Publications by authors named "Seth H Weinberg"

39 Publications

Intercalated disk nanoscale structure regulates cardiac conduction.

J Gen Physiol 2021 Aug 15;153(8). Epub 2021 Jul 15.

The Ohio State University, Columbus, OH.

The intercalated disk (ID) is a specialized subcellular region that provides electrical and mechanical connections between myocytes in the heart. The ID has a clearly defined passive role in cardiac tissue, transmitting mechanical forces and electrical currents between cells. Recent studies have shown that Na+ channels, the primary current responsible for cardiac excitation, are preferentially localized at the ID, particularly within nanodomains such as the gap junction-adjacent perinexus and mechanical junction-associated adhesion-excitability nodes, and that perturbations of ID structure alter cardiac conduction. This suggests that the ID may play an important, active role in regulating conduction. However, the structures of the ID and intercellular cleft are not well characterized and, to date, no models have incorporated the influence of ID structure on conduction in cardiac tissue. In this study, we developed an approach to generate realistic finite element model (FEM) meshes replicating nanoscale of the ID structure, based on experimental measurements from transmission electron microscopy images. We then integrated measurements of the intercellular cleft electrical conductivity, derived from the FEM meshes, into a novel cardiac tissue model formulation. FEM-based calculations predict that the distribution of cleft conductances is sensitive to regional changes in ID structure, specifically the intermembrane separation and gap junction distribution. Tissue-scale simulations predict that ID structural heterogeneity leads to significant spatial variation in electrical polarization within the intercellular cleft. Importantly, we found that this heterogeneous cleft polarization regulates conduction by desynchronizing the activation of postjunctional Na+ currents. Additionally, these heterogeneities lead to a weaker dependence of conduction velocity on gap junctional coupling, compared with prior modeling formulations that neglect or simplify ID structure. Further, we found that disruption of local ID nanodomains can either slow or enhance conduction, depending on gap junctional coupling strength. Our study therefore suggests that ID nanoscale structure can play a significant role in regulating cardiac conduction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1085/jgp.202112897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287520PMC
August 2021

Statistical Approach to Incorporating Experimental Variability into a Mathematical Model of the Voltage-Gated Na Channel and Human Atrial Action Potential.

Cells 2021 Jun 16;10(6). Epub 2021 Jun 16.

Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH 43210, USA.

The voltage-gated Na channel Na1.5 is critical for normal cardiac myocyte excitability. Mathematical models have been widely used to study Na1.5 function and link to a range of cardiac arrhythmias. There is growing appreciation for the importance of incorporating physiological heterogeneity observed even in a healthy population into mathematical models of the cardiac action potential. Here, we apply methods from Bayesian statistics to capture the variability in experimental measurements on human atrial Na1.5 across experimental protocols and labs. This variability was used to define a physiological distribution for model parameters in a novel model formulation of Na1.5, which was then incorporated into an existing human atrial action potential model. Model validation was performed by comparing the simulated distribution of action potential upstroke velocity measurements to experimental measurements from several different sources. Going forward, we hope to apply this approach to other major atrial ion channels to create a comprehensive model of the human atrial AP. We anticipate that such a model will be useful for understanding excitability at the population level, including variable drug response and penetrance of variants linked to inherited cardiac arrhythmia syndromes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells10061516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234464PMC
June 2021

Effects of substrate stiffness and actin velocity on in silico fibronectin fibril morphometry and mechanics.

PLoS One 2021 9;16(6):e0248256. Epub 2021 Jun 9.

Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA, United States of America.

Assembly of the extracellular matrix protein fibronectin (FN) into insoluble, viscoelastic fibrils is a critical step during embryonic development and wound healing; misregulation of FN fibril assembly has been implicated in many diseases, including fibrotic diseases and cancer. We have previously developed a computational model of FN fibril assembly that recapitulates the morphometry and mechanics of cell-derived FN fibrils. Here we use this model to probe two important questions: how is FN fibril formation affected by the contractile phenotype of the cell, and how is FN fibril formation affected by the stiffness of the surrounding tissue? We show that FN fibril formation depends strongly on the contractile phenotype of the cell, but only weakly on in vitro substrate stiffness, which is an analog for in vivo tissue stiffness. These results are consistent with previous experimental data and provide a better insight into conditions that promote FN fibril assembly. We have also investigated two distinct phenotypes of FN fibrils that we have previously identified; we show that the ratio of the two phenotypes depends on both substrate stiffness and contractile phenotype, with intermediate contractility and high substrate stiffness creating an optimal condition for stably stretched fibrils. Finally, we have investigated how re-stretch of a fibril affects cellular response. We probed how the contractile phenotype of the re-stretching cell affects the mechanics of the fibril; results indicate that the number of myosin motors only weakly affects the cellular response, but increasing actin velocity results in a decrease in the apparent stiffness of the fibril and a decrease in the stably-applied force to the fibril. Taken together, these results give novel insights into the combinatorial effects of substrate stiffness and cell contractility on FN fibril assembly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248256PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189481PMC
June 2021

Immunofluorescence Image Feature Analysis and Phenotype Scoring Pipeline for Distinguishing Epithelial-Mesenchymal Transition.

Microsc Microanal 2021 May 20:1-11. Epub 2021 May 20.

Biomedical Engineering Department, The Ohio State University, Columbus, OH, USA.

