ABSTRACT
Helical nanofibres play key roles in many biological processes. Entanglements between helices can aid gelation by producing thick, interconnected fibres, but the details of this process are poorly understood. Here, we describe the assembly of an achiral oligo(urea) peptidomimetic compound into supramolecular helices. Aggregation of adjacent helices leads to the formation of fibrils, which further intertwine to produce high-fidelity braids with periodic crossing patterns. A braid theory analysis suggests that braiding is governed by rigid topological constraints, and that branching occurs due to crossing defects in the developing braids. Mixed-chirality helices assemble into relatively complex, odd-stranded braids, but can also form helical bundles by undergoing inversions of chirality. The oligo(urea) assemblies are also highly sensitive to chiral amplification, proposed to occur through a majority-rules mechanism, whereby trace chiral materials can promote the formation of gels containing only homochiral helices.
ABSTRACT
We aimed to evaluate in a phase I dose-escalation study, the safety of intramuscular injections of a novel non-viral plasmid DNA expressing two isoforms of human hepatocyte growth factor (HGF) (VM202) in patients with critical limb ischemia (CLI). In total, 12 patients with CLI and unsuitable for revascularization were consecutively assigned to increasing doses (2 to 16 mg) of VM202 administered into the ischemic calf muscle at days 1 and 15. Patients were evaluated for safety and tolerability, changes in ankle- and toe brachial index (ABI and TBI), and pain severity score using a visual analog scale (VAS) throughout a 12-month follow-up period. Median age was 72 years and 53% of the patients were male. VM202 was safe and well tolerated with no death during the 12-month follow-up. Median ABI and TBI significantly increased from 0.35 to 0.52 (P=0.005) and from 0.15 to 0.24 (P=0.01) at 12 months follow-up. Median VAS decreased from 57.5 to 16.0 mm at 6 months follow-up (P=0.03). In this first human clinical trial, VM202, which expresses two isoforms of human HGF, appear to be safe and well tolerated with encouraging clinical results and thus supports the performance of a phase II randomized controlled trial.
Subject(s)
Genetic Therapy/adverse effects , Hepatocyte Growth Factor/genetics , Leg/blood supply , Peripheral Arterial Disease/therapy , Plasmids , Adult , Aged , Aged, 80 and over , Angiogenesis Inducing Agents/therapeutic use , Female , Gene Transfer Techniques , Genetic Therapy/methods , Hepatocyte Growth Factor/blood , Humans , Injections, Intramuscular , Ischemia/therapy , Male , Middle Aged , Pain Measurement , Protein Isoforms/geneticsABSTRACT
BACKGROUND: Enoxaparin has recently been shown to be superior to unfractionated heparin in patients with unstable angina/non-ST-elevation myocardial infarction. Theoretical advantages of low-molecular-weight heparin versus unfractionated heparin include a higher ratio of anti-Xa to anti-IIa activity (3:1 for enoxaparin), a more predictable dose response that precludes the need for frequent monitoring, and the convenience of subcutaneous administration. Both activated partial thromboplastin time and activated clotting time (ACT) are used to monitor anticoagulation with heparin, and ACTs are now standard during percutaneous coronary intervention (PCI) with heparin. At doses of up to 90 mg, subcutaneous enoxaparin leads to a modest dose-related increase in activated partial thromboplastin time, but the effect on ACT is unknown. METHODS: Thrombolysis In Myocardial Infarction (TIMI) 11A was a multicenter, dose-ranging trial to evaluate the safety and tolerability of subcutaneous enoxaparin in patients with unstable angina/non-ST-elevation myocardial infarction. We obtained peak (mean 4.3 hours after enoxaparin) and trough (mean 11.5 hours after enoxaparin) anti-Xa levels and ACTs for 26 patients in the TIMI 11A trial. RESULTS: Despite doses of enoxaparin in the range of 89 +/- 19 mg every 12 hours and significant increases in anti-Xa levels even at trough, there was no change in the ACT measured by HemoTec and only a small increase with Hemachron. The correlation of peak Hemachron ACT with peak anti-Xa levels was poor (R = 0.5, P =.08). CONCLUSIONS: In contrast to heparin, ACTs are not useful for assessment of anticoagulation with subcutaneous enoxaparin and should not be relied on in patients receiving enoxaparin who require acute PCI. Studies to determine the optimal dose, safety, and efficacy of enoxaparin in patients undergoing PCI are underway.
