Stephanie Thorn

ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy.

Diseases of ectopic calcification of the vascular wall range from lethal orphan diseases such as generalized arterial calcification of infancy (GACI), to common diseases such as hardening of the arteries associated with aging and calciphylaxis of chronic kidney disease (CKD). GACI is a lethal orphan disease in which infants calcify the internal elastic lamina of their medium and large arteries and expire of cardiac failure as neonates, while calciphylaxis of CKD is a ubiquitous vascular calcification in patients with renal failure. Both disorders are characterized by vascular Mönckeburgs sclerosis accompanied by decreased concentrations of plasma inorganic pyrophosphate (PPi). Here we demonstrate that subcutaneous administration of an ENPP1-Fc fusion protein prevents the mortality, vascular calcifications and sequela of disease in animal models of GACI, and is accompanied by a complete clinical and biomarker response. Our findings have implications for the treatment of rare and common diseases of ectopic vascular calcification.

Scatter and crosstalk corrections for (99m)Tc/(123)I dual-radionuclide imaging using a CZT SPECT system with pinhole collimators.

PURPOSE The energy spectrum for a cadmium zinc telluride (CZT) detector has a low energy tail due to incomplete charge collection and intercrystal scattering. Due to these solid-state detector effects, scatter would be overestimated if the conventional triple-energy window (TEW) method is used for scatter and crosstalk corrections in CZT-based imaging systems. The objective of this work is to develop a scatter and crosstalk correction method for (99m)Tc/(123)I dual-radionuclide imaging for a CZT-based dedicated cardiac SPECT system with pinhole collimators (GE Discovery NM 530c/570c). METHODS A tailing model was developed to account for the low energy tail effects of the CZT detector. The parameters of the model were obtained using (99m)Tc and (123)I point source measurements. A scatter model was defined to characterize the relationship between down-scatter and self-scatter projections. The parameters for this model were obtained from Monte Carlo simulation using SIMIND. The tailing and scatter models were further incorporated into a projection count model, and the primary and self-scatter projections of each radionuclide were determined with a maximum likelihood expectation maximization (MLEM) iterative estimation approach. The extracted scatter and crosstalk projections were then incorporated into MLEM image reconstruction as an additive term in forward projection to obtain scatter- and crosstalk-corrected images. The proposed method was validated using Monte Carlo simulation, line source experiment, anthropomorphic torso phantom studies, and patient studies. The performance of the proposed method was also compared to that obtained with the conventional TEW method. RESULTS Monte Carlo simulations and line source experiment demonstrated that the TEW method overestimated scatter while their proposed method provided more accurate scatter estimation by considering the low energy tail effect. In the phantom study, improved defect contrasts were observed with both correction methods compared to no correction, especially for the images of (99m)Tc in dual-radionuclide imaging where there is heavy contamination from (123)I. In this case, the nontransmural defect contrast was improved from 0.39 to 0.47 with the TEW method and to 0.51 with their proposed method and the transmural defect contrast was improved from 0.62 to 0.74 with the TEW method and to 0.73 with their proposed method. In the patient study, the proposed method provided higher myocardium-to-blood pool contrast than that of the TEW method. Similar to the phantom experiment, the improvement was the most substantial for the images of (99m)Tc in dual-radionuclide imaging. In this case, the myocardium-to-blood pool ratio was improved from 7.0 to 38.3 with the TEW method and to 63.6 with their proposed method. Compared to the TEW method, the proposed method also provided higher count levels in the reconstructed images in both phantom and patient studies, indicating reduced overestimation of scatter. Using the proposed method, consistent reconstruction results were obtained for both single-radionuclide data with scatter correction and dual-radionuclide data with scatter and crosstalk corrections, in both phantom and human studies. CONCLUSIONS The authors demonstrate that the TEW method leads to overestimation in scatter and crosstalk for the CZT-based imaging system while the proposed scatter and crosstalk correction method can provide more accurate self-scatter and down-scatter estimations for quantitative single-radionuclide and dual-radionuclide imaging.

