Citations

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.

Background The purpose of this study was to identify the predictors and sequelae of distal embolization from a multicenter, randomized trial of saphenous vein graft intervention. The CAVEAT-II trial demonstrated that saphenous vein graft directional coronary atherectomy (DCA) was associated with greater angiographic success and less need for repeat intervention compared with percutaneous transluminal coronary angioplasty (PTCA) but at the cost of more acute complications—notably distal embolization. Methods and Results In CAVEAT-II, 305 patients were randomly assigned to DCA (149 patients) or PTCA (156 patients) for lesions with >60% diameter stenosis in vein grafts ≥3 mm in diameter. Distal embolization occurred in 20 patients (13.4%) assigned to DCA and 8 patients (5.1%) assigned to PTCA ( P =.011). Independent predictors of distal embolization were use of DCA (71% in distal embolization patients versus 47% in patients without distal embolization, P =.011) and presence of thrombus (39% in distal embolization patients versus 14% in patients without distal embolization, P <.00). In-hospital adverse events were more frequent after distal embolization: 71% versus 20%, odds ratio plus (95% confidence intervals) 9.87 (4.65, 20.94). At 12-month follow-up, adverse event rates were also higher in patients with distal embolization (odds ratio, 3.05 [1.95, 4.76]). Conclusions In this first prospective multicenter trial of saphenous vein graft intervention, distal embolization was more common after DCA than PTCA and in lesions containing thrombus. It also was associated with worse in-hospital and 12-month outcomes. The risk and sequelae of distal embolization should be considered when choosing a treatment strategy for vein graft disease.

Background 99m Tc sestamibi is a recently developed radioisotope that has been used to measure myocardium at risk and infarct size. The relation between these measurements and subsequent patient outcome has not yet been demonstrated. Methods and Results Two hundred seventy-four consecutive patients with acute myocardial infarction underwent tomographic 99m Tc sestamibi imaging on arrival at the hospital (to measure myocardium at risk before reperfusion therapy) and at hospital discharge (to measure the amount of salvaged myocardium and final infarct size). Defect size on the sestamibi images was quantified using a threshold value of 60% of peak counts from the circumferential count profile curves generated for five representative slices of the left ventricle. Patients were followed after hospital discharge to evaluate the association between final infarct size and subsequent mortality. The median defect size measured was 27% of the left ventricle at presentation to the hospital (range, 0% to 77%) and was 12% of the left ventricle at hospital discharge (range, 0% to 68%). Almost one half of the patients had a final infarct size of ≤10%. The median amount of myocardium salvaged was 9% (range, −31% to 75%). During a median duration of follow-up of 12 months, there were 10 deaths (7 cardiac and 3 noncardiac) and 1 resuscitated out-of-hospital cardiac arrest. There was a significant association between infarct size and overall mortality (χ 2 =8.66, P =.003) and cardiac mortality (χ 2 =11.89, P <.001). Two-year mortality was 7% for patients whose infarct size was ≥12% versus 0% for patients whose infarct size was <12%. There also was a significant association between myocardium at risk and cardiac mortality (χ 2 =6.87, P =.009). There was no association between myocardium at risk and overall mortality or between amount of myocardium salvaged and either overall mortality or cardiac mortality. Conclusions Larger infarct size measured by 99m Tc sestamibi imaging after acute myocardial infarction is associated with increased mortality risk during short-term follow-up.

Background Adrenomedullin (ADM) is a newly discovered vasodilating and natriuretic peptide that may play an important role in cardiorenal regulation. Although ADM was originally isolated from human pheochromocytoma, ADM-like immunoreactivity has also been widely detected in various tissues, including the cardiovascular system. Methods and Results In view of reports that ADM circulates in the body and that ADM gene and ADM-like immunoreactivity are present in the heart, the present study was designed to determine the plasma concentration of ADM in healthy subjects and in patients with congestive heart failure (CHF) and to investigate the immunohistochemical presence and localization of ADM in normal and failing human hearts. Plasma ADM concentration was 13.2±2.3 pg/mL in healthy subjects (n=11) and increased to 47.3±6.7 pg/mL in patients with CHF (n=11, P <.05 versus normal). Human cardiac tissues were obtained from five patients with end-stage CHF undergoing cardiac transplantation. Five normal donor hearts that were used for cardiac transplantation served as sources for normal atrial tissues. Normal ventricular myocardium was also obtained by endomyocardial biopsy from the right ventricles of these donor hearts immediately before cardiac transplantation. Positive immunostaining was detected within the myocardia in both atria and ventricles of healthy and severely failing human transplanted hearts and was more intense in the atria than in the ventricles. Although there were no significant differences in the intensity of immunoreactivity between normal and failing atria, ADM immunoreactivity was significantly more intense in the ventricular myocytes from failing hearts compared with normal hearts. Conclusions The present study demonstrates that plasma concentration of ADM is increased in patients with CHF and that ADM is present in the human heart. ADM immunoreactivity is markedly increased in the failing human ventricle, suggesting that ventricular ADM expression may be influenced by the circumstances associated with CHF. This supports a potential role for this newly identified vasoactive and natriuretic peptide, ADM, in the neurohumoral activation that characterizes human CHF.