Biomedical subjects
Publications and source records attributed to H R Schelbert.
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Calculation of accurate stroke count ratios for the assessment of valvular regurgitation from equilibrium blood pool images has been difficult and did not permit computation of regurgitant fractions (RF) because of contamination of right ventricular (RV) stroke counts by right atrial activity. We describe a new approach to correct for this contamination by subtracting one half of the right atrial counts from the RV counts, assuming that in the standard or "modified" left anterior oblique projection commonly used about one half of the right atrial activity is superimposed to the RV. This new method was tested in 20 patients without valvular disease or shunts. Left ventricular (LV) to RV stroke count ratio approached unity (1.01 +/- 0.14). RV ejection fractions (EF) derived by this technique agreed well with those obtained by gated first-pass studies recorded in the right anterior oblique projection. In 9 normals and 17 patients with moderate severe or severe aortic (12 patients or mitral (7 patients) regurgitation, LVEF, RVEF, and RF were determined at rest and maximum exercise. In patients at rest, LVEF (56.0 +/- 6.4%) and RVEF (49.0 +/- 7.3%) did not differ significantly from LVEF (59.6 +/- 4.2%) and RVEF (52.5 +/- 6.4%) in normals. The calculated RF was negligible in normals (1.9 +/- 8.6%), but averaged 51.8 +/- 9.8% in patients with valvular disease. During exercise, LVEF fell significantly (p less than 0.001) to 44.1 +/- 7.2% in patients but increased to 70.5 +/- 3.8% in normals. RVEF increased in aortic regurgitation to 64.5 +/- 9.8% (NS to normals) but fell in mitral regurgitation to 36.6 +/- 5.9% (p greater than 0.001). In both patient subsets RF decreased with exercise to 25.4 +/- 15.0% in aortic and 39.1 +/- 12.7% in mitral regurgitation. The results indicate that this new approach permits assessment of RVEF and RF from gated equilibrium blood pool studies and is suitable to evaluate the hemodynamic response to physiologic and therapeutic interventions in patients with valvular regurgitation.
Positron-emission computed tomography (PCT) is a new means of studying regional myocardial metabolism. This new device permits quantitative, cross-sectional imaging of the tissue concentrations of positron-emitting tracers of blood flow and metabolism in the myocardium. To examine the potential value of PCT for evaluating regional alterations in myocardial metabolism, acute myocardial ischemia was induced by rapid atrial pacing in open-chest dogs with partial coronary stenoses. Regional myocardial glucose uptake and utilization of free fatty acids were examined with the glucose analog F-18 2-fluoro-2-deoxyglucose (FDG) and C-11-labeled palmitic acid. Myocardial blood flow was evaluated with N-13 ammonia. In the ischemic segment, uptake of C-11 palmitic acid was reduced in proportion to blood flow and its rate of clearance as an index of beta oxidation was delayed. There was a relative or absolute increase in FDG uptake (depending on the uptake of FDG in the normal myocardium). Similar observations were made in patients with ischemic heart disease and anginal symptoms at the time study. The observed alterations in the regional distribution of positron-emitting tracers of metabolic substrates in ischemic myocardium are in agreement with previously reported animal experimental studies in which a fall in free fatty acid utilization associated with an increase in glycolytic flux was observed. These studies indicate that metabolic alterations associated with acute myocardial ischemia observed previously in destructive animal experiments do indeed occur in humans and can now be demonstrated noninvasively in humans by PCT.
The value of phase analysis of multiple gated acquisition blood pool images for identifying wall motion abnormalities due to stress-induced ischemia was examined. Myocardial segments with an abnormal phase, i.e., delayed onset of wall motion, were localized on a phase distribution image of the LV and the synchrony of LV systolic wall motion was assessed from histograms of the LV phase distribution, i.e., the standard deviation (SD) from the mean of this peak, which was defined as SDP, its upper limits of normal at rest and exercise were established in seven normals as the mean +2 SD and were 12 degrees at rest and 10 degrees at maximum exercise. Of the 56 patients, 37 had coronary artery disease (CAD), 11 had valvular disease but normal coronary arteries, and eight had normal coronary arteries, no valvular disease, but had either cardiomyopathy or typical angina. In the CAD patients, SDP was abnormal in 95% during exercise while only 86% had an abnormal ejection fraction (EF) response and/Or exercise-induced wall motion abnormalities by visual interpretation. By contrast, in the 11 valvular heart disease patients, SDP was abnormal in only two despite exercise-induced wall motion abnormalities in five and an abnormal EF response in all 11. Thus, although an abnormal EF response to exercise is a sensitive indicator of cardiac disease, it is, however, like exercise-induced wall motion abnormalities, not specific for CAD. By contrast, phase analysis not only permitted separation of wall motion abnormalities induced by ischemia from those associated with valvular disease, but was also an objective, highly sensitive, and specific indicator of regional myocardial ischemia.
