The influence of attenuation and scatter compensation on the apparent distribution of Tc-99m sestamibi in cardiac slices.

BACKGROUND: Our objective was to study the differences in relative count distributions in the left ventricular walls with attenuation compensation (AC) versus AC and triple-energy-window scatter compensation (SC), compared with standard filtered backprojection (FBP). METHODS AND RESULTS: Two hundred patients identified as having normal cardiac perfusion with FBP after undergoing either pharmacologically or physiologically induced stress were included in this study. Projection data were reconstructed with FBP, 10 iterations of ordered-subset expectation-maximization (OSEM) with AC, and OSEM with AC+SC. A comparison was made of average percentage of maximum counts within each of 9 regions of CEqual (Marconi Medical Systems, Inc, Cleveland, Ohio) polar maps (ie, the apex, 4 midventricular regions, and 4 basal regions). Compared with OSEM(AC), a slight decrease at the apex exists when SC is included. The elevated inferior-to-anterior count ratio in the midventricular and basal regions noted with OSEM(AC) decreased to close to 1.0 with OSEM(AC+SC). The anterior-to-lateral ratio for both regions was closest to 1.0 for OSEM(AC+SC). In the midventricular region, the lateral-to-septal ratio decreased further below 1.0 with OSEM(AC+SC) than it did with OSEM(AC). This was the only basal ratio not to improve to close to 1.0 with OSEM(AC+SC). In a subset of patients identified at the time of clinical reading as having a possible attenuation-caused decrease in the inferior region, AC elevated the inferior-to-anterior ratio to above 1.0 for the midventricular region. AC+SC resulted in a ratio of near 1.0 for this region. In another subset of patients identified as having anterior attenuation artifacts, compensation methods (either AC or AC+SC) failed to show an improvement compared with FBP. CONCLUSIONS: AC and SC improve the uniformity of the polar map, especially by bringing the inferior-to-anterior ratio closer to 1.0. Further investigation is necessary to determine the cause of the increased midventricular septal polar map count. In addition, the subset of patients identified as having breast-like attenuation artifacts causing a decreased polar map count in the anterior wall (relative to the inferior wall) also needs further attention.

Stable labeled microspheres to measure perfusion: validation of a neutron activation assay technique.

Neutron activation is an accurate analytic method in which trace quantities of isotopes of interest in a sample are activated and the emitted radiation is measured with high-resolution detection equipment. This study demonstrates the application of neutron activation for the measurement of myocardial perfusion using stable isotopically labeled microspheres. Stable labeled and standard radiolabeled microspheres (15 microm) were coinjected in an in vivo rabbit model of myocardial ischemia and reperfusion. Radiolabeled microspheres were detected with a standard gamma-well counter, and stable labeled microspheres were detected with a high-resolution Ge detection after neutron activation of the myocardial and reference blood samples. Regional myocardial blood flow was calculated from the deposition of radiolabeled and stable labeled microspheres. Both sets of microspheres gave similar measurements of regional myocardial blood flow over a wide range of flow with a high linear correlation (r = 0.95-0.99). Neutron activation is capable of detecting a single microsphere in an intact myocardial sample while providing simultaneous quantitative measurements of multiple isotope labels. This high sensitivity and capability for measuring perfusion in intact tissue are advantages over other techniques, such as optical detection of microspheres. Neutron activation also can provide an effective method for reducing the production of low-level radioactive waste generated from biomedical research. Further applications of neutron activation offer the potential for measuring other stable labeled compounds, such as fatty acids and growth factors, in conjunction with microsphere measured flow, providing the capability for simultaneous measurement of regional metabolism and perfusion.

The effect of ischemic injury on the cardiac transport of Tc-99m N-NOET in the isolated rabbit heart.

