Noninvasive quantification of regional myocardial blood flow and ammonia extraction fraction using nitrogen-13 ammonia and positron emission tomography

This report describes the theoretical basis and a method to quantitate regional myocardial blood flow (RMBF) and ammonia extraction fraction (E) in man, noninvasively, with N-13 ammonia and positron emission tomography (PET). Two patients with hypertrophic cardiomyopathy, whose left ventricular (LV) walls were markedly thick, were employed in this study to avoid partial volume effects and cross contamination between LV walls and blood pool. RMBF and E were calculated from time-activity curves of myocardial tissue and left atrium derived from serial 6-second PET images of the heart. The time-activity curve of left atrium was used as an arterial input function. The results were RMBF = 67 +/- 4 ml/min/100 g, E = 80 +/- 13% and 65 +/- 10 ml/min/100 g, 81 +/- 16% for each patient. The validity of the present method was discussed.     

Impaired myocardial blood flow reserve in subjects with metabolic syndrome analyzed using positron emission tomography and N-13 labeled ammonia

Purpose

Coronary vasomotor response might be impaired in metabolic syndrome (MS); however, the precise abnormality has not been elucidated. The aim of this study was to assess coronary-vasomotor response in MS subjects using N-13 labeled ammonia and positron emission tomography.

Methods and Results

Myocardial blood flow (MBF) was measured at rest and during adenosine infusion in MS subjects (n?=?13, MS group) with no definite evidence of heart disease and in subjects without MS (n?=?14, non-MS group). Coronary vascular resistance (CVR) was calculated by dividing the mean aortic blood pressure by MBF. Myocardial blood flow reserve (MFR) was calculated as the ratio of the MBF during adenosine infusion to that during rest. Blood chemical parameters were measured to evaluate their relationship with MFR. During adenosine infusion, MBF was lower (p?=?0.0085) and CVR higher (p?=?0.0128) in the MS group than in the non-MS group and MFR was significantly lower in the MS group than in the non-MS group (2.13?±?0.99 vs. 3.38?±?0.95, p?=?0.0027). Multivariate analysis demonstrated that the homeostasis model assessment-insulin resistance (p?<?0.05) and the presence of hypertension (p?<?0.05) were independent determinants of MFR.

Conclusions

The results indicate that MFR was impaired in MS subjects, suggesting that an abnormal coronary microvascular response occurred in these subjects. This abnormality may have been partially due to insulin resistance and hypertension.     

Left atrial versus left ventricular input function for quantification of the myocardial blood flow with nitrogen-13 ammonia and positron emission tomography

Flow quantitation with nitrogen-13 ammonia (¹³NH₃) and positron emission tomography (PET) is dependent on an accurate blood time-activity curve. This is conveniently derived from the PET images by drawing a region of interest in the left ventricular cavity. The blood time-activity curve obtained in this way, however, may contain spillover from the myocardial wall. The purpose of this study was to analyse the effect of wall to blood pool spillover. Additionally, we analysed the application of a left atrial input function. Using computer simulations, we investigated the effect of spillover from the myocardial wall to the left ventricular input function and the effect of time delay on the left ventricular input function. An oxygen-15 carbon monoxide PET study of seven normal volunteers was used to investigate possible recovery issues regarding the left atrial input function. Finally, ¹³NH₃ studies of 31 normal volunteers during rest and dipyridamole stimulation were analysed using either a left atrial or a left ventricular input function. The simulation studies showed that myocardial wall to blood pool spillover causes a considerable underestimation of the regional blood flow values in hyperaemic flow studies. Neither time delay nor recovery issues prevent flow quantitation with a left atrial input function. The ¹³NH₃ studies revealed no significant difference between the resting blood flow values, whereas the hyperaemic blood flow values were underestimated by 8% (P<0.01) on average (up to 40% individually) when using a left ventricular input function compared with a left atrial input function. Spillover of activity from the left ventricular wall to the blood time-activity curve is of importance in hyperaemic flow studies using ¹³NH₃. Application of a left atrial input function is a possible solution to these issues.An abstract of this paper was presented at the Society of Nuclear Medicine meeting in San Antonio, 1997.     

Interobserver and interstudy variability of myocardial blood flow and flow-reserve measurements with nitrogen 13 ammonia-labeled positron emission tomography

Background  

Experimental studies have shown that positron emission tomography (PET) with ¹³N-labeled ammonia provides accurate quantification of regional myocardial blood flow (MBF) under rest and stress conditions. To establish the clinical utility of this method, the interobserver variability and the temporal variability of serial measurements of blood flow and coronary flow reserve (CFR) must be known. This study investigated the interobserver and temporal reproducibility of ¹³N-labeled PET for measurement of MBF and CFR.     

