Stefan de Haan

Hybrid Imaging Using Quantitative H215O PET and CT-Based Coronary Angiography for the Detection of Coronary Artery Disease

Hybrid imaging using PET in conjunction with CT-based coronary angiography (PET/CTCA) enables near-simultaneous quantification of myocardial blood flow (MBF) and anatomical evaluation of coronary arteries. CTCA is an excellent imaging modality to rule out obstructive coronary artery disease (CAD), but functional assessment is warranted in the presence of a CTCA-observed stenosis because the specificity of CTCA is relatively low. Quantitative H215O PET/CTCA may yield complementary information and enhance diagnostic accuracy. The purpose of this study was to evaluate the diagnostic accuracy of quantitative H215O PET/CTCA in a clinical cohort of patients with suspected CAD who underwent both cardiac H215O PET/CTCA and invasive coronary angiography (ICA). In addition, this study aimed to evaluate and compare the accuracy of hyperemic MBF versus coronary flow reserve (CFR). Methods: Patients (n = 120; mean age ± SD, 61 ± 10 y; 77 men and 43 women) with a predominantly intermediate pretest likelihood for CAD underwent both quantitative H215O PET/CTCA and ICA. A ≥50% stenosis at ICA or a fractional flow reserve ≤ 0.80 was considered significant. Results: Obstructive CAD was diagnosed in 49 of 120 patients (41%). The diagnostic accuracy of hyperemic MBF was significantly higher than CFR (80% vs. 68%, respectively, P = 0.02), with optimal cutoff values of 1.86 mL/min/g and 2.30, respectively. On a per-patient basis, the sensitivity, specificity, negative predictive value, and positive predictive value of CTCA were 100%, 34%, 100%, and 51%, respectively, as compared with 76%, 83%, 83%, and 76%, respectively, for quantitative hyperemic MBF PET. Quantitative H215O PET/CTCA reduced the number of false-positive CTCA studies from 47 to 6, although 12 of 49 true-positive CTCAs were incorrectly reclassified as false-negative hybrid scans on the basis of (presumably) sufficient hyperemic MBF. Compared with CTCA (61%) or H215O PET (80%) alone (both P < 0.05), the hybrid approach significantly improved diagnostic accuracy (85%). Conclusion: The diagnostic accuracy of quantitative H215O PET/CTCA is superior to either H215O PET or CTCA alone for the detection of clinically significant CAD. Hyperemic MBF was more accurate than CFR, implying that a single measurement of MBF in diagnostic protocols may suffice.

Automatic generation of absolute myocardial blood flow images using [15O]H2O and a clinical PET/CT scanner

PurposeParametric imaging of absolute myocardial blood flow (MBF) using [15O]H2O enables determination of MBF with high spatial resolution. The aim of this study was to develop a method for generating reproducible, high-quality and quantitative parametric MBF images with minimal user intervention.MethodsNineteen patients referred for evaluation of MBF underwent rest and adenosine stress [15O]H2O positron emission tomography (PET) scans. Ascending aorta and right ventricular (RV) cavity volumes of interest (VOIs) were used as input functions. Implementation of a basis function method (BFM) of the single-tissue model with an additional correction for RV spillover was used to generate parametric images. The average segmental MBF derived from parametric images was compared with MBF obtained using nonlinear least-squares regression (NLR) of VOI data. Four segmentation algorithms were evaluated for automatic extraction of input functions. Segmental MBF obtained using these input functions was compared with MBF obtained using manually defined input functions.ResultsThe average parametric MBF showed a high agreement with NLR-derived MBF [intraclass correlation coefficient (ICC) = 0.984]. For each segmentation algorithm there was at least one implementation that yielded high agreement (ICC > 0.9) with manually obtained input functions, although MBF calculated using each algorithm was at least 10% higher. Cluster analysis with six clusters yielded the highest agreement (ICC = 0.977), together with good segmentation reproducibility (coefficient of variation of MBF <5%).ConclusionParametric MBF images of diagnostic quality can be generated automatically using cluster analysis and a implementation of a BFM of the single-tissue model with additional RV spillover correction.

Low-Dose Quantitative Myocardial Blood Flow Imaging Using 15O-Water and PET Without Attenuation Correction

