Differentiation of regional perfusion and fatty acid uptake in zones of myocardial injury.

The relative myocardial distribution of 201Tl and modified fatty acid (123I-labelled 3-methyl-p-[iodo]-phenyl pentadecanoic acid, MFA) was determined in eight patients with unstable angina (UA) and six patients with acute myocardial infarction treated with reperfusion therapy within 4.1 h (MI). The results of radionuclide imaging were correlated with coronary angiography and quantitative left ventriculography performed within 10 days of the radionuclide procedures. Zones of injury were identified as areas with diminished 201Tl uptake distal to sites of coronary narrowing. A nearly parallel reduction in regional fatty acid concentration was observed in these areas. Comparison of the regional distributions of the two agents revealed subtle differences in their distributions in the ischaemic zones. Three patterns were recognized: (a) MFA uptake greater than Tl (MFA greater than Tl), (b) matched decrease of MFA and Tl (MFA = Tl), (c) MFA uptake less than Tl (MFA less than Tl). Seven of eight patients with UA had normokinesis or hypokinesis on quantitative left ventriculography. Five of the seven showed the MFA greater than Tl pattern, while one had the MFA less than Tl pattern and one had the MFA = Tl pattern. The eighth patient with UA had akinesis and the MFA = Tl pattern. All six patients with acute infarction had akinesis on ventriculography. One of these patients had the MFA greater than Tl pattern, two had the MFA = Tl pattern and three had the MFA less than Tl pattern. These results suggest that fatty acid and thallium have grossly similar distributions in areas of acute myocardial ischaemia. On careful inspection, zones of slight relative excess fatty acid concentration are observed more often in areas of acute ischaemia with normal wall motion.

Left ventricular performance during psychological stress.

Left ventricular ejection fraction, systolic blood pressure and plasma norepinephrine were measured in six normotensive and six mildly hypertensive subjects during rest and psychological stress. Compared with rest, 8 of the 12 subjects developed significant (P less than 0.05) changes in ejection fraction (increase in 6, decrease in 2); 10 of 12 subjects developed significant elevations of plasma norepinephrine; and all developed significant increases in systolic blood pressure. When the stress effects were examined for the total group, as opposed to within subjects, there were significant increases in plasma norepinephrine (P less than 0.001) and systolic blood pressure (P less than 0.001) but, interestingly, mean ejection fraction and stroke volume remained unchanged, implying stress led to increased left ventricular contractility.

The effect of captopril on renal blood flow in renal artery stenosis assessed by positron tomography with rubidium-82.

The sequence and magnitude of acute changes in renal blood flow following administration of captopril were determined in a canine model of acute unilateral renal artery stenosis using rubidium-82 and positron emission tomography. Data were recorded in each of nine dogs under three conditions: 1) during a baseline control interval, 2) during renal artery stenosis, and 3) during stenosis with intravenous injection of captopril (1.2 mg/kg). Mean arterial blood pressure was 108 +/- 12 mm Hg at control, increased significantly to 125 +/- 13 mm Hg (p less than 0.01) during stenosis, and decreased to 98 +/- 13 mm/Hg (p less than 0.01) after captopril infusion. Mean renal blood flow was calculated using a steady state single compartment model from the images produced by positron emission tomography. The estimated flow to the affected kidney was 3.37 +/- 1.48 ml/min/g at control, 0.86 +/- 0.62 ml/min/g during stenosis (p less than 0.01), and 0.64 +/- 0.57 ml/min/g after captopril administration (p = NS compared with precaptopril value). The estimated flow to the contralateral kidney was minimally reduced from a baseline of 3.84 +/- 0.95 to 3.24 +/- 1.13 ml/min/g (p = NS) during stenosis and increased after captopril infusion (4.08 +/- 0.94 ml/min/g; p = 0.01). These data suggest that repetitive imaging with positron emission tomography can be used to delineate acute changes in renal perfusion following captopril administration.

The effects of stress on left ventricular ejection fraction.

The left ventricular ejection fraction (EF) was studied in 17 healthy volunteers with a new ambulatory left ventricular function monitor. Heart rate, EF, and blood pressure measurements were made during rest, a psychiatric stress interview, cold exposure, exercise, and eating. An increase in EF was seen during emotional stress (from 0.45 +/- 0.09 to 0.51 +/- 0.13, P less than 0.001). This increase was comparable to that observed during exercise (0.52 +/- 0.14) and eating (0.52 +/- 0.10, P less than 0.001). In contrast, cold exposure caused a decrease in EF (0.43 +/- 0.13, P less than 0.05). These observations demonstrate the powerful hemodynamic consequences of common behaviors as well as the utility and feasibility of studying such behavioral factors in ambulatory subjects.

