Biology subjects

Moise, N.

Publications and source records attributed to Moise, N..

6 recordsLinked to original sources

bioRxiv2024

Calcium homeostatic feedback control predicts atrial fibrillation initiation, remodeling, and progression

Atrial fibrillation (AF) is a progressive disorder, with arrhythmia episodes becoming increasingly longer and ultimately permanent. The chaotic electrical activity by itself is well-known to drive progression, a process classically summarized as "AF begets AF." However, the mechanisms underlying this progression are not yet well defined. We hypothesize that calcium homeostatic feedback regulating ion channel expression is a critical mechanistic component of this pathological process. We propose a modeling framework that tracks both short-term beat-to-beat electrical and calcium activity and long-term tissue substrate remodeling as a single coupled dynamical system. Importantly, the full AF progression from healthy to pathological remodeled tissue is reproduced, in contrast with prior studies that consider "snapshots" of various AF stages. Simulations predict that single cells respond to fast pacing by maintaining intracellular calcium concentrations through dynamic ion channel expression and electrical phenotype changes. In two-dimensional (2D) homogeneous tissue, spontaneous spiral waves stabilize into permanent re-entry. In 2D heterogeneous tissue, we observe the initiation of re-entrant activity in response to fast pacing, followed by increasingly longer intermittent, and then permanent, arrhythmic activity. Simulations predict critical properties of re-entrant wave locations, leading to a novel hypothesis: spiral wave activity itself drives underlying substrate remodeling and the emergence of remodeled tissue "niches" that support the stabilization of fast re-entrant activity. Thus, the model joins multiple lines of inquiry (i.e., long-term calcium regulation, ion channel co-expression and remodeling, and tissue-scale arrhythmia spatiotemporal organization) into a single coherent framework, and for the first time, captures the dynamics of the long-term natural history of AF.

physiology↗

bioRxiv2024

Connecting Transcriptomics with Computational Modeling to Reveal Developmental Adaptations in the Human Pediatric Myocardium

BackgroundNearly 1% or 1.3 million babies are born with congenital heart disease (CHD) globally each year - many of whom will require palliative or corrective heart surgery within the first few years of life. A detailed understanding of cardiac maturation can help to expand our knowledge on cardiac diseases that develop during gestation, identify age-appropriate cardiovascular drug therapies, and inform clinical care decisions related to surgical repair, myocardial preservation, or postoperative management. Yet, to date, our knowledge of the temporal changes that cardiomyocytes undergo during postnatal development is largely limited to animal models. MethodsRight atrial tissue samples were collected from n=117 neonatal, infant, and pediatric patients undergoing correct surgery due to (acyanotic) CHD. Patients were stratified into five age groups: neonate (0-30 days), infant (31-364 days), toddler to preschool (1-5 years), school age (6-11 years), and adolescent to young adults (12-32 years). We measured age-dependent adaptations in cardiac gene expression, and used computational modeling to simulate action potential and calcium transients. ResultsEnrichment of differentially expressed genes (DEG) was explored, revealing age-dependent changes in several key biological processes (cell cycle, cell division, mitosis), cardiac ion channels, and calcium handling genes. Gene-associated changes in ionic currents exhibited both linear trends and sudden shifts across developmental stages, with changes in calcium handling (INCX) and repolarization (IK1) most strongly associated with an age-dependent decrease in the action potential plateau potential and increase in triangulation, respectively. We also note a shift in repolarization reserve, with lower IKr expression in younger patients, a finding likely tied to the increased amplitude of IKs triggered by elevated sympathetic activation in pediatric patients. ConclusionThis study provides valuable insights into age-dependent changes in human cardiac gene expression and electrophysiology among patients with CHD, shedding light on molecular mechanisms underlying cardiac development and function across different developmental stages.

cell biology↗

bioRxiv2023

Indirect Correlative Light and Electron Microscopy (iCLEM): A Novel Pipeline for Multiscale Quantification of Structure from Molecules to Organs

Correlative light and electron microscopy (CLEM) methods are powerful methods which combine molecular organization (from light microscopy) with ultrastructure (from electron microscopy). However, CLEM methods pose high cost/difficulty barriers to entry and have very low experimental throughput. Therefore, we have developed an indirect correlative light and electron microscopy (iCLEM) pipeline to sidestep the rate limiting steps of CLEM (i.e., preparing and imaging the same samples on multiple microscopes) and correlate multiscale structural data gleaned from separate samples imaged using different modalities by exploiting biological structures identifiable by both light and electron microscopy as intrinsic fiducials. We demonstrate here an application of iCLEM, where we utilized gap junctions and mechanical junctions between muscle cells in the heart as intrinsic fiducials to correlate ultrastructural measurements from transmission electron microscopy (TEM), and focused ion beam scanning electron microscopy (FIB-SEM) with molecular organization from confocal microscopy and single molecule localization microscopy (SMLM). We further demonstrate how iCLEM can be integrated with computational modeling to discover structure-function relationships. Thus, we present iCLEM as a novel approach that complements existing CLEM methods and provides a generalizable framework that can be applied to any set of imaging modalities, provided suitable intrinsic fiducials can be identified.