Epithelial–mesenchymal transition (EMT) is an essential biological process, also implicated in pathological settings such as cancer metastasis, in which epithelial cells transdifferentiate into mesenchymal cells. We devised an image analysis pipeline to distinguish between tissues comprised of epithelial and mesenchymal cells, based on extracted features from immunofluorescence images of differing biochemical markers. Mammary epithelial cells were cultured with 0 (control), 2, 4, or 10 ng/mL TGF-β1, a well-established EMT-inducer. Cells were fixed, stained, and imaged for E-cadherin, actin, fibronectin, and nuclei via immunofluorescence microscopy. Feature selection was performed on different combinations of individual cell markers using a Bag-of-Features extraction. Control and high-dose images comprised the training data set, and the intermediate dose images comprised the testing data set. A feature distance analysis was performed to quantify differences between the treatment groups. The pipeline was successful in distinguishing between control (epithelial) and the high-dose (mesenchymal) groups, as well as demonstrating progress along the EMT process in the intermediate dose groups. Validation using quantitative PCR (qPCR) demonstrated that biomarker expression measurements were well-correlated with the feature distance analysis. Overall, we identified image pipeline characteristics for feature extraction and quantification of immunofluorescence images to distinguish progression of EMT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S1431927621000428DOI Listing
May 2021

Cellular mitosis predicts vessel stability in a mechanochemical model of sprouting angiogenesis.

Biomech Model Mechanobiol 2021 Jun 14;20(3):1195-1208. Epub 2021 Mar 14.

Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA.

Angiogenesis, the formation of new vessels, occurs in both developmental and pathological contexts. Prior research has investigated vessel formation to identify cellular phenotypes and dynamics associated with angiogenic disease. One major family of proteins involved in angiogenesis are the Rho GTPases, which govern function related to cellular elongation, migration, and proliferation. Using a mechanochemical model coupling Rho GTPase activity and cellular and intercellular mechanics, we investigate the role of cellular mitosis on sprouting angiogenesis. Mitosis-GTPase synchronization was not a strong predictor of GTPase and thus vessel signaling instability, whereas the location of mitotic events was predicted to alter GTPase cycling instabilities. Our model predicts that middle stalk cells undergoing mitosis introduce irregular dynamics in GTPase cycling and may provide a source of aberrant angiogenesis. We also find that cellular and junctional tension exhibit spatial heterogeneity through the vessel, and that tension feedback, specifically in stalk cells, tends to increase the maximum forces generated in the vessel.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10237-021-01442-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274398PMC
June 2021

Mechanisms underlying age-associated manifestation of cardiac sodium channel gain-of-function.

J Mol Cell Cardiol 2021 04 26;153:60-71. Epub 2020 Dec 26.

Department of Biomedical Engineering, The Ohio State University, Columbus, OH, United States of America; Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, United States of America. Electronic address:

Cardiac action potentials are initiated by sodium ion (Na) influx through voltage-gated Na channels. Na channel gain-of-function (GOF) can arise in inherited conditions due to mutations in the gene encoding the cardiac Na channel, such as Long QT syndrome type 3 (LQT3). LQT3 can be a "concealed" disease, as patients with LQT3-associated mutations can remain asymptomatic until later in life; however, arrhythmias can also arise early in life in LQT3 patients, demonstrating a complex age-associated manifestation. We and others recently demonstrated that cardiac Na channels preferentially localize at the intercalated disc (ID) in adult cardiac tissue, which facilitates ephaptic coupling and formation of intercellular Na nanodomains that regulate pro-arrhythmic early afterdepolarization (EAD) formation in tissue with Na channel GOF. Several properties related to ephaptic coupling vary with age, such as cell size and Na channel and gap junction (GJ) expression and distribution: neonatal cells have immature IDs, with Na channels and GJs primarily diffusively distributed, while adult myocytes have mature IDs with preferentially localized Na channels and GJs. Here, we perform an in silico study varying critical age-dependent parameters to investigate mechanisms underlying age-associated manifestation of Na channel GOF in a model of guinea pig cardiac tissue. Simulations predict that total Na current conductance is a critical factor in action potential duration (APD) prolongation. We find a complex cell size/ Na channel expression relationship: increases in cell size (without concurrent increases in Na channel expression) suppress EAD formation, while increases in Na channel expression (without concurrent increases in cell size) promotes EAD formation. Finally, simulations with neonatal and early age-associated parameters predict normal APD with minimal dependence on intercellular cleft width; however, variability in cellular properties can lead to EADs presenting in early developmental stages. In contrast, for adult-associated parameters, EAD formation is highly dependent on cleft width, consistent with a mechanism underlying the age-associated manifestation of the Na channel GOF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yjmcc.2020.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026540PMC
April 2021

Dual regulation by subcellular calcium heterogeneity and heart rate variability on cardiac electromechanical dynamics.

Chaos 2020 Sep;30(9):093129

Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio 43210, USA.

Heart rate constantly varies under physiological conditions, termed heart rate variability (HRV), and in clinical studies, low HRV is associated with a greater risk of cardiac arrhythmias. Prior work has shown that HRV influences the temporal patterns of electrical activity, specifically the formation of pro-arrhythmic alternans, a beat-to-beat alternation in the action potential duration (APD), or intracellular calcium (Ca) levels. We previously showed that HRV may be anti-arrhythmic by disrupting APD and Ca alternations in a homogeneous cardiac myocyte. Here, we expand on our previous work, incorporating variation in subcellular Ca handling (also known to influence alternans) into a nonlinear map model of a cardiac myocyte composed of diffusively coupled Ca release units (CRUs). Ca-related parameters and initial conditions of each CRU are varied to mimic subcellular Ca heterogeneity, and a stochastic pacing sequence reproduces HRV. We find that subcellular Ca heterogeneity promotes the formation of spatially discordant subcellular alternans patterns, which decreases whole cell Ca and APD alternation for low and moderate HRV, while high subcellular Ca heterogeneity and HRV both promote electromechanical desynchronization. Finally, we find that for low and moderate HRV, both the specific subcellular Ca-related parameters and the pacing sequences influence measures of electromechanical dynamics, while for high HRV, these measures depend predominantly on the pacing sequence. Our results suggest that pro-arrhythmic subcellular discordant alternans tend to form for low levels of HRV, while high HRV may be anti-arrhythmic due to mitigated influence from subcellular Ca heterogeneity and desynchronization of APD from Ca instabilities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1063/5.0019313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502019PMC
September 2020

Intercellular Sodium Regulates Repolarization in Cardiac Tissue with Sodium Channel Gain of Function.

