Serial changes in 14C-deoxyglucose and 201Tl uptake in autoimmune myocarditis in rats.

UNLABELLED: This study was designed to examine the relationships between the uptake of 14C-deoxyglucose (DG) and the uptake of 201Tl in a rat model of autoimmune myocarditis. METHODS: Autoimmune myocarditis was induced in normal rats by immunization with pig cardiac myosin. Dual-tracer autoradiography with DG and 201Tl was performed on frozen slices of the animals' hearts 3 wk (acute phase), 8 wk (subacute phase), and 14 wk (chronic phase) (each n = 5) after immunization. The extent of inflammatory damage was classified histologically into three categories on the basis of cell infiltration: mild (Mi), moderate (Mo), and severe (Sv). The regional count in the region of interest set on the autoradiogram was normalized on the basis of that of control rats. The ratio of total cardiac uptake to the injected dose (%ID/g x BW, where ID is injected dose and BW is body weight) was calculated by tissue counting. Expressions of glucose transporters GLUT1 and 4 were evaluated by the enzyme-labeled antibody method. RESULTS: The total cardiac uptake of DG in the acute phase of myocarditis was significantly higher than in normal control rats (3.43% +/- 0.92% vs. 0.97% +/- 0.38%; P < 0.0001); it then decreased in the chronic phase but was still higher than in the controls (1.85% +/- 0.37% vs. 0.97% +/- 0.38%; P < 0.01). The total cardiac uptake of 201Tl in the acute phase of myocarditis was significantly lower than in the controls (7.4% +/- 0.7% vs. 12.0% +/- 3.3%; P < 0.005); it then increased in the chronic phase and reached normal levels (13.0% +/- 3.3% vs. 12.0% +/- 3.3%; not significant [NS]). In the acute phase, the regional uptakes of DG in the Mi, Mo, and Sv regions were 143.1% +/- 107.9%, 169.6% +/- 59.9%, and 317.5% +/- 103.3%, respectively, whereas those of 201Tl were 88.4% +/- 31.9%, 72.1% +/- 34.6%, and 48.4% +/- 21.5%, respectively. GLUT expression was evaluated visually and classified into four grades (0, 1, 2, and 3). In the acute phase, GLUT1 expression was higher in rats in the Sv group than in the controls (2.87 vs. 0.87). GLUT4 was not expressed in the Sv areas but was found in the Mi areas. CONCLUSION: In the acute phase of autoimmune myocarditis in rats, cardiac uptake of DG was accelerated by severe inflammation. Cardiac uptake of 201Tl, on the other hand, was suppressed. Our results suggest that GLUT1 expression accelerates DG uptake by cells in areas of severe inflammation.

Changes in perfusion and fatty acid metabolism of rat heart with autoimmune myocarditis.

To elucidate the change in perfusion and aerobic metabolism in myocarditis, tissue counting and dual tracer ex vivo autoradiography with Tl-201 and a free fatty acid analog, I-123- or I-125-labeled (p-iodophenyl)-methyl-pentadecanoic acid (BMIPP), were performed in rats with myocarditis induced by immunization with cardiac myosin. Inflammatory damage was classified histologically. At the acute stage (2-4 weeks after the antigen-injection), total heart uptakes of Tl and BMIPP and the ratio (BMIPP/Tl) were significantly reduced in myocarditis rats (N = 15) compared with the controls (N = 12). Myocardial distribution of Tl and BMIPP was not homogeneous. Relative uptake of Tl and BMIPP (N = 9, 128 regions) was gradually decreased with the extent of inflammation, and the regional BMIPP/Tl was smaller than the control. At the subacute stage (7 weeks after the antigen-injection), total Tl uptake in myocarditis rats (N = 5) recovered to the control level (N = 4), but that of BMIPP was still significantly lower than the control. BMIPP/Tl was still significantly lower in myocarditis. Myocardial distribution of Tl and BMIPP recovered to be more homogeneous. Relative uptake of Tl and BMIPP (N = 6, 78 regions) still gradually but significantly decreased with the extent of inflammation. Regional BMIPP/Tl was still depressed in myocarditis. These results indicate that myocardial perfusion and aerobic metabolism were discrepant and heterogeneously suppressed with severe inflammation during the acute stages, but the difference decreases with time. Examination with Tl-201 and BMIPP may provide information about the severity of myocarditis.

Assessment of left ventricular function by gated myocardial perfusion and gated blood-pool SPECT: can we use the same reference database?