Sterile, pyrogen-free L-[4-11C]aspartic acid was prepared from 11CO2 using phosphoenolpyruvate carboxylase and glutamic/oxaloacetic acid transaminase immobilized on Sepharose supports to determine if it is a useful indicator for in vivo, noninvasive determination of myocardial metabolism. An intracoronary bolus injection of L-[4-11C]aspartic acid into dog myocardium showed a triexponential clearance curve with maximal production of 11CO2 100 s after injection. Inactivation of myocardial transaminase activity modified the tracer clearance and inhibited the production of 11CO2. Positron-computed tomography imaging showed that the 11C activities retained in rhesus monkey myocardium are higher than those observed in dog heart after intravenous injection of L-[4-11C]aspartic acid. These findings demonstrated the rapid incorporation of the carbon skeleton of L-aspartic acid into the tricarboxylic acid cycle after enzymatic transamination in myocardium and suggested that L-[4-11C]aspartic acid could be of value for in vivo, noninvasive assessment of local myocardial metabolism.
We have explored the possibility of imaging the cardiac blood pool with dextran (Dx) labeled with Tc-99m (Tc) after Sn2+ reduction. Stannous dextran (SnDx) kits were prepared in advance and labeling was performed by adding Tc-99m. The labeling efficiency was greater than 95%. Technetium-99m dextran (TcDx) was highly stable both in vivo and in vitro. In seven dogs we compared the quality of blood-pool images obtained with TcDx of different molecular weights (4 X 10(4) = Dx-40; 5 X 10(5) = Dx-500; 2 X 10(6) = Dx-2000) and with Tc-99m red blood cells (TcRBC) labeled in vitro, and determined the organ distribution of this new agent by whole-body scanning and blood sampling. TcDx provided high-quality cardiac blood-pool images up to 60 min after injection. The heart-to-lung ratios averaged 3.7 for TcDx-40, 3.9 for TcDx-500, and 5.4 for TcRBC at 60 min. Whereas TcDx-40 showed a relatively rapid initial urinary excretion and TcDx-2000 was degraded rapidly, TcDx-500 demonstrated the best kinetics for blood-pool imaging. Thus, TcDx is a new radiopharmaceutical with high labeling efficiency and stability. It overcomes a number of the limitations of currently used blood-labeling agents and may become useful for blood-pool imaging in man.
Current agents for lymphoscintigraphy have limitations because of slow migration of the colloidal tracers from the injection site and the unknown effect of phagocytosis on the removal of the labeled particles. The usefulness of Tc-99m dextran (TcDx) with a molecular weight of 110,000 has been tested for lymphoscintigraphy. Computer-assisted dynamic imaging and serial blood sampling in 13 dog experiments demonstrated that the tracer cleared only by lymph drainage from an interstitial injection site. Following interdigital injection of 1.0 ml (0.5-5.0 mCi), TcDx reached the knee or elbow lymph nodes in 12.4 +/- 6.5 (1 s.d.) sec, and the inguinal or axillary lymph nodes in 98.0 +/- 42.3 sec. It cleared from the injection site with a half-time of 31.5 min. In a dog with surgically induced lymphedema, tracer migration was markedly delayed in the edematous leg and the radionuclide lymphoscintigram resembled the contrast lymphangiogram. Initial studies in man yielded high-quality radionuclide lymphograms of the leg, and the pelvic and paraaortic lymph nodes. We conclude that TcDx is very promising for lymphoscintigraphy.
To determine the usefulness of the rotating slant-hole (RSH) collimator, a new imaging device for tomographic myocardial imaging, we evaluated its performance in phantom studies. Perfusion defects of variable size, location, and tracer concentration were simulated and imaging was performed with a conventional parallel-hole collimator and the RSH collimator. Planar and depth resolutions assessed with a line source compared favorably with those reported previously for the seven-pinhole collimator. The results also showed RSH tomography to be more sensitive than planar imaging in detecting simulated myocardial defects but indicated some limitations, especially the occurrence of artifactual defects that may reduce the specificity of the imaging device for the detection of perfusion abnormalities.
The deoxyglucose method originally developed for measurements of the local cerebral metabolic rate for glucose has been investigated in terms of its application to cardiac studies with positron computed tomography (PCT) and fluorodeoxyglucose (FDG). Studies were performed in dogs to measure the tissue kinetics of FDG with PCT and by arterial and venous sampling. The operational equation developed in our laboratory as an extension of the Sokoloff model was used to analyze the data. Error propagation, primarily from corrections applied to remove spillover of activity from the myocardial blood pool to tissue and from partial-volume effects in the PCT images, limited accuracy in the estimation of the individual rate constants for transport, phosphorylation, and dephosphorylation. However, a constant representing the combination of transport and phosphorylation was accurately determined and yielded measured values of the myocardial metabolic rate for glucose (MMRGlc) that were in good agreement with direct determinations using the Fick method over a wide range of glucose metabolic rates (from 1.7 to 21.1 mg/min-100 g). The lumped constant (0.67 +/- 0.10) was also found accurate and stable over this range of metabolism. The FDG method accurately predicted the true MMRGlc even when the glucose metabolic rate was normal but myocardial blood flow (MBF) was five times the control value, or when metabolism was reduced to 10% of normal and MBF increased to five times normal. Improvements of PCT resolution are required to improve the accuracy of the estimates of the rate constant and the MMRGlc.
