulation and platelet function to define the risk of bleeding and thrombotic events after OPCAB. METHODS: In 76 patients, routine coagulation tests (i.e. prothrombin time, fibrinogen level, d-dimer, and platelet count), thrombelastography, and whole blood aggregometry were obtained perioperatively and on days 1 and 3 after OPCAB. Intra- and postoperative blood loss was determined. Early patency of venous bypass grafts was determined using CT angiography (Philips Medical, Corp.). RESULTS: Chest tube output and red cell volume loss at 24 h were 952+/-475 and 190+/-115 ml, respectively. Early graft failure developed in eight patients. Perioperative changes in routine coagulation tests showed no correlation with either bleeding or thrombosis. However, perioperative decline in platelet function as assessed by the area under the impedance curve for whole blood aggregometry correlated with intraoperative blood loss (R=0.42, P<0.05). A perioperative decline in the maximum amplitude of the thrombelastography trace showed a significant correlation with 24h hemoglobin loss (R=0.45, P<0.05). Compared to those with all patent grafts, patients with early graft failure demonstrated a reduction in platelet sensitivity to aspirin by both thrombelastography and aggregometry on day 3. CONCLUSIONS: In contrast to standard coagulation testing, platelet function predicted both bleeding and thrombosis after OPCAB. Titration of perioperative platelet function according to these tests may minimize thrombosis without increasing bleeding.

Virchow triad, but not use of an aortic connector device, predicts early graft failure after off-pump coronary bypass.

The risk of early thrombosis of coronary artery bypass (CAB) grafts may be increased after off-pump CAB, particularly after the use of an aortic connector device (ACD) to perform the proximal aortosaphenous anastomosis. We have been investigating tools that quantify the risk of early vein graft thrombosis after off-pump CAB on the basis of the Virchow triad of hypercoagulability, endothelial disease, and low conduit flow. These tools were applied in this prospective trial of a heterogeneous group of patients with varying degrees of aortic disease and who received the Symmetry ACD. After controlling for the Virchow risk factor triad, we hypothesized that the ACD does not independently influence graft thrombosis. There was no statistically significant difference in the early thrombosis rates of vein grafts connected with an ACD versus hand-sewn grafts (6.7% versus 6.5%). We found a wide range of graft flow measurements, platelet function, and vein endothelial phenotypes in patients with traditionally hand-sewn vein grafts and with grafts connected with an ACD in patients with a wide range of ascending aortic atherosclerosis. The perioperative combination of platelet hyperreactivity, marginal graft flow, and endothelial disease proved to be highly predictive of early graft failure as seen with postoperative computed tomographic angiography.

Is aprotinin safe to use in a cohort at increased risk for thrombotic events: results from a randomized, prospective trial in off-pump coronary artery bypass.

BACKGROUND: Multiple randomized trials have established a favorable safety profile for aprotinin use during cardiac surgery, but recent database analyses suggest an increased risk of adverse thrombotic events. Our group previously demonstrated that off-pump coronary artery bypass (OPCAB) is linked to a postoperative hypercoagulable state. In this study, we tested whether aprotinin influences thrombotic events after OPCAB. METHODS: Patients randomly received saline (n = 61) or aprotinin (2 x 10(6) kallikrein inhibiting units (KIU) loading dose, 0.5 x 10(6) KIU/hour [n = 59]) during OPCAB. Aprotinin levels (KIU/mL) were analyzed before, and 30 minutes (peak) and 4 hours after the loading dose. Estimated glomerular filtration rate (eGFR) was calculated daily based on Cockcroft equation with acute kidney injury (AKI) defined as eGFR less than 75% of baseline. Major adverse cardiac and cerebrovascular events (MACCE) were monitored during the first year, including acute graft failure by predischarge computed tomographic angiography. RESULTS: Compared with placebo, the aprotinin group developed a significantly lower eGFR on day 3 (p < 0.006), but this difference resolved by day 5. Peak aprotinin level correlated with the degree of eGFR decline noted on day 3 (r = 0.56, p < 0.03) and independently predicted postoperative AKI (odds ratio 8.8, p < 0.008). The receiver operating characteristic analysis demonstrated that peak aprotinin level strongly predicts AKI (area under the curve = 0.86, 95% confidence interval 0.69 to 1.00). The percentage of patients reaching the composite MACCE endpoint was significantly reduced in the aprotinin versus placebo group (12 vs 34%, p = 0.01). CONCLUSIONS: Compared with placebo, aprotinin use was associated with less MACCE but more AKI after OPCAB. The strong relationship between the peak aprotinin level and subsequent AKI suggests weight-based protocols for dosing aprotinin may reduce this risk.

