Citations

Background Thrombin plays an important role in the pathogenesis of acute coronary thrombosis. We studied the effects of a direct thrombin inhibitor, recombinant desulfatohirudin, and heparin on plasma levels (at 0, 4, 12, and 24 hours) of fibrinopeptide A (FPA), which reflects thrombin action, and prothrombin fragment F1.2, which reflects thrombin generation, in patients with unstable angina. Methods and Results Patients were randomized to one of two doses of heparin (n=50) (target activated partial thromboplastin time, 65 to 90 seconds or 90 to 110 seconds) or one of four doses of r-hirudin (n=113) (0.05, 0.10, 0.20, or 0.30 mg·kg −1 ·h −1 by infusion). r-Hirudin induced a dose-dependent decline in plasma FPA. At 24 hours, FPA levels with 0.1- to 0.3-mg·kg −1 ·h −1 r-hirudin regimens were significantly lower than with 0.05 mg·kg −1 ·h −1 r-hirudin; levels with 0.1- to 0.2-mg·kg −1 ·h −1 r-hirudin regimens were lower than with both heparin regimens. Plasma F1.2 did not decline significantly during therapy with heparin or hirudin except at 0.3 mg·kg −1 ·h −1 hirudin. At 24 hours, they were higher with the 0.05-mg·kg −1 ·h −1 r-hirudin regimen than with other regimens. For comparable levels of thrombin generation (F1.2 levels), FPA levels were higher in heparin patients than in hirudin patients. For the same FPA values, the corresponding F1.2 values were higher in the hirudin group. Conclusions Our findings provide evidence for distinct in vivo effects of the two agents and suggest that r-hirudin is a relatively more potent inhibitor of thrombin action but a less effective inhibitor of thrombin generation than heparin. The lower FPA levels in hirudin patients may reflect its ability to inactivate clot-bound thrombin. The relative clinical efficacies of the two agents need to be defined by clinical trials in progress.

Background Fibrin- and platelet-rich thrombus formations occur as the initial event after percutaneous transluminal coronary angioplasty. We therefore tested the hypothesis that short-term administration of the recombinant tick anticoagulant peptide (rTAP), a factor Xa inhibitor, would reduce the thickness of neointima at 28 days after injury in a porcine coronary balloon angioplasty model. Methods and Results Continuous intravenous infusion of rTAP (average dose, 194 μg·kg −1 ·min −1 ) or placebo (vehicle only) was given to the study pigs for 60 hours. The goal of anticoagulation was to maintain the activated clotting time at 200 seconds. A central venous catheter was inserted 2 days before the procedure. On the day of coronary injury, the animals were administered boluses of rTAP (6.5 mg) and then underwent injury with an oversized metallic coil by standard methods in the right, circumflex, or left anterior descending coronary artery. No significant difference in vascular injury between rTAP and vehicle control was observed after euthanasia at 28 days. Significantly less neointimal thickening occurred in the rTAP-treated animals (thickness, mean±SD: 0.30±0.08 mm) compared with the control (0.48±0.12 mm, P <.001). Conclusions The specific factor Xa inhibitor rTAP, when given in fully anticoagulant doses for a short duration after coronary artery injury in the porcine model, resulted in a long-term decrease in neointimal thickness. These results implicate thrombin generation in neointimal formation and suggest that administration of a potent antithrombotic for several days immediately after the procedure may influence the long-term outcome of the coronary injury with a decrease in neointimal formation.

