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Isolating the influences of fluid dynamics on selectin-mediated particle rolling at venular junctional regions.
Jung JJ, Grayson KA, King MR, Lamkin-Kennard KA
(2018) Microvasc Res 118: 144-154
MeSH Terms: Animals, Cell Adhesion, Humans, Hydrodynamics, Inflammation, Leukocyte Rolling, Leukocytes, Lewis X Antigen, Microspheres, Models, Cardiovascular, P-Selectin, Sialyl Lewis X Antigen, Signal Transduction, Venules
Show Abstract · Added April 15, 2019
The objective of this study was to isolate the impact of hydrodynamics on selectin-mediated cell rolling in branched microvessels. Significant advancements have been made in furthering the understanding of complex interactions between biochemical and physical factors in the inflammatory cascade in simplified planar geometries. However, few studies have sought to quantify the effects of branched configurations and to isolate the effects of associated fluid forces. Experimental techniques were developed to perform in vitro adhesion experiments in Y-shaped micro-slides. The micro-slides were coated with P-selectin and microspheres coated with Sialyl-Lewis were observed as they rolled in the chambers at different wall shear stresses. Study results revealed that microsphere rolling velocities and rolling flux were lowest in regions closest to the apex of a junctional region and were dependent on both branch angle and wall shear stress. The regions closest to the junctional region were shown to have low bulk flow velocities and shear stresses using computational fluid dynamics (CFD) modeling. Collectively, the study demonstrates that despite the presence of a uniform coating of P-selectin, hydrodynamic factors associated with the chamber geometry yield non-uniform effects on particle behavior. These findings could explain why cells have been observed to preferentially adhere or transmigrate near junctional regions. Future characterization of inflammatory processes in microvascular network configurations is therefore crucial for furthering our fundamental understanding of inflammation.
Copyright © 2018 Elsevier Inc. All rights reserved.
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14 MeSH Terms
Forward problem of electrocardiography: is it solved?
Bear LR, Cheng LK, LeGrice IJ, Sands GB, Lever NA, Paterson DJ, Smaill BH
(2015) Circ Arrhythm Electrophysiol 8: 677-84
MeSH Terms: Action Potentials, Animals, Body Surface Potential Mapping, Electrocardiography, Epicardial Mapping, Heart Conduction System, Models, Animal, Models, Cardiovascular, Pericardium, Predictive Value of Tests, Reproducibility of Results, Signal Processing, Computer-Assisted, Swine
Show Abstract · Added April 26, 2016
BACKGROUND - The relationship between epicardial and body surface potentials defines the forward problem of electrocardiography. A robust formulation of the forward problem is instrumental to solving the inverse problem, in which epicardial potentials are computed from known body surface potentials. Here, the accuracy of different forward models has been evaluated experimentally.
METHODS AND RESULTS - Body surface and epicardial potentials were recorded simultaneously in anesthetized closed-chest pigs (n=5) during sinus rhythm, and epicardial and endocardial ventricular pacing (65 records in total). Body surface potentials were simulated from epicardial recordings using experiment-specific volume conductor models constructed from magnetic resonance imaging. Results for homogeneous (isotropic electric properties) and inhomogeneous (incorporating lungs, anisotropic skeletal muscle, and subcutaneous fat) forward models were compared with measured body surface potentials. Correlation coefficients were 0.85±0.08 across all animals and activation sequences with no significant difference between homogeneous and inhomogeneous solutions (P=0.85). Despite this, there was considerable variance between simulated and measured body surface potential distributions. Differences between the body surface potential extrema predicted with homogeneous forward models were 55% to 78% greater than observed (P<0.05) and attenuation of potentials adjacent to extrema were 10% to 171% greater (P<0.03). The length and orientation of the vector between potential extrema were also significantly different. Inclusion of inhomogeneous electric properties in the forward model reduced, but did not eliminate these differences.
