Elevated cardiac troponin levels predict the risk of adverse outcome in patients with acute coronary syndromes.

BACKGROUND: Elevations of cardiac troponin T or I are predictive of adverse outcomes in patients with acute coronary syndromes. However, odds ratios (ORs) vary substantially between studies. This investigation refines these values by means of a meta-analysis. METHODS: Twenty-one studies were suitable. ORs were calculated for short-term (30 days) and long-term (5 months to 3 years) follow-up in patients with ST-segment elevation (ST upward arrow), in those without ST-segment elevation (no ST upward arrow), and in patients with unstable angina. The primary end point was a composite of death or nonfatal myocardial infarction. RESULTS: A total of 18,982 patients were included. At 30 days, the OR for death or myocardial infarction was 3.44 (95% confidence interval [CI], 2.94-4.03; P <. 00001) for patients with positive troponin. In the ST upward arrow group, troponin elevations carried a 2.86-fold (95% CI, 2.35-3.47; P <.0001) higher risk during short-term follow-up, which was maintained long term. The no-ST upward arrow patients with troponin elevations manifested a 4.93-fold (95% CI, 3.77-6.45; P <.0001) increase of adverse outcomes. The OR for patients with unstable angina and positive troponin was 9.39 (95% CI, 6.46-13.67; P <.0001). For cardiac death alone, the results were similar. CONCLUSIONS: Patients with acute coronary syndromes who have troponin elevations show a substantial increase in risk during short and long-term follow-up.

Soluble E-selectin is not a marker of unstable coronary plaque in serum of patients with ischemic heart disease.

Increased level of soluble cell adhesion molecules may be a marker for atherosclerosis and/or reflect complication of the atherosclerotic plaque. To test whether expression of cell adhesion molecules is more pronounced in unstable versus stable coronary plaques, we measured the serum level of soluble E-selectin (sE-selectin) in 99 consecutive patients admitted to the hospital for acute coronary syndromes (ACS) and in 61 patients with chronic coronary artery disease (CAD) using a commercially available ELISA kit. We also measured the sE-selectin concentration in 20 sex- and age-matched subjects without clinical evidence of atherosclerosis, who served as controls. The mean sE-selectin level was higher in both groups of patients compared with controls (ACS, 35.0 +/- 23.4 ng/mL; chronic CAD, 32.9 +/- 21.0 ng/mL; controls, 14.5 +/- 6.6 ng/mL; one-way ANOVA, P = 0.001), but there was no difference between patients with ACS and chronic CAD. Furthermore, there was a trend (P = 0.08) toward a decrease in sE-selectin with an increase in the extent and severity of CAD. In patients with ACS, the in-hospital cardiac event rate was 8%. Although mean sE-selectin concentration tended to be higher in patients with (49.2 +/- 42.1 ng/mL) than in those without (33.8 +/- 21.3 ng/mL) in-hospital cardiac events, the difference was not significant. In 53 patients with ACS, C-reactive protein was measured and showed no correlation with the sE-selectin concentration. These findings show that although sE-selectin concentration is elevated in the presence of clinically relevant atherosclerosis, it does not further increase during the unstable phase of the disease, indicating that sE-selectin is not a reliable indicator of a complicated atherosclerotic plaque.

Reduction in myocardial infarct size by basic fibroblast growth factor following coronary occlusion in a canine model.

In a canine model of permanent coronary occlusion it has been shown that basic fibroblast growth factor (bFGF) reduced infarct size and this was associated with an increase in myocardial capillary density a week after infarction. In a preliminary work from our own laboratory using a model of occlusion followed by prolonged reperfusion we observed a similar reduction in infarct size without evidence of myocardial neovascularization. The aim of the present investigation was to evaluate the effects of bFGF on infarct size and blood flow to the infarct zone in an acute experiment in which myocardial neovascularization would be excluded as a mechanism by the short duration of the study. Seventeen mongrel dogs were anesthetized and the heart was exposed through a left thoracotomy. The left anterior descending (LAD) coronary artery was isolated and occluded for 3 h. Fifteen min after LAD occlusion dogs received bFGF 20 microg of bFGF (n=6) or placebo (n=11) by intracoronary injection infused over 5 min. We measured heart rate, aortic pressure, regional coronary blood flow (CBF), regional shortening fraction (SF) at 1, 30 and 180 min of occlusion, then the LAD was reperfused for 5 min then the dogs were euthanized and infarct size was measured. Regional CBF was similar between the two groups of dogs throughout all the study. The SF was similar between the two groups prior the onset of ischemia and at the beginning of the ischemic period. After 180 min of ischemia SF was 2.7+/-4.1% for bFGF and -3.1+/-4.7 for placebo (P=0.049), and during reperfusion SF was 3.4+/-4.6% for bFGF and 0.4+/-1.0% for placebo treated dogs (P=0.023). The infarct size, normalized for the area at risk was 14.2+/-5.2% in bFGF group vs 25.8+/-8.2% in placebo group (P=0.015). In summary we have demonstrated that bFGF significantly limits myocardial necrosis after acute coronary occlusion, and that this occurred without an increase in regional myocardial perfusion and within a period of time too brief for angiogenesis to have occurred. By exclusion, it appears that the salutary effect of bFGF is likely to be mediated by a cellular mechanism. The mechanism or mechanisms responsible for myocardial salvage by bFGF may have significant potential to be exploited in the clinical arena as the basis for therapies to protect the acutely ischemic myocardium.

