Links Between Obstructive Sleep Apnea and Myocardial Blood Flow Changes Impacting Adverse Cardiovascular Disease-related Outcomes.

PURPOSE OF REVIEW: Recent studies have demonstrated an association between obstructive sleep apnea (OSA) and abnormal myocardial blood flow (MBF), myocardial flow reserve (MFR), and coronary microvascular dysfunction (CMD). Here, we review the evidence and describe the potential underlying mechanisms linking OSA to abnormal MBF. Examining relevant studies, we assess the impact of OSA-specific therapy, such as continuous positive airway pressure (CPAP), on MBF. RECENT FINDINGS: Recent studies suggest an association between moderate to severe OSA and abnormal MBF/MFR. OSA promotes functional and structural abnormalities of the coronary microcirculation. OSA also promotes the uncoupling of MBF to cardiac work. In a handful of studies with small sample sizes, CPAP therapy improved MBF/MFR. Moderate to severe OSA is associated with abnormal MFR, suggesting an association with CMD. Evidence suggests that CPAP therapy improves MBF. Future studies must determine the clinical impact of improved MBF with CPAP.

Multi-Task Learning for Motion Analysis and Segmentation in 3D Echocardiography.

Characterizing left ventricular deformation and strain using 3D+time echocardiography provides useful insights into cardiac function and can be used to detect and localize myocardial injury. To achieve this, it is imperative to obtain accurate motion estimates of the left ventricle. In many strain analysis pipelines, this step is often accompanied by a separate segmentation step; however, recent works have shown both tasks to be highly related and can be complementary when optimized jointly. In this work, we present a multi-task learning network that can simultaneously segment the left ventricle and track its motion between multiple time frames. Two task-specific networks are trained using a composite loss function. Cross-stitch units combine the activations of these networks by learning shared representations between the tasks at different levels. We also propose a novel shape-consistency unit that encourages motion propagated segmentations to match directly predicted segmentations. Using a combined synthetic and in-vivo 3D echocardiography dataset, we demonstrate that our proposed model can achieve excellent estimates of left ventricular motion displacement and myocardial segmentation. Additionally, we observe strong correlation of our image-based strain measurements with crystal-based strain measurements as well as good correspondence with SPECT perfusion mappings. Finally, we demonstrate the clinical utility of the segmentation masks in estimating ejection fraction and sphericity indices that correspond well with benchmark measurements.

The development of a novel endovascular grasper for challenging inferior vena cava filter retrieval.

OBJECTIVE: Although inferior vena cava (IVC) filters are commonly retrieved using a snare, lateral tilt and fibrosis around struts can complicate the procedure and sometimes require the use of off-label devices. We describe the development of a novel articulating endovascular grasper designed to remove permanent and retrievable IVC filters in any configuration. METHODS: For in vitro testing, the IVC filters were anchored to the inner wall of a flexible tube in a centered or tilted configuration. A high-contrast backlit camera view simulated the two-dimensional fluoroscopy projection during retrieval. The time from the retrieval device introduction into the camera field to complete filter retrieval was measured in seconds. The control experiment involved temporary IVC filter retrieval with a snare. There were four comparative groups: (1) retrievable filter in centered configuration; (2) retrievable filter in tilted configuration; (3) permanent filter in centered configuration; and (4) permanent filter in tilted configuration. Every experiment was repeated five times, with median retrieval time compared with the control group. For in vivo testing in a porcine model, six tilted infrarenal IVC filters were retrieved with grasper via right jugular approach. Comparison analysis between animal and patient procedures was performed for the following variables: total procedure time, the retrieval time, and fluoroscopy time. RESULTS: The in vitro experiments showed comparable retrieval times between the experimental groups 1, 2, and 4 and the control. However, grasper removal of a centered permanent filter (group 3) required significantly less time than in the control (29 vs 79 seconds; P = .009). In the animal model, all IVC filters were retrieved using the grasper with no adverse events. The total procedure time (21.2 vs 43.5 minutes; P = .01) and the fluoroscopy time (4.3 vs 10 minutes; P = .044) were significantly shorter in the animal model compared with the patient group. Moreover, in the patient group, 16.7% of retrievals required advanced endovascular techniques, and one IVC filter could not be retrieved (success rate = 91.7%), whereas all the IVC filters were successfully retrieved in the animal model without the use of additional tools. CONCLUSIONS: The novel endovascular grasper is effective in retrieving different types of IVC filters in different configurations and compared favorably with the snare in the in vitro model. In vivo experiments demonstrated more effective retrieval when compared with matched patient retrievals.

