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Background: Estimation of myocardial blood flow (MBF) with cardiac PET is often performed with conventional compartmental models. In this study, we developed and evaluated a physiologically and anatomically realistic axially distributed model. Unlike compartmental models, this axially distributed approach models both the temporal and the spatial gradients in uptake and retention along the capillary.Methods: We validated PET-derived flow estimates with microsphere studies in 19 (9 rest, 10 stress) studies in five dogs. The radiotracer, (13)N-ammonia, was injected intravenously while microspheres were administered into the left atrium. A regional reduction in hyperemic flow was forced by an external occluder in five of the stress studies. The flow estimates from the axially distributed model were compared with estimates from conventional compartmental models.Results: The mean difference between microspheres and the axially distributed blood flow estimates in each of the 17 segments was 0.03 mL/g/minute (95% CI [-0.05, 0.11]). The blood flow estimates were highly correlated with each regional microsphere value for the axially distributed model (y = 0.98x + 0.06 mL/g/minute; r = 0.74; P < .001), for the two-compartment (y = 0.64x + 0.34; r = 0.74; P < .001), and for three-compartment model (y = 0.69x + 0.54; r = 0.74; P < .001). The variance of the error of the estimates is higher with the axially distributed model than the compartmental models (1.7 [1.3, 2.1] times higher).Conclusion: The proposed axially distributed model provided accurate regional estimates of MBF. The axially distributed model estimated blood flow with more accuracy, but less precision, than the evaluated compartmental models. [ABSTRACT FROM AUTHOR]

Objectives: The study was done to determine whether the effects of parasympathetic withdrawal on heart rate, blood pressure (BP), and systolic and diastolic function are altered with normal aging.Background: Cardiac responses to beta-adrenergic sympathetic stimulation decline with aging as does the heart rate response to parasympathetic withdrawal, but the extent to which other responses to parasympathetic withdrawal decrease is less clear.Methods: Heart rate, BP, systolic function, and diastolic filling responses to parasympathetic withdrawal induced by atropine (0.02 mg/kg) were compared in 50 healthy subjects, 28 older (ages 65 to 80 years, mean 70 years; 18 females all on estrogen) and 22 young (age 18 to 32 years, mean 26 years; 12 females) subjects, using radionuclide angiography.Results: Parasympathetic withdrawal in the older group caused less of an increase in heart rate (+33 vs. +48 beats/min), cardiac index (+0.6 vs. +1.5 l/m(2)), systolic blood pressure (-1 vs. +7 mm Hg), and early diastolic filling rate (+1.7 vs. +2.4 end-diastolic volumes/s) (all p < or = 0.01). At similar declines in the diastolic filling period, end-diastolic volume index (EDVI) fell substantially more in the older group (-11.6 vs. -2.4 ml/m(2), p < 0.001). The only gender difference was in diastolic filling rate, which was similar in the young males and females, but significantly less in older males than in older females.Conclusions: The responses to parasympathetic withdrawal as well as sympathetic stimulation decline with aging, and both contribute to the reduced cardiovascular responses to stress with advancing age. [ABSTRACT FROM AUTHOR]

Voltage-gated sodium channels are clustered and immobilized at high densities in electrically excitable cells. A new study shows that ankyrins are essential to tether sodium channels and prevent synaptic fatigue at the neuromuscular junction., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Previous studies have demonstrated stimulation of endocrine pancreas function by vagal nerve electrical stimulation. While this increases insulin secretion, expected concomitant reductions in circulating glucose do not occur. A complicating factor is the non-specific nature of electrical nerve stimulation. Optogenetic tools, however, provide the potential for cell-type specific neural stimulation using genetic targeting and/or spatially shaped excitation light. Here, we demonstrate light-activated stimulation of the endocrine pancreas by targeting parasympathetic (cholinergic) axons. In a mouse model expressing ChannelRhodopsin2 (ChR2) in cholinergic cells, serum insulin and glucose were measured in response to (1) ultrasound image-guided optical stimulation of axon terminals in the pancreas or (2) optical stimulation of axons of the cervical vagus nerve. Measurements were made in basal-glucose and glucose-stimulated conditions. Significant increases in plasma insulin occurred relative to controls under both pancreas and cervical vagal stimulation, while a rapid reduction in glycemic levels were observed under pancreatic stimulation. Additionally, ultrasound-based measurements of blood flow in the pancreas were increased under pancreatic stimulation. Together, these results demonstrate the utility of in-vivo optogenetics for studying the neural regulation of endocrine pancreas function and suggest its therapeutic potential for the control of insulin secretion and glucose homeostasis.

Vagus nerve stimulation has shown many benefits for disease therapies but current approaches involve imprecise electrical stimulation that gives rise to off-target effects, while the functionally relevant pathways remain poorly understood. One method to overcome these limitations is the use of optogenetic techniques, which facilitate targeted neural communication with light-sensitive actuators (opsins) and can be targeted to organs of interest based on the location of viral delivery. Here, we tested whether retrograde adeno-associated virus (rAAV2-retro) injected in the heart can be used to selectively express opsins in vagus nerve fibers controlling cardiac function. Furthermore, we investigated whether perturbations in cardiac function could be achieved with photostimulation at the cervical vagus nerve. Viral injection in the heart resulted in robust, primarily afferent, opsin reporter expression in the vagus nerve, nodose ganglion, and brainstem. Photostimulation using both one-photon stimulation and two-photon holography with a GRIN-lens incorporated nerve cuff, was tested on the pilot-cohort of injected mice. Changes in heart rate, surface electrocardiogram, and respiratory responses were observed in response to both one- and two-photon photostimulation. The results demonstrate feasibility of retrograde labeling for organ targeted optical neuromodulation.