Biophys J 2020 06 21;118(11):2829-2843. Epub 2020 Apr 21.

Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Polytechnic Institute and State University, Roanoke, Virginia; Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, Virginia. Electronic address:

In cardiac myocytes, action potentials are initiated by an influx of sodium (Na) ions via voltage-gated Na channels. Na channel gain of function (GOF), arising in both inherited conditions associated with mutation in the gene encoding the Na channel and acquired conditions associated with heart failure, ischemia, and atrial fibrillation, enhance Na influx, generating a late Na current that prolongs action potential duration (APD) and triggering proarrhythmic early afterdepolarizations (EADs). Recent studies have shown that Na channels are highly clustered at the myocyte intercalated disk, facilitating formation of Na nanodomains in the intercellular cleft between cells. Simulations from our group have recently predicted that narrowing the width of the intercellular cleft can suppress APD prolongation and EADs in the presence of Na channel mutations because of increased intercellular cleft Na ion depletion. In this study, we investigate the effects of modulating multiple extracellular spaces, specifically the intercellular cleft and bulk interstitial space, in a novel computational model and experimentally via osmotic agents albumin, dextran 70, and mannitol. We perform optical mapping and transmission electron microscopy in a drug-induced (sea anemone toxin, ATXII) Na channel GOF isolated heart model and modulate extracellular spaces via osmotic agents. Single-cell patch-clamp experiments confirmed that the osmotic agents individually do not enhance late Na current. Both experiments and simulations are consistent with the conclusion that intercellular cleft narrowing or expansion regulates APD prolongation; in contrast, modulating the bulk interstitial space has negligible effects on repolarization. Thus, we predict that intercellular cleft Na nanodomain formation and collapse critically regulates cardiac repolarization in the setting of Na channel GOF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bpj.2020.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264809PMC
June 2020

A hybrid model of intercellular tension and cell-matrix mechanical interactions in a multicellular geometry.

Biomech Model Mechanobiol 2020 Dec 20;19(6):1997-2013. Epub 2020 Mar 20.

Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA, USA.

Epithelial cells form continuous sheets of cells that exist in tensional homeostasis. Homeostasis is maintained through cell-to-cell junctions that distribute tension and balance forces between cells and their underlying matrix. Disruption of tensional homeostasis can lead to epithelial-mesenchymal transition (EMT), a transdifferentiation process in which epithelial cells adopt a mesenchymal phenotype, losing cell-cell adhesion and enhancing cellular motility. This process is critical during embryogenesis and wound healing, but is also dysregulated in many disease states. To further understand the role of intercellular tension in spatial patterning of epithelial cell monolayers, we developed a multicellular computational model of cell-cell and cell-substrate forces. This work builds on a hybrid cellular Potts model (CPM)-finite element model to evaluate cell-matrix mechanical feedback of an adherent multicellular cluster. Cellular movement is governed by thermodynamic constraints from cell volume, cell-cell and cell-matrix contacts, and durotaxis, which arises from cell-generated traction forces on a finite element substrate. Junction forces at cell-cell contacts balance these traction forces, thereby producing a mechanically stable epithelial monolayer. Simulations were compared to in vitro experiments using fluorescence-based junction force sensors in clusters of cells undergoing EMT. Results indicate that the multicellular CPM model can reproduce many aspects of EMT, including epithelial monolayer formation dynamics, changes in cell geometry, and spatial patterning of cell-cell forces in an epithelial tissue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10237-020-01321-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502553PMC
December 2020

Attitudes Towards Forensic Autopsy Standard B3.7 and the Use of Physician Extenders in Select Autopsy Cases.

Acad Forensic Pathol 2019 Sep 31;9(3-4):181-190. Epub 2020 Jan 31.

Studies have demonstrated that autopsy is the gold standard for determining cause and manner of death. Indeed, the current National Association of Medical Examiners standard B3.7 states that a forensic pathologist (FP) shall perform a forensic autopsy when the death is by apparent intoxication by alcohol, drugs, or poison. Unfortunately, the recent increase in drug-related deaths has led to some question about the feasibility of maintaining compliance with standard B3.7. We constructed a voluntary survey to address consensus on standard B3.7 and the use of supervised accredited pathologists' assistants (PAs) in performing select medicolegal autopsies. Additional questions were included to help characterize variables related to FP's workload and experience. Each of these variables was predicted to influence FP's attitudes toward B3.7 and the use of PAs. Our respondent pool (n = 107) consisted primarily of actively practicing FPs with administrative responsibilities (42%) and actively practicing FPs without administrative responsibilities (41%). Sixty-five percent agreed that standard B3.7 is appropriate. Opinion on the use of PAs was split between those who agreed (45%) and those who did not (44%). Tendency to agree with either B3.7 or the use of PAs was not a function of FP's individual or office workload; however, respondents were more likely to agree with B3.7 if they previously experienced a case where internal autopsy findings radically altered diagnosis in an otherwise suggestive overdose case (P < 0.001). In certain offices and under certain conditions, the use of PAs may be one solution to ensuring all potential overdose deaths receive an autopsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1925362119895599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997985PMC
September 2019

Cell Fate Forecasting: A Data-Assimilation Approach to Predict Epithelial-Mesenchymal Transition.

Biophys J 2020 04 15;118(7):1749-1768. Epub 2020 Feb 15.

Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio; Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia; The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio. Electronic address:

Epithelial-mesenchymal transition (EMT) is a fundamental biological process that plays a central role in embryonic development, tissue regeneration, and cancer metastasis. Transforming growth factor-β (TGFβ) is a potent inducer of this cellular transition, which is composed of transitions from an epithelial state to intermediate or partial EMT state(s) to a mesenchymal state. Using computational models to predict cell state transitions in a specific experiment is inherently difficult for reasons including model parameter uncertainty and error associated with experimental observations. In this study, we demonstrate that a data-assimilation approach using an ensemble Kalman filter, which combines limited noisy observations with predictions from a computational model of TGFβ-induced EMT, can reconstruct the cell state and predict the timing of state transitions. We used our approach in proof-of-concept "synthetic" in silico experiments, in which experimental observations were produced from a known computational model with the addition of noise. We mimic parameter uncertainty in in vitro experiments by incorporating model error that shifts the TGFβ doses associated with the state transitions and reproduces experimentally observed variability in cell state by either shifting a single parameter or generating "populations" of model parameters. We performed synthetic experiments for a wide range of TGFβ doses, investigating different cell steady-state conditions, and conducted parameter studies varying properties of the data-assimilation approach including the time interval between observations and incorporating multiplicative inflation, a technique to compensate for underestimation of the model uncertainty and mitigate the influence of model error. We find that cell state can be successfully reconstructed and the future cell state predicted in synthetic experiments, even in the setting of model error, when experimental observations are performed at a sufficiently short time interval and incorporate multiplicative inflation. Our study demonstrates the feasibility and utility of a data-assimilation approach to forecasting the fate of cells undergoing EMT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bpj.2020.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136288PMC
April 2020

Death Certification in Northern Alberta: Error Occurrence Rate and Educational Intervention.

Am J Forensic Med Pathol 2020 Mar;41(1):11-17

Alberta Office of the Chief Medical Examiner, Edmonton, Alberta, Canada.

Errors in death certification can directly affect the decedent's survivors and the public register. We assessed the effectiveness of an educational seminar targeting frequent and important errors identified by local death certificate (DC) evaluation. Retrospective review of 1500 DCs categorized errors and physician specialty. A 60-minute didactic/case-based seminar was subsequently designed for family medicine physician (FAM) participants, with administration of presurvey, immediate post, and 2-month postsurveys. Most DCs were completed by FAM (73%), followed by internists (18%) and surgeons (3%). Error occurrence (EO) rate ranged between 32 and 75% across all specialities. Family medicine physician experienced in palliative care had the lowest EO rate (32%), significantly lower (P < 0.001) than FAM without interest in palliative care (62%), internal medicine (62%), and surgery (75%). Common errors were use of abbreviations (26%), mechanism as underlying cause of death (23%), and no underlying cause of death recorded (22%). Presurvey participants (n = 72) had an overall EO rate of 72% (64% excluding formatting errors). Immediate postsurvey (n = 75) and 2-month postsurvey (n = 24) participants demonstrated significantly lower overall EO (34% and 24%, respectively), compared with the Pre-S (P < 0.05). A 60-minute seminar on death certification reduced EO rate with perceived long-term effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAF.0000000000000527DOI Listing
March 2020

How to Boost Efficacy of a Sodium Channel Blocker: The Devil Is in the Details.

JACC Basic Transl Sci 2019 Oct 28;4(6):752-754. Epub 2019 Oct 28.

Department of Biomedical Engineering, Ohio State University, Columbus, Ohio.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacbts.2019.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834940PMC
October 2019

Mechanochemical Signaling of the Extracellular Matrix in Epithelial-Mesenchymal Transition.

Front Cell Dev Biol 2019 19;7:135. Epub 2019 Jul 19.

Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA, United States.

Epithelial-Mesenchymal Transition (EMT) is a critical process in embryonic development in which epithelial cells undergo a transdifferentiation into mesenchymal cells. This process is essential for tissue patterning and organization, and it has also been implicated in a wide array of pathologies. While the intracellular signaling pathways that regulate EMT are well-understood, there is increasing evidence that the mechanical properties and composition of the extracellular matrix (ECM) also play a key role in regulating EMT. In turn, EMT drives changes in the mechanics and composition of the ECM, creating a feedback loop that is tightly regulated in healthy tissues, but is often dysregulated in disease. Here we present a review that summarizes our understanding of how ECM mechanics and composition regulate EMT, and how in turn EMT alters ECM mechanics and composition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2019.00135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658819PMC
July 2019

Mechanochemical Coupling and Junctional Forces during Collective Cell Migration.

Biophys J 2019 07 28;117(1):170-183. Epub 2019 May 28.

Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia. Electronic address:

Cell migration, a fundamental physiological process in which cells sense and move through their surrounding physical environment, plays a critical role in development and tissue formation, as well as pathological processes, such as cancer metastasis and wound healing. During cell migration, dynamics are governed by the bidirectional interplay between cell-generated mechanical forces and the activity of Rho GTPases, a family of small GTP-binding proteins that regulate actin cytoskeleton assembly and cellular contractility. These interactions are inherently more complex during the collective migration of mechanically coupled cells because of the additional regulation of cell-cell junctional forces. In this study, we adapted a recent minimal modeling framework to simulate the interactions between mechanochemical signaling in individual cells and interactions with cell-cell junctional forces during collective cell migration. We find that migration of individual cells depends on the feedback between mechanical tension and Rho GTPase activity in a biphasic manner. During collective cell migration, waves of Rho GTPase activity mediate mechanical contraction/extension and thus synchronization throughout the tissue. Further, cell-cell junctional forces exhibit distinct spatial patterns during collective cell migration, with larger forces near the leading edge. Larger junctional force magnitudes are associated with faster collective cell migration and larger tissue size. Simulations of heterogeneous tissue migration exhibit a complex dependence on the properties of both leading and trailing cells. Computational predictions demonstrate that collective cell migration depends on both the emergent dynamics and interactions between cellular-level Rho GTPase activity and contractility and multicellular-level junctional forces.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bpj.2019.05.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626874PMC
July 2019

Analysis of heterogeneous cardiac pacemaker tissue models and traveling wave dynamics.