Improvement in cardiac function and regional LV strain following intramyocardial injection of a theranostic hydrogel early postmyocardial infarction in a porcine model.

Myocardial infarction (MI) is often complicated by left ventricular (LV) remodeling and heart failure. We evaluated the feasibility of a multimodality imaging approach to guide delivery of an imageable hydrogel and assessed LV functional changes with therapy. Yorkshire pigs underwent surgical occlusions of branches of the left anterior descending and/or circumflex artery to create an anterolateral MI. We evaluated the hemodynamic and mechanical effects of intramyocardial delivery of an imageable hydrogel in the central infarct area (Hydrogel group, n = 8) and a Control group (n = 5) early post-MI. LV and aortic pressure and ECG were measured and contrast cineCT angiography was performed at baseline, 60 min post-MI, and 90 min post-hydrogel delivery. LV hemodynamic indices, pressure-volume measures, and normalized regional and global strains were measured and compared. Both Control and Hydrogel groups demonstrated a decline in heart rate, LV pressure, stroke volume, ejection fraction, and pressure-volume loop area, and an increase in myocardial performance (Tei) index and supply/demand (S/D) ratio. After hydrogel delivery, Tei index and S/D ratio were reduced to baseline levels, diastolic and systolic functional indices either stabilized or improved, and radial strain and circumferential strain increased significantly in the MI regions (ENrr: +52.7%, ENcc: +44.1%). However, the Control group demonstrated a progressive decline in all functional indices to levels significantly below those of Hydrogel group. Thus, acute intramyocardial delivery of a novel imageable hydrogel to MI region resulted in rapid stabilization or improvement in LV hemodynamics and function.NEW & NOTEWORTHY Our study demonstrates that contrast cineCT imaging can be used to evaluate the acute effects of intramyocardial delivery of a therapeutic hydrogel to the central MI region early post MI, which resulted in a rapid stabilization of LV hemodynamics and improvement in regional and global LV function.

Co-attention spatial transformer network for unsupervised motion tracking and cardiac strain analysis in 3D echocardiography.

Myocardial ischemia/infarction causes wall-motion abnormalities in the left ventricle. Therefore, reliable motion estimation and strain analysis using 3D+time echocardiography for localization and characterization of myocardial injury is valuable for early detection and targeted interventions. Previous unsupervised cardiac motion tracking methods rely on heavily-weighted regularization functions to smooth out the noisy displacement fields in echocardiography. In this work, we present a Co-Attention Spatial Transformer Network (STN) for improved motion tracking and strain analysis in 3D echocardiography. Co-Attention STN aims to extract inter-frame dependent features between frames to improve the motion tracking in otherwise noisy 3D echocardiography images. We also propose a novel temporal constraint to further regularize the motion field to produce smooth and realistic cardiac displacement paths over time without prior assumptions on cardiac motion. Our experimental results on both synthetic and in vivo 3D echocardiography datasets demonstrate that our Co-Attention STN provides superior performance compared to existing methods. Strain analysis from Co-Attention STNs also correspond well with the matched SPECT perfusion maps, demonstrating the clinical utility for using 3D echocardiography for infarct localization.

Matrix Metalloproteinase-Targeted SPECT/CT Imaging for Evaluation of Therapeutic Hydrogels for the Early Modulation of Post-Infarct Myocardial Remodeling.