Subject(s)
Angina Pectoris/drug therapy , Anticoagulants/therapeutic use , Blood Coagulation/drug effects , Enoxaparin/therapeutic use , Insect Proteins , Myocardial Infarction/drug therapy , Angina Pectoris/blood , Anticoagulants/pharmacology , Cardiac Catheterization , Dose-Response Relationship, Drug , Drug Administration Schedule , Enoxaparin/administration & dosage , Enoxaparin/pharmacology , Humans , Injections, Subcutaneous , Myocardial Infarction/blood , Salivary Proteins and Peptides/blood , Whole Blood Coagulation TimeABSTRACT
BACKGROUND: Patients with severe myocardial ischemia who are not candidates for percutaneous or surgical revascularization have few therapeutic options. Therapeutic angiogenesis in animal models with use of recombinant human vascular endothelial growth factor (rhVEGF) has resulted in successful revascularization of ischemic myocardium. This was a dose escalation trial designed to determine the safety and tolerability of intracoronary rhVEGF infusions. METHODS AND RESULTS: Patients were eligible if they had stable exertional angina, a significant reversible perfusion defect by stress myocardial perfusion study, and coronary anatomy that was suboptimal for percutaneous coronary intervention or coronary artery bypass grafting. rhVEGF was administered to a total of 15 patients by 2 sequential (eg, right and left) intracoronary infusions, each for 10 minutes, at rates of 0.005 (n = 4), 0.017 (n = 4), 0.050 (n = 4), and 0.167 mg/kg/min (n = 3). Pharmacokinetic sampling and hemodynamic monitoring were performed for 24 hours. Radionuclide myocardial perfusion imaging was performed before treatment and at 30 and 60 days after treatment. Follow-up angiograms were performed on selected patients at 60 days. The maximally tolerated intracardiac dose of rhVEGF was 0.050 mg/kg/min. Minimal hemodynamic changes were seen at 0.0050 mg/kg/min (2% +/- 7% [SD] mean decrease in systolic blood pressure from baseline to nadir systolic blood pressure), whereas at 0.167 mg/kg/min there was a 28% +/- 7% mean decrease from baseline to nadir (136 to 95 mm Hg systolic). Myocardial perfusion imaging was improved in 7 of 14 patients at 60 days. All 7 patients with follow-up angiograms had improvements in the collateral density score. CONCLUSION: rhVEGF appears well tolerated by coronary infusion at rates up to 0.050 mg/kg/min. This study provides the basis for future clinical trials to assess the clinical benefit of therapeutic angiogenesis with rhVEGF.