BackgroundNumerous studies have demonstrated the ability of angiotensin II (Ang II) receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors to inhibit intimal hyperplasia after balloon dilatation of noncoronary arteries in small-animal models, suggesting an important role for Ang II in the response to injury. Although ACE inhibitors have not been similarly effective in nonhuman coronary models or in human restenosis trials, questions remain regarding the efficacy of ACE inhibitors against tissue ACE and the contributions of ACE-independent pathways of Ang II generation. Unlike ACE inhibitors, Ang II receptor antagonists have the potential to inhibit responses to Ang II independent of its biosynthetic origin.Methods and ResultsIn separate studies, three Ang II receptor antagonists, including AT1-selective (L-158,809), balanced AT1/AT2(L-163,082), and AT2-selective (L-164,282) agents, were evaluated for their ability to inhibit vascular intimal thickening in a porcine coronary artery model of vascular injury. Preliminary studies in a rat carotid artery model revealed that constant infusion of L-158,809 (0.3 or 1.0 mg·kg−1·d−1) reduced the neointimal cross-sectional area by up to 37% measured 14 days after balloon dilatation. In the porcine studies, animals were treated with vehicle or test compound beginning 2 days before and extending 28 days after experimental angioplasty. Left anterior descending, left circumflex, and/or right coronary arteries were injured by inflation of commercially available angioplasty balloons with placement of coiled metallic stents. Infusion of L-158,809 (1 mg·kg−1·d−1), L-163,082 (1 mg·kg−1·d−1), or L-164,282 (1.5 mg·kg−1·d−1) in the study animals yielded plasma drug levels sufficient either to chronically block or, for L-164,282, to spare pressor responses to exogenous Ang II. Neither L-158,809, L-163,082, nor L-164,282 had statistically significant effects (P=.12,P=.75, andP=.48, respectively, compared with vehicle-treated controls) on neointimal thickness (normalized for degree of injury) measured by morphometric analysis at day 28 after angioplasty.ConclusionsThese findings indicate that chronic blockade of Ang II receptors by either site-selective or balanced AT1/AT2antagonists is insufficient to inhibit intimal hyperplasia after experimental coronary vascular injury in the pig. The results further suggest that, unlike in the rat carotid artery, Ang II is not a major mediator of intimal thickening in the pig coronary artery.

Background Thrombolysis to normal flow in patients with acute myocardial infarction preserves left ventricular function and decreases mortality. Failure of early reperfusion, reocclusion, or residual thrombus may be due to concurrent activation of the platelet-coagulation system. Thus, we hypothesized that the best concomitant antithrombotic therapy (recombinant [r]-hirudin, heparin, or aspirin) will maximally accelerate thrombolysis by r–tissue-type plasminogen activator (rTPA) and reduce residual thrombus. Methods and Results Occlusive thrombi were formed in the carotid arteries of 29 pigs (by balloon dilatation followed by endarterectomy at the site of injury-induced vasospasm) and matured for 30 minutes before rTPA was started, with or without antithrombotic therapy. Thrombolysis was assessed with the use of angiography and measurement of residual thrombus. Pigs were allocated to one of five treatments: placebo, rTPA, rTPA plus r-hirudin, rTPA plus heparin, or rTPA plus intravenous aspirin. No placebo-treated pig reperfused. Two of six animals treated with rTPA alone reperfused compared with seven of seven animals treated with rTPA plus r-hirudin (reperfusion time, 33±10 minutes), six of seven animals treated with rTPA plus heparin (reperfusion time, 110±31 minutes), and two of six animals with rTPA plus aspirin. The activated partial thromboplastin time was prolonged in only the rTPA plus r-hirudin group (25±0.1 times baseline) and the rTPA plus heparin group (5.3±0.2 times baseline). Residual 111 In-platelet and 125 I-fibrin(ogen) depositions were lower in the heparin-treated group and lowest in the r-hirudin–treated group (heparin versus hirudin, respectively; incidence of residual macroscopic thrombus was six of six animals versus two of seven [ P =.01]; 125 I-fibrin(ogen), 170±76 versus 48±6 ×10 6 molecules/cm 2 [ P =.02]; 111 In-platelets, 47±15 versus 13±2 ×10 6 /cm 2 , P =.10). No pigs developed spontaneous bleeding. Conclusions Thrombin inhibition with heparin or r-hirudin significantly accelerated thrombolysis of occlusive platelet-rich thrombosis, but only the best antithrombotic therapy (r-hirudin) eliminated or nearly eliminated residual thrombus.

