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.

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.

Increasing angular sampling through deep learning for stationary cardiac SPECT image reconstruction.

BACKGROUND: The GE Discovery NM (DNM) 530c/570c are dedicated cardiac SPECT scanners with 19 detector modules designed for stationary imaging. This study aims to incorporate additional projection angular sampling to improve reconstruction quality. A deep learning method is also proposed to generate synthetic dense-view image volumes from few-view counterparts. METHODS: By moving the detector array, a total of four projection angle sets were acquired and combined for image reconstructions. A deep neural network is proposed to generate synthetic four-angle images with 76 ([Formula: see text]) projections from corresponding one-angle images with 19 projections. Simulated data, pig, physical phantom, and human studies were used for network training and evaluation. Reconstruction results were quantitatively evaluated using representative image metrics. The myocardial perfusion defect size of different subjects was quantified using an FDA-cleared clinical software. RESULTS: Multi-angle reconstructions and network results have higher image resolution, improved uniformity on normal myocardium, more accurate defect quantification, and superior quantitative values on all the testing data. As validated against cardiac catheterization and diagnostic results, deep learning results showed improved image quality with better defect contrast on human studies. CONCLUSION: Increasing angular sampling can substantially improve image quality on DNM, and deep learning can be implemented to improve reconstruction quality in case of stationary imaging.

Quantification of intramyocardial blood volume using 99mTc-RBC SPECT/CT: a pilot human study.

BACKGROUND: Quantification of intramyocardial blood volume (IMBV), the fraction of myocardium that is occupied by blood, is a promising Index to measure microcirculatory functions. In previous large animal SPECT/CT studies injected with 99mTc-labeled Red Blood Cell (RBC) and validated by ex vivo microCT, we have demonstrated that accurate IMBV can be measured. In this study, we report the data processing methods and results of the first-in-human pilot study. METHODS: Data from three subjects have been included to date. Each subject underwent rest and adenosine-induced stress 99mTc-RBC SPECT/CT on a dedicated cardiac system with both non-contrast and contrast-enhanced CT acquired. Corrections of attenuation (AC) and scatter (SC), respiratory and cardiac gating, and partial volume correction (PVC) were applied. We also performed automatic segmentation and registration approach based on the blood pool topology in both SPECT and CT images. RESULTS: The quantified IMBV across all subjects under resting conditions were 35.0% ± 3.3% for the end-diastolic phase and 24.1% ± 2.7% for the end-systolic phase. The cycle-dependent change in IMBV (ΔIMBV) between diastolic and systolic phases was 31.5% ± 3.0%. Under stress, IMBV were 40.6% ± 4.2% for the end-diastolic phase and 26.5% ± 2.8% for the end-systolic phase, and ΔIMBV was 34.7% ± 7.4%. CONCLUSIONS: It is feasible to quantify IMBV in resting and stress conditions in human studies using SPECT/CT with 99mTc-RBC.

Quantification of myocardial blood flow (MBF) and reserve (MFR) incorporated with a novel segmentation approach: Assessments of quantitative precision and the lower limit of normal MBF and MFR in patients.

BACKGROUND: Quantification of myocardial blood flow (MBF) and myocardial flow reserve (MFR) has shown diagnostic and prognostic values for the assessment of coronary artery disease (CAD). This study aimed to evaluate in patients a highly automatic Yale-MQ (myocardial blood flow quantification) software incorporated with a novel image segmentation approach for quantification of global and regional MBF and MFR from dynamic 82Rb cardiac positron emission tomography (PET). METHODS: Global and regional MBFs and MFRs were quantified in 80 patients (18 normal and 62 CAD subjects) by two different observers using the Yale-MQ software. Lower limits of normal (LLN) values and intra- and inter-observer variabilities of MBFs and MFRs were calculated for the assessment of quantitative precision. The Yale-MQ was compared with a commercially available software (Corridor 4DM) being used as a reference. RESULTS: The Yale-MQ method provided precise assessments of LLNs of MBF and MFR. The global and regional MBFs and MFR quantified via Yale-MQ were correlated strongly with those via Corridor4DM (R ≥ 0.867). The intra- and inter-observer variabilities of MBFs and MFRs quantified via Yale-MQ were small (≤ 7.7% for MBFs and ≤ 10.0% for MFRs) with excellent correlations (R ≥ 0.980 for MBFs and R ≥ 0.976 for MFRs). CONCLUSIONS: The new Yale-MQ software associated with the automatic processing scheme provides a highly reproducible clinical tool for precise quantification of MBF and MFR in patients with reliable LLN values.