Oestrogen increases myocardial blood flow in men: assessment by 13N-ammonia positron emission tomography

OBJECTIVES: Oestrogen has been shown to increase nitric oxide-mediated vasodilatation and modulate sympathetic tone in postmenopausal women. We investigated the acute effects of oestrogen on the coronary microcirculation in men. METHODS: Myocardial blood flow was quantified using N-ammonia positron emission tomography before and 20 min after an intravenous administration of conjugated oestrogen (10 mg) in nine healthy men. RESULTS: There were no significant changes in either systemic blood pressure or heart rate before and after oestrogen infusion. However, myocardial blood flow was increased by oestrogen from 0.88 +/-0.06 to 1.05+/-0.09 ml x g x min (P<0.05). Although serum levels of nitrite/nitrate (end products of nitric oxide) were not increased, circulating norepinephrine (noradrenaline) levels were decreased after the administration of oestrogen from 401+/-114 to 346+/-112 pg x ml (P<0.01). A significant negative correlation was found between myocardial blood flow and plasma norepinephrine levels (r=-0.67, P<0.05). CONCLUSIONS: A single administration of oestrogen enhanced myocardial circulation in healthy men. The oestrogen-induced increase in myocardial blood flow may be due to direct effects on the coronary circulation or through the modulation of norepinephrine levels, rather than the production of nitric oxide.     

Quantitation of the regional blood flow in the interventricular septum using positron emission tomography and nitrogen-13 ammonia

The purpose of the present study was to evaluate the effect of spillover of activity from the right ventricle (RV) on quantitation of the regional myocardial blood flow in the septum. Thirty-one healthy volunteers, 31 patients with ischemic heart disease, 7 patients with severe congestive heart failure, and 6 heart transplant patients underwent positron emission tomography (PET) with nitrogen-13 ammonia. Quantitation of the regional myocardial blood flow in the septum was performed using both a conventional two-compartment model and a previously validated two-compartment model taking RV spillover into account. Unaccounted RV spillover resulted in significant underestimation of the regional myocardial blood flow in the septum. The amount of underestimation was primarily dependent on the magnitude of spillover and the dispersion between the right and the left ventricular input functions. In healthy volunteers, the flow error was small but significant: on average 6% (range 5%-29%, P<0.00001), compared with 27% (range 0%-88%, P<0.002) in the group of patients with severe congestive heart failure, who had the most considerable amount of RV spillover. In the group of patients with ischemic heart disease and the group of heart transplant patients the flow errors were 10% (range 0%-55%, P<0.00001) and 6% (range 1%-19%, P<0.01), respectively. It is concluded that flow quantitation in the septum is significantly affected by RV spillover, resulting in a considerable underestimation of the septal blood flow unless correction is performed.     

Estimation of intersubject variability of cerebral blood flow measurements using MRI and positron emission tomography

Purpose:

To investigate the within and between subject variability of quantitative cerebral blood flow (CBF) measurements in normal subjects using various MRI techniques and positron emission tomography (PET).

Materials and Methods:

Repeated CBF measurements were performed in 17 healthy, young subjects using three different MRI techniques: arterial spin labeling (ASL), dynamic contrast enhanced T1 weighted perfusion MRI (DCE) and phase contrast mapping (PCM). All MRI measurements were performed within the same session. In 10 of the subjects repeated CBF measurements by ¹⁵O labeled water PET had recently been performed. A mixed linear model was used to estimate between subject (CV_betw) and within subject (CV_with) coefficients of variation.

Results:

Mean global CBF, CV_betw and CV_with using each of the four methods were for PCM 65.2 mL/100 g/min, 17.4% and 7.4%, for ASL 37.1 mL/100 g/min, 16.2% and 4.8%, for DCE 43.0 mL/100 g/min, 20.0%, 15.1% and for PET 41.9 mL/100 g/min, 16.5% and 11.9%, respectively. Only for DCE and PCM a significant positive correlation between measurements was demonstrated.

Conclusion:

These findings confirm large between subject variability in CBF measurements, but suggest also that in healthy subjects a subject‐method interaction is a possible source of between subject variability and of method differences. J. Magn. Reson. Imaging 2012;35:1290–1299. © 2012 Wiley Periodicals, Inc.     

