Right and left ventricular uptake with Rb-82 PET myocardial perfusion imaging: Markers of left main or 3 vessel disease

Arun Abraham^{1, 2}, Malek Kass¹, Terrence D. Ruddy^{1, 3}, Robert A. deKemp¹, Andrea K. Y. Lee¹, Michael C. Ling¹, Andrew Ha¹, Rob S. Beanlands^{1, 3} and Benjamin J. W. Chow^{1, 3}

Received: 11 May 2009 Accepted: 25 September 2009 Published online: 14 October 2009

Abstract

Background

Relative myocardial perfusion imaging may underestimate severity of coronary disease (CAD), particularly in cases of balanced ischemia. Can quantification of peak left (LV) and right (RV) ventricular Rb-82 uptake measurements identify patients with left main or 3 vessel disease?

Methods

Patients (N = 169) who underwent Rb-82 PET MPI and coronary angiography were categorized as having no significant coronary stenosis (n = 60), 1 or 2 vessel disease (n = 81), or left main disease/3 vessel disease (n = 28), based on angiography. Maximal LV and RV ventricular myocardial Rb-82 uptake was measured during stress and rest.

Results

Failure to augment LV uptake by ≥ 8500 Bq/cc at stress, predicted left main or 3 vessel disease with a sensitivity of 93% and specificity of 61% (area under curve = 0.83). A ≥10% increase in RV: LV uptake ratios with stress over rest was 93% specific (area under curve = 0.74) for left main or 3 vessel disease. These indices incrementally predicted left main or 3 vessel disease compared to models including age, gender, cardiac risk factors, and summed stress and difference scores.

Conclusion

Quantifying maximal rest and stress LV and RV uptake with PET myocardial perfusion imaging may independently and incrementally identify patients with left main or 3 vessel disease.

Keywords Coronary artery disease - left ventricle - myocardial perfusion imaging - positron emission tomography - right ventricle - rubidium-82

Background

Myocardial perfusion imaging (MPI) with positron emission tomography (PET) and single photon emission computed tomography (SPECT) plays an important role in the diagnosis and risk stratification of patients with suspected or documented coronary artery disease (CAD).1,2 Though PET has the benefit of dynamic image acquisition and quantification of coronary blood flow, it is not routinely used at all centers. MPI relies on relative differences in radiotracer uptake for the detection of CAD and occasionally may result in underestimation or misdiagnosis of ischemia in patients with balanced coronary ischemia. Surrogate markers such as transient ischemic dilation (TID), post-ischemic wall motion abnormalities, impaired ejection fraction reserve, and increased right ventricular (RV) uptake may enhance the identification of patients with multi-vessel disease.2-10

Abnormal increased RV uptake of Tc-99m and Tl-201 SPECT has been observed in patients with RV hypertrophy,11,12 RV pressure overload,11,13 pulmonary hypertension,14 congenital heart disease, and valvular disease.15,16 Also, increased stress RV: LV myocardial uptake ratio has been observed in patients with significant CAD and in patients with global left ventricular (LV) hypoperfusion (left main stenosis or multi-vessel disease) in exercise dual isotope SPECT.2,17 Though RV perfusion has been mostly studied with SPECT, increased RV uptake with N-13 ammonia positron emission tomography (PET) has been observed in patients with cyanotic congenital heart disease.18 Increased RV uptake with Rb-82 PET has not been well studied and PET criteria for defining abnormally increased right ventricular tracer uptake are required.19

The objective of this study is to determine if indices calculated from peak LV and RV Rb-82 uptake measurements, using static images at stress and rest, can identity patients with left main or 3 vessel disease. Additionally, we also evaluated their incremental value over baseline clinical characteristics and summed stress and rest scores.

Methods

Patient Population

Patients who underwent both dipyridamole stress Rb-82 PET myocardial perfusion imaging and coronary angiography (between 1998 and 2003) were included in this retrospective study. Patients with conditions associated with RV hypertrophy (such as pulmonary hypertension, congenital heart disease, and pulmonary disease), coronary artery bypass grafting, and valvular heart disease were excluded by medical record review. The study was approved by the institutional Human Research Ethics Board.