To evaluate the utility of labeled L-amino acids (AA) for imaging regional myocardial AA metabolism by positron computed tomography (PCT), the myocardial uptake and clearance of Ala,* Glu, Gln, Asp, Leu tagged with N-13, and of C-11-tagged Asp, and oxaloacetate (Oxal), were examined in 44 experiments at control, during ischemia, and after transaminase inhibition. The myocardial time-activity curves recorded after intracoronary tracer injection had two clearance phases (an early and a late) for all N-13 AA, and three (early, intermediate, late) for the two C-11 compounds, with significantly different clearance half-times of 18.7 +/- 8.0 (s.d.) sec for the early phase, 141.7 +/- 56.5 sec for the intermediate, and 61.2 +/- 43.5 min for the late phase. The residual fractions ranged from 0.07 to 0.23 in normal myocardium, and consistently increased with ischemia by 0.01-0.07 for N-13-labeled Ala, Glu, Asp, and Leu, but not for N-13 Gln and C-11 compounds. Transaminase inhibition shortened the half-times of the late phases of N-13-labeled Ala, Glu, Asp, and Leu; had no effect on t1/2 of N-13 Gln and C-11 Oxal; and resulted in a loss of C-11 CO2 production and of the intermediate phase for C-11 Asp. On the PCT images, N-13 activity from labeled Ala and Glu was not decreased in an ischemic segment despite a significant flow reduction, as demonstrated by N-13 NH3 imaging and labeled microspheres. From the results, a three-compartment tracer kinetic model is proposed for the noninvasive quantification of Krebscycle activity, protein synthesis, and metabolic derangements related to ischemia.
The hot cell synthesis of sterile, pyrogen-free 13N-labeled L-amino acids was accomplished by employing the appropriate immobilized enzymes on a CNBr-activated Sepharose support and using remote, semiautomated systems. The syntheses were completed 6-12 min after cyclotron production of [13N]ammonia. Myocardial time-activity curves after intracoronary injection of 13N-labeled L-amino acids in dogs were triexponential in both normal and ischemic myocardium. Higher retention of 13N activity was observed in ischemic segments. Positron computed tomography imaging also showed increased uptake of 13N-labeled L-glutamate and L-alanine in ischemic segments compared with normal myocardium when blood flow corrections were made. Myocardial transaminases are primarily responsible for the observed retention fractions. It suggests the participation of the carbon skeletons of these amino acids in the Krebs cycle.
The effect of beta-adrenergic blockade with oral propranolol on resting, exercise and postexercise ventricular performance was evaluated using multiple-gated equilibrium cardiac blood and pool images in normal volunteers and patients with coronary artery disease. Propranolol produced no detectable effect on basal left ventricular function in normal subjects at doses producing intermediate (160 mg propranolol/day) and maximal (434 +/- 99 mg propranolol/day) beta blockade and in patients with coronary artery disease at clinically effective antianginal doses (162 +/- 47 mg propranolol/day). During exercise, a dose-related, negative inotropic effect was observed in normal subjects: 160 mg propranolol/day produced a small but statistically insignificant decline in exercise left ventricular performance, whereas maximal beta blockade significantly depressed the left ventricular response to exercise. In patients with coronary artery disease, propranolol's effect on exercise ventricular performance depended on the presence or absence of ischemic dysfunction during exercise. In patients with an ischemic functional response to exercise, propranolol significantly improved regional and global performance during and after exercise; in coronary artery disease patients with a normal response to exercise, propranolol had no significant effect on exercise and postexercise ventricular function. These results imply increased sensitivity to the effects of beta blockade in ischemic myocardium. In coronary artery disease patients with an abnormal response to exercise and in normal volunteers during beta blockade, propranolol's effect on exercise left ventricular performance was independent of changes in ventricular preload and after load related to heart rate and blood pressure.
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A new method for attenuation correction in positron computed tomography (PCT) has been developed, and it can improve the quality of PCT images. The method requires a short transmission scan by the PCT system. Then boundaries between tissues with significantly different attenuation coefficients are determined from the transmission image by edge-finding techniques. Attenuation correction factors(ACF) are then calculated using these boundaries and the average attenuation coefficients within the enclosed regions. The method has been tested on computer-simulated data, on scans of phantoms, and on patient studies, and has been found effective in reducing the random noise in transmission measurements and in providing more accurate ACFs than the method using geometric attenuation correction. As a result, transmission scan times can be shortened, inconvenience to patients is reduced, and PCT images are improved.
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Positron emission computed tomography is a new technique of potential value for the noninvasive measurement of myocardial blood flow, mechanical function and, in particular, metabolism. The capability of this new study method is attributable to the technologic innovations of the imaging device and the availability of radioactive tracers that are specific for blood flow and metabolism. The device permits recording of cross-sectional images of the left ventricular myocardium that quantitatively reflect regional tracer tissue concentrations. Use of tracer kinetic models with this new technique permits measurements of regional glucose and fatty acid metabolism of the heart. Positron emission tomography is already an important new tool for investigative studies of cardiac physiology and pathophysiology; its clinical utility remains to be defined.