Absolute quantification of myocardial blood flow with 13N-ammonia and 3-dimensional PET.

The aim of this study was to compare 2-dimensional (2D) and 3-dimensional (3D) dynamic PET for the absolute quantification of myocardial blood flow (MBF) with (13)N-ammonia ((13)N-NH(3)). METHODS: 2D and 3D MBF measurements were collected from 21 patients undergoing cardiac evaluation at rest (n = 14) and during standard adenosine stress (n = 7). A lutetium yttrium oxyorthosilicate-based PET/CT system with retractable septa, enabling the sequential acquisition of 2D and 3D images within the same patient and study, was used. All 2D studies were performed by injecting 700-900 MBq of (13)N-NH(3). For 14 patients, 3D studies were performed with the same injected (13)N-NH(3) dose as that used in 2D studies. For the remaining 7 patients, 3D images were acquired with a lower dose of (13)N-NH(3), that is, 500 MBq. 2D images reconstructed by use of filtered backprojection (FBP) provided the reference standard for MBF measurements. 3D images were reconstructed by use of Fourier rebinning (FORE) with FBP (FORE-FBP), FORE with ordered-subsets expectation maximization (FORE-OSEM), and a reprojection algorithm (RP). RESULTS: Global MBF measurements derived from 3D PET with FORE-FBP (r = 0.97), FORE-OSEM (r = 0.97), and RP (r = 0.97) were well correlated with those derived from 2D FBP (all Ps < 0.0001). The mean +/- SD differences in global MBF measurements between 3D FORE-FBP and 2D FBP and between 3D FORE-OSEM and 2D FBP were 0.01 +/- 0.14 and 0.01 +/- 0.15 mL/min/g, respectively. The mean +/- SD difference in global MBF measurements between 3D RP and 2D FBP was 0.00 +/- 0.16 mL/min/g. The best correlation between 2D PET and 3D PET performed with the lower injected activity was found for the 3D FORE-FBP reconstruction algorithm (r = 0.95, P < 0.001). CONCLUSION: For this scanner type, quantitative measurements of MBF with 3D PET and (13)N-NH(3) were in excellent agreement with those obtained with the 2D technique, even when a lower activity was injected.     

Quantification of myocardial blood flow using 13N-ammonia and PET: comparison of tracer models.

Several tracer kinetic methods have been proposed for quantification of regional myocardial blood flow (MBF) with 13N-ammonia and PET. Merits and limitations specific to each approach, however, generally are not clear, because they have not been evaluated in the same experimental environment. Therefore, we compared six different commonly used methods (11 modifications) to characterize the accuracy of each approach. The methods included the two-parameter model (method 1), the modified two-parameter model (method 2), the four-parameter model (method 3), the graphical analysis (method 4), the first-pass extraction method (method 5) and the dose uptake index (DUI; method 6). METHODS: Eleven studies in four dogs, 16 studies in eight healthy human volunteers and 14 studies in seven patients were performed using 13N-ammonia and PET. MBF in dogs was varied with dipyridamole and coronary occlusions and was measured independently and simultaneously with microspheres. Volunteers and patients were studied at baseline and after dipyridamole. MBF and DUI were estimated using a time-activity curve (Qi[t]) derived from dynamic images and regions of interest (ROls) and using the six methods. DUI was defined as Qi(t = 2 min) x weight/dose. RESULTS: MBF estimated by methods 1-5 correlated well with microsphere MBF in dogs. MBF estimates by method 1 correlated well with those by methods 2, 4 and 5 and to a lesser degree with those by method 3 in both dog and human studies. DUI correlated poorly with MBF by microspheres and by methods 1-5 in both dog and human studies. MBF estimates by method 3 showed larger dispersion (SD/mean flow) and higher sensitivity to metabolites correction in arterial blood than those by methods 1, 2, 4 and 5. CONCLUSION: MBF can be measured accurately using 13N-ammonia PET and tracer kinetic methods. DUI is a poor indicator of MBF values. The results indicate that preference should be given to the two-parameter model, incorporating geometrical ROI representation (method 2) among the compartment models, and to the graphical analysis (method 4) among the noncompartmental approaches.     