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.

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: High resolution 3D T1 mapping is important for assessment of diffuse myocardial fibrosis in left atrium or other thin-walled structures. In this work, we investigated a fast single-TI 3D high resolution T1 mapping method that directly transforms a 3D late gadolinium enhancement (LGE) volume to a 3D T1 map. METHODS: The proposed method, T1-refBlochi, is based on Bloch equation modeling of the LGE signal, a single-point calibration, and assumptions that proton density and T2* are relatively uniform in the heart. Several sources of error of this method were analyzed mathematically and with simulations. Imaging was performed in phantoms, eight swine and five patients, comparing T1-refBlochi to a standard spin-echo T1 mapping, 3D multi-TI T1 mapping, and 2D ShMOLLI, respectively. RESULTS: The method has a good accuracy and adequate precision, even considering various sources of error. In phantoms, over a range of protocols, heart-rates and T1 s, the bias ±1SD was -3 ms ± 9 ms. The porcine studies showed excellent agreement between T1-refBlochi and the multi-TI method (bias ±1SD = -6 ± 22 ms). The proton density and T2* weightings yielded ratios for scar/blood of 0.94 ± 0.01 and for myocardium/blood of 1.03 ± 0.02 in the eight swine, confirming that sufficient uniformity of proton density and T2* weightings exists among heterogeneous tissues of the heart. In the patients, the mean T1 bias ±1SD in myocardium and blood between T1-refBlochi and ShMOLLI was -9 ms ± 21 ms. CONCLUSION: T1-refBlochi provides a fast single-TI high resolution 3D T1 map of the heart with good accuracy and adequate precision.

Effects of an endothelin receptor antagonist, Macitentan, on right ventricular substrate utilization and function in a Sugen 5416/hypoxia rat model of severe pulmonary arterial hypertension.

BACKGROUND: Altered myocardial energy metabolism has been linked to worsening of RV function in pulmonary arterial hypertension (PAH). The aim of this study was to evaluate RV glucose and fatty acid metabolism in vivo in a rat model of PAH using positron emission tomography (PET) and investigate the effects of Macitentan on RV substrate utilization. METHODS: PAH was induced in male Sprague-Dawley rats by a single subcutaneous injection of Sugen 5416 (20 mg/kg) followed by 3 weeks of hypoxia (10% oxygen). At week 5 post-injection, the PAH rats were randomized to Macitentan (30 mg/kg daily) treatment or no treatment. Substrate utilization was serially assessed 5 and 8 weeks post-injection with 2-[18F]fluoro-2-deoxyglucose (FDG) and 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid (FTHA) PET for glucose and fatty acid metabolism respectively and correlated with in vivo functional measurements. RESULTS: PAH induction resulted in a 2.5-fold increase in RV FDG uptake (standardized uptake value (SUV) of normal control: 1.6 ± 0.4, week 5: 4.1 ± 1.9, week 8: 4.0 ± 1.6, P < 0.05 for all groups vs. control). RV FTHA showed twofold increased uptake at week 5 (SUV control: 1.50 ± 0.39, week 5: 3.06 ± 1.10, P = 0.03). Macitentan significantly decreased RV FDG uptake at 8 weeks (SUV: 2.5 ± 0.9, P = 0.04), associated with improved RV ejection fraction and reduced RV systolic pressure, while FTHA uptake was maintained. CONCLUSION: PAH is associated with metabolic changes in the RV, characterized by a marked increase in FDG and FTHA uptake. Macitentan treatment reduced PAH severity and was associated with a decrease in RV FDG uptake and improved RV function.

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.

Glutaredoxin-2 is required to control oxidative phosphorylation in cardiac muscle by mediating deglutathionylation reactions.

