Phase II study of treatment of advanced ovarian cancer with folate-receptor-targeted therapeutic (vintafolide) and companion SPECT-based imaging agent (99mTc-etarfolatide).

BACKGROUND: This report examines (99m)Tc-etarfolatide imaging to identify the presence of folate receptor (FR) on tumors of women with recurrent/refractory ovarian or endometrial cancer and correlates expression with response to FR-targeted therapy (vintafolide). PATIENTS AND METHODS: In this phase II, single-arm, multicenter study, patients with advanced ovarian cancer were imaged with (99m)Tc-etarfolatide before vintafolide treatment. Up to 10 target lesions (TLs) were selected based on Response Evaluation Criteria In Solid Tumors criteria using computed tomography scans. Single-photon emission computed tomography images of TLs were assessed for (99m)Tc-etarfolatide uptake as either FR positive or negative. Patients were categorized by percentage of TLs positive and grouped as FR(100%), FR(10%-90%), and FR(0%). Lesion and patient response were correlated with etarfolatide uptake. RESULTS: Forty-nine patients were enrolled; 43 were available for analysis. One hundred thirty-nine lesions were (99m)Tc-etarfolatide evaluable: 110 FR positive and 29 FR negative. Lesion disease control rate (DCR = stable or response) was observed in 56.4% of FR-positive lesions versus 20.7% of FR-negative lesions (P < 0.001). Patient DCR was 57%, 36%, and 33% in FR(100%), FR(10%-90%), and FR(0%) patients, respectively. Median overall survival was 14.6, 9.6, and 3.0 months in FR(100%), FR(10%-90%), and FR(0%) patients, respectively. CONCLUSIONS: Overall response to FR-targeted therapy and DCR correlate with FR positivity demonstrated by (99m)Tc-etarfolatide imaging. CLINICAL TRIAL NUMBER: NCT00507741.

Annexin-V imaging for noninvasive detection of cardiac allograft rejection.

Heart transplant rejection is characterized pathologically by myocyte necrosis and apoptosis associated with interstitial mononuclear cell infiltration. Any one of these components can be targeted for noninvasive detection of transplant rejection. During apoptotic cell death, phosphatidylserine, a phospholipid that is normally confined to the inner leaflet of cell membrane bilayer, gets exteriorized. Technetium-99m-labeled annexin-V, an endogenous protein that has high affinity for binding to phosphatidylserine, has been administered intravenously for noninvasive identification of apoptotic cell death. In the present study of 18 cardiac allograft recipients, 13 patients had negative and five had positive myocardial uptake of annexin. These latter five demonstrated at least moderate transplant rejection and caspase-3 staining, suggesting apoptosis in their biopsy specimens. This study reveals the clinical feasibility and safety of annexin-V imaging for noninvasive detection of transplant rejection by targeting cell membrane phospholipid alterations that are commonly associated with the process of apoptosis.

Myocardial infarct imaging of antibodies to canine cardiac myosin with indium-111-diethylenetriamine pentaacetic acid.

Antibodies, by virtue of marked selectivity and affinity, may lend themselves to identification of structures of unique antigenic specificity in vivo. In experimental myocardial infarction in dogs, F(ab')2 fragments of antibodies to cardiac myosin that had been labeled with iodine-131 were shown to localize within the lesion. Because the energy characteristics of iodine isotopes are not ideal for imaging with a gamma camera, a new method for labeling antibody fragments with divalent or polyvalent radionuclides was developed. A bifunctional chelating agent, diethylenetriamine pentaacetic acid was covalently coupled, by an amide bond, to Fab fragments of antibodies to canine cardiac myosin. A stable chelate was then formed with indium-111, a nuclide that has appropriate half-life and energy characteristics for gamma imaging. Antibodies treated in this way retain their antigen-binding activity and are useful in locating myocardial infarcts in vivo.

Regional myocardial substrate uptake in hypertensive rats: a quantitative autoradiographic measurement.

