Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired platelet production and increased platelet clearance.

Mechanisms of thrombocytopenia were studied in 38 patients with mild to moderately severe chronic autoimmune thrombocytopenia (AITP). 51Cr and 111In-labeled autologous platelet turnover studies and in vitro analysis of committed megakaryocyte progenitors (CFU-Meg) were used as independent measures of platelet production. Autologous 111In-labeled platelet localization studies were performed to assess platelet clearance. Although there was no increase in the frequency of marrow CFU-Meg, a specific increase in the CFU-Meg [3H]TdR suicide rate was seen which was inversely correlated with the platelet count (P less than 0.001). Platelet turnover studies showed significant numbers of patients had inappropriate thrombopoietic responses to their reduced platelet counts. Platelet-associated antibody levels correlated inversely with platelet turnover suggesting that antiplatelet antibody impairs platelet production. The circulating platelet count was best predicted by an index relating platelet production (i.e., turnover) to the spleen-liver platelet clearance that correlated directly with platelet survival (P less than 0.001). In summary, both depressed platelet production and increased platelet clearance by the liver and spleen contribute to the thrombocytopenia of AITP.

Semirational design of a potent, artificial agonist of fibroblast growth factor receptors.

Fibroblast growth factors (FGFs) are being investigated in human clinical trials as treatments for angina, claudication, and stroke. We designed a molecule structurally unrelated to all FGFs, which potently mimicked basic FGF activity, by combining domains that (1) bind FGF receptors (2) bind heparin, and (3) mediate dimerization. A 26-residue peptide identified by phage display specifically bound FGF receptor (FGFR) 1c extracellular domain but had no homology with FGFs. When fused with the c-jun leucine zipper domain, which binds heparin and forms homodimers, the polypeptide specifically reproduced the mitogenic and morphogenic activities of basic FGF with similar potency (EC50 = 240 pM). The polypeptide required interaction with heparin for activity, demonstrating the importance of heparin for FGFR activation even with designed ligands structurally unrelated to FGF. Our results demonstrate the feasibility of engineering potent artificial agonists for the receptor tyrosine kinases, and have important implications for the design of nonpeptidic ligands for FGF receptors. Furthermore, artificial FGFR agonists may be useful alternatives to FGF in the treatment of ischemic vascular disease.

Comparative plasma catecholamine and hemodynamic responses to handgrip, cold pressor and supine bicycle exercise testing in normal subjects.

Serial hemodynamic and plasma catecholamine responses were compared among 10 healthy men (27 +/- 3 years) (+/- 1 standard deviation) during symptom-limited handgrip (33% maximal voluntary contraction for 4.4 +/- 1.8 minutes), cold pressor testing (6 minutes) and symptom-limited supine bicycle exercise (22 +/- 5 minutes). Plasma catecholamine concentrations were measured by radioenzymatic assays: ejection fraction and changes in cardiac volumes were assessed by equilibrium radionuclide angiography. During maximal supine exercise, plasma norepinephrine and epinephrine concentrations increased three to six times more than during either symptom-limited handgrip or cold pressor testing. Additionally, increases in heart rate, systolic blood pressure, rate-pressure product, stroke volume, ejection fraction and cardiac output were significantly greater during bicycle exercise than during the other two tests. A decrease in ejection fraction of 0.05 units or more was common in young normal subjects during the first 2 minutes of cold pressor testing (6 of 10 subjects) or at symptom-limited handgrip (3 of 10), but never occurred during maximal supine bicycle exercise. The magnitude of hemodynamic changes with maximal supine bicycle exercise was greater, more consistent and associated with much higher sympathetic nervous system activation, making this a potentially more useful diagnostic stress than either handgrip exercise or cold pressor testing.

Relation of global and regional left ventricular function to tomographic thallium-201 myocardial perfusion in patients with prior myocardial infarction.

