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Biomedical subjects

L C Becker

Publications and source records attributed to L C Becker.

At least 19 recordsLinked to original sources
PubMed1992

Anistreplase versus alteplase in acute myocardial infarction: comparative effects on left ventricular function, morbidity and 1-day coronary artery patency. The TEAM-3 Investigators.

OBJECTIVES: This double-blind, randomized, multicenter trial was designed to compare the effects of treatment with anistreplase (APSAC) and alteplase (rt-PA) on convalescent left ventricular function, morbidity and coronary artery patency at 1 day in patients with acute myocardial infarction. BACKGROUND: Anistreplase (APSAC) is a new, easily administered thrombolytic agent recently approved for treatment of acute myocardial infarction. Alteplase (rt-PA) is a rapidly acting, relatively fibrin-specific thrombolytic agent that is currently the most widely used agent in the United States. METHODS: Study entry requirements were age less than or equal to 75 years, symptom duration less than or equal to 4 h, ST segment elevation and no contraindications. The two study drugs, APSAC, 30 U/2 to 5 min, and rt-PA, 100 mg/3 h, were each given with aspirin (160 mg/day) and intravenous heparin. Prespecified end points were convalescent left ventricular function (rest/exercise), clinical morbidity and coronary artery patency at 1 day. A total of 325 patients were entered, stratified into groups with anterior (37%) or inferior or other (63%) acute myocardial infarction, randomized to receive APSAC or rt-PA and followed up for 1 month. RESULTS: At entry, patient characteristics in the two groups were balanced. Convalescent ejection fraction at the predischarge study averaged 51.3% in the APSAC group and 54.2% in the rt-PA group (p less than 0.05); at 1 month, ejection fraction averaged 50.2% versus 54.8%, respectively (p less than 0.01). In contrast, ejection fraction showed similar augmentation with exercise at 1 month after APSAC (+4.3% points) and rt-PA (+4.6% points), and exercise times were comparable. Coronary artery patency at 1 day was high and similar in both groups (APSAC 89%, rt-PA 86%). Mortality (APSAC 6.2%, rt-PA 7.9%) and the incidence of other serious clinical events, including stroke, ventricular tachycardia, ventricular fibrillation, heart failure within 1 month, recurrent ischemia and reinfarction were comparable in the two groups; and mechanical interventions were applied with equal frequency. A combined clinical morbidity index was determined and showed a comparable overall outcome for the two treatments. CONCLUSIONS: Convalescent rest ejection fraction was high after both therapies but higher after rt-PA; other clinical outcomes, including exercise function, morbidity index, and 1-day coronary artery patency, were favorable and comparable after APSAC and rt-PA.

Anistreplase↗
PubMed1992

Age-related decline in left ventricular filling at rest and exercise.

To determine whether the age-associated decline in resting left ventricular diastolic filling persists during aerobic exercise, rest and bicycle exercise filling indexes were measured from gated radionuclide blood pool scans in 88 healthy men aged 22-82 yr. To evaluate the effect of physical conditioning status on these age-related changes, a subset of the subjects consisted of endurance-trained senior athletes with a maximal O2 consumption of 50.5 +/- 5 compared with 32.6 +/- 7 ml.kg-1 x min-1 in age-matched controls. The contribution of beta-adrenergic stimulation to exercise-induced changes in filling was also evaluated by the administration of intravenous propranolol to another subset before testing. Peak filling rate increased progressively at all ages with increasing exercise work loads. The peak filling rates at rest, 50% maximal exercise, and maximum exercise inversely correlated with age (r = -0.64, -0.53, -0.64, respectively). Rest and exercise filling indexes in senior athletes were similar to those of sedentary older subjects. Propranolol decreased exercise peak filling rates in young (37.2 +/- 7.5 yr) but not in older (62.1 +/- 6 yr) subjects. Therefore, filling rates increase with exercise in both young and older healthy men, but age differences persist at comparable relative work loads. This decline is not secondary to a decline in physical conditioning status but appears to be related to a decrease in beta-adrenergic responsiveness in older individuals.

Adrenergic beta-Antagonists↗
PubMed1992

Relation between glycolysis and calcium homeostasis in postischemic myocardium.