Severe hypertension causes global and regional changes in myocardial perfusion and substrate utilization. Regional perfusion and fatty acid utilization were evaluated by dual-tracer autoradiography in normotensive and hypertensive rats of the Dahl strain. The regional distributions of perfusion and fatty acid utilization were homogeneous in normotensive rats. Severe hypertension was associated with a homogeneous pattern of regional perfusion, but fatty acid utilization was focally decreased in the free wall of the left ventricle. The decrease in fatty acid uptake was associated with a concomitant increase in glucose utilization. These findings suggest that severe hypertension is associated with uniform myocardial perfusion and focal alterations in the substrates used for the performance of myocardial work.

Beta receptor occupancy. Assessment in the intact animal.

Organ uptake of 125I-hydroxybenzylpindolol, a potent beta adrenergic antagonist, was determined after intravenous administration. Pretreatment with the beta agonist, epinephrine, inhibited an almost identical fraction of 125I-hydroxybenzylpindolol binding as did the antagonist, propranolol. Specific beta receptor binding accounted for 50% of total uptake in the lung and demonstrated the following characteristics. The dose-response curve for propranolol inhibition of 125I-hydroxybenzylpindolol binding duplicated that reported for its physiologic action. Simultaneous serum propranolol levels as determined by a sensitive radioimmunoassay allowed an apparent dissociation rate constant approximately 7 nM to be obtained that correlated closely with the results reported from membrane binding studies. Alpha blockade had no effect and inhibition of 125I-hydroxybenzylpindolol binding by propranolol demonstrated stereospecificity. After chemical sympathectomy with reserpine or 6-OH dopamine, there was a 100% increase in receptor specific binding. Finally, a scintillation camera was employed to visually and quantitatively detect 125I-hydroxybenzylpindolol displacement from the lung during intravenous propranolol administration in the living animal. Reversal of binding was rapid and an in vivo inhibition curve was generated. Such a method provides the potential for longitudinally assessing beta receptor occupancy and apparent affinity directly in man.

Detection of monocyte chemoattractant protein-1 receptor expression in experimental atherosclerotic lesions: an autoradiographic study.

BACKGROUND: Monocytes, a common component of atheroma, are attracted to the lesion site in response to chemotactic signals, particularly expression of monocyte chemoattractant peptide 1 (MCP-1). This study assessed the feasibility of using radiolabeled MCP-1 to identify monocytes and macrophages that have localized at sites of experimental arterial lesions. Methods and Results-- The biodistribution of radiolabeled MCP-1 was determined in normal mice, and localization in experimental atheroma was determined in cholesterol-fed rabbits 4 weeks after arterial injury of the iliac artery (9 rabbits) and the abdominal aorta (1 rabbit). Vessels were harvested and autoradiographed after intravenous administration of (125)I-labeled MCP-1 and Evans blue dye. The arteries were evaluated histologically by hematoxylin and eosin staining and immune staining with a monoclonal antibody specific for rabbit macrophages (RAM-11). (125)I-MCP-1 has a blood clearance half-time of approximately 10 minutes and circulates in association with cells. The liver, lungs, and kidneys had the highest concentration of (125)I-MCP-1 at 5 and 30 minutes after tracer administration. Autoradiograms revealed accumulation of (125)I-MCP-1 in the damaged artery wall, with an average ratio of lesion to normal vessel of 6:1 (maximum 45:1). The accumulation of (125)I-MCP-1 in the reendothelialized (plaque formation) areas was greater than in the deendothelialized (Evans blue-positive) areas (6.55+/-2.26 versus 4.34+/-1.43 counts/pixel, P<0.05). The uptake of (125)I-MCP-1 correlated with the number of macrophages per unit area (r=0.85, P<0.0001). CONCLUSIONS: Radiolabeled MCP-1 may be a useful tracer for imaging monocyte/macrophage-rich experimental atherosclerotic lesions.

Zinc-mediated reduction of apoptosis in cardiac allografts.