To determine the relation between regional myocardial perfusion and regional wall motion in humans, tomographic thallium-201 imaging and two-dimensional echocardiography at rest were performed on the same day in 83 patients 4 to 12 weeks after myocardial infarction. Myocardial perfusion and wall motion were assessed independently in five left ventricular regions (total 415 regions). Regional myocardial perfusion was quantitated as a percent of the region infarcted (range 0 to 100%) using a previously validated method. Wall motion was graded on a four point scale as 1 = normal (n = 266 regions), 2 = hypokinesia (n = 64), 3 = akinesia (n = 70), 4 = dyskinesia (n = 13) or not evaluable (n = 2). Regional wall motion correlated directly with the severity of the perfusion deficit (r = 0.68, p less than 0.0001). Among normally contracting regions, the mean perfusion defect score was only 2 +/- 4. Increasingly severe wall motion abnormalities were associated with larger perfusion defect scores (hypokinesia = 6 +/- 5, akinesia = 11 +/- 7 and dyskinesia = 18 +/- 5, all p less than 0.01 versus normal. Among regions with normal wall motion, only 3% had a perfusion defect score greater than or equal to 10. Conversely, among 68 regions with a large (greater than or equal to 10) perfusion defect, only 13% had normal motion whereas 87% had abnormal wall motion. The relation between perfusion and wall motion noted for the entire cohort was also present in subgroups of patients with anterior or inferior infarction. In patients with prior myocardial infarction, the severity of the tomographic thallium perfusion defect correlates directly with echocardiographically defined wall motion abnormalities, both globally and regionally.(ABSTRACT TRUNCATED AT 250 WORDS)

Late effects of intracoronary streptokinase on regional wall motion, ventricular aneurysm and left ventricular thrombus in myocardial infarction: results from the Western Washington Randomized Trial.

To determine whether intracoronary streptokinase improves late regional wall motion or reduces left ventricular aneurysm or thrombus formation in patients with acute myocardial infarction, two-dimensional echocardiography was performed at 8 +/- 3 weeks after infarction in 83 patients randomized to streptokinase (n = 45) or standard therapy (n = 38) in the Western Washington Intracoronary Streptokinase Trial. Among the patients treated with streptokinase, the average time to treatment was 4.7 +/- 2.5 hours after the onset of chest pain, and 67% had successful reperfusion. Regional wall motion was assessed in nine left ventricular segments on a scale of 1 to 4 (normal, hypokinetic, akinetic and dyskinetic). Left ventricular thrombus formation was interpreted as positive, equivocal or negative. All patients received anticoagulant therapy in the hospital and 52 received such therapy after hospital discharge. The mean (+/- SD) global (1.5 +/- 0.4 in both groups) and regional wall motion scores in the streptokinase-treated and control groups were not significantly different. The prevalence of aneurysm was 16% in both groups. Left ventricular thrombus was identified in only five patients (positive identification in four, and equivocal in one), all in the streptokinase-treated group (p = NS). There were also no differences between streptokinase and control treatment in any of the echocardiographic variables in subgroups of patients with anterior infarction, inferior infarction, no prior infarction or reperfusion with streptokinase. It is concluded that intracoronary streptokinase given relatively late in the course of acute myocardial infarction does not result in improved global or regional wall motion or a reduction in left ventricular thrombus or aneurysm formation in survivors studied 2 months after myocardial infarction.

Decreased numbers of platelet alpha-adrenergic binding sites in diabetes mellitus.

Eleven men with diabetes mellitus were compared with 45 male controls for platelet alpha-adrenergic binding sites by using [3H]dihydroergocryptine (DHE) as the radioligand antagonist. There was no difference between the two for binding affinity, but the number of sites was 430 +/- 30 (means +/- SEM) for diabetic subjects and 574 +/- 29 for controls (P = .005). Decreased sites were related to increased glycosylated hemoglobin levels (P = .002). There was no relationship between the decreased sites and catecholamine levels, duration of disease, body weight, or fasting blood sugar. Hence, binding sites were inversely related to control, but further studies are needed to define the pathophysiologic significance of this.

