Paco E. Bravo

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).

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.

Absolute myocardial flow quantification with (82)Rb PET/CT: comparison of different software packages and methods.

PurposeIn clinical cardiac 82Rb PET, globally impaired coronary flow reserve (CFR) is a relevant marker for predicting short-term cardiovascular events. However, there are limited data on the impact of different software and methods for estimation of myocardial blood flow (MBF) and CFR. Our objective was to compare quantitative results obtained from previously validated software tools.MethodsWe retrospectively analyzed cardiac 82Rb PET/CT data from 25 subjects (group 1, 62u2009±u200911xa0years) with low-to-intermediate probability of coronary artery disease (CAD) and 26 patients (group 2, 57u2009±u200910xa0years; Pu2009=u20090.07) with known CAD. Resting and vasodilator-stress MBF and CFR were derived using three software applications: (1) Corridor4DM (4DM) based on factor analysis (FA) and kinetic modeling, (2) 4DM based on region-of-interest (ROI) and kinetic modeling, (3) MunichHeart (MH), which uses a simplified ROI-based retention model approach, and (4) FlowQuant (FQ) based on ROI and compartmental modeling with constant distribution volume.ResultsResting and stress MBF values (in milliliters per minute per gram) derived using the different methods were significantly different: using 4DM-FA, 4DM-ROI, FQ, and MH resting MBF values were 1.47u2009±u20090.59, 1.16u2009±u20090.51, 0.91u2009±u20090.39, and 0.90u2009±u20090.44, respectively (Pu2009<u20090.001), and stress MBF values were 3.05u2009±u20091.66, 2.26u2009±u20091.01, 1.90u2009±u20090.82, and 1.83u2009±u20090.81, respectively (Pu2009<u20090.001). However, there were no statistically significant differences among the CFR values (2.15u2009±u20091.08, 2.05u2009±u20090.83, 2.23u2009±u20090.89, and 2.21u2009±u20090.90, respectively; Pu2009=u20090.17). Regional MBF and CFR according to vascular territories showed similar results. Linear correlation coefficient for global CFR varied between 0.71 (MH vs. 4DM-ROI) and 0.90 (FQ vs. 4DM-ROI). Using a cut-off value of 2.0 for abnormal CFR, the agreement among the software programs ranged between 76xa0% (MH vs. FQ) and 90xa0% (FQ vs. 4DM-ROI). Interobserver agreement was in general excellent with all software packages.ConclusionQuantitative assessment of resting and stress MBF with 82Rb PET is dependent on the software and methods used, whereas CFR appears to be more comparable. Follow-up and treatment assessment should be done with the same software and method.

Molecular Hybrid Positron Emission Tomography/Computed Tomography Imaging of Cardiac Angiotensin II Type 1 Receptors

OBJECTIVESnThe goal of this study was to explore the feasibility of targeted imaging of the angiotensin II type 1 receptor (AT1R) in cardiac tissue, using clinical hybrid positron emission tomography/computed tomography (PET/CT).nnnBACKGROUNDnAT1R is an attractive imaging target due to its key role in various cardiac pathologies, including post-infarct left ventricular remodeling.nnnMETHODSnUsing the novel AT1R ligand [(11)C]-KR31173, dynamic PET/CT was performed in young farm pigs under healthy conditions (n = 4) and 3 to 4 weeks after experimental myocardial infarction (n = 5). Ex vivo validation was carried out by immunohistochemistry and polymerase chain reaction. First-in-man application was performed in 4 healthy volunteers at baseline and under AT1R blocking.nnnRESULTSnIn healthy pigs, myocardial KR31173 retention was detectable, regionally homogeneous, and specific for AT1R, as confirmed by blocking experiments. Metabolism in plasma was low (85 ± 2% of intact tracer after 60 min). After myocardial infarction, KR31173 retention, corrected for regional perfusion, revealed AT1R up-regulation in the infarct area relative to remote myocardium, whereas retention was elevated in both regions when compared with myocardium of healthy controls (8.7 ± 0.8% and 7.1 ± 0.3%/min vs. 5.8 ± 0.4%/min for infarct and remote, respectively, vs. healthy controls; p < 0.01 each). Postmortem analysis confirmed AT1R up-regulation in remote and infarct tissue. First-in-man application was safe, and showed detectable and specific myocardial KR31173 retention, albeit at a lower level than pigs (left ventricular average retention: 1.2 ± 0.1%/min vs. 4.4 ± 1.2%/min for humans vs. pigs; p = 0.04).nnnCONCLUSIONSnNoninvasive imaging of cardiac AT1R expression is feasible using clinical PET/CT technology. Results provide a rationale for broader clinical testing of AT1R-targeted molecular imaging.