Background Endothelin (ET), a coronary vasoconstrictor, mediates its activity through the specific receptors ET-A and ET-B, which may demonstrate different activity under pathophysiological conditions. Thoracic inferior vena cava constriction (TIVCC) is an experimental model of congestive heart failure that is characterized by a decrease in cardiac output and an increase in circulating ET concentrations. The present study was designed to test the hypothesis that experimental heart failure altered coronary vascular responsiveness to ET-A– and ET-B–receptor stimulation in vivo. Methods and Results ET-1 was infused at a rate of 2 ng/kg per minute into the left circumflex coronary artery in normal dogs (n=5) and in dogs subjected to TIVCC (TIVCC dogs, n=6). Similarly, sarafotoxin, an ET-B–receptor agonist, was infused at the same dosage in normal (n=5) and TIVCC (n=6) dogs. Intracoronary infusion of ET-1 significantly decreased coronary blood flow and increased coronary vascular resistance in normal dogs; this effect was significantly attenuated in TIVCC compared with normal dogs. The percent changes in coronary blood flow and coronary vascular resistance in the TIVCC compared with the normal dogs was −11±8% versus −48±7% ( P <.01) and 29±10% versus 105±23% ( P <.01), respectively. There was no significant effect on coronary blood flow, coronary vascular resistance, or coronary artery diameter in normal dogs that received an intracoronary infusion of sarafotoxin. In contrast, the administration of intracoronary sarafotoxin in TIVCC compared with normal dogs resulted in significant percent changes in coronary blood flow and coronary vascular resistance (−31±4% versus −7±3% [ P <.001] and 53±12% versus 12±8% [ P <.02], respectively). Conclusions The present study demonstrates an attenuated coronary vasoconstrictor response to ET-1 with an enhanced vasoconstrictor response to sarafotoxin and suggests an alteration in coronary ET receptor sensitivity in experimental heart failure.

Background In patients with mitral regurgitation, surgical intervention produces immediate improvement in symptoms, but the long-term incidence and significance of postoperative congestive heart failure are unknown. Methods and Results The long-term outcome of 576 operative survivors of surgical correction of pure mitral regurgitation performed between 1980 and 1989 was analyzed. Survival was 77±2% and 56±3% at 5 and 10 years, respectively. Cumulative incidence of congestive heart failure was 23±2%, 33±3%, and 37±3% at 5, 10, and 14 years, respectively. Survival after the first episode of congestive heart failure was dismal, 44±4% at 5 years. Cause of congestive heart failure was left ventricular dysfunction in two thirds of the patients and valvular dysfunction in the other third. With multivariate analysis, the independent predictors of postoperative heart failure were preoperative ejection fraction ( P =.0001), coronary artery disease ( P =.0017), and New York Heart Association functional class ( P =.012), with borderline value for atrial fibrillation ( P =.10). The performance of valve repair was independently predictive of a lower incidence of the combined end point of death and heart failure ( P =.001), compared with valve replacement. Conclusions Congestive heart failure frequently occurs late after surgical correction of mitral regurgitation and portends dismal prognosis. This complication is due most often to left ventricular dysfunction; its main determinant is decreased left ventricular function preoperatively. These data should lead to earlier indication of surgical correction of mitral regurgitation, before left ventricular dysfunction occurs.

Background The endothelium modulates vascular tone through release of vasodilating substances, such as endothelium-derived relaxing factors, and vasoconstricting substances, such as endothelin. Endothelin concentrations are elevated in humans with atherosclerosis and in hypercholesterolemic pigs. Furthermore, the endothelium-dependent vasodilator acetylcholine increases endothelin in hypercholesterolemia in association with coronary vasoconstriction. The present study was designed to test the hypotheses that coronary endothelial dysfunction in humans is characterized by enhanced coronary and circulating endothelin and that the vasoconstriction associated with acetylcholine results in further release of coronary endothelin. Methods and Results Coronary and circulating endothelin concentrations were measured at baseline and during intracoronary acetylcholine administration in 20 patients undergoing diagnostic coronary angiography. Patients were divided into two groups on the basis of their response to intracoronary acetylcholine. Group 1 (n=7) demonstrated a normal vasodilatory response, but group 2 (n=13) demonstrated coronary vasoconstriction. Baseline coronary and circulating endothelin concentrations (as determined by coronary sinus and femoral artery measurements, respectively) were higher in patients who responded to acetylcholine with coronary vasoconstriction (group 2) than in group 1 patients (coronary sinus, 15.9±1.0 pg/mL versus 7.1±1.0 pg/mL; femoral, 14.1±0.9 pg/mL versus 6.8±1.0 pg/mL, respectively; P <.01). In response to intracoronary acetylcholine, a further increase in coronary endothelin was observed only in group 2; this increase correlated with changes in coronary artery diameter. Conclusions This study demonstrates that endothelin immunoreactivity is enhanced in the coronary and systemic circulation in humans with coronary endothelial dysfunction. Moreover, acetylcholine further increased coronary endothelin concentration in patients with coronary endothelial dysfunction and was associated with coronary vasoconstriction. These observations strongly support a role for endothelin as an early participant in and marker for coronary endothelial dysfunction in humans.