BACKGROUND: Apoptosis is thought to occur during immune-mediated acute rejection of cardiac allografts. In vitro studies have shown that zinc inhibits the activity of the proapoptotic enzyme caspase-3. We hypothesized that ZnCl(2) would reduce acute cardiac rejection in vivo via the blockade of caspase-3-dependent apoptosis. (99m)Tc-labeled annexin V was used to measure apoptosis in cardiac allografts through nuclear imaging. Annexin V binds to phosphatidylserines, which are externalized to the outer membrane of apoptotic cells. METHODS AND RESULTS: Twenty-seven PVG rat hearts were transplanted heterotopically into the abdomen of untreated ACI rats as controls (group 1). Fifteen were scanned and euthanized on postoperative day 4, and 12 were assessed for graft survival. Group 2 and 3 rats (n=15 each) received 1 and 5 mg/kg ZnCl(2) BID IP, respectively. Nine of each of these groups were scanned and euthanized on postoperative day 4, and 6 were studied for allograft survival. Group 4 rats (n=3) received isografts. Region-of-interest analysis demonstrated a dose-dependent reduction in (99m)Tc annexin uptake in ZnCl(2)-treated allografts: 2.43+/-0.37% for group 1, 1. 97+/-0.41% for group 2, 1.21+/-0.47% for group 3, and 0.55+/-0.19% for group 4 (ANOVA, P:=0.001). Graft survival times of 6.4+/-1.7, 9. 3+/-3.0, and 11.5+/-3.4 days for groups 1, 2, and 3, respectively, were also observed (ANOVA, P:=0.001). Caspase-3 activity in the allografts showed a 3.7-fold reduction in group 3 animals compared with group 1 animals (P:=0.004). CONCLUSIONS: Apoptosis that occurs in acute cardiac allograft rejection is reduced with ZnCl(2) in a dose-dependent manner via caspase-3 inhibition.

Technetium-99m isonitrile myocardial uptake at rest. I. Relation to severity of coronary artery stenosis.

To determine the potential of planar technetium-99m methoxybutyl isonitrile myocardial imaging as a method of detecting totally occluded or severely stenosed coronary arteries, the regional distribution of technetium-99m isonitrile at rest was compared with the coronary anatomy in 38 patients with prior myocardial infarction who underwent coronary arteriography. Left ventricular technetium-99m isonitrile tracer uptake at rest was assessed in the three major coronary vascular territories. When qualitative rest technetium-99m isonitrile uptake was markedly reduced or absent (grade 0), there was a 91% probability of finding a totally occluded or severely stenosed coronary artery. When qualitative tracer uptake was reduced (grade 1) or normal (grade 2), it excluded all territories supplied by a totally occluded vessel with poor collateral flow. Quantitative technetium-99m isonitrile uptake (mean +/- 1 standard deviation) in territories supplied by an occluded coronary artery with poor collateral flow (42 +/- 21%) was lower than in territories supplied by a vessel with less than 50% stenosis (87 +/- 10%) and 50 to 99% stenosis (74 +/- 19%) (p less than 0.001). Furthermore, technetium-99m isonitrile uptake in areas supplied by an occluded coronary artery with good collateral flow (61 +/- 23%) was lower than in areas supplied by a vessel with less than 50% stenosis (87 +/- 10%) (p less than 0.001). Because rest technetium-99m isonitrile imaging detects coronary occlusion with poor collateral flow, this method may be useful in assessing patients with acute myocardial infarction.

Technetium-99m isonitrile myocardial uptake at rest. II. Relation to clinical markers of potential viability.