This study examined the hypothesis that glycolysis is required for functional recovery of the myocardium during reperfusion by facilitating restoration of calcium homeostasis. [Ca2+]i was measured in isolated perfused rabbit hearts by using the Ca2+ indicator 1,2-bis(2-amino-5-fluorophenoxy)ethane-N,N,N',N'-tetraacetic acid (5F-BAPTA) and 19F nuclear magnetic resonance spectroscopy. In nonischemic control hearts, inhibition of glycolysis with iodoacetate did not alter [Ca2+]i. In hearts subjected to 20 minutes of global zero-flow ischemia, [Ca2+]i increased from 260 +/- 80 nM before ischemia to 556 +/- 44 nM after 15 minutes of ischemia (p less than 0.05). After reperfusion with 5 mM pyruvate as a carbon substrate, [Ca2+]i increased further in hearts with intact glycolysis to 851 +/- 134 nM (p less than 0.05 versus ischemia) during the first 10 minutes of reperfusion, before returning to preischemic levels. In contrast, inhibition of glycolysis during the reperfusion period resulted in persistent severe calcium overload ([Ca2+]i, 1,380 +/- 260 nM after 15 minutes of reperfusion, p less than 0.02 versus intact glycolysis group). Furthermore, despite the presence of pyruvate and oxygen, inhibition of glycolysis during early reperfusion resulted in greater impairment of functional recovery (rate/pressure product, 3,722 +/- 738 mm Hg/min) than did reperfusion with pyruvate and intact glycolysis (rate/pressure product, 9,851 +/- 590 mm Hg/min, p less than 0.01). Inhibition of glycolysis during early reperfusion was also associated with a marked increase in left ventricular end-diastolic pressure during reperfusion (41 +/- 5 mm Hg) compared with hearts with intact glycolysis (16 +/- 2 mm Hg, p less than 0.01). The detrimental effects of glycolytic inhibition during early reperfusion were, however, prevented by initial reperfusion with a low calcium solution ([Ca]o, 0.63 mM for 30 minutes, then 2.50 mM for 30 minutes). In these hearts, the rate/pressure product after 60 minutes of reperfusion was 12,492 +/- 1,561 mm Hg/min (p less than 0.01 versus initial reflow with [Ca]o of 2.50 mM). These findings indicate that the functional impairment observed in postischemic myocardium is related to cellular Ca2+ overload. Glycolysis appears to play an important role in restoration of Ca2+ homeostasis and recovery of function of postischemic myocardium.

Animals↗
PubMed1991

Usefulness of OPC-8212, a quinolinone derivative, for chronic congestive heart failure in patients with ischemic heart disease or idiopathic dilated cardiomyopathy.

To evaluate the safety and efficacy of the inotropic agent OPC-8212 in patients with chronic congestive heart failure, 76 patients with impaired cardiac function and diminished exercise tolerance were studied. They were randomized to 12 weeks of double-blind therapy with either 60 mg/day of OPC-8212 or placebo. The study drug was added to their baseline medical regimen. The primary study outcome was the combined outcome of the time to either mortality (of all cause) or substantial worsening of heart failure (major morbidity), whichever occurred first. Treatment with OPC-8212 significantly (p less than 0.01) decreased the combination of major morbidity/mortality over 12 weeks of therapy. Quality of life, assessed by the Sickness Impact Profile questionnaire, was significantly improved in patients receiving OPC-8212 (p less than 0.01). Furthermore, ventricular premature contractions as assessed by 24-hour Holter monitoring were not increased with OPC-8212 treatment. Although patients treated with OPC-8212 were able to reach a significantly higher peak oxygen uptake and exercise longer during symptom-limited exercise, when data were analyzed as percent change from baseline, the absolute increases were small. These results suggest that OPC-8212 is beneficial in treating patients with congestive heart failure and that further evaluation of this new inotropic agent is warranted.

Adolescent↗
PubMed1991

Do neutrophils contribute to myocardial stunning?