The purpose of this study was to compare left ventricular (LV) volume and ejection fraction (LVEF) measurements obtained with electrocardiographic gated single-photon emission computed tomographic (SPECT) myocardial perfusion imaging (GS-MPI) with those obtained with gated SPECT cardiac blood-pool imaging (GS-pool). Fifteen patients underwent GS-MPI with technetium-99m-tetrofosmin and GS-pool with technetium-99m-erythrocyte, within a mean interval of 8 +/- 3 days. Eight patients had suspected dilated cardiomyopathy and seven patients had angiographically significant coronary artery disease. End-diastolic volume (EDV), end-systolic volume (ESV) and LVEF measurements were estimated from GS-MPI images by means of Cedars-Sinai automatic quantitative program and from GS-pool images by the threshold technique. Mean differences between GS-MPI and GS-pool in EDV, ESV and LVEF measurements were -2.8 +/- 10.5 ml [95% confidence interval (CI): -8.6 +/- 3.0 ml], 2.6 +/- 7.3 ml (CI: -1.4 +/- 6.6 ml) and -2.3 +/- 5.1% (CI: -5.1 +/- 0.6%), respectively. No significant difference in the mean differences from 0 was found for EDV, ESV or LVEF measurements. Bland-Altman plots revealed no trend over the measured LV volumes and LVEF. For all parameters, regression lines approximated lines of identity. The excellent agreement between GS-MPI and GS-pool measurements suggests that, for estimation of LV volumes and LVEF, these two techniques may be used interchangeably and measurements by one method can serve as a reference for the other.

Exercise-induced stunning continues for at least one hour: evaluation with quantitative gated single-photon emission tomography.

To elucidate the after-effect of exercise on left ventricular (LV) function, end-diastolic volume (EDV), end-systolic volume (ESV) and ejection fraction (LVEF) were evaluated at 1 h after exercise and at rest by technetium-99m tetrofosmin gated myocardial single-photon emission tomography (SPET) using an automated program in 53 subjects. The subjects were grouped as follows: normal scan (n = 16), ischaemia (n = 19) and infarction (n = 18), based on the interpretation of perfusion images. Postexercise LVEF did not differ from resting LVEF in the groups with normal scan and infarction. In patients with ischaemia, postexercise EDV (90+/-17 ml, mean +/-SD) and ESV (44+/-15 ml) were significantly higher than EDV (84+/-15 ml, P = 0.001) and ESV (36+/-14 ml, P<0.0005) at rest. LVEF was significantly depressed 1 h after exercise (53%+/-9% vs 58%+/-9%, P<0.0001). In ischaemic patients with depressed postexercise LVEF, LVEF difference between rest and postexercise showed a significant correlation with the sum of defect scores, which were reversible from exercise to rest perfusion images (r = 0.92, P<0.0001). These results indicate that exercise-induced LV dysfunction (myocardial stunning) continues for at least 1 h in ischaemic patients and that the extent of LVEF depression is determined by the severity of ischaemia.

Comparison of dual-isotope acquisition of 201Tl and 99Tcm-tetrofosmin for the detection of ischaemic heart disease and determination of the optimal imaging time of 99Tcm-tetrofosmin.