Glutaredoxin-2 (Grx2) modulates the activity of several mitochondrial proteins in cardiac tissue by catalyzing deglutathionylation reactions. However, it remains uncertain whether Grx2 is required to control mitochondrial ATP output in heart. Here, we report that Grx2 plays a vital role modulating mitochondrial energetics and heart physiology by mediating the deglutathionylation of mitochondrial proteins. Deletion of Grx2 (Grx2(-/-)) decreased ATP production by complex I-linked substrates to half that in wild type (WT) mitochondria. Decreased respiration was associated with increased complex I glutathionylation diminishing its activity. Tissue glucose uptake was concomitantly increased. Mitochondrial ATP output and complex I activity could be recovered by restoring the redox environment to that favoring the deglutathionylated states of proteins. Grx2(-/-) hearts also developed left ventricular hypertrophy and fibrosis, and mice became hypertensive. Mitochondrial energetics from Grx2 heterozygotes (Grx2(+/-)) were also dysfunctional, and hearts were hypertrophic. Intriguingly, Grx2(+/-) mice were far less hypertensive than Grx2(-/-) mice. Thus, Grx2 plays a vital role in modulating mitochondrial metabolism in cardiac muscle, and Grx2 deficiency leads to pathology. As mitochondrial ATP production was restored by the addition of reductants, these findings may be relevant to novel redox-related therapies in cardiac disease.

Coordinated changes in hepatic amino acid metabolism and endocrine signals support hepatic glucose production during fetal hypoglycemia.

Reduced fetal glucose supply, induced experimentally or as a result of placental insufficiency, produces an early activation of fetal glucose production. The mechanisms and substrates used to fuel this increased glucose production rate remain unknown. We hypothesized that in response to hypoglycemia, induced experimentally with maternal insulin infusion, the fetal liver would increase uptake of lactate and amino acids (AA), which would combine with hormonal signals to support hepatic glucose production. To test this hypothesis, metabolic studies were done in six late gestation fetal sheep to measure hepatic glucose and substrate flux before (basal) and after [days (d)1 and 4] the start of hypoglycemia. Maternal and fetal glucose concentrations decreased by 50% on d1 and d4 (P < 0.05). The liver transitioned from net glucose uptake (basal, 5.1 ± 1.5 µmol/min) to output by d4 (2.8 ± 1.4 µmol/min; P < 0.05 vs. basal). The [U-¹³C]glucose tracer molar percent excess ratio across the liver decreased over the same period (basal: 0.98 ± 0.01, vs. d4: 0.89 ± 0.01, P < 0.05). Total hepatic AA uptake, but not lactate or pyruvate uptake, increased by threefold on d1 (P < 0.05) and remained elevated throughout the study. This AA uptake was driven largely by decreased glutamate output and increased glycine uptake. Fetal plasma concentrations of insulin were 50% lower, while cortisol and glucagon concentrations increased 56 and 86% during hypoglycemia (P < 0.05 for basal vs. d4). Thus increased hepatic AA uptake, rather than pyruvate or lactate uptake, and decreased fetal plasma insulin and increased cortisol and glucagon concentrations occur simultaneously with increased fetal hepatic glucose output in response to fetal hypoglycemia.

Beneficial and cautionary outcomes of resveratrol supplementation in pregnant nonhuman primates.

Resveratrol has been proposed as a potential therapeutic to improve metabolic health during pregnancy, yet little is known about the fetal effects of this maternal dietary supplement. We hypothesized that when administered to pregnant nonhuman primates (NHPs), resveratrol would increase uterine blood flow and mitigate the harmful consequences of maternal Western-style diet (WSD) consumption. NHPs were fed a WSD (36% fat) supplemented with 0.37% resveratrol throughout pregnancy. Outcomes were compared with cohorts fed WSD alone and control chow (14% fat) to distinguish between WSD and resveratrol-specific effects in these animals. In the early third trimester, uterine blood flow was measured by Doppler ultrasound before fetal delivery and tissue collection. Resveratrol resulted in 30% maternal weight loss and improved glucose tolerance, increased uterine artery volume blood flow, and decreased placental inflammation and liver triglyceride deposition. In addition, fetal pancreatic mass was enlarged by 42%, with a 12-fold increase in proliferation by Ki67 immunohistochemistry. These results demonstrate that resveratrol use during pregnancy yields improvements in maternal and placental phenotype with beneficial effects in the fetal liver but an unexplained and concerning alteration in fetal pancreatic development, which strongly cautions against the use of resveratrol by pregnant women.

Trans-10, cis-12 CLA dose-dependently inhibits milk fat synthesis without disruption of lactation in C57BL/6J mice.