Following myocardial infarction (MI), maladaptive upregulation of matrix metalloproteinase (MMP) alters extracellular matrix leading to cardiac remodeling. Intramyocardial hydrogel delivery provides a vehicle for local delivery of MMP tissue inhibitors (rTIMP-3) for MMP activity modulation. We evaluated swine 10-14 days following MI randomized to intramyocardial delivery of saline, degradable hyaluronic acid (HA) hydrogel, or rTIMP-3 releasing hydrogel with an MMP-targeted radiotracer (99mTc-RP805), 201Tl, and CT. Significant left ventricle (LV) wall thinning, increased wall stress, reduced circumferential wall strain occurred in the MI region of MI-Saline group along with left atrial (LA) dilation, while these changes were modulated in both hydrogel groups. 99mTc-RP805 activity increased twofold in MI-Saline group and attenuated in hydrogel animals. Infarct size significantly reduced only in rTIMP-3 hydrogel group. Hybrid SPECT/CT imaging demonstrated a therapeutic benefit of intramyocardial delivery of hydrogels post-MI and reduced remodeling of LA and LV in association with a reduction in MMP activation.

Cellular recovery after prolonged warm ischaemia of the whole body.

After cessation of blood flow or similar ischaemic exposures, deleterious molecular cascades commence in mammalian cells, eventually leading to their death1,2. Yet with targeted interventions, these processes can be mitigated or reversed, even minutes or hours post mortem, as also reported in the isolated porcine brain using BrainEx technology3. To date, translating single-organ interventions to intact, whole-body applications remains hampered by circulatory and multisystem physiological challenges. Here we describe OrganEx, an adaptation of the BrainEx extracorporeal pulsatile-perfusion system and cytoprotective perfusate for porcine whole-body settings. After 1 h of warm ischaemia, OrganEx application preserved tissue integrity, decreased cell death and restored selected molecular and cellular processes across multiple vital organs. Commensurately, single-nucleus transcriptomic analysis revealed organ- and cell-type-specific gene expression patterns that are reflective of specific molecular and cellular repair processes. Our analysis comprises a comprehensive resource of cell-type-specific changes during defined ischaemic intervals and perfusion interventions spanning multiple organs, and it reveals an underappreciated potential for cellular recovery after prolonged whole-body warm ischaemia in a large mammal.

Atrial AMP-activated protein kinase is critical for prevention of dysregulation of electrical excitability and atrial fibrillation.

Metabolic stress is an important cause of pathological atrial remodeling and atrial fibrillation. AMPK is a ubiquitous master metabolic regulator, yet its biological function in the atria is poorly understood in both health and disease. We investigated the impact of atrium-selective cardiac AMPK deletion on electrophysiological and structural remodeling in mice. Loss of atrial AMPK expression caused atrial changes in electrophysiological properties and atrial ectopic activity prior to the onset of spontaneous atrial fibrillation. Concomitant transcriptional downregulation of connexins and atrial ion channel subunits manifested with delayed left atrial activation and repolarization. The early molecular and electrophysiological abnormalities preceded left atrial structural remodeling and interstitial fibrosis. AMPK inactivation induced downregulation of transcription factors (Mef2c and Pitx2c) linked to connexin and ion channel transcriptional reprogramming. Thus, AMPK plays an essential homeostatic role in atria, protecting against adverse remodeling potentially by regulating key transcription factors that control the expression of atrial ion channels and gap junction proteins.

Regional heterogeneity in determinants of atrial matrix remodeling and association with atrial fibrillation vulnerability postmyocardial infarction.