Harmonic scalpel versus electrocautery for harvest of radial artery conduits: reduced risk of spasm and intimal injury on optical coherence tomography.

OBJECTIVE: Vasospasm is the primary obstacle to widespread adoption of the radial artery as a conduit in coronary artery bypass grafting. We used optical coherence tomography, a catheter-based intravascular imaging modality, to measure the degree of radial artery spasm induced by means of harvest with electrocautery or a harmonic scalpel in patients undergoing coronary artery bypass grafting. METHODS: Radial arteries were harvested from 44 consecutive patients with a harmonic scalpel (n = 15) or electrocautery (n = 29). Vessels were imaged before harvesting and after removal from the arm, with saphenous vein tracts serving as internal controls. Optical coherence tomographic findings for the degree of harvesting-induced injury were validated against histologic measures. RESULTS: Optical coherence tomographic measures of endovascular dimensions and injury correlated strongly with histologic findings. Mean luminal volume, a measure of vasospasm, decreased significantly less after harvesting with a harmonic scalpel (9% +/- 7%) than with electrocautery (35% +/- 6%, P = .015). Completely intact intima was present in 11 (73%) of 15 radial arteries harvested with a harmonic scalpel (73%) compared with 9 of 29 arteries harvested by means of electrocautery (31%, P = .011). Intraoperative flow measurements and patency rates at 5 days postoperatively were not significantly different among groups. CONCLUSIONS: Optical coherence tomography provides a level of speed and accuracy for quantifying endothelial injury and vasospasm that has not been described for any other modality, suggesting potential as an intraoperative quality assurance tool. Our optical coherence tomographic findings suggest that the harmonic scalpel induces less spasm and intimal injury compared with electrocautery.

Perioperative management of aspirin resistance after off-pump coronary artery bypass grafting: possible role for aprotinin.

BACKGROUND: Aspirin is the only drug proven to reduce saphenous vein graft (SVG) failure, but aspirin resistance (ASA-R) frequently occurs after off-pump coronary artery bypass grafting (OPCAB). The factors, mechanism, and best means for preventing and/or treating ASA-R have not been established. This study hypothesizes that thrombin production during OPCAB stimulates this acquired ASA-R. STUDY DESIGN AND METHODS: A nonrandomized prospective cohort of 255 patients (n=465 SVG) who underwent OPCAB with varied use of aprotinin (21%) and different SVG preparation techniques (standard, 56% vs. low-pressure, 44%) was analyzed. A surplus SVG segment was obtained to assess endothelial integrity. ASA-R was determined at baseline, after surgery, and on Days 1 and 3 by three assays. The effects of aprotinin on thrombin responsiveness were analyzed by means of whole-blood aggregometry, SVG tissue factor (TF) activity, and transcardiac thrombin production (i.e., F1.2 levels in aorta versus coronary sinus). SVG patency was assessed on Day 5 with multichannel CT angiography. RESULTS: ASA-R developed in 42 percent of patients after OPCAB. Multivariate analysis showed that ASA-R, endothelial integrity, and target size independently predicted early SVG failure. Aprotinin use was associated with: 1) reduced postoperative ASA-R (15%); 2) decreased platelet (PLT) response to thrombin; 3) reduced TF activity within SVG segments; 4) decreased transcardiac thrombin gradient; and 5) improved SVG patency. CONCLUSION: ASA-R is a common post-OPCAB event whose frequency may be reduced by intraoperative use of aprotinin, possibly via TF and thrombin suppression. Improved perioperative PLT function after OPCAB may also inadvertently enhance the clinical relevance of these potential antithrombotic effects.

