Subject(s)
Corpus Callosum/surgery , Craniotomy/methods , Epilepsy/surgery , Factor VII Deficiency/physiopathology , Child , Factor VII Deficiency/drug therapy , Factor VIIa/administration & dosage , Humans , Intracranial Hemorrhages/physiopathology , Male , Recombinant Proteins/administration & dosageABSTRACT
AIMS: Patients with Q waves and T-wave inversion are generally at a later stage of the infarction process than patients without these changes. Our aim was to investigate whether a single assessment of electrocardiographic parameters at presentation would predict the proportion of myocardium salvageable by thrombolytic therapy. METHODS AND RESULTS: Electrocardiographic algorithms to calculate the potential and final infarct size have been developed and allow the proportion of myocardium salvageable with therapy to be calculated. This was measured in 146 patients with acute myocardial infarction who had angiography at a median of 91 min after streptokinase. The relationship between myocardial salvage and the electrocardiographic parameters at presentation (Q waves, T-wave inversion, quantitative ST segment changes, and the initial QRS score), was examined together with the 90-min angiographic parameters (TIMI flow grade and collateral grade), clinical parameters (haemodynamics and age), and time to therapy. Parameters that correlated with myocardial salvage included the initial QRS score (r=-0.56, P<0.0001), Q wave grade (r=-0.36, P<0.0001), number of leads with ST depression (r=0.28, P<0.001), maximum ST depression (r=0.27, P<0.01), T-inversion grade (r=-0.26, P<0.01), and TIMI flow grade at 90 min (r=0.21, P<0.02). The time from symptom onset to thrombolytic therapy did not correlate with salvage (r=-0.09). On multivariate analysis, only the initial QRS score and T-inversion grade on the initial electrocardiogram were independent predictors of salvage (multivariate r using both variables combined=0.57, P<0.001). CONCLUSIONS: The QRS score and T-wave inversion grade on the presenting electrocardiogram provide important information in predicting myocardial salvage. These parameters may help triage patients to appropriate therapies.
Subject(s)
Myocardial Infarction/diagnosis , Myocardial Infarction/drug therapy , Thrombolytic Therapy , Angiography , Electrocardiography , Female , Humans , Male , Middle AgedABSTRACT
CONTEXT: Cardiac troponins I (cTnI) and T (cTnT) are useful for assessing prognosis in patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI). However, the use of cardiac troponins for predicting benefit of an invasive vs conservative strategy in this patient population is not clear. OBJECTIVE: To prospectively test whether an early invasive strategy provides greater benefit than a conservative strategy in acute coronary syndrome patients with elevated baseline troponin levels. DESIGN: Prospective, randomized trial conducted from December 1997 to June 2000. SETTING: One hundred sixty-nine community and tertiary care hospitals in 9 countries. PARTICIPANTS: A total of 2220 patients with acute coronary syndrome were enrolled. Baseline troponin level data were available for analysis in 1821, and 1780 completed the 6-month follow-up. INTERVENTIONS: Patients were randomly assigned to receive (1) an early invasive strategy of coronary angiography between 4 and 48 hours after randomization and revascularization when feasible based on coronary anatomy (n = 1114) or (2) a conservative strategy of medical treatment and, if stable, predischarge exercise tolerance testing (n = 1106). Conservative strategy patients underwent coronary angiography and revascularization only if they manifested recurrent ischemia at rest or on provocative testing. MAIN OUTCOME MEASURE: Composite end point of death, MI, or rehospitalization for acute coronary syndrome at 6 months. RESULTS: Patients with a cTnI level of 0.1 ng/mL or more (n = 1087) experienced a significant reduction in the primary end point with the invasive vs conservative strategy (15.3% vs 25.0%; odds ratio [OR], 0.54; 95% confidence interval [CI], 0.40-0.73). Patients with cTnI levels of less than 0.1 ng/mL had no detectable benefit from early invasive management (16.0% vs 12.4%; OR, 1.4; 95% CI, 0.89-2.05; P<.001 for interaction). The benefit of invasive vs conservative management through 30 days was evident even among patients with low-level (0.1-0.4 ng/mL) cTnI elevation (4.4% vs 16.5%; OR, 0.24; 95% CI, 0.08-0.69). Directionally similar results were observed with cTnT. CONCLUSION: In patients with clinically documented acute coronary syndrome who are treated with glycoprotein IIb/IIIa inhibitors, even small elevations in cTnI and cTnT identify high-risk patients who derive a large clinical benefit from an early invasive strategy.
