[Show abstract][Hide abstract] ABSTRACT: Off-pump coronary artery bypass (OPCAB) surgery is associated with a hypercoagulable state in which the platelet thrombin receptor, protease-activated receptor-1 (PAR-1), helps propagate a thrombin burst within saphenous vein grafts. Aprotinin, used in cardiothoracic surgery mainly for its antifibrinolytic properties, also spares platelet PAR-1 activation due to thrombin. We hypothesized that this PAR-1 antagonistic property provides an antithrombotic benefit during OPCAB surgery.
Patients were randomly assigned to receive saline (n = 38) or a modified full-dose regimen of aprotinin (n = 37) IV during OPCAB surgery. Blood sampled perioperatively from the coronary sinus, skin wounds, and systemic circulation was analyzed to test coagulation and platelet function. Major adverse cardiovascular events were monitored by obtaining troponin I at 24 h (myocardial infarction), predischarge computed tomography angiography (vein graft thrombosis), and by clinical examination for stroke.
Coronary sinus blood obtained immediately after OPCAB surgery showed significantly less activation in the aprotinin group, as judged by reduced formation of platelet-leukocyte conjugates (P < 0.02) and platelet-derived microparticles (P < 0.05). The aprotinin group showed inhibition of platelet aggregation induced by thrombin (P = 0.007) but not adenosine diphosphate. Thrombin generation, defined by F1.2 levels, was significantly reduced by aprotinin in the coronary sinus but not in skin wound incisions. Major adverse cardiovascular events were significantly reduced in aprotinin-treated patients (5.4% vs 29.7%, P < 0.05). Aprotinin also demonstrated antifibrinolytic properties through diminished red blood cell transfusion (P < 0.04) and reduced blood loss postoperatively (603 +/- 330 vs 810 +/- 415 mL, P < 0.004).
This study demonstrates that aprotinin protects patients undergoing OPCAB surgery from a hypercoagulable state by diminishing thrombin-induced platelet activation and thrombin generation within saphenous vein grafts, while maintaining systemic hemostatic and antifibrinolytic benefits. These results support further investigation of aprotinin and other PAR-1 antagonists in OPCAB surgery.
Anesthesia and analgesia 11/2009; 109(5):1387-94. DOI:10.1213/ANE.0b013e3181b81068 · 3.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The radial artery's (RA) tendency to spasm when used as a bypass graft may relate to features of the RA itself. We imaged RA conduits before and after CABG in order to characterize intimal abnormalities that might relate to the risk of spasm.
RA conduits from thirty-two CABG patients were imaged intraoperatively using catheter-based optical coherence tomography (OCT) and again on day 5 using 64-channel MDCT angiography. The change in luminal diameter between timepoints was measured in the proximal, mid and distal RA. "Spasm" was defined as focal or diffuse luminal narrowing to a diameter less than the target coronary. Lipid content in the RA was quantified by the degree of light attenuation on the OCT image.
Postoperative spasm was diagnosed in 18 of 32 (56%) RA grafts with the distal RA showing the most severe change versus the mid and proximal portions (-24.1+/-43.2% vs. -15.3+/-40.7%, -9.0+/-42.5% change in diameter respectively, p<0.01). The degree of attenuation of the OCT signal produced by the RA was strongly correlated with % diameter change (R=0.64, p=0.0005) and was significantly more pronounced in grafts with spasm versus no spasm (-1.97+/-0.61mm(-1) vs. -0.81+/-0.57mm(-1), p<0.0001). Histology confirmed lipid deposits in areas of RA with strong attenuation.
RA conduits otherwise considered acceptable for bypass grafting were often found by OCT imaging to have a substantial amount of lipid, which in turn strongly relates to the risk of postoperative spasm. Screening conduits based on characteristics of intimal quality may improve results following RA grafting.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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).
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.
The Annals of thoracic surgery 10/2008; 86(3):815-22; discussion 815-22. DOI:10.1016/j.athoracsur.2008.04.047 · 3.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Concerns about intimal disruption and spasm have limited enthusiasm for endoscopic radial artery harvest (ERAH), although the risk of these problems after this procedure remains uncertain. Radial artery conduits were screened intraoperatively before and after ERAH vs open harvest using catheter-based high-resolution optical coherence tomography (OCT) imaging.
Twenty-four cadavers and 60 coronary artery bypass graft (CABG) patients scheduled to receive a RA graft underwent OCT imaging before (in situ) and after (ex vivo) open harvest or ERAH. Spasm was quantified by the percentage change in luminal volume between images. Intimal disruption was classified as minor or severe depending on whether the defect was confined to branch ostia or involved the luminal surface. Histology was used to confirm OCT findings.