Subject(s)
Coronary Disease/drug therapy , Endothelial Growth Factors/administration & dosage , Lymphokines/administration & dosage , Protein Isoforms/administration & dosage , Coronary Circulation/drug effects , Endothelial Growth Factors/pharmacology , Endothelial Growth Factors/therapeutic use , Humans , Lymphokines/pharmacology , Lymphokines/therapeutic use , Neovascularization, Physiologic/drug effects , Protein Isoforms/pharmacology , Protein Isoforms/therapeutic use , Recombinant Proteins/administration & dosage , Recombinant Proteins/pharmacology , Recombinant Proteins/therapeutic use , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth FactorsABSTRACT
We compared clinical outcomes following percutaneous transluminal coronary angioplasty (PTCA) for 77 chronic renal failure (CRF) (dialysis and nondialysis) patients and a control group matched for history of myocardial revascularization, specific revascularization procedure, gender, age, diabetes, number of native vessels diseased, number of vessels dilated, and the specific vessel(s) dilated. CRF patients had a higher incidence of peripheral vascular disease, hypertension, and more complex PTCA target lesion types than controls: 5% vs. 16% Type A, 12% vs. 28% Type B1, 44% vs. 41% Type B2, 39% vs. 15% Type C (p < 0.001). The primary success rate for PTCA in CRF patients and controls was 89% and 97% (p < 0.05). Survival analysis 24 months following PTCA showed a lower composite cardiac event-free survival (angiographic restenosis, myocardial infarction, coronary artery bypass surgery, and cardiac death) for those with CRF than controls, 54% vs. 69% (p = 0.002). Over the study period, 26 CRF patients died (11 from cardiac causes) compared to only 3 control patients (one from a cardiac cause); p < 0.001 for all cause and p < 0.003 for cardiac mortality. We also compared PTCA results between two categories of CRF patients. The first consisted of 49 end-stage renal disease (ESRD) patients on dialysis and the second included 28 patients not on dialysis (13 with creatinine > 2. 0 mg/dL and 15 with ESRD post-renal transplant). Both subgroups had similar coronary anatomy, including PTCA, target lesion type, and acute and long-term outcomes. In conclusion, we observed acceptable primary success and complication rates for PTCA in CRF patients compared with controls matched for comorbid features despite more complex target lesion morphology. Poorer long-term outcomes, however, were apparent for those with CRF regardless of dialysis dependence and likely relate to more extensive atherosclerosis and complex target coronary lesions at index PTCA as well as other features related to CRF.
Subject(s)
Angioplasty, Balloon, Coronary , Coronary Disease/therapy , Kidney Failure, Chronic/complications , Renal Dialysis , Coronary Angiography , Coronary Disease/complications , Coronary Disease/diagnosis , Echocardiography , Female , Humans , Kidney Failure, Chronic/therapy , Male , Middle Aged , Radionuclide Ventriculography , Retrospective Studies , Treatment OutcomeABSTRACT
The objective of this study was to detect myocardial injury defined by an increase of plasma cardiac troponin I (cTnI) following percutaneous transluminal coronary angioplasty (PTCA) and compare plasma cTnI with the risk of cardiac complications at 30 days. Plasma cTnI, creatine kinase (CK) MB, and total CK were determined in 83 patients before (baseline) and 6, 12 and 24 h after PTCA. Thirty-eight patients underwent conventional PTCA, 39 PTCA-stent and six rotational atherectomy. Patients with acute myocardial infarction (AMI) and increased pre-procedural cTnI >0.8 microg/l were categorized into group 1 (n=23). The remaining 60 patients (pre-procedural cTnI=0.8 microg/l) were categorized as follows: group 2 (n=15) AMI; group 3 (n=20) unstable angina (UA); group 4 (n=25) coronary artery disease (CAD). Twelve hours post-procedure, all three cardiac markers were more frequently increased over baseline in group 2 patients (40-60%) compared to patients in group 3 (5-29%, P<0.03) or group 4 (0.5-5%, P<0.01). This was also true for patients undergoing PTCA-stent compared to conventional PTCA or rotational atherectomy (27-40 vs. 4-14%, P<0.02). cTnI was more sensitive (60%) to detect release of myocardial protein after PTCA compared to total CK (47%) or CKMB (43%). A moderate increase of cTnI (0.8-1.5 microg/l) in groups 2, 3 and 4 was associated with higher risk of complications 30 days post-procedure.