Subject(s)
Angina, Unstable/blood , Angina, Unstable/therapy , Myocardial Infarction/blood , Myocardial Infarction/therapy , Troponin I/blood , Troponin T/blood , Adult , Biomarkers/blood , Coronary Angiography , Female , Humans , Male , Myocardial Revascularization , Platelet Aggregation Inhibitors/therapeutic use , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Prognosis , Prospective Studies , RiskSubject(s)
Coronary Circulation/drug effects , Electrocardiography , Fibrinolytic Agents/therapeutic use , Myocardial Infarction/diagnosis , Myocardial Infarction/drug therapy , Streptokinase/therapeutic use , Ventricular Function, Left/drug effects , Aged , Coronary Angiography/methods , Drug Administration Schedule , Female , Follow-Up Studies , Humans , Male , Middle Aged , Myocardial Infarction/mortality , Probability , Severity of Illness Index , Survival Rate , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: There is continued debate as to whether a routine, early invasive strategy is superior to a conservative strategy for the management of unstable angina and myocardial infarction without ST-segment elevation. METHODS: We enrolled 2220 patients with unstable angina and myocardial infarction without ST-segment elevation who had electrocardiographic evidence of changes in the ST segment or T wave, elevated levels of cardiac markers, a history of coronary artery disease, or all three findings. All patients were treated with aspirin, heparin, and the glycoprotein IIb/IIIa inhibitor tirofiban. They were randomly assigned to an early invasive strategy, which included routine catheterization within 4 to 48 hours and revascularization as appropriate, or to a more conservative (selectively invasive) strategy, in which catheterization was performed only if the patient had objective evidence of recurrent ischemia or an abnormal stress test. The primary end point was a composite of death, nonfatal myocardial infarction, and rehospitalization for an acute coronary syndrome at six months. RESULTS: At six months, the rate of the primary end point was 15.9 percent with use of the early invasive strategy and 19.4 percent with use of the conservative strategy (odds ratio, 0.78; 95 percent confidence interval, 0.62 to 0.97; P=0.025). The rate of death or nonfatal myocardial infarction at six months was similarly reduced (7.3 percent vs. 9.5 percent; odds ratio, 0.74; 95 percent confidence interval, 0.54 to 1.00; P<0.05). CONCLUSIONS: In patients with unstable angina and myocardial infarction without ST-segment elevation who were treated with the glycoprotein IIb/IIIa inhibitor tirofiban, the use of an early invasive strategy significantly reduced the incidence of major cardiac events. These data support a policy involving broader use of the early inhibition of glycoprotein IIb/IIIa in combination with an early invasive strategy in such patients.