Misalignment between PET and low-dose CT (LD-CT) can cause severe artifacts in cardiac PET/CT because of attenuation-correction errors, even when using slow or cine LD-CT. Myocardial blood flow (MBF), as measured by 15O-water, can be determined from the rate of 15O-water washout from myocardial tissue, which is independent of tissue attenuation. The purpose of the present study was to assess the accuracy of these MBF measurements in the absence of attenuation correction. Methods: Twenty-five patients referred for evaluation of myocardial perfusion underwent 6-min rest and adenosine stress PET scans after the administration of 370 MBq of 15O-water; both scans were followed by slow LD-CT. Data were acquired on a PET/CT scanner and reconstructed by a 3-dimensional row-action maximum likelihood algorithm both with (CTAC) and without (NAC) attenuation correction. An ascending aorta volume of interest was used as input function. MBF and coronary flow reserve (CFR) were calculated for 17 myocardial segments using nonlinear regression of the standard single-tissue-compartment model with corrections for left and right ventricular spillover and perfusable tissue fraction. Results: High correlation (r2 = 0.99 and 0.97, with slopes of 0.96 and 0.91 for rest and stress, respectively) and excellent agreement (intraclass correlation coefficient [ICC], 1.00 and 0.98) between NAC- and CTAC-based MBF values were found. Absolute rest and stress MBF values were 3% and 8%, respectively, lower for NAC scans. The correlation coefficient between all NAC and CTAC CFR values was 0.95 (ICC, 0.95; slope, 0.92) and 0.97 (ICC, 0.99; slope, 1.01) when only CFR values below 2 were considered. Deviations between CTAC and NAC values were smallest for basal segments and increased toward the apex. Conclusion: MBF and CFR can be measured accurately using 15O-water and PET without correcting for attenuation, reducing the effective dose to the patient to 0.8 mSv for a complete rest–stress protocol. This dose is an order of magnitude lower than typical values for 82Rb, 99mTc-methoxyisobutylisonitrile, or CT perfusion scans.

Parametric Images of Myocardial Viability Using a Single 15O-H2O PET/CT Scan

Perfusable tissue index (PTI) is a marker of myocardial viability and requires acquisition of transmission, 15O-CO, and 15O-H2O scans. The aim of this study was to generate parametric PTI images from a 15O-H2O PET/CT scan without an additional 15O-CO scan. Methods: Data from 20 patients undergoing both 15O-H2O and 15O-CO scans were used, assessing correlation between PTI based on 15O-CO (PTICO) and on fitted blood volume fractions (PTIVb). In addition, parametric PTIVb images of 10 patients undergoing 15O-H2O PET/CT scans were generated using basis-function methods and compared with PTIVb obtained using nonlinear regression. Simulations were performed to study the effects of noise on PTIVb. Results: Correlation between PTICO and PTIVb was high (r2 = 0.73). Parametric PTIVb correlated well with PTIVb obtained using nonlinear regression (r2 = 0.91). Simulations showed low sensitivity to noise (coefficient of variation < 10% at 20% noise). Conclusion: Parametric PTI images can be generated from a single 15O-H2O PET/CT scan.

Impaired Hyperemic Myocardial Blood Flow Is Associated With Inducibility of Ventricular Arrhythmia in Ischemic Cardiomyopathy

Background—Risk stratification for ventricular arrhythmias (VAs) is important to refine selection criteria for primary prevention implantable cardioverter defibrillator therapy. Impaired hyperemic myocardial blood flow (MBF) is associated with increased mortality rate in ischemic and nonischemic cardiomyopathy, which may be attributed to electric instability inducing VAs. The aim of this pilot study was to assess whether hyperemic MBF impairment may be related with VA inducibility in patients with ischemic cardiomyopathy. Methods and Results—Thirty patients with ischemic cardiomyopathy referred for primary prevention implantable cardioverter defibrillator implantation were prospectively included (26 men; 65±8 years old; left ventricular ejection fraction, 29±6%). [15O]H2O positron-emission tomography was performed to quantify resting MBF, hyperemic MBF, and coronary flow reserve. Left ventricular dimensions, function, and scar burden were assessed with cardiovascular magnetic resonance imaging. An electrophysiological study was performed to test VA inducibility. Positive electrophysiological study patients (n=12) showed reduced hyperemic MBF (1.25±0.30 versus 1.66±0.38 mL·min−1·g−1; P<0.01) and coronary flow reserve (1.59±0.49 versus 2.12±0.48; P<0.01) compared with electrophysiological study negative patients (n=18). In electrophysiological study positive patients, the number of scar segments >75% transmurality was higher (P<0.05), although scar size and border zone did not differ. Receiver-operating characteristic curve analysis indicated that impaired hyperemic MBF (area under the curve, 0.84; 95% confidence intervals [0.69–0.99]) and coronary flow reserve (area under the curve, 0.77; 95% confidence intervals [0.57–0.96]) were associated with VA inducibility. Conclusions—In this pilot study, impaired hyperemic MBF and coronary flow reserve were associated with VA inducibility in patients with ischemic cardiomyopathy. These results are hypothesis generating for a potential role of quantitative positron-emission tomography perfusion imaging in risk stratification for VAs.