Acute myocardial infarct imaging with indium-111-labeled monoclonal antimyosin Fab.

Indium-111 monoclonal antimyosin Fab scintigraphy was used to detect myocardial necrosis in 52 of 54 patients (96.3%) with acute myocardial infarction. Infarcts were visualized when coronary arteries were persistently occluded (n = 10), became patent after thrombolysis (n = 33), or became patent after spontaneous reperfusion (n = 7). Posteroinferolateral visualizations were obtained in two patients with clinical and enzymatic evidence of infarction but normal electrocardiograms. Of the two patients in whom no infarcts were visualized, one had an anterior myocardial infarct. This patient underwent successful thrombolytic therapy, with attendant minimization of creatine kinase release. The other patient had a small, nonreperfused inferior myocardial infarct. Five patients with a history of remote infarction and acute necrosis showed antimyosin uptake only in regions concordant with the acute episodes of infarction, and radiolabeled antimyosin Fab localized in neither old infarcts nor normal, noninfarcted myocardium. Antimyosin Fab scintigraphy, thus, appears to be a highly specific means of delineating necrotic myocardium, at least in this limited and selected group of patients.

Accumulation of native and methylated low density lipoproteins by healing rabbit arterial wall.

To determine whether healing arterial wall accumulation of low density lipoproteins (LDL) is mediated by the high affinity LDL receptor, normocholesterolemic rabbits were injected with 125I-LDL, 99mTc-LDL, or the reductively methylated analogs of these compounds (125I-MeLDL, 99mTc-MeLDL), 1 month after balloon catheter deendothelialization of the abdominal aorta. If the mechanism of accumulation requires interaction with the LDL receptor, reductively methylated lipoproteins which do not bind to the receptor should not accumulate in healing arterial wall. Twenty-four hours after injection of labelled lipoproteins, each animal was injected with Evans blue dye, in order to distinguish reendothelialized from deendothelialized aorta. One hour after dye injection, the aorta was fixed, removed, divided into abdominal (ballooned) and thoracic (unballooned) regions and counted. For all lipoprotein preparations, there were three to four times as many counts in the abdominal as in the thoracic aorta. En face autoradiographs were made of the aortas that had been exposed to 125I-labelled lipoproteins. In the autoradiographs, the areas of the lowest activity corresponded to the centers of healing endothelial islands. The most intense radioactivity for both lipoproteins occurred in the region of the leading edge of the endothelial islands where active endothelial regeneration was in progress. The overall distribution of native and MeLDL accumulation was the same. The results suggest that low density lipoproteins are accumulated in areas of active endothelial regeneration by a mechanism that does not involve the high affinity LDL receptor.

Energy metabolism and blood perfusion in a mouse mammary adenocarcinoma during growth and following X irradiation.

Biochemical and blood perfusion changes in a mouse tumor system (MDAH MCaIV) were studied relative to normal tissues under conditions of normal blood flow and clamped blood supply. Further studies were performed during tumor growth and after local X irradiation. The biochemical profiles of three untreated human soft tissue sarcomas were also investigated. Animal tumors were irradiated in situ with either a single or fractionated regime to total doses of 20 or 49 Gy. Assays of lactate, pyruvate, AMP, ADP, and ATP were made on freeze-clamped tissue following authentic or sham treatments. Blood perfusion to tumors treated in the same way was measured using iv injection of 201Tl. The human tumors were found to have a lower lactate to pyruvate ratio (L/P) than the MCaIV tumors; their ATP levels were also lower. L/P was much higher in the MCaIV tumors than in normal liver, kidney, and muscle in the mouse. Occlusion of the blood supplies of the normal kidney and the MCaIV tumor caused an increase in the lactate and L/P levels in both cases. However, whereas the ATP level in the kidney fell, the level in the tumor was maintained. There was some evidence that the adenine nucleotides were not in equilibrium via the adenyl kinase catalyzed reaction. In addition, tumors were found to contain the enzyme creatine kinase. These results suggest that energy charge calculations cannot be computed in a meaningful manner because the creatine kinase catalyzed phosphorylation of ADP would maintain a higher than normal ATP level. Lactate and L/P ratio was found to increase during tumor growth and decrease following X irradiation. The total adenine nucleotides (AMP + ADP + ATP) exhibited a trend toward lower values with increasing tumor size. There was no significant change in total adenine nucleotides after a single 20-Gy dose; however, fractionated radiation caused some fall in total nucleotides. It is concluded that, in this tumor system, lactate level is a sensitive index of radiation-induced biochemical changes which are likely to reflect changes in tumor oxygenation.