Subject(s)
Angina, Unstable/therapy , Angioplasty, Balloon, Coronary , Myocardial Infarction/therapy , Platelet Aggregation Inhibitors/therapeutic use , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Tyrosine/analogs & derivatives , Tyrosine/therapeutic use , Aged , Angina, Unstable/drug therapy , Angina, Unstable/mortality , Aspirin/therapeutic use , Combined Modality Therapy , Coronary Angiography , Drug Therapy, Combination , Electrocardiography , Female , Fibrinolytic Agents/therapeutic use , Heparin/therapeutic use , Humans , Male , Middle Aged , Myocardial Infarction/drug therapy , Myocardial Infarction/mortality , Tirofiban , Treatment OutcomeABSTRACT
Aims Abciximab has previously been shown to enhance thrombolysis and improve myocardial perfusion when combined with reduced doses of alteplase. The purpose of the reteplase phase of TIMI 14 was to evaluate the effects of abciximab when used in combination with a reduced dose of reteplase for ST-elevation myocardial infarction. Methods and Results Patients (n=299) with ST-elevation myocardial infarction were treated with aspirin and randomized to a control arm with standard dose reteplase (10+10 U given 30 min apart) or abciximab (bolus of 0.25 mg. kg(-1)and 12-h infusion of 0.125 microg. kg(-1). min(-1)) in combination with reduced doses of reteplase (5+5 U or 10+5 U). Control patients received standard weight-adjusted heparin (bolus of 70 U. kg(-1); infusion of 15 U. kg(-1). h(-1)), while each of the combination arms with abciximab and reduced dose reteplase received either low dose heparin (bolus of 60 U. kg(-1); infusion of 7 U. kg(-1). h(-1)) or very low dose heparin (bolus of 30 U. kg(-1); infusion of 4 U. kg(-1). h(-1)). The rate of TIMI 3 flow at 90 min was 70% for patients treated with 10+10 U of reteplase alone (n=87), 73% for those treated with 5+5 U of reteplase with abciximab (n=88), and 77% for those treated with 10+5 U of reteplase with abciximab (n=75). Complete (>/=70%) ST resolution at 90 min was seen in 56% of patients receiving a reduced dose of reteplase in combination with abciximab compared with 48% of patients receiving reteplase alone. Conclusions Reduced doses of reteplase when administered in combination with abciximab were associated with higher TIMI 3 flow rates than reported previously for reduced doses of reteplase without abciximab and were at least as high as for full dose reteplase alone
Subject(s)
Antibodies, Monoclonal/administration & dosage , Immunoglobulin Fab Fragments/administration & dosage , Myocardial Infarction/drug therapy , Plasminogen Activators/administration & dosage , Platelet Aggregation Inhibitors/administration & dosage , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Recombinant Proteins/administration & dosage , Thrombolytic Therapy , Tissue Plasminogen Activator/administration & dosage , Abciximab , Adolescent , Adult , Aged , Canada , Coronary Angiography , Drug Administration Schedule , Drug Therapy, Combination , Electrocardiography , Europe , Female , Heparin/administration & dosage , Humans , Male , Middle Aged , Treatment Outcome , United StatesABSTRACT
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: 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.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Coronary Circulation/drug effects , Electrocardiography , Immunoglobulin Fab Fragments/administration & dosage , Myocardial Infarction/drug therapy , Myocardial Reperfusion , Tissue Plasminogen Activator/administration & dosage , Abciximab , Drug Therapy, Combination , Female , Humans , Male , Middle Aged , Myocardial Infarction/physiopathologyABSTRACT
OBJECTIVES: This study evaluated the determinants of coronary blood flow following thrombolytic administration in a large cohort of patients. BACKGROUND: Tighter residual stenoses following thrombolysis have been associated with slower coronary blood flow, but the independent contribution of other variables to delayed flow has not been fully explored. METHODS: The univariate and multivariate correlates of coronary blood flow at 90 min after thrombolytic administration were examined in a total of 2,195 patients from the Thrombolysis in Myocardial Infarction (TIMI) 4, 10A, 10B and 14 trials. The cineframes needed for dye to first reach distal landmarks (corrected TIMI frame count, CTFC) were counted as an index of coronary blood flow. RESULTS: The following were validated as univariate predictors of delayed 90-min flow in two cohorts of patients: a greater percent diameter stenosis (p < 0.0001 for both cohorts), a decreased minimum lumen diameter (p = 0.0003, p = 0.0008), a greater percent of the culprit artery distal to the stenosis (p = 0.03, p = 0.02) and the presence of any of the following: delayed achievement of patency (i.e., between 60 and 90 min) (p < 0.0001 for both cohorts), a culprit location in the left coronary circulation (left anterior descending or circumflex) (p = 0.02, p < 0.0001), pulsatile flow (i.e., reversal of flow in systole, a marker of heightened microvascular resistance, p = 0.0003, p < 0.0001) and thrombus (p = 0.002, p = 0.03). Despite a minimal 16.4% residual stenosis following stent placement, the mean post-stent CTFC (25.8 +/- 17.2, n = 181) remained significantly slower than normal (21.0 +/- 3.1, n = 78, p = 0.02), and likewise 34% of patients did not achieve a CTFC within normal limits (i.e., <28 frames, the upper limit of the 95th percent confidence interval previously reported for normal flow). Those patients who failed to achieve normal CTFCs following stent placement had a higher mortality than did those patients who achieved normal flow (6/62 or 9.7% vs. 1/118 or 0.8%, p = 0.003). CONCLUSIONS: Lumen geometry is not the sole determinant of coronary blood flow at 90 min following thrombolytic administration. Other variables such as the location of the culprit artery, the duration of patency, a pulsatile flow pattern and thrombus are also related to slower flow. Despite a minimal 16% residual stenosis, one-third of the patients treated with adjunctive stenting still have a persistent flow delay following thrombolysis, which carries a poor prognosis.