BACKGROUND: Bis (N-ethoxy, N-ethyl dithiocarbamato) nitrido technetium-99m (V) (TcN-NOET) is a neutral lipophilic myocardial perfusion agent. The effect of ischemic injury on the cardiac transport of TcN-NOET and thallium-201 was determined in isolated rabbit hearts. METHODS AND RESULTS: The multiple indicator dilution method was used to determine the maximum (Emax) and net extraction (Enet, at 5 minutes) of TcN-NOET and TI-201 at control and after 10 minutes (n = 4) or 45 minutes (n = 4) of no-flow ischemia. After 10 minutes of ischemia the mean Emax for T1-201 was unchanged, 0.86 +/- 0.03 vs 0.85 +/- 0.02, whereas TI-201 Enet showed a small decrease from 0.46 +/- 0.03 to 0.40 +/- 0.03, P < .001. Forty-five minutes of ischemia mildly reduced Emax for TI-201 (0.87 +/- 0.04 to 0.74 +/- 0.04, P < .001) and severely reduced Enet (0.46 +/-0.03 vs 0.16 +/- 0.04, P < .001). Neither Emax nor Enet for TcN-NOET was significantly affected by 10 minutes of ischemia (0.54 +/- 0.04 vs 0.58 +/- 0.03 and 0.24 +/- 0.04 vs 0.26 +/- 0.04, respectively). However, severe ischemic injury caused significant reductions versus control in both Emax (0.59 +/- 0.06 vs 0.42 +/- 0.05, P < .001) and Enet (0.27 +/- 0.03 vs 0.18 +/- 0.05, P < .01). CONCLUSIONS: TcN-NOET is a new myocardial perfusion agent with moderate myocardial extraction. Although less sensitive than TI-201 to mild ischemic injury, TcN-NOET extraction and retention are decreased by severe ischemic injury, making uptake of TcN-NOET a possible marker of myocardial viability.

Thallium reinjection versus standard stress/delay redistribution imaging for prediction of cardiac events.

OBJECTIVES: The purpose of this study was to compare thallium reinjection with standard stress/delay redistribution for the prediction of cardiac events. BACKGROUND: Although thallium reinjection enhances the detection of viable myocardium, its contribution to prognosis over stress/delay redistribution in a general referral population has not been clearly evaluated. METHODS: This retrospective analysis included 366 consecutive patients with coronary artery disease who underwent stress/delay redistribution imaging and thallium reinjection scintigraphy, with a mean follow-up of 33+/-12 months. RESULTS: Cardiac events occurred in 48 patients (40 deaths, 8 myocardial infarctions). Of the 366 original patients, 159 demonstrated ischemia by stress/delay redistribution, 107 showed ischemia by reinjection only, and 100 showed infarction only. Cardiac events occurred in 20 patients (12.6%) with stress/delay redistribution, 13 patients (12%) with ischemia detected by thallium reinjection only and 15 patients (15%) with infarction only. The size of the reversible thallium defect by either stress/delay redistribution imaging or reinjection scintigraphy did not predict cardiac events. Independent predictors of cardiac events included left ventricular cavity size, the size of the abnormal perfusion defect and patient age. CONCLUSIONS: Thallium reinjection does not contribute independent prognostic utility for cardiac events when compared with stress/delay redistribution. Left ventricular dilation and the size of the post-stress defect were predictors of cardiac events.

Direct detection of regional myocardial ischemia with technetium-99m nitroimidazole in rabbits.

UNLABELLED: Conventional perfusion scintigraphy assesses disparities in regional myocardial blood flow but does not directly detect hypoxic tissue. Nitroimidazoles labeled with positron-emitting radionuclides have recently shown promise as direct markers of myocardial hypoxia. This study evaluates a new 99mTc-labeled nitroimidazole of potential benefit in standard myocardial scintigraphy. METHODS: Technetium-99m-labeled nitroimidazole was administered to rabbits during the early reperfusion phase after 10 min (Group 1) or 60 (Group 2) min of coronary occlusion or after 10 min of a fixed coronary occlusion (Group 3). Tracer retention at 1 hr was assessed in relation to microsphere-determined blood flow during coronary occlusion and at tracer injection. The pattern of nitroimidazole retention on autoradiographs was then compared with the pattern of myocardial hypoperfusion defined by fluorescein photography to precisely define tracer localization. RESULTS: The retention of nitroimidazole in Group 1 rabbits (brief occlusion) was independent of both occlusion and reperfusion blood flow and was uniformly distributed on the autoradiographs. In contrast, nitroimidazole retention in Groups 2 and 3 increased with the severity of hypoperfusion during the occlusion phase and precisely delineated the ischemic zone on all autoradiographs. CONCLUSION: This 99mTc-labeled hypoxia-avid tracer delineates severe ischemia even after blood flow to the compromised myocardium has been restored. This class of compounds can potentially enhance the physiological assessment of patients with ischemic heart disease.