Adenoassociated viral vectors provide a safe and robust method for expression of transgenes in nondividing cells such as neurons. Intravenous injections of these vectors provide a means of transducing motoneurons of peripheral nerves. Previous research has demonstrated that serotypes 1, rh10 and PHP.B can transduce motor neuron cell bodies in the spinal cord, but has not quantified expression in the peripheral nerve axon. Axonal labeling is crucial for optogenetic stimulation and detection of action potentials in peripheral nerve. Therefore, in this study, serotypes 1, PHP.B, and rh10 were tested for their ability to label axons of the murine sciatic and tibial nerve following intravenous injection. Serotype rh10 elicits expression in 10% of acetylcholine transferase positive axons of the sciatic nerve in immunohistochemically-stained sections. Serotype rh10 transduces a variety of axon diameters from <1-12 μm, while PHP.B transduces larger axons of diameter (4-16 μm). Expression was not seen with serotype 1. These results show the potential of serotypes PHP.B and rh10 delivery of transgenic products to axons of the peripheral nerve., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background The accuracy of absolute myocardial blood flow (MBF) from dynamic contrast-enhanced cardiac computed tomography acquisitions has not been fully characterized. We evaluate computed tomography (CT) compared with rubidium-82 positron emission tomography (PET) MBF estimates in a high-risk population. Methods In a prospective trial, patients receiving clinically indicated rubidium-82 PET exams were recruited to receive a dynamic contrast-enhanced cardiac computed tomography exam. The CT protocol included a rest and stress dynamic portion each acquiring 12 to 18 cardiac-gated frames. The global MBF was estimated from the PET and CT exam. Results Thirty-four patients referred for cardiac rest-stress PET were recruited. Of the 68 dynamic contrast-enhanced cardiac computed tomography scans, 5 were excluded because of injection errors or mismatched hemodynamics. The CT-derived global MBF was highly correlated with the PET MBF (r=0.92; P<0.001) with a mean difference of 0.7±26.4%. The CT MBF estimates were within 20% of PET estimates ( P<0.02) with a mean of (1) MBF for resting flow of PET versus CT of 0.9±0.3 versus 1.0±0.2 mL/min per gram and (2) MBF for stress flow of 2.1±0.7 versus 2.0±0.8 mL/min per gram. Myocardial flow reserve was -14±28% underestimated with CT (PET versus CT myocardial flow reserve, 2.5±0.6 versus 2.2±0.6). The proposed rest+stress+computed tomography angiography protocol had a dose length product of 598±76 mGy×cm resulting in an approximate effective dose of 8.4±1.1 mSv. Conclusions In a high-risk clinical population, a clinically practical dynamic contrast-enhanced cardiac computed tomography provided unbiased MBF estimates within 20% of rubidium-82 PET. Although unbiased, the CT estimates contain substantial variance with an standard error of the estimate of 0.44 mL/min per gram. Myocardial flow reserve estimation was not as accurate as individual MBF estimates.

Improved neural interfacing strategies are needed for the full articulation of advanced prostheses. To address limitations of existing control interface designs, the work of our laboratory has presented an optical approach to reading activity from individual nerve fibers using activity-dependent calcium transients. Here, we demonstrate the feasibility of such signals to control prosthesis actuation by using the axonal fluorescence signal in an ex vivo mouse nerve to drive a prosthetic digit in real-time. Additionally, signals of varying action potential frequency are streamed post hoc to the prosthesis, showing graded motor output and the potential for proportional neural control. This proof-of-concept work is a novel demonstration of the functional use of activity-dependent optical read-out in the nerve.

Background: Determination of transgene expression in motor axons of peripheral nerves is important in evaluating the effectiveness of viral transduction. Currently only manual and semi-automatic methods of quantification have been employed for quantification in immunolabeled nerve sections, but automatic methods exist for axon counting only in brightfield sections. Manual and semi-automatic methods can suffer from inter- and intraobserver bias, sampling bias and can be time consuming to implement., New Method: A fully automated method using ImageJ and the Nucleus Counter plugin was developed to quantify the fraction of green fluorescent protein (GFP) labeled acetylcholine transferase positive axons in triple immunolabeled peripheral nerve sections. This method utilizes the Nucleus Counter to generate axonal regions of interest which are quantified for colocalization with GFP expression and nonoverlap with Laminin. Thresholding using histograms generated from control animals is used to remove noise., Results: The automated method is able to successfully distinguish transgenic GFP expressing mice from wild type. Using computer generated peripheral nerve sections, the automated method has less than 5% error at signal-to-noise ratios greater than 10% of baseline., Comparisons With Existing Methods: This method has comparable performance in false positive rates (<1%) and a 95% predictive interval that closely matches existing fully automated methods for quantification in brightfield sections. It outperforms the intra- and interobserver differences of manual and semi-automated methods for quantification., Conclusions: This automated quantification method provides a fast and robust means of determining the fraction of labeled axons in peripheral nerve sections., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Current neural interfaces are hampered by lack of specificity and selectivity for neural interrogation. A method that might improve these interfaces is an optical peripheral nerve interface which communicates with individual axons via optogenetic reporters. To determine the feasibility of such an interface, we delivered the genetically encoded calcium indicator GCaMP6f to the mouse peripheral nerve by intramuscular injection of adenoassociated viral vector (AAV1) under the control of the CAG (chicken beta actin- cytomegalovirus hybrid promoter). Small diameter axons in the common peroneal nerve were transduced and demonstrated electrically inducible calcium transients ex vivo. Responses to single electrical stimuli were resolvable, and increasing the number of stimuli resulted in a monotonic increase in maximum fluorescence and a prolongation of calcium transient kinetics. This work demonstrates the viability of using a virally-delivered, genetically-encoded calcium indicator to read-out from peripheral nerve axons.

Numerous clinical and research applications necessitate the ability to interface with peripheral nerve fibers to read and control relevant neural pathways. Visceral organ modulation and rehabilitative prosthesis are two areas which could benefit greatly from improved neural interfacing approaches. Therapeutic neural interfacing, or 'bioelectronic medicine', has potential to affect a broad range of disorders given that all the major organs of the viscera are neurally innervated. However, a better understanding of the neural pathways that underlie function and a means to precisely interface with these fibers are required. Existing peripheral nerve interfaces, consisting primarily of electrode-based designs, are unsuited for highly specific (individual axon) communication and/or are invasive to the tissue. Our laboratory has explored an optogenetic approach by which optically sensitive reporters and actuators are targeted to specific cell (axon) types. The nature of such an approach is laid out in this short perspective, along with associated technologies and challenges., Competing Interests: None declared.

