Experiment assessment of mass effects in the rat: implications for small animal PET imaging.

In vivo imaging using positron emission tomography (PET) is important in the development of new radiopharmaceuticals in rodent animal models for use as biochemical probes, diagnostic agents, or in drug development. We have shown mathematically that, if small animal imaging studies in rodents are to have the same "quality" as human PET studies, the same number of coincidence events must be detected from a typical rodent imaging "voxel" as from the human imaging voxel. To achieve this using the same specific activity preparation, we show that roughly the same total amount of radiopharmaceutical must be given to a rodent as to a human subject. At high specific activities, the mass associated with human doses, when administered to a rodent, may not decrease the uptake of radioactivity at non saturable sites or sites where an enzyme has a high capacity for a substrate. However, in the case of binding sites of low density such as receptors, the increased mass injected could saturate the receptor and lead to physiologic effects and non-linear kinetics. Because of the importance of the mass injected for small animal PET imaging, we experimentally compared high and low mass preparations using ex vivo biodistribution and phosphorimaging of three compounds: 2-fluoro-2-deoxyglucose (FDG), 6-fluoro-L-metatyrosine (FMT) and one receptor-directed compound, the serotonin 5HT1A receptor ligand, trans-4-fluoro-N-[2-[4-(2-methoxylphenyl) piperazino]ethyl]-N-(2-pyridyl) cyclohexane- carboxamide (FCWAY). Changes in the mass injected per rat did not affect the distribution of FDG, FMT, and FCWAY in the range of 0.6-1.9 nmol per rat. Changes in the target to nontarget ratio were observed for injected masses of FCWAY in the range of approximately 5-50 nmol per rat. If the specific activity of such compounds and/or the sensitivity of small animal scanners are not increased relative to human studies, small animal PET imaging will not correctly portray the "true" tracer distribution. These difficulties will only be exacerbated in animals smaller than the rat, e.g., mice.

Performance characteristics of the 3-D OSEM algorithm in the reconstruction of small animal PET images. Ordered-subsets expectation-maximixation.

Rat brain images acquired with a small animal positron emission tomography (PET) camera and reconstructed with the three-dimensional (3-D) ordered-subsets expectation-maximization (OSEM) algorithm with resolution recovery have better quality when the brain is imaged by itself than when inside the head with surrounding background activity. The purpose of this study was to characterize the dependence of this effect on the level of background activity, attenuation, and scatter. Monte Carlo simulations of the imaging system were performed. The coefficient of variation from replicate images, full-width at half-maximum (FWHM) from point sources and image profile fitting, and image contrast and uniformity were used to evaluate algorithm performance. A rat head with the typical levels of five and ten times the brain activity in the surrounding background requires additional iterations to achieve the same resolution as the brain-only case at a cost of 24% and 64% additional noise, respectively. For the same phantoms, object scatter reduced contrast by 3%-5%. However, attenuation degraded resolution by 0.2 mm and was responsible for up to 12% nonuniformity in the brain images suggesting that attenuation correction is useful. Given the effects of emission and attenuation distribution on both resolution and noise, simulations or phantom studies should be used for each imaging situation to select the appropriate number of OSEM iterations to achieve the desired resolution-noise levels.

Assessment of coronary artery disease by radionuclide cineangiography. History, current applications, and new directions.

In recent years, the utility of radionuclide cineangiography in prognostication has made it a mainstay of management decision making. With evolution of therapeutic modalities and concomitant alteration in management strategies, however, the technique and its application are undergoing parallel evolution to optimize response to current needs. Thus, in addition to standard planar rest and exercise assessment of left ventricular function, newer approaches are involving combined perfusion and function assessment, application of pharmacological stress to permit technically advantageous variations in imaging protocols, and application of SPECT technology in collecting blood pool data for tomographic display and analysis.

Isovolumic relaxation period in hypertrophic cardiomyopathy: assessment by radionuclide angiography.

