ORCID Profile
0000-0001-7421-5977
Current Organisation
Simula Research Laboratory AS
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Publisher: Wiley
Date: 12-02-2014
Publisher: Elsevier BV
Date: 11-2010
Publisher: Frontiers Media SA
Date: 24-04-2017
Publisher: Frontiers Media SA
Date: 04-09-2018
Publisher: American Association for the Advancement of Science (AAAS)
Date: 19-11-2021
Abstract: Found in translation: We present quantitative tools that map cardiac myocyte physiology and pharmacology across species.
Publisher: SAGE Publications
Date: 2017
Abstract: Excitation–contraction coupling in cardiac myocytes requires calcium influx through L-type calcium channels in the sarcolemma, which gates calcium release through sarcoplasmic reticulum ryanodine receptors in a process known as calcium-induced calcium release, producing a myoplasmic calcium transient and enabling cardiomyocyte contraction. The spatio-temporal dynamics of calcium release, buffering, and reuptake into the sarcoplasmic reticulum play a central role in excitation–contraction coupling in both normal and diseased cardiac myocytes. However, further quantitative understanding of these cells’ calcium machinery and the study of mechanisms that underlie both normal cardiac function and calcium-dependent etiologies in heart disease requires accurate knowledge of cardiac ultrastructure, protein distribution and subcellular function. As current imaging techniques are limited in spatial resolution, limiting insight into changes in calcium handling, computational models of excitation–contraction coupling have been increasingly employed to probe these structure–function relationships. This review will focus on the development of structural models of cardiac calcium dynamics at the subcellular level, orienting the reader broadly towards the development of models of subcellular calcium handling in cardiomyocytes. Specific focus will be given to progress in recent years in terms of multi-scale modeling employing resolved spatial models of subcellular calcium machinery. A review of the state-of-the-art will be followed by a review of emergent insights into calcium-dependent etiologies in heart disease and, finally, we will offer a perspective on future directions for related computational modeling and simulation efforts.
Publisher: Public Library of Science (PLoS)
Date: 31-05-2019
Publisher: Wiley
Date: 19-04-2021
DOI: 10.1002/CPT.2240
Abstract: Torsade de Pointes (TdP), a rare but lethal ventricular arrhythmia, is a toxic side effect of many drugs. To assess TdP risk, safety regulatory guidelines require quantification of hERG channel block in vitro and QT interval prolongation in vivo for all new therapeutic compounds. Unfortunately, these have proven to be poor predictors of torsadogenic risk, and are likely to have prevented safe compounds from reaching clinical phases. Although this has stimulated numerous efforts to define new paradigms for cardiac safety, none of the recently developed strategies accounts for patient conditions. In particular, despite being a well‐established independent risk factor for TdP, female sex is vastly under‐represented in both basic research and clinical studies, and thus current TdP metrics are likely biased toward the male sex. Here, we apply statistical learning to synthetic data, generated by simulating drug effects on cardiac myocyte models capturing male and female electrophysiology, to develop new sex‐specific classification frameworks for TdP risk. We show that (i) TdP classifiers require different features in females vs. males (ii) male‐based classifiers perform more poorly when applied to female data and (iii) female‐based classifier performance is largely unaffected by acute effects of hormones (i.e., during various phases of the menstrual cycle). Notably, when predicting TdP risk of intermediate drugs on female simulated data, male‐biased predictive models consistently underestimate TdP risk in women. Therefore, we conclude that pipelines for preclinical cardiotoxicity risk assessment should consider sex as a key variable to avoid potentially life‐threatening consequences for the female population.
