Comparison of Radiation Dose and Image Quality of Pediatric High-Resolution Chest CT Between Photon-Counting Detector CT and Energy-Integrated Detector CT: A Matched Study.

BACKGROUND. Photon-counting detector (PCD) CT has been shown to reduce radiation dose and improve image quality in adult chest CT examinations; its potential impact in pediatric CT is not well documented. OBJECTIVE. The purpose of our study was to compare radiation dose, objective image quality, and subjective image quality of PCD CT and energy-integrating detector (EID) CT in children undergoing high-resolution CT (HRCT) of the chest. METHODS. This retrospective study included 27 children (median age, 3.9 years; 10 girls, 17 boys) who underwent PCD CT between March 1, 2022, and August 31, 2022, and 27 children (median age, 4.0 years; 13 girls, 14 boys) who underwent EID CT between August 1, 2021, and January 31, 2022; all examinations comprised clinically indicated chest HRCT. The patients in the two groups were matched by age and water-equivalent diameter. Radiation dose parameters were recorded. One observer placed ROIs to measure objective parameters (lung attenuation, image noise, and SNR). Two radiologists independently assessed subjective measures (overall image quality and motion artifacts) using 5-point Likert scales (1 = highest quality). Groups were compared. RESULTS. PCD CT, in comparison with EID CT, showed lower median CTDIvol (0.41 vs 0.71 mGy, p < .001), DLP (10.2 vs 13.7 mGy × cm, p = .008), size-specific dose estimate (0.82 vs 1.34 mGy, p < .001), and tube current-exposure time product (48.0 vs 202.0 mAs, p < .001). PCD CT and EID CT showed no significant difference in right upper lobe (RUL) lung attenuation (mean, -793 vs -750 HU; p = .09), right lower lobe (RLL) lung attenuation (mean, -745 vs -716 HU; p = .23), RUL image noise (mean, 55 vs 51 HU; p = .27), RLL image noise (mean, 59 vs 57 HU; p = .48), RUL SNR (mean, -14.9 vs -15.8; p = .89), or RLL SNR (mean, -13.1 vs -13.6; p = .79). PCD CT and EID CT showed no significant difference in median overall image quality for reader 1 (1.0 vs 1.0, p = .28) or reader 2 (1.0 vs 1.0, p = .17) or median motion artifacts for reader 1 (1.0 vs 1.0, p = .07) or reader 2 (1.0 vs 1.0, p = .22). CONCLUSION. PCD CT showed significantly reduced dose levels without a significant difference in objective or subjective image quality compared with EID CT. CLINICAL IMPACT. These data expand understanding of the capabilities of PCD CT and support its routine use in children.

Influence of metabolic dysfunction on cardiac mechanics in decompensated hypertrophy and heart failure.

Alterations in energetic state of the myocardium are associated with decompensated heart failure in humans and in animal models. However, the functional consequences of the observed changes in energetic state on mechanical function are not known. The primary aim of the study was to quantify mechanical/energetic coupling in the heart and to determine if energetic dysfunction can contribute to mechanical failure. A secondary aim was to apply a quantitative systems pharmacology analysis to investigate the effects of drugs that target cross-bridge cycling kinetics in heart failure-associated energetic dysfunction. Herein, a model of metabolite- and calcium-dependent myocardial mechanics was developed from calcium concentration and tension time courses in rat cardiac muscle obtained at different lengths and stimulation frequencies. The muscle dynamics model accounting for the effect of metabolites was integrated into a model of the cardiac ventricles to simulate pressure-volume dynamics in the heart. This cardiac model was integrated into a simple model of the circulation to investigate the effects of metabolic state on whole-body function. Simulations predict that reductions in metabolite pools observed in canine models of heart failure can cause systolic dysfunction, blood volume expansion, venous congestion, and ventricular dilation. Simulations also predict that myosin-activating drugs may partially counteract the effects of energetic state on cross-bridge mechanics in heart failure while increasing myocardial oxygen consumption. Our model analysis demonstrates how metabolic changes observed in heart failure are alone sufficient to cause systolic dysfunction and whole-body heart failure symptoms.

Dynamics of cross-bridge cycling, ATP hydrolysis, force generation, and deformation in cardiac muscle.