Imaging of the hepatocellular carcinoma using dynamic positron emission tomography with nitrogen-13 ammonia

Dynamic PET using [13N]ammonia was performed in patients with primary hepatocellular carcinoma (hepatoma). All the tumors started to show remarkable accumulation of radioactivity from a very early period (within 150 sec after the radionuclide injection), whereas the radionuclide was more gradually accumulated in the liver. Central necroses of the tumors were visualized as low radioactivity areas. Daughter nodules of less than 2 cm were also visualized. This dynamic PET study is a valuable technique for the detection of the hepatoma.     

Changes in human cerebral blood flow and myocardial blood flow during mental stress measured by dual positron emission tomography

Mental stress causes a substantial sympathetic response, thus increasing myocardial blood flow (MBF). However, the effects of mental stress on global CBF have not been elucidated. In this study, changes in CBF and MBF in relation to mental stress were measured by a dual positron emission tomography system that can measure CBF and MBF simultaneously. CBF and MBF were measured in 10 healthy men with O-15 labeled water at rest (baseline) and during the performance of a mental task that required subtraction of 7s serially from a four-digit number. Baseline global CBF and values obtained during the mental activity were 0.42 +/- 0.05 and 0.45 +/- 0.06 ml/ml/min (mean +/- SD), respectively. Baseline MBF and values obtained during mental activity were 0.61 +/- 0.12 and 1.09 +/- 0.58 ml/ml/min, respectively. Percent changes in CBF and MBF during mental stress were 6 +/- 11% and 78 +/- 73%, respectively. No significant difference was observed in PaCO2 level between the mental stress and baseline conditions. MBF, blood pressure, heart rate, and plasma concentrations of adrenaline and noradrenaline increased significantly during mental stress. Sympathetic stimulation is reported to cause cerebral vasoconstriction and reduce CBF in animals. Although such a sympathetic response was observed in relation to mental stress, no significant change in CBF was observed in our subjects.     

Measurement of absolute bone blood flow by positron emission tomography

A method of measuring bone blood flow has been developed using ¹⁸F sodium fluoride and positron emission tomography. The blood flow levels are in line with those obtained experimentally from microsphere embolisation. This investigative method could be applied to elucidate a number of clinical questions involving bone perfusion.     

Quantitative measurement of regional myocardial blood flow in patients with coronary artery disease by intravenous injection of 13N-ammonia in positron emission tomography

Measurement of myocardial blood flow with 13N-ammonia, a technique previously employed successfully in animal experiments, was introduced into clinical use to study patients with coronary artery disease. This advance has become possible by the development of a high resolution gated scan positron emission tomographic (PET) scanner equipped with a real time decay correction mechanism, HEADTOME-IV. The information obtainable includes myocardial size and wall motion as well as the absolute quantity of blood flow in various myocardial regions. The technique is simple but requires continuous arterial blood withdrawal for calculation of the arterial input function time integral. The alternative to this technique, i.e. the computation of intra left ventricular blood pool activity by PET is also discussed.     

Ventilation imaging with positron emission tomography and nitrogen 13

Ventilation imaging using positron emission tomography (PET) and highly insoluble nitrogen 13 (N-13) was performed in one healthy volunteer and ten patients. These PET studies showed the three-dimensional distribution of ventilation abnormalities, such as peripheral air trapping, which xenon 133 studies had not revealed. Therefore, PET with N-13 may help elucidate more precisely the distribution and nature of ventilation abnormalities in various diseases.     

Assessment of pancreatic blood flow with positron emission tomography and oxygen-15 water

Dynamic positron emission tomography (PET) was performed following an intravenous bolus injection of 15O-water for the assessment of regional pancreatic blood flow in 4 normal volunteers and 11 patients with pancreatic cancer. The regional pancreatic blood flow index (PFI) was calculated by the autoradiographic method assuming the time-activity curves of the aorta as an input function. The mean PFI value was 0.514 +/- 0.098 in the normal pancreas but it was decreased in pancreatic cancer (0.249 +/- 0.076) (p less than 0.01), with a concomitant decrease in the pancreatic region distal to the tumor. On the other hand, in cases with body or tail cancer, the part proximal to the tumor (nontumorous head region) had a similar PFI value (0.554 +/- 0.211) to that of normal cases. Thus, a PET study with 15O-water permits quantitative assessment of pancreatic blood flow which decreased in both pancreatic cancer and concomitant obstructive pancreatitis distal to the tumor.     