To determine the utility of rest-injected technetium-99m methoxybutyl isonitrile (Tc-99m isonitrile) uptake as a marker of myocardial viability, the regional uptake of this agent was compared with regional wall motion by equilibrium gated blood pool scan in 26 patients with previous myocardial infarction and with postrevascularization uptake in 8 patients after coronary bypass surgery. Rest left ventricular Tc-99m isonitrile uptake was assessed qualitatively in three coronary vascular territories as grade 0 (markedly reduced) to grade 2 (normal), and quantitatively by circumferential profile analysis. Wall motion was scored qualitatively in corresponding vascular territories as normal, hypokinetic or akinetic/dyskinetic. There was an overall relation between qualitative Tc-99m isonitrile uptake and wall motion. Abnormal wall motion occurred in 74% of vascular territories with perfusion grade 0, in 61% of those with grade 1 and in 30% of those with grade 2; however, 26% of territories with grade 0 uptake had normal wall motion. In the territories visually assigned perfusion grade 0, quantitative isonitrile uptake (mean value +/- SD) was higher when corresponding wall motion was normal or hypokinetic (62 +/- 15%) than when akinesia was detected by gated blood pool scan (39 +/- 16%, p less than 0.02). Qualitative Tc-99m isonitrile uptake improved after coronary bypass surgery in 12 of 13 territories with reduced uptake preoperatively; this included all 5 territories with a preoperative Tc-99m isonitrile score of 0. Quantitative uptake in these regions increased from 55 +/- 18% to 73 +/- 21% (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Positron emission tomographic measurements of absolute regional myocardial blood flow permits identification of nonviable myocardium in patients with chronic myocardial infarction.

OBJECTIVES: This study tested the hypothesis that nonviable myocardium can be identified by quantitative measurements of regional myocardial blood flow obtained using positron emission tomography in conjunction with a mathematical model of nitrogen-13 (N-13) ammonia tracer kinetics. BACKGROUND: Under steady state basal conditions there is a minimal level of blood flow required to sustain myocardial viability. Therefore, the hypothesis predicts that regions with flow below a certain threshold are likely to be composed primarily of scar. METHODS: Studies were conducted in 26 patients with chronic myocardial infarction. Positron emission tomographic measurements of basal regional myocardial blood flow (N-13 ammonia) and fluorine-18 (F-18) fluorodeoxyglucose uptake were made and correlated with information about coronary anatomy and regional wall motion to assess myocardial viability. RESULTS: In patients with chronic myocardial infarction, normal zone blood flow (0.81 +/- 0.32 ml/min per g [mean +/- SD]) was greater (p < 0.02) than that of border zones (0.59 +/- 0.29 ml/min per g), which in turn exceeded (p < 0.001) that of infarct zone flow (0.27 +/- 0.17 ml/min per g). Good correlation was noted between relative F-18 fluorodeoxyglucose uptake and relative regional myocardial blood flow in all zones (r = 0.63, p < 0.001). Mismatch between blood flow and F-18 fluorodeoxyglucose uptake, with a single exception, was not observed in any segment with blood flow < 0.25 ml/min per g. All dyskinetic segments (n = 5) also had blood flow < 0.25 ml/min per g. In contrast, 43 of 45 myocardial segments (23 patients) with normal contraction or only mild hypokinesia had flow > or = 0.39 ml/min per g (average flow 0.78 +/- 0.35 ml/min per g). CONCLUSIONS: In patients with chronic myocardial infarction, myocardial viability is unlikely when basal regional myocardial blood flow is < 0.25 ml/min per g. Average basal flow in segments with normal or nearly normal wall motion is 0.78 +/- 0.35 ml/min per g. Thus, positron emission tomographic measurement of regional myocardial blood flow is helpful in identifying nonviable myocardium in these patients.

Comparison of ejection fraction and pulmonary blood volume ratio as markers of left ventricular function change after coronary angioplasty.