Although removal of neutrophils from the arterial blood by mechanical filtration has been reported to prevent or reduce the severity of myocardial stunning caused by a 15 minute coronary artery occlusion in the dog, neutrophil filtration does not protect against myocardial dysfunction following a 10-minute occlusion. Nonfilter methods to reduce neutrophil numbers or effectiveness with anti-neutrophil serum, monoclonal anti-CD11b antibodies, or the lipoxygenase inhibitor nafazatrom fail to modify myocardial dysfunction after brief ischemia, even though they effectively reduce infarct size after more prolonged ischemia. The brief durations of ischemia required to produce myocardial stunning but to avoid necrosis are insufficient to produce local activation of complement, formation of chemotactic factors, or activation or infiltration of neutrophils. Microvascular plugging with neutrophils cannot be demonstrated in stunned myocardium, and abnormalities of microvascular function can be dissociated from impaired postischemic myocardial function. Based on the weight of accumulated evidence, neutrophils appear to have no important role in the production of stunned myocardium.

Animals↗
PubMed1991

Comparison of indium-111 antimyosin antibody and technetium-99m pyrophosphate localization in reperfused and nonreperfused myocardial infarction.

Recent imaging studies suggest that technetium-99m (Tc-99m) pyrophosphate yields a considerably larger estimate of myocardial infarct size than does indium-111 (In-111) monoclonal antimyosin antibody. To determine whether Tc-99m pyrophosphate may be taken up by reversibly injured myocytes, particularly in the setting of coronary reperfusion, the tissue localization of Tc-99m pyrophosphate and antimyosin antibody was compared in 11 dogs 24 to 68 h after anterior descending coronary artery occlusion (4 dogs with permanent occlusion, 7 with reperfusion). Technetium-99m pyrophosphate and In-111 antimyosin antibody content was determined in serial 2 to 3 mm wide endocardial and epicardial samples taken through the infarct zone in multiple short-axis left ventricular slices. The number of samples with increased In-111 antimyosin antibody (defined as greater than or equal to mean + 2 SD of normal) was not significantly different from that with increased Tc-99m pyrophosphate. This was true in both reperfused and nonreperfused infarcts. However, the intensity of uptake of Tc-99m pyrophosphate exceeded that of In-111 antimyosin antibody, particularly in the border zones of reperfused infarcts, and the area with moderate to marked increase in tracer uptake (greater than or equal to 2 times normal) was significantly larger with Tc-99m pyrophosphate than In-111 antimyosin antibody (p less than 0.001). A specific zone of abnormal Tc-99m pyrophosphate with normal In-111 antimyosin antibody content could not be identified. Histologic evidence of myocardial necrosis was found in virtually every sample with increased In-111 antimyosin antibody, Tc-99m pyrophosphate, or both.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Effect of differential tracer washout during SPECT acquisition.

A central assumption in SPECT is that the projection data are "consistent," that is, the camera views an unchanging distribution during acquisition. Several new radiotracers of interest, including 99mTc-teboroxime (Cardiotec), have rapid clearance from the myocardium. Furthermore, the washout is different in normal and ischemic tissues. We used computer simulations to estimate the effect of this differential washout on quantification of the severity of ischemia. We simulated defect-to-normal myocardial activity ratios of 1 (no defect), 0.8, 0.6, 0.4, 0.2, and 0 (complete defect), with single defects placed either in the lateral wall or apex, and SPECT acquisitions of 1, 3, 6, 12, and 24 total minutes. We modeled washout with a monoexponential curve whose clearance half-time was 5.9 min for "normal myocardium" and 9.3 min for "ischemic myocardium." We found that differential washout from normal and ischemic zones produced image artifacts and errors in defect quantification for acquisitions longer than 3 min. With longer acquisitions, the degree of ischemia was significantly underestimated, with increasing error at longer acquisition times. In addition, in the "no defect" situation an apparent small lateral wall defect (relative to the apex) was present. Finally, lateral wall defects produced artifacts (streaks and reduced apparent activity) in the opposite (medial) wall. Differential normal/ischemic zone washout during SPECT acquisition produces artifacts and errors in quantification, whose severity is dependent on acquisition length, actual defect severity, and defect location.

Computer Simulation↗
PubMed1991

Tomographic myocardial perfusion imaging with technetium-99m-teboroxime at rest and after dipyridamole.