PET Image Acquisition

Each patient underwent a rest and dipyridamole stress Rb-82 PET scan, as previously described.20 In brief, each patient was positioned in the Siemens/CTI (Knoxville, TN) ECAT ART whole body partial ring scanner. A 4 minute cesium-137 singles transmission scan was acquired to confirm proper patient positioning and for attenuation correction.19 Following transmission imaging, 8 MBq/kg (370-1300 MBq) of Rb-82 was infused at rest. A 10 minute 24 frame dynamic 3D PET acquisition was started with the onset of scanner counts observed above background. Ten minutes after rest imaging acquisition, the stress protocol was initiated.

Dipyridamole Stress

Patients were abstained from caffeine, xanthine derivatives, and atrioventricular nodal blocking drugs for ≥12 hours. Patients were fasted (except for medications) for ≥6 hours prior to the study. Dipyridamole (0.14 mg/kg/min) was infused over 5 minutes. At 8 minutes, Rb-82 was administered. The same image acquisition parameters were used for the rest of the study. Aminophylline (2 mg/kg) was infused 12 minutes after initiation of dipyridamole infusion. A post-stress 4-minute transmission scan was acquired for attenuation correction after dipyridamole stress MPI.

PET Image Reconstruction and Analysis

Static stress and rest images summed from 2.5 to 10 minutes were reconstructed using filtered backprojection with a Hann window of the ramp filter cut-off at 18 mm full width at half maximum. All corrections were enabled including attenuation, randoms, scatter, isotope decay detector efficiency, and sensitivity using ECAT v7.2 reconstruction software. Detector dead-time losses were monitored and typically <10% in the static imaging phase, and were fully corrected in the reconstruction software.

The PET images were assessed qualitatively by two expert observers independently blinded to all clinical data. Using a 17-segment model and a 5-point grading system (0 = normal, 1 = mild, 2 = moderate, 3 = severe, 4 = absence of radiotracer uptake), summed stress (SSS), summed rest (SRS), and summed difference (SDS) scores were calculated on paired stress and rest studies21,22 with excellent inter-observer agreement for SSS (r = 0.99, difference between measurements on Bland-Altman analysis mean −0.2, 95% CI 1.7 to −2.2) and SDS (r = 0.98, difference between measurements on Bland-Altman analysis mean −0.2, 95% CI 2.1 to −2.5). Discrepancies in image analysis were resolved by consensus.

Determination of RV and LV Uptake

RV and LV uptake analysis was performed blinded to angiographic and clinical data. Additionally the observer was also blinded to the presence/absence of reversible perfusion defects. Areas of maximal LV and RV uptake were identified visually on the static short-axis images as shown in Figure 1. Care was taken to exclude potential areas of falsely elevated uptake such as subdiaphragmatic spillover in the inferior wall. Once identified, a small region of interest (ROI size > 2 × 2 pixels) was drawn on the corresponding transaxial slice and the maximal uptake (LV_stress, LV_rest, RV_stress, RV_rest) within the ROI was measured in Bq/cc. All measures were performed twice, at both stress and rest, for both right and left ventricles.

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Figure 1 Short axis images of patients with and without ‘increased RV uptake’ (red arrow) at stress (A and B, respectively). Maximal RV and LV uptake may not co-exist on the same transaxial slice, but for illustrative purposes, an RV ROI (pentagon) has been placed on the transaxial slice (red line) with maximal LV uptake (black ellipse)

Coronary Angiography

Coronary angiography, using multiple oblique views, was performed by experienced cardiologists. All angiograms were reviewed by two experienced angiographers, blinded to the imaging and clinical data and disagreements were resolved by consensus. Based on the presence of ≥50% left main stenosis or ≥70% stenosis of other coronary arteries, patients were categorized as having: (a) no significant obstructive CAD, (b) 1 or 2 vessel disease, or (c) left main or 3 vessel disease.