Design and baseline characteristics of the Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) trial. VANQWISH Trial Research Investigators.

OBJECTIVES: The Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) trial was designed to compare outcomes of patients with a non-Q wave myocardial infarction (NQMI) who were randomized prospectively to an early "invasive" strategy versus an early "conservative" strategy. The primary objective was to compare early and late outcomes between the two strategies using a combined trial end point (all-cause mortality or nonfatal infarction) during at least 1 year of follow-up. BACKGROUND: Because of the widely held view that survivors of NQMI are at high risk for subsequent cardiac events, management of these patients has become more aggressive during the last decade. There is a paucity of data from controlled trials to support such an approach, however. METHODS: Appropriate patients with a new NQMI were randomized to an early "invasive" strategy (routine coronary angiography followed by myocardial revascularization, if feasible) versus an early "conservative" strategy (noninvasive, predischarge stress testing with planar thallium scintigraphy and radionuclide ventriculography), where the use of coronary angiography and myocardial revascularization was guided by the development of ischemia (clinical course or results of noninvasive tests, or both). RESULTS: A total of 920 patients were randomized (mean follow-up 23 months, range 12 to 44). The mean patient age was 61 +/- 10 years; 97% were male; 38% had ST segment depression at study entry; 30% had an anterior NQMI; 54% were hypertensive; 26% had diabetes requiring insulin; 43% were current smokers; 43% had a previous acute myocardial infarction; and 45% had antecedent angina within 3 weeks of the index NQMI. CONCLUSIONS: Baseline characteristics were compatible with a moderate to high risk group of patients with an NQMI.

Neural network assessment of perioperative cardiac risk in vascular surgery patients.

Neural networks were developed to predict perioperative cardiac complications with data from 567 vascular surgery patients. Neural network scores were based on cardiac risk factors and dipyridamole thallium results. These scores were converted into likelihood ratios that predicted cardiac risk. The prognostic accuracy of the neural networks was similar to that of logistic regression models (ROC areas 76.0% vs 75.8%), but their calibration was better. Logistic regression overestimated event rates in a group of high-risk patients (predicted event rate, 64%; observed rate 30%; n=50, p<0.001). On a validation set of 514 patients, the neural networks still had ROC similar areas to those of logistic regression (68.3% vs 67.5%), but logistic regression again overestimated event rates for a group of high-risk patients. The calibration difference was reflected in the Hosmer-Lemeshow chi-square statistic (18.6 for the neural networks, 45.0 for logistic regression). The neural networks successfully estimated perioperative cardiac risk with better calibration than comparable logistic regression models.

Correlations between uptake of technetium-99m Q12 and thallium-201: myocardial perfusion and viability in a model of acute coronary reperfusion.

UNLABELLED: To investigate whether Q12 uptake is affected by myocardial viability, as has been noted for 201Tl and sestamibi, we analyzed the initial and delayed distribution patterns of Q12 in a rat coronary artery occlusion-reperfusion model. METHODS: Animals were intubated and ventilated, and their arterial pressures were monitored. A left thoracotomy was performed. After a 1-hr occlusion and a 1-hr reperfusion of a major branch of the circumflex artery, 201Tl and Q12 were injected intravenously. Radiolabeled microspheres were used to document the areas of risk and reperfusion. The animals were killed at 5 min or 1 hr after administration of the diffusible tracers. Tracer distribution was determined by segmental tissue analysis, and tissue viability was determined by histochemical staining. RESULTS: Both the initial uptake and delayed retention of Q12 are sensitive to myocardial viability as shown by significantly lower uptake (28% +/- 8%) and retention (41% +/- 13%) of Q12 in the nonviable as compared to the viable segments (p < 0.001). In addition, the myocardial retention of Q12 was significantly less in the nonviable tissue when compared to the initial uptake (p < 0.01). CONCLUSION: The clinical implication of these observations suggests that initial and delayed imaging after Q12 administration would reflect both the initial regional blood flow pattern and myocardial viability. Also, delayed imaging of Q12 may reflect viability better than the initial imaging.