Publisher: Wiley
Date: 28-11-2018
DOI: 10.1113/JP277360
Publisher: Springer Science and Business Media LLC
Date: 04-12-2018
DOI: 10.1038/S41598-018-35858-7
Abstract: While cardiomyocytes differentiated from human induced pluripotent stems cells (hiPSCs) hold great promise for drug screening, the electrophysiological properties of these cells can be variable and immature, producing results that are significantly different from their human adult counterparts. Here, we describe a computational framework to address this limitation, and show how in silico methods, applied to measurements on immature cardiomyocytes, can be used to both identify drug action and to predict its effect in mature cells. Our synthetic and experimental results indicate that optically obtained waveforms of voltage and calcium from microphysiological systems can be inverted into information on drug ion channel blockage, and then, through assuming functional invariance of proteins during maturation, this data can be used to predict drug induced changes in mature ventricular cells. Together, this pipeline of measurements and computational analysis could significantly improve the ability of hiPSC derived cardiomycocytes to predict dangerous drug side effects.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2019
DOI: 10.1161/CIRCEP.118.007045
Abstract: Circulating SN (secretoneurin) concentrations are increased in patients with myocardial dysfunction and predict poor outcome. Because SN inhibits CaMKIIδ (Ca 2+ /calmodulin-dependent protein kinase IIδ) activity, we hypothesized that upregulation of SN in patients protects against cardiomyocyte mechanisms of arrhythmia. Circulating levels of SN and other biomarkers were assessed in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT n=8) and in resuscitated patients after ventricular arrhythmia–induced cardiac arrest (n=155). In vivo effects of SN were investigated in CPVT mice (RyR2 [ryanodine receptor 2]-R2474S) using adeno-associated virus-9–induced overexpression. Interactions between SN and CaMKIIδ were mapped using pull-down experiments, mutagenesis, ELISA, and structural homology modeling. Ex vivo actions were tested in Langendorff hearts and effects on Ca 2+ homeostasis examined by fluorescence (fluo-4) and patch-cl recordings in isolated cardiomyocytes. SN levels were elevated in patients with CPVT and following ventricular arrhythmia–induced cardiac arrest. In contrast to NT-proBNP (N-terminal pro-B-type natriuretic peptide) and hs-TnT (high-sensitivity troponin T), circulating SN levels declined after resuscitation, as the risk of a new arrhythmia waned. Myocardial pro-SN expression was also increased in CPVT mice, and further adeno-associated virus-9–induced overexpression of SN attenuated arrhythmic induction during stress testing with isoproterenol. Mechanistic studies mapped SN binding to the substrate binding site in the catalytic region of CaMKIIδ. Accordingly, SN attenuated isoproterenol induced autophosphorylation of Thr287-CaMKIIδ in Langendorff hearts and inhibited CaMKIIδ-dependent RyR phosphorylation. In line with CaMKIIδ and RyR inhibition, SN treatment decreased Ca 2+ spark frequency and dimensions in cardiomyocytes during isoproterenol challenge, and reduced the incidence of Ca 2+ waves, delayed afterdepolarizations, and spontaneous action potentials. SN treatment also lowered the incidence of early afterdepolarizations during isoproterenol an effect paralleled by reduced magnitude of L-type Ca 2+ current. SN production is upregulated in conditions with cardiomyocyte Ca 2+ dysregulation and offers compensatory protection against cardiomyocyte mechanisms of arrhythmia, which may underlie its putative use as a biomarker in at-risk patients.
Publisher: eLife Sciences Publications, Ltd
Date: 08-2022
DOI: 10.7554/ELIFE.77725
Abstract: Ryanodine receptors (RyRs) exhibit dynamic arrangements in cardiomyocytes, and we previously showed that ‘dispersion’ of RyR clusters disrupts Ca 2+ homeostasis during heart failure (HF) (Kolstad et al., eLife, 2018). Here, we investigated whether prolonged β-adrenergic stimulation, a hallmark of HF, promotes RyR cluster dispersion and examined the underlying mechanisms. We observed that treatment of healthy rat cardiomyocytes with isoproterenol for 1 hr triggered progressive fragmentation of RyR clusters. Pharmacological inhibition of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) reversed these effects, while cluster dispersion was reproduced by specific activation of CaMKII, and in mice with constitutively active Ser2814-RyR. A similar role of protein kinase A (PKA) in promoting RyR cluster fragmentation was established by employing PKA activation or inhibition. Progressive cluster dispersion was linked to declining Ca 2+ spark fidelity and magnitude, and slowed release kinetics from Ca 2+ propagation between more numerous RyR clusters. In healthy cells, this served to d en the stimulatory actions of β-adrenergic stimulation over the longer term and protect against pro-arrhythmic Ca 2+ waves. However, during HF, RyR dispersion was linked to impaired Ca 2+ release. Thus, RyR localization and function are intimately linked via channel phosphorylation by both CaMKII and PKA, which, while finely tuned in healthy cardiomyocytes, underlies impaired cardiac function during pathology.