BACKGROUND: Left ventricular (LV) remodeling following a myocardial infarction (MI) is associated with new-onset atrial fibrillation (AF). LV remodeling post-MI is characterized by regional changes in matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), causing extracellular matrix (ECM) remodeling. OBJECTIVE: The purpose of this study was to test the hypothesis that a shift in regional atrial MMP activity, MMP/TIMP expression, and ECM remodeling occurs post-MI, which cause increased vulnerability to AF. METHODS: MI was induced in pigs (weight 25 kg; coronary ligation; n = 9). At approximately 14 days post-MI, an atrial electrical stimulation protocol was performed, after which an MMP radiotracer was infused, MMP/TIMP mRNA profiling performed, and ECM collagen assessed by histochemistry. An additional 7 non-MI pigs served as controls. RESULTS: AF could be induced in 89% (8/9) of the post-MI pigs but none of the controls. MMP activity (MMP radiotracer uptake) increased by approximately 2-fold in most atrial regions post-MI, whereas fibrillar collagen content was unchanged or actually reduced in right atrial regions and increased in left atrial regions. MMP/TIMP profiles revealed a heterogeneous pattern from the left atrial appendage to right atrial regions. CONCLUSION: AF vulnerability early post-MI was associated with a heterogeneous pattern of atrial ECM remodeling, detectable by noninvasive molecular imaging. Detection of early atrial MMP activation post-MI may help define the myocardial substrate underlying AF.

Imaging of Injectable Hydrogels Delivered into Myocardium with SPECT/CT.

Injectable hydrogels are being widely explored for treatment after myocardial infarction (MI) through mechanical bulking or the delivery of therapeutics. Despite this interest, there have been few approaches to image hydrogels upon injection to identify their location, volume, and pattern of delivery, features that are important to understand toward clinical translation. Using a hyaluronic acid (HA) hydrogel as an example, the aim of this study is to introduce radiopacity to hydrogels by encapsulating a clinically used contrast agent (Omnipaque Iohexol, GE Healthcare) for imaging upon placement in the myocardium. Specifically, iohexol is encapsulated into shear-thinning and self-healing hydrogels formed through the mixing of HA-hydrazide and HA-aldehyde. Upon examination of a range of iohexol concentrations, a concentration of 100 mg mL-1 iohexol is deemed optimal based on the greatest contrast, while maintaining hydrogel mechanical properties and acceptable injection forces. In an acute porcine model of MI, hybrid single-photon emission computed tomography/computed tomography (SPECT/CT) perfusion imaging is performed immediately and 3-4 days after hydrogel delivery to assess radiopacity and verify the hydrogel location within the perfusion defect. Hybrid SPECT/CT imaging demonstrates excellent radiopacity of the hydrogel within the perfusion defect immediately after intramyocardial hydrogel injection, demonstrating the feasibility of this method for short-term noninvasive hydrogel monitoring.

Application of Hybrid Matrix Metalloproteinase-Targeted and Dynamic 201Tl Single-Photon Emission Computed Tomography/Computed Tomography Imaging for Evaluation of Early Post-Myocardial Infarction Remodeling.

BACKGROUND: The induction of matrix metalloproteinases (MMPs) and reduction in tissue inhibitors of MMPs (TIMPs) plays a role in ischemia/reperfusion (I/R) injury post-myocardial infarction (MI) and subsequent left ventricular remodeling. We developed a hybrid dual isotope single-photon emission computed tomography/computed tomography approach for noninvasive evaluation of regional myocardial MMP activation with 99mTc-RP805 and dynamic 201Tl for determination of myocardial blood flow, to quantify the effects of intracoronary delivery of recombinant TIMP-3 (rTIMP-3) on I/R injury. METHODS: Studies were performed in control pigs (n=5) and pigs following 90-minute balloon occlusion-induced ischemia/reperfusion (I/R) of left anterior descending artery (n=9). Before reperfusion, pigs with I/R were randomly assigned to intracoronary infusion of rTIMP-3 (1.0 mg/kg; n=5) or saline (n=4). Three days post-I/R, dual isotope imaging was performed with 99mTc-RP805 and 201Tl along with contrast cineCT to assess left ventricular function. RESULTS: The ischemic to nonischemic ratio of 99mTc-RP805 was significantly increased following I/R in saline group (4.03±1.40), and this ratio was significantly reduced with rTIMP-3 treatment (2.22±0.57; P=0.03). This reduction in MMP activity in the MI-rTIMP-3 treatment group was associated with an improvement in relative MI region myocardial blood flow compared with the MI-saline group and improved myocardial strain in the MI region. CONCLUSIONS: We have established a novel hybrid single-photon emission computed tomography/computed tomography imaging approach for the quantitative assessment of regional MMP activation, myocardial blood flow, and cardiac function post-I/R that can be used to evaluate therapeutic interventions such as intracoronary delivery of rTIMP-3 for reduction of I/R injury in the early phases of post-MI remodeling.