J Theor Biol 2018 12 21;459:18-35. Epub 2018 Sep 21.

Department of Biomedical Engineering, Virginia Commonwealth University USA. Electronic address: http://www.shweinberglab.com.

The sinoatrial-node (SAN) is a complex heterogeneous tissue that generates a stable rhythm in healthy hearts, yet a general mechanistic explanation for when and how this tissue remains stable is lacking. Although computational and theoretical analyses could elucidate these phenomena, such methods have rarely been used in realistic (large-dimensional) gap-junction coupled heterogeneous pacemaker tissue models. In this study, we adapt a recent model of pacemaker cells (Severi et al., 2012), incorporating biophysical representations of ion channel and intracellular calcium dynamics, to capture physiological features of a heterogeneous population of pacemaker cells, in particular "center" and "peripheral" cells with distinct intrinsic frequencies and action potential morphology. Large-scale simulations of the SAN tissue, represented by a heterogeneous tissue structure of pacemaker cells, exhibit a rich repertoire of behaviors, including complete synchrony, traveling waves of activity originating from periphery to center, and transient traveling waves originating from the center. We use phase reduction methods that do not require fully simulating the large-scale model to capture these observations. Moreover, the phase reduced models accurately predict key properties of the tissue electrical dynamics, including wave frequencies when synchronization occurs, and wave propagation direction in a variety of tissue models. With the reduced phase models, we analyze the relationship between cell distributions and coupling strengths and the resulting transient dynamics. Further, the reduced phase model predicts parameter regimes of irregular electrical dynamics. Thus, we demonstrate that phase reduced oscillator models applied to realistic pacemaker tissue is a useful tool for investigating the spatial-temporal dynamics of cardiac pacemaker activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtbi.2018.09.023DOI Listing
December 2018

Heart rate variability alters cardiac repolarization and electromechanical dynamics.

J Theor Biol 2018 04 11;442:31-43. Epub 2018 Jan 11.

Department of Biomedical Engineering, Virginia Commonwealth University, 601 W. Main Street, Richmond, VA 23284, United States. Electronic address: http://www.shweinberglab.com.

Heart rate continuously varies due to autonomic regulation, stochasticity in pacemaking, and circadian rhythm, collectively termed heart rate variability (HRV), during normal physiological conditions. Low HRV is clinically associated with an elevated risk of cardiac arrhythmias. Alternans, a beat-to-beat alternation in action potential duration (APD) and/or intracellular calcium (Ca) transient, is a well-known risk factor associated with cardiac arrhythmias that is typically studied under conditions of a constant pacing rate, i.e., the absence of HRV. In this study, we investigate the effects of HRV on the interplay between APD, Ca, and electromechanical properties, employing a nonlinear discrete-time map model that governs APD and intracellular Ca cycling with a stochastic pacing period. We find that HRV can decrease variation in APD and peak Ca at fast pacing rates for which alternans is present. Further, increased HRV typically disrupts the alternating pattern for both APD and peak Ca and weakens the correlation between APD and peak Ca, thus decoupling Ca-mediated instabilities from repolarization alternation. We find that the efficacy of these effects is regulated by the sarcoplasmic reticulum Ca uptake rate. Overall, these results demonstrate that HRV disrupts arrhythmogenic alternans and suggests that HRV may be a significant factor in preventing life-threatening arrhythmias.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtbi.2018.01.007DOI Listing
April 2018

Multiple Cryptic Binding Sites are Necessary for Robust Fibronectin Assembly: An In Silico Study.

Sci Rep 2017 12 22;7(1):18061. Epub 2017 Dec 22.

Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA, 23298, USA.

The mechanism of assembly of the extracellular matrix protein fibronectin (FN) into elastic, insoluble fibrils is still poorly understood. FN fibrillogenesis requires cell-generated forces, which expose cryptic FN-FN binding sites buried in FN Type III domains. The number and location of cryptic binding sites have been debated, but experimental evidence suggests multiple domains may contain FN-FN binding sites. The requirement of cell-dependent forces to generate FN fibrils restricts investigation of the mechanism of assembly. To address this, we use a recently developed biophysical model of fibrillogenesis to test competing hypotheses for the location and number of cryptic FN-FN binding sites and quantify the effect of these molecular alterations on assembled FN fibril properties. Simulations predict that a single FN-FN binding site facilitates either negligible fibrillogenesis or produces FN fibrils that are neither robust nor physiological. However, inclusion of multiple FN-FN binding sites predicts robust fibrillogenesis, which minimally depends on individual domain properties. Multiple FN-FN binding site models predict a heterogeneous fibril population that contains two distinct phenotypes with unique viscoelastic properties, which we speculate may play a key role in generating heterogeneous mechanical signaling in the extracellular matrix of developing and regenerating tissues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-18328-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741729PMC
December 2017

Calcium Dynamics and Cardiac Arrhythmia.

Clin Med Insights Cardiol 2017 3;11:1179546817739523. Epub 2017 Dec 3.

Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.

This Special Collection will gather all studies highlighting recent advances in theoretical and experimental studies of arrhythmia, with a specific focus on research seeking to elucidate links between calcium homeostasis in cardiac cells and organ-scale disruption of heart rhythm.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1179546817739523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718302PMC
December 2017

Mechanotransduction Dynamics at the Cell-Matrix Interface.