Exercise-induced increases in pulmonary blood volume ratio have been shown to be a sensitive marker of coronary artery disease, and correlate well with exercise-induced increases in left ventricular filling pressure. To compare the impact of single vessel coronary disease on left ventricular systolic function (ejection fraction) versus diastolic filling pressure (pulmonary blood volume) before and after intervention, serial supine exercise gated blood pool scans were performed before and after coronary angioplasty in 32 patients with isolated left anterior descending coronary artery disease. By applying previously established criteria of abnormal ejection fraction (rest less than 50% or failure to rise by 5% with exercise) and pulmonary blood volume ratio (greater than 1.06), 66% of the patients were found to have abnormal responses before angioplasty by ejection fraction compared with 81% abnormal responses by pulmonary blood volume ratio (p = 0.15). After angioplasty, the proportion of patients with abnormal ejection fraction (59%) was essentially unchanged, whereas only 38% continued to have an abnormal pulmonary blood volume ratio (p less than 0.01 compared with before angioplasty). The mean pulmonary blood volume ratio also decreased significantly from 1.15 +/- 0.10 before angioplasty to 1.02 +/- 0.15 after angioplasty (p less than 0.001). It is concluded that in single vessel coronary artery disease: 1) pulmonary blood volume ratio is abnormal at least as frequently as is ejection fraction; 2) in contrast to ejection fraction, pulmonary blood volume ratio improves significantly after successful angioplasty; and 3) pulmonary blood volume ratio may be a more sensitive indicator of changes in ventricular function after an intervention in single vessel coronary disease.

Prognostic value of computer-quantitated exercise thallium imaging early after percutaneous transluminal coronary angioplasty.

To develop an approach to predicting adverse events after percutaneous transluminal coronary angioplasty (PTCA), 50 patients had thallium-201 exercise testing within 1 month after successful single vessel coronary angioplasty and were followed up for a mean of 18 months. Adverse events were: 1) clinical events consisting of recurrent angina (17 patients) and myocardial infarction (1 patient); 2) treatment events consisting of repeat coronary angioplasty (10 patients) and coronary bypass surgery (1 patient); and 3) restenosis, defined as a greater than 30% increase in luminal stenosis (15 of 38 recatheterized patients). There were no deaths. Of the clinical, exercise, angiographic and thallium scan variables analyzed by stepwise logistic regression, postangioplasty gradient greater than 20 mm Hg predicted clinical events and treatment events, and the number of segments with slower thallium clearance predicted clinical events, treatment events and restenosis. Using Cox Hazards model regression of survival without events, the number of transient qualitative thallium defects also predicted clinical events and restenosis. At 1 year after angioplasty, 24% of patients with these variables had restenosis compared with only 6% of those without these variables and 36% of patients with these variables had a clinical or treatment event compared with 8% of patients without these variables. Three measures of the adequacy of myocardial perfusion (post-angioplasty gradient, reduced thallium clearance and transient thallium defects) were additive predictors of adverse events after coronary angioplasty with the relative risk being approximately four times greater in patients with these variables than in those without. Such adverse events, therefore, are usually a consequence of inadequate revascularization.

Inotropic effect of enoximone in patients with severe heart failure: demonstration by left ventricular end-systolic pressure-volume analysis.

Left ventricular end-systolic pressure-volume analysis was employed to assess the inotropic effect of the phosphodiesterase inhibitor enoximone (formerly MDL-17,043) in nine patients with severe heart failure (New York Heart Association class IV symptoms, mean ejection fraction = 0.22). Left ventricular pressure-volume loops were constructed using high fidelity left ventricular pressure measured with micromanometer-tipped catheters and simultaneous left ventricular volume obtained by gated blood pool imaging. Afterload was reduced with the vasodilator nitroprusside to generate the baseline left ventricular end-systolic pressure-volume relation, a relatively load-independent measure of contractile function. The intravenous administration of enoximone (mean dose 75 mg) shifted the end-systolic pressure-volume point upward and leftward from the baseline pressure-volume relation in eight of the nine patients, demonstrating a positive inotropic effect of this agent. The maximal rate of left ventricular pressure development (peak positive dP/dt) increased from 1,030 +/- 142 to 1,381 +/- 219 mm Hg/s (p less than 0.01) on enoximone despite a significant decrease in preload (as assessed by left ventricular end-diastolic pressure and volume) and a small, insignificant decrease in mean arterial pressure. Two patients developed angina after enoximone administration; both patients had coronary artery disease and experienced a greater than 30% increase in heart rate-systolic blood pressure product. Thus, enoximone has a significant inotropic effect in patients with severe heart failure. Like other inotropic drugs, it has the potential to increase myocardial oxygen demand and thereby precipitate ischemia.