Comparative studies of thallium-201 (201Tl) and 99Tcm-tetrofosmin for the detection of ischaemic heart disease (IHD) have previously been reported. These 201Tl and 99Tcm-tetrofosmin studies were usually performed separately with different exercise loads at an interval of several days. Here, we used a dual-isotope technique with exercise myocardial SPET (single photon emission tomography) in 17 patients with IHD and 10 patients with normal coronary arteries. The triple-energy window (TEW) method was applied for cross-talk correction. SPET imaging was performed at 10 and 70 min (S1 and S2) after the injection of 99Tcm-tetrofosmin (222 MBq) and 201Tl (74 MBq) at peak exercise to determine the optimal imaging time of 99Tcm-tetrofosmin. The S2 value was obtained 35 min after the subject drank a glass of milk to accelerate hepatobiliary clearance. Twenty-five minutes after S2, 37 MBq of 201Tl were reinjected at rest and SPET imaging (S3) was performed. Immediately after S3, 666 MBq of 99Tcm-tetrofosmin were reinjected and SPET imaging (S4) was performed 50 min later. Representative short and vertical long axis tomograms were divided into 17 segments. Each segment was assessed using a 4-point scoring system. The defect score was defined as the sum of each segmental score. The defect scores for imaging at exercise were 14.3 +/- 11.4 for 201Tl at S1, 11.4 +/- 8 for 99Tcm-tetrofosmin at S1 and 9.7 +/-9.8 for 99Tcm-tetrofosmin at S2 (P < 0.01), respectively. The washout rate of 99Tcm-tetrofosmin for the first hour was 15.5 +/- 7.3% and 11.8 +/- 7.7% (P < 0.01), respectively, for the normal and ischaemic segments. The image quality of 201Tl at S1 was almost equivalent to that of 99Tcm-tetrofosmin at S1/S2. The overall sensitivity and specificity for the detection of ischaemia was 94% and 82% for 201Tl at S1, 89% and 86% for 99Tcm-tetrofosmin at S1, and 88% and 95% for 99Tcm-tetrofosmin at S2, respectively. The overall accuracy was 86%, 88% and 92%, respectively. The myocardial viability score was 7.4 +/- 7.1 for 201Tl at S3 and 5.8 +/- 7.0 for 99Tcm-tetrofosmin at S4 (P < 0.01). The results indicate that the diagnostic accuracy of 99Tcm-tetrofosmin for myocardial ischaemia is almost equivalent to that of 201Tl as assessed by dual SPET imaging, and that the optimal imaging time for 99Tcm-tetrofosmin is within 10-35 min (S1) after exercise.

Evaluation of left ventricular ejection fraction from radial long-axis tomography: a new reconstruction algorithm for ECG-gated technetium-99m sestamibi SPECT.

UNLABELLED: Radial long-axis tomography can provide views similar to contrast left ventriculography (LVG) including the basal and apical areas of the left ventricle, not possible in routine short-axis tomography. We applied this method to ECG-gated Tc-99m Sestamibi (MIBI) myocardial SPECT images to estimate the left ventricular ejection fraction (LVEF). METHODS: ECG-gated Tc-99m MIBI SPECT was performed with a temporal resolution of 10 frames per R-R interval. LVEF was calculated on the basis of left ventricular volume estimates at end diastole (ED) and end systole (ES) with using an ellipsoid body model. To validate this method, LVEF's derived from ECG-gated Tc-99m MIBI SPECT were compared with those from LVG in 11 patients with coronary artery disease. RESULTS: There was a close linear correlation between LVEF values calculated from Tc-99m MIBI SPECT and those from LVG (r = 0.89, p < 0.001), although the gated SPECT underestimated LVEF compared to LVG. The technique showed excellent reproducibility (intra-observer variability, r = 0.96, p < 0.001; inter-observer variability, r = 0.71, p < 0.005). CONCLUSION: The radial long-axis tomography technique gives a good estimate of LVEF, in agreement with estimates based on LVG. ECG-gated Tc-99m MIBI SPECT can, therefore, be applicable to assess myocardial perfusion and ventricular function at the same time.

Quantification of systolic count increase in technetium-99m-MIBI gated myocardial SPECT.

UNLABELLED: This study was performed to clarify the validity of quantification of myocardial wall thickening by the count increase method using electrocardiography (ECG)-gated SPECT. METHODS: We performed a phantom study to examine the quantification of this method and to clarify the relationship between the changes of relative counts and objective size (such as myocardial wall) under various conditions. In addition, in volunteers, the percent count increase (%CI) was analyzed in left ventricular segments based on circumferential profile curve analysis by ECG-gated SPECT with 99mTc-MIBI (methoxyisobutyl-isonitrile), and it was compared with the regional systolic wall thickness (%Th) assessed by echocardiography during low-dose dobutamine infusion. RESULTS: In our phantom study, the relative count changes were correlated linearly with the object size only within less than 20 mm. Recovery coefficient curves were influenced by acquisition parameters such as type of collimator, diameter of camera rotation, counts and photon scattering. In ECG-gated SPECT, the %CI value was increased gradually at each stage after dobutamine infusion, in relation to the increase of the %Th seen on echocardiography, although there are significant large deviations between these two parameters. CONCLUSIONS: In this study, quantitative analysis based on the %CI in ECG-gated SPECT may underestimate regional wall thickening. These data should be considered in the evaluation of the %CI as an index of myocardial function.

Myocardial iodine-123-metaiodobenzylguanidine images and autonomic nerve activity in normal subjects.