Clinical relevance of prodromal angina before acute myocardial infarction.

The term preconditioning was applied to the observation made in 1986 by Murry and colleagues that canine myocardium subjected to brief episodes of ischemia and reperfusion would tolerate a more prolonged episode of ischemia better than myocardium not previously exposed to ischemia. Since that seminal observation, protective effect of preconditioning was demonstrated in all animal species tested, resulting in the strongest form of in vivo protection against myocardial injury other than early reperfusion. Angina heralding acute myocardial infarction may represent the clinical correlate of preconditioning phenomenon in humans. Data from small pathophysiological studies demonstrated that prodromal angina (<48 hours prior to index myocardial infarction) causes a reduction of infarct size and consequently a better left ventricular function compared with patients without such clinical feature before myocardial infarction. The protective effect of prodromal angina was also confirmed in larger prospective studies; its presence translates into a significant reduction of a combination of death, cardiogenic shock and pulmonary edema during hospital stay. The exact mechanism of such clinical phenomenon is however not known, but it may include preconditioning. Other mechanisms have been also claimed to play an important role, like a more rapid lysis of the occlusive thrombus within the infarct-related artery, or a rapid opening of intramural collateral not visible at angiography. Whatever the mechanism, it appears that patients with prodromal angina before myocardial infarction exhibit, when rapidly reperfused, a better post-infarction clinical outcome. At the present "optimal preconditioning-mimetic agents" are yet to be found, and "putting preconditioning in a bottle" still remains a pharmacologic challenge.

Selective inhibition of factor Xa is more efficient than factor VIIa-tissue factor complex blockade at facilitating coronary thrombolysis in the canine model.

OBJECTIVES: We determined the effect of adjunctive inhibition of the extrinsic coagulation pathway by factor VIIa-tissue factor complex inhibitors, DEGR VIIa and tissue factor pathway inhibitor (TFPI), and the selective factor Xa inhibitor, tick anticoagulant peptide (TAP), after thrombolytic therapy with tissue-type plasminogen activator (t-PA) in a canine model of electrically induced coronary thrombosis. BACKGROUND: Ongoing thrombin generation is considered an important component of the heightened thrombin activity associated with thrombolytic therapy and may be responsible for reperfusion failure and reocclusion. METHODS: Forty-two dogs with electrically induced coronary thrombus undergoing thrombolysis with t-PA (1 mg/kg over 20 min) were randomly assigned to one of the following adjunctive regimens: TAP (30 micrograms/kg body weight per min for 90 min, n = 10); TFPI (100 to 150 micrograms/kg per min for 90 min, n = 10); DEGR VIIa (1- to 2-mg/kg bolus, n = 10) and saline control (n = 12). The dogs were observed for 120 min after thrombolysis for reocclusion. RESULTS: All three active study agents accelerated the time to reperfusion by an average of 12 min (all p < 0.05). Duration of reflow was greatest with TAP (117 +/- 8 min, p < 0.05 compared with saline control), whereas DEGR VIIa and TFPI did not prolong the duration of reflow. Reocclusion rates were similar among control, DEGR VIIa and TFPI groups (70%, 78% and 67%, respectively). Tick anticoagulant peptide reduced the occurrence of reocclusion (0%, p < 0.05 compared with saline control). CONCLUSIONS: In this experimental model, during systematic blockade of various extrinsic coagulation pathway proteins, we demonstrated that whereas acceleration of thrombolysis occurs with factor VIIa-tissue factor complex inhibition, optimal enhancement of thrombolysis was achieved through specific factor Xa blockade.

