RNA Profiling in Human and Murine Transplanted Hearts: Identification and Validation of Therapeutic Targets for Acute Cardiac and Renal Allograft Rejection.

Acute cellular rejection (ACR) is the adverse response of the recipient's immune system against the allogeneic graft. Using human surveillance endomyocardial biopsies (EMBs) manifesting ACR and murine allogeneic grafts, we profiled implicated microRNAs (miRs) and mRNAs. MiR profiling showed that miR-21, -142-3p, -142-5p, -146a, -146b, -155, -222, -223, and -494 increased during ACR in humans and mice, whereas miR-149-5p decreased. mRNA profiling revealed 70 common differentially regulated transcripts, all involved in immune signaling and immune-related diseases. Interestingly, 33 of 70 transcripts function downstream of IL-6 and its transcription factor spleen focus forming virus proviral integration oncogene (SPI1), an established target of miR-155, the most upregulated miR in human EMBs manifesting rejection. In a mouse model of cardiac transplantation, miR-155 absence and pharmacological inhibition attenuated ACR, demonstrating the causal involvement and therapeutic potential of miRs. Finally, we corroborated our miR signature in acute cellular renal allograft rejection, suggesting a nonorgan specific signature of acute rejection. We concluded that miR and mRNA profiling in human and murine ACR revealed the shared significant dysregulation of immune genes. Inflammatory miRs, for example miR-155, and transcripts, in particular those related to the IL-6 pathway, are promising therapeutic targets to prevent acute allograft rejection.

[Implementation of reperfusion therapy in ST segment elevation myocardial infarction (STEMI). A policy statement from the Belgian Society of Cardiology and its working group of acute cardiology and interventional cardiology]. / Mise en pratique du traitement de reperfusion dans les infarctus du myocarde avec élévation du segment ST.

Myocardial infarction remains a major healthcare problem. Reperfusion therapy has been shown to influence favourably short- and long-term patient survival. The authors reviewed the data of early recognition of STEMI (ST Elevation Myocardial Infarction), the reperfusion modalities including a flowchart management, as proposed by the Belgian working groups (BIWAC and BWGIC), and the lessons learned from European and American registries. Primary PCI often remains the treatment of choice. A national policy is still required to implement the guidelines and improve clinical practice for our STEMI patients.

[Implementation of reperfusion therapy in ST segment elevation myocardial infarction (STEMI). A policy statement from the Belgian Society of Cardiology and its working group of acute cardiology and interventional cardiology]. / Mise en pratique du traitement de reperfusion dans les infarctus du myocarde avec élévation du segment ST (STEMI). Recommandations actualisées de la Société Belge de Cardiologie et de ses groupes de travail: le Groupe Interdisciplinaire de Cardiologie Aiguë (BIWAC) et le Groupe de Cardiologie Interventionnelle (BWGIC).

Myocardial infarction remains a major healthcare problem. Reperfusion therapy has been shown to influence favourably short- and long-term patient survival. The authors reviewed the data of early recognition of STEMI (ST Elevation Myocardial Infarction), the reperfusion modalities including a flowchart management, as proposed by the Belgian working groups (BIWAC and BWGIC), and the lessons learned from European and American registries. Primary PCI often remains the treatment of choice. A national policy is still required to implement the guidelines and improve clinical practice for our STEMI patients.

The genesis of the third and fourth heart sounds. A pressure-flow study in dogs.

To examine the mechanism of mitral flow deceleration in diastole and its potential influence on the genesis of third (S3) and fourth (S4) heart sounds, we simultaneously recorded left atrial and left ventricular pressures (micromanometers), mitral flow velocity (electromagnetic catheter-tip flow velocity meter), and internal and external phonocardiograms in 25 open-chest dogs. Diastolic time intervals, transmitral pressure gradients (planimetry), maximum mitral flow velocity, and acceleration and deceleration of flow were measured under different loading conditions. It was found that deceleration of mitral flow in early and late diastole is always caused by a negative transmitral pressure gradient. After volume loading, diastolic pressures, positive (forward) and negative (backward) transmitral pressure gradients, and acceleration and deceleration of flow increased, and an S3 or S4 appeared (20:25 dogs). These sounds occurred during the phase of flow deceleration and could be recorded from the chest wall, inside the left ventricle, and directly from the epicardial surface of the freely exposed left ventricular wall. After balloon occlusion of the inferior vena cava (17:25 dogs), the opposite changes were observed and gallop sounds disappeared. The results indicate that the left ventricular pressure rise in response to filling reverses the transmitral pressure gradient and decelerates flow. Deceleration of inflow by the left ventricular wall in early and late diastole may represent a key mechanism in the genesis of S3 and S4.