Despite extensive study over the past six decades the coupling of chemical reaction and mechanical processes in muscle dynamics is not well understood. We lack a theoretical description of how chemical processes (metabolite binding, ATP hydrolysis) influence and are influenced by mechanical processes (deformation and force generation). To address this need, a mathematical model of the muscle cross-bridge (XB) cycle based on Huxley's sliding filament theory is developed that explicitly accounts for the chemical transformation events and the influence of strain on state transitions. The model is identified based on elastic and viscous moduli data from mouse and rat myocardial strips over a range of perturbation frequencies, and MgATP and inorganic phosphate (Pi) concentrations. Simulations of the identified model reproduce the observed effects of MgATP and MgADP on the rate of force development. Furthermore, simulations reveal that the rate of force re-development measured in slack-restretch experiments is not directly proportional to the rate of XB cycling. For these experiments, the model predicts that the observed increase in the rate of force generation with increased Pi concentration is due to inhibition of cycle turnover by Pi. Finally, the model captures the observed phenomena of force yielding suggesting that it is a result of rapid detachment of stretched attached myosin heads.

Computational analysis of the regulation of Ca(2+) dynamics in rat ventricular myocytes.

Force-frequency relationships of isolated cardiac myocytes show complex behaviors that are thought to be specific to both the species and the conditions associated with the experimental preparation. Ca(2+) signaling plays an important role in shaping the force-frequency relationship, and understanding the properties of the force-frequency relationship in vivo requires an understanding of Ca(2+) dynamics under physiologically relevant conditions. Ca(2+) signaling is itself a complicated process that is best understood on a quantitative level via biophysically based computational simulation. Although a large number of models are available in the literature, the models are often a conglomeration of components parameterized to data of incompatible species and/or experimental conditions. In addition, few models account for modulation of Ca(2+) dynamics via ß-adrenergic and calmodulin-dependent protein kinase II (CaMKII) signaling pathways even though they are hypothesized to play an important regulatory role in vivo. Both protein-kinase-A and CaMKII are known to phosphorylate a variety of targets known to be involved in Ca(2+) signaling, but the effects of these pathways on the frequency- and inotrope-dependence of Ca(2+) dynamics are not currently well understood. In order to better understand Ca(2+) dynamics under physiological conditions relevant to rat, a previous computational model is adapted and re-parameterized to a self-consistent dataset obtained under physiological temperature and pacing frequency and updated to include ß-adrenergic and CaMKII regulatory pathways. The necessity of specific effector mechanisms of these pathways in capturing inotrope- and frequency-dependence of the data is tested by attempting to fit the data while including and/or excluding those effector components. We find that: (1) ß-adrenergic-mediated phosphorylation of the L-type calcium channel (LCC) (and not of phospholamban (PLB)) is sufficient to explain the inotrope-dependence; and (2) that CaMKII-mediated regulation of neither the LCC nor of PLB is required to explain the frequency-dependence of the data.

Arterial stiffening provides sufficient explanation for primary hypertension.

Hypertension is one of the most common age-related chronic disorders, and by predisposing individuals for heart failure, stroke, and kidney disease, it is a major source of morbidity and mortality. Its etiology remains enigmatic despite intense research efforts over many decades. By use of empirically well-constrained computer models describing the coupled function of the baroreceptor reflex and mechanics of the circulatory system, we demonstrate quantitatively that arterial stiffening seems sufficient to explain age-related emergence of hypertension. Specifically, the empirically observed chronic changes in pulse pressure with age and the impaired capacity of hypertensive individuals to regulate short-term changes in blood pressure arise as emergent properties of the integrated system. The results are consistent with available experimental data from chemical and surgical manipulation of the cardio-vascular system. In contrast to widely held opinions, the results suggest that primary hypertension can be attributed to a mechanogenic etiology without challenging current conceptions of renal and sympathetic nervous system function.

Analysis of cardiovascular dynamics in pulmonary hypertensive C57BL6/J mice.

A computer model was used to analyze data on cardiac and vascular mechanics from C57BL6/J mice exposed to 0 (n = 4), 14 (n = 6), 21 (n = 8) and 28 (n = 7) days of chronic hypoxia and treatment with the VEGF receptor inhibitor SUGEN (HySu) to induce pulmonary hypertension. Data on right ventricular pressure and volume, and systemic arterial pressure obtained before, during, and after inferior vena cava occlusion were analyzed using a mathematical model of realistic ventricular mechanics coupled with a simple model of the pulmonary and systemic vascular systems. The model invokes a total of 26 adjustable parameters, which were estimated based on least-squares fitting of the data. Of the 26 adjustable parameters, 14 were set to globally constant values for the entire data set. It was necessary to adjust the remaining 12 parameters to match data from all experimental groups. Of these 12 individually adjusted parameters, three parameters representing pulmonary vascular resistance, pulmonary arterial elastance, and pulmonary arterial narrowing were found to significantly change in HySu-induced remodeling. Model analysis shows a monotonic change in these parameters as disease progressed, with approximately 130% increase in pulmonary resistance, 70% decrease in unstressed pulmonary arterial volume, and 110% increase in pulmonary arterial elastance in the 28-day group compared to the control group. These changes are consistent with prior experimental measurements. Furthermore, the 28-day data could be explained only after increasing the passive elastance of the right free wall compared to the value used for the other data sets, which is likely a consequence of the increased RV collagen accumulation found experimentally. These findings may indicate a compensatory remodeling followed by pathological remodeling of the right ventricle in HySu-induced pulmonary hypertension.

