Designed especially for neurobiologists, FluoRender is an interactive tool for multi-channel fluorescence microscopy data visualization and analysis.
Deep brain stimulation
BrainStimulator is a set of networks that are used in SCIRun to perform simulations of brain stimulation such as transcranial direct current stimulation (tDCS) and magnetic transcranial stimulation (TMS).
Developing software tools for science has always been a central vision of the SCI Institute.

Biomedical Computing

Biomedical computing combines the diagnostic and investigative aspects of biology and medical science with the power and problem-solving capabilities of modern computing. Computers are used to accelerate research learning, simulate patient behavior and visualize complex biological models.


Chris Johnson

Inverse Problems
Computational Electrophysiology

Rob MacLeod

ECG Imaging
Cardiac Disease
Computational Electrophysiology

Jeff Weiss

Computational Biomechanics

Orly Alter

Computational Biology

Tamara Bidone

Computational Models
Simulations of Biological Systems
Multi-Physics Models of Cancer Cells


Amir Arzani

Cardiovascular biomechanics
Scientific machine learning

Centers and Labs:

Funded Research Projects:

Publications in Biomedical Computing:

Data-driven prediction of αIIbβ3 integrin activation pathways using nonlinear manifold learning and deep generative modeling
S. Dasetty, T.C. Bidone, A.L. Ferguson. In Biophysical Journal, Vol. 123, 2024.

The integrin heterodimer is a transmembrane protein critical for driving cellular process and is a therapeutic target in the treatment of multiple diseases linked to its malfunction. Activation of integrin involves conformational transitions between bent and extended states. Some of the conformations that are intermediate between bent and extended states of the heterodimer have been experimentally characterized, but the full activation pathways remain unresolved both experimentally due to their transient nature and computationally due to the challenges in simulating rare barrier crossing events in these large molecular systems. An understanding of the activation pathways can provide new fundamental understanding of the biophysical processes associated with the dynamic interconversions between bent and extended states and can unveil new putative therapeutic targets. In this work, we apply nonlinear manifold learning to coarse-grained molecular dynamics simulations of bent, extended, and two intermediate states of aIIbb3 integrin to learn a low-dimensional embedding of the configurational phase space. We then train deep generative models to learn an inverse mapping between the low-dimensional embedding and high-dimensional molecular space and use these models to interpolate the molecular configurations constituting the activation pathways between the experimentally characterized states. This work furnishes plausible predictions of integrin activation pathways and reports a generic and transferable multiscale technique to predict transition pathways for biomolecular systems.

Influence of Material Parameter Variability on the Predicted Coronary Artery Biomechanical Environment via Uncertainty Quantification
Subtitled “arXiv preprint arXiv:2401.15047,” C.C. Berggren, D. Jiang, Y.F. Wang, J.A. Bergquist, L. Rupp, Z. Liu, R.S. MacLeod, A. Narayan, L. Timmins. 2024.

Central to the clinical adoption of patient-specific modeling strategies is demonstrating that simulation results are reliable and safe. Indeed, simulation frameworks must be robust to uncertainty in model input(s), and levels of confidence should accompany results. In this study, we applied a coupled uncertainty quantification-finite element (FE) framework to understand the impact of uncertainty in vascular material properties on variability in predicted stresses. Univariate probability distributions were fit to material parameters derived from layer-specific mechanical behavior testing of human coronary tissue. Parameters were assumed to be probabilistically independent, allowing for efficient parameter ensemble sampling. In an idealized coronary artery geometry, a forward FE model for each parameter ensemble was created to predict tissue stresses under physiologic loading. An emulator was constructed within the UncertainSCI software using polynomial chaos techniques, and statistics and sensitivities were directly computed. Results demonstrated that material parameter uncertainty propagates to variability in predicted stresses across the vessel wall, with the largest dispersions in stress within the adventitial layer. Variability in stress was most sensitive to uncertainties in the anisotropic component of the strain energy function. Moreover, unary and binary interactions within the adventitial layer were the main contributors to stress variance, and the leading factor in stress variability was uncertainty in the stress-like material parameter that describes the contribution of the embedded fibers to the overall artery stiffness. Results from a patient-specific coronary model confirmed many of these findings. Collectively, these data highlight the impact of material property variation on uncertainty in predicted artery stresses and present a pipeline to explore and characterize forward model uncertainty in computational biomechanics.