Exercise training delineates the importance of B-cell dysfunction to the glucose intolerance of human aging.

Aging has been associated with glucose intolerance, insulin resistance, hyperinsulinemia, and diminished islet B-cell function. The relative contribution of these factors to the aging-associated changes in glucose tolerance has been difficult to discern, particularly so for B-cell function, since insulin sensitivity itself is a determinant of B-cell function and, therefore, comparisons of insulin levels and responses between old and young subjects are difficult. To reduce this effect, we compared B-cell function in 14 healthy older men (aged 61-82 yr; body mass index, 21-30 kg/m2), who were exercise trained for 6 months to improve insulin sensitivity, to that of 11 healthy young men (aged 24-31 yr; body mass index, 19-31 kg/m2), who were also trained. Insulin-glucose interactions were assessed by measuring indices of insulin sensitivity (SI) and glucose effectiveness at zero insulin (GEZI) using Bergman's minimal model. B-Cell function was assessed by determining the acute insulin responses (AIR) to glucose (AIRgluc) and arginine at 3 different glucose levels: fasting, approximately 14 mM, and greater than 28 mM (AIRmax). AIRmax provides a measure of B-cell secretory capacity, while the glucose level at which 50% of AIRmax occurs is termed PG50 and is used to estimate B-cell sensitivity to glucose. The insulin sensitivity and glucose effectiveness at zero insulin of the trained older subjects was similar to that of the trained young [SI: old, 5.1 +/- 0.6; young, 6.5 +/- 0.7 x 10(-5) min-1/pM (mean +/- SEM; P = NS); GEZI: old, 1.3 +/- 0.2; young, 1.7 +/- 0.2 x 10(-2) min (P = NS)]. Under these conditions, the fasting glucose levels (old, 5.4 +/- 0.2; young, 5.1 +/- 0.1 mM) and basal insulin levels (old, 49 +/- 6; young, 63 +/- 11 pM) were also similar in the two groups. AIRgluc values were lower in the exercised elderly (old, 253 +/- 50; young, 543 +/- 101 pM; P = 0.01). This decrease in stimulated insulin release was due solely to a reduction in the AIRmax (old, 1277 +/- 179; young, 2321 +/- 225 pM; P less than 0.005); the PG50 was not different (old, 8.9 +/- 0.4; young, 8.8 +/- 0.2 mM; P = NS). These differences in the older subjects were associated with a reduction in iv glucose tolerance (old, 1.49 +/- 0.15; young, 1.95 +/- 0.13%/min; P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)

Factors influencing serial measurements of cardiac volumes by count-based methods: effects of elevated catecholamines, position, and exercise on technetium-99m-blood radioactivity concentration.

Most radionuclide methods for measuring cardiac volume require a determination of the blood radioactivity concentration. Thus, changes in blood radioactivity over time or during interventions might lead to spurious volume estimates unless blood radioactivity is serially measured. The effects of elevated epinephrine, posture and exercise on 99mTc-labeled blood radioactivity concentration were studied in 15 young (mean age = 28 yr) and 14 older (mean age = 68 yr) healthy males. An epinephrine infusion of 50 ng/kg/min resulted in a 4.1% +/- 1.0% increase in 99mTc-blood radioactivity (p less than or equal to 0.001) compared to baseline. Sitting increased blood radioactivity concentration by 12.3% +/- 3.0% (p less than 0.0002) compared to the supine position and peak supine bicycle exercise caused an 11.0% +/- 1.7% increase (p less than or equal to 0.0001) compared to supine rest. There was a significantly greater increase during peak supine exercise in the young compared to the older subjects (15.0% +/- 2.3% versus 6.3% +/- 2.0%, p less than or equal to 0.01). The mechanism of the increase in blood radioactivity concentration is uncertain, but presumably reflects the addition of hemoconcentrated red blood cells from the spleen and/or the loss of plasma volume. Failure to correct for the increased blood radioactivity concentration during exercise or pharmacological interventions will result in a significant error in serial measurements of cardiac volumes by methods requiring RBC radioactivity measurements.