CONCLUSIONS - These results demonstrate that homogeneous volume conductor models introduce substantial spatial inaccuracies in forward problem solutions. This probably affects the precision of inverse reconstructions of cardiac potentials, in which this assumption is made.
© 2015 American Heart Association, Inc.
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13 MeSH Terms
Inflammation, immunity, and hypertensive end-organ damage.
McMaster WG, Kirabo A, Madhur MS, Harrison DG
(2015) Circ Res 116: 1022-33
MeSH Terms: Adaptive Immunity, Animals, Benzylamines, Cardiovascular Diseases, Cytokines, Drug Evaluation, Preclinical, Humans, Hypertension, Immunity, Innate, Inflammation, Kidney, Lymphocyte Activation, Mice, Mice, Knockout, Models, Animal, Models, Cardiovascular, Models, Immunological, Oxidative Stress, Reactive Oxygen Species, Signal Transduction, T-Lymphocyte Subsets, Vascular Remodeling, Vascular Stiffness
Show Abstract · Added March 31, 2015
For >50 years, it has been recognized that immunity contributes to hypertension. Recent data have defined an important role of T cells and various T cell-derived cytokines in several models of experimental hypertension. These studies have shown that stimuli like angiotensin II, deoxycorticosterone acetate-salt, and excessive catecholamines lead to formation of effector like T cells that infiltrate the kidney and perivascular regions of both large arteries and arterioles. There is also accumulation of monocyte/macrophages in these regions. Cytokines released from these cells, including interleukin-17, interferon-γ, tumor necrosis factorα, and interleukin-6 promote both renal and vascular dysfunction and damage, leading to enhanced sodium retention and increased systemic vascular resistance. The renal effects of these cytokines remain to be fully defined, but include enhanced formation of angiotensinogen, increased sodium reabsorption, and increased renal fibrosis. Recent experiments have defined a link between oxidative stress and immune activation in hypertension. These have shown that hypertension is associated with formation of reactive oxygen species in dendritic cells that lead to formation of gamma ketoaldehydes, or isoketals. These rapidly adduct to protein lysines and are presented by dendritic cells as neoantigens that activate T cells and promote hypertension. Thus, cells of both the innate and adaptive immune system contribute to end-organ damage and dysfunction in hypertension. Therapeutic interventions to reduce activation of these cells may prove beneficial in reducing end-organ damage and preventing consequences of hypertension, including myocardial infarction, heart failure, renal failure, and stroke.
© 2015 American Heart Association, Inc.
2 Communities
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23 MeSH Terms
Modelling sarcomeric cardiomyopathies in the dish: from human heart samples to iPSC cardiomyocytes.
Eschenhagen T, Mummery C, Knollmann BC
(2015) Cardiovasc Res 105: 424-38
MeSH Terms: Animals, Cardiomyopathies, Cell Differentiation, Cells, Cultured, Genetic Markers, Genetic Predisposition to Disease, Humans, Induced Pluripotent Stem Cells, Models, Cardiovascular, Mutation, Myocytes, Cardiac, Phenotype, Sarcomeres, Translational Medical Research
Show Abstract · Added February 12, 2015
One of the obstacles to a better understanding of the pathogenesis of human cardiomyopathies has been poor availability of heart-tissue samples at early stages of disease development. This has possibly changed by the advent of patient-derived induced pluripotent stem cell (hiPSC) from which cardiomyocytes can be derived in vitro. The main promise of hiPSC technology is that by capturing the effects of thousands of individual gene variants, the phenotype of differentiated derivatives of these cells will provide more information on a particular disease than simple genotyping. This article summarizes what is known about the 'human cardiomyopathy or heart failure phenotype in vitro', which constitutes the reference for modelling sarcomeric cardiomyopathies in hiPSC-derived cardiomyocytes. The current techniques for hiPSC generation and cardiac myocyte differentiation are briefly reviewed and the few published reports of hiPSC models of sarcomeric cardiomyopathies described. A discussion of promises and challenges of hiPSC-modelling of sarcomeric cardiomyopathies and individualized approaches is followed by a number of questions that, in the view of the authors, need to be answered before the true potential of this technology can be evaluated.