Quantitative analysis of dynamic 123I-mIBG SPECT imaging data in healthy humans with a population-based metabolite correction method

Conventional 2-dimensional planar imaging of 123I-metaiodobenzylguanidine (123I-mIBG) is not fully quantitative. To develop a more accurate quantitative imaging approach, we investigated dynamic SPECT imaging with kinetic modeling in healthy humans to obtain the myocardial volume of distribution (VT) for 123I-mIBG. Methods: Twelve healthy humans underwent 5 serial 15-min SPECT scans at 0, 15, 90, 120, and 180 min after bolus injection of 123I-mIBG on a hybrid cadmium zinc telluride SPECT/CT system. Serial venous blood samples were obtained for radioactivity measurement and radiometabolite analysis. List-mode data of all the scans were binned into frames and reconstructed with attenuation and scatter corrections. Myocardial and blood-pool volumes of interest were drawn on the reconstructed images to derive the myocardial time–activity curve and input function. A population-based blood-to-plasma ratio (BPR) curve was generated. Both the population-based metabolite correction (PBMC) and the individual metabolite correction (IMC) curves were generated for comparison. VT values were obtained from different compartment models, using different input functions with and without metabolite and BPR corrections. Results: The BPR curve reached the peak value of 2.1 at 13 min after injection. Parent fraction was approximately 58% ± 13% at 15 min and stabilized at approximately 40% ± 5% by 180 min after injection. Two radiometabolite species were observed. When the reversible 2-tissue-compartment fit was used, the mean VT value was 29.0 ± 12.4 mL/cm3 with BPR correction and PBMC, a 188% ± 32% increase compared with that without corrections. There was significant difference in VT with BPR correction (P = 2.3e-04) as well as with PBMC (P = 1.6e-05). The mean difference in VT between PBMC and IMC was −3% ± 8%, which was insignificant (P = 0.39). The intersubject coefficients of variation after PBMC (43%) and IMC (42%) were similar. Conclusion: The myocardial VT of 123I-mIBG was established in healthy humans for the first time. Accurate kinetic modeling of 123I-mIBG requires both BPR and metabolite corrections. Population-based BPR correction and metabolite correction curves were developed, allowing more convenient absolute quantification of dynamic 123I-mIBG SPECT images.

Simplified Quantification and Acquisition Protocol for 123I-MIBG Dynamic SPECT

Previous studies have demonstrated the feasibility of absolute quantification of dynamic 123I-metaiodobenzylguanidine (123I-MIBG) SPECT imaging in humans. This work reports a simplified quantification method for dynamic 123I-MIBG SPECT using practical protocols with shortened acquisition time and voxel-by-voxel parametric imaging. Methods: Twelve healthy human volunteers underwent five 15-min dynamic SPECT scans at 0, 15, 90, 120, and 180 min after 123I-MIBG injection. List-mode SPECT data were binned into 29 frames and reconstructed with corrections for attenuation, scatter, and decay. Population-based blood-to-plasma correction and metabolite correction were applied to the image-derived input function. Likelihood estimation in graphical analysis (LEGA) was used as a simplified model to obtain volume of distribution (VT) values, which were compared with those obtained with the reversible 2-tissue (2T) compartment model. Three simplified protocols were evaluated with 2T and LEGA using a 30-min scan started simultaneously with tracer injection plus a 15-min scan at 90, 120, or 180 min after injection. Voxel-by-voxel LEGA fitting was applied to the aligned dynamic images using both the full protocol (five 15-min scans) and the simplified protocols. Results: Correlation analysis (y = 0.955x + 0.547, R2 = 0.997) and Bland–Altman plot (mean difference, −0.8 mL/cm3; 95% limits of agreement, [−2.5, 1.0] mL/cm3; normal VT range, 29.0 ± 12.4 mL/cm3) showed that LEGA can be used as a simplified model of 2T for 123I-MIBG. High-quality VT parametric images could be obtained with LEGA. Region-of-interest (ROI) modeling and parametric imaging results were in excellent agreement as determined by correlation analysis (y = 0.999x − 1.026, R2 = 0.982) and Bland–Altman plot (mean difference, −1.0 mL/cm3; 95% limits of agreement, [−4.2, 2.1] mL/cm3). VT correlated reasonably well between all simplified protocols and the full protocol with LEGA but not with 2T. The VT results were more reliable when there was a longer interval between the 2 acquisitions in the simplified protocols. Conclusion: For ROI-based kinetic modeling and parametric imaging, reliable quantification of dynamic 123I-MIBG SPECT can be achieved with LEGA using a simplified protocol of a 30-min scan starting with tracer injection plus a 15-min scan no earlier than 180 min after injection.