Subject(s)
Coronary Circulation , Myocardial Infarction/drug therapy , Myocardial Infarction/physiopathology , Thrombolytic Therapy , Angioplasty, Balloon, Coronary , Coronary Angiography , Female , Hemodynamics , Humans , Male , Myocardial Infarction/diagnostic imaging , Regional Blood Flow , Stents , Time Factors , Treatment OutcomeABSTRACT
The presenting electrocardiogram may contain information indicating the probability of successful reperfusion. The relation between 3 parameters in the presenting electrocardiogram (pathologic Q waves, T-wave inversion, and the slope of ST elevation) and Thrombolysis in Myocardial Infarction trial (TIMI) grade 3 flow in the infarct-related artery was assessed angiographically 90 minutes after beginning streptokinase in 362 patients. TIMI grade 3 flow was more common in patients without Q waves (55%) than in those with Q waves (35%; p <0.001), and more common in patients without T-wave inversion (50%) than in those with T-wave inversion (30%; p <0.002). There was no relation between the slope of the ST segment or the magnitude of its deviation and the achievement of TIMI grade 3 flow. Only 20% of the 59 patients with both Q waves and T-wave inversion had TIMI grade 3 flow, compared with 50% of the remaining patients (p <0.0001). Among patients treated within 3 hours, TIMI grade 3 flow was seen in 68% of those without versus 44% of those with Q waves (p <0.01), and in 62% of those without versus 43% of those with T-wave inversion (p = 0.06). Among patients treated after 3 hours, TIMI grade 3 flow was seen in 38% of those without versus 30% of those with Q waves (p = NS), and in 38% of those without versus 23% of those with T-wave inversion (p <0.05). On multivariate analysis, the absence of Q waves, the time from the onset of chest pain to treatment, and age were independent predictors of TIMI grade 3 flow. Pathologic Q waves in the presenting electrocardiogram provide valuable information as to the probability of achieving successful reperfusion following administration of streptokinase, and may be helpful for triage of patients to alternative reperfusion strategies, including percutaneous revascularization.
Subject(s)
Electrocardiography , Fibrinolytic Agents/therapeutic use , Myocardial Infarction/drug therapy , Myocardial Reperfusion , Streptokinase/therapeutic use , Anticoagulants/therapeutic use , Cohort Studies , Coronary Angiography , Female , Hirudin Therapy , Hirudins/analogs & derivatives , Humans , Logistic Models , Male , Middle Aged , Myocardial Infarction/diagnosis , Peptide Fragments/therapeutic use , Predictive Value of Tests , Recombinant Proteins/therapeutic useABSTRACT
OBJECTIVE: To assess whether the 90 minute corrected thrombolysis in myocardial infarction frame count (CTFC) in the infarct related artery predicts left ventricular function at 48 hours in patients with myocardial infarction treated with aspirin, streptokinase, and either heparin or Hirulog. DESIGN AND SETTING: Analysis of 251 patients with acute myocardial infarction enrolled in the international, multicentre Hirulog early reperfusion/occlusion (HERO-1) trial, who underwent both 90 minute coronary angiography and 48 hour left ventriculography. MAIN OUTCOME VARIABLES: The CTFC was determined in the infarct related artery 90 minutes after starting intravenous streptokinase (1.5 x 106 U over 30 to 60 minutes), and compared with indices of left ventricular function assessed by contrast ventriculography at 48 hours. RESULTS: A CTFC of = 27 frames (previously reported mean + 2 SD in coronary arteries of patients without acute infarction) occurred in 29% of infarct related arteries, and was associated with a lower infarct zone mean chord score (-2.06 v -2.54, p = 0.01), a lower fraction of chords > 2 SD below normal (37% v 51%, p = 0.005), and trends towards higher left ventricular ejection fractions (60.9% v 58.2%, p = 0.11) and lower end systolic volumes (50.1 ml v 55.9 ml, p = 0.23). A CTFC of = 40 at 90 minutes occurred in 50% of infarct related arteries, and was associated with a significantly lower mean chord score (-2.20 v -2.60, p = 0.02), a smaller fraction of chords > 2 SD below normal (41% v 52%, p = 0.025), a smaller end systolic volume (49.1 ml v 59.3 ml, p = 0.02), and a higher left ventricular ejection fraction (60.4% v 56.5%, p = 0.03). CONCLUSIONS: The 90 minute CTFC predicts left ventricular function at 48 hours following streptokinase. The CTFC associated with better ventricular function may be higher than values determined from a non-infarct population.