Ablation-induced left atrial mechanical dysfunction recovers in weeks after ablation,
J. Dong, E. Kwan, J.A. Bergquist, B.A. Steinberg, D.J. Dosdall, E. DiBella, R.S. MacLeod, T.J. Bunch, R. Ranjan. In Journal of Interventional Cardiac Electrophysiology, Springer, 2024.


The immediate impact of catheter ablation on left atrial mechanical function and the timeline for its recovery in patients undergoing ablation for atrial fibrillation (AF) remain uncertain. The mechanical function response to catheter ablation in patients with different AF types is poorly understood.


A total of 113 AF patients were included in this retrospective study. Each patient had three magnetic resonance imaging (MRI) studies in sinus rhythm: one pre-ablation, one immediate post-ablation (within 2 days after ablation), and one post-ablation follow-up MRI (≤ 3 months). We used feature tracking in the MRI cine images to determine peak longitudinal atrial strain (PLAS). We evaluated the change in strain from pre-ablation, immediately after ablation to post-ablation follow-up in a short-term study (< 50 days) and a 3-month study (3 months after ablation).


The PLAS exhibited a notable reduction immediately after ablation, compared to both pre-ablation levels and those observed in follow-up studies conducted at short-term (11.1 ± 9.0 days) and 3-month (69.6 ± 39.6 days) intervals. However, there was no difference between follow-up and pre-ablation PLAS. The PLAS returned to 95% pre-ablation level within 10 days. Paroxysmal AF patients had significantly higher pre-ablation PLAS than persistent AF patients in pre-ablation MRIs. Both type AF patients had significantly lower immediate post-ablation PLAS compared with pre-ablation and post-ablation PLAS.


The present study suggested a significant drop in PLAS immediately after ablation. Left atrial mechanical function recovered within 10 days after ablation. The drop in PLAS did not show a substantial difference between paroxysmal and persistent AF patients.

Contributions of the individual domains of αIIbβ3 integrin to its extension: Insights from multiscale modeling
O. Joshi, T. Skóra, A. Yarema, R.D. Rabbitt, T.C. Bidone. In Cytoskeleton, 2024.

The platelet integrin αIIbβ3 undergoes long-range conformational transitions between bent and extended conformations to regulate platelet aggregation during hemostasis and thrombosis. However, how exactly αIIbβ3 transitions between conformations remains largely elusive. Here, we studied how transitions across bent and extended-closed conformations of αIIbβ3 integrin are regulated by effective interactions between its functional domains. We first carried out μs-long equilibrium molecular dynamics (MD) simulations of full-length αIIbβ3 integrins in bent and intermediate conformations, the latter characterized by an extended headpiece and closed legs. Then, we built heterogeneous elastic network models, perturbed inter-domain interactions, and evaluated their relative contributions to the energy barriers between conformations. Results showed that integrin extension emerges from: (i) changes in interfaces between functional domains; (ii) allosteric coupling of the head and upper leg domains with flexible lower leg domains. Collectively, these results provide new insights into integrin conformational activation based on short- and long-range interactions between its functional domains and highlight the importance of the lower legs in the regulation of integrin allostery.

