Jennifer Merrill

Prediction of Short-Term Cardiovascular Events Using Quantification of Global Myocardial Flow Reserve in Patients Referred for Clinical 82Rb PET Perfusion Imaging

Current noninvasive tests for coronary artery disease detect atherosclerosis or regional ischemia. Global myocardial flow reserve is not routinely identified, although it may be an additional marker of disease development and progression. Methods: For the clinical work-up of suspected or known stable coronary artery disease, 275 individuals had undergone rest–dipyridamole 82Rb myocardial perfusion imaging using PET. In addition to clinical measures of regional perfusion and function, an experimentally validated approach to quantify global myocardial flow reserve was used. Follow-up was obtained for 362 ± 277 d. Results: Myocardial blood flow and flow reserve showed significant correlation to systemic and cardiac hemodynamics and a weak association with risk factors such as age and history of hyperlipidemia. Flow reserve was expectedly lower in subjects with regional ischemia (1.70 ± 0.65 vs. 2.31 ± 0.97 in those without; P < 0.0001), but a wide range was observed in those without regional perfusion abnormalities. We used a composite endpoint of hard and soft events to determine that flow reserve below the median was predictive of adverse outcome in the overall population (P = 0.001) and in subjects with normal regional perfusion (n = 178; P = 0.036), whereas stress flow was predictive only in the overall population (P = 0.001). Age-adjusted multivariate analysis confirmed regional perfusion defects (relative hazard, 2.51; 95% confidence interval, 1.24–5.10; P = 0.009) and low global flow reserve (relative hazard, 2.93; 95% confidence interval, 1.30–6.65; P = 0.011) as independent predictors of cardiac events. Conclusion: In clinical cardiac 82Rb PET, globally impaired flow reserve is a relevant marker for predicting short-term cardiovascular events. It may be used for integration with currently established functional and morphologic test results and for guidance of preventive measures, especially in the absence of regional flow–limiting disease.

Human Biodistribution and Radiation Dosimetry of 82Rb

Prior estimates of radiation-absorbed doses from 82Rb, a frequently used PET perfusion tracer, yielded discrepant results. We reevaluated 82Rb dosimetry using human in vivo biokinetic measurements. Methods: Ten healthy volunteers underwent dynamic PET/CT (6 contiguous table positions, each with separate 82Rb infusion). Source organ volumes of interest were delineated on the CT images and transferred to the PET images to obtain time-integrated activity coefficients. Radiation doses were estimated using OLINDA/EXM 1.0. Results: The highest mean absorbed organ doses (μGy/MBq) were observed for the kidneys (5.81), heart wall (3.86), and lungs (2.96). Mean effective doses were 1.11 ± 0.22 and 1.26 ± 0.20 μSv/MBq using the tissue-weighting factors of the International Commission on Radiological Protection (ICRP), publications 60 and 103, respectively. Conclusion: Our current 82Rb dosimetry suggests reasonably low radiation exposure. On the basis of this study, a clinical 82Rb injection of 2 × 1,480 MBq (80 mCi) would result in a mean effective dose of 3.7 mSv using the weighting factors of the ICRP 103—only slightly above the average annual natural background exposure in the United States (3.1 mSv).

Definition of Vascular Territories on Myocardial Perfusion Images by Integration with True Coronary Anatomy: A Hybrid PET/CT Analysis

For interpretation of myocardial perfusion studies, tissue segments are usually assigned to coronary vascular territories based on general assumptions about the most frequent vascular distribution pattern. These assumptions may be inaccurate because of interindividual variability of coronary anatomy. This limitation may be overcome by hybrid imaging through the individual integration of coronary anatomy with myocardial tissue regions. Methods: We studied 71 consecutive patients who underwent 82Rb perfusion PET/CT, including CT angiography, for work-up of coronary artery disease on a 64-slice PET/CT scanner. Coronary vessels as defined by CT were assigned to each of 17 myocardial segments for PET analysis using fusion images. Reassigned segmental maps were compared with standard assignment as proposed by the American Heart Association model, without knowledge of individual anatomy. The validity of segmental assignment was tested in 6 dogs by comparison of PET/CT with ex vivo dye staining of coronary territories. Results: Dog studies showed excellent agreement between PET/CT-defined segments and ex vivo–stained territories (κ, 0.80). In patients, 72% (51/71) demonstrated differences from the standard assignment in at least 1 myocardial segment; 112 of 1,207 segments were reassigned to nonstandard vascular territories. Most frequently, standard right coronary segments were reassigned to the left circumflex territory (39% of reassigned segments), standard circumflex segments were reassigned to the left anterior descending territory (30%), and standard left anterior descending segments were reassigned to either circumflex or right coronary (12% and 11%, respectively). In 27 studies with a myocardial perfusion defect, relative uptake in the vascular territory with the defect was significantly lower after CT-based reassignment and was higher in remote territories, resulting in better separation (ratio of defect to remote, 0.75 ± 0.13 vs. 0.81 ± 0.12 before reassignment; P = 0.0014). Conclusion: Standard assumptions about vascular territory distribution in myocardial perfusion analysis are frequently inaccurate because of morphologic variability of the coronary tree. If hybrid imaging has been used to study coronary anatomy and myocardial tissue perfusion, then localization of perfusion abnormalities should be based on CT-derived anatomy. This may bring about more accurate assignment to culprit vessels and thus improved guidance and monitoring of targeted therapy.