Publisher: Elsevier BV
Date: 07-2016
Publisher: Wiley
Date: 30-11-2009
Publisher: Elsevier BV
Date: 11-2017
Publisher: Elsevier BV
Date: 04-2023
Publisher: Elsevier BV
Date: 07-2016
Publisher: Frontiers Media SA
Date: 27-10-2021
DOI: 10.3389/FPHYS.2021.763584
Abstract: Computational modeling has contributed significantly to present understanding of cardiac electrophysiology including cardiac conduction, excitation-contraction coupling, and the effects and side-effects of drugs. However, the accuracy of in silico analysis of electrochemical wave dynamics in cardiac tissue is limited by the homogenization procedure (spatial averaging) intrinsic to standard continuum models of conduction. Averaged models cannot resolve the intricate dynamics in the vicinity of in idual cardiomyocytes simply because the myocytes are not present in these models. Here we demonstrate how recently developed mathematical models based on representing every myocyte can significantly increase the accuracy, and thus the utility of modeling electrophysiological function and dysfunction in collections of coupled cardiomyocytes. The present gold standard of numerical simulation for cardiac electrophysiology is based on the bidomain model. In the bidomain model, the extracellular (E) space, the cell membrane (M) and the intracellular (I) space are all assumed to be present everywhere in the tissue. Consequently, it is impossible to study biophysical processes taking place close to in idual myocytes. The bidomain model represents the tissue by averaging over several hundred myocytes and this inherently limits the accuracy of the model. In our alternative approach both E, M, and I are represented in the model which is therefore referred to as the EMI model. The EMI model approach allows for detailed analysis of the biophysical processes going on in functionally important spaces very close to in idual myocytes, although at the cost of significantly increased CPU-requirements.
Publisher: Informa UK Limited
Date: 24-06-2013
Publisher: Wiley
Date: 09-2012
Publisher: Wiley
Date: 10-11-2019
DOI: 10.1002/CPT.1647
Publisher: Frontiers Media SA
Date: 06-08-2019
Publisher: Frontiers Media SA
Date: 16-05-2014
Publisher: eLife Sciences Publications, Ltd
Date: 30-10-2018
DOI: 10.7554/ELIFE.39427
Abstract: Reduced cardiac contractility during heart failure (HF) is linked to impaired Ca 2+ release from Ryanodine Receptors (RyRs). We investigated whether this deficit can be traced to nanoscale RyR reorganization. Using super-resolution imaging, we observed dispersion of RyR clusters in cardiomyocytes from post-infarction HF rats, resulting in more numerous, smaller clusters. Functional groupings of RyR clusters which produce Ca 2+ sparks (Ca 2+ release units, CRUs) also became less solid. An increased fraction of small CRUs in HF was linked to augmented ‘silent’ Ca 2+ leak, not visible as sparks. Larger multi-cluster CRUs common in HF also exhibited low fidelity spark generation. When successfully triggered, sparks in failing cells displayed slow kinetics as Ca 2+ spread across dispersed CRUs. During the action potential, these slow sparks protracted and desynchronized the overall Ca 2+ transient. Thus, nanoscale RyR reorganization during HF augments Ca 2+ leak and slows Ca 2+ release kinetics, leading to weakened contraction in this disease.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2014
DOI: 10.1161/CIRCEP.113.001666
Abstract: Early afterdepolarizations (EADs) are triggers of cardiac arrhythmia driven by L-type Ca 2+ current (I CaL ) reactivation or sarcoplasmic reticulum Ca 2+ release and Na + /Ca 2+ exchange. In large mammals the positive action potential plateau promotes I CaL reactivation, and the current paradigm holds that cardiac EAD dynamics are dominated by interaction between I CaL and the repolarizing K + currents. However, EADs are also frequent in the rapidly repolarizing mouse action potential, which should not readily permit I CaL reactivation. This suggests that murine EADs exhibit unique dynamics, which are key for interpreting arrhythmia mechanisms in this ubiquitous model organism. We investigated these dynamics in myocytes from arrhythmia-susceptible calcium calmodulin-dependent protein kinase II delta C (CaMKIIδC)-overexpressing mice (Tg), and via computational simulations. In Tg myocytes, β-adrenergic challenge slowed late repolarization, potentiated sarcoplasmic reticulum Ca 2+ release, and initiated EADs below the I CaL activation range (–47±0.7 mV). These EADs were abolished by caffeine and tetrodotoxin (but not ranolazine), suggesting that sarcoplasmic reticulum Ca 2+ release and Na + current (I Na ), but not late I Na , are required for EAD initiation. Simulations suggest that potentiated sarcoplasmic reticulum Ca 2+ release and Na + /Ca 2+ exchange shape late action potential repolarization to favor nonequilibrium reactivation of I Na and thereby drive the EAD upstroke. Action potential cl experiments suggest that lidocaine eliminates virtually all inward current elicited by EADs, and that this effect occurs at concentrations (40–60 μmol/L) for which lidocaine remains specific for inactivated Na + channels. This strongly suggests that previously inactive channels are recruited during the EAD upstroke, and that nonequilibrium I Na dynamics underlie murine EADs. Nonequilibrium reactivation of I Na drives murine EADs.