A computational analysis of the long-term regulation of arterial pressure.

The asserted dominant role of the kidneys in the chronic regulation of blood pressure and in the etiology of hypertension has been debated since the 1970s. At the center of the theory is the observation that the acute relationships between arterial pressure and urine production-the acute pressure-diuresis and pressure-natriuresis curves-physiologically adapt to perturbations in pressure and/or changes in the rate of salt and volume intake. These adaptations, modulated by various interacting neurohumoral mechanisms, result in chronic relationships between water and salt excretion and pressure that are much steeper than the acute relationships. While the view that renal function is the dominant controller of arterial pressure has been supported by computer models of the cardiovascular system known as the "Guyton-Coleman model", no unambiguous description of a computer model capturing chronic adaptation of acute renal function in blood pressure control has been presented. Here, such a model is developed with the goals of: 1. representing the relevant mechanisms in an identifiable mathematical model; 2. identifying model parameters using appropriate data; 3. validating model predictions in comparison to data; and 4. probing hypotheses regarding the long-term control of arterial pressure and the etiology of primary hypertension. The developed model reveals: long-term control of arterial blood pressure is primarily through the baroreflex arc and the renin-angiotensin system; and arterial stiffening provides a sufficient explanation for the etiology of primary hypertension associated with ageing. Furthermore, the model provides the first consistent explanation of the physiological response to chronic stimulation of the baroreflex.

Specification, construction, and exact reduction of state transition system models of biochemical processes.

Biochemical reaction systems may be viewed as discrete event processes characterized by a number of states and state transitions. These systems may be modeled as state transition systems with transitions representing individual reaction events. Since they often involve a large number of interactions, it can be difficult to construct such a model for a system, and since the resulting state-level model can involve a huge number of states, model analysis can be difficult or impossible. Here, we describe methods for the high-level specification of a system using hypergraphs, for the automated generation of a state-level model from a high-level model, and for the exact reduction of a state-level model using information from the high-level model. Exact reduction is achieved through the automated application to the high-level model of the symmetry reduction technique and reduction by decomposition by independent subsystems, allowing potentially significant reductions without the need to generate a full model. The application of the method to biochemical reaction systems is illustrated by models describing a hypothetical ion-channel at several levels of complexity. The method allows for the reduction of the otherwise intractable example models to a manageable size.

Identifying physiological origins of baroreflex dysfunction in salt-sensitive hypertension in the Dahl SS rat.

Salt-sensitive hypertension is known to be associated with dysfunction of the baroreflex control system in the Dahl salt-sensitive (SS) rat. However, neither the physiological mechanisms nor the genomic regions underlying the baroreflex dysfunction seen in this rat model are definitively known. Here, we have adopted a mathematical modeling approach to investigate the physiological and genetic origins of baroreflex dysfunction in the Dahl SS rat. We have developed a computational model of the overall baroreflex heart rate control system based on known physiological mechanisms to analyze telemetry-based blood pressure and heart rate data from two genetic strains of rat, the SS and consomic SS.13(BN), on low- and high-salt diets. With this approach, physiological parameters are estimated, unmeasured physiological variables related to the baroreflex control system are predicted, and differences in these quantities between the two strains of rat on low- and high-salt diets are detected. Specific findings include: a significant selective impairment in sympathetic gain with high-salt diet in SS rats and a protection from this impairment in SS.13(BN) rats, elevated sympathetic and parasympathetic offsets with high-salt diet in both strains, and an elevated sympathetic tone with high-salt diet in SS but not SS.13(BN) rats. In conclusion, we have associated several important physiological parameters of the baroreflex control system with chromosome 13 and have begun to identify possible physiological mechanisms underlying baroreflex impairment and hypertension in the Dahl SS rat that may be further explored in future experimental and modeling-based investigation.