Coronary thrombolysis and infarct size reduction after intravenous infusion of recombinant tissue-type plasminogen activator in nonhuman primates.

Occlusive thrombus was produced by thrombin-induced coagulation in the left anterior descending coronary artery (LAD) of 16 open-chest baboons. In six control animals, occlusive thrombosis persisting over a period of 4 h as evidenced by coronary arteriography resulted in large transmural infarction (63.1 +/- 3.5% of the perfusion area). In 10 animals, tissue-type plasminogen activator obtained by recombinant DNA technology (rt-PA) was infused systemically at a rate of 1,000 IU (10 micrograms)/kg per min for 30 min after 30-80 min of coronary thrombosis. Reperfusion occurred within 30 min in nine animals. In one animal, intravenous infusion was followed by an intracoronary infusion at the same rate, which resulted in thrombolysis within 8 min. In the rt-PA group, mean duration of occlusion before reperfusion was 77 +/- 24 min. Reocclusion occurred in one animal. Recanalization resulted in an overall reduction of infarct size (37.8 +/- 5.9%, P less than 0.05 versus controls). Residual infarction was related to the duration of occlusion (r = 0.80, P less than 0.01). Reperfusion was associated with reduced reflow. Myocardial blood flow in the perfusion area of the LAD was only 70% of normal after 4 h despite perfect angiographic refilling. The infusion of rt-PA was not associated with systemic activation of the fibrinolytic system, fibrinogen breakdown, or clinically evident bleeding. It is concluded that intravenous infusion of rt-PA may recanalize thrombosed coronary vessels without inducing systemic lysis. The extent of residual infarction is closely related to the duration of coronary artery occlusion before thrombolysis.

Right atrial angiographic evaluation of the posterior isthmus: relevance for ablation of typical atrial flutter.

BACKGROUND: Gaining anatomic information about the posterior isthmus is not generally part of flutter ablation procedures. We postulated that right atrial (RA) angiography could rationalize the ablation approach by revealing the conformation of the isthmus. METHODS AND RESULTS: In 100 consecutive patients, biplane RA angiography was performed before ablation to guide catheter contact with the isthmus along its length. Angiography showed a wide variation in the width of the isthmus (17 to 54 mm; 31.3+/-7.9), its angle with the inferior vena cava in the right anterior oblique projection (68 degrees to 114 degrees; 90.3+/-9.0 degrees ), and its lateral position relative to the inferior vena cava in the left anterior oblique projection. A deep sub-Eustachian recess was revealed in 47%, with a mean depth of 4.3+/-2.1 mm (1.5 to 9.4). A Eustachian valve was visualized in 24%. Ablation resulted in bidirectional conduction block (which could be transient) in all, with a median of 2 dragging radiofrequency (RF) applications (2.3+/-2.5 RF applications; 57 degrees C, < or =99 seconds each). Permanent block was achieved in 99%, with a median of 3 RF applications (3.4+/-3.0). The presence of a Eustachian valve or concave isthmus was associated with statistically more RF applications; the same trend was seen for patients with deep pouches. The number of RF applications decreased statistically throughout the study, indicating a learning curve. No patient had a recurrence after a follow-up of 13+/-11 months. CONCLUSIONS: Right atrial angiography reveals a highly variable isthmus anatomy, often showing particular configurations that can make ablation more laborious. Rational adaptation of the ablation approach to these anatomic findings may contribute to successful ablation.

Time to treatment influences the impact of ST-segment resolution on one-year prognosis: insights from the assessment of the safety and efficacy of a new thrombolytic (ASSENT-2) trial.