Angiotensin Receptor Neprilysin Inhibitor Attenuates Myocardial Remodeling and Improves Infarct Perfusion in Experimental Heart Failure.

Angiotensin receptor blocker-neprilysin inhibitor (ARNi) therapy improves the prognosis of heart failure patients. However, the mechanisms remain unclear. This study investigated the biological effects of ARNi with neprilysin inhibitor sacubitril and angiotensin receptor blocker valsartan on myocardial remodeling and cardiac perfusion in experimental heart failure (HF) after myocardial infarction (MI). Male Lewis rats (10-weeks old) with confirmed HF were randomized one-week post-MI to treatment with vehicle (water), sacubitril/valsartan or valsartan, as comparator group, for either 1 or 5 weeks. Sacubitril/valsartan for 1-week limited LV contractile dysfunction vs. vehicle and both sacubitril/valsartan and valsartan attenuated progressive LV dilation after 1 and 5 weeks treatment. After 5 weeks, both sacubitril/valsartan and valsartan reduced CTGF expression in the remote myocardium, although only sacubitril/valsartan prevented interstitial fibrosis. In the border zone, sacubitril/valsartan and valsartan reduced hypertrophic markers, but only sacubitril/valsartan reduced cardiomyocyte size and increased VEGFA expression. In the infarct, sacubitril/valsartan induced an early uptake of 99mTc-NC100692 (a radiotracer of angiogenesis) and improved perfusion, as determined by 201Tl microSPECT/CT imaging. In conclusion, ARNi improved global LV function, limited remodeling in the remote and border zones, and increased perfusion to the infarct. Sacubitril/valsartan had more consistent effects than valsartan on LV remodeling in experimental HF.

Incisional Negative Pressure Wound Therapy Augments Perfusion and Improves Wound Healing in a Swine Model Pilot Study.

BACKGROUND: A commonly used treatment for open wounds, negative pressure wound therapy (NPWT) has recently been used to optimize wound healing in the setting of surgically closed wounds; however, the specific mechanisms of action by which NPWT may benefit patients after surgery remain unknown. Using a swine wound healing model, the current study investigates angiogenesis as a candidate mechanism. METHODS: Multiple excisional wounds were created on the dorsa of 10 male Yorkshire pigs and closed by primary suture. The closed wounds underwent treatment with either NPWT dressing or control dressings in the absence of negative pressure. Dressings were maintained for 8 days followed by euthanasia of the animal. Scar evaluation of the wounds by photographic analysis was performed, and wounds were analyzed for angiogenesis markers by enzyme-linked immunosorbent assay and immunohistochemistry. RESULTS: Scar evaluation scores were observed to be significantly higher for the NPWT-treated sites compared with the control sites (P < 0.05). The enzyme-linked immunosorbent assay results demonstrated increases for vascular endothelial growth factor (VEGF) staining at the incision site treated with NPWT compared with other treatment groups (P < 0.05). In addition, an approximately 3-fold elevation in VEGF expression was observed at the NPWT-treated sites (2.8% vs. 1%, respectively; P < 0.0001).). However, there was no significant difference in immunohistochemistry staining. CONCLUSIONS: The use of NPWT improves the appearance of wounds and appears to increase VEGF expression after 8 days in the setting of a closed excisional wound model, suggesting that improved angiogenesis is one mechanism by which NPWT optimizes wound healing when applied to closed surgical wound sites.

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.

Quantitative Analysis of Dynamic 123I-mIBG SPECT Imaging Data in Healthy Humans with a Population-Based Metabolite Correction Method.