Characterizing the normal range of myocardial blood flow with 82rubidium and 13N-ammonia PET imaging

Background

Diagnosis of coronary disease and microvascular dysfunction may be improved by comparing myocardial perfusion scans with a database defining the lower limit of normal myocardial blood flow and flow reserve (MFR). To maximize disease detection sensitivity, a small normal range is desirable. Both ¹³N-ammonia and ⁸²Rb tracers are used to quantify blood flow and MFR using positron emission tomography (PET). The goal of this study was to investigate the trade-off between noise and accuracy in both ⁸²Rb and ¹³N-ammonia normal databases formed using a net retention model.

Methods

Fourteen subjects with <5% risk of CAD underwent rest and stress ⁸²Rb and ¹³N-ammonia dynamic PET imaging in a randomized order within 2 weeks. Myocardial blood flow was quantified using a one-compartment model for ⁸²Rb, and a two-compartment model for ¹³N-ammonia. A simplified model was used to estimate tracer retention, with tracer-specific net extraction functions derived to obtain flow estimates.

Results

Normal variability of retention reserve was equivalent for both tracers (±15% globally, ±16% regionally) and was lower in comparison to compartment model results (P < .05). The two-compartment model for ¹³N-ammonia had the smallest normal range of global blood flow resulting in a lower limit of normal MFR = 2.2 (mean ? 2 SD).

Conclusion

These results suggest that the retention model may have higher sensitivity for detection and localization of abnormal flow and MFR using ⁸²Rb and ¹³N-ammonia, whereas the ¹³N-ammonia two-compartment model has higher precision for absolute flow quantification.     

Validation of an axially distributed model for quantification of myocardial blood flow using 13N-ammonia PET

Background

Estimation of myocardial blood flow (MBF) with cardiac PET is often performed with conventional compartmental models. In this study, we developed and evaluated a physiologically and anatomically realistic axially distributed model. Unlike compartmental models, this axially distributed approach models both the temporal and the spatial gradients in uptake and retention along the capillary.

Methods

We validated PET-derived flow estimates with microsphere studies in 19 (9 rest, 10 stress) studies in five dogs. The radiotracer, ¹³N-ammonia, was injected intravenously while microspheres were administered into the left atrium. A regional reduction in hyperemic flow was forced by an external occluder in five of the stress studies. The flow estimates from the axially distributed model were compared with estimates from conventional compartmental models.

Results

The mean difference between microspheres and the axially distributed blood flow estimates in each of the 17 segments was 0.03 mL/g/minute (95% CI [?0.05, 0.11]). The blood flow estimates were highly correlated with each regional microsphere value for the axially distributed model (y = 0.98x + 0.06 mL/g/minute; r = 0.74; P < .001), for the two-compartment (y = 0.64x + 0.34; r = 0.74; P < .001), and for three-compartment model (y = 0.69x + 0.54; r = 0.74; P < .001). The variance of the error of the estimates is higher with the axially distributed model than the compartmental models (1.7 [1.3, 2.1] times higher).

Conclusion

The proposed axially distributed model provided accurate regional estimates of MBF. The axially distributed model estimated blood flow with more accuracy, but less precision, than the evaluated compartmental models.     

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.     

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.     

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.     