systems biology↗

bioRxiv2023

Unraveling Chamber-specific Differences in Intercalated Disc Ultrastructure and Molecular Organization and Their Impact on Cardiac Conduction

During each heartbeat, the propagation of action potentials through the heart coordinates the contraction of billions of individual cardiomyocytes and is thus, a critical life process. Unsurprisingly, intercalated discs, which are cell-cell contact sites specialized to provide electrical and mechanical coupling between adjacent cardiomyocytes, have been the focus of much investigation. Slowed or disrupted propagation leads to potentially life-threatening arrhythmias in a wide range of pathologies, where intercalated disc remodeling is a common finding. Hence, the importance and urgency of understanding intercalated disc structure and its influence on action potential propagation. Surprisingly, however, conventional modeling approaches cannot predict changes in propagation elicited by perturbations that alter intercalated disc ultrastructure or molecular organization, owing to lack of quantitative structural data at subcellular through nano scales. In order to address this critical gap in knowledge, we sought to quantify intercalated disc structure at these finer spatial scales in the healthy adult mouse heart and relate them to function in a chamber-specific manner as a precursor to understanding the impacts of pathological intercalated disc remodeling. Using super-resolution light microscopy, electron microscopy, and computational image analysis, we provide here the first ever systematic, multiscale quantification of intercalated disc ultrastructure and molecular organization. By incorporating these data into a rule-based model of cardiac tissue with realistic intercalated disc structure, and comparing model predictions of electrical propagation with experimental measures of conduction velocity, we reveal that atrial intercalated discs can support faster conduction than their ventricular counterparts, which is normally masked by inter-chamber differences in myocyte geometry. Further, we identify key ultrastructural and molecular organization features underpinning the ability of atrial intercalated discs to support faster conduction. These data provide the first stepping stone to elucidating chamber-specific impacts of pathological intercalated disc remodeling, as occurs in many arrhythmic diseases.

physiology↗

bioRxiv2022

Emergent Electrical Activity, Tissue Heterogeneity, and Robustness in a Calcium Feedback Regulatory Model of the Sinoatrial Node

The sinoatrial node (SAN) is the primary pacemaker of the heart. SAN activity emerges at an early point in life and maintains a steady rhythm for the lifetime of the organism. The ion channel composition and currents of SAN cells can be influenced by a variety of factors. Therefore, the emergent activity and long-term stability imply some form of dynamical feedback control of SAN activity. We adapt a recent feedback model - previously utilized to describedion conductances in neurons - to a model of SAN cells and tissue. The model describes a minimal regulatory mechanism of ion channel conductances via feedback between intracellular calcium and an intrinsic target calcium level. By coupling a SAN cell to the calcium feedback model, we show that spontaneous electrical activity emerges from quiescence and is maintained at steady-state. In a 2D SAN tissue, spatial variability in intracellular calcium targets lead to significant, self-organized heterogeneous ion channel expression and calcium transients throughout the tissue. Further, multiple pacemaking regions appear, which interact and lead to time-varying cycle length, demonstrating that variability in heart rate is an emergent property of the feedback model. Finally, we demonstrate that the SAN tissue is robust to the silencing of leading cells or ion channel knockouts. Thus, the calcium feedback model can reproduce and explain many fundamental emergent properties of activity in the SAN that have been observed experimentally based on a minimal description of intracellular calcium and ion channel regulatory networks. Key Points SummaryO_LIThe robust function of the sinoatrial node (SAN) is reproduced in an intracellular calcium feedback model governing ion channel conductances C_LIO_LIThe feedback model predicts the emergence and long-term maintenance of spontaneous oscillatory electrical activity C_LIO_LIIntegrating the feedback model into a 2D SAN tissue leads to emergent spatial heterogeneity, multiple pacemaking regions, and variable cycle length C_LIO_LISAN cells and tissue with feedback are robust to cell injury and channel knock-outs C_LI

bioengineering↗

bioRxiv2021

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 are 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.

bioengineering↗