This study was done to determine whether the rapidly clearing myocardial perfusion agent 99mTc-teboroxime (SQ 30217, Cardiotec) could be combined with tomographic imaging to accurately quantify regional myocardial blood flow distribution in anesthetized dogs. Following stenosis of the anterior descending (LAD, n = 10) or circumflex (LCX, n = 5) coronary arteries, teboroxime was administered simultaneously with radioactive microspheres, at rest and following infusion of dipyridamole (0.15 mg/kg/min x 4 min). Tomographic imaging began 1 min after each teboroxime injection and continued for 12 min. For LAD stenosis, when the dipyridamole study was performed first, teboroxime activity in the center of the ischemic region was closely correlated with tissue microsphere content. However, the severity of the dipyridamole-induced flow deficit was underestimated by teboroxime when the rest study was performed first. Our results show that despite rapid myocardial clearance, tomographic imaging of 99mTc-teboroxime provides reasonably accurate quantitation of dipyridamole-induced anterior wall perfusion defects, but that the flow deficit is underestimated when a rest study is performed first or when the defect is located in the inferior wall.

Animals↗
PubMed1990

The effects of antihypertensive therapy on left ventricular mass in elderly patients.

Left ventricular mass sometimes decreases during treatment of hypertension, but this response is inconsistent and its effects on left ventricular function are unknown. In a six-month randomized trial, we studied the ability of verapamil and atenolol to reduce left ventricular mass in 42 elderly patients with hypertension and the effects of this reduction in mass on cardiac function. The mean blood pressure (+/- SE) decreased in both the group that received verapamil (from 171.4 +/- 3.2/93.0 +/- 2.5 mm Hg to 142.9 +/- 2.8/79.0 +/- 2.0 mm Hg) and the group that received atenolol (from 179.6 +/- 4.6/98.5 +/- 2.4 mm Hg to 148.1 +/- 3.3/83.4 +/- 1.2 mm Hg), but the atenolol-treated patients more frequently required the addition of chlorthalidone to achieve blood-pressure reduction (P less than 0.01). Verapamil resulted in a reduction in the left-ventricular-mass index from 104 +/- 5 g per square meter of body-surface area to 85 +/- 5 g per square meter (P less than 0.01). Atenolol did not produce a reduction in the left-ventricular-mass index (109 +/- 9 g per square meter before treatment vs. 112 +/- 10 g per square meter after treatment). Two weeks after the withdrawal of antihypertensive therapy, blood pressure returned to pretreatment values. Nevertheless, in patients whose left ventricular mass had decreased, two measures of diastolic filling, the peak diastolic filling rate to the peak ejection rate, were significantly higher than before treatment (2.42 +/- 0.2 vs. 3.31 +/- 0.4 [P less than 0.05] and 0.61 +/- 0.03 to 0.85 +/- 0.05 [P less than 0.05], respectively). Diastolic filling was unchanged in the group that had no reduction in left ventricular mass. Cardiac output and the ejection fraction at rest and during mild exercise were unchanged in both groups as compared with baseline values. We conclude that left ventricular mass can be reduced in elderly patients with hypertension and mild ventricular hypertrophy who receive antihypertensive therapy. Reduction occurs more frequently with verapamil than with atenolol therapy, increases diastolic filling, and does not impair systolic function.

Atenolol↗
PubMed1990

Progressive failure of coronary flow during reperfusion of myocardial infarction: documentation of the no reflow phenomenon with positron emission tomography.