PET心肌灌注显像测定心肌血流量及冠状动脉血流储备的研究进展

PET心肌灌注显像可绝对定量测定局部心肌血流量（MBF）和冠状动脉血流储备（CFR）。由于显像剂半衰期短,允许在短时间内重复进行PET心肌灌注显像,获得静息态、冷加压试验和药物负荷试验等不同状态下的MBF,进而评价冠状动脉血管内皮依赖性和非依赖性的CFR功能。在早期诊断冠心病,准确诊断冠状动脉多支病变,评价微血管病变,早期检测冠状动脉内皮细胞功能异常及CFR功能的异常,估测预后,帮助临床治疗方案的制定以及检测疗效等方面,PET心肌灌注显像有重要的临床价值。该文将介绍PET心肌灌注显像相关知识及其在心血管领域的主要应用。     

13N-NH3·H2O动物体内分布及临床应用

目的研究13N-NH3·H2O的临床前药理、PET显像方法及其在心肌显像中的应用.方法进行犬全身和动态心肌PET显像,测定13N-NH3·H2O在犬体内的分布,并对健康志愿者进行心肌PET显像.结果心肌PET显像发现,心脏和肺是首过器官,心肌摄取率最高.心肌摄取快而清除相对较慢,血、肝和肺的本底清除快,心脏影像清晰.注射13N-NH3·H2O后30 s,左右心室放射性达到峰值,1 min后开始下降,在4～20 min保持相对平稳的水平;左心室间壁和侧壁心肌在注射后10 s开始摄取,间壁摄取高于侧壁,2 min后侧壁摄取略高于间壁;肝和肺在第30 s摄取达峰值,此后急剧下降,5 min后摄取逐渐下降并维持在较低的水平,心/肝和心/肺比值均高于2.0.动物全身显像发现,13N-NH3·H2O主要分布在血液供应丰富的组织,主要经肾脏清除.动态心肌显像和注射13N-NH3·H2O 4～5 min后进行的静态显像可获得一致的心肌血流灌注图像.结论 13N-NH3*H2O有较高的心/肝和心/肺比值,灌注图像清晰,是理想的心肌血流灌注显像剂.     

Assessment of intra- and interobserver reproducibility of rest and cold pressor test-stimulated myocardial blood flow with <Superscript>13</Superscript>N-ammonia and PET

Purpose We investigated the intraobserver reproducibility of myocardial blood flow (MBF) measurements with PET at rest and during cold pressor test (CPT), and the interobserver agreement. Methods Twenty normal volunteers were studied. Using ¹³N-ammonia, MBF was measured at rest and during CPT and measurement was repeated in a 1-day session (short-term reproducibility; SR). After a follow-up of 2 weeks, MBF was measured again at rest and during CPT and compared with the initial baseline measurement (long-term reproducibility; LR). In addition, adenosine-induced hyperemic MBF increases were assessed. Results Assessment of the SR did not show a significant absolute difference in MBF at rest, MBF during CPT or the endothelium-related change in MBF from rest to CPT (ΔMBF) (0.09 ± 0.10, 0.11 ± 0.09, and 0.08 ± 0.05 ml/g/min; p = NS), and they were linearly correlated (r = 0.72, r = 0.76 and r = 0.84; p < 0.0001). Corresponding values for standard error of the estimate (SEE), as indicative for the range of MBF measurement error, were 0.14, 0.14, and 0.09 ml/g/min. The LR yielded relatively higher but non-significant absolute differences in the MBF at rest, MBF during CPT and ΔMBF (0.10 ± 0.10, 0.14 ± 0.10, and 0.19 ± 0.10 ml/g/min; p = NS), and paired MBFs significantly correlated (r = 0.75, r = 0.71, and r = 0.60; p < 0.001). Corresponding SEEs were 0.13, 0.15, and 0.16 ml/g/min. The interobserver analysis yielded a high correlation for MBF at rest, MBF during CPT, and hyperemic MBF (r = 0.96, SEE=0.04; r = 0.78, SEE=0.11; and r = 0.87, SEE=0.28; p < 0.0001, respectively), and also a good interobserver correlation for ΔMBF (r = 0.62, SEE=0.09; p < 0.003). Conclusion Short- and long-term MBF responses to CPT, as an index for endothelium-related coronary vasomotion, can be measured reproducibly with ¹³N-ammonia PET. In addition, the high interobserver reproducibility for repeat analysis of MBF values suggests the measurements to be largely operator independent. Thomas H. Schindler and Xiao-Li Zhang contributed equally to this paper.     