Imaging arterial thrombosis: comparison of technetium-99m-labeled monoclonal antifibrin antibodies and indium-111-platelets.

UNLABELLED: Imaging with the 99mTc-T2G1s monoclonal antifibrin antibody fragment (Fab') has demonstrated promise in the noninvasive detection of venous thrombi in humans. The purpose of this study was to determine whether chronic arterial thrombi can also be detected by antifibrin antibody imaging. METHODS: Eighteen subjects with chronic arterial thrombi were studied with planar and tomographic imaging at 0 to 24 hr postinjection of 99mTc-labeled T2G1s monoclonal antifibrin antibody fragment. Imaging with 111In-labeled platelets was also performed. Images were visually graded by two observers as 0, 1, 2 or 3 (no, faint, moderate or marked) uptake, and quantitative analysis of tomographic images was done in 13 subjects. RESULTS: On visual analysis of planar images, 44% (8 of 18) of antifibrin patient studies were 1.0 or more and 66% (10 of 18) were judged negative compared with 94% (15 of 16) of platelet patient studies judged 1.0 or more and 6% (1 of 16) judged as negative (p < 0.01). Visual analysis of tomographic images was similar, with 61% (11 of 18) of antifibrin studies graded 1.0 or more compared with 100% (17 of 17) of platelet studies (p < 0.01). The tomographic target-to-background ratio was higher with platelets than with antifibrin antibody (2.5 +/- 1.4 versus 1.8 +/- 1.0, p < 0.05). CONCLUSION: In the large-vessel chronic arterial thrombi studied, the results of 99mTc-labeled monoclonal T2G1s antifibrin Fab' imaging were positive in only one-half of the patients studied, significantly less than the findings with platelet imaging, which were positive in all subjects. The higher rate of positive images with labeled platelets than with labeled antifibrin antibodies may be largely due to thrombus age, with continued platelet deposition but little active fibrin deposition.

Platelet destruction in autoimmune thrombocytopenic purpura: kinetics and clearance of indium-111-labeled autologous platelets.

Using autologous 111In-labeled platelets, platelet kinetics and the sites of platelet destruction were assessed in 16 normal subjects (13 with and three without spleens), in 17 studies of patients with primary autoimmune thrombocytopenic purpura (AITP), in six studies of patients with secondary AITP, in ten studies of patients with AITP following splenectomy, and in five thrombocytopenic patients with myelodysplastic syndromes. In normal subjects, the spleen accounted for 24 +/- 4% of platelet destruction and the liver for 15 +/- 2%. Untreated patients with primary AITP had increased splenic destruction (40 +/- 14%, p less than 0.001) but not hepatic destruction (13 +/- 5%). Compared with untreated patients, prednisone treated patients did not have significantly different spleen and liver platelet sequestration. Patients with secondary AITP had similar platelet counts, platelet survivals, and increases in splenic destruction of platelets as did patients with primary AITP. In contrast, patients with myelodysplastic syndromes had a normal pattern of platelet destruction. In AITP patients following splenectomy, the five nonresponders all had a marked increase (greater than 45%) in liver destruction compared to five responders (all less than 40%). Among all patients with primary or secondary AITP, there was an inverse relationship between the percent of platelets destroyed in the liver plus spleen and both the platelet count (r = 0.75, p less than 0.001) and the platelet survival (r = 0.86, p less than 0.001). In a stepwise multiple linear regression analysis, total liver plus spleen platelet destruction, the platelet survival and the platelet turnover were all significant independent predictors of the platelet count. Thus platelet destruction is shifted to the spleen in primary and secondary AITP. Failure of splenectomy is associated with a marked elevation in liver destruction. The magnitude of spleen and liver destruction appears to be of considerable importance in the severity of the disease, as reflected in the platelet survival and platelet count.