BACKGROUND: Early ST resolution after reperfusion is a prognostic indicator in acute myocardial infarction. Little information exists regarding the prognostic utility of ST resolution beyond 4 hours after fibrinolysis. Furthermore, the relation between time to treatment, ST resolution at 24 to 36 hours, and 1-year outcome has not been well studied. Accordingly, we undertook a prospective ECG substudy in the Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) trial to examine this. METHODS AND RESULTS: Patients (n=13 100) were stratified into 3 ST-resolution categories, based on baseline and 24- to 36-hour ECGs: complete resolution (>/=70%) in 6698 (51.1%) patients, partial resolution (30% to 70%) in 4610 (35.2%) patients, and no resolution (<30%) in 1792 (13.7%) patients; 1-year mortality rate was 5.1%, 8.0%, and 9.7%, respectively (P<0.001). Among patients treated <2 hours after symptom onset, 55.6% had complete ST resolution, whereas 52.1% and 43% of patients treated between 2 to 4 hours and 4 to 6 hours, respectively, had complete ST resolution (P<0.001). Within each category of ST resolution, patients treated <2 hours had lower 1-year mortality rates as compared with patients treated between 2 to 4 hours or >4 hours (3.8% versus 5.2% and 6.6%, P=0.002 in complete ST resolution; 5.7% versus 8.4% and 9.9%, P=0.001 in partial ST resolution; 7.1% versus 8.7% and 13%, P=0.006 in no resolution). The extent of ST resolution was closely and inversely correlated with 1-year mortality rates (r=-0.963, P<0.001). CONCLUSIONS: ST resolution at 24 to 36 hours after fibrinolysis is influenced by time to treatment and inversely related to 1-year mortality rates. Time to treatment further differentiates between high- and low-risk patients and further highlights the importance of reducing time delay to initiation of fibrinolysis in acute myocardial infarction.

Polyethylene glycol-derivatized cysteine-substitution variants of recombinant staphylokinase for single-bolus treatment of acute myocardial infarction.

BACKGROUND: Thrombolytic therapy of acute myocardial infarction (AMI) is evolving toward bolus administration. Derivatization of proteins with polyethylene glycol (PEG) may reduce their clearance. METHODS AND RESULTS: A staphylokinase (SakSTAR) variant with 12 amino acid substitutions to reduce its antigenicity, SakSTAR (K35A, E65Q, K74R, E80A, D82A, T90A, E99D, T101S, E108A, K109A, K130T, K135R), and with Ser in position 3 mutated into Cys (code SY161), was derivatized with maleimide-PEG with M:(r) of 5,000 (P5), 10,000 (P10), or 20,000 (P20). The PEGylated variants recognized only one third of the antibodies elicited with wild-type SakSTAR in AMI patients. In experimental animals, plasma clearances were reduced 2. 5- to 5-fold with P5, 5- to 20-fold with P10, and 20-fold with P20, and bolus injection induced pulmonary plasma clot lysis at doses inversely related to their clearance. Intravenous bolus injection of 5 mg of the P5, P10, or P20 variants in AMI patients was associated with plasma half-lives (t(1/2alpha)) of 13, 30, and 120 minutes and clearances of 75, 43, and 8 mL/min, respectively, compared with 3 minutes and 360 mL/min for SakSTAR. Injection of 5 mg P5 variant restored TIMI-3 flow within 60 minutes in 14 of 18 AMI patients (78%, 95% CI 55% to 91%) and of 2.5 mg in 7 of 11 patients (63%, 95% CI 35% to 85%), both in the absence of fibrinogen degradation. The immunogenicity of the variants was significantly (P:<0.002) reduced. CONCLUSIONS: The staphylokinase variant SY161-P5, derivatized with one linear polyethylene glycol molecule of M:(r) 5000, is a promising fibrin-selective agent for single-bolus coronary thrombolysis.

Enhanced Ca(2+) release and Na/Ca exchange activity in hypertrophied canine ventricular myocytes: potential link between contractile adaptation and arrhythmogenesis.

BACKGROUND: Ventricular arrhythmias are a major cause of sudden death in patients with heart failure and hypertrophy. The dog with chronic complete atrioventricular block (CAVB) has biventricular hypertrophy and ventricular arrhythmias and is a useful model to study underlying cellular mechanisms. We investigated whether changes in Ca(2+) homeostasis are part of the contractile adaptation to CAVB and might contribute to arrhythmogenesis. METHODS AND RESULTS: In enzymatically isolated myocytes, cell shortening, Ca(2+) release from the sarcoplasmic reticulum (SR), and SR Ca(2+) content were enhanced at low stimulation frequencies. Ca(2+) influx through L-type Ca(2+) channels was unchanged, but Ca(2+) influx via the Na/Ca exchanger was increased and contributed to Ca(2+) loading of the SR. Inward Na/Ca exchange currents were also larger. Changes in Ca(2+) fluxes were less pronounced in the right versus left ventricle. CONCLUSIONS: Enhanced Na/Ca exchange activity may improve contractile adaptation to CAVB but at the same time facilitate arrhythmias by (1) increasing the propensity to Ca(2+) overload, (2) providing more inward current leading to (nonhomogeneous) action potential prolongation, and (3) enhancing (arrhythmogenic) currents during spontaneous Ca(2+) release.