Use of a Single 11C-Meta-Hydroxyephedrine Scan for Assessing Flow–Innervation Mismatches in Patients with Ischemic Cardiomyopathy

Mismatch between areas of reduced myocardial blood flow (MBF) and reduced myocardial innervation (defect areas) may be used to estimate the risk for ventricular arrhythmias. The presence of a mismatch zone can be derived using a combined protocol consisting of both an MBF scan and an 11C-meta-hydroxyephedrine (11C-HED) scan. The rate of influx from blood to myocardium (K1) of 11C-HED is proportional to MBF and can potentially be used as an index for defining MBF defects. The aim of this study was to assess whether K1 derived from an 11C-HED scan can be used as an index of MBF, potentially allowing for an assessment of MBF–innervation mismatch areas from a single 11C-HED scan. Methods: Seventeen patients with known ischemic cardiomyopathy underwent dynamic 15O-water and 11C-HED scans. Discrete arterial blood samples were taken during 11C-HED scans for metabolite correction of the image-derived input function. 11C-HED influx rate was obtained using a single-tissue-compartment model and compared with transmural MBF (MBFT), defined as MBF as measured with 15O-water multiplied by perfusable tissue fraction. Defect sizes were obtained from parametric K1 and MBFT images, using 50% of a remote control segment as the cutoff value. Results: There was a significant correlation between MBFT and K1 (y = 0.40x + 0.05 mL·g−1·min−1, r = 0.80, P < 0.001), although K1 was significantly lower than MBFT (slope of the regression line significantly different from 1, P < 0.001). Correlation between MBFT and K1 defect sizes was high (y = 0.89x + 1.38%, r = 0.95, P < 0.001), with no significant difference in mean defect size based on K1 or MBFT (20.9% ± 11.3% and 20.1% ± 10.7% for MBFT and K1, respectively, P = 0.41). Conclusion: 11C-HED influx rate K1 can be used as an alternative to a separate MBF scan for assessing mismatch areas between MBF and myocardial innervation.

Carotid artery intima-media thickness, but not coronary artery calcium, predicts coronary vascular resistance in patients evaluated for coronary artery disease.

AIMS There is growing evidence that coronary artery disease (CAD) affects not only the conduit epicardial coronary arteries, but also the microvascular coronary bed. Moreover, coronary microvascular dysfunction (CMVD) often precedes the stage of clinically overt epicardial CAD. Coronary artery calcium (CAC) and carotid intima-media thickness (C-IMT) measured with computed tomography (CT) and ultrasound, respectively, are among the available techniques to non-invasively assess atherosclerotic burden. An increased CAC score and C-IMT have also been associated with CMVD. It is therefore of interest to explore and compare the potential of CAC against C-IMT to predict minimal coronary vascular resistance (CVR). METHODS AND RESULTS We evaluated 120 patients (mean age 56 ± 9 years, 58 men) without a documented history of CAD in whom obstructive CAD was excluded. All patients underwent C-IMT measurements, CAC scoring, and vasodilator stress (15)O-water positron emission tomography (PET)/CT, during which the coronary flow reserve (CFR) and minimal CVR were analysed. Minimal CVR increased significantly with increasing tertiles of C-IMT (22 ± 6, 27 ± 11, and 28 ± 9 mmHg mL(-1)min(-1) g(-1), P < 0.01), whereas the CFR was comparable across all C-IMT groups (P = 0.50). Minimal CVR increased significantly with an increase in CAC score (23 ± 9, 27 ± 8, 32 ± 10, and 32 ± 7 mmHg mL(-1) min(-1) g(-1), P < 0.01), whereas the CFR did not show a significant decrease with higher CAC scores (P = 0.18). Multivariable regression analysis revealed that C-IMT (P = 0.03), but not CAC, was independently associated with minimal CVR. CONCLUSION C-IMT, but not CAC score, independently predicts minimal CVR in patients with multiple cardiovascular risk factors and suspected of CAD.

Effects of QRS Duration and Pacing Location on Pressure-Volume Loop Evaluation of Cardiac Resynchronization Therapy in End-Stage Heart Failure