Transmyocardial Laser Revascularization Enhances Blood Flow within Bypass Grafts.

OBJECTIVE: : Early benefits from transmyocardial laser revascularization (TMR) may be related to acute sympathetic denervation. This study hypothesized that TMR as an adjunct to off-pump coronary artery bypass (OPCAB) would improve myocardial runoff in the TMR-treated regions and increase graft flow. METHODS: : Graft blood flow was measured in 145 consecutive OPCAB patients. In patients with graft flow <40 mL/min (n = 25), the myocardial region served by the graft was treated with TMR. Blood flow was reassessed 10 minutes after TMR and compared with graft flow in the nontreated regions. Postoperative outcomes, transcardiac thrombin production, coagulation activation, myocardial, and inflammatory markers were assessed. A control group not treated with TMR (n = 14) was selected with similar graft flows and other baseline characteristics. RESULTS: : Risk factors, comorbidities, and preoperative medications were similar in all groups. TMR led to a 48% increase in bypass graft flow in 12 patients, but no significant change in flow in the remainder (n = 13). The control group also showed no change in graft flow measured during the same time-points. Compared with those that did not respond to TMR, responders showed a greater drop in pH during warm ischemia caused by distal anastomoses during OPCAB and significantly higher transcardiac gradients of F1.2, IL-8, TNFα, and VCAM. CONCLUSIONS: : TMR acutely improves venous bypass graft flow in regions with more severe myocardial acidosis and inflammation during and after OPCAB. Acute sympathetic denervation after TMR may provide mechanistic insight into the early clinical benefits of TMR as an adjunct to OPCAB.

Catheter-based infrared light scanner as a tool to assess conduit quality in coronary artery bypass surgery.

OBJECTIVES: Endothelial disruption within saphenous vein and radial artery grafts increases thrombosis risk. However, no clinically applicable method for imaging the intima currently exists. We used a novel infrared imaging technology, optical coherence tomography (OCT; LightLab Imaging, Inc, Westford, Mass), to visualize the intima within harvested conduits. METHODS: Conduits were procured endoscopically (37 saphenous vein grafts and 8 radial artery grafts) or with the open technique (9 radial artery grafts) from 50 patients. Surplus segments were analyzed by means of OCT for evidence of preexisting pathology or traumatic injury. Focal plaques in radial artery grafts and the intimal hyperplasia area in saphenous vein grafts were quantified as having an intimal/medial thickness ratio of greater than 0.5. Biopsy specimens were obtained for histologic confirmation and to analyze matrix metalloproteinase 2 levels (saphenous vein grafts) and prostacyclin/nitric oxide metabolites (radial artery grafts). Interobserver kappa coefficients and a Bland-Altman analysis were used to determine the reproducibility and accuracy of OCT interpretations. RESULTS: Radial artery imaging revealed plaque in 76%. Endoscopically harvested vessels showed intraluminal clot (38%) and intimal tears ranging from severe (6%) to mild (88%). In saphenous vein grafts intimal thickening was detected in 86% and intraluminal clotting in 68%. The intimal/medial thickness ratio determined by means of OCT correlated directly with matrix metalloproteinase 2 levels (R = 0.6804) in saphenous vein grafts and inversely with metabolites of prostacyclin (R = -0.55) and nitric oxide (R = -0.58) in radial artery grafts. OCT imaging was reproducible (interobserver kappa coefficients of >0.81 for the characterization of plaque types) and showed a strong correlation with histology (R = 0.8, P < .001). CONCLUSIONS: OCT imaging provides an accurate, real-time, and reproducible means for assessing saphenous vein graft and radial artery graft bypass conduits. As a quality assurance tool, this technology might afford a more objective basis for conduit selection.