Left ventricular isovolumic relaxation and the relation between relaxation and filling were studied in 90 patients with hypertrophic cardiomyopathy and 29 control subjects using radionuclide angiography. The isovolumic relaxation period was determined automatically on left ventricular time-activity curves as the interval between minimal volume and onset of rapid filling. In 17 patients, M-mode echocardiography performed simultaneously with radionuclide angiography demonstrated that onset of mitral valve opening correlated well with onset of rapid filling (r = 0.84, p less than 0.001). The isovolumic relaxation period was longer in patients with hypertrophic cardiomyopathy than in control subjects (95 +/- 44 versus 50 +/- 23 ms, p less than 0.01) and was longer in patients without an outflow tract gradient at rest than in patients with a gradient (109 +/- 37 versus 86 +/- 35 ms, p less than 0.05). In these patients without obstruction, a weak linear relation between duration of the isovolumic period and peak filling rate was found (r = 0.48, p less than 0.02). Filling was impaired in patients with hypertrophic cardiomyopathy, as assessed by lower peak filling rate (3.2 +/- 1.2 versus 3.5 +/- 0.5 end-diastolic volume/s, p less than 0.05) and prolonged time to peak filling rate (185 +/- 44 versus 145 +/- 20 ms, p less than 0.01) compared with values in control subjects. The delay in time to peak filling rate was caused primarily by the prolonged isovolumic period, because the interval from onset of rapid filling to peak filling rate was similar in patients with hypertrophic cardiomyopathy and control subjects (87 +/- 31 versus 95 +/- 25 ms, NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of regional left ventricular function by sector analysis: a method for objective evaluation of radionuclide blood pool studies.

Regional wall motion abnormalities are most often detected visually, and hence subjectively, in gated blood pool studies of the heart. Therefore, an automated method was developed to objectively assess regional left ventricular (LV) function. The method was tested in 26 normal volunteers and 29 patients with angiographically proved coronary artery disease. Fifteen patients with coronary artery disease had a normal LV ejection fraction (EF) at rest, and all had an abnormal EF response with exercise; 23 had visual regional wall motion abnormalities with rest or exercise. The left ventricle was divided into 28 sectors that radiated from the LV center of gravity, with 1 region at the LV center. A time-activity curve was generated for each sector and the EF and Fourier phase were computed from each curve. Rest and exercise sector EF versus sector number plots were superimposed and the area difference between these 2 curves was taken as an index of regional contraction. Similarly, an estimator of sector phase differences, obtained from the plot of phase versus sector number, was taken as an index of wall motion asynchrony. Analysis of the reliability of these 2 indexes suggests that this automated technique has at least the same efficiency as subjective evaluation of gated blood pool studies, but possesses the advantage of objectivity. The technique may also be useful in localizing regional defects and, perhaps, in detecting mild abnormalities not readily perceived visually.

Impaired left ventricular diastolic filling in patients with coronary artery disease: assessment with radionuclide angiography.

To assess left ventricular (LV) diastolic filling at rest in patients with coronary artery disease (CAD), we analyzed high-resolution time-activity curves (10-20 msec/frame) obtained from gated radionuclide angiograms in 231 patients. Peak LV filling rate (PFR), expressed in end-diastolic volumes per second (EDV/sec), was subnormal in CAD patients (1.8 +/- 0.6 [+/- SD] vs normal mean of 3.3 +/- 0.6, p les than 0.001) and time to PFR (TPFR), measured from end-systole to PFR, was prolonged (171 +/- 41 msec vs normal mean of 136 +/- 23 msec, p less than 0.001). These indexes were also abnormal in the 141 patients with normal resting LV ejection fraction (PFR = 2.1 +/- 0.5 EDV/sec; TPFR = 175 +/- 36 msec) and in 123 patients without Q waves on the ECG (PFR = 2.1 +/- 0.5 EDV/sec; TPFR = 168 +/- 38 msec). Abnormal LV filling at rest (PFR less than 2.5 EDV/sec or TPFR greater than 180 msec) was found in 91% of all patients with CAD, 86% of patients with normal resting LV ejection fractions, 85% of patients without Q waves, and 82% of patients with normal resting LV ejection fraction, no resting regional wall motion abnormalities and no Q waves. Thus, LV diastolic filling, evaluated noninvasively by radionuclide angiography, is abnormal in a high percentage of patients with CAD at rest independent of LV systolic function or previous myocardial infarction.

Doxorubicin cardiotoxicity: assessment of late left ventricular dysfunction by radionuclide cineangiography.