UNLABELLED: Conventional 2-dimensional planar imaging of (123)I-metaiodobenzylguanidine ((123)I-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 (123)I-mIBG. METHODS: Twelve healthy humans underwent 5 serial 15-min SPECT scans at 0, 15, 90, 120, and 180 min after bolus injection of (123)I-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/cm(3) 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 (123)I-mIBG was established in healthy humans for the first time. Accurate kinetic modeling of (123)I-mIBG requires both BPR and metabolite corrections. Population-based BPR correction and metabolite correction curves were developed, allowing more convenient absolute quantification of dynamic (123)I-mIBG SPECT images.

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.

Deletion of MLIP (muscle-enriched A-type lamin-interacting protein) leads to cardiac hyperactivation of Akt/mammalian target of rapamycin (mTOR) and impaired cardiac adaptation.

Aging and diseases generally result from tissue inability to maintain homeostasis through adaptation. The adult heart is particularly vulnerable to disequilibrium in homeostasis because its regenerative abilities are limited. Here, we report that MLIP (muscle enriched A-type lamin-interacting protein), a unique protein of unknown function, is required for proper cardiac adaptation. Mlip(-/-) mice exhibited normal cardiac function despite myocardial metabolic abnormalities and cardiac-specific overactivation of Akt/mTOR pathways. Cardiac-specific MLIP overexpression led to an inhibition of Akt/mTOR, providing evidence of a direct impact of MLIP on these key signaling pathways. Mlip(-/-) hearts showed an impaired capacity to adapt to stress (isoproterenol-induced hypertrophy), likely because of deregulated Akt/mTOR activity. Genome-wide association studies showed a genetic association between Mlip and early response to cardiac stress, supporting the role of MLIP in cardiac adaptation. Together, these results revealed that MLIP is required for normal myocardial adaptation to stress through integrated regulation of the Akt/mTOR pathways.

Cardiac ß-Adrenoceptor Expression Is Reduced in Zucker Diabetic Fatty Rats as Type-2 Diabetes Progresses.

OBJECTIVES: Reduced cardiac ß-adrenoceptor (ß-AR) expression and cardiovascular dysfunction occur in models of hyperglycemia and hypoinsulinemia. Cardiac ß-AR expression in type-2 diabetes models of hyperglycemia and hyperinsulinemia, remain less clear. This study investigates cardiac ß-AR expression in type-2 diabetic Zucker diabetic fatty (ZDF) rats. METHODS: Ex vivo biodistribution experiments with [3H]CGP12177 were performed in Zucker lean (ZL) and ZDF rats at 10 and 16 weeks of age as diabetes develops. Blood glucose, body mass, and diet consumption were measured. Western blotting of ß-AR subtypes was completed in parallel. Echocardiography was performed at 10 and 16 weeks to assess systolic and diastolic function. Fasted plasma insulin, free fatty acids (FFA), leptin and fed-state insulin were also measured. RESULTS: At 10 weeks, myocardial [3H]CGP12177 was normal in hyperglycemic ZDF (17±4.1mM) compared to ZL, but reduced 16-25% at 16 weeks of age as diabetes and hyperglycemia (22±2.4mM) progressed. Reduced ß-AR expression not apparent at 10 weeks also developed by 16 weeks of age in ZDF brown adipose tissue. In the heart, Western blotting at 10 weeks indicated normal ß1-AR (98±9%), reduced ß2-AR (76±10%), and elevated ß3-AR (108±6). At 16 weeks, ß1-AR expression became reduced (69±16%), ß2-AR expression decreased further (68±14%), and ß3-AR remained elevated, similar to 10 weeks (112±9%). While HR was reduced at 10 and 16 weeks in ZDF rats, no significant changes were observed in diastolic or systolic function. CONCLUSIONS: Cardiac ß-AR are reduced over 6 weeks of sustained hyperglycemia in type-2 diabetic ZDF rats. This indicates cardiac [3H]CGP12177 retention and ß1- and ß2-AR expression are inversely correlated with the progression of type-2 diabetes.