Prediction of 1-year survival after thrombolysis for acute myocardial infarction in the global utilization of streptokinase and TPA for occluded coronary arteries trial.

BACKGROUND: When a patient survives thrombolysis for acute myocardial infarction, little information from large studies exists from which to estimate prognosis during follow-up visits. METHODS AND RESULTS: Baseline, in-hospital, and later survival data were collected from 41 021 patients enrolled in Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries, a randomized trial of 4 thrombolytic-heparin regimens with standard aspirin and beta-blockade. Cox proportional hazards models were developed to predict 1-year survival in 30-day survivors (n=37 869) from baseline clinical and ECG factors and in-hospital factors; a combined model then was developed (C-index 0.800). The model was simplified into a nomogram to predict individual outcomes (C-index 0.754). Factors reflecting demographics (advanced age, lighter weight), larger infarctions (higher Killip class, lower blood pressure, faster heart rate, longer QRS duration), cardiac risk (smoking, hypertension, prior cerebrovascular disease), and arrhythmia were important predictors of death between 30 days and 1 year. Black race was associated with a substantial increase in risk after considering other factors. Revascularization was associated with reduced risk between 30 days and 1 year. CONCLUSIONS: When evaluating a patient who has survived acute infarction treated with thrombolysis, clinicians can estimate the likelihood of survival from factors easily measured during admission. Although many risk factors clearly relate to age, left ventricular dysfunction, or clinical instability, black race is an unexplained risk factor requiring further examination.

Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs.

BACKGROUND: Although improved epicardial blood flow (as assessed with either TIMI flow grades or TIMI frame count) has been related to reduced mortality after administration of thrombolytic drugs, the relationship of myocardial perfusion (as assessed on the coronary arteriogram) to mortality has not been examined. METHODS AND RESULTS: A new, simple angiographic method, the TIMI myocardial perfusion (TMP) grade, was used to assess the filling and clearance of contrast in the myocardium in 762 patients in the TIMI (Thrombolysis In Myocardial Infarction) 10B trial, and its relationship to mortality was examined. TMP grade 0 was defined as no apparent tissue-level perfusion (no ground-glass appearance of blush or opacification of the myocardium) in the distribution of the culprit artery; TMP grade 1 indicates presence of myocardial blush but no clearance from the microvasculature (blush or a stain was present on the next injection); TMP grade 2 blush clears slowly (blush is strongly persistent and diminishes minimally or not at all during 3 cardiac cycles of the washout phase); and TMP grade 3 indicates that blush begins to clear during washout (blush is minimally persistent after 3 cardiac cycles of washout). There was a mortality gradient across the TMP grades, with mortality lowest in those patients with TMP grade 3 (2.0%), intermediate in TMP grade 2 (4.4%), and highest in TMP grades 0 and 1 (6.0%; 3-way P=0.05). Even among patients with TIMI grade 3 flow in the epicardial artery, the TMP grades allowed further risk stratification of 30-day mortality: 0.73% for TMP grade 3; 2.9% for TMP grade 2; 5.0% for TMP grade 0 or 1 (P=0.03 for TMP grade 3 versus grades 0, 1, and 2; 3-way P=0.066). TMP grade 3 flow was a multivariate correlate of 30-day mortality (OR 0.35, 95% CI 0.12 to 1.02, P=0.054) in a multivariate model that adjusted for the presence of TIMI 3 flow (P=NS), the corrected TIMI frame count (OR 1.02, P=0.06), the presence of an anterior myocardial infarction (OR 2.3, P=0.03), pulse rate on admission (P=NS), female sex (P=NS), and age (OR 1.1, P<0.001). CONCLUSIONS: Impaired perfusion of the myocardium on coronary arteriography by use of the TMP grade is related to a higher risk of mortality after administration of thrombolytic drugs that is independent of flow in the epicardial artery. Patients with both normal epicardial flow (TIMI grade 3 flow) and normal tissue level perfusion (TMP grade 3) have an extremely low risk of mortality.

Relationship between TIMI frame count and clinical outcomes after thrombolytic administration. Thrombolysis In Myocardial Infarction (TIMI) Study Group.