UNLABELLED: We studied the relationship between myocardial [123I]metaiodobenzylguanidine (MIBG) uptake and autonomic nerve activity in normal subjects. METHODS: MIBG scintigraphy and power spectral analysis (PSA) of heart rate variability were performed simultaneously in 15 normal subjects. Anterior planar images and SPECT images were taken at five and two points after the injection of [123I]MIBG, respectively. In 10 of 15 subjects, 201TI myocardial SPECT was performed immediately after MIBG scintigraphy. RESULTS: The heart/upper mediastinum MIBG uptake ratio in the planar image obtained at 240 min (r = 0.64, p < 0.01) and the washout rate of MIBG in the heart between 15 min and 240 min (r = 0.51, p < 0.05) showed significant correlation with the percentage of low frequency component of PSA (percent LF), an index of sympathetic nerve activity. Regional MIBG uptake in the inferior wall normalized by individual maximal uptake among all pixels was significantly correlated with the high frequency component of PSA, an index of parasympathetic nerve activity (r = -0.58, p < 0.05) and with mean R-R interval in a resting ECG (r = -0.82, p < 0.001) but did not correlate with percent LF, percent uptake of 201TI in the inferior wall or the liver/heart uptake ratio. CONCLUSION: These results indicate that myocardial MIBG uptake correlates with sympathetic nerve activity in normal subjects. Our data indicate that heterogeneous MIBG distribution in the left ventricle is a physiologic rather than artifactual phenomenon and may be related to vagal tone rather than sympathetic nerve activity.

The effects of proteins on [Ca2+] measurement: different effects on fluorescent and NMR methods.

Previous reports showed that the presence of proteins shifts the apparent dissociation constant (Kd) of a fluorescent dye indicator to Ca2+. To elucidate the sensitivity of Kd of an NMR-sensitive Ca2+ indicator, 5-fluoro-1,2-bis(2-amino-phenoxy)ethane N,N,N'N'-tetraacetic acid (5F-BAPTA) to proteins, and compare with that of a dye indicator, Fura-2, we measured Kd of Fura-2 or 5F-BAPTA using Ca-EGTA buffer with or without proteins. Aldolase (ALD) or bovine cardiac protein (BCP) extracted from bovine hearts was used at concentrations of 10, 25, or 50 mg/ml. ALD significantly increased the apparent Kd of Fura-2 to Ca2+ from 164.1 +/- 5.6 nM (mean +/- SE, N = 8) to 757.2 +/- 2.1 nM (n = 4, P < 0.05) at the concentration of 50 mg/ml. In contrast, Kd of 5F-BAPTA was not markedly changed by ALD (298.4 +/- 3. nM without ALD (n = 8), 385.1 +/- 2.7 nM (n = 4) with 50 mg/ml ALD). BCP (50 mg/ml) also significantly increased Kd of Fura-2 (928.5 +/- 3.3 nM, n = 4, P < 0.05), but did not change Kd of 5F-BAPTA (316.0 +/- 2.9 nM, n = 4). These results indicate that Kd of 5F-BAPTA is much less sensitive to the presence of proteins than Fura-2, and that 19F-NMR coupled with 5F-BAPTA is a more robust method to measure intracellular Ca2+ concentration than a fluorescent method with Fura-2.

[Experience with mild exercise 123I-BMIPP myocardial imaging in two cases of ischemic heart disease].

During mild to moderate ischemia, glycolytic flux is enhanced and free fatty acid uptake is reduced in proportion to the reduction in mitochondrial metabolism. We considered that mild exercise may induce the reduction of 123I-BMIPP, reflecting myocardial fatty acid metabolism, in ischemic myocardium compared to normal myocardium. Therefore, mild exercise 123I-BMIPP myocardial imaging was carried out to detect myocardial ischemia in 2 cases of ischemic heart disease. Mild exercise was performed using a bicycle ergometer with 25-50 W loading. At seven minutes before cessation of exercise, 111 MBq of 123I-BMIPP was injected. Case 1 was a 12 year-old boy with Kawasaki's disease. The study showed a reduction of mild exercise 123I-BMIPP uptake in the anteroseptal wall. In contrast, stress 201T1 myocardial imaging did not show perfusion defect in the anteroseptal wall. Case 2 was a 64 year-old female with triple vessels disease. Mild exercise 123I-BMIPP myocardial imaging showed similar with those of stress 99mTc-sestamibi. We conclude that mild exercise 123I-BMIPP myocardial SPECT may be a sensitive method to detect myocardial ischemia.