Heart preservation using continuous ex vivo perfusion improves viability and functional recovery.

BACKGROUND: Cold static storage (CS) is a proven preservation method for heart transplantion, yet early postoperative graft dysfunction remains prevalent, so continuous perfusion (CP) during ex vivo transport may improve viability and function of heart grafts. METHODS AND RESULTS: Canine hearts underwent CP (n=9) or CS (n=9) for 6 h while intramyocardial pH was continuously monitored. Biopsies were assayed for ATP, caspase-3, malondialdehyde (MDA), and endothelin-1 (ET-1) levels at baseline, after preservation (t1), and after 1 h of blood reperfusion on a Langendorff model (t2). Functional recovery was determined at t2 by +dP/dt, -dP/dt, developed pressure, peak pressure and end-diastolic pressure. CP resulted in higher tissue pH and ATP stores and reduced caspase-3, MDA and ET-1 levels compared with CS at both t1 and t2. Post reperfusion recovery was significantly greater in CP vs CS for all myocardial functional parameters except end-diastolic pressure. Weight gain was significantly increased in CP vs CS at t1, but not at t2. CONCLUSIONS: Low-grade tissue acidosis and energy depletion occur during CS and are associated with oxidative injury and apoptosis during reperfusion. CP attenuates these biochemical and pathologic manifestations of tissue injury, together with improved myocardial recovery, despite mild, transient edema.

Use of diffusion tensor imaging to predict myocardial viability after warm global ischemia: possible avenue for use of non-beating donor hearts.

BACKGROUND: The assessment of myocardial viability after global warm ischemia (WI) but before reperfusion is challenging. We hypothesized that fractional anisotropy (FA), a magnetic resonance imaging (MRI) parameter of water diffusion that characterizes cellular integrity within tissues, provides a rapid and useful method for evaluating the viability of hearts after WI. METHODS: Dog hearts were exposed to 60 minutes of WI after exanguination, explanted and preserved in a cold, non-beating state for 6 hours, using continuous perfusion (CP) or static cold storage (CS). Toward the end of preservation, a global FA assessment, acquired using MRI, was compared with analyses obtained from myocardial biopsies that included adenosine triphosphate (ATP), endothelin-1 (ET-1) and caspase-3 levels, light microscopy and tetrazolium staining. Functional recovery was analyzed after restoration of blood flow on a non-working Langendorff preparation. RESULTS: FA measured at the end of CP showed strong correlations with all parameters of functional recovery (developed pressure, R = 0.60; dP/dt, R = 0.96; -dP/dt, R = 0.96). Although FA also correlated with tissue levels of ATP, ET-1 and caspase-3 (R = 0.77, -0.84, -0.64), recovery of myocardial function did not correlate with these markers or any other conventional analyses of myocardial injury (troponin I, changes on light microscopy or tetrazolium staining). CONCLUSIONS: FA, an MRI-based parameter that indicates cellular integrity, was found to reflect better myocardial ATP stores, less induction of ET-1 and caspase-3 and improved functional recovery of hearts after global WI. As a clinically applicable tool capable of rapidly differentiating reversible from lethal injury, diffusion tensor imaging may prove useful in the eventual adoption of non-beating donor hearts for transplantation.

The role of preexisting pathology in the development of neointimal hyperplasia in coronary artery bypass grafts.