Biophys J 2017 May;112(9):1962-1974

Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia. Electronic address:

The ability of cells to sense and respond to mechanical cues from the surrounding environment has been implicated as a key regulator of cell differentiation, migration, and proliferation. The extracellular matrix (ECM) is an oft-overlooked component of the interface between cells and their surroundings. Cells assemble soluble ECM proteins into insoluble fibrils with unique mechanical properties that can alter the mechanical cues a cell receives. In this study, we construct a model that predicts the dynamics of cellular traction force generation and subsequent assembly of fibrils of the ECM protein fibronectin (FN). FN fibrils are the primary component in primordial ECM and, as such, FN assembly is a critical component in the cellular mechanical response. The model consists of a network of Hookean springs, each representing an extensible domain within an assembling FN fibril. As actomyosin forces stretch the spring network, simulations predict the resulting traction force and FN fibril formation. The model accurately predicts FN fibril morphometry and demonstrates a mechanism by which FN fibril assembly regulates traction force dynamics in response to mechanical stimuli and varying surrounding substrate stiffness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bpj.2017.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425358PMC
May 2017

Revealing the Concealed Nature of Long-QT Type 3 Syndrome.

Circ Arrhythm Electrophysiol 2017 Feb;10(2):e004400

From the Virginia Tech Carilion Research Institute, Virginia Polytechnic Institute and State University, Roanoke (A.G.-S., S.A.G., S.P.); and Department of Biomedical Engineering, Virginia Commonwealth University, Richmond (S.H.W.).

Background: Gain-of-function mutations in the voltage-gated sodium channel (Nav1.5) are associated with the long-QT-3 (LQT3) syndrome. Nav1.5 is densely expressed at the intercalated disk, and narrow intercellular separation can modulate cell-to-cell coupling via extracellular electric fields and depletion of local sodium ion nanodomains. Models predict that significantly decreasing intercellular cleft widths slows conduction because of reduced sodium current driving force, termed "self-attenuation." We tested the novel hypothesis that self-attenuation can "mask" the LQT3 phenotype by reducing the driving force and late sodium current that produces early afterdepolarizations (EADs).

Methods And Results: Acute interstitial edema was used to increase intercellular cleft width in isolated guinea pig heart experiments. In a drug-induced LQT3 model, acute interstitial edema exacerbated action potential duration prolongation and produced EADs, in particular, at slow pacing rates. In a computational cardiac tissue model incorporating extracellular electric field coupling, intercellular cleft sodium nanodomains, and LQT3-associated mutant channels, myocytes produced EADs for wide intercellular clefts, whereas for narrow clefts, EADs were suppressed. For both wide and narrow clefts, mutant channels were incompletely inactivated. However, for narrow clefts, late sodium current was reduced via self-attenuation, a protective negative feedback mechanism, masking EADs.

Conclusions: We demonstrated a novel mechanism leading to the concealing and revealing of EADs in LQT3 models. Simulations predict that this mechanism may operate independent of the specific mutation, suggesting that future therapies could target intercellular cleft separation as a compliment or alternative to sodium channels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCEP.116.004400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319726PMC
February 2017

Role of Cytosolic Calcium Diffusion in Murine Cardiac Purkinje Cells.

Clin Med Insights Cardiol 2016 20;10(Suppl 1):17-26. Epub 2016 Jul 20.

Department of Engineering, Norfolk State University, Norfolk, VA, USA.

Cardiac Purkinje cells (PCs) are morphologically and electrophysiologically different from ventricular myocytes and, importantly, exhibit distinct calcium (Ca(2+)) homeostasis. Recent studies suggest that PCs are more susceptible to action potential (AP) abnormalities than ventricular myocytes; however, the exact mechanisms are poorly understood. In this study, we utilized a detailed biophysical mathematical model of a murine PC to systematically examine the role of cytosolic Ca(2+) diffusion in shaping the AP in PCs. A biphasic spatiotemporal Ca(2+) diffusion process, as recorded experimentally, was implemented in the model. In this study, we investigated the role of cytosolic Ca(2+) dynamics on AP and ionic current properties by varying the effective Ca(2+) diffusion rate. It was observed that AP morphology, specifically the plateau, was affected due to changes in the intracellular Ca(2+) dynamics. Elevated Ca(2+) concentration in the sarcolemmal region activated inward sodium-Ca(2+) exchanger (NCX) current, resulting in a prolongation of the AP plateau at faster diffusion rates. Artificially clamping the NCX current to control values completely reversed the alterations in the AP plateau, thus confirming the role of NCX in modifying the AP morphology. Our results demonstrate that cytosolic Ca(2+) diffusion waves play a significant role in shaping APs of PCs and could provide mechanistic insights in the increased arrhythmogeneity of PCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4137/CMC.S39705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4955978PMC
August 2016

Impaired Sarcoplasmic Reticulum Calcium Uptake and Release Promote Electromechanically and Spatially Discordant Alternans: A Computational Study.

Authors:
Seth H Weinberg

Clin Med Insights Cardiol 2016 23;10(Suppl 1):1-15. Epub 2016 Jun 23.

Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA, USA.

Cardiac electrical dynamics are governed by cellular-level properties, such as action potential duration (APD) restitution and intracellular calcium (Ca) handling, and tissue-level properties, including conduction velocity restitution and cell-cell coupling. Irregular dynamics at the cellular level can lead to instabilities in cardiac tissue, including alternans, a beat-to-beat alternation in the action potential and/or the intracellular Ca transient. In this study, we incorporate a detailed single cell coupled map model of Ca cycling and bidirectional APD-Ca coupling into a spatially extended tissue model to investigate the influence of sarcoplasmic reticulum (SR) Ca uptake and release properties on alternans and conduction block. We find that an intermediate SR Ca uptake rate and larger SR Ca release resulted in the widest range of stimulus periods that promoted alternans. However, both reduced SR Ca uptake and release promote arrhythmogenic spatially and electromechanically discordant alternans, suggesting a complex interaction between SR Ca handling and alternans characteristics at the cellular and tissue level.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4137/CMC.S39709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4920205PMC
July 2016

Microdomain [Ca(2+)] Fluctuations Alter Temporal Dynamics in Models of Ca(2+)-Dependent Signaling Cascades and Synaptic Vesicle Release.