Radionuclide cardiac volumes: effects of region of interest selection and correction for Compton scatter using a buildup factor.

The effects of region of interest (ROI) selection and correction for Compton-scattered photons using a buildup factor on radionuclide left ventricular volumes calculated by the Links method were compared in 19 humans with contrast ventriculography and in phantoms. Three different methods of ROI selection were compared: a manual ROI, a second derivative ROI and a 50% count-threshold ROI. In phantoms without Compton scatter correction, volumes were overestimated by 30% (manual ROI), 20% (derivative ROI) and 1% (count threshold ROI). In subjects, results without Compton scatter correction were similar with overestimates of 50% (manual ROI) and 20% (derivative ROI) and an underestimate by 3% (count threshold method). Correction for Compton-scattered photons with the use of a phantom-derived buildup factor resulted in improved accuracy for the manual ROI (+15%) and the derivative ROI (0%). A 50% count threshold ROI following interpolative background subtraction allows the accurate calculation of cardiac volumes without the need for scatter correction, while a second derivative ROI method requires a correction for Compton scatter with the use of a buildup factor.

Four radionuclide methods for left ventricular volume determination: comparison of a manual and an automated technique.

This study compared the accuracy and reproducibility of three previously described and one new radionuclide method of measuring left ventricular volumes in 19 subjects using contrast ventriculographic volumes (n = 38, mean volume = 126.6 ml) as the gold standard. The four methods were compared using both manual and automated ROIs. For manual ROIs, the Links (189.7 ml, r = 0.85), Starling (183.2 ml, r = 0.77) and the new count ratio method (141.4 ml, r = 0.90) overestimated contrast volumes, while the Massardo method (122.5 ml, r = 0.91) provided accurate volumes. For the automated ROIs, we performed an interpolative background subtraction and used a 50% threshold of the highest count pixel to define the ventricular regions. The automated Massardo method severely underestimated the contrast volume (59.5 ml, r = 0.90), while the other automated methods yielded accurate volumes: Links (122.4 ml, r = 0.89), Starling (118.1 ml, r = 0.81) and the new count ratio method (125.0 ml, r = 0.90). The interobserver reproducibility of the automated methods was excellent (mean difference = 1%-4%) compared to the manual methods (2%-8%). Because no additional images, blood counting, attenuation, or decay correction were necessary, the manual Massardo method and the automated count ratio method are the simplest to perform. We conclude that automated determination of left ventricular volumes using the new count ratio method is rapid, accurate, reproducible and could readily be incorporated into routine clinical use.

Seven-pinhole emission tomography with thallium-201 in patients with prior myocardial infarction.

Thirty-six patients with prior myocardial infarction, and 14 patients without, had myocardial imaging at rest using both seven-pinhole emission tomography and planar imaging with thallium-201. The sensitivity and specificity of the two approaches for the detection of prior myocardial infarction were compared. Qualitatively, planar imaging yielded sensitivities of 69% (25 of 36) and 80% (29 of 36) with Polaroid and video display formats, respectively. A semiquantitative analysis gave a sensitivity of 75% (27 of 36). Specificities for these three planar approaches were, respectively, 100% (14 of 14), 93% (13 of 14), and 71% (10 of 14) for the Polaroid, video, and semiquantitative analyses. Seven-pinhole tomography had a sensitivity of 83% (30 of 36) by qualitative or visual inspection and 86% (31 of 36) by semiquantitative analysis. Specificities by these two techniques were 71% (10 of 14) and 57% (8 of 14). There were no statistically significant differences in either sensitivity or specificity between the planar and tomographic approaches. Repeat seven-pinhole images were identical in 95% (46 of 48) of patients, showing that reproducibility was satisfactory. We conclude that the seven-pinhole tomographic approach has no advantage over standard planar imaging in the detection of prior myocardial infarction.