Grand Challenges at the Interface of Engineering and Medicine
S. Subramaniam, M. Miller, several co-authors, Chris R. Johnson, et al.. In IEEE Open Journal of Engineering in Medicine and Biology, Vol. 5, IEEE, pp. 1--13. 2024.
DOI: 10.1109/OJEMB.2024.3351717

Over the past two decades Biomedical Engineering has emerged as a major discipline that bridges societal needs of human health care with the development of novel technologies. Every medical institution is now equipped at varying degrees of sophistication with the ability to monitor human health in both non-invasive and invasive modes. The multiple scales at which human physiology can be interrogated provide a profound perspective on health and disease. We are at the nexus of creating “avatars” (herein defined as an extension of “digital twins”) of human patho/physiology to serve as paradigms for interrogation and potential intervention. Motivated by the emergence of these new capabilities, the IEEE Engineering in Medicine and Biology Society, the Departments of Biomedical Engineering at Johns Hopkins University and Bioengineering at University of California at San Diego sponsored an interdisciplinary workshop to define the grand challenges that face biomedical engineering and the mechanisms to address these challenges. The Workshop identified five grand challenges with cross-cutting themes and provided a roadmap for new technologies, identified new training needs, and defined the types of interdisciplinary teams needed for addressing these challenges. The themes presented in this paper include: 1) accumedicine through creation of avatars of cells, tissues, organs and whole human; 2) development of smart and responsive devices for human function augmentation; 3) exocortical technologies to understand brain function and treat neuropathologies; 4) the development of approaches to harness the human immune system for health and wellness; and 5) new strategies to engineer genomes and cells.

Modeling Coupled 1D PDEs of Cardiovascular Flow with Spatial Neural ODEs
H. Csala, A. Mohan, D. Livescu, A. Arzani. In Machine Learning and the Physical Sciences Workshop, NeurIPS 2023, 2023.

Tackling coupled sets of partial differential equations (PDEs) through scientific machine learning presents a complex challenge, but it is essential for developing data-driven physics-based models. We employ a novel approach to model the coupled PDEs that govern the blood flow in stenosed arteries with deformable walls, while incorporating realistic inlet flow waveforms. We propose a low-dimensional model based on neural ordinary differential equations (ODEs) inspired by 1D blood flow equations. Our unique approach formulates the problem as ODEs in space rather than time, effectively overcoming issues related to time-dependent boundary conditions and PDE coupling. This innovative framework accurately captures flow rate and area variations, even when extrapolating to unseen waveforms. The promising results from this approach offer a different perspective on deploying neural ODEs to model coupled PDEs with unsteady boundary conditions, which are prevalent in many engineering applications.

UncertainSCI: A Python Package for Noninvasive Parametric Uncertainty Quantification of Simulation Pipelines
J. Tate, Z. Liu, J.A. Bergquist, S. Rampersad, D. White, C. Charlebois, L. Rupp, D. Brooks, R. MacLeod, A. Narayan. In Journal of Open Source Software, Vol. 8, No. 90, 2023.

We have developed UncertainSCI (UncertainSCI, 2020) as an open-source tool designed to make modern uncertainty quantification (UQ) techniques more accessible in biomedical simulation applications. UncertainSCI is implemented in Python with a noninvasive interface to meet our software design goals of 1) numerical accuracy, 2) simple application programming interface (API), 3) adaptability to many applications and methods, and 4) interfacing with diverse simulation software. Using a Python implementation in UncertainSCI allowed us to utilize the popularity and low barrier-to-entry of Python and its common packages and to leverage the built-in integration and support for Python in common simulation software packages and languages. Additionally, we used noninvasive UQ techniques and created a similarly noninvasive interface to external modeling software that can be called in diverse ways, depending on the complexity and level of Python integration in the external simulation pipeline. We have developed and included examples applying UncertainSCI to relatively simple 1D simulations implemented in Python, and to bioelectric field simulations implemented in external software packages, which demonstrate the use of UncertainSCI and the effectiveness of the architecture and implementation in achieving our design goals. UnceratainSCI differs from similar software, notably UQLab, Uncertainpy, and Simnibs, in that it can be efficiently and non-invasively used with external simulation software, specifically with high resolution 3D simulations often used in Bioelectric field simulations. Figure 1 illustrates the use of UncertainSCI in computing UQ with modeling pipelines for bioelectricity simulations

A Grid Search of Fibrosis Thresholds for Uncertainty Quantification in Atrial Flutter Simulations
B.A. Orkild, J.A. Bergquist, E.N. Paccione, M. Lange, E. Kwan, B. Hunt, R. MacLeod, A. Narayan, R. Ranjan. In Computing in Cardiology, 2023.