BACKGROUND: Trans-10, cis-12 conjugated linoleic acid (10,12 CLA) is a potent inhibitor of milk fat synthesis in mammals. In the cow, 10 g/d of 10,12 CLA specifically and reversibly inhibits mammary lipogenesis, whereas substantially higher doses are not specific and cause a generalized inhibition of milk synthesis. OBJECTIVE: The objective of this study was to validate a lactating mouse model by establishing the dose response, specificity, and reversibility of the inhibition of milk fat synthesis by 10,12 CLA. METHODS: Lactating mice (C57BL/6J) received daily doses of 0 (control), 7, 20, or 60 mg of 10,12 CLA for 5 d during established lactation. A second group of lactating mice was treated with 20 mg/d of 10,12 CLA for 4 d and followed post-treatment to evaluate reversibility. RESULTS: CLA decreased pup growth with a 49% decrease occurring with 60 mg/d of CLA. Milk fat percentage was decreased 11% and 20% with the 7 and 20 mg/d dose, respectively, and all CLA treatments had a decreased concentration of de novo synthesized fatty acids (FAs) in milk fat. In agreement, 20 mg/d of 10,12 CLA decreased the lipogenic capacity of mammary tissue by 30% and mammary expression of FA synthase (Fasn), sterol response element binding protein 1 (Srebf1), and thyroid hormone responsive spot 14 (Thrsp) by 30-60%, whereas milk protein percentage and mammary expression of α-lactalbumin (Lalba) were unaltered. This dose of CLA reduced pup growth by nearly 20% and milk de novo synthesized FAs by >35%, and these effects were completely reversed 5 d after 10,12 CLA treatment was terminated. CONCLUSION: Inhibition of mammary lipogenesis by 10,12 CLA is dose-dependent in the mouse, with a specific and reversible reduction in milk fat synthesis at the 20 mg/d dose and additional nonspecific effects on milk synthesis at higher CLA doses.

Effectiveness of the Smoking Cessation and Reduction in Pregnancy Treatment (SCRIPT) dissemination project: a science to prenatal care practice partnership.

This study evaluated the effectiveness of the Smoking Cessation and Reduction in Pregnancy Treatment (SCRIPT) Program selected by the West Virginia-Right From The Start Project for state-wide dissemination. A process evaluation documented the fidelity of SCRIPT delivery by Designated Care Coordinators (DCC), licensed nurses and social workers who provide home-based case management to Medicaid-eligible clients in all 55 counties. We implemented a quasi-experimental, non-randomized, matched Comparison (C) Group design. The SCRIPT Experimental E Group (N = 259) were all clients in 2009-2010 that wanted to quit, provided a screening carbon monoxide (CO), and received a SCRIPT home visit. The (C) Group was derived from all clients in 2006-2007 who had the same CO assessments as E Group clients and reported receiving cessation counseling. We stratified the baseline CO of E Group clients into 10 strata, and randomly selected the same number of (C) Group clients (N = 259) from each matched strata to evaluate the effectiveness of the SCRIPT Program. There were no significant baseline differences in the E and (C) Group. A Process Evaluation documented a significant increase in the fidelity of DCC delivery of SCRIPT Program procedures: from 63 % in 2006 to 74 % in 2010. Significant increases were documented in the E Group cessation rate (+9.3 %) and significant reduction rate (+4.5 %), a ≥50 % reduction from a baseline CO. Perinatal health case management staff can deliver the SCRIPT Program, and Medicaid-supported clients can change smoking behavior, even very late in pregnancy. When multiple biases were analyzed, we concluded the SCRIPT Dissemination Project was the most plausible reason for the significant changes in behavior.

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.

Coordinate-Independent 3-D Ultrasound Principal Stretch and Direction Imaging.