Radiation Dosimetry of 82Rb in Humans Under Pharmacologic Stress

82Rb is used with PET for cardiac perfusion studies. Using human biokinetic measurements, in vivo, we recently reported on the resting-state dosimetry of this agent. The objective of this study was to obtain 82Rb dose estimates under stress. Methods: 82Rb biokinetics were obtained in 10 healthy volunteers (5 male, 5 female; mean age ± SD, 33 ± 10 y; age range, 18–50 y) using whole-body PET/CT. The 76-s half-life of 82Rb and the corresponding need for pharmacologic vasodilation require that all imaging be completed within 10 min. To accommodate these constraints, while acquiring the data needed for dosimetry we used the following protocol. First, a whole-body attenuation correction CT scan was obtained. Then, a series of 3 whole-body PET scans was acquired after a single infusion of 1.53 ± 0.12 GBq of 82Rb at rest. Four minutes after the infusion of a 0.56 mg/kg dose of the vasodilator, dipyridamole, 3 serial whole-body PET scans were acquired after a single infusion of 1.50 ± 0.16 GBq of 82Rb under stress. The time-integrated activity coefficient (TIAC) for stress was obtained by scaling the mean rest TIAC obtained from our previous rest study by the stress-to-rest TIAC ratio obtained from the rest–stress measurements described in this report. Results: The highest mean organ-absorbed doses under stress were as follows: heart wall, 5.1, kidneys, 5.0, lungs, 2.8, and pancreas, 2.4 μGy/MBq (19, 19, 10.4, and 8.9 mrad/mCi, respectively). The mean effective doses under stress were 1.14 ± 0.10 and 1.28 ± 0.10 μSv/MBq using the tissue-weighting factors of the International Commission on Radiological Protection, publications 60 and 103, respectively. Conclusion: Appreciable differences in source-organ biokinetics were observed for heart wall and kidneys during stress when compared with the previously reported rest study. The organ receiving the highest dose during stress was the heart wall. The mean effective dose calculated during stress was not significantly different from that obtained at rest.

Integration of Infarct Size, Tissue Perfusion and Metabolism by Hybrid Cardiac PET–CT–Evaluation in a Porcine Model of Myocardial Infarction

Background—Hybrid positron emission tomography/computed tomography (PET-CT) allows for combination of PET perfusion/metabolism imaging with infarct detection by CT delayed contrast enhancement. We used this technique to obtain biomorphological insights into the interrelation between tissue damage, inflammation, and microvascular obstruction early after myocardial infarction. Methods and Results—A porcine model of left anterior descending coronary artery occlusion/reperfusion was studied. Seven animals underwent PET-CT within 3 days of infarction, and a control group of 3 animals was scanned at >4 weeks. Perfusion and glucose uptake were assessed by [13N]-ammonia/[18F]-deoxyglucose (FDG), and 64-slice CT delayed contrast enhancement was measured. In the acute infarct model, CT revealed a no-reflow phenomenon suggesting microvascular obstruction in 80% of all infarct segments. PET showed increased FDG uptake in 68% of the CT-defined infarct segments. Ex vivo staining and histology showed active inflammation in the acute infarct area as an explanation for increased glucose uptake. In chronic infarction, CT showed no microvascular obstruction and agreed well with matched perfusion/metabolism defects on PET. Conclusions—Perfusion/metabolism PET and delayed enhancement CT can be combined within a single hybrid PET-CT session. Increased regional FDG uptake in the acute infarct area is frequently observed. In contrast to the chronic infarct setting, this indicates tissue inflammation that is commonly associated with microvascular obstruction as identified by no reflow on CT. The consequences of these pathophysiological findings for subsequent ventricular remodeling should be explored in further studies.