Luminal volume significantly declined after harvest in all RAs from CABG patients, but there was no difference between groups: -43% +/- 29% vs -35% +/- 38% change after ERAH (n = 21) vs open harvest (n = 39; p = 0.342). Significantly more intimal injury was noted after ERAH vs open harvest (34/41 vs 9/43, intimal tears/total evaluated RAs, p < 0.0001). Most intimal injury was minor: only 2 tears involved the luminal surface of the RA (both after ERAH). Serial imaging in cadavers revealed that 86% of ostial tears occur in ERAH during the initial blunt dissection step using the endoscope.
Although branch injury is a pitfall of ERAH, OCT imaging documented that the quality of RA procured is acceptable and comparable with open harvest. Catheter-based OCT provides an important quality assurance tool for RA harvest.
The Annals of thoracic surgery 04/2008; 85(4):1271-7. DOI:10.1016/j.athoracsur.2007.12.044 · 3.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Less-invasive options are available for surgical treatment of multivessel coronary artery disease. We hypothesized that stenting combined with grafting of the left anterior descending artery with the left internal thoracic artery through a minithoracotomy (hybrid procedure) would provide the best outcome.
Patients with equivalent numbers of coronary lesions (2.8 +/- 0.4) underwent either hybrid (n = 15) or off-pump coronary artery bypass through a sternotomy (n = 30). Early and 1-year outcomes were compared. Blood drawn from the aorta and coronary sinus immediately postoperatively was analyzed for activation of coagulation (prothrombin fragment 1.2 and activated Factor XII), myocardial injury (myoglobin), and inflammation (interleukin 8) by using an enzyme-linked immunosorbent assay. Target-vessel patency was determined by means of computed tomographic angiographic analysis.
The hybrid procedure was associated with significantly shorter lengths of intubation and stays in the intensive care unit and hospital and perioperative morbidity (P < .05). Intraoperative costs were increased but postoperative costs were reduced for the hybrid procedure compared with off-pump coronary artery bypass through a sternotomy. As a result, overall total costs were not significantly different between the groups. After adjusting for potential confounders, assignment to the hybrid group was an independent predictor of shortened time to return to work (t = -2.12, P = .04). Patient satisfaction after the hybrid procedure, as judged on a 6-point scale, was greater versus that after off-pump coronary artery bypass through a sternotomy. Finally, the hybrid procedure showed significantly reduced transcardiac gradients of markers of coagulation, myocardial injury, and inflammation and a trend toward significant improvement in target-vessel patency.
Perhaps because of reduced myocardial injury, inflammation, and activation of coagulation, patients undergoing the hybrid procedure had better perioperative outcomes and satisfaction, with excellent patency at 1 year's follow-up. These promising preliminary findings warrant further investigation of this procedure.
The Journal of thoracic and cardiovascular surgery 03/2008; 135(2):367-75. DOI:10.1016/j.jtcvs.2007.09.025 · 3.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Accumulating evidence suggests that a hypercoagulable state influences early graft failure after off-pump coronary artery bypass (OPCAB). We hypothesized that regional myocardial ischemia caused by obligatory periods of coronary occlusion during OPCAB is an important trigger for this prothrombotic state.
Using a series of biomarkers, 60 consecutive patients undergoing OPCAB were monitored for myocardial injury (myoglobin), inflammation (TNF-alpha, IL-8) and thrombosis (thrombin generation-F1.2, contact activation pathway-FXII-a, platelet derived microparticles-via flow cytometry). The transcardiac gradients of these markers were determined by assaying both arterial and coronary sinus blood just after protamine administration. Intramyocardial pH was monitored continuously during coronary occlusion in a subset (N=30 grafts, 11 patients). The influence of management strategies affecting hemostasis (e.g. antiplatelet therapy, anti-fibrinolytics, peak activated clotting time (ACT) during heparinization) was analyzed.
Ischemic injury, depicted by the transcardiac myoglobin gradient, significantly correlated with intramyocardial acidosis during coronary occlusion (R=0.96, p<0.0001) and predicted the transcardiac gradients of TNF-alpha (R=0.83, p<0.001) and F1.2 (R=0.72, p<0.0001). Transcardiac F1.2 strongly correlated with TNF-alpha (R=0.73, p=0.01) and IL-8 (R=0.51, p=0.02). Patients receiving aprotinin (N=20) showed significantly lower transcardiac gradients for myoglobin (4.1+/-7.5% vs 72.9+/-108.8% change, p=0.002), F1.2 (31+/-37% vs 89+/-149%, p=0.03), FXII-a (2.6+/-4.1% vs 19.2+/-34%, p=0.04) and microparticles (7+/-3.9% vs 12.9+/-8%, p=0.01).
Strong correlations between myocardial ischemia and the transcardiac gradients of markers for inflammation and thrombosis suggest that even brief episodes of coronary occlusion in the beating heart may have pathophysiologic consequences. Aprotinin, but not other factors that influence the coagulation system, appears to mitigate this process during OPCAB.
European Journal of Cardio-Thoracic Surgery 03/2008; 33(2):215-21. DOI:10.1016/j.ejcts.2007.11.008 · 2.81 Impact Factor