Reduction in myocardial infarct size by basic fibroblast growth factor after temporary coronary occlusion in a canine model.

BACKGROUND: Basic fibroblast growth factor (bFGF) has been shown to reduce infarct size in canine acute myocardial infarction; however, the mechanism of tissue salvage remains uncertain. We evaluated the effect of bFGF on infarct size in a model of acute infarction in which coronary occlusion was followed by prolonged reperfusion and sought to determine whether reperfusion attenuates the stimulus for myocardial neovascularization. METHODS AND RESULTS: Anesthetized dogs undergoing 4-hour balloon occlusion of the left anterior descending coronary artery were treated with intracoronary bFGF (n = 8) or vehicle (n = 6). Ten-microgram doses of bFGF were administered 10 minutes after occlusion and again immediately before reperfusion. Left ventriculograms were obtained before occlusion, after reperfusion, and preceding euthanasia on day 7. Infarct size, expressed as a percentage of the area at risk, was reduced in bFGF-treated dogs (13.7 +/- 2.1% versus 28 +/- 3.4%; P = .002). Changes in left ventricular ejection fraction, capillary density, and cellular proliferation-assessed immunohistochemically with factor VIII and proliferating cell nuclear antigen antibodies-were similar in both groups. To assess coronary vasomotor responses to bFGF, a separate hemodynamic study was performed in five anesthetized nonischemic dogs in which incremental bFGF doses up to 100 micrograms induced no vasodilator response. CONCLUSIONS: Treatment with bFGF was associated with a reduction in infarct size without hemodynamic effects or evidence of neovascularization. These data suggest that bFGF mediates myocardial salvage independently of angiogenesis and that reperfusion after infarction may attenuate the stimulus for neovascularization.

Inducible carboxypeptidase activity. A role in clot lysis in vivo.

BACKGROUND: An inducible carboxypeptidase activity in human plasma delays tissue-type plasminogen activator (TPA)-induced clot lysis in vitro. We investigated whether carboxypeptidase activity is induced in vivo during thrombosis and thrombolytic therapy in a canine model of myocardial infarction. METHODS AND RESULTS: By use of synthetic substrate assays, dog plasma was shown to contain an inducible carboxypeptidase activity that is efficiently inhibited by potato carboxypeptidase inhibitor. This inhibitor accelerates TPA-mediated clot lysis in vitro by an average of 27% (n = 5, P = .046). Analysis of the inducible carboxypeptidase activity in plasma samples of dogs with electrically induced thrombosis of the circumflex coronary artery treated with TPA revealed that (1) inducible carboxypeptidase activity is increased during thrombosis (8.7 +/- 2.0 U/L, P < .013) and thrombolytic therapy (9.9 +/- 1.8 U/L, P < .024) compared with baseline (3.2 +/- 2.0 U/L); (2) thrombosis is a prerequisite of carboxypeptidase induction during and after TPA infusion, since carboxypeptidase levels were lower in dogs without a coronary thrombus; and (3) a significant positive correlation (r = .6, P < .0069) of carboxypeptidase activity with time to restoration of blood flow was observed. CONCLUSIONS: These data indicate that carboxypeptidase activity is induced in vivo and may influence thrombolysis.

Selective inhibition of factor Xa during thrombolytic therapy markedly improves coronary artery patency in a canine model of coronary thrombosis.