Comparison of Measures of Left Ventricular Function from Electrocardiographically Gated 82Rb PET with Contrast-Enhanced CT Ventriculography : A Hybrid PET/CT Analysis

Because of the ultrashort tracer half-life and high positron energy of 82Rb, PET images acquired with this tracer are noisier and of lower resolution than those obtained with other PET tracers. The validity of electrocardiographic gating using 82Rb for assessment of left ventricular (LV) function is not well established. To support feasibility, we compared functional parameters from gated 82Rb PET with simultaneous high-resolution contrast-enhanced CT ventriculography, obtained as a byproduct a CT coronary angiography during hybrid cardiac PET/CT. Methods: A total of 24 patients underwent PET/CT, consisting of rest and dipyridamole 82Rb perfusion studies and contrast-enhanced CT angiography, using a 64-slice scanner, for the workup of coronary artery disease. From gated PET images, LV ejection fraction (EF), end-diastolic volume (EDV), and end-systolic volume (ESV) were calculated using 2 commercial products. For functional CT analysis, commercial software using endocardial contour detection was applied. Results: Inter- and intraobserver agreement was good for all methods. On CT, EF was 66% ± 13%, ESV was 41 ± 29 mL, and EDV was 115 ± 36 mL. On PET, EF during dipyridamole was 56% ± 15% and 52% ± 15% using the 2 commercial products (P < 0.05 vs. CT), ESV was 36 ± 28 and 47 ± 35 mL (P = not significant vs. CT), and EDV was 75 ± 30 and 91 ± 33 mL (P < 0.05 vs. CT). Correlations with CT were 0.85 and 0.87 for EF using commercial software, 0.76 and 0.88 for ESV, and 0.60 and 0.68 for EDV (P < 0.01 for all). Bland–Altman analysis confirmed systematic underestimation of EF and EDV by PET versus CT but did not show a significant deviation from linearity. Conclusion: Global LV function can be measured reproducibly from gated 82Rb PET, using different available software products. However, underestimation of EF by 82Rb PET, compared with CT ventriculography, is present, which is a result of underestimation of EDV from count-poor ED frames. This underestimation needs to be considered for clinical interpretation of 82Rb PET.

PET/CT Assessment of Symptomatic Individuals with Obstructive and Nonobstructive Hypertrophic Cardiomyopathy

Patients with obstructive hypertrophic cardiomyopathy (HCM) exhibit elevated left ventricular outflow tract gradients (LVOTGs) and appear to have a worse prognosis than those with nonobstructive HCM. The aim of this study was to evaluate whether patients with obstruction, compared with nonobstructive HCM, demonstrate significant differences in PET parameters of microvascular function. Methods: PET was performed in 33 symptomatic HCM patients at rest and during dipyridamole stress (peak) for the assessment of regional myocardial perfusion (rMP), left ventricular ejection fraction (LVEF), myocardial blood flow (MBF), and myocardial flow reserve (MFR). Myocardial wall thickness and LVOTG were measured with an echocardiogram. Patients were divided into the following 3 groups: nonobstructive (LVOTG < 30 mm Hg at rest and after provocation test with amyl nitrite), obstructive (LVOTG ≥ 30 mm Hg at rest and with provocation), and latent HCM (LVOTG < 30 at rest but ≥ 30 mm Hg with provocation). Results: Eleven patients were classified as nonobstructive (group 1), 12 as obstructive (group 2), and 10 as latent HCM (group 3). Except for age (42 ± 18 y for group 1, 58 ± 7 y for group 2, and 58 ± 12 y for group 3; P = 0.01), all 3 groups had similar baseline characteristics, including maximal wall thickness (2.3 ± 0.5 cm for group 1, 2.2 ± 0.4 cm for group 2, and 2.1 ± 0.7 cm for group 3; P = 0.7). During peak flow, most patients in groups 1 and 2, but fewer in group 3, exhibited rMP defects (73% for group 1, 100% for group 2, and 40% for group 3; P = 0.007) and a drop in LVEF (73% for group 1, 92% for group 2, and 50% for group 3; P = 0.09). Peak MBF (1.58 ± 0.49 mL/min/g for group 1, 1.72 ± 0.46 mL/min/g for group 2, and 1.97 ± 0.32 mL/min/g for group 3; P = 0.14) and MFR (1.62 ± 0.57 for group 1, 1.90 ± 0.31 for group 2, and 2.27 ± 0.51 for group 3; P = 0.01) were lower in the nonobstructive and higher in the latent HCM group. LVOTGs demonstrated no significant correlation with any flow dynamics. In a multivariate regression analysis, maximal wall thickness was the only significant predictor for reduced peak MBF (β = −0.45, P = 0.003) and MFR (β = −0.63, P = 0.0001). Conclusion: Maximal wall thickness was identified as the strongest predictor of impaired dipyridamole-induced hyperemia and flow reserve in our study, whereas outflow tract obstruction was not an independent determinant.