A fast nonlinear method for parametric imaging of myocardial perfusion by dynamic (13)N-ammonia PET.

A parametric image of myocardial perfusion (mL/min/g) is a quantitative image generated by fitting a tracer kinetic model to dynamic (13)N-ammonia PET data on a pixel-by-pixel basis. There are several methods for such parameter estimation problems, including weighted nonlinear regression (WNLR) and a fast linearizing method known as Patlak analysis. Previous work showed that sigmoidal networks can be used for parameter estimation of mono- and biexponential models. The method used in this study is a hybrid of WNLR and sigmoidal networks called nonlinear regression estimation (NRE). The purpose of the study is to compare NRE with WNLR and Patlak analysis for parametric imaging of perfusion in the canine heart by (13)N-ammonia PET. METHODS: A simulation study measured the statistical performance of NRE, WNLR, and Patlak analysis for a probabilistic model of time-activity curves. Four canine subjects were injected with 740 MBq (13)N-ammonia and scanned dynamically. Images were reconstructed with filtered backprojection and resliced into short-axis cuts. Parametric images of a single midventricular plane per subject were generated by NRE, WNLR, and Patlak analysis. Small regions of interest (ROIs) were drawn on each parametric image (8 ROIs per subject for a total of 32). RESULTS: For the simulation study, the median absolute value of the relative error for a perfusion value of 1.0 mL/min/g was 16.6% for NRE, 17.9% for WNLR, 19.5% for Patlak analysis, and 14.5% for an optimal WNLR method (computable by simulation only). All methods are unbiased conditioned on a wide range of perfusion values. For the canine studies, the least squares line fits comparing NRE (y) and Patlak analysis (z) with WNLR (x) for all 32 ROIs were y = 1.02x - 0.028 and z = 0.90x + 0.019, respectively. Both NRE and Patlak analysis generate 128 x 128 parametric images in seconds. CONCLUSION: The statistical performance of NRE is competitive with WNLR and superior to Patlak analysis for parametric imaging of myocardial perfusion. NRE is a fast nonlinear alternative to Patlak analysis and other fast linearizing methods for parametric imaging. NRE should be applicable to many other tracers and tracer kinetic models.     

Evaluation of the endothelial function in hypertensive patients with 13N-ammonia PET

Background

Essential hypertension is one of the main risk factors for the development of coronary artery disease (CAD). Hypertension causes endothelial dysfunction which is considered an early sign for the development of CAD. Positron emission tomography is a non-invasive imaging technique that measures myocardial blood flow (MBF), allowing us to identify patients with endothelial dysfunction.

Methods and Results

19 patients without comorbidities recently diagnosed hypertensive, as well as 21 healthy volunteers were studied. A three-phase (rest, cold pressor test, and adenosine-induced hyperemia) ¹³N-ammonia PET was performed, and MBF was measured. Endothelial-Dependent Vasodilation Index, ??MBF, and coronary flow reserve (CFR) were calculated for each patient. Hypertensive patients had a significantly higher systolic and diastolic blood pressures compared with the control group (134.6?±?11.7/86.4?±?10.6?mm?Hg and 106.0?±?11.8/71.4?±?6.6?mm?Hg, respectively, P?<?.001). The ENDEVI (1.28?±?0.26 vs 1.79?±?0.30, P?<?.001), the ??MBF (0.81?±?0.50 vs 0.25?±?0.21, P?<?.001) and the CFR (2.18?±?0.88 vs 3.17?±?0.68, P?=?.001) were significantly lower in the hypertensive patients compared to the control group, 84% of the former group had endothelial dysfunction i.e., ENDEVI?<?1.5 and 58% had vasomotor abnormalities, i.e., CFR?<?2.5.