Statistical Analysis

Statistical analysis was performed using SAS™ 9.1.3 (Carey, NC). Categorical variables were expressed as frequencies and percentages. Continuous variables were expressed as means and standard deviations. Measures of RV uptake were evaluated using one-way ANOVA. Post hoc tests were performed using the Tukey-Kramer method. Logistic regression was performed to assess the predictive ability for left main or 3 vessel disease. Receiver operator characteristic curves (ROC) were generated to evaluate the ability of selected continuous variables to predict left main or 3 vessel disease. ‘Cut-off values’ were selected using ROC curves. Findings were statistically significant when P < .05. Bonferroni correction was applied, when multiple comparisons were made. Nested multivariate logistic regression models were compared for determination of incremental predictive value by computation of area under the receiver operator curve after ascertaining that the same observations were contributing to models compared;23 statistical significance of the incremental predictive value of nested models were compared using deviance.

Results

The total study population comprised 169 subjects (mean age = 61 ± 11 years) (Table 1). Older age, male gender, diabetes, smoking, peripheral vascular, and cerebrovascular diseases were more prevalent in patients with left main or 3 vessel disease. Summed stress scores (SSS), summed rest scores (SRS), and summed difference scores (SDS) for each group were calculated (Table 2). Mean duration between PET study and coronary angiogram was 48 days (inter-quartile range = 108 days). As expected, SSS and SDS increased with severity of CAD. On pair-wise comparison, SSS (P = .01 and .0005, respectively) and SDS (P = .01 and .02, respectively) were significantly different for patients without obstructive CAD versus those with 1 or 2 vessel disease and those with left main or 3 vessel disease. SSS and SDS did not differ statistically between 1 or 2 vessel disease versus left main or 3 vessel disease.

Table 1 Baseline characteristics

Variables	No significant CAD	1 or 2 vessel disease	Left main or 3 vessel disease	All patients
N (%)	60(36)	81(48)	28(17)	169
Age in years (mean ± SD)	57 ± 10	62 ± 10	66 ± 11	61 ± 11
Male (%)	35(58)	53(65)	22(79)	110(65)
History of smoking (%)	8(13)	18(22)	8(29)	34(20)
Diabetes (%)	10(17)	12(15)	11(39)	33(20)
Hyperlipidemia (%)	15(25)	21(26)	6(21)	42(25)
Hypertension (%)	12(20)	22(27)	7(25)	41(24)
Previous MI (%)	5(8.3)	10(12)	3(11)	18(11)
Peripheral vascular disease (%)	3(5)	1(1.2)	4(14)	8(4.7)
Cerebrovascular disease (%)	0	0	2(7.1)	2(1.2)

CAD, Coronary artery disease; MI, myocardial infarction.

Table 2 Sum stress, rest, and difference scores (mean ± standard deviation)

	No obstructive CAD	1 or 2 VD	Left main or 3 VD
Sum stress score	5.8 ± 7.2	10.0 ± 8.4	13.3 ± 11.2
Sum rest score	2.7 ± 4.7	4.0 ± 5.6	6.5 ± 7.7
Sum difference score	3.2 ± 5.0	6.0 ± 6.3	6.9 ± 6.5

On pair-wise comparison, summed stress (P = .01 and .0005, respectively) and summed difference scores (P = .01 and .02, respectively) were significantly different for patients without obstructive CAD versus those with 1 or 2 vessel disease and those with left main or 3 vessel disease, although they did not differ statistically between 1 or 2 vessel disease versus left main or 3 vessel disease.

CAD, Coronary artery disease; VD, vessel disease.