The success of current thrombolytic strategies is undermined by ongoing thrombin activity, but it is uncertain whether prevention of thrombin generation or direct thrombin antagonism is effective in achieving more optimal thrombolysis. To address this question, 24 dogs with electrically induced coronary thrombus undergoing thrombolysis with tissue-type plasminogen activator (1 mg/kg) over 20 min, were given one of the following adjunctive regimens in a random fashion. Twelve dogs received saline, and served as the control group; a direct thrombin antagonist, hirudin, was given at a dose of 20 micrograms/kg/min for 90 min to six dogs, and a selective factor Xa inhibitor, tick anticoagulant peptide (TAP), was administered to six dogs at a dose of 30 micrograms/kg/min for 90 min. The time to reperfusion was similar in the saline and hirudin groups (34 +/- 4 vs 37 +/- 7 min; P = NS) but shorter in the TAP group (21 +/- 4 min; P < 0.05). Coronary blood flow was restored to 100% of its baseline value for 7 +/- 2 min in control dogs, and for 20 +/- 6 min in the hirudin group (P < 0.05). In the TAP group, coronary blood flow was restored to 100% of its baseline value for more than 120 min in all dogs (P < 0.01 vs others treatments). Reocclusion occurred in 89% and 50% of dogs receiving saline and hirudin, respectively (P = NS), but in none of the TAP-treated dogs (P < 0.01). Plasma fibrinopeptide A (FpA) and thrombin-antithrombin III complex (TAT) levels were determined in all dogs as indicators of thrombin activation. In the saline group, FpA and TAT during reperfusion were 19 +/- 2 ng/ml and 104 +/- 24 ng/ml respectively (P < 0.02 vs baseline) indicating high thrombin activity. In contrast, during reperfusion in hirudin-treated dogs FpA and TAT remained similar to baseline (10 +/- 3 ng/ml and 53 +/- 4 ng/ml respectively; both P < 0.05 vs saline). Reperfusion in TAP-treated dogs did not alter FpA and TAT in plasma, which remained similar to baseline (9 +/- 1 ng/ml and 39 +/- 5 ng/ml respectively; both P < 0.05 vs saline). Scanning electron microscopy of coronary arteries showed residual thrombi with intense platelet and fibrin deposition adherent to the deendothelialized surface of the vessels following saline and hirudin therapy. In contrast, TAP-treated arteries were characterized by the absence of fibrin and minimal platelet deposition. In conclusion, these hemodynamic, biochemical and morphologic data suggest that adjunctive treatment with a higher tier blockade of the coagulation cascade is superior to direct thrombin inhibition in maintaining coronary artery patency following thrombolysis in the experimental canine electrolytic model. These findings highlight the potential adverse effects of unchecked thrombin generation in the setting of thrombolytic therapy.

Adjunctive selectin blockade successfully reduces infarct size beyond thrombolysis in the electrolytic canine coronary artery model.

BACKGROUND: An adjunctive pharmacological strategy to thrombolytic therapy that is tailored to limit reperfusion injury after thrombolysis could further maximize the unquestioned benefit of restoring flow to ischemic myocardium. Ischemia-reperfusion injury exhibits features characteristic of an acute inflammatory response, including the rapid activation and infiltration of neutrophils. The initial process of neutrophil migration from the circulation to injured tissue is modulated by a group of adhesion molecules called selectins. The purpose of the present study was to assess the efficacy of a selectin blocker (CY 1503) given as an adjunct to thrombolytic therapy to interfere with the inflammatory response after ischemia-reperfusion and subsequently reduce myocardial infarct size in the electrolytic canine model. METHODS AND RESULTS: A fully occlusive thrombus was formed in the left circumflex coronary artery by electrolytic injury in 20 anesthetized open-chest dogs. After occlusion, an infusion of 1 mg/kg recombinant tissue-type plasminogen activator (rTPA) was administered over 20 minutes with either a bolus of placebo or the selectin blocker CY 1503 (40 mg/kg). At the onset of reperfusion, 20 micrograms/kg per minute rTPA was administered for 1 hour to prevent reocclusion. After 1 hour of reperfusion, infarct size, myocardial myeloperoxidase activity, and reperfusion arrhythmias were measured. In CY 1503-treated dogs, there was a significant 69% reduction in infarct size when expressed as a percentage of the area at risk (6.7 +/- 8.4% versus 21.8 +/- 13.6%; P = .008) and a marked reduction in myeloperoxidase activity (0.014 +/- 0.009 versus 0.0370 +/- 0.025 U/min per gram; P = .02) compared with the placebo group. There was no difference between the groups in the occurrence of reperfusion arrhythmias. CONCLUSIONS: Selectin blockade as an adjunct to rTPA-mediated thrombolysis significantly reduces infarct size and myocardial neutrophil infiltration well beyond thrombolysis alone in the electrolytic canine model. These data suggest that selectin blockade is extremely effective at reducing ischemia-reperfusion injury and myocardial infarct size in this model and that the neutrophil is a potent mediator of ischemia-reperfusion injury.

Failure of brief ischemic episodes to protect against myocardial dysfunction caused by ischemia and reperfusion in isolated rat hearts.

