Division of Nuclear Medicine, The Mount Sinai Medical Centre, New York, NY, USA

Abstract

Background

We evaluated the repeatability of the calculation of myocardial blood flow (MBF) at rest and pharmacological stress, and calculated the coronary flow reserve (CFR) utilizing ^{82}Rb PET imaging. The aim of the research was to prove high repeatability for global MBF and CFR values and good repeatability for regional MBF and CFR values. The results will have significant impact on cardiac PET imaging in terms of making it more affordable and increasing its use.

Methods

12 normal volunteers were imaged at rest and during pharmacological stress, with 2220 MBq of ^{82}Rb each. A GE Advance PET system was used to acquire dynamic 50-frame studies. MBF was calculated with a 2-compartmental model using a modified PMOD program (PMOD; University Hospital Zurich, Zurich, Switzerland). Two differential equations, describing a 2-compartmental model, were solved by numerical integration and using Levenberg-Marquardt's method for fitting data. The PMOD program defines 16 standard segments and calculates myocardial flow for each segment, as well as average septal, anterior, lateral, inferior and global flow. Repeatability was evaluated according to the method of Bland and Altman.

Results

Global rest and stress MBF, as well as global CFR, showed very good repeatability. No significant differences were found between the paired resting global MBF (0.63 ± 0.13 vs. 0.64 ± 0.13 mL/min/g; mean difference, -1.0% ± 2.6%) and the stress global MBF (1.37 ± 0.23 vs. 1.37 ± 0.24; mean difference, 0.1% ± 2.3%). Global CFR was highly reproducible (2.25 ± 0.56 vs. 2.22 ± 0.54,

Conclusion

The results of the study show that software calculation of MBF and CFR with ^{82}Rb myocardial PET imaging is highly repeatable for global values and has good repeatability for regional values.

Background

In noninvasive evaluation of coronary heart disease, cardiac positron emission tomography (PET) has been shown to have high sensitivity and specificity for assessing myocardial perfusion and metabolism

The three most widely used PET perfusion tracers are ^{13}NH_{3}, ^{15}O-labeled water (H_{2}^{15}O), and the cationic potassium analog ^{82}Rb ^{82}Rb is generator-produced and does not require an on site cyclotron. The use of ^{82}Rb for PET myocardial perfusion imaging is expected to increase in the near future due to widespread availability of this tracer and the dramatic increase in the number of PET scanners that has occurred over the last 10 years. However, there are several issues related to quantification of regional MBF using ^{82}Rb. First, cardiac images obtained with ^{82}Rb tend to be count-poor due to the short half-life of ^{82}Rb (75 s). Second, the high positron energy (3.15 MeV) results in decreased resolution compared to other PET tracers. Third, there is heavy dependence of myocardial extraction of this tracer on the prevailing flow rate and myocardial metabolic state

The low-count imaging has recently been addressed with the higher sensitivity 3D mode of PET imaging evaluated for myocardial perfusion ^{82}Rb PET imaging

In this paper, we wish to evaluate the repeatability of the PMOD software approach for MBF measurements at rest and pharmacological stress, and calculation of CFR utilizing 2D ^{82}Rb PET imaging.

Methods

A GE ADVANCE (General Electric Medical Systems, Milwaukee, WI) system was used for all acquisitions. The system has 18 detector rings and 12,096 bismuth germanate (BGO) 4 × 8 × 30 mm crystals. In the 2D acquisition mode, which was used in this study, the system uses a tungsten collimator 1 × 120 mm in size. The axial field of view is 15.2 cm covered by 35 image planes. The axial sampling interval is 4.25 mm. The transaxial field of view is 55.0 cm. The coincidence window width is 12.5 ns and the energy window is in a range of 300–650 keV. All 2D acquisitions were performed in high sensitivity mode. The images were reconstructed using a filtered backprojection reconstruction method and a Hanning smoothing filter with a 0.5 cy/cm cutoff. The matrix size was 128 × 128 and the pixel size was 4.29 mm. Attenuation correction using an 8-min transmission scan was applied in all studies. In addition, standard corrections for randoms and scatter provided by the vendor were applied. 12 normal volunteers, mean age 35 ± 9.5, were imaged at rest and pharmacological stress, following an i.v. injection of 2220 MBq of ^{82}Rb each. Pharmacologic stress was achieved with a standard dose of adenosine (140 mg/kg/min infused over 6 min) or dipyridamole (0.56 mg/kg infused over 4 min). For each dynamic study, 50 frames were acquired. The time per frame was 5 sec between 0–3 min, 15 sec between 3–5 min and 30 sec between 5–8 min. The institutional review board granted ethical approval for the study and each subject signed a consent form.