Intercellular adhesion molecule-1 induction: a sensitive and quantitative marker for cardiac allograft rejection.

OBJECTIVES: Rats with abdominal heterotopic heart transplants were studied to determine whether cardiac allograft rejection could be assessed by immunoscintigraphy targeting intercellular adhesion molecule-1 (ICAM-1), which was induced on allografted organ cells in association with rejection. BACKGROUND: It is important to detect early rejection before development of myocyte necrosis. Although a variety of methods for the detection of cardiac rejection have been investigated, histologic inspection of biopsied samples is still used routinely for clinical diagnosis of rejection. METHODS: DA rat (RT-1a) hearts were transplanted into PVG rats (RT-1c). Immunohistologic examination of the allografts demonstrated that ICAM-1 induction on vascular endothelial cells was observed as early as 4 days after transplantation in this combination. Thirty-nine allografted rats and seven isografted rats were studied. One day after injection of 100 microCi of 111Inlabeled anti-ICAM-1 monoclonal antibody (1A29), planar images were obtained. RESULTS: Rejecting allografts showed increased radiotracer uptake and could be identified on the images as early as 5 days after transplantation. In contrast, nonrejecting cardiac allografts and isografts did not show specific uptake. Mildly rejecting allografts, with mononuclear cell infiltration but without significant myocyte necrosis, could be scintigraphically identified, and the level of radiotracer uptake reflected the histologic severity of rejection. Accumulation of 111In-labeled monoclonal antibody of isotype-matched irrelevant specificity was not detected in the rejecting allografts. CONCLUSIONS: These data indicate that ICAM-1 induction can be assessed quantitatively by radioimmunoscintigraphy. Radioimmunoscitigraphy is a sensitive method for early detection and assessment of cardiac allograft rejection.

Right ventricular ejection fraction response to exercise in patients with coronary artery disease: influence of both right coronary artery disease and exercise-induced changes in right ventricular afterload.

To determine the influence of proximal right coronary artery disease and right ventricular afterload on right ventricular ejection fraction response to exercise, 64 patients were studied at rest and after supine exercise with gated equilibrium radionuclide angiography and coronary angiography. Right ventricular afterload response to exercise was estimated from determinations of exercise-induced changes in pulmonary blood volume, previously shown to correlate with exercise-induced changes in pulmonary capillary wedge pressure. Values for right ventricular ejection fraction decreased from rest to exercise (48 +/- 5% to 42 +/- 9%, p less than 0.001) in patients with an elevated pulmonary blood volume ratio. Values were unchanged in patients with isolated proximal right coronary artery disease (rest 49 +/- 3%, exercise 47 +/- 7%), decreased in patients with combined right and left coronary disease (rest 48 +/- 6%, exercise 39 +/- 10%, p less than 0.001) and increased (rest 47 +/- 5%, exercise 52 +/- 6%, p less than 0.001) in patients with isolated left coronary artery disease. To determine the coinfluence of coronary anatomy and changes in pulmonary blood volume, patients were classified by pulmonary blood volume ratio. Among patients with a normal pulmonary blood volume ratio, right ventricular ejection fraction did not change significantly in those with proximal right coronary artery disease during exercise, but increased significantly in patients with isolated left coronary disease. Among patients with an elevated pulmonary blood volume ratio, right ventricular ejection fraction during exercise increased significantly in those with proximal right coronary artery disease but was unchanged in patients with isolated left coronary disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of exercise perfusion and ventricular function imaging: an analysis of factors affecting the diagnostic accuracy of each technique.

