Biomedical subjects

Roger C Barr

Publications and source records attributed to Roger C Barr.

10 recordsLinked to original sources

PubMed2006

Electric fields in tumors exposed to external voltage sources: implication for electric field-mediated drug and gene delivery.

The intratumoral field, which determines the efficiency of electric field-mediated drug and gene delivery, can differ significantly from the applied field. Therefore, we investigated the distribution of the electric field in mouse tumors and tissue phantoms exposed to a large range of electric stimuli, and quantified the resistances of tumor, skin, and electrode-tissue interface. The samples used in the study included 4T1 and B16.F10 tumors, mouse skin, and tissue phantoms constructed with 1% agarose gel with or without 4T1 cells. When pulsed electric fields were applied to samples using a pair of parallel-plate electrodes, we determined the electric field and resistances in each sample as well as the resistance at the electrode-tissue interface. The electric fields in the center region of tissue phantoms and tumor slices ex vivo were macroscopically uniform and unidirectional between two parallel-plate electrodes. The field strengths in tumor tissues were significantly lower than the applied field under both ex vivo and in vivo conditions. During in vivo stimulation, the ratio of intratumoral versus applied fields was approximately either 20% or 55%, depending on the applied field. Meanwhile, the total resistance of skin and electrode-tissue interface was decreased by approximately 70% and the electric resistance at the center of both tumor models was minimally changed when the applied field was increased from 50 to 400 V/cm. These results may be useful for improving electric field-mediated drug and gene delivery in solid tumors.

Animals↗

PubMed2005

Cardiac microimpedance measurement in two-dimensional models using multisite interstitial stimulation.

We analyzed central interstitial potential differences during multisite stimulation to assess the feasibility of using those recordings to measure cardiac microimpedances in multidimensional preparations. Because interstitial current injected and removed using electrodes with different proximities allows modulation of the portion of current crossing the membrane, we hypothesized that multisite interstitial stimulation would give rise to central interstitial potential differences that depend on intracellular and interstitial microimpedances, allowing measurement of those microimpedances. Simulations of multisite stimulation with fine and wide spacing in two-dimensional models that included dynamic membrane equations for guinea pig ventricular myocytes were performed to generate test data ( partial differentialphio). Isotropic interstitial and intracellular microimpedances were prescribed for one set of simulations, and anisotropic microimpedances with unequal ratios (intracellular to interstitial) along and across fibers were prescribed for another set of simulations. Microimpedance measurements were then obtained by making statistical comparisons between partial differentialphio values and interstitial potential differences from passive bidomain simulations (Deltaphio) in which a wide range of possible microimpedances were considered. Possible microimpedances were selected at 25% increments. After demonstrating the effectiveness of the overall method with microimpedance measurements using one-dimensional test data, we showed microimpedance measurements within 25% of prescribed values in isotropic and anisotropic models. Our findings suggest that development of microfabricated devices to implement the procedure would facilitate routine measurement as a component of cardiac electrophysiological study.

Animals↗

PubMed2005

The perplexing complexity of cardiac arrhythmias: beyond electrical remodeling.

Cardiac arrhythmias continue to pose a major medical challenge and significant public health burden. Atrial fibrillation, the most prevalent arrhythmia, affects more than two million Americans annually and is associated with a twofold increase in mortality. In addition, more than 250,000 Americans each year suffer ventricular arrhythmias, often resulting in sudden cardiac death. Despite the high incidence and societal impact of cardiac arrhythmias, presently there are insufficient insights into the molecular mechanisms involved in arrhythmia generation, propagation, and/or maintenance or into the molecular determinants of disease risk, prognosis, and progression. In addition, present therapeutic strategies for arrhythmia abatement often are ineffective or require palliative device therapy after persistent changes in the electrical and conduction characteristics of the heart have occurred, changes that appear to increase the risk for arrhythmia progression. This article reviews our present understanding of the complexity of mechanisms that regulate cardiac membrane excitability and cardiac function and explores the role of derangements in these mechanisms that interact to induce arrhythmogenic substrates. Approaches are recommended for future investigations focused on providing new mechanistic insights and therapeutic interventions.