Effect of a benzodiazepine (alprazolam) on plasma epinephrine and norepinephrine levels during exercise stress.

To determine whether a benzodiazepine central nervous system depressant, alprazolam, inhibits sympathetic discharge during exercise stress, 11 healthy men, aged 21 to 35 years, performed symptom-limited treadmill tests before and on the third day of drug therapy (0.5 mg 3 times daily). Plasma epinephrine and norepinephrine levels were measured at rest and at 8 minutes, 11 minutes and maximal exercise. Owing to catheter malfunction during vigorous exercise, paired samples could be obtained from only 8 subjects at 8 minutes and from only 4 subjects at 11 minutes of exercise. During drug treatment, the plasma epinephrine level was lower at rest (30 +/- 4 vs 53 +/- 7 pg/ml, p less than 0.01), and at 8 minutes (60 +/- 13 vs 117 +/- 19 pg/ml, p less than 0.01), 11 minutes (120 +/- 39 vs 193 +/- 52 pg/ml, p less than 0.05), and maximal exercise (520 +/- 125 vs 970 +/- 324 pg/ml, p = 0.13). Plasma norepinephrine was unchanged at rest (452 +/- 57 vs 413 +/- 45 pg/ml) but lower at 8 minutes (730 +/- 75 vs 886 +/- 82 pg/ml, p less than 0.01), 11 minutes (1,077 +/- 197 vs 1,447 +/- 301 pg/ml, p less than 0.05) and at maximal exercise (3,453 +/- 487 vs 5,590 +/- 1,100 pg/ml, p = 0.09). Exercise duration (17 +/- 1 and 17 +/- 1 minutes) was unchanged on drug. Thus, alprazolam reduces the plasma catecholamine response to exercise stress, possibly by inhibiting centrally mediated sympathetic discharge. Blunting of sympathetic activation may be beneficial in cardiac disorders in which increased sympathetic tone is potentially deleterious.

Effect of suloctidil on tomographically quantitated platelet accumulation in Dacron aortic grafts.

Platelet deposition contributes to the thrombotic and embolic complications of prosthetic materials in man. To determine if the investigational platelet inhibitory drug suloctidil (200 mg 3 times daily) reduces platelet deposition on Dacron aortic grafts, a randomized, double-blind, crossover trial was conducted in 12 men with grafts that had been in place more than 9 months. Platelet deposition in the graft was assessed by quantitative analysis of planar images obtained at 24, 48 and 72 hours after injection of indium-111-labeled platelets. Also, a tomographic method of imaging and quantitating labeled platelet deposition in the graft was developed. Tomographic imaging was performed at 24 and 72 hours after platelet injection and was quantitated by a graft/blood ratio that compared indium-111 platelet activity in summed 1.8-cm-thick transaxial tomographic slices of the aortic graft to indium-111 platelet activity in well-counted whole blood. Compared with placebo, suloctidil failed to decrease the tomographic graft/blood ratio at 24 hours (6.2 +/- 1.3 vs 5.7 +/- 0.8) and 72 hours (11.4 +/- 2.9 vs 10.7 +/- 2.2). Similarly, the graft/blood ratio determined by planar imaging was not different between placebo and suloctidil therapy at 24 hours (1.7 +/- 0.3 vs 1.6 +/- 0.2), 48 hours (2.2 +/- 0.4 vs 2.4 +/- 0.4) or 72 hours (2.6 +/- 0.5 vs 2.8 +/- 0.5) after labeled platelet injection. Thus, suloctidil does not significantly reduce platelet deposition on chronically implanted Dacron grafts in humans.

Influence of myocardial infarction size on radionuclide and Doppler echocardiographic measurements of diastolic function.