Subject(s)
Coronary Angiography , Fibrinolytic Agents/therapeutic use , Myocardial Infarction/diagnostic imaging , Streptokinase/therapeutic use , Thrombolytic Therapy , Ventricular Dysfunction, Left/diagnostic imaging , Female , Humans , Male , Middle Aged , Myocardial Infarction/drug therapy , Myocardial Infarction/physiopathology , Predictive Value of Tests , Prognosis , Regional Blood Flow , Time FactorsABSTRACT
BACKGROUND: Thrombolytic therapy improves survival after myocardial infarction through reperfusion of the infarct-related artery. Thrombin generated during thrombolytic administration may reduce the efficacy of thrombolysis. A direct thrombin inhibitor may improve early patency rates. METHODS AND RESULTS: Four hundred twelve patients presenting within 12 hours with ST-segment elevation were given aspirin and streptokinase and randomized in a double-blind manner to receive up to 60 hours of either heparin (5000 U bolus followed by 1000 to 1200 U/h), low-dose hirulog (0.125 mg/kg bolus followed by 0.25 mg x kg(-1) x h(-1) for 12 hours then 0.125 mg x kg(-1) x h(-1)), or high-dose hirulog (0.25 mg/kg bolus followed by 0.5 mg x kg(-1) x h(-1) for 12 hours then 0.25 mg x kg(-1) x h(-1)). The primary outcome was Thrombolysis In Myocardial Infarction trial (TIMI) grade 3 flow of the infarct-related artery at 90 to 120 minutes. TIMI 3 flow was 35% (95% CI, 28% to 44%) with heparin, 46% (95% CI, 38% to 55%) with low-dose hirulog, and 48% (95% CI, 40% to 57%) with high-dose hirulog (heparin versus hirulog, P=.023; heparin versus high-dose hirulog, P=.03). At 48 hours, reocclusion had occurred in 7% of heparin, 5% of low-dose hirulog, and 1% of high-dose hirulog patients (P=NS). By 35 days, death, cardiogenic shock, or reinfarction had occurred in 25 heparin (17.9%), 19 low-dose hirulog (14%), and 17 high-dose hirulog patients (12.5%) (P=NS). Two strokes occurred with heparin, none with low-dose hirulog, and two with high-dose hirulog. Major bleeding (40% from the groin site) occurred in 28% of heparin, 14% of low-dose hirulog, and 19% of high-dose hirulog patients (heparin versus low-dose hirulog, P<.01). CONCLUSIONS: Hirulog was more effective than heparin in producing early patency in patients treated with aspirin and streptokinase without increasing the risk of major bleeding. Direct thrombin inhibition may improve clinical outcome.