Subject(s)
Angioplasty, Balloon, Coronary/adverse effects , Heart Diseases/etiology , Troponin I/blood , Aged , Angina, Unstable/etiology , Creatine Kinase/blood , Female , Heart Arrest/etiology , Humans , Isoenzymes/blood , Male , Middle Aged , Risk Factors , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: RPR 109891 is a modified tetrapeptide glycoprotein IIb/IIIa inhibitor available in intravenous and oral formulations. Two phase II dose-ranging studies were performed to investigate pharmacodynamics and safety in acute coronary syndromes. METHODS: The Thrombolysis In Myocardial Infarction (TIMI) 15A trial was a randomized, open-label, study of RPR 109891 administered intravenously for 24 to 96 hours in 91 patients. TIMI 15B was a randomized, double-blind comparison of intravenous RPR 109891 plus 4 weeks of oral RPR 109891 (n = 142) compared with placebo (n = 50). RESULTS: Intravenous RPR 109891 exhibited a dose-response inhibition of platelet aggregation; mean inhibition after a bolus ranged from 53% to 92%, and at steady state 49% to 98%. Oral RPR 109891 demonstrated less platelet inhibition (peaks, range 48% to 59%; troughs, range 18% to 39%). Mean glycoprotein IIb/IIIa receptor occupancy and platelet inhibition were highly correlated (r = 0.82, 95% confidence interval 0.74-0.88). There were trends for increased major hemorrhage (10% vs 6%, P =.57), thrombocytopenia <90,000 cells/mm(3) (13% vs 4%, P =.11), and profound thrombocytopenia <20, 000 (3.5% vs 0%, P =.33) with intravenous plus oral RPR 109891 compared with placebo. In 3 of 5 cases of profound thrombocytopenia, RPR 109891 had been interrupted because of bypass surgery, and a precipitous fall in platelet count occurred after the first postoperative oral dose. CONCLUSIONS: Intravenous RPR 109891 is a potent, predictable, dose-related platelet inhibitor. Oral RPR 109891 (=600 mg/d) achieves moderate platelet inhibition. Interrupted glycoprotein IIb/IIIa blockade may be associated with a higher risk of profound thrombocytopenia and deserves closer examination in future studies.
Subject(s)
Myocardial Infarction/drug therapy , Peptides/administration & dosage , Platelet Aggregation Inhibitors/administration & dosage , Administration, Oral , Adolescent , Adult , Aged , Dose-Response Relationship, Drug , Double-Blind Method , Female , Follow-Up Studies , Hemorrhage/chemically induced , Hemorrhage/epidemiology , Humans , Infusions, Intravenous , Male , Middle Aged , Myocardial Infarction/mortality , Peptides/adverse effects , Platelet Aggregation Inhibitors/adverse effects , Probability , Reference Values , Survival Rate , Thrombocytopenia/chemically induced , Thrombocytopenia/epidemiology , Treatment OutcomeABSTRACT
BACKGROUND: Animal models of therapeutic angiogenesis have stimulated development of clinical application in patients with limited options for coronary revascularization. The impact of recombinant human vascular endothelial growth factor (rhVEGF) on myocardial perfusion in humans has not been reported. METHODS AND RESULTS: Fourteen patients underwent exercise (n=11), dobutamine (n=2), or dipyridamole (n=1) myocardial perfusion single photon emission CT (SPECT) before as well as 30 and 60 days after rhVEGF administration. After uniform processing and display, 2 observers blinded to the timing of the study and dose of rhVEGF reviewed the SPECT images. By a visual, semiquantitative 20-segment scoring method, summed stress scores (SSS) and summed rest scores (SRS) were generated. Although the SSS did not change from baseline to 30 days (21.6 versus 21.5; P=NS), the SRS improved after rhVEGF (13.2 versus 10.4; P<0.05). Stress and rest perfusion improved in >2 segments infrequently in patients treated with low-dose rhVEGF. However, 5 of 6 patients had improvement in >2 segments at rest and stress with the higher rhVEGF doses. Furthermore, although neither the SSS nor the SRS changed in patients treated with the low doses, the SRS decreased in the high-dose rhVEGF patients at 60 days (14.7 versus 10.7; P<0.05). Quantitative analysis was consistent with the visual findings but failed to demonstrate statistical significance. CONCLUSIONS: Although not designed to demonstrate rhVEGF efficacy, these phase 1 data support the concept that rhVEGF improves myocardial perfusion at rest and provide evidence of a dose-dependent effect.