BACKGROUND: The corrected TIMI frame count (CTFC) is the number of cine frames required for dye to first reach standardized distal coronary landmarks, and it is an objective and quantitative index of coronary blood flow. METHODS AND RESULTS: The CTFC was measured in 1248 patients in the TIMI 4, 10A, and 10B trials, and its relationship to clinical outcomes was examined. Patients who died in the hospital had a higher CTFC (ie, slower flow) than survivors (69. 6+/-35.4 [n=53] versus 49.5+/-32.3 [n=1195]; P=0.0003). Likewise, patients who died by 30 to 42 days had higher CTFCs than survivors (66.2+/-36.4 [n=57] versus 49.9+/-32.1 [n=1059]; P=0.006). In a multivariate model that excluded TIMI flow grades, the 90-minute CTFC was an independent predictor of in-hospital mortality (OR=1.21 per 10-frame rise [95% CI, 1.1 to 1.3], an approximately 0.7% increase in absolute mortality for every 10-frame rise; P<0.001) even when other significant correlates of mortality (age, heart rate, anterior myocardial infarction, and female sex) were adjusted for in the model. The CTFC identified a subgroup of patients with TIMI grade 3 flow who were at a particularly low risk of adverse outcomes. The risk of in-hospital mortality increased in a stepwise fashion from 0.0% (n=41) in patients with a 90-minute CTFC that was faster than the 95% CI for normal flow (0 to 13 frames, hyperemia, TIMI grade 4 flow), to 2.7% (n=18 of 658 patients) in patients with a CTFC of 14 to 40 (a CTFC of 40 has previously been identified as the cutpoint for distinguishing TIMI grade 3 flow), to 6.4% (35/549) in patients with a CTFC >40 (P=0.003). Although the risk of death, recurrent myocardial infarction, shock, congestive heart failure, or left ventricular ejection fraction 20 to

Noninvasive quantification of the contractile reserve of stunned myocardium by ultrasonic strain rate and strain.

BACKGROUND: We sought to investigate ultrasonic strain rate and strain as new indices to quantify the contractile reserve of stunned myocardium during dobutamine infusion. METHODS AND RESULTS: Stunning of the left ventricular posterior wall was induced in 9 closed-chest pigs after 30 minutes of severe hypoperfusion followed by 60 minutes of reperfusion of the left circumflex coronary artery territory. A second group of 7 animals had no coronary occlusion and served as normal controls. An incremental dobutamine infusion protocol was used in both groups. Changes in regional radial function were monitored by use of ultrasound-derived maximal systolic radial strain rate (SR) and systolic strain (epsilon). In the control group, dobutamine induced an increase in both SR and maximal dP/dt, which correlated linearly (r=0.85). Conversely, epsilon values increased at low doses of dobutamine (2.5 to 5 microg. kg(-1). min(-1)) but decreased during higher infusion rates (10 to 20 microg. kg(-1). min(-1)). During circumflex hypoperfusion, SR and epsilon of the posterior wall decreased from 5.0+/-0.3 s(-1) and 63+/-6% to 2.9+/-0.3 s(-1) and 27+/-4%, respectively (P<0.01). After 60 minutes of reperfusion, SR and epsilon failed to fully resume because of stunning, averaging 3.6+/-0.2 s(-1) and 35+/-3%, respectively (P=0.12 versus ischemia, P<0.05 versus baseline). During dobutamine infusion, SR increased at 5 microg. kg(-1). min(-1) and exceeded baseline values at 20 microg. kg(-1). min(-1) (P<0.05), whereas epsilon increased only at high doses and remained below baseline levels (P<0.05). CONCLUSIONS: The changes in regional function of stunned myocardium during inotropic stimulation could be characterized by use of ultrasonic deformation parameters. During dobutamine infusion, strain-rate values quantified the contractile reserve better than strain values.

Dose-finding, safety, and tolerability study of an oral platelet glycoprotein IIb/IIIa inhibitor, lotrafiban, in patients with coronary or cerebral atherosclerotic disease.