Maximal right and left ventricular uptake values were measured twice and compared. Reproducibility of RV and LV measures was excellent with correlation coefficients (r = 0.993, 0.998, 0.997, 0.997 for RV_rest, LV_rest, RV_stress, and LV_stress, respectively) (Table 3). The analyses performed using stress and rest right and left ventricular Rb-82 uptake indices are shown in Table 4. Peak stress and rest RV and LV uptake values did not distinguish between coronary disease severity groups. Difference between peak stress and rest left ventricular uptake (LV_stress − LV_rest) appeared to discriminate between coronary disease severity groups (P < .001) (Figure 2), even after adjustment for age, gender, SSS and SDS (adjusted P = .002). Additionally, LV_stress − LV_rest was able to distinguish between the group of patients with left main or 3 vessel disease and the group without obstructive coronary disease (P < .0001) and those with 1 or 2 vessel disease (P < .0001) on post hoc tests. LV_stress − LV_rest had an area under (AUC) the ROC curve (Figure 3) of 0.83 (95% CI 0.76-0.90). LV_stress − LV_rest ≤8500 Bq/cc was 93% sensitive and 61% specific for left main or 3 vessel disease and ≤7100 Bq/cc had a sensitivity and specificity of 86% and 70%, respectively.

Table 3 Intra-observer variability of maximal right and left ventricular Rb-82 uptake

	Stress				Rest
	R	Mean difference	Upper 95% CL	Lower 95% CL	R	Mean difference	Upper 95% CL	Lower 95% CL
Right ventricle	0.997*	358	2496.2	−1780.2	0.993*	343.3	2854.8	−2168.1
Left ventricle	0.997*	862.9	6067.9	−4342.0	0.998*	779.5	4017.6	−2458.6

CL, Confidence limit; R, Pearson’s correlation coefficient.

*P < .0001.

Table 4 Left and right ventricular peak stress and rest uptake

Measures of peak ventricular uptake	No obstructive CAD	1 or 2 VD	Left main or 3 VD	P value*
RV_stress − RV_rest
Mean	6481.6	6669.2	5031.1	.48
SD	6641.0	6442.7	4543.3	.48
LV_stress − LV_rest
Mean	14042.0	12137.1	1886.7	<.0001*
SD	14130.6	8906.7	6228.6	<.0001*
RV_stress/RV_rest
Mean	1.550	1.285	1.247	.34
SD	1.924	0.261	0.211	.34
LV_stress/LV_rest
Mean	1.554	1.250	1.053	.19
SD	2.167	0.168	0.129	.19
(RV_stress − RV_rest)/(LV_stress − LV_rest)
Mean	0.292	0.636	1.081	.10
SD	1.302	1.088	3.008	.10
RV_stress/LV_stress
Mean	0.463	0.478	0.536	.0004*
SD	0.072	0.073	0.109	.0004*
RV_rest/LV_rest
Mean	0.457	0.472	0.453	.39
SD	0.072	0.080	0.074	.39
(RV_stress/LV_stress):(RV_rest/LV_rest)
Mean	1.027	1.031	1.197	.0001*
SD	0.173	0.177	0.228	.0001*
(RV_stress/LV_stress) − (RV_rest/LV_rest)
Mean	0.006	0.006	0.083	<.0001*
SD	0.073	0.077	0.099	<.0001*

CAD, Coronary artery disease; LV, left ventricle; RV, right ventricle; SD, standard deviation; VD, vessel disease.

*Versus left main or 3 vessel disease.

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Figure 2 LV stress minus LV rest uptake. The difference in peak left ventricular uptake between stress and rest is lower in patients with left main or 3 vessel disease

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Figure 3 Receiver operator characteristic curve of difference between peak left ventricular uptake at stress and rest as a predictor of left main or 3 vessel disease. A difference in peak left ventricular uptake between stress and rest of ≤8500 Bq/cc is 93% sensitive and 61% specific for left main or 3 vessel disease. AUC, Area under the curve; CI, confidence interval

Difference between peak right and left ventricular uptake ratios at stress and rest (RV_stress/LV_stress) − (RV_rest/LV_rest) also appeared to discriminate between the three groups (P < .0001), even after adjustment for age, gender, SSS, and SDS (adjusted P = .0002). Additionally (RV_stress/LV_stress) − (RV_rest/LV_rest) was able to distinguish between the group of patients with left main or 3 vessel disease and the group without obstructive coronary disease (P = .0001) and those with 1 or 2 vessel disease (P < .0001). This variable had an area under the ROC curve of 0.72 (95% CI 0.60-0.84) and (RV_stress/LV_stress) − (RV_rest/LV_rest) ≥0.1 was 93% specific and 47% sensitive for left main or 3 vessel disease (Figure 4).