Cardiac resynchronization therapy (CRT) decreases the morbidity and mortality in patients with end-stage heart failure. However, patient selection remains challenging, because a considerable 30% to 50% do not respond. Controversy exists on the cutoff values for the QRS duration and the optimal lead location. The present study relates these parameters on an individual basis to acute pump function improvement using invasively obtained pressure-volume loops. Fifty-seven patients with symptomatic end-stage heart failure were included in our temporary biventricular stimulation study and were grouped according to the QRS duration (QRS <20 ms, QRS ≥120 ms but <150 ms, and QRS ≥150 ms). All patients underwent pressure-volume loop assessment of the response to biventricular pacing, comparing the baseline measurements to both right ventricular apex pacing combined with a left ventricular lead in the posterolateral and anterolateral region of the LV. Group analysis during conventional (posterolateral and right ventricular apex) CRT did not show improvement in stroke work and dP/dt(max) (-2%, p = NS; and -7%; p <0.001) in the narrow QRS group but a significant increase in the intermediate (+27%, p = 0.020, and +5%, p = 0.044) and wide (+48%, p = 0.002, and +18%, p <0.001) QRS groups. CRT using the anterolateral and right ventricular apex configuration evoked a consistently lower response compared to posterolateral and right ventricular apex, resulting in a significant hemodynamic deterioration in the narrow QRS group. However, analysis on an individual basis identified 25% of patients with narrow QRS duration showing possible hemodynamic benefit from CRT compared to 83% of patients with intermediate and wide QRS combined. In contrast, 15% of patients had deterioration by conventional (posterolateral right ventricular apex) CRT in the intermediate and wide QRS groups compared to 31% in the narrow QRS group; 19% of patients could be improved by lead placement in the anterolateral rather than the posterolateral region. In conclusion, the acute hemodynamic response to CRT is generally in line with the long-term results from large randomized trials; however, the individual variation is large. The temporary biventricular stimulation protocol might aid in individual patient selection and in research aiming at a reduction of nonresponders and improvement in lead positioning.

Quantification of [ 11 C]- meta -hydroxyephedrine uptake in human myocardium

BackgroundThe aims of this study were to determine the optimal tracer kinetic model for [11C]-meta- hydroxyephedrine ([11C]HED) and to evaluate the performance of several simplified methods.MethodsThirty patients underwent dynamic 60-min [11C]HED scans with online arterial blood sampling. Single-tissue and both reversible and irreversible two-tissue models were fitted to the data using the metabolite-corrected arterial input function. For each model, reliable fits were defined as those yielding outcome parameters with a coefficient of variation (CoV) <25%. The optimal model was determined using Akaike and Schwarz criteria and the F-test, together with the number of reliable fits. Simulations were performed to study accuracy and precision of each model. Finally, quantitative results obtained using a population-averaged metabolite correction were evaluated, and simplified retention index (RI) and standardized uptake value (SUV) results were compared with quantitative volume of distribution (VT) data.ResultsThe reversible two-tissue model was preferred in 75.8% of all segments, based on the Akaike information criterion. However, VT derived using the single-tissue model correlated highly with that of the two-tissue model (r2 = 0.94, intraclass correlation coefficient (ICC) = 0.96) and showed higher precision (CoV of 24.6% and 89.2% for single- and two-tissue models, respectively, at 20% noise). In addition, the single-tissue model yielded reliable fits in 94.6% of all segments as compared with 77.1% for the reversible two-tissue model. A population-averaged metabolite correction could not be used in approximately 20% of the patients because of large biases in VT. RI and SUV can provide misleading results because of non-linear relationships with VT.ConclusionsAlthough the reversible two-tissue model provided the best fits, the single-tissue model was more robust and results obtained were similar. Therefore, the single-tissue model was preferred. RI showed a non-linear correlation with VT, and therefore, care has to be taken when using RI as a quantitative measure.

Non-invasive imaging to identify susceptibility for ventricular arrhythmias in ischaemic left ventricular dysfunction

Objective Non-invasive imaging of myocardial perfusion, sympathetic denervation and scar size contribute to enhanced risk prediction of ventricular arrhythmias (VA). Some of these imaging parameters, however, may be intertwined as they are based on similar pathophysiology. The aim of this study was to assess the predictive role of myocardial perfusion, sympathetic denervation and scar size on the inducibility of VA in patients with ischaemic cardiomyopathy in a head-to-head fashion. Methods 52 patients with ischaemic heart disease and left ventricular ejection fraction (LVEF) ≤35%, referred for primary prevention implantable cardioverter-defibrillator (ICD) implantation, were included. Late gadolinium-enhanced cardiovascular MRI was performed to assess LV volumes, function and scar size. Using [15O]H2O and [11C]hydroxyephedrine positron emission tomography, both resting and hyperaemic myocardial blood flow (MBF), and sympathetic innervation were assessed. After ICD implantation, an electrophysiological study (EPS) was performed and was considered positive in case of sustained VA. Results Patients with a positive EPS (n=25) showed more severely impaired global hyperaemic MBF (p=0.003), larger sympathetic denervation size (p=0.048) and tended to have larger scar size (p=0.07) and perfusion defect size (p=0.06) compared with EPS-negative patients (n=27). No differences were observed in LV volumes, LVEF and innervation-perfusion mismatch size. Multivariable analysis revealed that impaired hyperaemic MBF was the single best independent predictor for VA inducibility (OR 0.78, 95% CI 0.65 to 0.94, p=0.007). A combination of risk markers did not yield incremental predictive value over hyperaemic MBF alone. Conclusions Of all previously validated approaches to evaluate the arrhythmic substrate, global impaired hyperaemic MBF was the only independent predictor of VA inducibility. Moreover, a combined approach of different imaging variables did not have incremental value.