BACKGROUND: Antiplatelet therapy is the mainstay of the treatment and secondary prevention of cardiovascular and cerebrovascular ischemic events. We assessed the safety, tolerability, and pharmacodynamics of lotrafiban, an oral platelet glycoprotein IIb/IIIa inhibitor, as a secondary prevention strategy in patients with cerebrovascular or cardiovascular disease. METHODS AND RESULTS: Overall, 451 patients with a recent cardiovascular or cerebrovascular acute ischemic event were randomized in a double-blind fashion to 1 of 5 dosing regimens for 12 weeks: placebo or 5, 20, 50, or 100 mg lotrafiban, both twice daily with 300 to 325 mg/d aspirin. The primary end point was the incidence and tolerability of major and minor bleeding during treatment. Secondary end points included inhibition of platelet aggregation and clinical events. The placebo and lotrafiban 5-mg groups had similarly low rates of minor and major bleeding, but the 100-mg arm was terminated early because of excess major bleeding. Protocol-defined thrombocytopenia (<100 000 platelets/microL) occurred in 5 lotrafiban-treated patients (1.4%, 95% CI 0.2% to 2.7%) and 1 placebo patient (1.1%, 95% CI 0% to 3.1%). Three lotrafiban-treated patients had a nadir platelet count <20 000/microL (0.9%, 95% CI 0% to 1.8%). Lotrafiban produced dose-dependent inhibition of platelet aggregation; 5 mg lotrafiban did not differ significantly from placebo, whereas 100 mg inhibited aggregation by nearly 100%. CONCLUSIONS: -Lotrafiban provides dose-dependent platelet inhibition when administered to a range of patients with atherosclerosis. The level of platelet inhibition appears to correlate with bleeding risk and drug tolerability.

Treatment of reinfarction after thrombolytic therapy for acute myocardial infarction: an analysis of outcome and treatment choices in the global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries (gusto I) and assessment of the safety of a new thrombolytic (assent 2) studies.

BACKGROUND: Early reinfarction after thrombolytic therapy is associated with adverse outcomes and increased mortality. Among patients with reinfarction in the 1992 Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO I) and the 1998 Assessment of the Safety of a New Thrombolytic (ASSENT 2) trials, we investigated temporal and regional differences in the use of repeat thrombolysis, revascularization (angioplasty and/or bypass surgery), or conservative measures and the outcomes of each management strategy. METHODS AND RESULTS: Data from the 4% of patients (n=2301) who experienced reinfarction after thrombolytic therapy were studied. Baseline characteristics, 30-day mortality, and incidence of total and hemorrhagic strokes were compared among the 3 treatment groups. The 30-day mortality did not differ between the repeat thrombolysis and revascularization groups (P=0.72), and it was significantly lower among patients treated by these 2 strategies than in those treated conservatively (11% and 11% versus 28%, respectively; P<0.001). Stroke rates did not differ significantly between the 3 treatment strategies (P=0.49). From 1992 to 1998, the percentage of reinfarction patients treated with repeat thrombolysis decreased from 29.3% to 18.5% in US centers and from 51.4% to 41.9% in all other centers (P<0.001). In contrast, use of revascularization procedures increased from 33.5% to 47.9% in US centers and from 8.1% to 23.0% in all other centers (P<0.001). CONCLUSIONS: Repeat thrombolysis and revascularization are associated with significantly lower mortality among reinfarction patients. Randomized trials are necessary to assess the exact risks and benefits of rethrombolysis versus interventional revascularization in this subset of high-risk patients presenting with reinfarction after thrombolytic therapy.

Benefit of glycoprotein IIb/IIIa inhibition in patients with acute coronary syndromes and troponin t-positive status: the paragon-B troponin T substudy.

BACKGROUND: Troponin T (TnT) is valuable for short- and long-term risk stratification of patients with acute coronary syndromes (ACS). It also may predict which ACS patients will benefit from glycoprotein (GP) IIb/IIIa blockade. METHODS AND RESULTS: We prospectively studied 1160 patients with non-ST-segment elevation ACS randomized in PARAGON-B to receive lamifiban, an intravenous GP IIb/IIIa antagonist, or placebo. TnT levels were obtained before study treatment began and 24 to 72 hours later; assays were performed by a blinded core laboratory. At baseline, 40.2% of patients were TnT-positive (>/=0.1 ng/mL); these patients were older and more often male or smokers. Patients positive at baseline had a significantly higher rate of the primary end point (composite of death, myocardial [re]infarction, or severe recurrent ischemia at 30 days; odds ratio, 1.5; 95% CI, 1.1 to 2.1) than those who were TnT-negative. Lamifiban was associated with significant reduction in the primary end point (from 19.4% to 11.0%, P=0.01) among TnT-positive patients but not among TnT-negative patients (11.2% for placebo versus 10.8% for lamifiban, P=0.86; P=0.08 for test of interaction between TnT status and treatment assignment). This pattern held for the end points of death alone and death or myocardial (re)infarction at 30 days. Peak TnT level at 48 hours did not differ with lamifiban treatment. CONCLUSIONS: TnT predicts poor short-term outcomes in non-ST-segment elevation ACS. Treatment benefit with lamifiban is limited almost exclusively to TnT-positive patients, reducing 30-day adverse outcomes to a rate nearly identical to that of negative patients.