Subject(s)
Coronary Circulation/drug effects , Endothelial Growth Factors/administration & dosage , Lymphokines/administration & dosage , Cardiotonic Agents , Coronary Disease/physiopathology , Coronary Vessels/diagnostic imaging , Dipyridamole , Dobutamine , Dose-Response Relationship, Drug , Double-Blind Method , Endothelial Growth Factors/therapeutic use , Exercise Test , Humans , Injections, Intra-Arterial , Lymphokines/therapeutic use , Recombinant Proteins/therapeutic use , Tomography, Emission-Computed, Single-Photon , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors , Vasodilator AgentsSubject(s)
Endothelial Growth Factors/therapeutic use , Myocardial Ischemia/therapy , Neovascularization, Physiologic , Forecasting , Humans , Lymphokines/therapeutic use , Myocardial Reperfusion/methods , Neovascularization, Pathologic/etiology , Risk Factors , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth FactorsABSTRACT
The presence of thrombus increases the rate of acute complications and restenosis in percutaneous revascularization of native coronary arteries and saphenous vein grafts. Rheolytic thrombectomy uses high velocity saline jets to create a Bernoulli effect for thrombus entrainment, dissociation, and evacuation of debris, providing a novel approach to the treatment of thrombotic lesions. The study objective was to determine the preclinical safety and effectiveness of a 5 French rheolytic thrombectomy catheter designed for use in coronary arteries and saphenous vein grafts. In vitro testing was performed to evaluate catheter effectiveness (clot removal rate) and safety (particle generation and hemolysis). This was followed by acute (n = 6) and chronic (n = 6) canine studies to determine hemodynamic, angiographic, and histopathologic effects of the catheter. The results showed effective clot removal with minimal embolization: 99.4% of the total clot volume was removed with only 0.1% proximal embolization and 0.5% distal embolization. 98.4% of the embolic particles were less than 10 microm. Canine studies revealed no significant angiographic, hemodynamic, histopathologic, or electrocardiographic abnormalities with the exception of transient heart block in one animal. There was transient hemolysis which normalized within 24 hours with no adverse effects. These results demonstrate the effectiveness and safety of coronary rheolytic thrombectomy and provided the basis for clinical trials to further evaluate this promising new approach for coronary thrombectomy.
Subject(s)
Catheterization , Coronary Thrombosis/therapy , Thrombectomy/instrumentation , Thrombectomy/methods , Animals , Coronary Artery Bypass , Coronary Vessels , Dogs , Equipment Design , Hemorheology , Models, Cardiovascular , Saphenous Vein , Sodium Chloride/administration & dosage , Sodium Chloride/therapeutic use , Swine/bloodABSTRACT
BACKGROUND: Inhibitors of the platelet glycoprotein IIb/IIIa receptor given intravenously have been shown to be effective in reducing ischemic complications after coronary angioplasty and in unstable angina, making this a promising new class of agents for the treatment and prevention of ischemic events in patients with acute coronary syndromes. Sibrafiban (Ro 48-3657) is an oral, peptidomimetic, selective antagonist of the glycoprotein IIb/IIIa receptor. METHODS AND RESULTS: The Thrombolysis in Myocardial Infarction (TIMI) 12 trial was a phase II, double-blind, dose-ranging trial designed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of sibrafiban in 329 patients after acute coronary syndromes. In the PK/PD cohort of TIMI 12, 106 patients were randomized to receive one of seven dosing regimens of sibrafiban, ranging from 5 mg daily to 10 mg twice daily for 28 days. In the safety cohort, 223 patients were randomized to one of four dose regimens of sibrafiban (ranging from 5 mg twice daily to 15 mg once daily) or aspirin for 28 days. High levels of platelet inhibition were achieved: mean peak values ranged from 47% to 97% inhibition of 20 micromol/L ADP-induced platelet aggregation on day 28 across the seven doses. Twice-daily dosing provided more sustained platelet inhibition (mean inhibition, 36% to 86% on day 28), whereas platelet inhibition returned to baseline levels by 24 hours with once-daily dosing. Major hemorrhage occurred in 1.5% of patients treated with sibrafiban and in 1.9% of patients treated with aspirin. Protocol-defined "minor" bleeding, usually mucocutaneous, occurred in 0% to 32% of patients in the various sibrafiban groups and in none of the patients treated with aspirin. Minor bleeding was related to total daily dose (P=.002), once- versus twice-daily dosing (P<.0001), renal function (P<.0001), and presentation with unstable angina (P<.01). CONCLUSIONS: The oral glycoprotein IIb/IIIa antagonist sibrafiban achieved effective, long-term platelet inhibition with a clear dose-response but at the expense of a relatively high incidence of minor bleeding. Oral IIb/IIIa inhibition deserves further study as a new treatment strategy in patients after acute coronary syndromes.