Radionuclide cineangiography was used to evaluate 32 patients who sustained long-term remission of soft tissue sarcoma after adjuvant therapy with a cumulative doxorubicin dose from 480 to 550 mg/m body surface area. Left ventricular ejection fraction at rest was below normal (less than 45%) in eight of 32 patients. The abnormal response of ejection fraction to exercise identified an additional 12 patients with diminished left ventricular functional reserve. Ejection fraction determined at rest or during exercise did not differ 1 to 9 months) and those studied 30 months (range, 21 to 43 months) after completing doxorubicin treatment. Sequential studies in 13 patients, done 6 to 15 months after initial post-doxorubicin evaluation also showed persistent depression of average ejection fraction at rest and with exercise, with the continued deterioration of left ventricular function in six patients. Left ventricular dysfunction, evident in over half of asymptomatic patients even long after "acceptable" cumulative doses of doxorubicin, may persist for years.

Left ventricular function in mitral valve prolapse: assessment with radionuclide cineangiography.

Abnormalities of left ventricular contraction in patients with mitral valve prolapse have suggested a myocardial factor in this disease. To determine systolic left ventricular function in mitral valve prolapse, technetium-99m gated equilibrium radionuclide cineangiography was performed in 47 patients with this diagnosis. In 39 patients without mitral regurgitation the average ejection fraction was normal at rest (average [+/- standard error of the mean] 57 +/- 3 percent, normal 57 +/- 1 percent, difference not significant) and exceeded the lower limits of normal in all but 1 patient, whose ejection fraction was 41 percent. However, ejection fraction during maximal exercise was lower for the group of patients with mitral prolapse without mitral regurgitation than for normal subjects (average 64 +/- 2 percent, normal 71 +/- 2 percent, p < 0.005). In eight patients with mitral prolapse and mitral regurgitation, the average ejection fraction was normal at rest but was diminished with exercise in comparison with both normal subjects and patients with mitral valve prolapse without mitral regurgitation. Chest pain, arrhythmia and the pattern or extent of mitral valve prolapse on echocardiography were not independently associated with impaired left ventricular functional reserve. We conclude that, although many patients with mitral valve prolapse have normal left ventricular function, there is a subgroup without mitral regurgitation in whom diminished left ventricular functional reserve is suggestive of a cardiomyopathic process.

Exercise-induced left ventricular dysfunction in symptomatic and asymptomatic patients with aortic regurgitation: assessment with radionuclide cineangiography.

In patients with aortic regurgitation,, left ventricular dysfunction at rest, which is associated with a poor long-term prognosis, often develops before severe symptoms. To determine whether evidence of left ventricular dysfunction could be detected before it appeared at rest, 43 patients with severe aortic regurgitation were studied using radionuclide cineangiography during exercise. In 30 normal subjects, left ventricular ejection fraction increased during exercise (57 +/- 1 percent [mean +/- standard error] at rest, 71 +/- 2 percent during exercise, P less than 0.001). In contrast, among 21 symptomatic patients, ejection fraction was normal at rest in 14 patients (average 47 +/- 2 percent) but normal during exercise in only one patient (average 38 +/- 2 percent, P less than 0.001). Ejection fraction was normal at rest in 21 of 22 asymptomatic patients (average 62 +/- 2 percent) but was normal during exercise in only 13 (average 57 +/- 3 percent, P less than 0.001). Thus, exericse-induced left ventricular dysfunction can precede symptoms and dysfunction at rest. Radionuclide assessment of left ventricular function during exercise may prove valuable in sequentially following the state of left ventricular function in patients before the onset of symptoms or of irreversible left ventricular failure.

Effect of nitroglycerin on exercise-induced abnormalities of left ventricular regional function and ejection fraction in coronary artery disease. Assessment by radionuclide clineagiography in symptomatic and asymptomatic patients.

The effects of nitroglycerin (TNG) on exercise-induced abnormalities of left ventricular wall motion and ejection fraction are unknown in symptomatic and asymptomatic patients with coronary artery disease (CAD). In the present investigation radionuclide cineangiographic studies were performed in 47 patients with CAD (14 without angina during exercise) and in 25 normal subjects. All CAD patients, including those without symptoms, demonstrated regional wall motion abnormalities during exercise. In all patients, ejection fraction (EF) also responded abnormally to exercise: EF decreased from 48% at rest to 36% during exercise (P less than 0.001). EF increased in all normal subjects from an average of 58% at rest to 71% during exercise (P less than 0.001). In all CAD patients TNG reduced exercise-induced regional wall abnormalities and increased EF attained during exercise from an average of 36 to 48% (P less than 0.001). EF in normal subjects was unchanged by TNG. Thus, exercise can cause abnormalities in left ventricular regional function and ejection fraction in patients with or without symptoms; these abnormalities can be mitigated by prophylactic TNG.