Efficacy and safety of tenecteplase in combination with the low-molecular-weight heparin enoxaparin or unfractionated heparin in the prehospital setting: the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 PLUS randomized trial in acute myocardial infarction.

BACKGROUND: The combination of a single-bolus fibrinolytic and a low-molecular-weight heparin may facilitate prehospital reperfusion and further improve clinical outcome in patients with ST-elevation myocardial infarction. METHODS AND RESULTS: In the prehospital setting, 1639 patients with ST-elevation myocardial infarction were randomly assigned to treatment with tenecteplase and either (1) intravenous bolus of 30 mg enoxaparin (ENOX) followed by 1 mg/kg subcutaneously BID for a maximum of 7 days or (2) weight-adjusted unfractionated heparin (UFH) for 48 hours. The median treatment delay was 115 minutes after symptom onset (53% within 2 hours). ENOX tended to reduce the composite of 30-day mortality or in-hospital reinfarction, or in-hospital refractory ischemia to 14.2% versus 17.4% for UFH (P=0.080), although there was no difference for this composite end point plus in-hospital intracranial hemorrhage or major bleeding (18.3% versus 20.3%, P=0.30). Correspondingly, there were reductions in in-hospital reinfarction (3.5% versus 5.8%, P=0.028) and refractory ischemia (4.4% versus 6.5%, P=0.067) but increases in total stroke (2.9% versus 1.3%, P=0.026) and intracranial hemorrhage (2.20% versus 0.97%, P=0.047). The increase in intracranial hemorrhage was seen in patients >75 years of age. CONCLUSIONS: Prehospital fibrinolysis allows 53% of patients to receive reperfusion treatment within 2 hours after symptom onset. The combination of tenecteplase with ENOX reduces early ischemic events, but lower doses of ENOX need to be tested in elderly patients. At present, therefore, tenecteplase and UFH are recommended as the routine pharmacological reperfusion treatment in the prehospital setting.

Abciximab improves both epicardial flow and myocardial reperfusion in ST-elevation myocardial infarction. Observations from the TIMI 14 trial.

BACKGROUND: In the presence of ST-elevation myocardial infarction, patients with successful epicardial reperfusion (TIMI 3 flow) but persistent ST elevation on a 12-lead ECG are at high risk for subsequent death and left ventricular dysfunction. In the TIMI 14 trial, a dose-ranging angiographic study, combined therapy with abciximab plus reduced-dose tPA enhanced the speed and efficacy of epicardial reperfusion. We determined whether the combination of abciximab plus reduced-dose tPA provided additional benefit in terms of myocardial reperfusion, as evidenced by greater resolution of ST elevation. METHODS AND RESULTS: All 346 patients with interpretable baseline and 90-minute ECGs, treated with either tPA alone or abciximab plus reduced-dose tPA (combination therapy), were included. Patients receiving combination therapy (n=221) had a 59% rate of complete (>/=70%) ST resolution at 90 minutes versus 37% in those treated with tPA alone (n=125) (P<0.0001). When the analysis was limited to patients with TIMI 3 flow, patients treated with combination therapy (n=151) remained significantly more likely to achieve complete ST resolution than those receiving tPA alone (n=80) (69% versus 44%; P=0.0002). CONCLUSIONS: Combination therapy with abciximab and reduced-dose tPA improves myocardial (microvascular) reperfusion, as reflected in greater ST-segment resolution, in addition to epicardial flow. This finding may translate into improved clinical outcomes by enhancing myocardial salvage.

High levels of platelet inhibition with abciximab despite heightened platelet activation and aggregation during thrombolysis for acute myocardial infarction: results from TIMI (thrombolysis in myocardial infarction) 14.