Publisher: Wiley
Date: 05-2021
DOI: 10.1111/CTS.13038
Abstract: Only a handful of US Food and Drug Administration (FDA) Emergency Use Authorizations exist for drug and biologic therapeutics that treat severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) infection. Potential therapeutics include repurposed drugs, some with cardiac liabilities. We report on a chronic preclinical drug screening platform, a cardiac microphysiological system (MPS), to assess cardiotoxicity associated with repurposed hydroxychloroquine (HCQ) and azithromycin (AZM) polytherapy in a mock phase I safety clinical trial. The MPS contained human heart muscle derived from induced pluripotent stem cells. The effect of drug response was measured using outputs that correlate with clinical measurements, such as QT interval (action potential duration) and drug‐biomarker pairing. Chronic exposure (10 days) of heart muscle to HCQ alone elicited early afterdepolarizations and increased QT interval past 5 days. AZM alone elicited an increase in QT interval from day 7 onward, and arrhythmias were observed at days 8 and 10. Monotherapy results mimicked clinical trial outcomes. Upon chronic exposure to HCQ and AZM polytherapy, we observed an increase in QT interval on days 4–8. Interestingly, a decrease in arrhythmias and instabilities was observed in polytherapy relative to monotherapy, in concordance with published clinical trials. Biomarkers, most of them measurable in patients’ serum, were identified for negative effects of monotherapy or polytherapy on tissue contractile function, morphology, and antioxidant protection. The cardiac MPS correctly predicted clinical arrhythmias associated with QT prolongation and rhythm instabilities. This high content system can help clinicians design their trials, rapidly project cardiac outcomes, and define new monitoring biomarkers to accelerate access of patients to safe coronavirus disease 2019 (COVID‐19) therapeutics.
Publisher: American Chemical Society (ACS)
Date: 29-07-2022
Publisher: Public Library of Science (PLoS)
Date: 06-11-2018
Publisher: Springer Science and Business Media LLC
Date: 17-11-2017
DOI: 10.1038/S41398-017-0007-4
Abstract: Schizophrenia patients have an increased risk of cardiac dysfunction. A possible factor underlying this comorbidity are the common variants in the large set of genes that have recently been discovered in genome-wide association studies (GWASs) as risk genes of schizophrenia. Many of these genes control the cell electrogenesis and calcium homeostasis. We applied biophysically detailed models of layer V pyramidal cells and sinoatrial node cells to study the contribution of schizophrenia-associated genes on cellular excitability. By including data from functional genomics literature to simulate the effects of common variants of these genes, we showed that variants of voltage-gated Na + channel or hyperpolarization-activated cation channel-encoding genes cause qualitatively similar effects on layer V pyramidal cell and sinoatrial node cell excitability. By contrast, variants of Ca 2+ channel or transporter-encoding genes mostly have opposite effects on cellular excitability in the two cell types. We also show that the variants may crucially affect the propagation of the cardiac action potential in the sinus node. These results may help explain some of the cardiac comorbidity in schizophrenia, and may facilitate generation of effective antipsychotic medications without cardiac side-effects such as arrhythmia.