Brief periods of ischemia have been suggested to protect against myocardial injury caused by a subsequent episode of prolonged ischemia and reperfusion. However, the protective effects of brief ischemic periods against myocardial dysfunction after prolonged myocardial ischemia are controversial. To examine whether the protective effects of brief ischemic episodes relate to the extent of prior ischemic events, isolated rat hearts were subjected to either no preischemia (group A); one 5-minute episode of preischemia and 10 minutes of reperfusion (group B); or two 1-minute episodes of ischemia, each followed by 5 minutes of reperfusion (group C). All hearts were then subjected to 15 minutes of total ischemia and 10 minutes of reperfusion. In group A, after 10 min of reperfusion coronary perfusion pressure (CPP) was 31% +/- 10% (mean +/- SEM) higher than the control value, peak force of cardiac contraction (FCC) was 64% +/- 5% lower, and heart rate was 18% +/- 3% lower. In group B, CPP increased 26% +/- 6%, FCC fell 58% +/- 7%, and heart rate decreased 22% +/- 8% (group B vs group A, P value not significant) after ischemia and reperfusion. In group C, CPP increased 23% +/- 7%, FCC decreased 57% +/- 8%, and heart rate fell 8% +/- 4% on reperfusion (group C vs groups A and B, P value not significant). Creatine kinase (CK) was measured in the hearts from different groups and was found to be similar. Release of the adenosine triphosphate (ATP) metabolites hypoxanthine, inosine, and adenosine was also not different in the coronary effluents of the three groups of hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Concurrent nitroglycerin therapy impairs tissue-type plasminogen activator-induced thrombolysis in patients with acute myocardial infarction.

Nitroglycerin given with tissue-type plasminogen activator (t-PA) has been shown to decrease the thrombolytic effect of t-PA in animal models of coronary artery thrombosis. The present study was conducted to determine whether such an interaction between nitroglycerin and t-PA occurs in patients with acute myocardial infarction undergoing thrombolytic treatment. Patients with acute myocardial infarction were treated with t-PA plus saline solution (group 1; n = 11) or t-PA plus nitroglycerin (group 2; n = 36). Stable coronary artery reperfusion assessed by continuous ST-segment monitoring in 2 electrocardiographic leads, and release of creatine kinase occurred in 91% of group 1 patients and in 44% of group 2 patients (95% confidence interval, 14% to 82%; p < 0.02). Plasma levels of t-PA antigen were consistently (p < 0.005) higher in group 1 than in group 2 patients up to 6 hours after t-PA infusion. Conversely, plasminogen activator inhibitor-1 (PAI-1) levels were slightly higher in group 2 than in group 1 patients. These observations indicate that nitroglycerin given with t-PA significantly decreases the plasma t-PA antigen concentrations and impairs the thrombolytic effect of t-PA in patients with acute myocardial infarction.

Attenuation of coronary flow reserve and myocardial function after temporary subtotal coronary artery occlusion and increased myocardial oxygen demand in dogs.

OBJECTIVES: We examined whether subtotal coronary artery occlusion and reperfusion alter coronary flow reserve and regional myocardial function. BACKGROUND: Total coronary artery occlusion followed by reperfusion results in decreased coronary flow reserve and regional myocardial dysfunction. METHODS: Thirteen anesthetized dogs were subjected to subtotal occlusion of the left anterior descending coronary artery for 1 h, followed by reperfusion for 1 h. During subtotal left anterior descending occlusion, heart rate was increased by atrial pacing. After reperfusion, coronary flow reserve, indicated by reactive hyperemia, as well as coronary flow responses to acetylcholine and nitroglycerin, regional myocardial function and myocardial leukocyte accumulation were measured. RESULTS: After reperfusion, coronary flow reserve was decreased in the ischemic left anterior descending but not the nonischemic circumflex coronary artery region. Myocardial function was also depressed in the left anterior descending coronary region and did not improve on reperfusion. Histologic study showed no leukocyte infiltration in the ischemic left anterior descending coronary region. Myeloperoxidase, an index of myocardial leukocyte accumulation, was similar in the left anterior descending and circumflex coronary regions. Sensitivity of epicardial left anterior descending coronary artery rings to the thromboxane A2 analog U46,619 was enhanced, and relaxation of these rings in response to endothelium-dependent relaxants was decreased. CONCLUSIONS: Coronary flow reserve is reduced and regional myocardial function depressed after subtotal coronary artery occlusion and increased heart rate. A decreased synthesis or increased breakdown of endothelium-derived relaxing factor may be related to a decrease in coronary flow reserve. However, the reduction in coronary flow reserve appears to be unrelated to leukocyte accumulation in the reperfused region.