Exercise thallium-201 perfusion scans and gated equilibrium blood pool scans were performed in 120 catheterized patients with a chest pain syndrome. Eighty-six patients had coronary artery disease and 34 patients did not. The effects of gender, propranolol, exercise level, exercise ischemia, history of typical angina, history of previous myocardial infarction, electrocardiographic Q waves, number of diseases vessels and extent of coronary artery obstruction on diagnostic accuracy were evaluated. The overall sensitivity and specificity of thallium scans were 76 and 68%, respectively, and those of gated blood pool scans 80 and 62% (p = not significant). Propranolol decreased the specificity of thallium scans (propranolol = 42%; no propranolol = 87%, p less than 0.05). Thallium scans and anginal history were less sensitive for detecting coronary disease in women (men: thallium = 79%; angina = 77%; women: 54 and 46%, respectively; p less than 0.05). Exercise level did not significantly affect the diagnostic accuracy of either scan. Thallium and gated scans were both highly sensitive (95%) in detecting disease in 20 patients with a prior myocardial infarction, angina and a positive electrocardiogram. The sensitivity of the thallium scan significantly decreased as the number of diseased vessels decreased. Both thallium and gated scans were less frequently positive in patients with atypical angina or no Q waves, but were not significantly influenced by electrocardiographic ischemia. The sensitivity and specificity of both scans were low in 57 patients with the combination of atypical angina, no history of infarction and equivocal stress electrocardiogram thallium = 61 and 63%, respectively; gated = 61 and 67%). When stress thallium scan evaluation included the electrocardiogram and thallium scan interpretation, the diagnostic accuracy was 81%. When all the information from gated scans (wall motion, ejection fraction, pulmonary blood volume) was combined for final gated scan evaluation, the diagnostic accuracy was 83%. When electrocardiographic data were added to all three gated scan variables, diagnostic accuracy was 77%. In conclusion, thallium perfusion and gated blood pool scans have reasonable diagnostic accuracy for coronary artery disease in a group of patients with a moderately high prevalence of disease. However, combined variables from each test are needed to provide reliable diagnostic accuracy.

Quantitative analysis of dipyridamole-thallium images for the detection of coronary artery disease.

To determine if the detection of coronary artery disease by dipyridamole-thallium imaging is improved by quantitative versus qualitative analysis, and combining quantitative variables, 80 patients with chest pain (53 with and 27 without coronary artery disease) who underwent cardiac catheterization were studied. Segmental thallium initial uptake, linear clearance, monoexponential clearance and redistribution were measured from early, intermediate and delayed images acquired in three projections. Normal values were determined from 13 other clinically normal subjects. When five segments per view were used for quantitative analysis, sensitivity and specificity were 87 and 63%, respectively, for uptake, 77 and 67% for linear clearance, 60 and 60% for monoexponential clearance and 62 and 56% for redistribution. Of the four variables, uptake and linear clearance were the most sensitive (p less than 0.01) and specificity did not differ significantly. Using three segments per view, the specificity of uptake increased (p less than 0.05) to 78% without a significant change in sensitivity (85%). With this approach, sensitivity and specificity did not differ from those of qualitative analysis (85 and 78%, respectively). Stepwise logistic regression analysis demonstrated that the best quantitative thallium correlate of the presence of coronary artery disease was a combination variable of "either abnormal uptake or abnormal linear clearance, or both." Using five segments per view, the model's specificity (85%) was greater than that of uptake alone (p less than 0.02), with similar sensitivity (92%). Using three segments per view, the model's specificity (93%) was greater than that of uptake alone (p less than 0.05) and of qualitative analysis (p less than 0.05), with similar sensitivity (85%).(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial uptake and clearance of thallium-201 in normal subjects: comparison of dipyridamole-induced hyperemia with exercise stress.