Atypical Atrial Flutter (AAF) is the most common cardiac arrhythmia to develop following catheter ablation for atrial fibrillation. Patient-specific computational simulations of propagation have shown promise in prospectively predicting AAF reentrant circuits and providing useful insight to guide successful ablation procedures. These patient-specific models require a large number of inputs, each with an unknown amount of uncertainty. Uncertainty quantification (UQ) is a technique to assess how variability in a set of input parameters can affect the output of a model. However, modern UQ techniques, such as polynomial chaos expansion, require a well-defined output to map to the inputs. In this study, we aimed to explore the sensitivity of simulated reentry to the selection of fibrosis threshold in patient-specific AAF models. We utilized the image intensity ratio (IIR) method to set the fibrosis threshold in the LGE-MRI from a single patient with prior ablation. We found that the majority of changes to the duration of reentry occurred within an IIR range of 1.01 to 1.39, and that there was a large amount of variability in the resulting arrhythmia. This study serves as a starting point for future UQ studies to investigate the nonlinear relationship between fibrosis threshold and the resulting arrhythmia in AAF models.

Uncertainty quantification of the effect of cardiac position variability in the inverse problem of electrocardiographic imaging
J. A. Bergquist, B. Zenger, L. Rupp, A. Busatto, J. D. Tate, D. H. Brooks, A. Narayan, R. MacLeod. In Journal of Physiological Measurement, IOP Science, 2023.
DOI: 10.1088/1361-6579/acfc32

Objective:&#xD;Electrocardiographic imaging (ECGI) is a functional imaging modality that consists of two related problems, the forward problem of reconstructing body surface electrical signals given cardiac bioelectric activity, and the inverse problem of reconstructing cardiac bioelectric activity given measured body surface signals. ECGI relies on a model for how the heart generates bioelectric signals which is subject to variability in inputs. The study of how uncertainty in model inputs affects the model output is known as uncertainty quantification (UQ). This study establishes develops, and characterizes the application of UQ to ECGI.&#xD;&#xD;Approach:&#xD;We establish two formulations for applying UQ to ECGI: a polynomial chaos expansion (PCE) based parametric UQ formulation (PCE-UQ formulation), and a novel UQ-aware inverse formulation which leverages our previously established ``joint-inverse" formulation (UQ joint-inverse formulation). We apply these to evaluate the effect of uncertainty in the heart position on the ECGI solutions across a range of ECGI datasets.&#xD;&#xD;Main Results:&#xD;We demonstrated the ability of our UQ-ECGI formulations to characterize the effect of parameter uncertainty on the ECGI inverse problem. We found that while the PCE-UQ inverse solution provided more complex outputs such as sensitivities and standard deviation, the UQ joint-inverse solution provided a more interpretable output in the form of a single ECGI solution. We find that between these two methods we are able to assess a wide range of effects that heart position variability has on the ECGI solution.&#xD;&#xD;Significance:&#xD;This study, for the first time, characterizes in detail the application of UQ to the ECGI inverse problem. We demonstrated how UQ can provide insight into the behavior of ECGI using variability in cardiac position as a test case. This study lays the groundwork for future development of UQ-ECGI studies, as well as future development of ECGI formulations which are robust to input parameter variability.

Nascent adhesions shorten the period of lamellipodium protrusion through the Brownian ratchet mechanism
K.R. Carney, A.M. Khan, S. Stam, S.C. Samson, N. Mittal, S. Han, T.C. Bidone, M. Mendoza. In Mol Biol Cell, 2023.