Measurement of both left ventricular function and regional myocardial perfusion with 133Xe in dogs.

A technique to measure left ventricular (LV) function and myocardial perfusion was validated in 12 dogs. 133Xe in saline was injected into the left atrium (LA) or LV and two data sets were obtained using gamma camera imaging: 1) A first pass gated scan for LV function; followed by 2) Sequential images for regional myocardial perfusion. LV ejection fraction and wall motion measurements from the 133Xe blood pool images were compared to ejection fraction (r = 0.88, P less than 0.01) and wall motion (r = 0.83, P less than 0.01) data from 99mTc labeled blood pool scans. The perfusion measurements obtained with the 133Xe method were compared to microsphere data (r = 0.79, P less than 0.01). Measurements after LV 133Xe injection were similar to data following LA injection. Thus, quantitative assessment of global LV function, regional wall motion and myocardial perfusion is possible with LA or LV 133Xe injection and gamma camera imaging.

Tumor-derived interleukin-2-dependent lymphocytes in adoptive immunotherapy of lung cancer.

A trial of adoptive immunotherapy was performed in which long-term cultured, interleukin-2 (IL2)-dependent T-lymphocytes were administered to patients with metastatic adenocarcinoma of the lung. Lymphocytes were isolated from explants of cancer tissues that were cultured in medium with recombinant IL-2. These T-cells expressed surface markers of activation, and killed a broad panel of tumor targets. Intravenously injected 111indium-labeled T-cell blasts distributed primarily to lungs, liver, and spleen. Despite a paucity of infused lymphocytes detected by external imaging at sites of tumor, five of seven patients showed reduction of their cancers. However, in no case was greater than 50% reduction of total tumor burden achieved. Evidence of increased delayed cutaneous hypersensitivity to protein antigens was observed in three patients following therapy. We conclude that long-term cultured tumor-derived T-cells can be transferred safely into humans and that these cells may be capable of enhancing immune responses and mediating tumor reduction in vivo.

Multigated blood-pool tomography: new method for the assessment of left ventricular function.

A technique for the semiautomatic calculation of left ventricular volumes from multigated blood-pool tomograms (MGBPT) was tested in a series of 12 patients undergoing contrast ventriculography within 48 hr of gated tomography. The parameters necessary for the calculation of volume were developed in a chest phantom study performed with a series of 99mTc-filled balloons representing the right and left ventricles. The images were analyzed for volume using a percentage of peak count-threshold of the left ventricular balloon. This technique resulted in a correlation of r = 0.99 of the calculated to the true phantom volumes (y = 0.87x + 27.4, p less than 0.01, s.e.e. = 7.87 ml). The patient studies were recorded at 16 frames/cardiac cycle at each of 60 angles over a 360 degree rotation. Reconstructed data were presented in an endless loop cine format producing a set of sequential "beating tomographic slices" in the transverse, apical four-chamber, short-axis, and long-axis oblique views. Measurements of end systolic volume (y = 0.79x + 30, r = 0.93, p less than 0.001, s.e.e. = 24 ml), end-diastolic volume (y = 0.63x + 60, r = 0.94, p less than 0.0001, s.e.e. = 20 ml) and ejection fraction (y = 0.88x - 0.02, r = 0.92, p less than 0.001, s.e.e. = 0.08) determined from the semiautomated volume method correlated well with those determined by left ventricular contrast angiography. A qualitative comparison of MGBPT, planar imaging, and left ventricular angiography in 12 patients revealed that the visual assessment of wall motion using the 16-frame tomographic slices had significant advantages over planar and single plane angiographic data in the identification of inferior, basal, and septal wall motion abnormalities as well as the extent of involvement by aneurysm formation. A quantitative comparison of wall motion in the long-axis oblique view of the MGBPT to the RAO 30 degree ventriculogram (y = 0.74x + 8.7, r = 0.82, p less than 0.0001, s.e.e. = 14%) confirmed the qualitative similarity of these two views. We conclude that MGBPT is promising as a method for accurately measuring left ventricular volumes and assessing regional wall motion.