Background: Prior studies have shown that late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) and fluorodeoxyglucose (FDG) positron emission tomography (PET) confer incremental risk assessment in patients with cardiac sarcoidosis (CS). However, the incremental prognostic value of the combined use of LGE and FDG compared to either test alone has not been investigated, and this is the aim of the present study., Methods: Retrospective observational study of 56 symptomatic patients with high clinical suspicion for CS who underwent LGE-CMR and FDG-PET and were followed for the occurrence of death and/or malignant ventricular arrhythmias (VA)., Results: The combination of PET and CMR yielded the following groups: 1) LGE-negative/normal-PET (n=20), 2) LGE-positive/abnormal-FDG (n=20), and 3) LGE-positive/normal FDG (n=16). After a median follow-up of 2.6years (IQR 1.2-4.1), 16 patients had events (7 deaths, 10 VA). All, but 1, events occurred in patients with LGE. LGE-positive/abnormal-FDG (7 events, HR 10.1 [95% CI 1.2-84]; P=0.03) and LGE-positive/normal-FDG (8 events, HR 13.3 [1.7-107]; P=0.015) patients had comparable risk of events compared to the reference LGE-negative/normal-PET group. In adjusted Cox-regression analysis, presence of LGE (HR 18.1 [1.8-178]; P=0.013) was the only independent predictor of events., Conclusion: CS patients with LGE alone or in association with FDG were at similar risk of future events, which suggests that outcomes may be driven by the presence of LGE (myocardial fibrosis) and not FDG (inflammation)., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Current neural interface technologies have serious limitations for advanced prosthetic and therapeutic applications due primarily to their lack of specificity in neural communication. An optogenetic approach has the potential to provide single cell/axon resolution in a minimally invasive manner by optical interrogation of light-sensitive reporters and actuators. Given the aim of reading neural activity in the peripheral nervous system, this work has investigated an activity-dependent signaling mechanism in the peripheral nerve. We demonstrate action potential evoked calcium signals in mammalian tibial nerve axons using an in vitro mouse model with a dextran-conjugated fluorescent calcium indicator. Spatial and temporal dynamics of the signal are presented, including characterization of frequency-modulated amplitude. Pharmacological experiments implicate T-type Ca V channels and sodium-calcium exchanger (NCX) as predominant mechanisms of calcium influx. This work shows the potential of using calcium-associated optical signals for neural activity read-out in peripheral nerve axons.

Introduction: Resting heart rate (RHR) declines with exercise training. Possible mechanisms include: 1) increased parasympathetic tone, 2) decreased responsiveness to beta-adrenergic stimulation, 3) decreased intrinsic heart rate or 4) combination of these factors., Objective: To determine whether an increase in resting parasympathetic tone or decrease in response to beta-adrenergic stimulation contributes to the decrease in RHR with training., Methods: 51 screened healthy subjects aged 18-32 (n=20, mean age 26, 11 female) or 65-80 (n=31, mean age 69, 16 female) were tested before and after 6months of supervised exercise training. Heart rate response to parasympathetic withdrawal was assessed using atropine and beta-adrenergic responsiveness during parasympathetic withdrawal using isoproterenol., Results: Training increased VO2 max by 17% (28.7±7.7 to 33.6±9.20ml/kg/min, P<0.001). RHR decreased from 62.8±6.6 to 57.6±7.2 beats per minute (P<0.0001). The increase in heart rate in response to parasympathetic withdrawal was unchanged after training (+37.3±12.8 pre vs. +36.4±12.2 beats per min post, P=0.41). There was no change in the heart rate response to isoproterenol after parasympathetic blockade with training (+31.9±10.9 pre vs. +31.0±12.0 post beats per min, P=0.56). The findings were similar in all four subgroups., Conclusions: We did not find evidence that an increase in parasympathetic tone or a decrease in responsiveness to beta-adrenergic activity accounts for the reduction in resting heart rate with exercise training. We suggest that a decline in heart rate with training is most likely due to decrease in the intrinsic heart rate., Competing Interests: There are no conflict interests for this study. The results of the present study do constitute endorsement by ACSM., (Published by Elsevier Ireland Ltd.)

Background: Using positron emission tomography (PET) imaging, we sought to determine whether normal age or exercise training cause changes in the cardiac sympathetic nervous system function in male or female healthy volunteers., Methods: Healthy sedentary participants underwent PET studies before and after 6 months of supervised exercise training. Presynaptic uptake by the norepinephrine transporter-1 function was measured using PET imaging of [(11)C]-meta-hydroxyephedrine, a norepinephrine analog, and expressed as a permeability-surface area product (PSnt in mL/min/mL). Postsynaptic function was measured as β-adrenergic receptor density (β'max in pmol/mL tissue) by imaging the β-receptor antagonist [(11)C]-CGP12177. Myocardial blood flow (MBF in mL/min/mL tissue) was measured by imaging [(15)O]-water., Results: At baseline, there was no age difference in β'max or MBF but PSnt declined with age (1.12±0.11 young vs 0.87±0.06 old, p = .036). Before training, women had significantly greater MBF (0.87±0.03 vs 0.69±0.03, p < .0001) and PSnt (1.14±0.08 vs 0.75±0.07, p < .001) than men. Training increased VO2 max by 13% (p < .0001), but there were no training effects on β'max, PSnt, or MBF. Greater MBF in females and a trend to increased PSnt post-training persisted., Conclusion: With age, presynaptic uptake as measured by PSnt declines, but there were no differences in β'max. Endurance training significantly increased VO2 max but did not cause any changes in the measures of cardiac sympathetic nervous system function. These findings suggest that significant changes do not occur or that current PET imaging methods may be inadequate to measure small serial differences in a highly reproducible manner., (Published by Oxford University Press on behalf of the Gerontological Society of America 2016.)