During reperfusion of a myocardial infarct, development of microvascular occlusion may result in regional hypoperfusion ("no reflow") despite a patent infarct-related artery. This study examined the extent and time course of no reflow with use of rubidium-82 positron emission tomography. In 12 anesthetized dogs, the left anterior descending coronary artery was occluded for 90 min and then freely reperfused. Regional myocardial perfusion was imaged by serial rubidium-82 positron emission tomography during coronary occlusion and every 30 min during reperfusion. After 4 h of reperfusion, infarct size and no reflow zone were measured postmortem by triphenyltetrazolium and thioflavin staining, respectively. Perfusion defects evident on rubidium-82 images during coronary occlusion rapidly resolved during the early reflow period. However, a recurrent perfusion defect appeared after 1 to 2 h of reflow in all dogs. The severity of recurrent perfusion defects progressed with time; after 5 min of reflow, relative perfusion in the left anterior descending artery territory was 97 +/- 6% of that in the normal circumflex artery region, but perfusion decreased progressively to 68 +/- 5% after 2 h (p less than 0.05) and to 55 +/- 4% after 4 h of reperfusion (p less than 0.05 versus 2 h). As measured by radioactive tracer microspheres, endocardial blood flow decreased similarly in the postischemic left anterior descending artery region from 1.2 +/- 0.2 ml/min per g after 5 min of reflow to 0.4 +/- 0.1 ml/min per g after 3 h of reflow (p less than 0.01). Residual infarct perfusion, measured by rubidium-82 after 4 h of reflow, was related to both infarct size (r = -0.88) and the extent of the no reflow zone (r = -0.84) in the postmortem left ventricular sections. Thus, serial positron emission tomography with rubidium-82 demonstrates a progressive loss of infarct perfusion, beginning 1 to 2 h after initial restoration of blood flow despite patency of the infarct-related artery. This phenomenon is probably a manifestation of progressive microvascular occlusion within the reperfused myocardium.

Animals↗
PubMed1990

Pharmacokinetics of recombinant human superoxide dismutase.

Superoxide dismutase (SOD) disposition was studied in order to design a rational approach for drug administration in the setting of acute myocardial infarction. Four chronically instrumented conscious dogs received the following dosage regimens of recombinant human SOD (rhSOD) on successive days: (a) 5 mg/kg left atrial (LA) bolus, (b) 5 mg/kg central vein (CV) bolus, (c) 15 mg/kg CV bolus, and (d) 5 mg/kg CV infusion over 60 min; additionally, all dogs received (e) a 5 mg/kg CV bolus under pentobarbital anesthesia. Serial serum samples were obtained after each dose and serial myocardial samples were obtained after dose (e). The serum rhSOD concentration was measured by radioimmunoassay and the data were fit to a two-compartment model. The distribution half-life was 7.8 +/- 1.7 min (mean +/- SEM), and the elimination half-life was 51.1 +/- 5.9 min; the central compartment volume of distribution (Vc) was 81 +/- 26 ml/kg and the steady-state volume of distribution was 156 +/- 20 ml/kg. The dosage regimen had no influence on clearance rates. Peak plasma concentrations (micrograms/ml) for the dosage regimens were (a) 65 +/- 28, (b) 89 +/- 19, (c) 214 +/- 61, (d) 20 +/- 5, and (e) 86 +/- 9. The peak level following continuous infusion did not occur until 50 min of infusion and was only one-fourth of the level achieved with a bolus of the same dose. Myocardial levels were less than 1% of serum levels, suggesting negligible rhSOD penetration into the myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

The age-associated decline in glomerular filtration in healthy normotensive volunteers. Lack of relationship to cardiovascular performance.

Whether the well-documented age-associated decline in the glomerular filtration rate, manifest as a decline in creatinine clearance, is secondary to an age-related change in cardiovascular performance is at present unknown. To answer this question, we measured arterial blood pressure, 24-hour creatinine clearance, and cardiac output determined from gated cardiac blood pool scans in the sitting position in healthy normotensive men (n = 75) and women (n = 42) (ages 25 to 82 years), from the Baltimore Longitudinal Study on Aging. These subjects were selected for the absence of cardiovascular disease, renal disease, and confounding medications. By linear regression analysis, creatinine clearance, expressed in mL/min/m2, declined cross-sectionally with age (creatinine clearance = 90 -0.33[age], r = .31, P less than .001), whereas systolic blood pressure in mm Hg increased with age (systolic blood pressure = 111 + 0.27[age], r = .30, P less than .001); cardiac output in L/min/m2 did not vary with age (r = .03, P = .74). In stepwise multiple regression analysis with age, cardiac index, and systolic blood pressure as independent variables and creatinine clearance as the dependent variable, only age was a significant predictor of creatinine clearance. (F = 11.31, DF + 116, r = .30, P less than .001). Thus, the age-associated decline in creatinine clearance is not modulated by changes in cardiac index or systolic blood pressure in healthy normotensive subjects.

Adult↗
PubMed1990

Interaction between left ventricular end-diastolic and end-systolic volumes in normal humans.