Increased secretion of tumor necrosis factor-alpha and interferon-gamma by mononuclear leukocytes in patients with ischemic heart disease. Relevance in superoxide anion generation.

BACKGROUND: There is growing evidence for a pathogenic role for cytokines in atherogenesis. The presence of certain cytokines has been documented in human atherosclerotic vessels. This study was designed to investigate cytokine production by mononuclear leukocytes from patients with ischemic heart disease. METHODS AND RESULTS: We measured kinetics of secretion of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) by mononuclear leukocytes from 8 control subjects, 10 patients with stable angina pectoris, and 10 patients with unstable angina pectoris. Mononuclear leukocytes were isolated and incubated with or without the plant lectin mitogen concanavalin A for 48 hours. TNF-alpha and IFN-gamma secretion were measured by ELISA. The effect of TNF-alpha and IFN-gamma on superoxide radical generation by neutrophils was also examined. Secretion of both TNF-alpha and IFN-gamma by mononuclear leukocytes increased progressively over 48 hours, and it was consistently higher (P < .02) in patients compared with control subjects. A similar increase in cytokine secretion was observed in patients with stable or unstable angina pectoris. In addition, there was no relation between the severity of coronary artery disease by angiography and cytokine secretion. Basal neutrophil superoxide radical generation was increased in patients with ischemic heart disease, and incubation with cytokines failed to further stimulate superoxide generation in these patients. CONCLUSIONS: Similar increases in cytokine secretion by mononuclear leukocytes in stable or unstable angina pectoris indicate that the increased cytokine release is not a nonspecific inflammatory response in acute myocardial ischemia. Increased cytokine secretion in ischemic heart disease may play a role in superoxide radical generation, endothelial injury, deposition and activation of cellular elements on the vessel wall, and possibly in the progression of atherosclerosis.

Neutrophil elastase inhibitor ICI 200,880 protects against attenuation of coronary flow reserve and myocardial dysfunction following temporary coronary artery occlusion in the dog.

OBJECTIVE: Diminished coronary flow reserve and myocardial dysfunction following coronary artery occlusion and reperfusion have been attributed to neutrophil infiltration into the reperfused regions. Release of free radicals and elastase during reperfusion may also contribute to ischaemia-reperfusion induced changes. The aim of this study was to determine the effect of an elastase inhibitor on reperfusion induced attenuated coronary flow reserve and myocardial dysfunction. METHODS: Anaesthetised dogs were subjected to 1 h of left anterior descending coronary artery occlusion and 2 h of reperfusion. Ten minutes before reperfusion, dogs were randomly given saline or the neutrophil elastase inhibitor ICI 200,880 (10 mg.kg-1) and treatment was continued for the next 70 min. While the regional myocardial shortening fraction and coronary blood flow responses to acetylcholine and glyceryl trinitrate were attenuated following coronary reperfusion in saline treated dogs, similar reductions were not observed in the ICI 200,880 treated dogs (p < 0.01). Histopathology showed myocardial injury and extensive neutrophil infiltration in the reperfused regions in saline treated animals. In contrast, neutrophil infiltration was minimal in the ICI 200,880 treated dogs, in spite of myocardial injury. Myeloperoxidase, an index of neutrophil infiltration, was increased (p < 0.02 v control regions) in the reperfused regions in saline treated dogs, but not in the ICI 200,880 treated dogs. Flow cytometry also showed diminished neutrophil infiltration and oxidative burst in reperfused myocardium of ICI 200,880 treated (v saline treated) dogs. CONCLUSIONS: The elastase inhibitor ICI 200,880 protects against ischaemia-reperfusion induced attenuated coronary flow reserve and myocardial dysfunction, and this protective effect is associated with decreased neutrophil infiltration into the reperfused regions.

Adenosine protects against attenuation of flow reserve and myocardial function after coronary occlusion and reperfusion.