Serial analysis of renal blood flow by positron tomography with rubidium-82.

To determine whether renal blood flow can be measured by positron-emission tomography (PET) during constant infusion of rubidium-82 (82Rb) using a steady-state kinetic model, studies were performed in 10 dogs at control (n = 10), during mild flow reduction (n = 7), during severe flow reduction (n = 10), and after reperfusion of the kidney (n = 3). PET data were quantified to determine mean concentration of 82Rb (Ct) in each transverse section of the kidney. The arterial concentration (Ca) of 82Rb was measured by well counting of arterial blood samples during the equilibrium scan. 82Rb renal uptake (Ct/Ca) correlated nonlinearly with microsphere renal blood flow according to a steady-state kinetic model (r = 0.90). 82Rb estimated flow was 3.16 +/- 1.36 ml X min-1 X g-1 at control and 1.56 +/- 0.57 and 0.37 +/- 0.59 during mild and severe flow reductions, respectively. Microsphere determined flow was 2.89 +/- 0.77 ml X min-1 X g-1 at control, 1.58 +/- 0.42 at mild reduction, and 0.27 +/- 0.49 at severe reduction. In the occlusion and reperfusion model, the 82Rb estimated flow during occlusion was 0.21 +/- 0.15 ml X min-1 X g-1 and on reperfusion went up to 2.13 +/- 1.08. The contralateral kidney demonstrated reductions in the 82Rb estimated flow of 3.02 +/- 1.62 ml X min-1 X g-1 (63%) and 2.92 +/- 0.89 (61%) during mild and severe flow reductions, respectively. We conclude that PET with 82Rb permits serial quantitative assessment of renal flood flow.

Scintigraphic quantification of myocardial necrosis in patients after intravenous injection of myosin-specific antibody.

The Fab fragments of antimyosin antibodies, labeled with 99mTc, were used in the scintigraphic examination of 30 patients with myocardial infarction. The ability to detect necrosis and determine its extent from the antimyosin scan were compared with the results of quantitative regional wall motion analysis by contrast ventriculography at 10 to 14 days and 99mTc-pyrophosphate imaging. Antimyosin images recorded by planar and single photon-emission computed tomography (SPECT) delineated areas of myocardial necrosis in 27 of 30 patients (90%) compared with a 91% sensitivity of pyrophosphate in 21 of 23 patients. Infarct size was determined by both antimyosin and pyrophosphate SPECT images. Results by both techniques showed a significant correlation with computer-derived hypokinetic segment length (r = .79 for both, p = .002) and peak creatine kinase (r = .9 for both, p less than .01). Although sensitivity for and correlations with markers of necrosis were similar with both techniques, infarct size by pyrophosphate SPECT was 1.7 times larger than infarct size by antimyosin SPECT (p less than .01). Certain zones in the infarct area were differentially labeled; the nature and irreversibility of injury within these zones remains to be clarified.

Adrenal imaging with technetium-99m-labelled low density lipoproteins.

Evaluation of adrenal cortical function by external imaging is currently accomplished by injection of radiolabelled analogs of cholesterol. Although the adrenals do utilized exogenous cholesterol for steroid hormone synthesis, the cholesterol is delivered to the glands not as free cholesterol but through the uptake of low density lipoproteins (LDL), which are subsequently degraded within the adrenal cortical cells to provide cholesterol. Thus, we sought to assess the use of 99mTc-labelled LDL injected into rabbits to obtain external images of the adrenal glands. Adrenal images of all nine rabbits tested were obtained within 18 to 21 hours after injection of 99mTc-LDL. Seven of the rabbits were subjected to adrenal cortical suppression with dexamethasone and then all nine rabbits were imaged a second time. In the untreated animals, visualization of the adrenal glands was accompanied by normal serum cortisol concentrations and accumulation of radiolabel in the adrenals, whereas in the dexamethasone-treated animals, lack of visualization of the adrenal glands was correlated with low serum cortisols, and greatly decreased accumulation of the radionuclide in the adrenals. These findings demonstrate for the first time that LDL, when labelled with 99mTc, can be used to evaluate adrenal cortical function by external imaging.

Radioiodinated beta-methyl phenyl fatty acids as potential tracers for myocardial imaging and metabolism.