The extent to which the end-systolic volume (ESV) "follows" the end-diastolic volume (EDV) when the latter changes in response to various perturbations is a major determinant of the cardiac ejection fraction (EF) and has not been studied in humans. We measured EDV, ESV, and EF, determined by gated blood pool scans, during a change in posture from the supine to the upright seated position and during graded upright bicycle exercise. The experimental group consisted of 119 healthy individuals (79 males and 40 females) ranging in age from 21 to 81 yr and in physical-conditioning status (75-225 W maximum work load); rigorous screening excluded cardiac disease. Multiple regression analysis showed that the change in ESV (delta ESV) during a postural shift or during graded exercise was highly statistically correlated with the change in EDV (delta EDV) that occurred (r2 ranged from 0.34 to 0.49, correlation is positive) regardless of age, sex, or exercise work load. The correlation of delta ESV with delta EDV observed in this large sample, heterogeneous with respect to age, sex, and physical fitness, was also present in additional 31 subjects who exercised during beta-adrenergic blockade (propranolol 0.15 mg/kg). The delta EF with posture change and exercise in all subjects under all conditions was highly and inversely correlated with the delta ESV (r2 ranged from 0.38 to 0.81). Thus the delta ESV during the circulatory adaptive response to orthostatic and exercise stresses in humans is related to the delta EDV, and this relationship modulates the delta EF in response to these stresses.

Adult↗
PubMed1990

Prevalence and prognostic significance of exercise-induced silent myocardial ischemia detected by thallium scintigraphy and electrocardiography in asymptomatic volunteers.

Although a silent ischemic electrocardiographic response to treadmill exercise in clinically healthy populations is associated with an increased likelihood of future coronary events (i.e., angina pectoris, myocardial infarction, or cardiac death), such a response has a low predictive value for future events because of the low prevalence of disease in asymptomatic populations. To examine whether detection of reduced regional perfusion by thallium scintigraphy improved the predictive value of exercise-induced ST segment depression, we performed maximal treadmill exercise electrocardiography (ECG) and thallium scintigraphy (201Tl) in 407 asymptomatic volunteers 40-96 years of age (mean = 60) from the Baltimore Longitudinal Study on Aging. The prevalence of exercise-induced silent ischemia, defined by concordant ST segment depression and a thallium perfusion defect, increased more than sevenfold from 2% in the fifth and sixth decades to 15% in the ninth decade. Over a mean follow-up period of 4.6 years, cardiac events developed in 9.8% of subjects and consisted of 20 cases of new angina pectoris, 13 myocardial infarctions, and seven deaths. Events occurred in 7% of individuals with both negative 201Tl and ECG, 8% of those with either test positive, and 48% of those in whom both tests were positive (p less than 0.001). By proportional hazards analysis, age, hypertension, exercise duration, and a concordant positive ECG and 201Tl result were independent predictors of coronary events. Furthermore, those with positive ECG and 201Tl had a 3.6-fold relative risk for subsequent coronary events, independent of conventional risk factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Myocardial redistribution of technetium-99m-methoxyisobutyl isonitrile (SESTAMIBI).

To determine whether technetium-99m-hexakis-2-methoxyisobutyl isonitrile (SESTAMIBI) remains fixed in the myocardium following its initial uptake or undergoes time-related redistribution, anesthetized dogs underwent occlusion of the anterior descending coronary artery for 6 min, followed by 3-hr reperfusion. Technetium-99m-SESTAMIBI and thallium-201 (201Tl) were injected intravenously after 1 min occlusion and regional myocardial blood flow was measured with radioactive microspheres. Tomographic imaging of Tc-SESTAMIBI revealed a perfusion defect with slight but definite filling in over 2 hr. Quantitative analysis indicated a significant rise in the nadir and decrease in the width of the defect in circumferential profile curves. After 3-hr of reperfusion, Tc-SESTAMIBI activity in the previously ischemic area was always greater than the activity of microspheres injected during coronary occlusion (mean normalized values, 0.32 versus 0.11, p less than 0.0001). Our results indicate that following transient ischemia and reperfusion, Tc-SESTAMIBI clearly undergoes myocardial redistribution, although more slowly and less completely than 201Tl.

Animals↗