Relationship of Delayed Enhancement by Magnetic Resonance to Myocardial Perfusion by Positron Emission Tomography in Hypertrophic Cardiomyopathy

Background— Presence of delayed enhancement (DE) on cardiac magnetic resonance (CMR) is associated with worse clinical outcomes in hypertrophic cardiomyopathy. We investigated the relationship between DE on CMR and myocardial ischemia in hypertrophic cardiomyopathy. Methods and Results— Hypertrophic cardiomyopathy patients (n=47) underwent CMR for assessment of DE and vasodilator stress ammonia positron emission tomography to quantify myocardial blood flow and coronary flow reserve. The summed difference score for regional myocardial perfusion was also assessed. Patients in the DE group (n=35) had greater left ventricular wall thickness (2.09±0.44 versus 1.78±0.34 cm; P=0.03). Stress myocardial blood flow (2.25±0.46 versus 1.78±0.43 mL/min per gram; P=0.01) and coronary flow reserve (2.78±0.32 versus 2.01±0.52; P<0.001) were significantly lower in DE-positive patients. Summed difference score (median, 5 versus 0; P<0.0001) was significantly higher in patients with DE. A coronary flow reserve <2.00 was seen in 18 patients (51%) with DE but in none of the DE-negative patients (P<0.0001). CMR and positron emission tomography showed visually concordant DE and regional myocardial perfusion abnormalities in 31 patients and absence of DE and perfusion defects in 9 patients. Four DE-positive patients demonstrated normal regional myocardial perfusion, and 3 DE-negative patients had (apical) regional myocardial perfusion abnormalities. Conclusions— We found a close relationship between DE by CMR and microvascular function in most of the patients studied. However, a small proportion of patients had DE in the absence of perfusion abnormalities, suggesting that microvascular dysfunction and ischemia are not the sole causes of DE in hypertrophic cardiomyopathy patients.

Radionuclide Imaging of Angiotensin II Type 1 Receptor Upregulation After Myocardial Ischemia–Reperfusion Injury

The renin–angiotensin system (RAS) mediates proapoptotic, profibrotic, and proinflammatory processes in maladaptive conditions. Activation after myocardial infarction may initialize and promote cardiac remodeling. Using a novel positron-emitting ligand, we sought to determine the presence and time course of regional myocardial upregulation of the angiotensin II type 1 receptor (AT1R) and the blocking efficacy of various anti-RAS agents. Methods: In male Wistar rats (n = 31), ischemia–reperfusion damage was induced by 20- to 25-min ligation of the left coronary artery. The AT1R blocker 11C-2-butyl-5-methoxymethyl-6-(1-oxopyridin-2-yl)-3-[[2-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-3H-imidazo[4,5-b]pyridine (11C-KR31173) was injected intravenously at different times until 6 mo after surgery and sacrifice. Autoradiography, histology, and immunohistochemistry were performed for ex vivo validation. Additional in vivo PET was conducted in 3 animals. A second series of experiments (n = 16) compared untreated animals with animals treated with oral valsartan (50 mg/kg/d), oral enalapril (10 mg/kg/d), and complete intravenous blockage (SK-1080, 2 mg/kg, 10 min before imaging). Results: Transient regional AT1R upregulation was detected in the infarct area, with a peak at 1–3 wk after surgery (autoradiographic infarct-to-remote ratio, 1.07 ± 0.09, 1.68 ± 0.34, 2.54 ± 0.40, 2.98 ± 0.70, 3.16 ± 0.57, 1.86 ± 0.65, and 1.28 ± 0.27 at control, day 1, day 3, week 1, week 3, month 3, and month 6, respectively). The elevated uptake of 11C-KR31173 in the infarct area was detectable by small-animal PET in vivo, and it was blocked completely by intravenous SK-1080. Although oral treatment with enalapril did not reduce focal tracer uptake, oral valsartan resulted in partial blockade (infarct-to-remote ratio, 2.94 ± 0.52, 2.88 ± 0.60, 2.07 ± 0.25, and 1.26 ± 0.10 for no treatment, enalapril, valsartan, and SK-1080, respectively). Conclusion: After ischemic myocardial damage in a rat model, transient regional AT1R upregulation is detectable in the infarct area using 11C-KR31173. Inhibitory effects of the clinical AT1R blocker valsartan can be identified, whereas blockage of upstream angiotensin-converting enzyme with enalapril does not affect AT1R density. These results provide a rationale for subsequent testing of AT1R-targeted imaging to predict the risk for ventricular remodeling and to monitor the efficacy of anti-RAS drug therapy.