To assess the relation between myocardial infarction size and diastolic function as measured by radionuclide ventriculography and Doppler echocardiography, 83 patients (aged 58 +/- 9 years) without significant valvular disease were studied 8 to 12 weeks after an acute myocardial infarction. Myocardial infarction size was measured by resting thallium-201 tomography. Peak early filling rate (in end-diastolic volumes/s) was measured by gated blood pool scintigraphy. Doppler measures of mitral inflow were peak early (E) and atrial (A) filling velocities, slopes of E and A, percent E and A filling, E/A ratio and diastolic filling period. In univariate analyses, there was a significant inverse correlation between infarction size and the peak early filling rate (r = -0.59, p less than 0.001), and this remained significant (r = -0.63, p less than 0.0001) in an analysis that included 2 other determinants of the filling rate, age and diastolic filling period. Infarction size was directly correlated to the peak E velocity (r = 0.37, p less than 0.01), deceleration of E (r = 0.41, p less than 0.01) and percent E filling (r = 0.31, p less than 0.01), and was inversely correlated to peak A (r = -0.27, p less than 0.05) and percent A filling (r = -0.26, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of sympathetic stimulation and parasympathetic withdrawal on Doppler echocardiographic left ventricular diastolic filling velocities in young normal subjects.

To determine the effects of parasympathetic withdrawal or sympathetic stimulation on Doppler echocardiographic measures of left ventricular diastolic filling, we studied 10 young normal subjects aged 21 to 29 years during separate infusions of atropine (0.8 mg followed by 0.4 mg every 10 minutes until heart rate greater than 110 beats/min or a total dose of 2 mg was attained) and epinephrine (10, 25 and 50 ng/kg/min for 12 minutes each). At the highest atropine dose, heart rate increased from 60 +/- 9 to 105 +/- 8 beats/min (mean +/- standard deviation), the diastolic filling period decreased by 61% (573 +/- 141 to 222 +/- 34 ms), the peak early (E) filling decreased 23% (77 +/- 12 to 61 +/- 11 cm/s), the peak atrial (A) filling increased 103% (40 +/- 6 to 81 +/- 17 cm/s), and the E/A ratio decreased by 60% (2.0 +/- 0.5 to 0.8 +/- 0.3) (all p less than 0.001). These alterations were not correlated to changes in systolic function, preload, blood pressure or plasma catecholamines, all of which were unchanged. However, atropine-induced changes in diastolic filling period were highly correlated to changes in E peak (r = 0.64, p less than 0.01), A peak (r = -0.95, p less than 0.001) and the E/A ratio (r = 0.93, p less than 0.001). The effects of atropine on the E/A ratio were normalized by dividing the E/A ratio by the diastolic filling period (E/A/diastolic filling period).(ABSTRACT TRUNCATED AT 250 WORDS)

Natural history of platelet deposition on Dacron aortic bifurcation grafts in the first year after implantation.

This study defined the dynamics of platelet deposition on Dacron arterial grafts up to 1 year after implantation in human subjects. Indium-111 platelet imaging was performed on 8 men 1 to 2 weeks after graft implantation and on 5 of these patients at a mean of 31 weeks (range 28 to 34) and again at 55 weeks (range 50 to 62). Serial imaging was performed at 24 to 96 hours after platelet labeling and injection in each study. Quantitative analysis was performed using a graft/blood ratio that compared background-corrected indium-111 platelet activity in the graft region to whole-blood indium-111 platelet activity. Additionally, blinded qualitative visual analysis of the images compared graft activity with the activity in adjacent native arteries. The mean of all graft/blood ratios (24, 48, 72, and 96 hours) progressively decreased from 4.4 +/- 2.1 (+/- 1 standard deviation) at 1 to 2 weeks to 3.0 +/- 1.8 at 31 weeks (p = 0.002). There was no further decrease at 55 weeks (2.8 +/- 2.0). For comparison, 12 normal subjects without grafts had a mean ratio of 1.8 +/- 0.7. Visual analysis detected platelet deposition in 7 of 8 grafts at 1 to 2 weeks, 4 of 5 at 31 weeks, and 4 of 5 at 55 weeks. Deposition decreased qualitatively in 2 of 5 patients at late study. It is concluded that there is consistent, early platelet deposition on Dacron grafts in man. Although deposition decreases over 31 weeks, it remains readily detectable in most patients at 1 year. These findings suggest absent or incomplete endothelialization of the graft flow surface in humans in the first year after implantation.