Insulin therapy normalizes reduced myocardial β-adrenoceptors at both the onset and after sustained hyperglycemia in diabetic rats.

AIMS Reduced cardiac β-adrenoceptors (β-AR) and cardiovascular (CV) dysfunction occur in diabetes mellitus (DM) and can be normalized by insulin. It is unclear how the duration of untreated hyperglycemia prior to intervention impacts insulins effects. This study assesses insulins effect on reduced myocardial β-AR and CV function, comparing insulin therapy at the onset of hyperglycemia and after a sustained period of hyperglycemia in streptozotocin (STZ) rats. MAIN METHODS Ex vivo biodistribution experiments with [(3)H]CGP12177 were performed in high-fat fed STZ rats after 8 weeks of hyperglycemia evaluating cardiac β-AR expression. Western blotting of β-AR subtypes was completed in parallel. Serial echocardiography at 0, 6, and 8 weeks post-STZ investigated CV function. Sub-groups of hyperglycemic rats were treated with insulin early, at 1 week post-STZ (InsE) for 7 weeks, or late at 6 weeks post-STZ (InsL) for 2 weeks to observe how the duration of hyperglycemia prior to insulin impacts its effects. KEY FINDINGS Reduced myocardial [(3)H]CGP12177 binding occurred 8 weeks post-STZ in hyperglycemics, but was normal in both insulin treatments. Western blotting supported reduced β1-AR in hyperglycemics, but not in either treatment. InsE and InsL treatments improved prolonged mitral valve deceleration (MVD) observed in hyperglycemic animals, but hyperglycemic and InsL still displayed reduced heart rates (HR). SIGNIFICANCE This work supports that glycemic control with insulin normalizes cardiac β-AR effectively regardless of prior hyperglycemia but HR may not recover as readily, indirectly supporting the utility of [(11)C]CGP12177 positron emission tomography (PET) in assessing cardiac β-AR and their modulation with glycemic therapy.

Towards high-resolution fat-suppressed T1-mapping of atrial fibrosis in the left atrium: a fit-free three-point method

Background Atrial fibrosis identification by late gadolinium enhancement (LGE) CMR is important as a precursor to atrial fibrillation, and may impact the outcome of catheter ablation. However, the LGE enhancement in the thin atrial wall is difficult to accurately and reproducibly detect. We sought to improve identification of fibrosis through T1-mapping, generating an index of the extracellular volume fraction (ECV). In order to achieve high spatial resolution mapping for a narrow range of relevant T1-values (250-500ms) in a feasible scan time, we applied fit-free T1-mapping with only 3 TI values (3-pt). Preliminary data measuring the ECV of normal myocardium and the aortic valves—a thin fibrotic structure– are presented.

Evaluation of structural remodeling of the atria with OCT in a chronic rat model of myocardial infarction (Conference Presentation)

Atrial fibrillation (AF) occurs following myocardial infarction (MI) and is associated with left ventricular dysfunction, which promotes the development of atrial remodeling and permanent atrial fibrosis. The purpose of this study was determining the effects of MI on left atrial (LA) remodeling with and without therapy with an angiotensin converting enzyme inhibition (ACEi) utilizing optical coherence tomography (OCT). As the composition of the myocardial tissue changes during LA remodeling the optical attenuation of the light will also change providing a metric to quantify the structural remodeling process. Lewis rats (240-275 g) underwent either surgical ligation of left coronary artery creating chronic MI, or SHAM surgery. 13 weeks post-surgery, ex vivo OCT imaging was performed of the LA appendage. Depth-resolved, attenuation coefficient volumes were calculated and the resulting atrial wall attenuation values were analyzed for four experimental groups: SHAM, SHAM with ACEi, MI no ACEi, and MI with ACEi. Quantification of tissue attenuation was performed and shown to significantly increase with MI in association with increases in collagen as verified with corresponding histological sectioning. Fractal analysis of the LA wall trabeculation patterns, 100 µm below the surface, was performed to quantify wall thickening associated with LA remodeling. A significant increase in fractal dimension was determined post MI compared to SHAM corresponding to a loss of the trabeculation pattern and wall thickening. The results from this study demonstrate OCT as an imaging technique capable of investigate LA remodeling with high resolution and label-free optical contrast processing.