OBJECTIVE: Saphenous vein grafts (SVG) used for coronary artery bypass surgery (CABG) often develop a gradual luminal narrowing over the first year due to neointimal hyperplasia (NH). Although the basic science of NH is well studied, our clinical understanding of this issue is limited. The purpose of this cohort study was to investigate clinical risk factors for NH by monitoring luminal narrowing within SVG using multichannel CT angiography (CTA). METHODS: Thirty patients underwent CABG involving SVG (N = 44) and arterial grafts (N = 36). Patient variables were recorded and the baseline quality of each conduit determined intraoperatively by analyzing surplus segments for intima-media thickness ratio (IMT) by histology and matrix metalloproteinase-2 by enzyme-linked immunosorbent assay. Percent luminal narrowing (%LN) was calculated for each patent graft by comparing the CTA appearance on day 5 to a repeat study at 1 y. RESULTS: Compared with arterial grafts, SVG showed significantly higher IMT at baseline (0.9 +/- 0.65 versus 0.22 +/- 0.17, P < 0.0001) and more %LN over the first year (6.9 +/- 7.5 versus 25.3 +/- 13.3% LN, P< 0.0001). Of all of the measured variables, the only significant predictors of %LN included baseline IMT (r = 0.58, P = 0.002) and matrix metalloproteinase-2 levels (r = 0.60, P = 0.002) in SVG. CONCLUSIONS: The degree of NH at baseline, a phenomenon exclusive to SVG and not found in arterial grafts, was significantly related to the development of lumen loss in the conduit over the first year after CABG. The study of SVG using serial CTA may provide unique insights into the natural history of SVG remodeling and to identify factors that influence the long-term function of this conduit.

Role of procurement-related injury in early saphenous vein graft failure after coronary artery bypass surgery.

Saphenous vein graft thrombosis after coronary artery bypass graft surgery is a poorly understood problem that lessens the benefits of this procedure. Recent studies highlight the importance of injury sustained at the time of saphenous vein graft procurement in the pathogenesis of acute graft thrombosis. In particular, damage to the graft endothelium that occurs secondary to ex vivo pressure distention, a common practice during vein harvest, leads to a loss of antithrombotic factors and increased activity of subendothelial prothrombotic factors. The prothrombotic potential of damaged grafts is further exacerbated by an ischemic storage interval and subsequent exposure to arterial flow conditions after grafting. A clearer understanding of the mechanisms by which endothelial disruption leads to acute saphenous vein graft thrombosis may result in interventions for improving our procurement techniques, interrupting the downstream effects of the damaged saphenous vein graft and/or discriminating damage that is beyond an acceptable threshold of thrombotic risk.

Aprotinin shows both hemostatic and antithrombotic effects during off-pump coronary artery bypass grafting.

BACKGROUND: Hemostatic drugs are widely thought to be unnecessary and potentially detrimental in off-pump coronary artery bypass graft surgery (OPCABG), despite well-established use in on-pump surgery. In a randomized, prospective OPCABG trial, we assessed efficacy and safety of aprotinin through a comprehensive assessment of graft patency and hematologic function. METHODS: Sixty patients were randomly assigned to full-dose aprotinin or placebo. Heparin was titrated to a kaolin-based activated clotting time of greater than 300 seconds. Exclusionary criteria included creatinine greater than 2 mg/dL, conversion to on-pump CABG, and preoperative GPIIb/IIIa inhibition. Hematologic assessments were obtained preoperatively, at the end of surgery, and on days 1 and 3: mean platelet volume, thrombin generation (prothrombin fragment 1.2 assay), and aspirin resistance using a modified thrombelastography, whole blood aggregometry, 11-dehydro-thromboxane B2 levels, and flow cytometry. Thrombotic events were defined as postoperative myocardial infarction by electrocardiography or elevated troponin I, clinical stroke by examination and head computed tomography, and bypass graft failure by multichannel computed tomography angiography on day 5. RESULTS: Aprotinin was associated with a significant reduction in intraoperative and postoperative blood loss compared with placebo but had no effect on transfusion rates. Patients treated with aprotinin had significantly fewer thrombotic events (3% versus 23%, p < 0.05, Fisher's exact test) and less postoperative aspirin resistance (20% versus 46%, respectively, p < 0.05, Fisher's exact test). Postoperative prothrombin fragment 1.2 level was reduced by aprotinin use. CONCLUSIONS: Aprotinin reduced perioperative bleeding after OPCABG. Preserved aspirin sensitivity in the aprotinin group may explain the observed reduction in thrombotic events and might be related to the suppression of perioperative and transmyocardial thrombin formation.