Directional cell migration is driven by the conversion of oscillating edge motion into lasting periods of leading edge protrusion. Actin polymerization against the membrane and adhesions control edge motion, but the exact mechanisms that determine protrusion period remain elusive. We addressed this by developing a computational model in which polymerization of actin filaments against a deformable membrane and variable adhesion dynamics support edge motion. Consistent with previous reports, our model showed that actin polymerization and adhesion lifetime power protrusion velocity. However, increasing adhesion lifetime decreased the protrusion period. Measurements of adhesion lifetime and edge motion in migrating cells confirmed that adhesion lifetime is associated with and promotes protrusion velocity, but decreased duration. Our model showed that adhesions’ control of protrusion persistence originates from the Brownian ratchet mechanism for actin filament polymerization. With longer adhesion lifetime or increased adhesion density, the proportion of actin filaments tethered to the substrate increased, maintaining filaments against the cell membrane. The reduced filament-membrane distance generated pushing force for high edge velocity, but limited further polymerization needed for protrusion duration. We propose a mechanism for cell edge protrusion in which adhesion strength regulates actin filament polymerization to control the periods of leading edge protrusion.

Multi-Omic Integration of Blood-Based Tumor-Associated Genomic and Lipidomic Profiles Using Machine Learning Models in Metastatic Prostate Cancer
S. Fang, S. Zhe, H.M. Lin, A.A. Azad, H. Fettke, E.M. Kwan, L. Horvath, B. Mak, T. Zheng, P. Du, S. Jia, R.M. Kirby, M. Kohli. In Clinical Cancer Informatics, 2023.

To determine prognostic and predictive clinical outcomes in metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castrate-resistant prostate cancer (mCRPC) on the basis of a combination of plasma-derived genomic alterations and lipid features in a longitudinal cohort of patients with advanced prostate cancer.

A multifeature classifier was constructed to predict clinical outcomes using plasma-based genomic alterations detected in 120 genes and 772 lipidomic species as informative features in a cohort of 71 patients with mHSPC and 144 patients with mCRPC. Outcomes of interest were collected over 11 years of follow-up. These included in mHSPC state early failure of androgen-deprivation therapy (ADT) and exceptional responders to ADT; early death (poor prognosis) and long-term survivors in mCRPC state. The approach was to build binary classification models that identified discriminative candidates with optimal weights to predict outcomes. To achieve this, we built multi-omic feature-based classifiers using traditional machine learning (ML) methods, including logistic regression with sparse regularization, multi-kernel Gaussian process regression, and support vector machines.

The levels of specific ceramides (d18:1/14:0 and d18:1/17:0), and the presence of CHEK2 mutations, AR amplification, and RB1 deletion were identified as the most crucial factors associated with clinical outcomes. Using ML models, the optimal multi-omics feature combination determined resulted in AUC scores of 0.751 for predicting mHSPC survival and 0.638 for predicting ADT failure; and in mCRPC state, 0.687 for prognostication and 0.727 for exceptional survival. The models were observed to be superior than using a limited candidate number of features for developing multi-omic prognostic and predictive signatures.

Using a ML approach that incorporates multiple omic features improves the prediction accuracy for metastatic prostate cancer outcomes significantly. Validation of these models will be needed in independent data sets in future.

Computational model of integrin adhesion elongation under an actin fiber
S. Campbell, M. C. Mendoza, A. Rammohan, M. E. McKenzie, T. C. Bidone. In PLOS Computatonal Biology, Vol. 19, No. 7, Public Library of Science, pp. 1-19. 7, 2023.
DOI: 10.1371/journal.pcbi.1011237