Arrhythmias, Cardiac↗

PubMed2004

Feasibility of cardiac microimpedance measurement using multisite interstitial stimulation.

This study was designed to test the hypothesis that analyses of central interstitial potential differences recorded during multisite stimulation with a set of interstitial electrodes provide sufficient data for accurate measurement of cardiac microimpedances. On theoretical grounds, interstitial current injected and removed using electrodes in close proximity does not cross the membrane, whereas equilibration of intracellular and interstitial potentials occurs distant from electrodes widely separated. Multisite interstitial stimulation should therefore give rise to interstitial potential differences recorded centrally that depend on intracellular and interstitial microimpedances, allowing independent measurement. Simulations of multisite stimulation with fine (25 microm) and wide (400 microm) spacing in one-dimensional models that included Luo-Rudy dynamic membrane equations were performed. Constant interstitial and intracellular microimpedances were prescribed for initial analyses. Discrete myoplasmic and gap-junctional components were prescribed intracellularly in later simulations. With constant microimpedances, multisite stimulation using 29 total electrode combinations allowed interstitial and intracellular microimpedance measurements at errors of 0.30% and 0.34%, respectively, with errors of 0.05% and 0.40% achieved using 6 combinations and 10 total electrodes. With discrete myoplasmic and junctional components, comparable accuracy was maintained following adjustments to the junctions to reflect uncoupling. This allowed uncoupling to be quantified as relative increases in total junctional resistance. Our findings suggest development of microfabricated devices to implement the procedure would facilitate routine measurement as a component of cardiac electrophysiological study.

Artifacts↗

PubMed2004

Cell size and communication: role in structural and electrical development and remodeling of the heart.

With the advent of new information about alterations of cardiac gap junctions in disease conditions associated with arrhythmias, there have been major advances in the genetic and metabolic manipulation of gap junctions. In contrast, in naturally occurring cardiac preparations, little is known about cell-to-cell transmission and the subcellular events of propagation or about structural mechanisms that may affect conduction events at this small size scale. Therefore, the aim of this article is to review results that produce the following unifying picture: changes in cardiac conduction due to remodeling cardiac morphology ultimately are limited to changes in three morphologic parameters: (1) cell geometry (size and shape), (2) gap junctions (distribution and conductivity), and (3) interstitial space (size and distribution). In this article, we consider changes in conduction that result from the remodeling of cell size and gap junction distribution that occurs with developmental ventricular hypertrophy from birth to maturity. We then go on to changes in longitudinal and transverse propagation in aging human atrial bundles that are produced by remodeling interstitial space due to deposition of collagenous septa. At present, experimental limitations in naturally occurring preparations prevent measurement of the conductance of individual gap junctional plaques, as well as the delays in conduction associated with cell-to-cell transmission. Therefore, we consider the development of mathematical electrical models based on documented cardiac microstructure to gain insight into the role of specific morphologic parameters in generating the changes in anisotropic propagation that we measured in the tissue preparations. A major antiarrhythmic implication of the results is that an "indirect" therapeutic target is interstitial collagen, because regulation of its deposition and turnover to prevent or alter microfibrosis can enhance side-to-side electrical coupling between small groups of cells in aging atrial bundles.

Action Potentials↗

PubMed2004

Field stimulation of 2-D sheets of excitable tissue.

This paper develops equations for the transmembrane potentials (Vm) that occur in two-dimensional (2-D) sheets of tissue in response to field stimulation from an electrode near but not on the surface of the tissue. Comparison of results with those for one dimension shows that an additional term is present in the 2-D equations that influences the evolution of Vm in the interval between the end of the stimulus and the active propagation that may follow. The results provide an analytical framework for understanding Vm in response to field stimulation in two dimensions, both during the tissue's critical linear phase and thereafter.

Cell Physiological Phenomena↗

PubMed2004

Electric fields within cells as a function of membrane resistivity--a model study.