Thallium-201 uptake and clearance after dipyridamole infusion may differ from that after exercise stress because the hemodynamic effects of these two interventions are different. In this study of normal volunteers, thallium kinetics after dipyridamole (n = 13) were determined from three serial image sets (early, intermediate and delayed) and from serial blood samples and compared with thallium kinetics after exercise (n = 15). Absolute myocardial thallium uptake was greater after dipyridamole compared with exercise (p less than 0.0001), although the relative myocardial distribution was similar. The myocardial clearance (%/h) of thallium was slower after dipyridamole than it was after exercise. Comparing dipyridamole and exercise, the differences in clearance were large from the early to the intermediate image (anterior, -11 +/- 17 versus 24 +/- 5, p = 0.0005; 50 degrees left anterior oblique, -7 +/- 11 versus 15 +/- 8, p = 0.004; 70 degrees left anterior oblique, 3 +/- 9 versus 21 +/- 6, p = 0.001). In contrast, the differences in clearance were small from the intermediate to the delayed image (anterior, 15 +/- 4 versus 20 +/- 2, p = 0.025; 50 degrees left anterior oblique, 15 +/- 4 versus 19 +/- 3, p = 0.13; 70 degrees left anterior oblique, 15 +/- 3 versus 18 +/- 2, p = 0.047). Thallium uptake and clearance in the liver, splanchnic region and spleen were greater after dipyridamole (p less than 0.001). Blood thallium levels were greater after dipyridamole (p less than 0.05) and cleared more slowly (p = 0.07). Thus, myocardial thallium-201 uptake and clearance after dipyridamole infusion differ from thallium kinetics after exercise. This difference is, in part, related to associated differences in extracardiac and blood kinetics. Diagnostic criteria for the detection of abnormal thallium-201 clearance must be specific for the type of intervention.

Continuous monitoring of left ventricular function by an ambulatory radionuclide detector in patients with coronary artery disease.

Global left ventricular function and a modified V5 electrocardiographic (ECG) lead were continuously monitored by a radionuclide recorder in 12 normal subjects and 39 patients with coronary artery disease while the subjects were performing various daily activities. The ambulatory studies revealed that walking on a level surface caused 11 of 12 normal subjects and 18 of 32 patients to increase their left ventricular ejection fraction by greater than 6% units. A transient decrease in left ventricular ejection fraction (6 to 18%) lasting greater than or equal to 1 min was observed on 36 occasions in 16 patients with coronary artery disease; 12 episodes were accompanied by chest pain or shortness of breath and 24 were asymptomatic. Electrocardiographic ST segment depression suggestive of ischemia was recorded in 6 of the 12 symptomatic and 5 of the 24 asymptomatic episodes. In 10 of the 12 symptomatic episodes, left ventricular ejection fraction began to decrease 30 to 90 s before the onset of symptoms. These studies suggest that continuous monitoring of both left ventricular function and the ECG may permit stratification of episodes of ST depression suggesting ischemia by the degree of left ventricular dysfunction they produce.

Determination of the quantitative thallium imaging variables that optimize detection of coronary artery disease.

Although quantification of exercise thallium images has been previously reported, the relative value of different imaging variables for detection of coronary artery disease has not been analyzed in a large group of patients with cardiac catheterization data. Regional initial thallium uptake, redistribution and clearance on thallium study were measured in 325 patients also undergoing cardiac catheterization (281 patients with and 44 patients without coronary artery disease). Normal values were defined in 55 other clinically normal subjects. When five myocardial segments were analyzed in each view, the respective values for sensitivity and specificity were 95 and 50% for initial thallium uptake, 60 and 87% for redistribution and 74 and 66% for clearance. Initial thallium uptake was the most sensitive but least specific (p less than 0.001), whereas redistribution was the least sensitive and most specific (p less than 0.001). Using stepwise logistic regression analysis, the best correlate of coronary artery disease was initial thallium uptake. Addition of redistribution to a mathematical model of the probability of coronary artery disease did not alter sensitivity, but increased specificity from 50 to 70% (p less than 0.001). Once initial uptake and redistribution were considered, myocardial thallium clearance provided no additional improvement in the correlation. Excluding the two basal segments in each view from the analysis increased the specificity from 70 to 80% (p less than 0.001) without affecting sensitivity. Of the 15 patients (5%) with coronary disease not detected using this approach, none had left main disease and 10 (67%) had one vessel disease. A combination of variables derived from quantification of exercise thallium images provides a superior sensitivity and specificity for the detection of coronary artery disease compared with the use of a single variable.