New approach to the estimation of the extent of myocardial fibrosis in patients with dilated cardiomyopathy: use of signal-averaged electrocardiography.

To determine whether the extent of myocardial fibrosis in dilated cardiomyopathy could be estimated noninvasively, signal-averaged electrocardiograms were recorded in 32 patients with dilated cardiomyopathy, followed by left ventricular endomyocardial biopsy. The root mean square voltage for the last 40 msec (V40), the duration of the filtered QRS complex (fQRSd) and the duration of low amplitude signals < 40 microV (LAS) were obtained by signal-averaged electrocardiography. The extent of fibrosis in all biopsy samples was measured by the point-counting method. The extent of myocardial fibrosis closely correlated with fQRSd (r = 0.623, p < 0.001), LAS (r = 0.570, p < 0.001), and V40 (r = -0.355, p < 0.05). When fibrosis was classified into intercellular and interfascicular types, the extent of intercellular fibrosis more closely correlated with fQRSd (r = 0.695, p < 0.0001), LAS (r = 0.640, p < 0.0001), and V40 (r = -0.533, p < 0.005). These results suggest that signal-averaged electrocardiograms might be useful for estimation of the extent of myocardial fibrosis, especially intercellular fibrosis in patients with dilated cardiomyopathy.

Which subgroup of patients with dilated cardiomyopathy would benefit from long-term beta-blocker therapy? A histologic viewpoint.

OBJECTIVES: The purpose of this study was to elucidate whether the effectiveness of long-term beta-blocker therapy could be predicted before this therapy is started. BACKGROUND: Long-term beta-blocker therapy has recently been reported to provide a favorable effect in treatment of congestive heart failure due to dilated cardiomyopathy. METHODS: Several measurements including histologic variables before administration of metoprolol were retrospectively compared among 18 good responders (showing improvement of at least one New York Heart Association functional class or an increase in ejection fraction > or = 0.10 12 months after drug administration) and 12 poor responders without such improvement. RESULTS: Although there were no significant differences between the two groups in age, gender, functional class, heart rate, blood pressure, pulmonary capillary wedge pressure, cardiac index, left ventricular end-diastolic dimension and ejection fraction, percent fibrosis estimated by the point-counting method in endomyocardial biopsy specimens was significantly lower in good than in poor responders (7.6 +/- 5.7 vs. 14.2 +/- 9.7%, p < 0.05). Moreover, when the types of fibrosis were classified as interfascicular and intercellular by the dominance of counted points, there were 13 cases of interfascicular fibrosis and 5 cases of intercellular fibrosis in good responders and 1 case of interfascicular fibrosis and 11 cases of intercellular fibrosis in poor responders (p < 0.001, sensitivity 72%, specificity 91%, predictive accuracy 80%). These results suggest that improvement with long-term beta-blocker therapy may be more likely to occur in patients with less myocardial fibrosis, with interfascicular fibrosis the dominant type. CONCLUSIONS: The extent and type of fibrosis may be important factors in the prediction of the effectiveness of long-term beta-blocker therapy for dilated cardiomyopathy.

Dynamic process between the clotting and the lytic activities on intracardiac thrombi--its relationship with systemic embolization.

To clarify the relationship between clotting and lytic activities of intracardiac thrombi, and to elucidate whether this could be used to evaluate the embolic risk the ratio of indium-111 radioactivity accumulated on thrombi to that in the blood pool using dual-tracer technique %IE as a parameter of the clotting activity, and D-dimer, which is a fibrin specific degradation product, as a parameter of lytic activity were measured in 37 patients with intracardiac thrombi. Fifteen of the 37 patients had past histories of arterial embolization. The values of D-dimer correlated significantly with those of %IE (r = 0.758, p less than 0.01), e.g., the higher the values of D-dimer the higher the values of %IE. 37 patients were divided into 2 groups using the regression line for the D-dimer and %IE domains. Eleven patients above the regression line had thrombosis in excess of fibrinolysis but the remaining 26 patients under the regression line had fibrinolysis in excess of thrombosis. The incidence of past embolic episodes was 82% (9/11) in patients with thrombosis in excess of fibrinolysis but 23% (6/26) in patients with fibrinolysis in excess of thrombosis. These results demonstrated that intracardiac thrombi were under the dynamic process between the clotting and the lytic activities and moreover patients with intracardiac thrombi and thrombosis in excess of fibrinolysis had a substantial risk of arterial embolization.