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.

The impact of viability assessment using myocardial perfusion imaging on patient management and outcome

BackgroundPrior studies show that ischemic cardiomyopathy (ICM) patients with substantial viable myocardium have better survival with coronary revascularization (CR) than medical therapy (MT). When myocardial perfusion imaging (MPI) is used, the analysis is often based on visual scoring. We sought to determine the value of automated quantitative viability analysis in guiding management and predicting outcome.MethodsWe identified 246 consecutive ICM patients who had rest-redistribution gated SPECT thallium-201 MPI. Size and severity of perfusion defects were assessed by automated method. Regions with <50% activity vs normal were considered nonviable. Mortality was verified against the social security death index database.ResultsOf the 246 patients, 37% underwent CR within 3xa0months of MPI. The initial images showed a total perfusion defect size of 32xa0±xa017%, redistribution of 3.5xa0±xa04.6% and nonviable myocardium of 13xa0±xa014%LV. Using multivariate logistic regression analysis, independent predictors of CR included chest pains (OR 2.74) and rest-delayed transient ischemic dilatation (OR 4.49), while a prior history of CR or ventricular arrhythmias favored MT. The cohort was followed-up for 41xa0±xa030xa0m during which 111 patients (45%) died. Survival was better with CR than MT (Pxa0<xa0.0001). For CR, survival was better for those with a smaller area of nonviable myocardium (risk of death increased by 5%/1% increase in size of nonviable myocardium, Pxa0=xa0.009) but this was not seen in MT. CR had a mortality advantage over MT when the area of nonviable myocardium was ≤20%LV but not larger.ConclusionsAutomated quantitative analysis of MPI is useful in predicting survival in ICM, but the decision for or against CR is a complex one as it depends on multiple other factors and “viability testing” is just one variable that needs to be incorporated in the decision-making process.

Cardiac PET/CT Misregistration Causes Significant Changes in Estimated Myocardial Blood Flow

Misregistration of cardiac PET/CT data can lead to misinterpretation of regional myocardial perfusion. However, the effect of misregistration on the quantification of myocardial blood flow (MBF) has not been studied. Methods: Cardiac 82Rb-PET/CT scans of 10 patients with normal regional myocardial perfusion were analyzed. Realignment was done for the baseline and stress PET/CT images as necessary, and MBF was obtained from dynamic data. Then, the stress images were misregistered by 5 mm along the x-axis (left) and z-axis (cranial) and again by 10 mm. A 10-mm misregistration in the opposite direction (−10 mm along the x-axis [right] and z-axis [caudal]) was also tested. Stress MBF was recalculated for 5-, 10-, and −10-mm misregistrations. Results: Stress MBF of the left ventricle decreased by 10% ± 6% (P = 0.005) after 5-mm misregistration and by 24% ± 15% (P = 0.001) after 10-mm misregistration. In descending order, the most important stress MBF changes occurred in the anterior (39% ± 9%), lateral (34% ± 9%), apical (20% ± 16%), inferior (12% ± 10%), and septal (10% ± 12%) walls after 10-mm misregistration. Lesser changes were observed after 5-mm misregistration, with the same wall distribution. In contrast, −10-mm misregistration increased global MBF by 9% ± 6% (P = 0.004). In descending order, the overestimation of estimated MBF after −10-mm misregistration occurred in the lateral (15% ± 8%), apical (15% ± 18%), anterior (9% ± 5%), and inferior (9% ± 11%) walls. Conclusion: Misregistration of the stress PET/CT dataset leads to significant global and regional artifactual alterations in the estimated MBF. Quantitative error was observed throughout the myocardium and was not confined to those heart regions that extended into the lung on misregistered CT.