Total coronary artery occlusion and reperfusion result in attenuation of coronary blood flow reserve, regional myocardial dysfunction, and myocardial leukocyte infiltration. To examine the effects of intracoronary adenosine on these occlusion and reperfusion-induced perturbations, we subjected 14 dogs to total left anterior descending (LAD) coronary artery occlusion (1 hour) and reperfusion (1 hour). Seven dogs received adenosine (3.75 mg/min into the LAD distal to the occlusion) over a 1-hour period starting 5 minutes before reperfusion, and the remaining seven dogs received saline solution. One dog in each group died of ventricular fibrillation during coronary artery occlusion. Coronary flow reserve, measured as peak reactive hyperemia (10 and 20 seconds of total coronary artery occlusion) and peak coronary blood flow response to acetylcholine (0.01 to 1.0 micrograms) and nitroglycerin (5 to 25 micrograms), was impaired in the LAD region after LAD occlusion and reperfusion in the saline-treated dogs (all p < 0.01 vs before occlusion and reperfusion); LAD regional myocardial shortening fraction measured by ultrasonic crystals was also diminished after occlusion and reperfusion in saline-treated dogs (-5% +/- 1% vs 12% +/- 2%; p < 0.02). The adenosine-treated dogs showed total protection against loss of coronary flow reserve (peak reactive hyperemia and blood flow increase in response to acetylcholine and nitroglycerin; all p values not significant vs before LAD occlusion and reperfusion). LAD regional myocardial shortening fraction was also preserved in adenosine-treated dogs (9% +/- 2% vs 14% +/- 2%; p not significant). Myocardial myeloperoxidase activity, measured as an index of myocardial leukocyte infiltration, was greater (p < 0.02) in the LAD ischemic-reperfused regions than in nonischemic circumflex regions in the saline-treated dogs. A similar difference in myeloperoxidase activities in the reperfused and control regions was not observed in the adenosine-treated dogs. Thus adenosine protects against loss of coronary flow reserve and regional myocardial function in dogs subjected to coronary artery occlusion and reperfusion.

Combination of platelet fibrinogen receptor antagonist and direct thrombin inhibitor at low doses markedly improves thrombolysis.

BACKGROUND: We evaluated the effects of a novel platelet fibrinogen receptor antagonist, Integrelin, and a direct thrombin inhibitor, recombinant hirudin, given together with recombinant tissue plasminogen activator (rTPA) in a canine experimental model of intracoronary thrombosis. We tested the hypothesis that combination of both agents at low doses would have an additive antithrombotic effect, resulting in a significant improvement in the efficacy of rTPA. METHODS AND RESULTS: Thirty-two dogs with an electrically induced coronary thrombus were treated with rTPA (1 mg/kg over 20 minutes) together with one of the following adjunctive treatments in a random fashion. Eight dogs received saline for 90 minutes; Integrelin (5 micrograms.kg-1.min-1 for 90 minutes) was given to 8 dogs; 8 dogs received recombinant hirudin (20 micrograms.kg-1.min-1 for 90 minutes); and 8 dogs were treated with a low-dose combination of Integrelin (2.5 micrograms.kg-1.min-1) plus recombinant hirudin (10 micrograms.kg-1.min-1) for 90 minutes. Integrelin or recombinant hirudin, when given as single adjunct to rTPA, enhanced the lysis of the occlusive thrombus, causing full restoration of coronary blood flow (100% of its baseline value) for 29 +/- 16 and 26 +/- 5 minutes, respectively, whereas coronary blood flow was fully restored for only 5 +/- 1 minutes in dogs receiving rTPA plus saline (both P < .05). However, either Integrelin or recombinant hirudin failed to modify the reocclusion rate (57% and 63%, respectively) compared with saline (83%; all P = NS). Conversely, the low-dose combination therapy led to complete restoration of coronary blood flow for 92 +/- 19 minutes (P < .01 versus all treatments) and significantly reduced the reocclusion rate (25%; P < .05 versus saline). CONCLUSIONS: These data show that inhibition of specific pathways of platelet and thrombin activity improves the extent and duration of rTPA-induced thrombolysis in the electrolytic canine model. Furthermore, our findings suggest that low doses of platelet IIb/IIIa and direct thrombin antagonists in combination may be used successfully during thrombolysis.

Failure of prostacyclin analog iloprost to sustain coronary blood flow after recombinant tissue-type plasminogen-induced thrombolysis in dogs.