Intracoronary Doppler assessment of moderate coronary artery disease: comparison with 201Tl imaging and coronary angiography. FACTS Study Group.

BACKGROUND: Coronary angiography may not reliably predict whether a stenosis causes exercise-induced ischemia. Intracoronary Doppler ultrasound may enhance diagnostic accuracy by providing a physiological assessment of stenosis severity. The goal of this study was to compare intracoronary Doppler ultrasound with both 201Tl imaging and coronary angiography. METHODS AND RESULTS: Fifty-five patients with 67 stenotic coronary arteries underwent coronary angiography with intracoronary Doppler ultrasound and had exercise 201Tl testing within a 1-week period. Coronary flow reserve was measured, and analyses were performed by independent core laboratories. The mean stenosis was 59+/-12%; 51 of 67 stenoses were intermediate in severity (40% to 70%). A coronary flow reserve < 1.7 predicted the presence of a stress 201Tl defect in 56 of 67 stenoses (agreement=84%; kappa=0.67; 95% CI=0.48 to 0.86). In the patients who achieved 75% of their predicted maximum heart rate, the Doppler and 201Tl imaging data agreed in 46 of 52 stenoses (agreement=88%; kappa=0.77; 95%CI=0.57 to 0.97). Scatter was evident when angiography was compared with coronary flow reserve (r=.43), and the angiogram did not reliably predict the results of the 201Tl stress test (kappa=0.21; agreement=57% to 63%). CONCLUSIONS: Doppler-derived coronary flow reserve accurately predicts the presence of exercise-induced ischemia on stress 201Tl imaging, and coronary angiography does not reliably assess the physiological significance of an intermediate coronary stenosis.

Is coronary angiography necessary for vascular surgery patients who have positive results of dipyridamole thallium scans?

PURPOSE: Because dipyridamole thallium (DT) scanning is a useful predictor of perioperative cardiac events, a positive results of a DT scan is frequently the basis for performing more invasive cardiac evaluation and for consideration for performing coronary revascularization procedures before performing peripheral vascular surgery. The rationale for this approach has been that the treatment of anatomically significant coronary artery disease would lower the risk of performing a subsequent vascular operation. However, the benefit of performing aggressive diagnostic and therapeutic cardiac procedures in such patients remains unproved. To examine this issue, data from patients who underwent coronary angiography because of thallium redistribution were compared with data from matched control subjects who underwent peripheral vascular operations without further cardiac evaluation. METHODS: The medical records of 70 consecutive patients who underwent coronary angiography because of the presence of two or more segments of redistribution on DT scan were reviewed and compared with 70 other patients matched with respect to age, gender, peripheral vascular operation, and number of segments of redistribution on DT scan who did not undergo additional cardiac evaluation. RESULTS: DT scans were performed on 934 preoperative peripheral vascular surgery patients to help in the assessment of operative risk. Ischemic responses, defined as two or more segments of redistribution, were observed in 297. Of these, 70 underwent cardiac catheterization and 25 underwent coronary revascularization procedures. Adverse outcomes affected 46% of the coronary angiography group and 44% of the control group (p = NS). Patients who underwent coronary angiography and were considered for myocardial revascularization had fewer cardiac events with a subsequent vascular operation than did the control subjects. However, any possible benefit from invasive cardiac evaluation was offset by the three deaths and two myocardial infarctions (MIs) that complicated the cardiac evaluation. There was no significant difference between the angiography group and the matched control subjects with respect to perioperative nonfatal MI (13% vs 9%), fatal MI (4% vs 3%), late nonfatal MI (16% vs 19%), or late cardiac death (10% vs 13%). In long-term follow-up, MIs occurred later in patients who underwent coronary angiography than the control subjects (p = 0.049), but this difference was not associated with an improvement in the overall survival rate. CONCLUSIONS: The risks of extended cardiac evaluation and treatment did not produce any improvement in either the perioperative or the long-term survival rate. For most vascular surgery patients who have a positive result of a DT scan, coronary angiography does not provide any additional useful information.