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Figure 4 Receiver operator characteristic curve of difference (in green) and ratio (in blue) of peak left ventricular and right ventricular uptake at stress and rest as a predictor of left main or 3 vessel disease. A difference in peak left ventricular uptake between stress and rest of ≥10% is 93% specific for left main or 3 vessel disease. Similarly, if the stress rest ratio ≥1.25 false positive rate drops to 7%

The ratio between peak right and left ventricular uptake ratios at stress and rest (RV_stress/LV_stress):(RV_rest/LV_rest) identified patients in the different CAD severity groups (P < .001) and remained statistically significant after adjusting for age, gender, SSS, and SDS (adjusted P < .001). (RV_stress/LV_stress):(RV_rest/LV_rest) was able to distinguish between the group of patients with left main or 3 vessel disease and the group without obstructive coronary disease (P = .0003) and those with 1 or 2 vessel disease (P = .0002) on post hoc tests. This variable had an area under the ROC curve of 0.72 (95% CI 0.60-0.84) (Figure 4). A cut-off value of 1.25 was 93% specific and 44% sensitive for left main or 3 vessel disease.

The peak right to left ventricular stress uptake ratio (RV_stress/LV_stress) discriminated between the CAD groups (P = .0004) with a trend toward significance upon adjustment for age, gender, SSS, and SDS (adjusted P = .006). By comparison, SSS and SDS had area under the ROC curves of 0.63 and 0.60, respectively.

Incremental value of indices of RV and LV maximal uptake is illustrated in Figure 5. A model (model A) including cardiac risk factors (age, gender, diabetes, hypertension, smoking, and dyslipidemia) had an area under the ROC curve of 0.69. Model B (Model A + summed stress and difference scores) increased the area under the ROC curve to 0.77 but failed to achieve statistical significance at α = 0.005. Addition of (RV_stress/LV_stress) − (RV_rest/LV_rest) to model B (Model C) resulted in an increase in area under the ROC curve to 0.83 (P < .001). Similarly, addition of LV_stress − LV_rest to model B resulted in an increase in area under the ROC curve to 0.87 (P < .00001). This model was not further significantly improved by addition of (RV_stress/LV_stress) − (RV_rest/LV_rest) (AUC 0.88, P = NS).

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Figure 5 Comparison of models including cardiac risk factors (age, gender, diabetes, hypertension, smoking, dyslipidemia), summed stress and rest scores (SSS, SRS) and indices of maximal right and left ventricular uptake for incremental predictive value

Discussion

Myocardial perfusion imaging plays an important role in the diagnosis and risk stratification in patients with symptoms or with documented CAD. Since SPECT MPI relies on relative differences in radiotracer uptake for the detection of CAD, the presence of surrogate markers such as: TID,5,7-9 post-ischemic wall motion abnormalities,3,4,6 and increased right ventricular (RV) uptake2 may assist with the identification of patients with left main or 3 vessel disease. Though the quantification of coronary blood flow with PET has been demonstrated to define greater extents of disease than static images in patients with 3 vessel disease,24 it is not routinely performed at many centers.25-35 Our results suggest that stress-induced LV and RV Rb-82 uptake, measured using static emission data, may independently and incrementally predict left main or 3 vessel disease. Since this method does not require dynamic imaging or sophisticated quantification software, it could potentially be implemented into existing practices.

Patients with left main or 3 vessel disease had smaller increases in LV_stress Rb-82 uptake compared to LV_rest. This is most likely due to impaired peak flow at stress in patients with 3 VD and left main disease who are less likely to have a normal region of myocardium. As such, peak ventricular uptake is a simple parameter that reflects absolute increases in perfusion that is easier to determine than absolute quantification. This may be a useful adjunct to relative perfusion imaging.