This study sought to discover which atherosclerotic plaque components co-localize with enhanced [(18)F]-fluorodeoxyglucose (FDG) uptake in carotid positron emission tomography (PET) images. Although in vivo PET currently lacks the resolution, high-resolution ex vivo FDG-microPET with histology validation of excised carotid plaque might accomplish this goal. Thirteen patients were injected with FDG before carotid endarterectomy. After excision, the plaque specimens were scanned by microPET and magnetic resonance imaging, and then serially sectioned for histological analysis. Two analyses were performed using generalized linear mixed models: (1) a PET-driven analysis which sampled high and low FDG uptake areas from PET images to identify their components in matched histology specimens; and (2) a histology-driven analysis where specific plaque components were selected and matched to corresponding PET images. In the PET-driven analysis, regions of high FDG uptake were more likely to contain inflammatory cells (p < 0.001) and neovasculature (p = 0.008) than regions of low FDG uptake. In the histology-driven analysis, regions with inflammatory cells (p = 0.001) and regions with loose extracellular matrix (p = 0.001) were associated with enhanced FDG uptake. Furthermore, areas of complex inflammatory cell infiltrate (co-localized macrophages, lymphocytes and foam cells) had the highest FDG uptake among inflammatory subgroups (p < 0.001). In conclusion, in carotid plaque, regions of inflammatory cell infiltrate, particularly complex one, co-localized with enhanced FDG uptake in high-resolution FDG-microPET images. Loose extracellular matrix and areas containing neovasculature also produced FDG signal. This study points to the potential ability of FDG-PET to detect the cellular components of the vulnerable plaque.

The amyloid precursor protein family (APP/APLPs) has essential roles for neuromuscular synapse development and for the formation and plasticity of synapses within the CNS. Despite this, it has remained unclear whether APP mediates its functions primarily as a cell surface adhesion and signaling molecule or via its numerous proteolytic cleavage products. To address these questions, we followed a genetic approach and used APPΔCT15 knockin mice lacking the last 15 amino acids of APP, including the highly conserved YENPTY protein interaction motif. To circumvent functional compensation by the closely related APLP2, these mice were bred to an APLP2-KO background to generate APPΔCT15-DM double mutants. These APPΔCT15-DM mice were partially viable and displayed defects in neuromuscular synapse morphology and function with impairments in the ability to sustain transmitter release that resulted in muscular weakness. In the CNS, we demonstrate pronounced synaptic deficits including impairments in LTP that were associated with deficits in spatial learning and memory. Thus, the APP-CT15 domain provides essential physiological functions, likely via recruitment of specific interactors. Together with the well-established role of APPsα for synaptic plasticity, this shows that multiple domains of APP, including the conserved C-terminus, mediate signals required for normal PNS and CNS physiology. In addition, we demonstrate that lack of the APP-CT15 domain strongly impairs Aβ generation in vivo, establishing the APP C-terminus as a target for Aβ-lowering strategies., Significance Statement: Synaptic dysfunction and cognitive decline are early hallmark features of Alzheimer's disease. Thus, it is essential to elucidate the in vivo function(s) of APP at the synapse. At present, it is unknown whether APP family proteins function as cell surface receptors, or mainly via shedding of their secreted ectodomains, such as neurotrophic APPsα. Here, to dissect APP functional domains, we used APP mutant mice lacking the last 15 amino acids that were crossed onto an APLP2-KO background. These APPΔCT15-DM mice showed defects in neuromuscular morphology and function. Synaptic deficits in the CNS included impairments of synaptic plasticity, spatial learning, and memory. Collectively, this indicates that multiple APP domains, including the C-terminus, are required for normal nervous system function., (Copyright © 2015 the authors 0270-6474/15/3516019-16$15.00/0.)

Multiple-gated blood pool angiography (MUGA) using 99mTc-UltraTag (Mallinckrodt Inc., Maryland Heights, MO) labeled RBCs was performed in a patient with B-cell lymphoma for evaluation of the left ventricular ejection fraction before starting chemotherapy. Quantitative measurements from MUGA demonstrated normal left ventricular ejection fraction. However, cine images revealed delayed contraction of the left ventricle compared with that of the right, and phase contrast images demonstrated offset of the ventricles' phases. Evaluation with ECG showed delayed depolarization of the left ventricle consistent with LBBB. Phase imaging abnormalities detected on MUGA may be overlooked. Specific patterns of phase abnormalities may direct the physicians' attention toward yet unrecognized diagnoses.

Myocardial tissue engineering currently represents one of the most realistic strategies for cardiac repair. We have recently discovered the ability of carbon nanotube scaffolds to promote cell division and maturation in cardiomyocytes. Here, we test the hypothesis that carbon nanotube scaffolds promote cardiomyocyte growth and maturation by altering the gene expression program, implementing the cell electrophysiological properties and improving networking and maturation of functional syncytia. In our study, we combine microscopy, biological and electrophysiological methodologies, and calcium imaging, to verify whether neonatal rat ventricular myocytes cultured on substrates of multiwall carbon nanotubes acquire a physiologically more mature phenotype compared to control (gelatin). We show that the carbon nanotube substrate stimulates the induction of a gene expression profile characteristic of terminal differentiation and physiological growth, with a 2-fold increase of α-myosin heavy chain (P < 0.001) and upregulation of sarcoplasmic reticulum Ca(2+) ATPase 2a. In contrast, markers of pathological hypertrophy remain unchanged (β-myosin heavy chain, skeletal α-actin, atrial natriuretic peptide). These modifications are paralleled by an increase of connexin-43 gene expression, gap junctions and functional syncytia. Moreover, carbon nanotubes appear to exert a protective effect against the pathologic stimulus of phenylephrine. Finally, cardiomyocytes on carbon nanotubes demonstrate a more mature electrophysiological phenotype of syncytia and intracellular calcium signaling. Thus, carbon nanotubes interacting with cardiomyocytes have the ability to promote physiological growth and functional maturation. These properties are unique in the current vexing field of tissue engineering, and offer unprecedented perspectives in the development of innovative therapies for cardiac repair.