© The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.
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14 MeSH Terms
Transmembrane current imaging in the heart during pacing and fibrillation.
Gray RA, Mashburn DN, Sidorov VY, Roth BJ, Pathmanathan P, Wikswo JP
(2013) Biophys J 105: 1710-9
MeSH Terms: Action Potentials, Algorithms, Animals, Cardiac Pacing, Artificial, Membrane Potentials, Models, Cardiovascular, Rabbits, Ventricular Fibrillation, Voltage-Sensitive Dye Imaging
Show Abstract · Added March 7, 2014
Recently, we described a method to quantify the time course of total transmembrane current (Im) and the relative role of its two components, a capacitive current (Ic) and a resistive current (Iion), corresponding to the cardiac action potential during stable propagation. That approach involved recording high-fidelity (200 kHz) transmembrane potential (Vm) signals with glass microelectrodes at one site using a spatiotemporal coordinate transformation via measured conduction velocity. Here we extend our method to compute these transmembrane currents during stable and unstable propagation from fluorescence signals of Vm at thousands of sites (3 kHz), thereby introducing transmembrane current imaging. In contrast to commonly used linear Laplacians of extracellular potential (Ve) to compute Im, we utilized nonlinear image processing to compute the required second spatial derivatives of Vm. We quantified the dynamic spatial patterns of current density of Im and Iion for both depolarization and repolarization during pacing (including nonplanar patterns) by calibrating data with the microelectrode signals. Compared to planar propagation, we found that the magnitude of Iion was significantly reduced at sites of wave collision during depolarization but not repolarization. Finally, we present uncalibrated dynamic patterns of Im during ventricular fibrillation and show that Im at singularity sites was monophasic and positive with a significant nonzero charge (Im integrated over 10 ms) in contrast with nonsingularity sites. Our approach should greatly enhance the understanding of the relative roles of functional (e.g., rate-dependent membrane dynamics and propagation patterns) and static spatial heterogeneities (e.g., spatial differences in tissue resistance) via recordings during normal and compromised propagation, including arrhythmias.
Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.
1 Communities
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9 MeSH Terms
Diastolic field stimulation: the role of shock duration in epicardial activation and propagation.
Woods MC, Uzelac I, Holcomb MR, Wikswo JP, Sidorov VY
(2013) Biophys J 105: 523-32
MeSH Terms: Animals, Diastole, Electric Countershock, Epicardial Mapping, In Vitro Techniques, Models, Cardiovascular, Myocardial Perfusion Imaging, Pericardium, Rabbits, Time Factors
Show Abstract · Added March 7, 2014
Detailed knowledge of tissue response to both systolic and diastolic shock is critical for understanding defibrillation. Diastolic field stimulation has been much less studied than systolic stimulation, particularly regarding transient virtual anodes. Here we investigated high-voltage-induced polarization and activation patterns in response to strong diastolic shocks of various durations and of both polarities, and tested the hypothesis that the activation versus shock duration curve contains a local minimum for moderate shock durations, and it grows for short and long durations. We found that 0.1-0.2-ms shocks produced slow and heterogeneous activation. During 0.8-1 ms shocks, the activation was very fast and homogeneous. Further shock extension to 8 ms delayed activation from 1.55 ± 0.27 ms and 1.63 ± 0.21 ms at 0.8 ms shock to 2.32 ± 0.41 ms and 2.37 ± 0.3 ms (N = 7) for normal and opposite polarities, respectively. The traces from hyperpolarized regions during 3-8 ms shocks exhibited four different phases: beginning negative polarization, fast depolarization, slow depolarization, and after-shock increase in upstroke velocity. Thus, the shocks of >3 ms in duration created strong hyperpolarization associated with significant delay (P < 0.05) in activation compared with moderate shocks of 0.8 and 1 ms. This effect appears as a dip in the activation-versus-shock-duration curve.
Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.
1 Communities
2 Members
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10 MeSH Terms
Mechanistic analysis of challenge-response experiments.
Shotwell MS, Drake KJ, Sidorov VY, Wikswo JP
(2013) Biometrics 69: 741-7
MeSH Terms: Action Potentials, Animals, Biometry, Computer Simulation, Heart, Hypoxia, Least-Squares Analysis, Models, Cardiovascular, Models, Statistical, Monte Carlo Method, Nonlinear Dynamics, Rabbits, Regression Analysis, Systems Biology
Show Abstract · Added March 27, 2014
We present an application of mechanistic modeling and nonlinear longitudinal regression in the context of biomedical response-to-challenge experiments, a field where these methods are underutilized. In this type of experiment, a system is studied by imposing an experimental challenge, and then observing its response. The combination of mechanistic modeling and nonlinear longitudinal regression has brought new insight, and revealed an unexpected opportunity for optimal design. Specifically, the mechanistic aspect of our approach enables the optimal design of experimental challenge characteristics (e.g., intensity, duration). This article lays some groundwork for this approach. We consider a series of experiments wherein an isolated rabbit heart is challenged with intermittent anoxia. The heart responds to the challenge onset, and recovers when the challenge ends. The mean response is modeled by a system of differential equations that describe a candidate mechanism for cardiac response to anoxia challenge. The cardiac system behaves more variably when challenged than when at rest. Hence, observations arising from this experiment exhibit complex heteroscedasticity and sharp changes in central tendency. We present evidence that an asymptotic statistical inference strategy may fail to adequately account for statistical uncertainty. Two alternative methods are critiqued qualitatively (i.e., for utility in the current context), and quantitatively using an innovative Monte-Carlo method. We conclude with a discussion of the exciting opportunities in optimal design of response-to-challenge experiments.
© 2013, The International Biometric Society.
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14 MeSH Terms
Ultrasonic characterization of the nonlinear properties of canine livers by measuring shear wave speed and axial strain with increasing portal venous pressure.
Rotemberg V, Byram B, Palmeri M, Wang M, Nightingale K
(2013) J Biomech 46: 1875-81
MeSH Terms: Animals, Biomechanical Phenomena, Dogs, Liver, Liver Circulation, Models, Cardiovascular, Nonlinear Dynamics, Portal Pressure, Portal Vein, Ultrasonography, Vascular Stiffness
Show Abstract · Added May 29, 2014
Elevated hepatic venous pressure is the primary source of complications in advancing liver disease. Ultrasound imaging is ideal for potential noninvasive hepatic pressure measurements as it is widely used for liver imaging. Specifically, ultrasound based stiffness measures may be useful for clinically monitoring pressure, but the mechanism by which liver stiffness increases with hepatic pressure has not been well characterized. This study is designed to elucidate the nonlinear properties of the liver during pressurization by measuring both hepatic shear wave speed (SWS) and strain with increasing pressure. Tissue deformation during hepatic pressurization was tracked in 8 canine livers using successively acquired 3-D B-mode volumes and compared with concurrently measured SWS. When portal venous pressure was increased from clinically normal (0-5mmHg) to pressures representing highly diseased states at 20mmHg, the liver was observed to expand with axial strain measures up to 10%. At the same time, SWS estimates were observed to increase from 1.5-2m/s at 0-5mmHg (baseline) to 3.25-3.5m/s at 20mmHg.
Copyright © 2013 Elsevier Ltd. All rights reserved.
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11 MeSH Terms
Parameter sensitivity analysis of stochastic models provides insights into cardiac calcium sparks.