Endothelial injury and acquired aspirin resistance as promoters of regional thrombin formation and early vein graft failure after coronary artery bypass grafting.

OBJECTIVE: The predominant mechanism of early graft failure after coronary artery bypass grafting remains in doubt. Aspirin administered in the initial hours after coronary artery bypass grafting improves graft patency, implicating prostanoid synthesis in the pathogenesis. We hypothesized that synergy between endothelial disruption in the venous conduit and aspirin resistance would cause vein graft failure. METHODS: Aspirin resistance, defined by diagnostic findings on at least two of three separate assays, was serially assessed in 225 patients undergoing off-pump coronary artery bypass grafting. Endothelial cell integrity was determined in surplus segments obtained from 408 vein grafts. The deposition of intraluminal thrombin within the vein was determined by comparing serum F1.2 levels between the coronary sinus and the aorta after grafting. Intraoperative blood flow in the grafts was measured with transit-time technology, and patency was assessed with electrocardiographically gated multichannel computed tomographic coronary angiography on day 5. Aspirin was the sole antithrombotic agent used during the study. RESULTS: Thrombosed grafts (16/408) showed more endothelial cell loss at the time of grafting than did those grafts that remained patent (10.8% +/- 21.5% vs 51.4% +/- 39.1% integrity, P < .01). Aspirin resistance occurred in 67 patients (30%). Graft thrombosis was associated with aspirin resistance (P < .04) and reduced endothelial integrity (P < .01). These factors coexisted in 14 of 16 grafts that failed and were associated with elevated coronary sinus F1.2 levels. CONCLUSION: Aspirin resistance and relatively compromised venous endothelial cell integrity together marked patients whose vein grafts failed within days after off-pump coronary artery bypass grafting. These observations form a basis for identifying patients at risk and developing approaches to prevent vein injury or to selectively intervene in high-risk circumstances.

Disruption of graft endothelium correlates with early failure after off-pump coronary artery bypass surgery.

BACKGROUND: Saphenous vein graft failure after coronary artery bypass surgery may be as high as 5% to 10% in the first postoperative week. We hypothesized that identifying damage sustained by saphenous vein endothelium before grafting predicts early graft attrition after off-pump coronary artery bypass graft surgery. METHODS: Intraoperative graft flow, platelet function, and endothelial integrity were analyzed in 125 patients undergoing off-pump coronary artery bypass graft surgery. Endothelial integrity was assessed in an excess vein segment from each graft using immunohistochemistry (CD31 staining). Platelet function was monitored just before and immediately after revascularization and on postoperative days 1 and 3 using whole blood aggregometry, thrombelastography, and platelet activated clotting time. Platelet activation was monitored using flow cytometry. Intraoperative conduit blood flow, measured by transit time ultrasonography, was used to detect and rectify anastomotic problems. Early graft patency was determined on postoperative day 5 using gated multichannel computed tomography angiography. RESULTS: In 106 patients undergoing postoperative computed tomography evaluation, 10 vein grafts in 10 patients were discovered to have developed early thrombosis, representing 4% (10 of 217) of all vein grafts. Endothelial integrity was 10.75% +/- 17.56% in 10 grafts that failed early compared with 51.45% +/- 36.29% in patent grafts (p = 0.04). Perioperative platelet function and graft flow did not differ significantly between the two groups. CONCLUSIONS: Although endothelial disruption predicts early failure of bypass grafts, the importance of a hypercoaguable state and low graft flow as a cause of early graft thrombosis after off-pump coronary artery bypass graft surgery was not supported by our preliminary results. A means to assess, prevent, and treat intraoperative vein graft damage will likely improve early graft patency.

Hypercoagulability affecting early vein graft patency does not exist after off-pump coronary artery bypass.