Compelling evidence from in vivo model systems within the past decade shows that the APP family of proteins is important for synaptic development and function in the central and peripheral nervous systems. The synaptic role promises to be complex and multifaceted for several reasons. The three family members have overlapping and redundant functions in mammals. They have both adhesive and signaling properties and may, in principle, act as both ligands and receptors. Moreover, they bind a multitude of synapse-specific proteins, and we predict that additional interacting protein partners will be discovered. Transgenic mice with modified or abolished expression of APP and APLPs have synaptic defects that are readily apparent. Studies of the neuromuscular junction (NMJ) in these transgenic mice have revealed molecular and functional deficits in neurotransmitter release, in organization of the postsynaptic receptors, and in coordinated intercellular development. The results summarized here from invertebrate and vertebrate systems confirm that the NMJ with its accessibility, large size, and homogeneity provides a model synapse for identifying and analyzing molecular pathways of APP actions., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objective: Coronary CT angiography has high sensitivity, but modest specificity, to detect acute coronary syndrome. We studied whether adding resting CT myocardial perfusion imaging improved the detection of acute coronary syndrome., Subjects and Methods: Patients with low-to-intermediate cardiac risk presenting with possible acute coronary syndrome received both the standard of care evaluation and a research thoracic 64-MDCT examination. Patients with an obstructive (> 50%) stenosis or a nonevaluable coronary segment on CT were diagnosed with possible acute coronary syndrome. CT perfusion was determined by applying gray and color Hounsfield unit maps to resting CT angiography images. Adjudicated patient diagnoses were based on the standard of care and 3-month follow-up. Patient-level diagnostic performance for acute coronary syndrome was calculated for coronary CT, CT perfusion, and combined techniques., Results: A total of 105 patients were enrolled. Of the nine (9%) patients with acute coronary syndrome, all had obstructive CT stenoses but only three had abnormal CT perfusion. CT perfusion was normal in all other patients. To detect acute coronary syndrome, CT angiography had 100% sensitivity, 89% specificity, and a positive predictive value of 45%. For CT perfusion, specificity and positive predictive value were each 100%, and sensitivity was 33%. Combined cardiac CT and CT perfusion had similar specificity but a higher positive predictive value (100%) than did CT angiography., Conclusion: Resting CT perfusion using CT angiographic images may have high specificity and may improve CT positive predictive value for acute coronary syndrome without added radiation and contrast. However, normal resting CT perfusion cannot exclude acute coronary syndrome.

Purpose: The purpose of this study was to assess the diagnostic accuracy and one year prognosis of whole chest, "multiple rule out" CT for coronary artery disease (CAD) in Emergency Department patients., Methods and Findings: One hundred and two Emergency Department patients at low to intermediate risk of acute coronary syndrome (ACS), pulmonary embolism and/or acute aortic syndrome underwent a research 64 channel ECG-gated, whole chest CT and a standard of care evaluation. Patients were classified with obstructive CAD with either a coronary CT stenosis greater than 50% or a non-evaluable coronary segment. SOC and 3 month follow up data were used to determine an adjudicated clinical diagnosis. The diagnostic ability of obstructive CAD on CT to identify clinical diagnoses was determined. Patients were followed up for 1 year for cardiac events. Seven (7%) patients were diagnosed with ACS. CT sensitivity to detect obstructive CAD in ACS patients was 100% (95% CI 65%, 100%), negative predictive value 100% (96%, 100%), specificity 88% (80%, 94%), and positive predictive value 39% (17%, 64%). Pulmonary embolism and acute aortic syndrome were not identified in any patients. No cardiac events occurred in patients without obstructive CAD over 1 year., Conclusions: Whole chest CT has high sensitivity and negative predictive value for ACS with excellent one year prognosis in patients without obstructive CAD on CT. The frequency of pulmonary embolism or acute aortic syndrome and the higher radiation dose suggest whole chest CT should be limited to select patients. ClinicalTrials.org #: NCT00855231.

Background: The Seattle Heart Failure Model (SHFM) is a multivariable model that uses demographic and clinical markers to predict survival in patients with heart failure. Inappropriate activation of the sympathetic nervous system, which contributes to the progression of heart failure and increased mortality, can be assessed using iodine-123 meta-iodobenzylguanidine (MIBG) cardiac imaging. This study investigated the incremental value of MIBG cardiac imaging when added to the SHFM for prediction of all-cause mortality., Methods: Survival data from 961 NYHA II-III subjects in the ADMIRE-HFX trial were included in this analysis. The predictive value of the SHFM alone and in combination with MIBG heart-to-mediastinum ratio (H/M) was compared for all-cause mortality (101 deaths during a median follow-up of 2 years)., Results: The addition of H/M to the SHFM in a Cox model significantly improved risk prediction (P < .0001), with a greater utility in higher risk SHFM patients. The observed 2-year mortality in the highest-risk SHFM subjects (rounded SHFM score of 1) was 24%, but varied from 46% with H/M <1.2 to 0% with H/M >1.8. Net reclassification improvement was 22.7% (P < .001), with 14.9% of subjects who died reclassified into a higher risk category than suggested by SHFM score alone (P = .01) and 7.9% of subjects who survived reclassified into a lower risk category (P < .0001). The 2-year integrated discrimination improvement (+4.14%, P < .0001) and the 1-year area under the receiver-operator characteristic curve (+0.04, P = .026) both showed significant improvement for the combined model with H/M compared to the SHFM alone., Conclusion: The addition of MIBG imaging to the SHFM improves risk stratification, especially in higher risk patients. MIBG may have clinical utility in higher risk patients who are being considered for devices such as ICD, CRT-D, LVAD, and cardiac transplantation.

Nanoscale manipulations of the extracellular microenvironment are increasingly attracting attention in tissue engineering. Here, combining microscopy, biological, and single-cell electrophysiological methodologies, we demonstrate that neonatal rat ventricular myocytes cultured on substrates of multiwall carbon nanotubes interact with carbon nanotubes by forming tight contacts and show increased viability and proliferation. Furthermore, we observed changes in the electrophysiological properties of cardiomyocytes, suggesting that carbon nanotubes are able to promote cardiomyocyte maturation., (© 2012 American Chemical Society)

Purpose: Explore the extent to which stress myocardial perfusion imaging (MPI) studies for coronary heart disease detection met published appropriate use criteria (AUC), and the association between AUC classification and image findings., Data Sources: Retrospective, descriptive review of stress studies performed at the University of Washington Medical Center (UWMC n= 1377) and the Veterans Health Administration of Puget Sound (VA n= 1445) in the 31 months following AUC publication., Conclusions: At UWMC and VA, 69% and 89% of MPI studies, respectively, were classified as appropriate, 16% and 3% as inappropriate, and 15% and 8% as uncertain. All differences were significant, p < .001. At UWMC, 11% of appropriate studies and 10% of inappropriate or uncertain studies were abnormal (demonstrating myocardial ischemia or myocardial infarction), p= .93; these analyses were not performed on VA studies., Implications for Practice: Most studies at both sites were classified as appropriate. At UWMC, the likelihood of a study classified as appropriate demonstrating an abnormality was not significantly different from a study classified as uncertain or inappropriate. AUC are imperfect tools but are increasingly created and referenced; as such, it is vital that practicing nurse practitioners are knowledgeable about their creation, application, and evaluation., (©2011 The Author(s) Journal compilation ©2011 American Academy of Nurse Practitioners.)