Creation of clinically relevant model of chronic heart failure: Application of multi-modality imaging to define physiology

Heart failure (HF) remains a major cause of mortality and morbidity in the world. Despite significant improvement in both medical and surgical therapies for HF, the mortality rate persists in excess of 50% after 5 years. Ischemic heart disease remains a leading cause of HF, and has a complex and incompletely understood pathophysiology with acute ischemic injury evolving to progressive left ventricular (LV) dysfunction and structural remodeling. These chronic functional and structural changes are associated with compensatory neurohormonal and metabolic alterations. The complex natural progress of atherosclerosis in humans can lead to either acute or slowly progressive coronary occlusion with the initial ischemic insult not easily emulated in an animal model. Pre-clinical approaches and large animal models to mimic ischemic heart disease have included single and multi-step catheter-based and surgical interventions. Generally, these interventions are performed in normal animals without the same pathophysiological substrate that leads to atherosclerosis or modulates the repair processes in humans. Therefore, the initial injury, repair, and remodeling processes may not be completely comparable to the clinical scenario. However, robust large animal models have tried to reproduce the fundamental characteristics of the process of repair and LV remodeling, including changes in LV geometry and dilatation, eccentric hypertrophy, infarct expansion, alterations in regional and global LV systolic and diastolic performance and functional reserve under stress, alterations in LV mass, and changes in regional wall thickness. Ideally, these animal models should have a mortality rate that is comparable to the clinical scenario and be highly reproducible in order to provide proper predicative value for clinical investigations into the pathophysiological mechanisms, and evaluation of novel therapeutics and interventions. While several large animal models have been employed to model ischemic heart disease in humans (including canine, porcine, and ovine), the coronary and gross cardiac anatomy in swine is fairly equivocal to humans. Unlike canine models, that have a significant native collateral circulation, swine have less native preformed collateral circulation in the mid-myocardium and sub-endocardium. Therefore, the porcine model is frequently used to test devices and therapies in models of acute ischemic heart disease, as well as models of chronic ventricular remodeling post-ischemic injury, and HF. The size of swine also allow for the use of standardized clinical investigational tools and equipment, including advanced clinical imaging systems. Recent reviews have summarized the animal models of HF, and some have even focused specifically on porcine models. Large animal models of HF with preserved ejection fraction (HFpEF) have been more difficult to establish partly due to the incomplete pathological understanding of HFpEF. There is one proposed swine model that is thought to mimic HFpEF that involves staged banding of Reprint requests: Albert J. Sinusas, MD, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, P.O. Box 208017, New Haven, CT 06520-8017; albert.sinusas@yale.edu J Nucl Cardiol 2015;22:673–6. 1071-3581/

Left atrial function after myocardial infarction in swine

34.00 Copyright 2015 American Society of Nuclear Cardiology.

T1-refBlochi: high resolution 3D post-contrast T1 myocardial mapping based on a single 3D late gadolinium enhancement volume, Bloch equations, and a reference T1

Background Atrial fibrillation is the most common arrhythmia in United States, and is associated with atrial fibrosis. Although the cause of atrial fibrosis development is not understood, its etiology is related to cardiac dysfunction, mitral regurgitation (MR), and coronary artery disease. This study focuses on determining the acute effects of myocardial infarction (MI) on left atrial (LA) function. Our hypothesis is that MI may result in changes in left ventricular relaxation, MR, and LA pressure and volume overload, leading to changes in LA geometry and mechanics, which will result in later atrial fibrosis. We studied the changes in LA size, ejection fraction, and the relative contributions of passive and active emptying, comparing controls with post-MI animals. Methods Eleven Yorkshire pigs (average weight 37 ± 7 kg) were studied, including 5 control animals, and 6 pigs imaged one to two weeks after a transmural MI. The MI was induced by percutaneous balloon occlusion of left coronary artery (90 min) followed by reperfusion. All animals were imaged on a 1.5T Siemens scanner (Siemens Healthcare, Erlangen, Germany). A stack of short-axis cine images covering the left atrium were obtained with balanced SSFP, with a 1.3 x 1.3 x 3 mm spatial resolution (no gaps), and 25 frames, breath-holding and retrospective ECG-gating. All image processing was performed in Matlab (v 2014). To measure LA volume through the cardiac cycle, the cine images were segmented using thresholding, and regions of