OBJECTIVE: Hypercoagulability may compromise the patency of bypass grafts. The authors hypothesized that perioperative in vitro platelet responses to varying agonists (eg, thrombin, platelet activating factor, collagen, adenosine diphosphate) correlate with early graft thrombosis after off-pump coronary artery bypass grafting (OPCAB). DESIGN AND PARTICIPANTS: Prospective study of 78 OPCAB patients with 151 venous bypass grafts treated with perioperative aspirin and intraoperative heparin (250 U/kg). SETTING: Tertiary, academic medical center. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Hypercoagulability, defined by TEG (maximum amplitude [MA]>70 mm), whole-blood aggregometry (>15 ohms after 5 mcl/mL collagen) or hemoSTATUS (Ch5CR>0.5), was serially assessed around OPCAB. An immediate decline in platelet function after surgery and on postoperative day 1 returned to normal by postoperative day 3 in most patients. Graft blood flow was analyzed intraoperatively, and vein biopsies were analyzed for endothelial disruption. Graft patency was assessed by multichannel computed tomography coronary angiography on postoperative day 5. No differences in any of the platelet function assays were noted for the 8 patients with graft thrombosis (n=8 grafts) versus the 68 patients with all patent grafts (n=129 grafts). Ten patients developed a rise in platelet function postoperatively >1 SD above baseline; only 1 developed graft thrombosis (p=not significant v patients with normal platelet function). CONCLUSIONS: OPCAB is not associated with a significant activation in postoperative platelet function. This study suggests that if hypercoagulability exists after OPCAB, it is not involved in the pathogenesis of arterial thrombotic events such as early bypass graft failure.

Optimizing donor heart outcome after prolonged storage with endothelial function analysis and continuous perfusion.

BACKGROUND: By minimizing tissue ischemia, continuous perfusion (CP) during organ transport may increase the safety of "marginal donors." My colleagues and I investigated whether an analysis of donor heart viability predicts recovery of grafts challenged with a 24-hour preservation interval. METHODS: Dog hearts underwent cold static storage (CS) for 8 hours (n = 8) or 24 hours (n = 2) or CP for 24 hours with cold asanguinous, oxygenated solution (n = 8). Myocardial systolic and diastolic function and oxygen and lactate consumption were assessed at base line, during CP, and after Langendorff blood reperfusion. Base line endothelial function was evaluated by the percentage transcoronary change ([coronary sinus - aorta]/aorta) in myeloperoxidase and by platelet function and coronary flow reserve after 20 seconds of coronary artery occlusion. During CP, the endothelium was assessed by transcoronary protein release and coronary resistance. Edema was assessed by weight gain and histology. RESULTS: Base line systolic and metabolic functions showed no relation to post-Langendorff function. Compared with CS, CP resulted in a greater recovery in systolic function (87% +/- 35% vs 65% +/- 15% of baseline; p = 0.05) and a shorter interval required for lactate consumption to exceed production (7.0 +/- 6.8 minutes vs 15.0 +/- 8.9 minutes; p = 0.06). Endothelial function was heterogeneous: coronary flow reserve, 2.7 +/- 0.7; percentage change in myeloperoxidase, -8.4% +/- 6.8%; and change in platelet function, 4.3% +/- 3.5%, as determined by thromboelastography angle at base line. Protein release during CP for 24 hours was 8.3 +/- 7.1 g. Two factors predicted more than 75% systolic pressure generation recovery: use of CP and normal endothelial function (p = 0.05; Fisher's exact test). However, CP led to edema according to histology, weight gain (72 +/- 29 g), and impaired diastolic function versus CS (end-diastolic pressure-volume relationship, 1.4 +/- 0.4 mm Hg/mL vs 0.8 +/- 0.3 mm Hg/mL; p = 0.08). CONCLUSIONS: Better systolic function despite 16 hours' more preservation than cold storage corroborates the idea that CP supports aerobic metabolism at physiologically important levels. Viability analysis focused on endothelial function and identified organs that were able to tolerate this 24-hour preservation interval.