Transient Ischemic Dilation Ratio in 82Rb PET Myocardial Perfusion Imaging: Normal Values and Significance as a Diagnostic and Prognostic Marker

In myocardial perfusion SPECT, transient ischemic dilation ratio (TID) is a well-established marker of severe ischemia and adverse outcome. However, its role in the setting of 82Rb PET is less well defined. Methods: We analyzed 265 subjects who underwent clinical rest–dipyridamole 82Rb PET/CT. Sixty-two subjects without a prior history of cardiac disease and with a normal myocardial perfusion study had either a low or a very low pretest likelihood of coronary artery disease or negative CT angiography. These subjects were used to establish a reference range of TID. In the remaining 203 patients with an intermediate or high pretest likelihood, subgroups with normal and abnormal TID were established and compared with respect to clinical variables, perfusion defect scores, left ventricular function, and absolute myocardial flow reserve. Follow-up was obtained for 969 ± 328 d to determine mortality by review of the social security death index. Results: In the reference group, TID ratio was 0.98 ± 0.06. Accordingly, a threshold for abnormal TID was set at greater than 1.13 (0.98 + 2.5 SDs). In the study group, 19 of 203 patients (9%) had an elevated TID ratio. Significant differences between subgroups with normal and abnormal TID ratio were observed for ejection fraction reserve (5.0 ± 6.4 vs. 1.8 ± 7.9; P < 0.05), difference between end-systolic volume (ESV) at rest and stress (ΔESV[stress–rest]; 1.8 ± 7.4 vs. 12.3 ± 13.0 mL; P < 0.0001), difference between end-diastolic volume (EDV) at rest and stress (ΔEDV[stress–rest]; 10.8 ± 11.5 vs. 23.8 ± 14.6 mL; P < 0.0001), summed rest score (1.8 ± 3.8 vs. 3.8 ± 7.6; P < 0.05), summed stress score (3.0 ± 5.4 vs. 7.5 ± 9.8; P < 0.002), summed difference score (1.3 ± 2.6 vs. 3.7 ± 5.3; P < 0.02), and global myocardial flow reserve (2.1 ± 0.8 vs. 1.7 ± 0.6; P < 0.02). Additionally, TID-positive patients had a significantly lower overall survival probability (P < 0.05). In a subgroup analysis of patients without regional perfusion abnormalities, TID-positive patients’ overall survival probability was significantly smaller (P < 0.03), and TID was an independent predictor (exponentiation of the B coefficients [Exp(b)] = 6.22; P < 0.009) together with an ejection fraction below 45% (Exp[b] = 6.16; P < 0.002). Conclusion: The present study suggests a reference range of TID for 82Rb PET myocardial perfusion imaging that is in the range of previously established values for SPECT. Abnormal TID in 82Rb PET is associated with more extensive left ventricular dysfunction, ischemic compromise, and reduced global flow reserve. Preliminary outcome analysis suggests that TID-positive subjects have a lower overall survival probability.

Impaired Global Myocardial Flow Dynamics Despite Normal Left Ventricular Function and Regional Perfusion in Chronic Kidney Disease: A Quantitative Analysis of Clinical 82Rb PET/CT Studies