Quantitative measurement of regional myocardial blood flow in patients with coronary artery disease by intravenous injection of13N-ammonia in positron emission tomography

Measurement of myocardial blood flow with¹³N-ammonia, a technique previously employed sucessfully in animal experiments, was introduced into clinical use to study patients with coronary artery disease. This advance has become possible by the development of a high resultion gated scan positron emission tomographic (PET) scanner equipped with a real time decay correction mechanism, HEADTOME-IV. The information obtainable includes myocardial size and wall motion as well as the absolute quantity of blood flow in various myocardial regions. The technique is simple but requires continuous arterial blood withdrawal for calculation of the arterial input function time integral. The alternative to this technique, i.e. the computation of intra left ventricular blood pool activity by PET is also discussed.     

Value and limitation of stress thallium-201 single photon emission computed tomography: comparison with nitrogen-13 ammonia positron tomography

The diagnostic value of exercise 201Tl single photon emission computed tomography (SPECT) for assessing coronary artery disease (CAD) was comparatively evaluated with exercise [13N] ammonia positron emission tomography (PET). Fifty-one patients underwent both stress-delayed SPECT imaging using a rotational gamma camera and stress-rest PET imaging using a high resolution PET camera. Of 48 CAD patients, SPECT showed abnormal perfusion in 46 patients (96%), while PET detected perfusion abnormalities in 47 (98%). The sensitivity for detecting disease in individual coronary arteries (greater than 50% stenosis) was also similar for SPECT (81%) and PET (88%). When their interpretations were classified as normal, transient defect, and fixed defect in 765 myocardial segments, SPECT and PET findings were concordant in 606 segments (79%). However, 66 segments showed a fixed defect by SPECT but a transient defect by PET, whereas there were only nine segments showing a transient defect by SPECT and a fixed defect by PET. PET identified transient defects in 34% of the myocardial segments showing a fixed defect by SPECT. We conclude that both stress SPECT and PET showed high and similar sensitivities for detecting CAD and individual stenosed vessels. Since stress-delayed SPECT with single tracer injection detected fewer transient defects, it may underestimate the presence of myocardial ischemia, compared with high resolution PET imaging with two tracer injections.     

Nitrogen-13 ammonia cardiac positron emission tomography in mice: effects of clonidine-induced changes in cardiac work on myocardial perfusion

We explored the feasibility of imaging myocardial perfusion and of demonstrating the flow changes in response to reduction of cardiac work non-invasively in anesthetized mice using high spatial resolution, dedicated small-animal positron emission tomography (microPET). In 31 C57BL/6 mice anesthetized with pentobarbital or isoflurane, ¹³N-ammonia was injected intravenously and images were recorded with microPET from 4 to 20 min. Fifteen mice (group 1) were studied consecutively at baseline (BL) and after reduction of heart rate (HR) with intraperitoneal injection of clonidine (CLN) to investigate effects of CLN-induced reduction of cardiac work on myocardial ¹³N-ammonia uptake. Eight mice (group 2) were imaged repeatedly at BL and eight mice (group 3) twice after CLN to examine reproducibility. Total myocardial ¹³N-ammonia accumulation was determined from the transaxial images and normalized for injected dose (%ID). HR was 412±97 beats/min at BL and 212±44 beats/min after CLN (P<0.0001). In group 1, the %ID significantly decreased from 1.50%±0.27% at BL to 1.29%±0.28% after CLN (P<0.0001). In groups 2 and 3, reproducibility of %ID was good (y=0.96x+0.105, SEE=0.212%, r ²=0.749, P<0.0001). In conclusion, ¹³N-ammonia microPET imaging demonstrated non-invasively a reduction of myocardial perfusion induced by clonidine in mice. We believe this study is of importance as the first report on myocardial perfusion imaging and flow validation in in vivo mouse hearts with a left ventricular size of only 5 mm using ¹³N-ammonia and PET. MicroPET will aid in elucidating cardiac pathophysiology in transgenic mice and monitoring effects of gene therapies on myocardial perfusion.     

Development of myocardial perfusion tracers for positron emission tomography

Six positron-emitting cations were investigated as possible perfusion tracers: [13N]NH4, 38K, 51Mn, 52mMn, 81Rb, and 82Rb. Aspects of the production of the radionuclides and their separations from the irradiated target materials were addressed. The thick target, saturated yields of several nuclear reactions leading to these radionuclides were studied theoretically and experimentally in the energy range 6-10 MeV. A figure-of-merit describing the production aspects of each tracer was calculated, and tomographic imaging results in normal human subjects were reported.