Subject(s)
Antithrombins/therapeutic use , Aspirin/therapeutic use , Heparin/therapeutic use , Hirudins/analogs & derivatives , Myocardial Infarction/drug therapy , Peptide Fragments/therapeutic use , Streptokinase/therapeutic use , Thrombolytic Therapy , Analysis of Variance , Antithrombins/adverse effects , Cardiac Catheterization , Double-Blind Method , Drug Administration Schedule , Drug Therapy, Combination , Female , Heparin/adverse effects , Hirudin Therapy , Hirudins/adverse effects , Humans , Male , Middle Aged , Peptide Fragments/adverse effects , Recombinant Proteins/adverse effects , Recombinant Proteins/therapeutic use , RecurrenceABSTRACT
BACKGROUND: Aortic counterpulsation has been observed to reduce the rate of reocclusion of the infarct-related artery after patency has been restored during acute myocardial infarction in observational studies. To evaluate the benefit-to-risk ratio of aortic counterpulsation during the early phase of myocardial infarction, a multicenter randomized clinical trial was performed. METHODS AND RESULTS: Patients who had patency restored during acute cardiac catheterization within the first 24 hours of onset of myocardial infarction were randomly assigned to aortic counterpulsation for 48 hours versus standard care. Intravenous heparin was used similarly in both groups and was continued for a median (25th, 75th percentile) of 5 (2,7) days. A total of 182 patients were enrolled; 96 were assigned to aortic counterpulsation and 86 to standard care. Repeat cardiac catheterization was performed at a median of 5 (4,6) days after randomization in 89% of patients assigned to aortic counterpulsation and in 90% of control patients. Patients randomized to aortic counterpulsation had similar rates of severe bleeding complications (2% versus 1%), number of units of blood transfused (mean, 1.3 +/- 2.6 versus 0.9 +/- 1.8 units), and vascular repair or thrombectomy (5% versus 2%) compared with patients treated in a conventional manner. Patients randomized to aortic counterpulsation had significantly less reocclusion of the infarct-related artery during follow-up compared with control patients (8% versus 21%, P < .03). In addition, there was a significantly lower event rate in patients assigned to aortic counterpulsation in terms of a composite clinical end point (death, stroke, reinfarction, need for emergency revascularization with angioplasty or bypass surgery, or recurrent ischemia): 13% versus 24%, P < .04. CONCLUSIONS: This randomized trial showed that careful use of prophylactic aortic counterpulsation can prevent reocclusion of the infarct-related artery and improve overall clinical outcome in patients undergoing acute cardiac catheterization during myocardial infarction.
Subject(s)
Coronary Disease/therapy , Coronary Vessels/physiopathology , Intra-Aortic Balloon Pumping , Myocardial Infarction/therapy , Angioplasty, Balloon, Coronary , Cardiac Catheterization , Coronary Angiography , Coronary Artery Bypass , Coronary Disease/diagnostic imaging , Coronary Disease/epidemiology , Female , Humans , Male , Middle Aged , Myocardial Infarction/epidemiology , Myocardial Infarction/physiopathology , Recurrence , Vascular Patency/physiologyABSTRACT
Changes in the beta-adrenergic receptor-G protein-adenylate cyclase complex were investigated in an experimental canine model of low-output heart failure produced by chronic rapid ventricular pacing. The contractile response occurring after exposure to the beta-adrenergic agonist dobutamine, measured as peak left ventricular + dP/dt, was decreased after 3 weeks of pacing. To further characterize the diminished functional responsiveness to beta-adrenergic receptor stimulation, beta-adrenergic receptor-adenylate cyclase coupling was investigated using membranes prepared from both control and paced animals. The density of beta-adrenergic receptors was decreased by 40% with a selective downregulation of the beta 1-subtype. The affinity of the receptor for the antagonist radioligand [125I]iodocyanopindolol remained unchanged. A defect in coupling was suggested by a decreased ability of isoproterenol, fluoride, and forskolin to stimulate adenylate cyclase in membranes prepared from failing hearts. Determination of the levels of Gi alpha (the alpha-subunit of Gi) by immunoblotting and pertussis toxin labeling revealed modest increases of approximately 30%. Furthermore, Mn2+ and purified Gs failed to stimulate adenylate cyclase in membranes prepared from failing hearts, indicating an impairment in the catalytic moiety of adenylate cyclase itself or in the ability of adenylate cyclase to couple to Gs. In contrast, complementation assay did not reveal differences in the functional activity of Gs alpha (the alpha-subunit of Gs). Taken together, these data demonstrate a selective decrease in the beta 1-subtype of adrenergic receptors and an increase in a 40-kd G1-like protein in the failing heart. Similar changes have been described in human idiopathic dilated cardiomyopathy. In addition to these changes, we identified a possible defect at the level of the catalytic subunit of adenylate cyclase.