Subject(s)
Coronary Disease/drug therapy , Oximes/administration & dosage , Piperidines/administration & dosage , Platelet Aggregation Inhibitors/administration & dosage , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Acute Disease , Administration, Oral , Aged , Cohort Studies , Coronary Disease/physiopathology , Dose-Response Relationship, Drug , Double-Blind Method , Female , Hemorrhage/chemically induced , Humans , Male , Middle Aged , Oximes/adverse effects , Oximes/therapeutic use , Piperidines/adverse effects , Piperidines/therapeutic use , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/adverse effects , Platelet Aggregation Inhibitors/therapeutic use , RecurrenceABSTRACT
Patients with cocaine-related chest pain with electrocardiographic (ECG) abnormalities are often admitted to rule out acute myocardial infarction (AMI). Cardiac troponin I and T should be superior to measurement of creatine kinase (CK)-MB for detecting cardiac injury in patients with coexisting skeletal muscle injury. We prospectively evaluated 19 consecutive patients with acute chest pain related to cocaine use who were hospitalized to rule out AMI. The admission ECG was abnormal in 16 of 19 patients. Total CK and CK-MB were elevated during the hospital course in 14 and 3 patients, respectively. Cardiac troponin I and cardiac troponin T levels were within normal limits in all patients demonstrating that recent myocardial injury did not occur. Clinically, no patient had an AMI. Cocaine-induced thoracic skeletal muscle injury or transient cocaine-induced coronary vasospasm should be considered as alternative sources of chest pain in these patients.
Subject(s)
Chest Pain/metabolism , Cocaine/adverse effects , Myocardium/chemistry , Troponin I/analysis , Troponin/analysis , Adult , Biomarkers/chemistry , Chest Pain/chemically induced , Diagnosis, Differential , Electrocardiography , Humans , Middle Aged , Myocardial Infarction/diagnosis , Prospective Studies , Troponin TABSTRACT
The authors report the use of cardiac troponin I (cTnI) for the early, noninvasive determination of coronary reperfusion following thrombolytic therapy. Cardiac troponin I, creatine kinase (CK)-MB, and myoglobin concentrations were measured in early serum specimens at 30, 60, and 90 minutes after initiation of therapy (0 minutes) in 25 consecutive patients given front-loaded rt-PA during acute myocardial infarction. Angiography, determined at 90 minutes after therapy, was used to classify patients as follows: group I (n = 17) reperfusion (TIMI flow grade 2, 3); and group 2 (n = 8) absence of reperfusion (TIMI flow grade 0, 1). The authors calculated the ratio increase in cTnI (delta cTnI), CK-MB (delta CK-MB), and myoglobin (delta myoglobin) 90 minutes after therapy in group 1 and 2. Serum cTnI, CK-MB and myoglobin concentrations significantly increased at 60 and 90 minutes in group 1, but not in group 2. Delta cTnI, delta CK-MB, and delta myoglobin levels were significantly increased in group 1 versus group 2 at 90 minutes. Further, delta cTnI was significantly greater at 90 minutes within group 1 compared to delta CK-MB and delta myoglobin. The sensitivity for detecting reperfusion at 90 minutes angiography using threshold values of 6.0 for delta cTnI, 7.0 for delta CK-MB, and 5.0 for delta myoglobin were: delta cTnI 82.4%; delta CK-MB 64.7%; delta myoglobin 76.5%; respectively. This study indicates that early serial measurements of cTnI were a more accurate predictor of early coronary artery reperfusion 90 minutes after thrombolytic therapy compared to CK-MB and myoglobin. Larger population studies will be necessary to confirm these finding.
