Ran Klein

Quantification of myocardial blood flow with 82Rb dynamic PET imaging

PurposeThe PET tracer 82Rb is commonly used to evaluate regional perfusion defects for the diagnosis of coronary artery disease. There is limited information on the quantification of myocardial blood flow and flow reserve with this tracer. The goal of this study was to investigate the use of a one-compartment model of 82Rb kinetics for the quantification of myocardial blood flow.MethodsFourteen healthy volunteers underwent rest and dipyridamole stress imaging with both 13N-ammonia and 82Rb within a 2-week interval. Myocardial blood flow was estimated from the time-activity curves measured with 13N-ammonia using a standard two-compartment model. The uptake parameter of the one-compartment model was estimated from the time-activity curves measured with 82Rb. To describe the relationship between myocardial blood flow and the uptake parameter, a nonlinear extraction function was fitted to the data. This function was then used to convert estimates of the uptake parameter to flow estimates. The extraction function was validated with an independent data set obtained from 13 subjects with documented evidence of coronary artery disease (CAD).ResultsThe one-compartment model described 82Rb kinetics very well (median R-square = 0.98). The flow estimates obtained with 82Rb were well correlated with those obtained with 13N-ammonia (r = 0.85), and the best-fit line did not differ significantly from the identity line. Data obtained from the subjects with CAD confirmed the validity of the estimated extraction function.ConclusionIt is possible to obtain accurate estimates of myocardial blood flow and flow reserve with a one-compartment model of 82Rb kinetics and a nonlinear extraction function.

Quantification of myocardial blood flow and flow reserve: Technical aspects.

Myocardial perfusion imaging (MPI) is a powerful tool for detection of impaired myocardial blood supply due to atherosclerotic lesions in the epicardial arteries. MPI is commonly conducted using single photon emission computed tomography (SPECT) with Tlor Tc-based tracers, under conditions of rest and hyperemic stress. Regions of high tracer uptake are assumed to be normally perfused, while regions with relatively low uptake (perfusion defects) typically reflect stenosis of the upstream arteries. Regions of reversible myocardial ischemia are identified as stress perfusion defects that normalize at rest. In recent years, positron emission tomography (PET) has been utilized increasingly for MPI due to its superior image quality. PET images can be corrected accurately for attenuation losses and may have higher diagnostic accuracy than SPECT. Attenuation effects are particularly important in overweight patients, women with large or dense breast tissue and men with high abdominal fat. Thus, PET MPI is generally accepted to have improved specificity (fewer false-positives) compared to SPECT MPI, and fewer inconclusive exams, especially in obese patients and in women. Furthermore PET images provide quantitative measurements of activity concentration, and dynamic imaging can be used to quantify myocardial blood flow (MBF) in absolute terms of mL/minute/g. This provides an added quantitative dimension to routine MPI, and is sensitive to disease in both the epicardial conduit vessels as well as the resistance vessels of the microvasculature. MBF quantification has been shown to be beneficial in detecting multivessel disease that can cause a global reduction in flow, producing false-negative results with standard relative MPI. In addition, MBF has been shown to detect subclinical or presymptomatic disease in the microvasculature in diabetes, hypertension, hyperlipidemia, and obesity. Routine perfusion imaging uses radio-labeled tracers that are extracted from the blood and retained by the myocardium, ideally in proportion to blood flow. The net tracer concentration (uptake) in the tissue is therefore related to the rate of blood supply. As opposed to MPI which uses static images of the relative tracer distribution following blood clearance, MBF quantification uses dynamic sequences of images measured during the entire tracer uptake and clearance phases. Time-activity-curves (TAC) are measured in arterial blood and in regions of myocardial tissue. A tracer kinetic model is used to describe the exchange of tracer between arterial blood and myocardium during the course of the scan. In particular, the rate of tracer uptake (transport) from blood to tissue is closely related to MBF, depending only on the tracer extraction fraction. This article describes the technical considerations associated with MBF quantification with PET, mainly using the MPI tracers Rb and N-ammonia, and quality assurance methods needed to ensure clinical measurements of high quality.

Multisoftware Reproducibility Study of Stress and Rest Myocardial Blood Flow Assessed with 3D Dynamic PET/CT and a 1-Tissue-Compartment Model of 82Rb Kinetics

Routine quantification of myocardial blood flow (MBF) requires robust and reproducible processing of dynamic image series. The goal of this study was to evaluate the reproducibility of 3 highly automated software programs commonly used for absolute MBF and flow reserve (stress/rest MBF) assessment with 82Rb PET imaging. Methods: Dynamic rest and stress 82Rb PET scans were selected in 30 sequential patient studies performed at 3 separate institutions using 3 different 3-dimensional PET/CT scanners. All 90 scans were processed with 3 different MBF quantification programs, using the same 1-tissue-compartment model. Global (left ventricle) and regional (left anterior descending, left circumflex, and right coronary arteries) MBF and flow reserve were compared among programs using correlation and Bland–Altman analyses. Results: All scans were processed successfully by the 3 programs, with minimal operator interactions. Global and regional correlations of MBF and flow reserve all had an R2 of at least 0.92. There was no significant difference in flow values at rest (P = 0.68), stress (P = 0.14), or reserve (P = 0.35) among the 3 programs. Bland–Altman coefficients of reproducibility (1.96 × SD) averaged 0.26 for MBF and 0.29 for flow reserve differences among programs. Average pairwise differences were all less than 10%, indicating good reproducibility for MBF quantification. Global and regional SD from the line of perfect agreement averaged 0.15 and 0.17 mL/min/g, respectively, for MBF, compared with 0.22 and 0.26, respectively, for flow reserve. Conclusion: The 1-tissue-compartment model of 82Rb tracer kinetics is a reproducible method for quantification of MBF and flow reserve with 3-dimensional PET/CT imaging.

Dynamic SPECT Measurement of Absolute Myocardial Blood Flow in a Porcine Model

Absolute myocardial blood flow (MBF) and myocardial flow reserve (MFR) provide incremental diagnostic and prognostic information over relative perfusion alone. Recent development of dedicated cardiac SPECT cameras with better sensitivity and temporal resolution make dynamic SPECT imaging more practical. In this study, we evaluate the measurement of MBF using a multipinhole dedicated cardiac SPECT camera in a pig model of rest and transient occlusion at stress using 3 common tracers: 201Tl, 99mTc-tetrofosmin, and 99mTc-sestamibi. Methods: Animals (n = 19) were injected at rest/stress with 99mTc radiotracers (370/1,100 MBq) or 201Tl (37/110 MBq) with a 1-h delay between rest and dipyridamole stress. With each tracer, microspheres were injected simultaneously as the gold standard measurement for MBF. Dynamic images were obtained for 11 min starting with each injection. Residual resting activity was subtracted from stress data and images reconstructed with CT-based attenuation correction and energy window–based scatter correction. Dynamic images were processed with kinetic analysis software using a 1-tissue-compartment model to obtain the uptake rate constant K1 as a function of microsphere MBF. Results: Measured extraction fractions agree with those obtained previously using ex vivo techniques. Converting K1 back to MBF using the measured extraction fractions produced accurate values and good correlations with microsphere MBF: r = 0.75–0.90 (P < 0.01 for all). The correlation in the MFR was between r = 0.57 and 0.94 (P < 0.01). Conclusion: Noninvasive measurement of absolute MBF with stationary dedicated cardiac SPECT is feasible using common perfusion tracers.

Is There an Association Between Clinical Presentation and the Location and Extent of Myocardial Involvement of Cardiac Sarcoidosis as Assessed by 18F- Fluorodoexyglucose Positron Emission Tomography?

Background— Positron emission tomography using 18F-Fluorodeoxyglucose (FDG) is an emerging modality for diagnosis of cardiac sarcoidosis (CS). We compared the location and degree of FDG uptake in CS patients presenting with either advanced atrioventricular block (AVB) or ventricular tachycardia (VT). Methods and Results— We included consecutive patients who presented with either AVB or VT with a diagnosis of CS. A cohort of patients with clinically silent CS was included as controls. FDG activity was quantified as standardized uptake values (SUV) and both the overall mean left ventricular (LV) SUV as well as the Maximum Mean Segmental SUV was recorded for each patient. Receiver operator characteristic (ROC) analysis was performed to identify cutoff SUV values that best identified patients with VT. A total of 27 patients with CS were included (13 females; mean age, 56±8 years; 8 VT, 12 AVB, and 7 controls). Both mean LV SUV and Max SUV in CS patients presenting with VT were significantly higher compared with those with AVB (mean SUV: VT median 5.33, range 4.7–9.35 versus AVB median 2.48, range 0.86–8.59, P=0.016; max SUV: VT median 11.07, range 9.24–14.4 versus AVB median 5.63, range 3.42–15.71, P=0.005) and compared with controls. There was no significant difference in SUV values between AVB patients and controls. ROC analysis for identification of patients with VT showed AUCs of 0.93 and 0.895 for a mean LV SUV of >3.42 and a max SUV >8.56, respectively (P<0.001). Conclusions— CS patients with VT displayed significantly higher FDG uptake when compared with those with AVB and asymptomatic controls. Further prospective studies are required to evaluate this finding.

Precision-controlled elution of a 82Sr/82Rb generator for cardiac perfusion imaging with positron emission tomography.

A rubidium-82 ((82)Rb) elution system is described for use with positron emission tomography. Due to the short half-life of (82)Rb (76 s), the system physics must be modelled precisely to account for transport delay and the associated activity decay and dispersion. Saline flow is switched between a (82)Sr/(82)Rb generator and a bypass line to achieve a constant-activity elution of (82)Rb. Pulse width modulation (PWM) of a solenoid valve is compared to simple threshold control as a means to simulate a proportional valve. A predictive-corrective control (PCC) algorithm is developed which produces a constant-activity elution within the constraints of long feedback delay and short elution time. The system model parameters are adjusted through a self-tuning algorithm to minimize error versus the requested time-activity profile. The system is self-calibrating with 2.5% repeatability, independent of generator activity and elution flow rate. Accurate 30 s constant-activity elutions of 10-70% of the total generator activity are achieved using both control methods. The combined PWM-PCC method provides significant improvement in precision and accuracy of the requested elution profiles. The (82)Rb elution system produces accurate and reproducible constant-activity elution profiles of (82)Rb activity, independent of parent (82)Sr activity in the generator. More reproducible elution profiles may improve the quality of clinical and research PET perfusion studies using (82)Rb.

Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) IMAGE HF Project I-A: study protocol for a randomized controlled trial

BackgroundIschemic heart disease (IHD) is the most common cause of heart failure (HF); however, the role of revascularization in these patients is still unclear. Consensus on proper use of cardiac imaging to help determine which candidates should be considered for revascularization has been hindered by the absence of clinical studies that objectively and prospectively compare the prognostic information of each test obtained using both standard and advanced imaging.Methods/DesignThis paper describes the design and methods to be used in the Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) multi-center trial. The primary objective is to compare the effect of HF imaging strategies on the composite clinical endpoint of cardiac death, myocardial infarction (MI), cardiac arrest and re-hospitalization for cardiac causes.In AIMI-HF, patients with HF of ischemic etiology (n = 1,261) will follow HF imaging strategy algorithms according to the question(s) asked by the physicians (for example, Is there ischemia and/or viability?), in agreement with local practices. Patients will be randomized to either standard (SPECT, Single photon emission computed tomography) imaging modalities for ischemia and/or viability or advanced imaging modalities: cardiac magnetic resonance imaging (CMR) or positron emission tomography (PET). In addition, eligible and consenting patients who could not be randomized, but were allocated to standard or advanced imaging based on clinical decisions, will be included in a registry.DiscussionAIMI-HF will be the largest randomized trial evaluating the role of standard and advanced imaging modalities in the management of ischemic cardiomyopathy and heart failure. This trial will complement the results of the Surgical Treatment for Ischemic Heart Failure (STICH) viability substudy and the PET and Recovery Following Revascularization (PARR-2) trial. The results will provide policy makers with data to support (or not) further investment in and wider dissemination of alternative ‘advanced’ imaging technologies.Trial registrationNCT01288560

Quantitative analysis of coronary endothelial function with generator-produced 82Rb PET: comparison with 15O-labelled water PET

PurposeEndothelial dysfunction is the earliest abnormality in the development of coronary atherosclerosis. 82Rb is a generator-produced positron emission tomography (PET) myocardial perfusion tracer that is becoming more widely used. We aimed to (1) develop a method for quantitative assessment of coronary endothelial function using the myocardial blood flow (MBF) response during a cold pressor test (CPT) in smokers, measured using 82Rb PET, and (2) compare the results with those measured using 15O-water PET.MethodsMBF was assessed at rest and during the CPT with 82Rb and 15O-water in nine controls and ten smokers. A one-compartment model with tracer extraction correction was used to estimate MBF with both tracers. CPT response was calculated as the ratio of MBF during the CPT to MBF at rest.ResultsAt rest, measurements of MBF for smokers vs controls were not different using 15O-water (0.86 ± 0.18 vs 0.70 ± 0.13, p = 0.426) than they were using 82Rb (0.83 ± 0.23 vs 0.62 ± 0.20, p = 0.051). Both methods showed a reduced CPT response in smokers vs controls (15O-water, 1.03 ± 0.21 vs 1.42 ± 0.29, p = 0.006; 82Rb, 1.02 ± 0.28 vs 1.70 ± 0.52, p < 0.001). There was high reliability [intraclass correlation coefficients: 0.48 (0.07, 0.75)] of MBF measurement between 82Rb and 15O-water during the CPT.ConclusionUsing a CPT, 82Rb MBF measurements detected coronary endothelial dysfunctions in smokers. 82Rb MBF measurements were comparable to those made using the 15O-water approach. Thus, 82Rb PET may be applicable for risk assessments or evaluation of risk factor modification in subjects with coronary risk factors.

Repeatable Noninvasive Measurement of Mouse Myocardial Glucose Uptake with 18F-FDG: Evaluation of Tracer Kinetics in a Type 1 Diabetes Model

A noninvasive and repeatable method for assessing mouse myocardial glucose uptake with 18F-FDG PET and Patlak kinetic analysis was systematically assessed using the vena cava image–derived blood input function (IDIF). Methods: Contrast CT and computer modeling was used to determine the vena cava recovery coefficient. Vena cava IDIF (n = 7) was compared with the left ventricular cavity IDIF, with blood and liver activity measured ex vivo at 60 min. The test–retest repeatability (n = 9) of Patlak influx constant Ki at 10–40 min was assessed quantitatively using Bland–Altman analysis. Myocardial glucose uptake rates (rMGU) using the vena cava IDIF were calculated at baseline (n = 8), after induction of type 1 diabetes (streptozotocin [50 mg/kg] intraperitoneally, 5 d), and after acute insulin stimulation (0.08 mU/kg of body weight intraperitoneally). These changes were analyzed with a standardized uptake value calculation at 20 and 40 min after injection to correlate to the Patlak time interval. Results: The proximal mouse vena cava diameter was 2.54 ± 0.30 mm. The estimated recovery coefficient, calculated using nonlinear image reconstruction, decreased from 0.76 initially (time 0 to peak activity) to 0.61 for the duration of the scan. There was a 17% difference in the image-derived vena cava blood activity at 60 min, compared with the ex vivo blood activity measured in the γ-counter. The coefficient of variability for Patlak Ki values between mice was found to be 23% with the proposed method, compared with 51% when using the left ventricular cavity IDIF (P < 0.05). No significant bias in Ki was found between repeated scans with a coefficient of repeatability of 0.16 mL/min/g. Calculated rMGU values were reduced by 60% in type 1 diabetic mice from baseline scans (P < 0.03, ANOVA), with a subsequent increase of 40% to a level not significantly different from baseline after acute insulin treatment. These results were confirmed with a standardized uptake value measured at 20 and 40 min. Conclusion: The mouse vena cava IDIF provides repeatable assessment of the blood time–activity curve for Patlak kinetic modeling of rMGU. An expected significant reduction in myocardial glucose uptake was demonstrated in a type 1 diabetic mouse model, with significant recovery after acute insulin treatment, using a mouse vena cava IDIF approach.

Long-Term Follow-Up of Outcomes With F-18-Fluorodeoxyglucose Positron Emission Tomography Imaging–Assisted Management of Patients With Severe Left Ventricular Dysfunction Secondary to Coronary Disease

Background—Whether viability imaging can impact long-term patient outcomes is uncertain. The PARR-2 study (Positron Emission Tomography and Recovery Following Revascularization) showed a nonsignificant trend toward improved outcomes at 1 year using an F-18-fluorodeoxyglucose positron emission tomography (PET)–assisted strategy in patients with suspected ischemic cardiomyopathy. When patients adhered to F-18-fluorodeoxyglucose PET recommendations, outcome benefit was observed. Long-term outcomes of viability imaging–assisted management have not previously been evaluated in a randomized controlled trial. Methods and Results—PARR-2 randomized patients with severe left ventricular dysfunction and suspected CAD being considered for revascularization or transplantation to standard care (n= 195) versus PET-assisted management (n=197) at sites participating in long-term follow-up. The predefined primary outcome was time to composite event (cardiac death, myocardial infarction, or cardiac hospitalization). After 5 years, 105 (53%) patients in the PET arm and 111 (57%) in the standard care arm experienced the composite event (hazard ratio for time to composite event =0.82 [95% confidence interval 0.62–1.07]; P=0.15). When only patients who adhered to PET recommendations were included, the hazard ratio for the time to primary outcome was 0.73 (95% confidence interval 0.54–0.99; P=0.042). Conclusions—After a 5-year follow-up in patients with left ventricular dysfunction and suspected CAD, overall, PET-assisted management did not significantly reduce cardiac events compared with standard care. However, significant benefits were observed when there was adherence to PET recommendations. PET viability imaging may be best applied when there is likely to be adherence to imaging-based recommendations. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00385242.