Cells create physical connections with the extracellular environment through adhesions. Nascent adhesions form at the leading edge of migrating cells and either undergo cycles of disassembly and reassembly, or elongate and stabilize at the end of actin fibers. How adhesions assemble has been addressed in several studies, but the exact role of actin fibers in the elongation and stabilization of nascent adhesions remains largely elusive. To address this question, here we extended our computational model of adhesion assembly by incorporating an actin fiber that locally promotes integrin activation. The model revealed that an actin fiber promotes adhesion stabilization and elongation. Actomyosin contractility from the fiber also promotes adhesion stabilization and elongation, by strengthening integrin-ligand interactions, but only up to a force threshold. Above this force threshold, most integrin-ligand bonds fail, and the adhesion disassembles. In the absence of contraction, actin fibers still support adhesions stabilization. Collectively, our results provide a picture in which myosin activity is dispensable for adhesion stabilization and elongation under an actin fiber, offering a framework for interpreting several previous experimental observations.

Editorial: Image-based computational approaches for personalized cardiovascular medicine: improving clinical applicability and reliability through medical imaging and experimental data
S. Pirola, A. Arzani, C. Chiastra, F. Sturla. In Frontiers in Medical Technology, Vol. 5, 2023.
DOI: 10.3389/fmedt.2023.1222837

Halide Code Generation Framework in Phylanx,
R. Tohid, S. Shirzad, C. Taylor, S.A. Sakin, K.E. Isaacs, H. Kaiser. In Euro-Par 2022: Parallel Processing Workshops, Springer Nature Switzerland, pp. 32--45. 2023.
ISBN: 978-3-031-31209-0
DOI: 10.1007/978-3-031-31209-0_3

Separating algorithms from their computation schedule has become a de facto solution to tackle the challenges of developing high performance code on modern heterogeneous architectures. Common approaches include Domain-specific languages (DSLs) which provide familiar APIs to domain experts, code generation frameworks that automate the generation of fast and portable code, and runtime systems that manage threads for concurrency and parallelism. In this paper, we present the Halide code generation framework for Phylanx distributed array processing platform. This extension enables compile-time optimization of Phylanx primitives for target architectures. To accomplish this, (1) we implemented new Phylanx primitives using Halide, and (2) partially exported Halide's thread pool API to carry out parallelism on HPX (Phylanx's runtime) threads. (3) showcased HPX performance analysis tools made available to Halide applications. The evaluation of the work has been done in two steps. First, we compare the performance of Halide applications running on its native runtime with that of the new HPX backend to verify there is no cost associated with using HPX threads. Next, we compare performances of a number of original implementations of Phylanx primitives against the new ones in Halide to verify performance and portability benefits of Halide in the context of Phylanx.

Multiscale models of integrins and cellular adhesions
T.C. Bidone, D.J. Odde. In Current Opinion in Structural Biology, Vol. 80, Elsevier, 2023.

Computational models of integrin-based adhesion complexes have revealed important insights into the mechanisms by which cells establish connections with their external environment. However, how changes in conformation and function of individual adhesion proteins regulate the dynamics of whole adhesion complexes remains largely elusive. This is because of the large separation in time and length scales between the dynamics of individual adhesion proteins (nanoseconds and nanometers) and the emergent dynamics of the whole adhesion complex (seconds and micrometers), and the limitations of molecular simulation approaches in extracting accurate free energies, conformational transitions, reaction mechanisms, and kinetic rates, that can inform mechanisms at the larger scales. In this review, we discuss models of integrin-based adhesion complexes and highlight their main findings regarding: (i) the conformational transitions of integrins at the molecular and macromolecular scales and (ii) the molecular clutch mechanism at the mesoscale. Lastly, we present unanswered questions in the field of modeling adhesions and propose new ideas for future exciting modeling opportunities.