Subject(s)
Coronary Circulation , Myocardial Infarction/drug therapy , Myocardial Reperfusion , Thrombolytic Therapy , Troponin/blood , Creatine Kinase/blood , Female , Humans , Isoenzymes , Male , Myoglobin/blood , Sensitivity and Specificity , Time Factors , Troponin IABSTRACT
Because time to treatment in AMI is a critical factor in long-term outcome, it is important that complex trials designed to improve reperfusion therapy do not delay the time to treatment. Participation in the TIMI 5 trial did not significantly prolong our door-to-needle time. These results indicate that, if done carefully, complex, labor-intensive studies can be performed within a reasonable time limit. Care should be taken to design protocols incorporating easy drug preparation, informed consent by the ED, and efficiency of trial initiation.
Subject(s)
Clinical Trials as Topic , Emergency Service, Hospital , Myocardial Infarction/drug therapy , Thrombolytic Therapy , Electrocardiography , Heparin/therapeutic use , Hirudin Therapy , Humans , Italy , Myocardial Infarction/diagnosis , Research , Streptokinase/therapeutic use , Time Factors , United StatesABSTRACT
It is important to establish as soon as possible whether patients who present with chest pain are having an acute myocardial infarction (AMI). Ideally, sensitive and specific serum myocardial markers could provide the basis for early detection as well as determine the status of reperfusion following thrombolytic therapy. The present study examined the utility of cardiac troponin I (cTnI), CK-MB, and myoglobin for the sensitive and specific detection of AMI in 98 consecutive patients presenting to the emergency department (ED) with chest pain. In addition, cardiac troponin T (cTnT), CK-MB, and myoglobin samples were measured over a 90 min time period following thrombolytic therapy in nine separate AMI patients to assess reperfusion. In the ED study, CK-MB, myoglobin, and cTnI were equally sensitive (100%) for the detection of AMI in patients who presented 7.4-14 h after onset of chest pain. However, cTnI was the most specific serum marker (specificity 91.9% compared to CK-MB 85.6%, myoglobin 61.4%). Five of the six non-related AMI patients who had an elevated cTnI had clinically documented myocardial involvement. In the reperfusion study, cTnT, CK-MB and myoglobin, relative increases were greater in reperfused compared to non-reperfused patients. Within the reperfused group, the relative increase of cTnT was greater than CK-MB and myoglobin at 90 min following thrombolytic therapy. These findings show the clinical utility of cardiac-specific troponins as markers for the early detection of AMI and monitoring of reperfusion following thrombolytic therapy.
Subject(s)
Creatine Kinase/blood , Myocardial Infarction/diagnosis , Myocardial Reperfusion , Myoglobin/blood , Thrombolytic Therapy , Troponin/blood , Humans , Isoenzymes , Myocardial Infarction/blood , Myocardial Infarction/drug therapy , Troponin TABSTRACT
OBJECTIVES: The purpose of this study was to assess the value of recombinant desulfatohirudin (hirudin) as adjunctive therapy to thrombolysis in acute myocardial infarction. BACKGROUND: Failure to achieve initial reperfusion and reocclusion of the infarct-related artery remain major limitations of thrombolytic therapy despite aggressive regimens of heparin and aspirin. Hirudin, a direct thrombin inhibitor, has been shown in experimental models to enhance thrombolysis and reduce reocclusion. METHODS: The Thrombolysis in Myocardial Infarction (TIMI) 5 trial was a randomized, dose-ranging, pilot trial of hirudin versus heparin, given with front-loaded tissue-type plasminogen activator and aspirin to 246 patients with acute myocardial infarction. Patients received either intravenous heparin or hirudin at one of four ascending doses for 5 days. Patients underwent coronary angiography at 90 min and at 18 to 36 h, unless rescue angioplasty was performed. RESULTS: The primary end point, TIMI grade 3 flow in the infarct-related artery at 90 min and 18 to 36 h without death or reinfarction before the 18- to 36-h catheterization was achieved in 97 (61.8%) of 157 evaluable hirudin-treated patients compared with 39 (49.4%) of 79 evaluable heparin-treated patients (p = 0.07). All four doses of hirudin led to similar findings in the angiographic and clinical end points. At 90 min, TIMI grade 3 flow was present in 105 (64.8%) of 162 hirudin-treated patients compared with 48 (57.1%) of 84 heparin-treated patients (p = NS). Infarct-related artery patency (TIMI grade 2 or 3 flow) was similar in the two groups (82.1% and 78.6%, respectively). At 18 to 36 h, 129 (97.8%) of 132 hirudin-treated patients had a patent infarct-related artery compared with 58 (89.2%) of 65 heparin-treated patients (p = 0.01). Reocclusion by 18 to 36 h occurred in 2 (1.6%) of 123 hirudin-treated patients versus 4 (6.7%) of 60 heparin-treated patients (p = 0.07). Death or reinfarction occurred during the hospital period in 11 (6.8%) of 162 hirudin-treated patients compared with 14 (16.7%) of 84 heparin-treated patients (p = 0.02). Major spontaneous hemorrhage occurred in 1.2% of hirudin-treated patients versus 4.7% of heparin-treated patients (p = 0.09), and major hemorrhage at an instrumented site occurred in 16.3% and 18.6%, respectively (p = NS). CONCLUSIONS: Hirudin is a promising agent compared with heparin as adjunctive therapy with thrombolysis for acute myocardial infarction, and its evaluation in larger trials is warranted.