Conclusions

In this study, we showed that recently diagnosed hypertensive patients have coronary endothelial dysfunction and vasomotor disturbances which are early signs for the development of CAD.     

Coronary calcium score scans for attenuation correction of quantitative PET/CT 13N-ammonia myocardial perfusion imaging

Purpose  

The aim of this study was to evaluate whether ECG-triggered coronary calcium scoring (CCS) scans can be used for attenuation correction (AC) to quantify myocardial blood flow (MBF) and coronary flow reserve (CFR) assessed by PET/CT with ¹³N-ammonia.     

Measurement of myocardial blood flow with PET using 1-11C-acetate.

11C-acetate has been used extensively for the noninvasive assessment of myocardial oxygen consumption and viability with PET. The use of early uptake of acetate by the heart to measure myocardial perfusion has been proposed. This study evaluated the application of 11C-acetate for absolute measurement of myocardial blood flow using a simple compartmental model that does not require blood sampling. METHODS: Eight healthy volunteers and 13 subjects with concentric left ventricular hypertrophy were studied under resting conditions with both 11Cacetate and 15O-water. Myocardial blood flow with 11C-acetate was obtained by fitting the first 3 min of the blood and tissue tracer activity curves to a two-compartment model. Flows obtained were compared with a validated approach using 15O-water. RESULTS: In healthy volunteers, regional myocardial perfusion at rest estimated with 11C-acetate was comparable with values obtained with 15O-water (1.06 +/- 0.25 and 0.96 +/- 0.12 mL/g/min, respectively). Perfusion in subjects with left ventricular hypertrophy was also comparable if the recovery coefficient (FMM) used was corrected for ventricular mass. If a fixed FMM was used, flow was greatly overestimated. FMM could be estimated from left ventricular mass (FMM = 0.46 + 0.002 x mass, r = 0.86, P < 0.0001). CONCLUSION: The results of this study suggest that 11C-acetate can be applied to quantitatively estimate myocardial perfusion under resting conditions using a two-compartment model without the need for blood sampling, provided that an appropriate FMM is chosen. This approach should increase the usefulness of this tracer and obviate administration of a separate tracer to independently measure perfusion.     

13N-NH3 PET脑血流灌注显像诊断缺血性脑血管病变

目的探讨13N-NH3 PET脑血流灌注显像对缺血性脑血管病变的诊断价值.方法对5例健康志愿者,20例缺血性脑血管病变患者静脉注射13N-NH3 740～925 MBq,3～5 min后行T+E 二维方式脑血流灌注显像.图像分析采用视图分析和脑皮质标准摄取值(SUV)半定量分析,镜像比值法测量左/右两侧相应脑区SUV比值(SUV_r).其中9例短暂性脑缺血发作(TIA)行乙酰唑胺(ACZ)脑负荷试验,观察口服ACZ前后脑区影像、SUV和SUV_r变化.结果正常左/右脑区平均SUV_r为0.99±0.15,患侧/健侧(L/N)比值<0.85为稀疏区,<0.7为缺损区.13例TIA 13 N-NH3 PET显像示7例阳性,8例行MRI 2例阳性,6例行CT 1例阳性.7例TIA13N-NH3 PET显像阳性患者发现29个缺血灶,平均SUV 1.78±0.41,低于对照组(2.51±0.52,t=8.78,P<0.05).脑梗死(CI)患者共发现13个梗死灶,平均SUV 1.05±0.23,明显低于对照组和TIA组(t=5.9,P<0.001).9例ACZ脑负荷试验,缺血灶由静息29处增至35处,检出率提高17.1%;TIA阳性率由53.8%提高到62.5%;静息平均SUV_r为0.87±0.11,口服ACZ后减低至0.77±0.07(t=6.47,P<0.05).结论 13N-NH3PET脑灌注显像安全、无创伤性,灵敏度高且病灶定位准确.口服ACZ脑负荷试验安全、简便、可靠,对评价局部脑血流储备功能有重要价值.