Protein-metabolite interactomics of carbohydrate metabolism reveal regulation of lactate dehydrogenase
K. G. Hicks, A. A. Cluntun, H. L. Schubert, S. R. Hackett, J. A. Berg, P. G. Leonard, M. A. Ajalla Aleixo, Y. Zhou, A. J. Bott, S. R. Salvatore, F. Chang, A. Blevins, P. Barta, S. Tilley, A. Leifer, A. Guzman, A. Arok, S. Fogarty, J. M. Winter, H. Ahn, K. N. Allen, S. Block, I. A. Cardoso, J. Ding, I. Dreveny, C. Gasper, Q. Ho, A. Matsuura, M. J. Palladino, S. Prajapati, P. Sun, K. Tittmann, D. R. Tolan, J. Unterlass, A. P. VanDemark, M. G. Vander Heiden, B. A. Webb, C. Yun, P. Zhap, B. Wang, F. J. Schopfer, C. P. Hill, M. C. Nonato, F. L. Muller, J. E. Cox, J. Rutter. In Science, Vol. 379, No. 6636, pp. 996-1003. 2023.
DOI: 10.1126/science.abm3452

Metabolic networks are interconnected and influence diverse cellular processes. The protein-metabolite interactions that mediate these networks are frequently low affinity and challenging to systematically discover. We developed mass spectrometry integrated with equilibrium dialysis for the discovery of allostery systematically (MIDAS) to identify such interactions. Analysis of 33 enzymes from human carbohydrate metabolism identified 830 protein-metabolite interactions, including known regulators, substrates, and products as well as previously unreported interactions. We functionally validated a subset of interactions, including the isoform-specific inhibition of lactate dehydrogenase by long-chain acyl–coenzyme A. Cell treatment with fatty acids caused a loss of pyruvate-lactate interconversion dependent on lactate dehydrogenase isoform expression. These protein-metabolite interactions may contribute to the dynamic, tissue-specific metabolic flexibility that enables growth and survival in an ever-changing nutrient environment. Understanding how metabolic state influences cellular processes requires systematic analysis of low-affinity interactions of metabolites with proteins. Hicks et al. describe a method called MIDAS (mass spectrometry integrated with equilibrium dialysis for the discovery of allostery systematically), which allowed them to probe such interactions for 33 enzymes of human carbohydrate metabolism and more than 400 metabolites. The authors detected many known and many new interactions, including regulation of lactate dehydrogenase by ATP and long-chain acyl coenzyme A, which may help to explain known physiological relations between fat and carbohydrate metabolism in different tissues. —LBR A mass spectrometry and dialysis method detects metabolite-protein interactions that help to control physiology.

Contribution of atrial myofiber architecture to atrial fibrillation
R. Kamali, E. Kwan, M. Regouski, T.J. Bunch, D.J. Dosdall, E. Hsu, R. S. Macleod, I. Polejaeva, R. Ranjan. In PLOS ONE, Vol. 18, No. 1, Public Library of Science, pp. 1--16. Jan, 2023.
DOI: 10.1371/journal.pone.0279974


The role of fiber orientation on a global chamber level in sustaining atrial fibrillation (AF) is unknown. The goal of this study was to correlate the fiber direction derived from Diffusion Tensor Imaging (DTI) with AF inducibility.


Transgenic goats with cardiac-specific overexpression of constitutively active TGF-β1 (n = 14) underwent AF inducibility testing by rapid pacing in the left atrium. We chose a minimum of 10 minutes of sustained AF as a cut-off for AF inducibility. Explanted hearts underwent DTI to determine the fiber direction. Using tractography data, we clustered, visualized, and quantified the fiber helix angles in 8 different regions of the left atrial wall using two reference vectors defined based on anatomical landmarks.

Sustained AF was induced in 7 out of 14 goats. The mean helix fiber angles in 7 out of 8 selected regions were statistically different (P-Value < 0.05) in the AF inducible group. The average fractional anisotropy (FA) and the mean diffusivity (MD) were similar in the two groups with FA of 0.32±0.08 and MD of 8.54±1.72 mm2/s in the non-inducible group and FA of 0.31±0.05 (P-value = 0.90) and MD of 8.68±1.60 mm2/s (P-value = 0.88) in the inducible group.