99mTc-labeled duramycin as a novel phosphatidylethanolamine-binding molecular probe.

UNLABELLED: With only 19 amino acids, duramycin is the smallest known polypeptide that has a defined 3-dimensional binding structure. Duramycin binds phosphatidylethanolamine (PtdE) at a 1:1 ratio with high affinity and exclusive specificity. As an abundant binding target, PtdE is a major phospholipid and accounts for about 20% of the phospholipid content in mammalian cellular membranes. PtdE is externalized to the surface of apoptotic cells and also becomes accessible in necrotic cells because of compromised plasma membrane integrity. Given the unique physicochemical properties of duramycin and the availability of PtdE in acute cell death, the goal of this study was to develop and evaluate 99mTc-duramycin as a novel molecular probe for imaging PtdE. METHODS: Duramycin is covalently modified with succinimidyl 6-hydrazinonicotinate acetone hydrazone (HYNIC) and labeled with 99mTc using a coordination chemistry involving tricine-phosphine coligands. The retention of PtdE-binding activities was confirmed using competition assays with PtdE-containing liposomes. The blood clearance, pharmacokinetics, and biodistribution of 99mTc-duramycin were measured in rats. Finally, 99mTc-duramycin binding to acute cell death in vivo was demonstrated using a rat model of acute myocardial infarction induced by ischemia and reperfusion and confirmed using autoradiography and histology. RESULTS: HYNIC-derivatized duramycin with 1:1 stoicheometry was synthesized and confirmed by mass spectrometry. The radiolabeling efficiency was 80%-85%, radiochemical purity was 78%-89%, and specific activity was 54 GBq. The radiotracer was purified with high-performance liquid chromatography radiodetection before use. The specific uptake of 99mTc-duramycin in apoptotic cells, compared with that in viable control cells, was enhanced by more than 30-fold. This binding was competitively diminished in the presence of PtdE-containing liposomes but not by liposomes consisting of other phospholipid species. Intravenously injected 99mTc-duramycin has favorable pharmacokinetic and biodistribution profiles: it quickly clears from the circulation via the renal system, with a blood half-life of less than 4 min in rats. The hepatic and gastrointestinal uptake were very low. 99mTc-duramycin is completely unmetabolized in vivo, and the intact agent is recovered from the urine. Combined with a fast clearance and low hepatic background, the avid binding of 99mTc-duramycin to the infarcted myocardium quickly becomes conspicuous shortly after injection. The uptake of radioactivity in infarcted tissues was confirmed by autoradiography and histology. CONCLUSION: 99mTc-duramycin is a stable, low-molecular-weight PtdE-binding radiopharmaceutical, with favorable in vivo imaging profiles. It is a strong candidate as a molecular probe for PtdE imaging and warrants further development and characterization.

Molecular networks in Dahl salt-sensitive hypertension based on transcriptome analysis of a panel of consomic rats.

The Dahl salt-sensitive (SS) rat is a widely used model of human salt-sensitive hypertension and renal injury. We studied the molecular networks that underlie the complex disease phenotypes in the SS model, using a design that involved two consomic rat strains that were protected from salt-induced hypertension and one that was not protected. Substitution of Brown Norway (BN) chromosome 13 or 18, but not 20, into the SS genome was found to significantly attenuate salt-induced hypertension and albuminuria. Gene expression profiles were examined in the kidneys of SS and consomic SS-13(BN), SS-18(BN), and SS-20(BN) rats with a total of 240 cDNA microarrays. The substituted chromosome was overrepresented in genes differentially expressed between a consomic strain and SS rats on a 0.4% salt diet. F5, Serpinc1, Slc19a2, and genes represented by three other expressed sequence tags (ESTs), which are located on chromosome 13, were found to be differentially expressed between SS-13(BN) and all other strains examined. Likewise, Acaa2, B4galt6, Colec12, Hsd17b4, and five other ESTs located on chromosome 18 exhibited expression patterns unique to SS-18(BN). On exposure to a 4% salt diet, there were 184 ESTs in the renal cortex and 346 in the renal medulla for which SS-13(BN) and SS-18(BN) shared one expression pattern, while SS and SS-20(BN) shared another, mirroring the phenotypic segregation among the four strains. Molecular networks that might contribute to the development of Dahl salt-sensitive hypertension and albuminuria were constructed with an approach that merged biological knowledge-driven analysis and data-driven Bayesian probabilistic analysis.