Background We hypothesized that a simple, unmeasured posterior annuloplasty technique (two thirds of a 27-mm Duran ring) offered advantages of standardization and ease of insertion. Methods and Results A consecutive series of all patients (n=418; median age, 67 years) having mitral valve repair performed by two surgeons was analyzed to determine the outcome of three different annuloplasty techniques: commissural annuloplasty (n=124), complete ring annuloplasty (n=113), and an unmeasured, posterior, partial ring annuloplasty (n=181). Intraoperatively, before repair, severity of mitral regurgitation as measured by double sampling dye curves and transesophageal echocardiography was similar in all three groups; after mitral valve repair, intraoperative assessment showed a similar degree of reduction in regurgitation in the three annuloplasty groups. Before hospital dismissal, transthoracic echocardiography demonstrated that the mean mitral valve areas and gradients were similar in the three groups; more patients having commissural annuloplasty were classified as having grade II or greater regurgitation. Mortality (n=7, 1.7%) and need for reoperation (n=8, 1.9%) was low in all groups despite the fact that additional procedures were performed in 48.8% of patients. Durations of cardiopulmonary bypass and aortic cross-clamping were significantly less in patients having commissural or posterior annuloplasties compared with those receiving a complete ring annuloplasty. Conclusions These early results indicate that the posterior annuloplasty method is reproducible and expeditious. Postoperative valve function as assessed by degree of regurgitation, transvalvular gradient, and valve area was similar to that obtained by measured, complete ring annuloplasty and superior to that found in patients having commissural annuloplasty.

Background Aprotinin is a serine protease inhibitor that reduces blood loss and transfusion requirements when administered prophylactically to cardiac surgical patients. To examine the safety and dose-related efficacy of aprotinin, a prospective, multicenter, placebo-controlled trial was conducted in patients undergoing repeat coronary artery bypass graft (CABG) surgery. Methods and Results Two hundred eighty-seven patients were randomly assigned to receive either high-dose aprotinin, low-dose aprotinin, pump-prime-only aprotinin, or placebo. Drug efficacy was determined by the reduction in donor-blood transfusion up to postoperative day 12 and in postoperative thoracic-drainage volume. The percentage of patients requiring donor–red-blood-cell (RBC) transfusions in the high- and low-dose aprotinin groups was reduced compared with the pump-prime-only and placebo groups (high-dose aprotinin, 54%; low-dose aprotinin, 46%; pump-prime only, 72%; and placebo, 75%; overall P =.001). The number of units of donor RBCs transfused was significantly lower in the aprotinin-treated patients compared with placebo (high-dose aprotinin, 1.6±0.2 U; low-dose aprotinin, 1.6±0.3 U; pump-prime-only, 2.5±0.3 U; and placebo, 3.4±0.5 U; P =.0001). There was also a significant difference in total blood-product exposures among treatment groups (high-dose aprotinin, 2.2±0.4 U; low-dose aprotinin, 3.4±0.9 U; pump-prime-only, 5.1±0.9 U; placebo, 10.3±1.4 U). There were no differences among treatment groups for the incidence of perioperative myocardial infarction (MI). Conclusions This study demonstrates that high- and low-dose aprotinin significantly reduces the requirement for donor-blood transfusion in repeat CABG patients without increasing the risk for perioperative MI.