Effects of acute ischemia and reperfusion on the myocardial kinetics of technetium 99m-labeled tetrofosmin and thallium-201.

BACKGROUND: Effects of no-flow ischemia and reperfusion on myocardial extraction and retention of 99mTc-labeled tetrofosmin and 201Tl were investigated in seven isolated, blood-perfused rat hearts with isotope dilution studies at constant coronary perfusion. METHODS AND RESULTS: After a control injection of tracers, no-flow ischemia was induced for 20 minutes. After coronary reflow, tracers were injected. Both maximal fractional extraction and capillary permeability-surface area product for tetrofosmin were significantly less than those for 201Tl (maximal fractional extraction 0.30 +/- 0.01 and 0.70 +/- 0.09, respectively, p < 0.001; capillary permeability-surface area product 0.66 +/- 0.14 and 2.29 +/- 0.61, respectively, p < 0.001). After no-flow ischemia-reperfusion, both maximal fractional extraction and capillary permeability-surface area product decreased for both tetrofosmin and 201Tl (decreases in maximal fractional extraction of 23% and 7%, respectively; decreases in capillary permeability-surface area product of 27% and 16%, respectively), although the difference reached statistical significance only for tetrofosmin. Net extraction at 5 minutes of both tracers decreased significantly after no-flow ischemia-reperfusion (tetrofosmin 20% decrease, p < 0.01; 201Tl 23% decrease, p < 0.02). Early (0 to 5 minutes) washout of tetrofosmin did not change after no-flow ischemia-reperfusion, whereas the 201Tl value increased significantly. Although late (5 to 19 minutes) washout of both tracers increased significantly after no-flow ischemia-reperfusion, the myocardial clearance rates for tetrofosmin were always significantly less than those noted for 201Tl. CONCLUSIONS: The myocardial uptake of tetrofosmin is depressed (independent of blood flow) after severe ischemic injury, apparently resulting mainly from decreased transcapillary exchange. In contrast, the depressed uptake of 201Tl is related more to an accelerated early washout from injured myocardium than to a fairly stable initial transcapillary exchange.

Comparison of pharmacologic stress agents.

In choosing a pharmacologic agent for stress testing, the clinician must keep a number of things in mind, such as the diagnostic utility of the agent or in what situations a vasodilator or catecholamine will be the better choice. Although all stress agents produce similar diagnostic accuracy for CAD, vasodilators have a higher cardiac uptake than catecholamines, and the addition of exercise improves the heart/background contrast ratios. With regard to physiologic comparisons, exercise or dobutamine will double coronary perfusion compared with baseline flow, but vasodilators produce a threefold or fourfold increase. The clinician should also keep in mind that adenosine will produce the shortest duration of hyperemia, whereas dobutamine and arbutamine produce a longer effect, and dipyridamole has the longest duration. If electrophysiologic considerations are important, exercise and catecholamines accelerate sinoatrial and atrioventricular conduction and are not typically associated with heart block. In contrast, adenosine can cause transient atrioventricular block, but this rarely occurs with dipyridamole. Clinical factors also must be considered. Although clinical utility of pharmacologic stress agents in the first 24 hours after infarction has not been demonstrated, the prognostic utility of vasodilators in the subsequent 2- to 4-day period has been shown. With patients with pulmonary disease (asthma) who do not have wheezing, dipyridamole can be used, but dobutamine or arbutamine should be used in patients with recent respiratory failure or bronchospasm before testing. In patients with left bundle branch block, vasodilators are the preferred stress agents rather than synthetic catecholamines or dynamic exercise. In the first crossover thallium imaging, there was good overall agreement in segmental perfusion comparing adenosine and dipyridamole, but there was a tendency for adenosine to detect more ischemia. The clinical significance (if any) for these findings has yet to be determined.

Myocardial uptake of 99mTc-tetrofosmin, sestamibi, and 201Tl in a model of acute coronary reperfusion.