Subject(s)
Adenylyl Cyclases/physiology , GTP-Binding Proteins/physiology , Heart Failure/physiopathology , Receptors, Adrenergic, beta/physiology , Adenylate Cyclase Toxin , Animals , Catecholamines/blood , Dihydropyridines/metabolism , Dobutamine/pharmacology , Dogs , Electric Stimulation , Heart Rate , Hemodynamics , Pertussis Toxin , Virulence Factors, Bordetella/metabolismABSTRACT
Heart failure is known to impair arterial baroreceptor control of heart rate. To determine if baroreceptor control of peripheral vascular resistance is also impaired, heart rate and hind limb vascular responses to phenylephrine and nitroglycerin administration were compared in control dogs and in dogs with heart failure produced by chronic rapid ventricular pacing. Baroreflex control of the heart rate was depressed in the dogs with heart failure, as evidenced by a reduced slope of the blood pressure-to-heart rate relationship (controls: -2.5 +/- 0.3 beats/mm Hg versus heart failure: -1.5 +/- 0.2 beats/mm Hg [(p less than 0.04)]). Arterial blood pressure in the dogs with heart failure was also reduced (controls: 90 +/- 3 mm Hg versus heart failure: 75 +/- 3 mm Hg [(p less than 0.01)]). Nevertheless, dogs with heart failure exhibited normal slopes of the blood pressure versus hind limb vascular resistance relationship (controls: -2.4 +/- 0.4 units/mm Hg versus heart failure: -2.9 +/- 0.5 units/mm Hg [(p = NS)]), consistent with preserved baroreflex control of the peripheral vasculature. These data suggest that heart failure impairs arterial baroreflex control of heart rate and lowers the baroreflex pressure operating range but does not alter baroreflex control of peripheral resistance.
Subject(s)
Heart Failure/physiopathology , Pressoreceptors/physiology , Vascular Resistance/physiology , Animals , Blood Pressure/drug effects , Dogs , Male , Nitroglycerin/pharmacology , Phenylephrine/pharmacology , Pressoreceptors/drug effects , Vagotomy , Vascular Resistance/drug effectsABSTRACT
To investigate whether heart failure alters beta-adrenergic receptors on skeletal muscle and its associated vasculature, the density of beta-adrenergic receptors, isoproterenol-stimulated adenylate cyclase activity, and coupling of the guanine nucleotide-binding regulatory protein were compared in 18 control dogs and 16 dogs with heart failure induced by 5-8 wk of ventricular pacing at 260 beats/min. Hindlimb vascular responses to isoproterenol were compared in eight controls and eight of the dogs with heart failure. In dogs with heart failure, the density of beta-receptors on skeletal muscle was reduced in both gastrocnemius (control: 50 +/- 5; heart failure: 33 +/- 8 fmol/mg of protein) and semitendinosus muscle (control: 43 +/- 9; heart failure: 27 +/- 9 fmol/mg of protein, both P less than 0.05). Receptor coupling to the ternary complex, as determined by isoproterenol competition curves with and without guanosine 5'-triphosphate (GTP), was unchanged. Isoproterenol-stimulated adenylate cyclase activity was significantly decreased in semitendinosus muscle (control: 52.4 +/- 4.6; heart failure: 36.5 +/- 9.5 pmol.mg-1.min-1; P less than 0.05) and tended to be decreased in gastrocnemius muscle (control: 40.1 +/- 8.5; heart failure: 33.5 +/- 4.5 pmol.mg-1.min-1; P = NS). Isoproterenol-induced hindlimb vasodilation was not significantly different in controls and in dogs with heart failure. These findings suggest that heart failure causes downregulation of skeletal muscle beta-adrenergic receptors, probably due to receptor exposure to elevated catecholamine levels, but does not reduce beta-receptor-mediated vasodilation in muscle.