Authors:
Seth H Weinberg

Neural Comput 2016 Mar 6;28(3):493-524. Epub 2016 Jan 6.

Virginia Modeling, Analysis and Simulation Center, Old Dominion University, Suffolk, Virginia 23435, U.S.A.

Ca(2+)-dependent signaling is often localized in spatially restricted microdomains and may involve only 1 to 100 Ca(2+) ions. Fluctuations in the microdomain Ca(2+) concentration (Ca(2+)) can arise from a wide range of elementary processes, including diffusion, Ca(2+) influx, and association/dissociation with Ca(2+) binding proteins or buffers. However, it is unclear to what extent these fluctuations alter Ca(2+)-dependent signaling. We construct Markov models of a general Ca(2+)-dependent signaling cascade and Ca(2+)-triggered synaptic vesicle release. We compare the hitting (release) time distribution and statistics for models that account for [Ca(2+)] fluctuations with the corresponding models that neglect these fluctuations. In general, when Ca(2+) fluctuations are much faster than the characteristic time for the signaling event, the hitting time distributions and statistics for the models with and without Ca(2+) fluctuation are similar. However, when the timescale of Ca(2+) fluctuations is on the same order as the signaling cascade or slower, the hitting time mean and variability are typically increased, in particular when the average number of microdomain Ca(2+) ions is small, a consequence of a long-tailed hitting time distribution. In a model of Ca(2+)-triggered synaptic vesicle release, we demonstrate the conditions for which [Ca(2+)] fluctuations do and do not alter the distribution, mean, and variability of release timing. We find that both the release time mean and variability can be increased, demonstrating that Ca(2+) fluctuations are an important aspect of microdomain Ca(2+) signaling and further suggesting that Ca(2+) fluctuations in the presynaptic terminal may contribute to variability in synaptic vesicle release and thus variability in neuronal spiking.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1162/NECO_a_00811DOI Listing
March 2016

Calcium Ion Fluctuations Alter Channel Gating in a Stochastic Luminal Calcium Release Site Model.

IEEE/ACM Trans Comput Biol Bioinform 2017 May-Jun;14(3):611-619. Epub 2015 Nov 6.

Stochasticity and small system size effects in complex biochemical reaction networks can greatly alter transient and steady-state system properties. A common approach to modeling reaction networks, which accounts for system size, is the chemical master equation that governs the dynamics of the joint probability distribution for molecular copy number. However, calculation of the stationary distribution is often prohibitive, due to the large state-space associated with most biochemical reaction networks. Here, we analyze a network representing a luminal calcium release site model and investigate to what extent small system size effects and calcium fluctuations, driven by ion channel gating, influx and diffusion, alter steady-state ion channel properties including open probability. For a physiological ion channel gating model and number of channels, the state-space may be between approximately 10-10 elements, and a novel modified block power method is used to solve the associated dominant eigenvector problem required to calculate the stationary distribution. We demonstrate that both small local cytosolic domain volume and a small number of ion channels drive calcium fluctuations that result in deviation from the corresponding model that neglects small system size effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1109/TCBB.2015.2498552DOI Listing
November 2017

Spatial discordance and phase reversals during alternate pacing in discrete-time kinematic and cardiomyocyte ionic models.

Authors:
Seth H Weinberg

Chaos 2015 Oct;25(10):103119

Virginia Modeling, Analysis and Simulation Center, Old Dominion University, Suffolk, Virginia 23435, USA.

Alternans, a beat-to-beat alternation in the cardiac action potential duration (APD), is a dynamical instability linked with the initiation of arrhythmias and sudden cardiac death, and arises via a period-doubling bifurcation when myocytes are stimulated at fast rates. In this study, we analyze the stability of a propagating electrical wave in a one-dimensional cardiac myocyte model in response to an arrhythmogenic rhythm known as alternate pacing. Using a discrete-time kinematic model and complex frequency (Z) domain analysis, we derive analytical expressions to predict phase reversals and spatial discordance in the interbeat interval (IBI) and APD, which, importantly, cannot be predicted with a model that neglects the influence of cell coupling on repolarization. We identify key dimensionless parameters that determine the transition from spatial concordance to discordance. Finally, we show that the theoretical predictions agree closely with numerical simulations of an ionic myocyte model, over a wide range of parameters, including variable IBI, altered ionic current gating, and reduced cell coupling. We demonstrate a novel approach to predict instability in cardiac tissue during alternate pacing and further illustrate how this approach can be generalized to more detail models of myocyte dynamics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1063/1.4932961DOI Listing
October 2015

Population Density and Moment-based Approaches to Modeling Domain Calcium-mediated Inactivation of L-type Calcium Channels.

Acta Biotheor 2016 Mar 30;64(1):11-32. Epub 2015 Sep 30.

Department of Applied Science, The College of William & Mary, McGlothlin-Street Hall, Rm 305, Williamsburg, VA, 23187, USA.

