NEUR-MS08

Modeling cardiac electrophysiology and pharmacology in health and disease

Tuesday, June 15 at 11:30am (PDT)
Tuesday, June 15 at 07:30pm (BST)
Wednesday, June 16 03:30am (KST)

SMB2021 Follow Tuesday (Wednesday) during the "MS08" time block.

Seth Weinberg (The Ohio State University, United States) & Eleonora Grandi (UC Davis, United States)

Description:

Computational models of cardiac electrophysiology have progressed rapidly in recent years and yielded a vast body of knowledge regarding normal heart physiology and disease mechanisms that would be inimaginable with experimental approaches alone. Models have been successfully applied to understand the mechanisms of cardiac rhythm dysregulation, inform therapeutic anti-arrhythmic strategies, and utilized in defining new predictive paradigms for cardiac safety. These frameworks have become increasingly complex and detailed, e.g., to account for various interacting cell functions and regulation (e.g., by the autonomic nervous system) in (patho)physiological states, and to capture the spatial and temporal details of intracellular and inter-cellular signaling. Although models are generally simplified and computational approaches are not yet truly multiscale with respect to pharmacology, we will present initial efforts to model molecular details of drug-ion channel interaction. While pharmacology applications are still relatively distant from the ultimate goal of model-based personalized treatment, we will discuss novel approaches that use models as a foundation for developing general rules about the interaction of pharmacologic targeting with cardiac dynamic substrate and provide an important intermediate step to the preclinical and clinical pipelines.

Eric Sobie

(Icahn School of Medicine at Mount Sinai, United States)

"Creating cell-specific models to infer changes to pig myocyte physiology after myocardial infarction"

Following myocardial infarction (MI), the region surrounding the infarct scar, known as the border zone (BZ), undergoes heterogeneous remodeling. These changes impact the cardiomyocytes’ electrophysiological behavior resulting in variable changes between myocytes depending on whether cells are near or remote from the BZ. In this study we sought to understand these heterogeneous electrophysiological changes by constraining model parameters, in a cell-by-cell manner, to fit data obtained in individual cells. In experiments, action potentials and intracellular calcium were recorded in cells with and without MI, in the border zone and remote from the MI. A genetic algorithm was run to estimate the ionic conductances in each cell studied (> 40), and repeated runs were performed to estimate the extent to which each conductance was identifiable. Results indicate which conductances exhibit more or less variability than others, and how conductances are altered by MI, in both regions. Overall, the study suggests a methodology for understanding complex disease states in which several variables have been altered.

Haibo Ni

(University of California Davis, United States)

"Quantifying cAMP- and Ca(2+)-dependent proarrhythmic mechanisms using populations of atrial myocyte and tissue models"

The β-adrenergic receptor (βAR)/cAMP/PKA and multifunctional Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) signaling pathways are key regulators of cardiac excitation-contraction coupling (ECC) by modulating multiple common downstream targets. Hyperactivation of both signaling pathways contributes to the initiation and maintenance of atrial fibrillation (AF), the world’s most common arrhythmia. Here, we developed a novel computational model of human atrial myocytes to couple electrophysiology and Ca(2+) handling with detailed descriptions of βAR/cAMP/PKA and CaMKII pathways. Populations of atrial myocytes revealed a synergy between the PKA and CaMKII effects on the atrial ECC proteins by promoting a vicious cycle of Ca(2+) and membrane potential instabilities. Logistic regression analyses uncovered the relative roles of the ECC proteins and the signaling components in generating cellular arrhythmogenic events. Further, we constructed 2D heterogeneous atrial tissue models and demonstrated that βAR stimulation and CaMKII hyperactivation promote arrhythmogenicity by invoking spontaneous Ca(2+)-overload-mediated action potentials, whereas CaMKII inhibition substantially reduced the vulnerability. Our simulations highlight a novel role of CaMKII-dependent cell-to-cell uncoupling in exacerbating the arrhythmia. Collectively, our simulations reveal synergy in PKA and CaMKII effects on cellular- and tissue-level arrhythmogenic outcomes, and depict a novel paradigm for Ca(2+)-CaMKII-dependent involvement in both enhanced triggered activity and conduction disturbances in AF. These findings suggest that interrupting the vicious cycle of Ca(2+)-CaMKII-Ca(2+) (e.g., via CaMKII inhibition) may be a valuable pharmacotherapy approach to counteract both triggers and functional substrate in AF.

Nicolae Moise

(The Ohio State University, United States)

"Intercalated Disk Nanoscale Structure Regulates Cardiac Conduction"

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 around mechanical and gap junctions, 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 structure 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 ID nanoscale structure, based on experimental measurements from transmission electron microscopy (TEM) 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 demonstrated that ID structural heterogeneity leads to significant spatial variation in electrical polarization within the intercellular cleft. Importantly, we find that this heterogeneous cleft polarization regulates conduction by desynchronizing the activation of post-junctional 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 find that disruption of local ID nanodomains can lead to either conduction slowing or enhancing, depending on gap junctional coupling strength. Overall, our study demonstrates that ID nanoscale structure can play a significant role in regulating cardiac conduction.

Jonathan Silva

(Washington University in St. Louis, United States)

"Using molecular detail and genetic background to predict patient response to anti-arrhythmic therapy"

Small molecule anti-arrhythmic therapies are generally considered to be moderately effective in suppressing arrhythmia, and patient outcomes are highly variable. This situation persists even when the genetic background that predisposes patients with congenital arrhythmias is known. We investigated the variability in patient response to the class I anti-arrhythmic molecule, mexiletine, in patients who were diagnosed with Long QT Syndrome Type 3. These patients harbor disease-linked variants in the gene that encodes the cardiac Na+ channel. Our results showed that variant effects on the voltage sensing domain of repeat III (VSD-III) of the Na+ channel could be used to predict whether patients were well-treated with mexiletine therapy with a partial least squares regression approach. A follow-on kinetic model that described the molecular details of the channel and block by mexiletine suggests a novel therapeutic approach by targeting VSD-III. Ongoing work is focused on developing new methods to create optimized kinetic channel models and testing whether the correlation between variant effects on VSD-III and mexiletine therapeutic outcomes holds for the general population.

Hosted by SMB2021 Follow

Virtual conference of the Society for Mathematical Biology, 2021.