In the spring of 2004, we collaborated with PMOD developers from University Hospital of Zurich, Switzerland ^{82}Rb model for regional MBF calculation. The PMOD software is developed primarily for image quantification and kinetic modelling of PET data. PMOD has been written in Java 2 and is currently offered under Windows, Linux and MacOS X. As data can be read and written in DICOM, as well as some other formats (GE PET format, Advance, etc.), it can be applied on different PET data and on different computer platforms. We tested a beta version of the PMOD ^{82}Rb model, which we used to compare with our results. Our results were obtained using Herrero's 2-compartmental model ^{15}O-labeled water PET studies _{d}) was fixed at 0.75 mL/mL

Short-axis slices

**Short-axis slices**. A) Summed dynamic images were used to reorient images and obtain short-axis slices which B) were used to determine LV ROI and LV blood pool ROI. The ROIs were then used in the original dynamic study in order to create time-activity-curves (TAC).

Time activity curves (TACs)

**Time activity curves (TACs)**. PMOD (2.65) creates TACs from different areas of the myocardium as well as from the LV cavity (light blue) which is used as an input curve in the kinetic modelling. In total, 16 LV segments TAC are created in addition to global myocardial curve (shown in red). The apical-anterior segment TAC is shown in light green. The TAC derived from the RV VOI (not shown here) was used for blood spillover correction during kinetic modelling.

Results of MBF calculations

**Results of MBF calculations**. Result of the PMOD (version 2.65) ^{82}Rb model program. In addition to flow, it calculates 2-compartmental constants, k1, k2, cross-talk from blood pool to tissue (FBM) and respective standard deviations for 16 standard segments as well as average septal, anterior, lateral, inferior and global area.

The Passing & Bablok regression scatter diagrams

Results

The average of all 12 subjects, regional and global MBF values at rest and stress are given in Table

Global flow results

**Global flow results**. The Passing & Bablok regression scatter diagram with the regression line (solid line), the confidence interval for the regression line (dashed lines) and identity line (x = y, dotted line), for global MBF values at (A) rest (n = 12, r = 0.99) and (B) stress (n = 12, r = 0.99) for two different runs. Altman-Bland plots for rest (C) and stress (D) global myocardial blood flow, respectively.

Regional flow results

**Regional flow results**. The Passing & Bablok regression scatter diagram with the regression line (solid line), the confidence interval for the regression line (dashed lines) and identity line (x = y, dotted line), for regional apex-septal MBF, at (A) rest (n = 12, r = 0.99) and (B) stress (n = 12, r = 0.99) for two different runs. Altman-Bland plots for the same regional apex-septal MBF, for rest (C) and stress (D), respectively short-axis slices profile ROI.

Rest MBF (mL/min/g) regional and global values averaged for 12 healthy subjects, for two processing runs.

Segment

MBF1 (mL/min/g)

MBF2 (mL/min/g)

reproducibility (mL/min/g)

reproducibility%

SEPTUM

0.46

0.46

0.019

4.06

APEX_Sep

0.47

0.47

0.024

5.06

MID_Sep-I

0.49

0.49

0.030

6.03

MID_Sep-A

0.45

0.45

0.012

2.62

BASAL_Sep-I

0.45

0.46

0.025

5.54

BASAL_Sep-A

0.44

0.43

0.089

20.56

ANTERIOR

0.64

0.64

0.033

5.15

APEX_Ant

0.64

0.65

0.030

4.61

MID_Ant

0.63

0.63

0.034

5.42

BASAL_Ant

0.66

0.66

0.038

5.77

LATERAL

0.68

0.70

0.090

13.12

APEX_Lat

0.71

0.73

0.063

8.80

MID_Lat

0.67

0.70

0.191

27.91

BASAL_Lat

0.68

0.68

0.051

7.46

INFERIOR

0.79

0.80

0.057

7.24

APEX_Inf

0.81

0.83

0.115

14.00

MID_Inf-P

0.82

0.84

0.062

7.44

MID_Inf-I

0.90

0.91

0.053

5.85

BASAL_Inf-P

0.76

0.77

0.052

6.83

BASAL_Inf-I

0.70

0.71

0.047

6.64

GLOBAL

0.63

0.64

0.033

5.18

Stress MBF(mL/min/g) regional and global values averaged for 12 healthy subjects, for two processing runs.