BACKGROUND: To investigate whether tetrofosmin uptake is affected by myocardial viability as has been noted for 201Tl and sestamibi, we analyzed the initial and delayed distribution patterns of tetrofosmin in a rat coronary artery occlusion-reperfusion model. METHODS AND RESULTS: Animals were intubated and ventilated, and their arterial pressures were monitored. A left thoracotomy was performed. After 1-hour occlusion and 1-hour reperfusion of a major branch of the circumflex artery, 201Tl and either tetrofosmin or sestamibi were injected intravenously. Radiolabeled microspheres were used to document the area at risk and reperfusion. Five minutes or 1 hour after administration of the diffusible tracers, the animals were killed. Tracer distribution was determined by use of segmental tissue analysis, and tissue viability was determined by use of histochemical staining. Both the initial and delayed retention of tetrofosmin were sensitive to myocardial viability, as shown by significantly lower uptake (30 +/- 14%) and retention (24 +/- 12%) of tetrofosmin in the nonviable segments compared with the viable segments. In addition, the initial myocardial distribution of tetrofosmin was similar to that noted for 201Tl, but after 1 hour of tracer circulation, the tetrofosmin tissue distribution appeared unchanged compared with the initial regional blood flow distribution. This is in direct contrast to our present observations of significant 201Tl redistribution and some changes in sestamibi distribution as well. CONCLUSIONS: The clinical implication of these observations suggests that initial and delayed imaging after tetrofosmin administration would reflect both the initial regional blood flow pattern and myocardial viability.

An approach to myocardial viability based on perfusion, function and metabolic substrates.

In the clinical assessment of myocardial viability, the concept of down-regulation of contractile function is important in understanding the interaction between coronary flow and ventricular function. In this state, the myocardium remains viable, although lacking overt contractile function, and may be totally reversible with complete revascularization. This abnormality is also associated with altered cellular metabolism, and individual substrate determinations are not necessarily as predictive of myocardial viability as are evaluations of overall oxidative metabolism. Nuclear cardiology imaging techniques can monitor oxidative phosphorylation and predict the overall viability of cardiac tissue. In addressing the clinical challenge of identifying those patients who would receive the most benefit from coronary revascularization, it is clear that a diagnostic test which combines blood flow and an evaluation of left ventricular wall motion would be of great potential value. One can make a strong case for the use of thallium imaging as an acceptable and readily available method, but the use of positron emission tomography (PET) tracers has been a strong gold standard. Recent work suggests that PET data do have a clinical impact in patient management, treatment, and the prediction of long-term morbidity and mortality. Patients with known coronary artery disease and significant left ventricular dysfunction need a functional evaluation of myocardial viability. Given this type of evaluation, patients should not be condemned to end-stage heart disease without performing at least one test for potential reversibility.

Prognostic utility of increased pulmonary thallium uptake in patients without ischemia.

BACKGROUND: Although the combination of increased pulmonary thallium uptake and ischemia has demonstrated prognostic utility, the value of pulmonary uptake independent of ischemia has not been evaluated critically. Accordingly, our purpose was to evaluate the prognostic utility of thallium lung uptake in patients who do not have stress-induced defects. METHODS AND RESULTS: We studied 184 patients who were divided into three groups. Patients with increased pulmonary uptake were grouped into either the normal perfusion (n = 48) or fixed defect (n = 44) scan group and were compared with a third group (n = 92) of control patients who had normal scans and no lung uptake. During a mean follow-up of 23 +/- 13 months, there were 13 cardiac events (death or myocardial infarction) and the incidence per year was 0.6%, 2%, and 12% in the control, normal, and fixed defect groups, respectively (p < 0.00001). Life table analysis demonstrated greater event-free survival rates in the control and normal groups compared with the group with fixed defects. A Cox regression analysis showed that the number of fixed defects (infarct segments) was the most important independent prognostic factor (p < 0.00001) for future cardiac events. CONCLUSION: In patients with increased pulmonary thallium uptake and no stress perfusion defects, the prognosis is similar to that of control patients. However, patients with infarct segments and lung uptake have a significantly worse prognosis.