Impaired global myocardial flow reserve (MFR) may be associated with increased risk for cardiac events and coronary artery disease progression. Chronic kidney disease (CKD) is also considered a risk factor for cardiovascular disease. We sought to investigate the effect of CKD on the myocardial microcirculation in patients referred for clinical 82Rb PET/CT, who had normal left ventricular (LV) function and no flow-limiting coronary artery disease. Methods: Estimated glomerular filtration rate (eGFR) was available for 230 patients who had undergone rest and pharmacologic stress 82Rb PET/CT for suspected coronary artery disease. CKD was defined as an eGFR less than 60 mL/min/1.73 m2. After patients with hemodialysis, a renal transplant, abnormal regional perfusion (summed stress score > 4), or reduced LV function (LV ejection fraction < 45%) were excluded, 40 CKD patients remained. Those were compared with a control group without CKD, which was matched for age, sex, coronary risk factors, and systemic hemodynamics (n = 42). List-mode acquisition of PET enabled quantification of myocardial blood flow (MBF) and MFR using a previously validated retention model with correction for 82Rb extraction. Rest MBF was normalized to rate–pressure product. Results: Mean eGFR in the CKD group was reduced (44 ± 14 vs. 99 ± 28 mL/min/1.73 m2; P < 0.0001), and creatinine was significantly elevated, compared with controls (1.9 ± 1.1 vs. 0.8 ± 0.2 mg/dL; P < 0.0001). MFR was significantly reduced in CKD (2.2 ± 1.0 vs. 3.0 ± 1.2 for controls; P = 0.027). This reduction was mainly due to increased rest MBF (1.1 ± 0.4 in CKD vs. 0.8 ± 0.2 mL/min/g in controls; P = 0.007). Stress myocardial flow was comparable between both groups (2.3 ± 0.9 vs. 2.3 ± 0.8 mL/min/g; P = 0.08). Overall, MFR was significantly correlated with eGFR (r = 0.41; P = 0.0005). Stress MBF did not correlate with eGFR (r = 0.002; P = 0.45), but rest MBF showed an inverse correlation (r = −0.49; P < 0.0001). Rest MBF was also inversely correlated with hemoglobin (r = −0.28; P = 0.014), but only eGFR was an independent correlate at multivariate analysis. Conclusion: MFR is impaired in patients with renal insufficiency with normal regional perfusion and LV function, mostly because of elevated rest flow. Absolute quantification of flow may be useful to identify microvascular dysfunction as a precursor of clinically overt coronary disease in this specific risk group.

Reference Ranges for LVEF and LV Volumes from Electrocardiographically Gated 82Rb Cardiac PET/CT Using Commercially Available Software

Electrocardiographic gating is increasingly used for 82Rb cardiac PET/CT, but reference ranges for global functional parameters are not well defined. We sought to establish reference values for left ventricular ejection fraction (LVEF), end systolic volume (ESV), and end diastolic volume (EDV) using 4 different commercial software packages. Additionally, we compared 2 different approaches for the definition of a healthy individual. Methods: Sixty-two subjects (mean age ± SD, 49 ± 9 y; 85% women; mean body mass index ± SD, 34 ± 10 kg/m2) who underwent 82Rb-gated myocardial perfusion PET/CT were evaluated. All subjects had normal myocardial perfusion and no history of coronary artery disease (CAD) or cardiomyopathy. Subgroup 1 consisted of 34 individuals with low pretest probability of CAD (<10%), and subgroup 2 comprised 28 subjects who had no atherosclerosis on a coronary CT angiogram obtained concurrently during the PET/CT session. LVEF, ESV, and EDV were calculated at rest and during dipyridamole-induced stress, using CardIQ Physio (a dedicated PET software) and the 3 major SPECT software packages (Emory Cardiac Toolbox, Quantitative Gated SPECT, and 4DM-SPECT). Results: Mean LVEF was significantly different among all 4 software packages. LVEF was most comparable between CardIQ Physio (62% ± 6% and 54% ± 7% at stress and rest, respectively) and 4DM-SPECT (64% ± 7% and 56% ± 8%, respectively), whereas Emory Cardiac Toolbox yielded higher values (71% ± 6% and 65% ± 6%, respectively, P < 0.001) and Quantitated Gated SPECT lower values (56% ± 8% and 50% ± 8%, respectively, P < 0.001). Subgroup 1 (low likelihood) demonstrated higher LVEF values than did subgroup 2 (normal CT angiography findings), using all software packages (P < 0.05). However, mean ESV and EDV at stress and rest were comparable between both subgroups (p = NS). Intra- and interobserver agreement were excellent for all methods. Conclusion: The reference range of LVEF and LV volumes from gated 82Rb PET/CT varies significantly among available software programs and therefore cannot be used interchangeably. LVEF results were higher when healthy subjects were defined by a low pretest probability of CAD than by normal CT angiography results.