Rationale and Objectives: Cardiac computed tomography (CCT) in the emergency department may be cost saving for suspected acute coronary syndrome (ACS), but economic outcome data are limited. The objective of this study was to compare the cost of CCT-based evaluation versus standard of care (SOC) using the results of a clinical trial., Materials and Methods: We developed a decision analytic cost-minimization model to compare CCT-based and SOC evaluation costs to obtain a correct diagnosis. Model inputs, including Medicare-adjusted patient costs, were primarily obtained from a cohort study of 102 patients at low to intermediate risk for ACS who underwent an emergency department SOC clinical evaluation and a 64-channel CCT. SOC costs included stress testing in 77% of patients. Data from published literature completed the model inputs and expanded data ranges for sensitivity analyses., Results: Modeled mean patient costs for CCT-based evaluation were $750 (24%) lower than the SOC ($2384 and $3134, respectively). Sensitivity analyses indicated that CCT was less expensive over a wide range of estimates and was only more expensive with a CCT specificity below 67% or if more than 44% of very low risk patients had CCT. Probabilistic sensitivity analysis suggested that CCT-based evaluation had a 98.9% probability of being less expensive compared to SOC., Conclusion: Using a decision analytic model, CCT-based evaluation resulted in overall lower cost than the SOC for possible ACS patients over a wide range of cost and outcome assumptions, including computed tomography-related complications and downstream costs., (Copyright © 2012 AUR. Published by Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to test the diagnostic accuracy of myocardial CT perfusion (CTP) imaging using color and gray-scale image analysis., Background: Current myocardial CTP techniques have varying diagnostic accuracy and are prone to artifacts that impair detection. This study evaluated the diagnostic accuracy of color and/or gray-scale CTP and the application of artifact criteria to detect hypoperfusion., Methods: Fifty-nine prospectively enrolled patients with abnormal single-photon emission computed tomography (SPECT) studies were analyzed. True hypoperfusion was defined if SPECT hypoperfusion corresponded to obstructive coronary stenoses on CT angiography (CTA). CTP applied color and gray-scale myocardial perfusion maps to resting CTA images. Criteria for identifying artifacts were also applied during interpretation., Results: Using combined SPECT plus CTA as the diagnostic standard, abnormal myocardial CTP was present in 33 (56%) patients, 19 suggesting infarction and 14 suggesting ischemia. Patient-level color and gray-scale myocardial CTP sensitivity to detect infarction was 90%, with specificity 80%, and negative and positive predictive value of 94% and 68%. To detect ischemia or infarction, CTP specificity and positive predictive value were 92% whereas sensitivity was 70%. Gray-scale myocardial CTP had slightly lower specificity but similar sensitivity. Myocardial CTP artifacts were present in 88% of studies and were identified using our criteria., Conclusions: Color and gray-scale myocardial CTP using resting CTA images identified myocardial infarction with high sensitivity as well as infarction or ischemia with high specificity and positive predictive value without additional testing or radiation. Color and gray-scale CTP had slightly better specificity than gray-scale alone., (Copyright © 2011 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Despite its key role in Alzheimer pathogenesis, the physiological function(s) of the amyloid precursor protein (APP) and its proteolytic fragments are still poorly understood. Previously, we generated APPsα knock-in (KI) mice expressing solely the secreted ectodomain APPsα. Here, we generated double mutants (APPsα-DM) by crossing APPsα-KI mice onto an APLP2-deficient background and show that APPsα rescues the postnatal lethality of the majority of APP/APLP2 double knockout mice. Surviving APPsα-DM mice exhibited impaired neuromuscular transmission, with reductions in quantal content, readily releasable pool, and ability to sustain vesicle release that resulted in muscular weakness. We show that these defects may be due to loss of an APP/Mint2/Munc18 complex. Moreover, APPsα-DM muscle showed fragmented post-synaptic specializations, suggesting impaired postnatal synaptic maturation and/or maintenance. Despite normal CNS morphology and unaltered basal synaptic transmission, young APPsα-DM mice already showed pronounced hippocampal dysfunction, impaired spatial learning and a deficit in LTP that could be rescued by GABA(A) receptor inhibition. Collectively, our data show that APLP2 and APP are synergistically required to mediate neuromuscular transmission, spatial learning and synaptic plasticity.

Objectives: The aim of this study was to discern the role of the cardiac voltage-gated sodium ion channel SCN5A in the etiology of dilated cardiomyopathy (DCM)., Background: Dilated cardiomyopathy associates with mutations in the SCN5A gene, but the frequency, phenotype, and causative nature of these associations remain the focus of ongoing investigation., Methods: Since 1991, DCM probands and family members have been enrolled in the Familial Cardiomyopathy Registry and extensively evaluated by clinical phenotype. Genomic deoxyribonucleic acid samples from 338 individuals among 289 DCM families were obtained and screened for SCN5A mutations by denaturing high-performance liquid chromatography and sequence analysis., Results: We identified 5 missense SCN5A mutations among our DCM families, including novel mutations E446K, F1520L, and V1279I, as well as previously reported mutations D1275N and R222Q. Of 15 SCN5A mutation carriers in our study, 14 (93%) manifested arrhythmia: supraventricular arrhythmia (13 of 15), including sick sinus syndrome (5 of 15) and atrial fibrillation (9 of 15), ventricular tachycardia (5 of 15), and conduction disease (9 of 15)., Conclusions: Mutations in SCN5A were detected in 1.7% of DCM families. Two-thirds (6 of 9) of all reported DCM mutations in SCN5A localize to the highly conserved homologous S3 and S4 transmembrane segments, suggesting a shared mechanism of disruption of the voltage-sensing mechanism of this channel leading to DCM. Not surprisingly, SCN5A mutation carriers show a strong arrhythmic pattern that has clinical and diagnostic implications., (2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Patients with diabetes mellitus have accelerated progression of heart failure and often have impaired cardiac sympathetic innervation. The present study examines the implications for heart failure progression of cardiac sympathetic denervation, assessed by I-123 metaiodobenzylguanidine imaging, in diabetic compared with nondiabetic subjects., Methods and Results: We evaluated 343 diabetic and 618 nondiabetic subjects with New York Heart Association class II or III heart failure and a left ventricular ejection fraction ≤35% over a median follow-up of 17 months. A multivariable Cox proportional hazards model was used to examine the influence of clinical variables, b-type natriuretic peptide, plasma norepinephrine, left ventricular ejection fraction, and I-123 metaiodobenzylguanidine imaging parameters on time to a heart failure event. The late heart-to-mediastinum (H/M) ratio and the interaction term of diabetes mellitus with the prospectively selected late H/M ratio <1.6 were independent predictors of heart failure progression, providing incremental prognostic information beyond that available from all other variables. In diabetic subjects, late H/M ratio <1.6 was associated with a 2.99-fold greater 2-year rate of heart failure progression (33.5%) than late H/M ratio ≥1.6 (11.2% event rate)., Conclusions: The combination of diabetes mellitus and I-123 metaiodobenzylguanidine H/M ratio is an independent predictor of heart failure progression, confirming the high risk of diabetic subjects with impaired cardiac sympathetic nerve function.