The coronary artery often reoccludes soon after the flow has been restored with recombinant tissue-type plasminogen activator (TPA) in dogs with electrically-induced thrombosis. The coronary artery reocclusion relates to intense in situ platelet activation and thrombin generation in the reperfused coronary artery. To determine the effect of a potent platelet inhibitor, the prostacyclin analog iloprost, in the prevention of coronary artery reocclusion, an occlusive thrombus was created in the left anterior descending coronary artery in 23 dogs. Coronary artery reflow occurred in 17 dogs after TPA (1 mg/kg over 20 minutes intravenously) administration. After the reflow was established, 10 dogs were given saline and 7 dogs were given iloprost (4 micrograms/kg over 40 minutes). In the saline-treated group, the coronary artery reoccluded in 8 of 10 dogs over 90 minutes (reocclusion rate 80%). In the iloprost-treated group, the coronary artery reoccluded in five of seven dogs (reocclusion rate 71%; p = NS vs TPA alone). The magnitude of peak coronary blood flow and duration of flow were similar in dogs given saline or iloprost after TPA-induced thrombolysis. Scanning electron microscopy showed residual thrombus and the appearance of coronary arterial narrowing distal to the thrombus in all dogs examined. Thus residual thrombus formation and coronary artery narrowing continue to occur after TPA-induced thrombolysis in dogs whether the animals are treated with saline or iloprost. Administration of iloprost after reflow does not modulate the frequency of coronary artery reocclusion.

Decreased endothelium-dependent vascular relaxation following subtotal coronary artery occlusion in dogs.

Total coronary artery occlusion followed by reperfusion leads to neutrophil accumulation in the reperfused myocardium and a reduction in endothelium-dependent coronary artery relaxation. Attenuated coronary artery relaxation in the affected regions is thought to be related to breakdown of endothelium-derived relaxing factor (EDRF) by free oxygen radicals released during reperfusion. To determine if temporary subtotal coronary artery narrowing leads to similar alteration in vascular reactivity, eight open-chest dogs were subjected to 1 h of left anterior descending (LAD) coronary artery narrowing (70% reduction in basal flow) and pacing-induced increase in heart rate (30% above baseline) followed by reperfusion for 1 h. Thereafter reactivity of ischemic-reperfused LAD and nonischemic circumflex (Cx) coronary artery rings to the thromboxane A2 analog U46,619 and EDRF-dependent vasorelaxants acetylcholine (ACh), thrombin, and adenosine diphosphate (ADP), as well as to EDRF-independent vasorelaxant nitroglycerin (NTG), was examined. Unlike in the setting of total coronary artery occlusion, reperfused myocardium or LAD did not reveal neutrophil infiltration. However, contraction in response to U46,619 was markedly (P < .001) increased in the LAD rings compared to that in the Cx rings. ACh-induced relaxation was only modestly decreased (P < .05) in the LAD coronary artery rings, but the relaxation in response to both thrombin and ADP was markedly diminished (P < .01) as compared to that in the Cx rings. Coronary artery ring relaxation in response to NTG was preserved in the LAD rings. Pretreatment of coronary artery rings with indomethacin did not alter the enhanced contraction or diminished endothelium-dependent relaxation of LAD coronary artery rings.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased production of thromboxane A2 by coronary arteries after thrombolysis.

The coronary artery produces large amounts of prostacyclin (PGI2) and a small amount of thromboxane A2 (TXA2); this high PGI2/TXA2 ratio contributes to the antithrombotic properties of the coronary artery. This study was designed to determine whether this ratio changes after coronary artery thrombosis and thrombolysis and accounts for coronary artery reocclusion. Anesthetized dogs (N = 12) were subjected to electrically induced coronary artery thrombosis and tissue plasminogen activator-induced thrombolysis. Thrombolysis was achieved in 11 dogs, and the coronary artery reoccluded in five of these dogs after the initial reperfusion. Spontaneous and ionophore A23,187-stimulated PGI2 and TXA2 synthesis in normal circumflex and ischemic-reperfused left anterior descending coronary artery segments was measured by radioimmunoassay of thromboxane B2 and 6-keto-prostaglandin F1 alpha, respectively. Production of TXA2 was 413% to 656% greater in left anterior descending segments (from the region of thrombosis and sites proximal and distal to the thrombus) compared with normal circumflex segments (p < 0.001). Production of PGI2 was also increased but only by 46% to 80% in the left anterior descending segments compared with normal circumflex segments (p < 0.05). TXA2 production was greater in coronary artery segments that reocculded compared with segments that stayed open (p < 0.02). Scanning electron microscopy revealed platelet deposition in thrombosed left anterior descending segments but not in segments proximal or distal to the thrombus site, indicating that the vascular wall per se may be a source of increased production of TXA2.(ABSTRACT TRUNCATED AT 250 WORDS)