Lee YS, Liu OZ, Hwang HS, Knollmann BC, Sobie EA
(2013) Biophys J 104: 1142-50
MeSH Terms: Animals, Calcium, Calcium Signaling, Carrier Proteins, Computer Simulation, Logistic Models, Mice, Mice, Knockout, Models, Cardiovascular, Multivariate Analysis, Muscle Proteins, Myocardium, Stochastic Processes
Show Abstract · Added February 12, 2015
We present a parameter sensitivity analysis method that is appropriate for stochastic models, and we demonstrate how this analysis generates experimentally testable predictions about the factors that influence local Ca(2+) release in heart cells. The method involves randomly varying all parameters, running a single simulation with each set of parameters, running simulations with hundreds of model variants, then statistically relating the parameters to the simulation results using regression methods. We tested this method on a stochastic model, containing 18 parameters, of the cardiac Ca(2+) spark. Results show that multivariable linear regression can successfully relate parameters to continuous model outputs such as Ca(2+) spark amplitude and duration, and multivariable logistic regression can provide insight into how parameters affect Ca(2+) spark triggering (a probabilistic process that is all-or-none in a single simulation). Benchmark studies demonstrate that this method is less computationally intensive than standard methods by a factor of 16. Importantly, predictions were tested experimentally by measuring Ca(2+) sparks in mice with knockout of the sarcoplasmic reticulum protein triadin. These mice exhibit multiple changes in Ca(2+) release unit structures, and the regression model both accurately predicts changes in Ca(2+) spark amplitude (30% decrease in model, 29% decrease in experiments) and provides an intuitive and quantitative understanding of how much each alteration contributes to the result. This approach is therefore an effective, efficient, and predictive method for analyzing stochastic mathematical models to gain biological insight.
Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.
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13 MeSH Terms
A novel technique for quantifying mouse heart valve leaflet stiffness with atomic force microscopy.
Sewell-Loftin MK, Brown CB, Baldwin HS, Merryman WD
(2012) J Heart Valve Dis 21: 513-20
MeSH Terms: Animals, Aortic Valve, Aortic Valve Insufficiency, Apolipoproteins E, Biomechanical Phenomena, Heterozygote, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Microscopy, Atomic Force, Models, Cardiovascular, Receptor, Notch1, Stress, Mechanical, Swine
Show Abstract · Added February 12, 2015
BACKGROUND AND AIM OF THE STUDY - The use of genetically altered small animal models is a powerful strategy for elucidating the mechanisms of heart valve disease. However, while the ability to manipulate genes in rodent models is well established, there remains a significant obstacle in determining the functional mechanical properties of the genetically mutated leaflets. Hence, a feasibility study was conducted using micromechanical analysis via atomic force microscopy (AFM) to determine the stiffness of mouse heart valve leaflets in the context of age and disease states.
METHODS - A novel AFM imaging technique for the quantification of heart valve leaflet stiffness was performed on cryosectioned tissues. Heart valve leaflet samples were obtained from wild-type mice (2 and 17 months old) and genetically altered mice (10-month-old Notch1 heterozygous and 20-month-old ApoE homozygous). Histology was performed on adjacent sections to determine the extracellular matrix characteristics of the scanned areas.
RESULTS - The 17-month-old wild-type, 10-month-old Notch1, and 20-month-old ApoE aortic valve leaflets were all significantly stiffer than leaflets from 2-month-old wild-type mice. Notch1 leaflets were significantly stiffer than all other leaflets examined, indicating that the Notch1 heterozygous mutation may alter leaflet stiffness, both earlier and to a greater degree than the homozygous ApoE mutation. However, these conclusions must be considered only preliminary due to the small sample size used in this proof-of-concept study.
CONCLUSION - It is believed that this technique can provide a powerful end-point analysis for determining the mechanical properties of heart valve leaflets from genetically altered mice. Further, the technique is complementary to standard histological processing, and does not require excess tissue for mechanical testing. In this proof-of-concept study, AFM was shown to be a powerful tool for investigators of heart valve disease who develop genetically altered animals for their studies.
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14 MeSH Terms