Some patients without obstructive CAD had low LV uptake at stress compared to rest. Possible explanations would include: (1) suboptimal persantine stress (patients who failed to abstain from caffeine or methylxanthine use), (2) endothelial dysfunction or microvascular disease, or (3) overestimation of rest uptake due to increased noise or gut spillover.

Abnormal increased RV uptake has been observed in patients with right ventricular hypertrophy,11,12 RV pressure overload,11,13 pulmonary hypertension,14 and congenital heart disease and valvular disease.15,16,18 In these patients increased RV uptake is likely related to RV hypertrophy and increased RV perfusion. Increased SPECT post-exercise RV: LV myocardial uptake ratio has been observed in patients with significant CAD and has been observed in patients with global left ventricular (LV) hypoperfusion (left main stenosis or multi-vessel disease).2,17 Conversely, in patients with CAD, RV uptake may be normal or reduced, but in the setting of global hypoperfusion of the LV, the RV uptake (with relative perfusion imaging) appears increased. Our results support this hypothesis by demonstrating that RV_stress − RV_rest uptake is relatively constant across all patients, but the LV_stress − LV_rest is lower in patients with left main or 3 vessel disease.

Using semi-quantitative analysis, a (RV_stress/LV_stress) − (RV_rest/LV_rest) ≥10% suggests the presence of left main or 3 vessel disease (specificity = 93%) with a false positive rate of only 7% (Figure 4). From a visual perspective, if the appearance of RV uptake relative to LV increases with stress (by ≥ 10%), this is a highly specific means to identify 3 vessel or LMCA disease. Similarly, an increase in (RV_stress/LV_stress):(RV_rest/LV_rest) ≥1.25 has high specificity (93%) for left main or 3 vessel disease with a false positive rate of only 7% (Figure 4).

We acknowledge that absolute stress and rest uptake values are affected by injected activity, patient weight, and isotope decay. In this study injected activity was standardized by patient weight (8 MBq/kg) to minimize this effect, and images were decay-corrected consistently to the start time of the static imaging phase. Despite some residual variability in patient weights, the absolute stress-rest difference did still show incremental value over the RV/LV ratio method. This suggests that simple ‘relative ratio’ analysis does not fully utilize the absolute scale information in the quantitative PET data. Future studies using absolute flow quantification may help to fully characterize the incremental value of the stress-rest difference in uptake versus flow.

Limitations

This is a single center retrospective observational study, subject to biases associated with this study design. Since the study population comprised patients proceeding to coronary angiography, this study is also subject to verification bias and would benefit from prospective validation. Though a medical history was obtained to exclude patients with RV hypertrophy or pulmonary hypertension, no formal testing was performed; however, we do not believe they significantly affected our result. The potential inclusion of patients with RV disease may have affected the RV measures; it would not have affected LV peak measurements.

The study was performed on a dedicated PET scanner and thus the results may not be directly translatable to hybrid PET systems which may be prone to more sources of artifact. At the time of the study, routine quantification of coronary flow reserve and TID was not performed therefore could not be used for analysis. Similarly, post-stress dysfunction and wall motion assessment were not feasible and therefore could not be incorporated into our study. Recognizing that coronary flow reserve, TID, and wall motion assessment have potential incremental value, this should be a focus for future studies.

Peak uptake values were not corrected for Rb-82 dose and patient size, because dosing was administered based upon body weight. We also recognize the limitation of sampling error when multiple parameters for RV and LV uptake were considered; however, this was accounted for with the use of the Bonferonni correction.

Conclusions

Quantifying maximal rest and stress LV and RV uptake on static PET myocardial perfusion images appears to be independently and incrementally predictive of left main or 3 vessel disease compared to conventional approaches. Maximal LV uptake appears to have very good operating characteristics for identifying patients with left main or 3 vessel disease. Indices involving RV peak uptake may help diagnose left main or 3 vessel disease with high specificity.

Acknowledgments The authors extend their gratitude to Quintin Armour, May Aung, Sandina Jamieson, Ann Guo, Kim Gardner, and Matt Raegele for their technical assistance and expertise.

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Original Article

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