Segment

MBF1 (mL/min/g)

MBF2 (mL/min/g)

reproducibility (mL/min/g)

reproducibility%

SEPTUM

0.97

0.97

0.029

2.93

APEX_Sep

1.01

1.01

0.038

3.74

MID_Sep-I

1.15

1.15

0.035

3.05

MID_Sep-A

0.96

0.96

0.042

4.33

BASAL_Sep-I

0.98

0.98

0.046

4.65

BASAL_Sep-A

0.82

0.82

0.046

5.62

ANTERIOR

1.31

1.31

0.125

9.55

APEX_Ant

1.24

1.23

0.057

4.63

MID_Ant

1.30

1.29

0.093

7.20

BASAL_Ant

1.38

1.38

0.214

15.49

LATERAL

1.39

1.39

0.089

6.41

APEX_Lat

1.50

1.50

0.093

6.21

MID_Lat

1.33

1.33

0.085

6.35

BASAL_Lat

1.36

1.35

0.092

6.84

INFERIOR

1.92

1.91

0.087

4.54

APEX_Inf

2.15

2.15

0.114

5.32

MID_Inf-P

1.97

1.95

0.117

5.94

MID_Inf-I

1.88

1.85

0.188

10.08

BASAL_Inf-P

1.58

1.58

0.094

5.94

BASAL_Inf-I

1.72

1.72

0.107

6.20

GLOBAL

1.37

1.37

0.062

4.54

The resting global MBF values for the first and the second run were 0.63 ± 0.13 and 0.64 ± 0.13 mL/min/g, respectively, with a mean difference of -1% ± 2.6% (P = not statistically significant [NS]). The repeatability coefficient was 0.033 mL/min/g (5.18% of the mean). The pharmacological induced stress global MBF values were significantly higher, 1.37 ± 0.23 mL/min/g for the first run and 1.37 ± 0.24 mL/min/g for the second run, with a mean difference 0.1% ± 2.3% (P = NS) and a repeatability coefficient of 0.062 mL/min/g (4.54% of the mean).

The average per sector repeatability coefficients for rest MBF were 0.056 mL/min/g (8.5% of the mean) and stress MBF 0.089 mL/min/g (6.3% of the mean), which shows excellent repeatability for a majority of the segments. The range for the rest regional MBF values was from a very good mid_septum_A reproducibility of 0.012 mL/min/g (2.62% of the mean) to a marginal mid_lateral 0.191 mL/min/g (27.91% of the mean). The regional stress MBF values ranged from a very good mid_septum_I reproducibility of 0.035 mL/min/g (3.05% of the mean) to 0.214 mL/min/g (15.49% of the mean) basal_anterior reproducibility.

Table

CFR results

**CFR results**. (A) The Passing & Bablok regression scatter diagram with the regression line (solid line), the confidence interval for the regression line (dashed lines) and identity line (x = y, dotted line), for global CFR values (n = 12, r = 0.99) and (B) corresponding Altman-Bland plots. (C) The Passing & Bablok regression scatter diagram (n = 12, r = 0.99) for regional apex_septal CFR and (D) corresponding Altman-Bland plot for regional apex_septal CFR.

CFR regional and global values averaged for 12 healthy subjects, for two processing runs.

Segment

CFR1

CFR2

reproducibility

reproducibility%

SEPTUM

2.22

2.22

0.11

4.76

APEX_Sep

2.30

2.31

0.15

6.56

MID_Sep-I

2.56

2.59

0.25

9.51

MID_Sep-A

2.19

2.22

0.09

4.02

BASAL_Sep-I

2.33

2.29

0.19

8.25

BASAL_Sep-A

1.95

1.98

0.50

25.19

ANTERIOR

2.11

2.09

0.25

12.06

APEX_Ant

2.04

2.00

0.14

6.73

MID_Ant

2.11

2.08

0.22

10.66

BASAL_Ant

2.16

2.16

0.43

19.81

LATERAL

2.23

2.18

0.25

11.25

APEX_Lat

2.27

2.22

0.24

10.56

MID_Lat

2.13

2.07

0.30

14.16

BASAL_Lat

2.36

2.30

0.28

11.90

INFERIOR

2.70

2.66

0.19

7.10

APEX_Inf

2.83

2.80

0.25

8.86

MID_Inf-P

2.72

2.66

0.26

9.72

MID_Inf-I

2.53

2.49

0.23

8.98

BASAL_Inf-P

2.51

2.45

0.23

9.45

BASAL_Inf-I

3.15

3.12

0.39

12.43

GLOBAL

2.25

2.22

0.15

6.90

The first and second run global CFR values were 2.25 ± 0.56 and 2.22 ± 0.54, respectively, with a mean difference, 1.3% ± 14.3% (P = NS). The repeatability coefficient was 0.15 (6.9% of the mean).