Effects of metoprolol on rest and exercise cardiac function and plasma catecholamines in chronic congestive heart failure secondary to ischemic or idiopathic cardiomyopathy.

To define the effects of 2 months of metoprolol therapy on cardiac function, aerobic performance and sympathetic nervous system activity, metoprolol (75 to 100 mg/day) was administered to 10 patients with chronic congestive heart failure (CHF). Metoprolol was discontinued in 2 patients because of worsening CHF. In the remaining 8 patients, peak oxygen uptake increased significantly (14.8 +/- 3.0 to 16.1 +/- 2.5 ml/kg/min, p less than 0.05) as did the oxygen pulse (9.0 +/- 2.2 to 12.6 +/- 1.8 ml/beat, p less than 0.02). Resting heart rate (87 +/- 18 to 62 +/- 9 beats/min, p less than 0.05) and peak exercise heart rate (133 +/- 13 to 105 +/- 30 beats/min, p less than 0.02) were both reduced. Mean resting ejection fraction increased from 0.15 +/- 0.06 to 0.25 +/- 0.11 and peak exercise ejection fraction also tended to increase (0.19 +/- 0.11 to 0.28 +/- 0.15, difference not significant). Both resting plasma norepinephrine (613 +/- 706 to 303 +/- 142 pg/ml, p less than 0.05) and epinephrine (71 +/- 50 to 40 +/- 21 pg/ml, p less than 0.05) were reduced. Circulating lymphocyte beta-adrenergic receptor number was unchanged (1,334 +/- 292 to 1,344 +/- 456 receptors/cell, difference not significant). It is concluded that metoprolol therapy is associated with improvements in rest and exercise ventricular performance and maximal aerobic capacity. These improvements are associated with a decline in resting sympathetic nervous system activity.

Echocardiographic evaluation of segmental wall motion early and late after thrombolytic therapy in acute myocardial infarction: the Western Washington Tissue Plasminogen Activator Emergency Room Trial.

In 92 acute myocardial infarction (AMI) patients treated with tissue plasminogen activator 2.3 +/- 1.2 hours after the onset of chest pain, echocardiography was performed at 11 +/- 14 hours (early) and, in 49 patients, again at 13 +/- 7 weeks (late). Infarct location and the left ventricular wall motion score index--the average score (normal = 1, hypokinetic = 2, akinetic = 3, dyskinetic = 4) for 20 segments--were determined by 2 observers unaware of clinical, angiographic or electrocardiographic data. Concordance between noninvasive infarct location by electrocardiography or echocardiography and infarct-related artery at angiography 4 +/- 2 days later (n = 85) was 76 and 81%, respectively. The early wall motion score index was worse for anterior (1.8 +/- 0.4) versus inferior (1.3 +/- 0.2, p less than 0.0001) or posterior-lateral (1.6 +/- 0.2, p = 0.0003) infarcts. Overall, the wall motion score index improved from early to late echocardiography (n = 49, 1.5 +/- 0.3 to 1.3 +/- 0.3, p = 0.0008). However, improvement was confined to those with time to treatment less than or equal to 2 hours (n = 22, 1.4 +/- 0.3 to 1.2 +/- 0.2, p less than 0.0001), and evidence of reperfusion at angiography (n = 38, 1.5 +/- 0.3 to 1.2 +/- 0.3, p less than 0.0001). The decrease in the wall motion score index was related to a decrease in the number of adjacent involved segments (5.5 +/- 3.0 to 3.7 +/- 3.9/patient, p = 0.0006). Thus, echocardiography early after AMI identifies infarct location. Improvement in regional wall motion is seen after early treatment with intravenous tissue plasminogen activator.