BACKGROUND: We evaluated platelet activation and aggregation in patients with acute myocardial infarction (AMI) treated with thrombolytic therapy alone or with reduced-dose thrombolysis and concomitant abciximab. METHODS AND RESULTS: The study was performed in 20 control subjects and 51 patients with AMI before and after reperfusion with either alteplase or reteplase or reduced doses of these agents with concomitant abciximab. Platelet activation was assayed by platelet surface expression of P-selectin. Turbidometric platelet aggregation in response to ADP was measured in patients before thrombolytic therapy and 90 minutes and 24 hours after the beginning of thrombolytic therapy. P-selectin expression was greater at baseline in patients than normal control subjects (30.4% versus 9. 8%, P<0.0001) but was identical between the 2 groups after stimulation with ADP (64.4% versus 69.3%, P=0.37). However, at 24 hours, basal P-selectin expression declined in patients (P=0.0025 versus baseline), whereas ADP-stimulated P-selectin expression was lower in patients than in control subjects (48% versus 69%, P=0. 0004). When combined with reduced doses of either alteplase or reteplase, abciximab achieved 91% and 83% inhibition of 5 and 20 micromol/L ADP-induced platelet aggregation, which decreased to 46% and 40%, respectively, at 24 hours. No appreciable difference in the platelet inhibition profile of abciximab was observed between the 2 thrombolytics. CONCLUSIONS: Platelet activation and aggregation are heightened in the setting of thrombolysis for AMI. Despite this enhanced level of platelet activation, abciximab, combined with a reduced-dose thrombolytic, inhibited platelet aggregation similarly to the level reported in elective settings.

Abciximab facilitates the rate and extent of thrombolysis: results of the thrombolysis in myocardial infarction (TIMI) 14 trial. The TIMI 14 Investigators.

BACKGROUND: The TIMI 14 trial tested the hypothesis that abciximab, the Fab fragment of a monoclonal antibody directed to the platelet glycoprotein (GP) IIb/IIIa receptor, is a potent and safe addition to reduced-dose thrombolytic regimens for ST-segment elevation MI. METHODS AND RESULTS: Patients (n=888) with ST-elevation MI presenting <12 hours from onset of symptoms were treated with aspirin and randomized initially to either 100 mg of accelerated-dose alteplase (control) or abciximab (bolus 0.25 mg/kg and 12-hour infusion of 0.125 microg. kg-1. min-1) alone or in combination with reduced doses of alteplase (20 to 65 mg) or streptokinase (500 000 U to 1.5 MU). Control patients received standard weight-adjusted heparin (70-U/kg bolus; infusion of 15 U. kg-1. h-1), whereas those treated with a regimen including abciximab received low-dose heparin (60-U/kg bolus; infusion of 7 U. kg-1. h-1). The rate of TIMI 3 flow at 90 minutes for patients treated with accelerated alteplase alone was 57% compared with 32% for abciximab alone and 34% to 46% for doses of streptokinase between 500 000 U and 1.25 MU with abciximab. Higher rates of TIMI 3 flow at both 60 and 90 minutes were observed with increasing duration of administration of alteplase, progressing from a bolus alone to a bolus followed by either a 30- or 60-minute infusion (P<0.02). The most promising regimen was 50 mg of alteplase (15-mg bolus; infusion of 35 mg over 60 minutes), which produced a 76% rate of TIMI 3 flow at 90 minutes and was tested subsequently in conjunction with either low-dose or very-low-dose (30-U/kg bolus; infusion of 4 U. kg-1. h-1) heparin. TIMI 3 flow rates were significantly higher in the 50-mg alteplase plus abciximab group versus the alteplase-only group at both 60 minutes (72% versus 43%; P=0.0009) and 90 minutes (77% versus 62%; P=0.02). The rates of major hemorrhage were 6% in patients receiving alteplase alone (n=235), 3% with abciximab alone (n=32), 10% with streptokinase plus abciximab (n=143), 7% with 50 mg of alteplase plus abciximab and low-dose heparin (n=103), and 1% with 50 mg of alteplase plus abciximab with very-low-dose heparin (n=70). CONCLUSIONS: Abciximab facilitates the rate and extent of thrombolysis, producing early, marked increases in TIMI 3 flow when combined with half the usual dose of alteplase. This improvement in reperfusion with alteplase occurred without an increase in the risk of major bleeding. Substantial reductions in heparin dosing may reduce the risk of bleeding even further. Modest improvements in TIMI 3 flow were seen when abciximab was combined with streptokinase, but there was an increased risk of bleeding.