Subject(s)
Cardiac Output, Low/metabolism , Isoproterenol/pharmacology , Muscles/metabolism , Receptors, Adrenergic, beta/metabolism , Vasodilation/drug effects , Adenylyl Cyclases/metabolism , Animals , Binding, Competitive , Data Interpretation, Statistical , Dogs , Guanosine Triphosphate/metabolism , Hemodynamics , Hindlimb , Iodine Radioisotopes , Muscles/blood supply , Muscles/drug effectsABSTRACT
In this article, we have reviewed the impact of the new technique of Doppler ultrasound upon the assessment of aortic stenosis, aortic regurgitation, and diastolic left ventricular function. It is a powerful new technique that greatly extends our ability to understand the pathophysiology of these conditions. However, its use must be tempered with an appreciation of the limitations of the new technique and knowledge of the circumstances in which it may yield erroneous results.
Subject(s)
Aortic Valve Insufficiency/physiopathology , Aortic Valve Stenosis/physiopathology , Cardiac Output , Echocardiography, Doppler , Myocardial Contraction , Aortic Valve/pathology , Aortic Valve/physiopathology , Heart Ventricles/physiopathology , Hemodynamics , HumansABSTRACT
In patients with heart failure, exercise is thought to increase sympathetic vasoconstrictor tone. To investigate the extent of this sympathetic activation, we studied the effect of maximal exercise on nonexercising vascular beds in 35 patients with left ventricular failure (ejection fraction, 21 +/- 8%; peak exercise oxygen uptake (VO2), 12.3 +/- 3.5 ml/min/kg). In 28 patients, cardiac output and leg blood flow were measured during maximal upright bicycle exercise. Total flow to nonexercising tissue was then calculated as cardiac output--(2 x leg flow). In seven patients and six normal subjects, forearm blood flow was measured during supine bicycle exercise before and after alpha-adrenergic blockade with intravenous phentolamine. Maximal upright exercise increased the vascular resistance of nonexercising tissue from 34 +/- 16 units at upright rest to 45 +/- 25 units (p less than 0.02) but did not affect total flow to nonexercising tissue (rest, 2.9 +/- 1.0; maximal exercise, 2.8 +/- 1.4 l/min; p = NS). Supine exercise had no significant effect on forearm blood flow or vascular resistance in the normal subjects. In the patients with heart failure, supine exercise increased forearm vascular resistance from 45 +/- 17 to 58 +/- 25 mm Hg/ml/min/100 ml (p less than 0.02), again with no change in tissue flow (rest, 2.4 +/- 0.1; maximal exercise, 2.4 +/- 0.9 ml/min/100 ml; p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Exercise , Heart Failure/physiopathology , Sympathetic Nervous System/physiopathology , Vasoconstriction , Cardiac Output , Exercise Test , Forearm/blood supply , Humans , Leg/blood supply , Male , Middle Aged , Norepinephrine/blood , Phentolamine , Regional Blood Flow , Vascular ResistanceABSTRACT
The effect of maximal exercise on lymphocyte beta-adrenergic receptors was examined in 26 normal subjects. Exercise increased O2 consumption (Vo2) from 5 +/- 1 to 50 +/- 4 ml.min-1.kg-1, plasma norepinephrine level from 188 +/- 28 to 2,682 +/- 160 pg/ml, and plasma epinephrine level from 94 +/- 72 to 857 +/- 180 pg/ml. The density of beta-adrenergic receptors on lymphocytes obtained at rest was 31 +/- 3.7 fmol/mg protein; exercise increased the density of receptors by 86 +/- 33% (range 0-257%) to 58.3 +/- 1.5 fmol/mg protein but did not alter the affinity of the receptor for [125I]iodopindolol or the coupling of the receptor to the guanine nucleotide-binding regulatory protein. The density of beta-adrenergic receptors increased progressively throughout exercise and paralleled the increase in heart rate. The magnitude of the change in the density of beta-adrenergic receptors did not correlate with the magnitude of the increase in heart rate, Vo2, or plasma levels of catecholamines. The density of receptors was still elevated 15 min after completion of exercise but fell below base line 1 h after peak exercise to 18.2 +/- 6.7 fmol/mg protein (P less than 0.05 vs. base-line levels). These results demonstrate that exhaustive exercise results in a progressive increase in the number of beta-adrenergic receptors on lymphocyte membranes, followed by a reduction in the density of receptors during the recovery phase of exercise. Despite a significant increase in the level of plasma catecholamines, the receptor remains coupled to the guanine nucleotide-binding regulatory protein.