We present a population density and moment-based description of the stochastic dynamics of domain [Formula: see text]-mediated inactivation of L-type [Formula: see text] channels. Our approach accounts for the effect of heterogeneity of local [Formula: see text] signals on whole cell [Formula: see text] currents; however, in contrast with prior work, e.g., Sherman et al. (Biophys J 58(4):985-995, 1990), we do not assume that [Formula: see text] domain formation and collapse are fast compared to channel gating. We demonstrate the population density and moment-based modeling approaches using a 12-state Markov chain model of an L-type [Formula: see text] channel introduced by Greenstein and Winslow (Biophys J 83(6):2918-2945, 2002). Simulated whole cell voltage clamp responses yield an inactivation function for the whole cell [Formula: see text] current that agrees with the traditional approach when domain dynamics are fast. We analyze the voltage-dependence of [Formula: see text] inactivation that may occur via slow heterogeneous domain [[Formula: see text]]. Next, we find that when channel permeability is held constant, [Formula: see text]-mediated inactivation of L-type channels increases as the domain time constant increases, because a slow domain collapse rate leads to increased mean domain [[Formula: see text]] near open channels; conversely, when the maximum domain [[Formula: see text]] is held constant, inactivation decreases as the domain time constant increases. Comparison of simulation results using population densities and moment equations confirms the computational efficiency of the moment-based approach, and enables the validation of two distinct methods of truncating and closing the open system of moment equations. In general, a slow domain time constant requires higher order moment truncation for agreement between moment-based and population density simulations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10441-015-9271-yDOI Listing
March 2016

Membrane capacitive memory alters spiking in neurons described by the fractional-order Hodgkin-Huxley model.

Authors:
Seth H Weinberg

PLoS One 2015 13;10(5):e0126629. Epub 2015 May 13.

Virginia Modeling, Analysis and Simulation Center, Old Dominion University, 1030 University Boulevard, Suffolk, Virginia, USA.

Excitable cells and cell membranes are often modeled by the simple yet elegant parallel resistor-capacitor circuit. However, studies have shown that the passive properties of membranes may be more appropriately modeled with a non-ideal capacitor, in which the current-voltage relationship is given by a fractional-order derivative. Fractional-order membrane potential dynamics introduce capacitive memory effects, i.e., dynamics are influenced by a weighted sum of the membrane potential prior history. However, it is not clear to what extent fractional-order dynamics may alter the properties of active excitable cells. In this study, we investigate the spiking properties of the neuronal membrane patch, nerve axon, and neural networks described by the fractional-order Hodgkin-Huxley neuron model. We find that in the membrane patch model, as fractional-order decreases, i.e., a greater influence of membrane potential memory, peak sodium and potassium currents are altered, and spike frequency and amplitude are generally reduced. In the nerve axon, the velocity of spike propagation increases as fractional-order decreases, while in a neural network, electrical activity is more likely to cease for smaller fractional-order. Importantly, we demonstrate that the modulation of the peak ionic currents that occurs for reduced fractional-order alone fails to reproduce many of the key alterations in spiking properties, suggesting that membrane capacitive memory and fractional-order membrane potential dynamics are important and necessary to reproduce neuronal electrical activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126629PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4430543PMC
February 2016

Ca(2+)-activation kinetics modulate successive puff/spark amplitude, duration and inter-event-interval correlations in a Langevin model of stochastic Ca(2+) release.

Math Biosci 2015 Jun 2;264:101-7. Epub 2015 Apr 2.

Department of Applied Science, The College of William and Mary, Williamsburg, VA 23187, United States.

Through theoretical analysis of the statistics of stochastic calcium (Ca(2+)) release (i.e., the amplitude, duration and inter-event interval of simulated Ca(2+) puffs and sparks), we show that a Langevin description of the collective gating of Ca(2+) channels may be a good approximation to the corresponding Markov chain model when the number of Ca(2+) channels per Ca(2+) release unit (CaRU) is in the physiological range. The Langevin description of stochastic Ca(2+) release facilitates our investigation of correlations between successive puff/spark amplitudes, durations and inter-spark intervals, and how such puff/spark statistics depend on the number of channels per release site and the kinetics of Ca(2+)-mediated inactivation of open channels. When Ca(2+) inactivation/de-inactivation rates are intermediate-i.e., the termination of Ca(2+) puff/sparks is caused by an increase in the number of inactivated channels-the correlation between successive puff/spark amplitudes is negative, while the correlations between puff/spark amplitudes and the duration of the preceding or subsequent inter-spark interval are positive. These correlations are significantly reduced or change signs when inactivation/de-inactivation rates are extreme (slow or fast) and puff/sparks terminate via stochastic attrition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mbs.2015.03.012DOI Listing
June 2015

High frequency stimulation of cardiac myocytes: a theoretical and computational study.

Authors:
Seth H Weinberg

Chaos 2014 Dec;24(4):043104

Virginia Modeling, Analysis and Simulation Center, Old Dominion University, Suffolk, Virginia 23435, USA.

High-frequency stimulation (HFS) has recently been identified as a novel approach for terminating life-threatening cardiac arrhythmias. HFS elevates myocyte membrane potential and blocks electrical conduction for the duration of the stimulus. However, low amplitude HFS can induce rapidly firing action potentials, which may reinitiate an arrhythmia. The cellular level mechanisms underlying HFS-induced electrical activity are not well understood. Using a multiscale method, we show that a minimal myocyte model qualitatively reproduces the influence of HFS on cardiac electrical activity. Theoretical analysis and simulations suggest that persistent activation and de-inactivation of ionic currents, in particular a fast inward window current, underlie HFS-induced action potentials and membrane potential elevation, providing hypotheses for future experiments. We derive analytical expressions to describe how HFS modifies ionic current amplitude and gating dynamics. We show how fast inward current parameters influence the parameter regimes for HFS-induced electrical activity, demonstrating how the efficacy of HFS as a therapy for terminating arrhythmias may depend on the presence of pathological conditions or pharmacological treatments. Finally, we demonstrate that HFS terminates cardiac arrhythmias in a one-dimensional ring of cardiac tissue. In this study, we demonstrate a novel approach to characterize the influence of HFS on ionic current gating dynamics, provide new insight into HFS of the myocardium, and suggest mechanisms underlying HFS-induced electrical activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1063/1.4897618DOI Listing
December 2014
-->