Objective: The purpose of this article is to determine the frequency of adverse cardiac events during the year following a negative cardiac CT angiogram in a population of patients presenting to the emergency department with low-to-moderate risk chest pain., Subjects and Methods: Eighty-one consecutive patients who had standard of care evaluation for low-to-moderate risk chest pain in the emergency department were enrolled and consented to have a cardiac CT angiogram added to their workup and to have follow-up for 1 year. Eleven patients were excluded, six because their cardiac CT examinations were unsuccessful, four because of a positive cardiac CT angiogram result, and one was lost to follow-up. Seventy patients with negative cardiac CT angiographic results (< 50% stenosis) were included and were interviewed in detail at 3, 6, and 12 months about intervening cardiac events, diagnostic testing, and therapy. Electronic medical records were also reviewed at each time point., Results: None of the 70 patients reported an adverse cardiac event over the 12-month follow-up period. At 1 year, the cause of chest pain was unknown in 49 patients, gastrointestinal in nine patients, anxiety in seven patients, musculoskeletal in three patients, and other in two patients. Three of four patients with 50% or greater stenosis on their cardiac CT had subsequent cardiac catheterization and stent placement., Conclusion: In patients with low-to-moderate risk chest pain evaluated in the emergency department, adverse cardiac events may be rare during the 12 months following a negative cardiac CT angiogram.

Screening for coronary artery disease is common practice in the evaluation of liver transplantation candidates. However, it is unclear whether coronary screening influences transplantation eligibility. We sought to determine the association between screening stress myocardial perfusion imaging (MPI) results and the eligibility for liver transplantation. Within a retrospective cohort of liver transplantation candidates referred for screening stress MPI at a single institution from April 1998 to February 2004, we obtained the baseline characteristics, stress MPI results, transplantation eligibility, and transplantation denial criteria by chart review. Of 294 patients (39%) denied transplantation, the denial criteria were multifactorial for 91 (31%) of the candidates. Compared to candidates with low-risk stress MPI results, the odds of being denied transplantation were the same for candidates with intermediate-risk MPI results (odds ratio 0.93, 95% confidence interval 0.45 to 1.82) or high-risk MPI results (odds ratio 1.42, 95% confidence interval 0.54 to 3.73). This lack of association persisted in our analysis with additional stratification of stress MPI results into negative, positive-low-risk, positive-intermediate-risk, and positive-high-risk. In conclusion, the screening stress MPI results were not associated with liver transplantation eligibility. The large number of competing factors considered before transplantation listing and the low proportion of positive stress MPI results suggests that targeting screening to patients deemed otherwise acceptable for transplantation might increase the influence of stress MPI findings on transplantation eligibility., (Copyright 2010 Elsevier Inc. All rights reserved.)

Purpose: In cardiac PET and PET/CT imaging, misaligned transmission and emission images are a common problem due to respiratory and cardiac motion. This misalignment leads to erroneous attenuation correction and can cause errors in perfusion mapping and quantification. This study develops and tests a method for automated alignment of attenuation and emission data., Methods: The CT-based attenuation map is iteratively transformed until the attenuation corrected emission data minimize an objective function based on the Radon consistency conditions. The alignment process is derived from previous work by Welch et al. ["Attenuation correction in PET using consistency information," IEEE Trans. Nucl. Sci. 45, 3134-3141 (1998)] for stand-alone PET imaging. The process was evaluated with the simulated data and measured patient data from multiple cardiac ammonia PET/CT exams. The alignment procedure was applied to simulations of five different noise levels with three different initial attenuation maps. For the measured patient data, the alignment procedure was applied to eight attenuation-emission combinations with initially acceptable alignment and eight combinations with unacceptable alignment. The initially acceptable alignment studies were forced out of alignment a known amount and quantitatively evaluated for alignment and perfusion accuracy. The initially unacceptable studies were compared to the proposed aligned images in a blinded side-by-side review., Results: The proposed automatic alignment procedure reduced errors in the simulated data and iteratively approaches global minimum solutions with the patient data. In simulations, the alignment procedure reduced the root mean square error to less than 5 mm and reduces the axial translation error to less than 1 mm. In patient studies, the procedure reduced the translation error by > 50% and resolved perfusion artifacts after a known misalignment for the eight initially acceptable patient combinations. The side-by-side review of the proposed aligned attenuation-emission maps and initially misaligned attenuation-emission maps revealed that reviewers preferred the proposed aligned maps in all cases, except one inconclusive case., Conclusions: The proposed alignment procedure offers an automatic method to reduce attenuation correction artifacts in cardiac PET/CT and provides a viable supplement to subjective manual realignment tools.