DTI based fiber direction shows significant variability across subjects with a significant difference between animals that are AF inducible versus animals that are not inducible. Fiber direction might be contributing to the initiation and sustaining of AF, and its role needs to be investigated further.

Heart Position Uncertainty Quantification in the Inverse Problem of ECGI
J.A. Bergquist, L.C. Rupp, A. Busatto, B. Orkild, B. Zenger, W. Good, J. Coll-Font, A. Narayan, J. Tate, D. Brooks, R.S. MacLeod. In Computing in Cardiology, Vol. 49, 2022.

Electrocardiographic imaging (ECGI) is a clinical and research tool for noninvasive diagnosis of cardiac electrical dysfunction. The position of the heart within the torso is both an input and common source of error in ECGI. Many studies have sought to improve cardiac localization accuracy, however, few have examined quantitatively the effects of uncertainty in the position of the heart within the torso. Recently developed uncertainty quantification (UQ) tools enable the robust application of UQ to ECGI reconstructions. In this study, we developed an ECGI formulation, which for the first time, directly incorporated uncertainty in the heart position. The result is an ECGI solution that is robust to variation in heart position. Using data from two Langendorff experimental preparations, each with 120 heartbeats distributed across three activation sequences, we found that as heart position uncertainty increased above ±10 mm, the solution quality of the ECGI degraded. However, even at large heart position uncertainty (±40 mm) our novel UQ-ECGI formulation produced reasonable solutions (root mean squared error < 1 mV, spatial correlation >0.6, temporal correlation >0.75).

Unipolar R:S Development in Chronic Atrial Fibrillation
E. Paccione, B. Hunt, E. Kwan, D. Dosdall, R. MacLeod, R. Ranjan. In Computing in Cardiology, Vol. 49, 2022.

Past studies have examined the differences between R and S waves of unipolar atrial signals in patients with atrial fibrillation (AF) and have shown a difference in the R to S ratio (R:S) in certain regions of the atria compared to a healthy population. This work indicates a potential use of R:S as a marker for AF. In this study, we further examine these claims and investigate temporal changes in R:S over AF development in animals.

Four canines underwent AF development protocols and endocardial sinus rhythm maps were recorded as AF progressed. Unipolar signals gathered from mapping were used to calculate R:S within the left atrium of each animal. Calculations were performed at time points: before AF initiation, 3-4 months of chronic AF, and 6 months of chronic AF. From our analysis, we observed an increase in R-dominant signals within the left atrium once AF is induced. Temporal results show that R dominance may be an indicator for chronic AF patients and may be associated with the presence of arrhythmogenic substrate. With the addition of regional information, this unipolar signal analysis could guide therapeutic strategies.

A Sliding Window Approach to Regularization in Electrocardiographic Imaging
B.A. Orkild, J.A. Bergquist, L.C. Rupp, A. Busatto, B. Zenger, W.W. Good, J. Coll-Font, R.S. MacLeod. In Computing in Cardiology, Vol. 49, 2022.

Introduction: The inverse problem of ECGI is ill-posed, so regularization must be applied to constrain the solution. Regularization is typically applied to each individual time point (instantaneous) or to the beat as a whole (global). These techniques often lead to over- or underregularization. We aimed to develop an inverse formulation that strikes a balance between these two approaches that would realize the benefits of both by implementing a sliding-window regularization. Methods: We formulated sliding-window regularization using the boundary element method with Tikhonov 0 and 2nd order regularization. We applied regularization to a varying time window of the body-surface potentials centered around each time sample. We compared reconstructed potentials from the sliding-window, instantaneous, and global regularization techniques to ground truth potentials for 10 heart beats paced from the ventricle in a large-animal model. Results: The sliding-window technique provided smoother transitions of regularization weights than instantaneous regularization while improving spatial correlation over global regularization. Discussion: Although the differences in regularization weights were nuanced, smoother transitions provided by the sliding-window regularization have the ability to eliminate discontinuities in potential seen with instantaneous regularization.