OBJECTIVE: In clinical ultrasound, current 2-D strain imaging faces challenges in quantifying three orthogonal normal strain components. This requires separate image acquisitions based on the pixel-dependent cardiac coordinate system, leading to additional computations and estimation discrepancies due to probe orientation. Most systems lack shear strain information, as displaying all components is challenging to interpret. METHODS: This paper presents a 3-D high-spatial-resolution, coordinate-independent strain imaging approach based on principal stretch and axis estimation. All strain components are transformed into three principal stretches along three normal principal axes, enabling direct visualization of the primary deformation. We devised an efficient 3-D speckle tracking method with tilt filtering, incorporating randomized searching in a two-pass tracking framework and rotating the phase of the 3-D correlation function for robust filtering. The proposed speckle tracking approach significantly improves estimates of displacement gradients related to the axial displacement component. Non-axial displacement gradient estimates are enhanced using a correlation-weighted least-squares method constrained by tissue incompressibility. RESULTS: Simulated and in vivo canine cardiac datasets were evaluated to estimate Lagrangian strains from end-diastole to end-systole. The proposed speckle tracking method improves displacement estimation by a factor of 4.3 to 10.5 over conventional 1-pass processing. Maximum principal axis/direction imaging enables better detection of local disease regions than conventional strain imaging. CONCLUSION: Coordinate-independent tracking can identify myocardial abnormalities with high accuracy. SIGNIFICANCE: This study offers enhanced accuracy and robustness in strain imaging compared to current methods.

Increased amino acid supply potentiates glucose-stimulated insulin secretion but does not increase ß-cell mass in fetal sheep.

Amino acids and glucose acutely stimulate fetal insulin secretion. In isolated adult pancreatic islets, amino acids potentiate glucose-stimulated insulin secretion (GSIS), but whether amino acids have this same effect in the fetus is unknown. Therefore, we tested the effects of increased fetal amino acid supply on GSIS and morphology of the pancreas. We hypothesized that increasing fetal amino acid supply would potentiate GSIS. Singleton fetal sheep received a direct intravenous infusion of an amino acid mixture (AA) or saline (CON) for 10-14 days during late gestation to target a 25-50% increase in fetal branched-chain amino acids (BCAA). Early-phase GSIS increased 150% in the AA group (P < 0.01), and this difference was sustained for the duration of the hyperglycemic clamp (105 min) (P < 0.05). Glucose-potentiated arginine-stimulated insulin secretion (ASIS), pancreatic insulin content, and pancreatic glucagon content were similar between groups. ß-Cell mass and area were unchanged between groups. Baseline and arginine-stimulated glucagon concentrations were increased in the AA group (P < 0.05). Pancreatic α-cell mass and area were unchanged. Fetal and pancreatic weights were similar. We conclude that a sustained increase of amino acid supply to the normally growing late-gestation fetus potentiated fetal GSIS but did not affect the morphology or insulin content of the pancreas. We speculate that increased ß-cell responsiveness (insulin secretion) following increased amino acid supply may be due to increased generation of secondary messengers in the ß-cell. This may be enhanced by the paracrine action of glucagon on the ß-cell.

Increased fetal insulin concentrations for one week fail to improve insulin secretion or ß-cell mass in fetal sheep with chronically reduced glucose supply.

Maternal undernutrition during pregnancy and placental insufficiency are characterized by impaired development of fetal pancreatic ß-cells. Prolonged reduced glucose supply to the fetus is a feature of both. It is unknown if reduced glucose supply, independent of other complications of maternal undernutrition and placental insufficiency, would cause similar ß-cell defects. Therefore, we measured fetal insulin secretion and ß-cell mass following prolonged reduced fetal glucose supply in sheep. We also tested whether restoring physiological insulin concentrations would correct any ß-cell defects. Pregnant sheep received either a direct saline infusion (CON = control, n = 5) or an insulin infusion (HG = hypoglycemic, n = 5) for 8 wk in late gestation (75 to 134 days) to decrease maternal glucose concentrations and reduce fetal glucose supply. A separate group of HG fetuses also received a direct fetal insulin infusion for the final week of the study with a dextrose infusion to prevent a further fall in glucose concentration [hypoglycemic + insulin (HG+I), n = 4]. Maximum glucose-stimulated insulin concentrations were 45% lower in HG fetuses compared with CON fetuses. ß-Cell, pancreatic, and fetal mass were 50%, 37%, and 40% lower in HG compared with CON fetuses, respectively (P < 0.05). Insulin secretion and ß-cell mass did not improve in the HG+I fetuses. These results indicate that chronically reduced fetal glucose supply is sufficient to reduce pancreatic insulin secretion in response to glucose, primarily due to reduced pancreatic and ß-cell mass, and is not correctable with insulin.

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.