Large-scale models accounting for the processes supporting metabolism and function in an organ or tissue with a marked heterogeneity of flows and metabolic rates are computationally complex and tedious to compute. Their use in the analysis of data from positron emission tomography (PET) and magnetic resonance imaging (MRI) requires model reduction since the data are composed of concentration-time curves from hundreds of regions of interest (ROI) within the organ. Within each ROI, one must account for blood flow, intracapillary gradients in concentrations, transmembrane transport, and intracellular reactions. Using modular design, we configured a whole organ model, GENTEX, to allow adaptive usage for multiple reacting molecular species while omitting computation of unused components. The temporal and spatial resolution and the number of species are adaptable and the numerical accuracy and computational speed is adjustable during optimization runs, which increases accuracy and spatial resolution as convergence approaches. An application to the interpretation of PET image sequences after intravenous injection of 13NH3 provides functional image maps of regional myocardial blood flows.

Positron emission tomography (PET) is a nuclear medicine imaging modality based on the administration of a positron-emitting radiotracer, the imaging of the distribution and kinetics of the tracer, and the interpretation of the physiological events and their meaning with respect to health and disease. PET imaging was introduced in the 1970s and numerous advances in radiotracers and detection systems have enabled this modality to address a wide variety of clinical tasks, such as the detection of cancer, staging of Alzheimer's disease, and assessment of coronary artery disease (CAD). This review provides a description of the logic and the logistics of the processes required for PET imaging and a discussion of its use in guiding the treatment of CAD. Finally, we outline prospects and limitations of nanoparticles as agents for PET imaging.

Objective: The current standard-of-care workup of low-risk patients with chest pain in an emergency department takes 12-36 hours and is expensive. We hypothesized that negative 64-MDCT coronary angiography early in the workup of such patients may enable a shorter length of stay and reduce charges., Materials and Methods: The standard-of-care evaluation consisted of serial cardiac enzyme tests, ECGs, and stress testing. After informed consent, we added cardiac CT early in the standard-of-care workup of 53 consecutive patients. Fifty patients had negative CT findings and were included in this series. The length of stay and charges were analyzed using actual patient data for all patients in the standard-of-care workup and for two earlier discharge scenarios based on negative cardiac CT results: First, CT plus serial enzyme tests and ECGs during an observation period followed by discharge if all were negative; and second, CT plus one set of enzyme tests and one ECG followed by discharge if all were negative. Comparisons were made using paired Student's t tests., Results: For standard of care and the two CT-based earlier discharge analyses, the mean lengths of stay were 25.4, 14.3, and 5.0 hours; mean charges were $7,597, $6,153, and $4,251. Length of stay and charges were both significantly less (p < 0.001) for the two CT-based analyses., Conclusion: In low-risk patients with chest pain, discharge from the emergency department based on negative cardiac CT, enzyme tests, and ECG may significantly decrease both length of stay and hospital charges compared with the standard of care.

Objective: The purpose of this study was to compare the patient radiation dose and coronary artery image quality of long-z-axis whole-chest 64-MDCT performed with retrospective ECG gating with those of CT performed with prospective ECG triggering in the evaluation of emergency department patients with nonspecific chest pain., Subjects and Methods: Consecutively registered emergency department patients with nonspecific low-to-moderate-risk chest pain underwent whole-chest CT with retrospective gating (n = 41) or prospective triggering (n = 31). Effective patient radiation doses were estimated and compared by use of unpaired Student's t tests. Two reviewers independently scored the quality of images of the coronary arteries, and the scores were compared by use of ordinal logistic regression., Results: Age, heart rate, body mass index, and z-axis coverage were not statistically different between the two groups. For retrospective gating, the mean effective radiation dose was 31.8 +/- 5.1 mSv; for prospective triggering, the mean effective radiation dose was 9.2 +/- 2.2 mSv (prospective triggering 71% lower, p < 0.001). Two of 512 segments imaged with retrospective gating were nonevaluable (0.4%), and two of 394 segments imaged with prospective triggering were nonevaluable (0.5%). Prospectively triggered images were 2.2 (95% CI, 1.1-4.5) times as likely as retrospectively gated images to receive a high image quality score for each segment after adjustment for segment differences (p < 0.05)., Conclusion: For long-z-axis whole-chest 64-MDCT of emergency department patients with nonspecific chest pain, use of prospective ECG triggering may result in substantially lower patient radiation doses and better coronary artery image quality than is achieved with retrospective ECG gating.

Background: Better insight into the psychosocial factors associated with prehospital delays in seeking care for acute coronary syndromes is needed to inform the design of future interventions. Delay in presenting for care after the onset of symptoms is common, limits the potential benefit of acute reperfusion, and has not been reduced by interventions tested thus far., Methods and Results: Seven hundred ninety-six patients with suspected ischemic heart disease scheduled for clinically indicated imaging stress tests completed questionnaires concerning psychological distress and attachment styles (worthiness to receive care, trustworthiness of others to provide care). The primary dependent variable for this study was response to a question from the rapid early action for coronary treatment trial concerning intention to "wait until very sure" before seeking care for a possible "heart attack." Responses to this question were strongly associated with actual emergency department-reported and self-reported care delay in the rapid early action for coronary treatment trial. In multivariable ordinal regression models, a more negative view of the trustworthiness of others, greater physical limitations from angina, and no previous revascularization were independently associated with increased intention to wait to seek care for a myocardial infarction. Intention to wait was not associated with inducible ischemia or self-perceived risk of myocardial infarction., Conclusions: Intention to delay seeking care for acute coronary syndromes is associated with a patient's view of the trustworthiness of others, previous experience with revascularization, and functional limitations, even after adjustment for objective and perceived acute coronary syndromes risk. These findings provide insight into novel factors contributing to longer delay times and may inform future interventions to reduce delay time.

Congestive heart failure increasingly contributes to the overall morbidity and mortality associated with cardiovascular disease. Although significant advances in therapies allow patients to feel better and have improved functional status and survival, not all patients respond equally to these therapies. Moreover, for any given level of left ventricular systolic dysfunction, it is difficult to predict who will have progressive heart failure leading to death or transplantation or who will die suddenly. It has long been recognized that the sympathetic nervous system plays a major role in the morbidity and mortality associated with congestive heart failure from systolic left ventricular dysfunction. Although some of the sympathetic effect occurs at the systemic level, malfunction at the ventricular myocyte-sympathetic nerve terminal interface is likely a major contributor to sudden death and progressive heart failure. Imaging the cardiac sympathetic nervous system can be used to evaluate this myoneural interface and to predict outcome.