Since fatty acids provide the majority of myocardial energy requirements under basal conditions, an alteration in the global or regional utilization of these substrates may be an early indicator of myocardial disease. To determine areas of potential clinical utility of fatty acid imaging, we synthesized a radioiodinated modified fatty acid 14-(p-iodophenyl) beta methyltetradecanoic acid IPBMTA, which cannot undergo beta-oxidation. Preliminary biodistribution and imaging studies were performed in animals and man. These studies suggest that radioiodinated beta-methyl phenyl fatty acids localized rapidly in the myocardium and had prolonged myocardial retention time. The long residence time permits the recording of high quality planar and SPECT images.

The effect of glucose-insulin-potassium on thallium-201 myocardial redistribution.

Intravenous infusion of glucose-insulin-potassium (GIK) has been shown to alter the net rate of clearance of 201Tl from transiently ischemic and normally perfused canine myocardium. This study was performed to determine if GIK would also decrease the extent of thallium redistribution after transient myocardial ischemia. Six anesthetized, open-chest dogs underwent two studies, one with GIK and another with saline infusion. The left anterior descending coronary artery was occluded, 201Tl injected, and the occlusion released 5-min later. An i.v. infusion of either GIK (4 dogs) or saline (2 dogs) was then begun and continued for the 120-min duration of serial myocardial imaging using a standard scintillation camera. The experiment was then repeated with an infusion of saline (4 dogs) or GIK (2 dogs). The dose of 201Tl for the second study was at least 5 times more than was used for the first study. The serial 2-min images were then displayed on computer and regions of interest were drawn over the areas of transient ischemia (TI) and normal perfusion (NP). The ratio of average counts per picture element for the area of TI compared to NP was calculated. One hundred and twenty minutes after 201Tl administration, the change in the TI/NP ratio (% fill-in) was significantly less for the GIK infusion compared to saline infusion (control) 15.4 +/- 4.0% vs 26.2 +/- 6.0% (mean +/- SE) (P less than 0.01), respectively. Therefore, GIK infusion appeared to decrease the extent of thallium redistribution compared to saline control.

Rest and exercise right and left ventricular function late after the Mustard operation: assessment by radionuclide ventriculography.

To evaluate ventricular function late after atrial repair of transposition of the great arteries (TGA), 26 asymptomatic patients had rest and exercise radionuclide ventriculography performed a mean of 9 years (range 5 to 15) after undergoing the Mustard operation. The mean resting right (systemic) ventricular (RV) ejection fraction (EF) was 0.50 +/- 0.10 (+/- 1 standard deviation); the RVEF was less than 0.45 in 8 patients. With exercise the RVEF increased in 9 patients and either failed to increase or decreased in 15 (including all 8 patients with resting values less than 0.45). The weight-adjusted work load performed was a first predictor of RV exercise response (sensitivity 87%, specificity 92%); patients whose RVEF increased did more work. The mean resting left (pulmonary) ventricular (LV) EF was 0.58 +/- 0.09; the LVEF was less than 0.50 in 3 patients. With exercise the LVEF increased in 14 patients and did not increase in 10 (including all 3 with resting values less than 0.50). The presence of complex ventricular arrhythmia documented on Holter monitoring was a first predictor of failure of the LVEF to increase with exercise (sensitivity 84%, specificity 71%). The patient's age, operative age, postoperative interval, residual arterial desaturation, preoperative large ventricular septal defect or pulmonary stenosis, postoperative pulmonary stenosis or superior vena caval obstruction, or performance of a second open-heart procedure was predictive of the rest or exercise EF of either ventricle.

Diagnosis of alcoholic cirrhosis with the right-to-left hepatic lobe ratio: concise communication.

Since scans of cirrhotic livers commonly show a reduction in size and colloid uptake of the right lobe, a quantitative measure of uptake was made using a minicomputer to determine total counts in regions of interest defined over each lobe. Right-to-left ratios were then compared in 103 patients. For normal patients the mean ratio +/- 1 s.d. was 2.85 +/- 0.65, and the mean for patients with known cirrhosis was 1.08 +/- 0.33. Patients with other liver diseases had ratios similar to the normal group. The normal range of the right-to-left lobe ratio was 1.55-4.15. The sensitivity of the ratio for alcoholic cirrhosis was 85.7% and the specificity was 100% in this patient population. The right-to-left lobe ratio was more sensitive and specific for alcoholic cirrhosis than any other criterion tested. An hypothesis is described to explain these results.