Subject(s)
Adjuvants, Pharmaceutic/therapeutic use , Fibrinolytic Agents/therapeutic use , Heparin/therapeutic use , Hirudins/analogs & derivatives , Myocardial Infarction/drug therapy , Thrombolytic Therapy/methods , Adult , Aged , Aspirin/therapeutic use , Coronary Angiography , Dose-Response Relationship, Drug , Female , Hirudin Therapy , Humans , Male , Middle Aged , Myocardial Infarction/diagnostic imaging , Partial Thromboplastin Time , Pilot Projects , Recombinant Proteins/therapeutic use , Survival Rate , Tissue Plasminogen Activator/therapeutic use , Treatment Outcome , Vascular PatencyABSTRACT
Percutaneous transluminal coronary balloon angioplasty (PTCA) has had limited success with higher complication and restenosis rates in aorto-ostial lesions. Directional coronary atherectomy (DCA) has been advocated as an alternative to PTCA in such lesions. In this report, we describe a potential complication of DCA in right coronary ostial lesions.
Subject(s)
Atherectomy, Coronary , Cardiac Catheterization/instrumentation , Coronary Artery Disease/surgery , Aged , Coronary Angiography , Coronary Artery Disease/diagnostic imaging , Humans , Intraoperative Complications , MaleABSTRACT
The initial electrocardiogram is crucial in accurately selecting patients with chest pain for thrombolytic therapy. An electrocardiogram with a large amount of ST-segment elevation and depression is "visually alarming," and therefore, may influence the efficiency of patient treatment with thrombolytic therapy. It was hypothesized that the amount of ST-segment deviation present on the initial electrocardiogram was an important variable in determining the time to initiation of thrombolysis in the emergency department. The time from arrival at the emergency department to thrombolysis was measured in 93 consecutive patients with suspected acute myocardial infarction (AMI) who were treated with intravenous thrombolytic therapy by emergency department physicians. This was correlated with the sum of ST-segment elevation and depression present on the initial electrocardiogram. AMI was proved in 83 patients (89%). In patients with proved AMI, the average time to thrombolysis was 50.8 +/- 25.6 minutes. Treatment began within the goal of < or = 30 minutes in 18 patients (22%) and was excessively delayed at > or = 60 minutes in 24 (29%). Regression analysis of multiple clinical variables revealed that ST-segment sum was the only variable that significantly influenced the time to thrombolysis (r = -0.42; p < 0.001). For patients treated in < or = 30 minutes, the average ST-segment sum was 21.1 +/- 13.5 vs 11.5 +/- 11.4 mm for those treated in > or = 60 minutes (p = 0.01). In 10 patients mistakenly treated with thrombolytic therapy, the electrocardiographic processes responsible for ST-segment elevation included the early repolarization variant, left ventricular hypertrophy, old anterior AMI with persistent ST-segment elevation, and conduction delay.(ABSTRACT TRUNCATED AT 250 WORDS)