The average per sector repeatability coefficient for CFR was 0.25 (10.6% of the mean) and it ranged from mid_septal_A regional reproducibility of 0.09 (4.02% of the mean) till basal_septal_A regional reproducibility of 0.50 (25.19% of the mean).

Discussion

The advantages of ^{13}NH_{3}, ^{15}O-labeled water (H_{2}^{15}O) over ^{82}Rb for quantitative assessment of MBF are well known ^{13}NH_{3 }and ^{15}O is restricted to sites with a cyclotron. In addition, ^{15}O-labeled water is neither an approved tracer nor reimbursed for clinical imaging in the United States. The ability of ^{15}O-labeled water to diffuse freely across plasma membranes makes this tracer a favourite for quantification of myocardial blood flow. However, this very property leads to poor contrast between the myocardium and cardiac blood pool. ^{13}NH_{3 }allows good quality gated and ungated images taking full advantage of the superior resolution of PET imaging. However, ^{13}N ammonia images may be degraded by occasional intense liver activity, and increased lung activity in patients with lung congestion.

The main advantage of the ^{82}Rb myocardium perfusion PET imaging is its availability without an expensive cyclotron.

Using the Daubechies wavelets for temporal smoothing of the dynamic data significantly improved MBF and CFR reproducibility. Without wavelet smoothing, the rest MBF values in both runs, although they were very similar (0.76 ± 0.61 vs. 0.76 ± 0.49 mL/min/g), had large standard deviations and global reproducibility was very marginal 0.23 mL/min/g (30% of the mean). The same held true for the stress global MBF values (1.75 ± 0.95 and 1.80 ± 1.06 mL/min/g) with poor reproducibility of 0.65 mL/min/g (36.6% of the mean).

Without wavelet smoothing, our results suggested that the regional reproducibility of MBF rest and stress values for many segments were even worse than global values and in general was not reproducible. As was shown before ^{82}Rb MBF values are lower than uncorrected MBF values. Our MBF values were reasonably close to those reported in the literature. For example, the recent ^{82}Rb and ^{13}NH_{3 }rest MBF values ^{82}Rb corrected stress MBF values (1.37 ± 0.23 mL/min/g and 1.37 ± 0.24 mL/min/g) were slightly lower than those reported in the literature

We believe that further improvement of assessing ^{82}Rb rest and stress MBF values and CFR can be obtained by optimization of acquisition parameters, through additional comparisons with ^{13}NH_{3 }and ^{15}O water measurements at sites with a cyclotron and using a larger population of subjects in comparisons. Also, separation of subjects by gender, age or disease, probably will make the assessment of ^{82}Rb rest and stress MBF values more accurate. Recent results have also shown that factor analysis

The PMOD program itself can also be improved by a faster reading of data and by allowing creation of input TAC using the left atrium (LA) area in addition or instead of the LV cavity area. In some subjects with a small heart, a small LV cavity may not be the best choice for creating the input TAC, due to high cross talk from LV wall activity.

With these improvements, we believe that assessing ^{82}Rb rest and stress MBF values and CFR, can be moved out from the research setting and applied more widely in the clinical environment.

Conclusion

The results of the study demonstrate that processing of dynamic ^{82}Rb images for PET assessment of MBF and CFR is repeatable. The rest and stress, global, as well as regional, MBF and CFR values were, in most cases, highly repeatable. The main advantage of the PMOD approach is that it automatically creates 16 cardiac segment MBF values, in addition to the septum, anterior, lateral, inferior and global value. Second, the PMOD has an option of wavelet temporal smoothing, which significantly improves the repeatability of MBF and CFR assessment.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

All authors have made substantial contributions in acquisition, processing and analysing of data, and writing the manuscript.

Pre-publication history

The pre-publication history for this paper can be accessed here: