Quantitative cardiac 15O-water PET : Assessment of left-ventricular function, remodeling, and impact of patient motion

International guidelines advocate the use of noninvasive cardiac imaging as the initial diagnostic test for coronary artery disease, the global leading cause of death according to the world health organization. Within the wide spectrum of cardiac imaging, 15O-water PET is the gold standard for noninvasive quantification of myocardial blood flow (MBF). However, because 15O-water is a metabolically inert and freely diffusible tracer, the net retention of 15O-water in the myocardium is zero and there is no contrast between the myocardial wall and the cavity in a standard uptake image of 15O-water. The lack of contrast poses difficulties for the measurement of cardiac function and remodeling, paramount assessments for coronary artery disease evaluation along with MBF. Part one of the aim of this thesis is the development and evaluation of methods for assessment of cardiac function and remodeling in terms of left-ventricular (LV) volumes and ejection fraction (EF), LV mass (LVM), and LV wall thickness (WT). Part two is focused on patient motion, which occurs frequently in all cardiac PET studies and represents a possible source for induced error in the quantification of MBF.  The feasibility of LV volumes and EF calculations was shown in paper I, where cardiac-gated parametric blood-pool images and first-pass images were imported into a commercially available software for SPECT. The method was, however, too laborious for clinical practice but served as an important proof-of-concept. In paper II, LV volumes and EF calculations were performed using first-pass images in the same software used for standard analysis of 15O-water PET and MBF assessment. The results were improved compared to paper I and the method was feasible for clinical implementation. In paper III, LVM and WT calculations were performed using segmentation of perfusable tissue fraction (PTF) images. The results showed high accuracy compared to cardiac magnetic resonance (MR) imaging, and the method was highly automated, allowing for ready clinical implementation. In papers IV-V, the impact of patient motion on the quantitative accuracy of 15O-water PET was investigated. Simulations showed a minimal impact of PET-CT misalignment on MBF, but did show that impact of dynamic motion during PET acquisition was more pronounced. Visual inspection of clinical scans showed frequent motion, but at a small amplitude with generally limited impact according to the simulations. An automated motion detection algorithm was developed which was highly accurate in detecting larger types of motion. A clear pattern of motion-induced artifacts were discovered, which may help improve their visual detection

Quantitative cardiac 15O-water PET : Assessment of left-ventricular function, remodeling, and impact of patient motion

International guidelines advocate the use of noninvasive cardiac imaging as the initial diagnostic test for coronary artery disease, the global leading cause of death according to the world health organization. Within the wide spectrum of cardiac imaging, 15O-water PET is the gold standard for noninvasive quantification of myocardial blood flow (MBF). However, because 15O-water is a metabolically inert and freely diffusible tracer, the net retention of 15O-water in the myocardium is zero and there is no contrast between the myocardial wall and the cavity in a standard uptake image of 15O-water. The lack of contrast poses difficulties for the measurement of cardiac function and remodeling, paramount assessments for coronary artery disease evaluation along with MBF. Part one of the aim of this thesis is the development and evaluation of methods for assessment of cardiac function and remodeling in terms of left-ventricular (LV) volumes and ejection fraction (EF), LV mass (LVM), and LV wall thickness (WT). Part two is focused on patient motion, which occurs frequently in all cardiac PET studies and represents a possible source for induced error in the quantification of MBF.  The feasibility of LV volumes and EF calculations was shown in paper I, where cardiac-gated parametric blood-pool images and first-pass images were imported into a commercially available software for SPECT. The method was, however, too laborious for clinical practice but served as an important proof-of-concept. In paper II, LV volumes and EF calculations were performed using first-pass images in the same software used for standard analysis of 15O-water PET and MBF assessment. The results were improved compared to paper I and the method was feasible for clinical implementation. In paper III, LVM and WT calculations were performed using segmentation of perfusable tissue fraction (PTF) images. The results showed high accuracy compared to cardiac magnetic resonance (MR) imaging, and the method was highly automated, allowing for ready clinical implementation. In papers IV-V, the impact of patient motion on the quantitative accuracy of 15O-water PET was investigated. Simulations showed a minimal impact of PET-CT misalignment on MBF, but did show that impact of dynamic motion during PET acquisition was more pronounced. Visual inspection of clinical scans showed frequent motion, but at a small amplitude with generally limited impact according to the simulations. An automated motion detection algorithm was developed which was highly accurate in detecting larger types of motion. A clear pattern of motion-induced artifacts were discovered, which may help improve their visual detection

Influence of image reconstruction on quantitative cardiac 15O-water positron emission tomography

Background The impact on quantitative 15O-water PET/CT of a wide range of different reconstruction settings, including regularized reconstruction by block-sequential regularized expectation maximization (BSREM), was investigated. Methods Twenty clinical stress scans from patients referred for assessment of myocardial ischemia were included. Patients underwent a 4-min dynamic stress PET scan with 15O-water on a digital PET/CT scanner. Twenty-two reconstructions were generated from each scan and a clinical reconstruction was used as reference. Varied parameters were number of iterations, filter, exclusion of time-of-flight and point-spread function, and regularization parameter with BSREM. Analyses were performed in aQuant utilizing two different methods and resulting regional myocardial blood flow (MBF), perfusable tissue fraction (PTF), and transmural MBF (MBFt) values were evaluated. Results Across the two analyses, correlations toward the reference reconstruction were strong for all parameters (ρ ≥ 0.83). Using automated analysis and the diagnostic threshold of hyperemic MBF at 2.3 mL⋅g−1⋅min−1, diagnosis was unchanged irrespective of reconstruction method in all patients except for one, where only four of the most extreme reconstruction methods resulted in a change of diagnosis. Conclusion The low sensitivity of MBF values to reconstruction method and, as previously shown, scanner type and PET/CT misalignment, confirms that diagnostic hyperemic MBF cutoff values can be consistently used for 15O-water

Influence of patient motion on quantitative accuracy in cardiac 15O-water positron emission tomography.

BACKGROUND: Patient motion is a common problem during cardiac PET. The purpose of the present study was to investigate to what extent motions influence the quantitative accuracy of cardiac 15O-water PET/CT and to develop a method for automated motion detection. METHOD: Frequency and magnitude of motion was assessed visually using data from 50 clinical 15O-water PET/CT scans. Simulations of 4 types of motions with amplitude of 5 to 20 mm were performed based on data from 10 scans. An automated motion detection algorithm was evaluated on clinical and simulated motion data. MBF and PTF of all simulated scans were compared to the original scan used as reference. RESULTS: Patient motion was detected in 68% of clinical cases by visual inspection. All observed motions were small with amplitudes less than half the LV wall thickness. A clear pattern of motion influence was seen in the simulations with a decrease of myocardial blood flow (MBF) in the region of myocardium to where the motion was directed. The perfusable tissue fraction (PTF) trended in the opposite direction. Global absolute average deviation of MBF was 3.1% ± 1.8% and 7.3% ± 6.3% for motions with maximum amplitudes of 5 and 20 mm, respectively. Automated motion detection showed a sensitivity of 90% for simulated motions ≥ 10 mm but struggled with the smaller (≤ 5 mm) simulated (sensitivity 45%) and clinical motions (accuracy 48%). CONCLUSION: Patient motion can impair the quantitative accuracy of MBF. However, at typically occurring levels of patient motion, effects are similar to or only slightly larger than inter-observer variability, and downstream clinical effects are likely negligible

Left ventricular volumes and ejection fraction from cardiac ECG-gated 15O-water positron emission tomography compared to cardiac magnetic resonance imaging using simultaneous hybrid PET/MR

Background 15O-water PET is the gold standard for noninvasive quantification of myocardial blood flow. In addition to evaluation of ischemia, the assessment of cardiac function and remodeling is important in all cardiac diseases. However, since 15O-water is freely diffusible and standard uptake images show little contrast between the myocardium and blood pool, the assessment of left-ventricular (LV) volumes and ejection fraction (EF) is challenging. Therefore, the aim of the present study was to investigate the feasibility of calculating LV volumes and EF from first-pass analysis of 15O-water PET, by comparison with cardiac magnetic resonance imaging (CMR) using a hybrid PET/MR scanner. Methods Twenty-four patients with known or suspected CAD underwent a simultaneous ECG-gated cardiac PET/MR scan. The 15O-water first-pass images (0-50 seconds) were analyzed using the CarPET software and the CMR images were analyzed using the software Segment, for LV volumes and EF calculations. The LV volumes and EF were compared using correlation and Bland–Altman analysis. In addition, inter- and intra-observer variability of LV volumes and EF were assessed for both modalities. Results The correlation between PET and CMR was strong for volumes (r > 0.84) and moderate for EF (r = 0.52), where the moderate correlation for EF was partly due to the small range of EF values. Agreement was high for all parameters, with a slight overestimation of PET values for end-diastolic volume but with no significant mean bias for other parameters. Inter- and intra-observer agreement of volumes was high and comparable between PET and CMR. For EF, inter-observer agreement was higher for PET and intra-observer agreement was higher for CMR. Conclusion LV volumes and EF can be calculated by first-pass analysis of a 15O-water PET scan with high accuracy and comparable precision as with CMR

Quantitative myocardial blood flow imaging with integrated time-of-flight PET-MR

Abstract Background The use of integrated PET-MR offers new opportunities for comprehensive assessment of cardiac morphology and function. However, little is known on the quantitative accuracy of cardiac PET imaging with integrated time-of-flight PET-MR. The aim of the present work was to validate the GE Signa PET-MR scanner for quantitative cardiac PET perfusion imaging. Eleven patients (nine male; mean age 59\ua0years; range 46\u201374\ua0years) with known or suspected coronary artery disease underwent 15 O-water PET scans at rest and during adenosine-induced hyperaemia on a GE Discovery ST PET-CT and a GE Signa PET-MR scanner. PET-MR images were reconstructed using settings recommended by the manufacturer, including time-of-flight (TOF). Data were analysed semi-automatically using Cardiac VUer software, resulting in both parametric myocardial blood flow (MBF) images and segment-based MBF values. Correlation and agreement between PET-CT-based and PET-MR-based MBF values for all three coronary artery territories were assessed using regression analysis and intra-class correlation coefficients (ICC). In addition to the cardiac PET-MR reconstruction protocol as recommended by the manufacturer, comparisons were made using a PET-CT resolution-matched reconstruction protocol both without and with TOF to assess the effect of time-of-flight and reconstruction parameters on quantitative MBF values. Results Stress MBF data from one patient was excluded due to movement during the PET-CT scanning. Mean MBF values at rest and stress were (0.92\u2009\ub1\u20090.12) and (2.74\u2009\ub1\u20091.37) mL/g/min for PET-CT and (0.90\u2009\ub1\u20090.23) and (2.65\u2009\ub1\u20091.15) mL/g/min for PET-MR ( p \u2009=\u20090.33 and p \u2009=\u20090.74). ICC between PET-CT-based and PET-MR-based regional MBF was 0.98. Image quality was improved with PET-MR as compared to PET-CT. ICC between PET-MR-based regional MBF with and without TOF and using different filter and reconstruction settings was 1.00. Conclusions PET-MR-based MBF values correlated well with PET-CT-based MBF values and the parametric PET-MR images were excellent. TOF and reconstruction settings had little impact on MBF values

Effect of PET-CT misalignment on the quantitative accuracy of cardiac 15O-water PET

BACKGROUND: Quantification of myocardial blood flow (MBF) with PET requires accurate attenuation correction, which is performed using a separate CT. Misalignment between PET and CT scans has been reported to be a common problem. The purpose of the present study was to assess the effect of PET CT misalignment on the quantitative accuracy of cardiac 15O-water PET. METHODS: Ten clinical patients referred for evaluation of ischemia and assessment of MBF with 15O-water were included in the study. Eleven different misalignments between PET and CT were induced in 6 different directions with 10 and 20 mm amplitudes: caudal (+Z), cranial (- Z), lateral (±X), anterior (+Y), and anterior combined with cranial (+ Y and - Z). Blood flow was quantified from rates of washout (MBF) and uptake (transmural MBF, MBFt) for the whole left ventricle and the three coronary territories. The results from all misalignments were compared to the original scan without misalignment. RESULTS: MBF was only minorly affected by misalignments, but larger effects were seen in MBFt. On the global level, average absolute deviation across all misalignments for MBF was 1.7% ± 1.4% and for MBFt 5.4% ± 3.2 Largest deviation for MBF was - 4.8% ± 5.8% (LCX, X + 20) and for MBFt - 19.3% ± 9.6% (LCX, X + 20). In general, larger effects were seen in LAD and LCX compared to in RCA. CONCLUSION: The quantitative accuracy of MBF from 15O-water PET, based on the washout of the tracer, is only to a minor extent affected by misalignment between PET and CT

Positron emission tomography (O-15-water, C-11-acetate, C-11-HED) risk markers and nonsustained ventricular tachycardia in hypertrophic cardiomyopathy

Background: The objectives of the study were to describe positron emission tomography (PET) parameters, using the tracers O-15-water at rest/stress, C-11-acetate, and C-11-HED, with regard to nonsustained ventricular tachycardia (NSVT) in hypertrophic cardiomyopathy (HCM). PET offers quantitative assessment of pathophysiology throughout the left ventricular segments, including the endocardium/epicardium. The potential use PET in risk stratification remains to be elucidated. NSVT provides a marker for sudden cardiac death. Methods: Patients with a validated diagnosis of HCM who had an implantable cardioverter-defibrillator were interrogated at 12 months and independently of PET-examinations. Results: In total, 25 patients (mean age 56.8 +/- 12.9 years, 76% males) were included and 10 reported NSVT. Mean myocardial blood flow (MBF) at rest was 0.91 ml/g/min and decreased at stress, 1.59 ml/ g/min. The mean gradient (endocardium/epicardium quotient) at rest was 1.14 +/- 0.09, while inverse at stress (mean 0.92 +/- 0.16). Notably, MBF gradient at stress was significantly lower in patients with NSVT (p = 0.022) and borderline at rest (p = 0.059) while global MBF at rest and stress were not. Mean myocardial oxygen consumption (MVO2) was 0.088 ml/g/min (higher in NSVT, p = 0.023) and myocardial external efficiency 18.5%. Using C-11-HED, the mean retention index was 0.11 min (1) and a higher volume of distribution (p = 0.089) or transmural gradient of clearance rate (p = 0.061) or lower clearance rate (p = 0.052) showed a tendency of association of NSVT. Conclusions: The endocardium/epicardium MBF gradient at stress is significantly lower in HCM patients with NSVT. This provides a novel approach to further refine risk stratification of sudden cardiac death

Calculation of left ventricular volumes and ejection fraction from dynamic cardiac-gated 15O-water PET/CT : 5D-PET

BACKGROUND: Quantitative measurement of myocardial blood flow (MBF) is of increasing interest in the clinical assessment of patients with suspected coronary artery disease (CAD). (15)O-water positron emission tomography (PET) is considered the gold standard for non-invasive MBF measurements. However, calculation of left ventricular (LV) volumes and ejection fraction (EF) is not possible from standard (15)O-water uptake images. The purpose of the present work was to investigate the possibility of calculating LV volumes and LVEF from cardiac-gated parametric blood volume (V B) (15)O-water images and from first pass (FP) images. Sixteen patients with mitral or aortic regurgitation underwent an eight-gate dynamic cardiac-gated (15)O-water PET/CT scan and cardiac MRI. V B and FP images were generated for each gate. Calculations of end-systolic volume (ESV), end-diastolic volume (EDV), stroke volume (SV) and LVEF were performed with automatic segmentation of V B and FP images, using commercially available software. LV volumes and LVEF were calculated with surface-, count-, and volume-based methods, and the results were compared with gold standard MRI. RESULTS: Using V B images, high correlations between PET and MRI ESV (r = 0.89, p < 0.001), EDV (r = 0.85, p < 0.001), SV (r = 0.74, p = 0.006) and LVEF (r = 0.72, p = 0.008) were found for the volume-based method. Correlations for FP images were slightly, but not significantly, lower than those for V B images when compared to MRI. Surface- and count-based methods showed no significant difference compared with the volume-based correlations with MRI. The volume-based method showed the best agreement with MRI with no significant difference on average for EDV and LVEF but with an overestimation of values for ESV (14%, p = 0.005) and SV (18%, p = 0.004) when using V B images. Using FP images, none of the parameters showed a significant difference from MRI. Inter-operator repeatability was excellent for all parameters (ICC > 0.86, p < 0.001). CONCLUSION: Calculation of LV volumes and LVEF from dynamic (15)O-water PET is feasible and shows good correlation with MRI. However, the analysis method is laborious, and future work is needed for more automation to make the method more easily applicable in a clinical setting

Quantitation of mitral regurgitation using positron emission tomography

Background: Cardiac positron emission tomography (PET) offers non-invasive assessment of perfusion and left ventricular (LV) function from a single dynamic scan. However, no prior assessment of mitral regurgitation severity by PET has been presented. Application of indicator dilution techniques and gated image analyses to PET data enables calculation of forward stroke volume and total LV stroke volume. We aimed to evaluate a combination of these methods for measurement of regurgitant volume (RegVol) and fraction (RegF) using dynamic 15O-water and 11C-acetate PET in comparison to cardiovascular magnetic resonance (CMR). Results: Twenty-one patients with severe primary mitral valve regurgitation underwent same-day dynamic PET examinations (O-15-water and C-11-acetate) and CMR. PET data were reconstructed into dynamic series with short time frames during the first pass, gated O-15-water blood pool images, and gated C-11-acetate myocardial uptake images. PET-based RegVol and RegF correlated strongly with CMR (RegVol: O-15-water r = 0.94, C-11-acetate r = 0.91 and RegF: O-15-water r = 0.88, C-11-acetate r = 0.84, p < 0.001). A systematic underestimation (bias) was found for PET (RegVol: O-15-water - 11 +/- 13 mL, p = 0.002, C-11-acetate - 28 +/- 16 mL, p < 0.001 and RegF: O-15-water - 4 +/- 6%, p = 0.01, C-11-acetate - 10 +/- 7%, p < 0.001). PET measurements in patients were compared to healthy volunteers (n = 18). Mean RegVol and RegF was significantly lower in healthy volunteers compared to patients for both tracers. The accuracy of diagnosing moderately elevated regurgitant volume (> 30mL) was 95% for O-15-water and 92% for C-11-acetate. Conclusions: LV regurgitation severity quantified using cardiac PET correlated with CMR and showed high accuracy for discriminating patients from healthy volunteers