Externally applied electric fields play an important role in many therapeutic modalities, but the fields they produce inside cells remain largely unknown. This study makes use of a three-dimensional model to determine the electric field that exists in the intracellular domain of a 10-microm spherical cell exposed to an applied field of 100 V/cm. The transmembrane potential resulting from the applied field was also determined and its change was compared to those of the intracellular field. The intracellular field increased as the membrane resistance decreased over a wide range of values. The results showed that the intracellular electric field was about 1.1 mV/cm for Rm of 10,000 omega x cm2, increasing to about 111 mV/cm as Rm decreased to 100 omega x cm2. Over this range of Rm the transmembrane potential was nearly constant. The transmembrane potential declined only as Rm decreased below 1 omega x cm2. The simulation results suggest that intracellular electric field depends on Rm in its physiologic range, and may not be negligible in understanding some mechanisms of electric field-mediated therapies.

Cell Membrane↗

PubMed2003

Interactions between extracellular stimuli and excitation waves in an atrial reentrant loop.

UNLABELLED: Extracellular Stimuli in an Atrial Reentrant Loop. INTRODUCTION: The interactions between extracellular stimuli and excitation waves propagating in a reentrant loop are a complex function of stimulus parameters, structural properties, membrane state, and timing. Here the goal was a comprehensive understanding of the mechanisms and frequencies of the major interactions between the advancing excitation wave and a single extracellular stimulus, separated from issues of anatomic or geometric complexity. METHODS AND RESULTS: A modernized computer model of a thin ring of uniform tissue that included a pair of extracellular stimulus electrodes (anode/cathode) was used to model one-dimensional cardiac reentry. Questions and results included the following: (1) What are the major interactions between a stimulus and the reentrant propagation wave, and are they induced near the cathode or near the anode; and, for each interaction, what are the initiating amplitude range and timing interval? At the cathode, the well-known mechanism of retrograde excitation terminated reentry; changes in timing or amplitude produced double-wave reentry or phase reset. At the anode, termination occurred at different cells depending on stimulus amplitude. (2) Relatively how often did termination occur at the anode? For most stimulus amplitudes, termination occurred more often at the anode than at the cathode, although not always at the same cell. (3) With random timing, what is the probability of terminating reentry? Stimulation for 5 msec terminated reentry with a probability from 0% to approximately 10%, as a function of increasing stimulus amplitude. CONCLUSION: A single extracellular stimulus can initiate major changes in reentrant excitation via multiple mechanisms, even in a simple geometry. Termination of reentry, phase shifts, or double-wave reentry each occurs over well-defined ranges of stimulus amplitude and timing.

Action Potentials↗

PubMed2003

Membrane current from transmembrane potentials in complex core-conductor models.

Core-conductor models, used to integrate the behavior of the longitudinal currents with the distributed voltages of electrically active tissue, have evolved for over a century. A critical step in the use of such models is the computation of membrane current from the set of distributed transmembrane potential values that exist at a given moment, where the potentials are obtained either experimentally or computationally. Over time, interest has developed in a number of substantial extensions of the original model to include such features as nonuniform spatial resistances, loop instead of linear structure, and multiple sites of extracellular stimulation. This paper concisely restates and extends the equations for calculation of transmembrane currents with the systematic inclusion of alternative cases, noting how they reduce to the standard forms. An important issue is how complex the calculation of membrane current has to be. Thus, the paper goes on to show criteria (based on the uniformity of resistance and the presence of stimulation) for deciding when membrane currents can be obtained with a relatively simple calculation with a single equation involving local variables versus with a more complex calculation involving the simultaneous solution of a (possibly large) set of equations.

Electric Impedance↗

PubMed2003

Electrode systems for measuring cardiac impedances using optical transmembrane potential sensors and interstitial electrodes--theoretical design.

The cardiac electrical substrate is a challenge to direct measurement of its properties. Optical technology together with the capability to fabricate small electrodes at close spacings opens new possibilities. Here, those possibilities are explored from a theoretical viewpoint. It appears that with careful measurements from a well-designed set of electrodes one can obtain structural conductivities, separating intracellular from interstitial values, and longitudinal from transverse. Resting membrane resistance also can be obtained.

Body Surface Potential Mapping↗