Publisher: SAGE Publications
Date: 2017
Abstract: Although ventricular arrhythmia remains a leading cause of morbidity and mortality, available antiarrhythmic drugs have limited efficacy. Disappointing progress in the development of novel, clinically relevant antiarrhythmic agents may partly be attributed to discrepancies between humans and animal models used in preclinical testing. However, such differences are at present difficult to predict, requiring improved understanding of arrhythmia mechanisms across species. To this end, we presently review interspecies similarities and differences in fundamental cardiomyocyte electrophysiology and current understanding of the mechanisms underlying the generation of afterdepolarizations and reentry. We specifically highlight patent shortcomings in small rodents to reproduce cellular and tissue-level arrhythmia substrate believed to be critical in human ventricle. Despite greater ease of translation from larger animal models, discrepancies remain and interpretation can be complicated by incomplete knowledge of human ventricular physiology due to low availability of explanted tissue. We therefore point to the benefits of mathematical modeling as a translational bridge to understanding and treating human arrhythmia.
Publisher: Wiley
Date: 29-09-2022
DOI: 10.1113/JP283602
Abstract: Disruption of the transverse‐axial tubule system (TATS) in diseases such as heart failure and atrial fibrillation occurs in combination with changes in the expression and distribution of key Ca 2+ ‐handling proteins. Together this ultrastructural and ionic remodelling is associated with aberrant Ca 2+ cycling and electrophysiological instabilities that underlie arrhythmic activity. However, due to the concurrent changes in TATs and Ca 2+ ‐handling protein expression and localization that occur in disease it is difficult to distinguish their in idual contributions to the arrhythmogenic state. To investigate this, we applied our novel 3D human atrial myocyte model with spatially detailed Ca 2+ diffusion and TATS to investigate the isolated and interactive effects of changes in expression and localization of key Ca 2+ ‐handling proteins and variable TATS density on Ca 2+ ‐handling abnormality driven membrane instabilities. We show that modulating the expression and distribution of the sodium–calcium exchanger, ryanodine receptors and the sarcoplasmic reticulum (SR) Ca 2+ buffer calsequestrin have varying pro‐ and anti‐arrhythmic effects depending on the balance of opposing influences on SR Ca 2+ leak–load and Ca 2+ –voltage relationships. Interestingly, the impact of protein remodelling on Ca 2+ ‐driven proarrhythmic behaviour varied dramatically depending on TATS density, with intermediately tubulated cells being more severely affected compared to detubulated and densely tubulated myocytes. This work provides novel mechanistic insight into the distinct and interactive consequences of TATS and Ca 2+ ‐handling protein remodelling that underlies dysfunctional Ca 2+ cycling and electrophysiological instability in disease. image In our companion paper we developed a 3D human atrial myocyte model, coupling electrophysiology and Ca 2+ handling with subcellular spatial details governed by the transverse‐axial tubule system (TATS). Here we utilize this model to mechanistically examine the impact of TATS loss and changes in the expression and distribution of key Ca 2+ ‐handling proteins known to be remodelled in disease on Ca 2+ homeostasis and electrophysiological stability. We demonstrate that varying the expression and localization of these proteins has variable pro‐ and anti‐arrhythmic effects with outcomes displaying dependence on TATS density. Whereas detubulated myocytes typically appear unaffected and densely tubulated cells seem protected, the arrhythmogenic effects of Ca 2+ handling protein remodelling are profound in intermediately tubulated cells. Our work shows the interaction between TATS and Ca 2+ ‐handling protein remodelling that underlies the Ca 2+ ‐driven proarrhythmic behaviour observed in atrial fibrillation and may help to predict the effects of antiarrhythmic strategies at varying stages of ultrastructural remodelling.
Publisher: Wiley
Date: 13-03-2015
Publisher: Public Library of Science (PLoS)
Date: 12-08-2021
DOI: 10.1371/JOURNAL.PCBI.1009233
Abstract: Mutations are known to cause perturbations in essential functional features of integral membrane proteins, including ion channels. Even restricted or point mutations can result in substantially changed properties of ion currents. The additive effect of these alterations for a specific ion channel can result in significantly changed properties of the action potential (AP). Both AP shortening and AP prolongation can result from known mutations, and the consequences can be life-threatening. Here, we present a computational method for identifying new drugs utilizing combinations of existing drugs. Based on the knowledge of theoretical effects of existing drugs on in idual ion currents, our aim is to compute optimal combinations that can ‘repair’ the mutant AP waveforms so that the baseline AP-properties are restored. More specifically, we compute optimal, combined, drug concentrations such that the waveforms of the transmembrane potential and the cytosolic calcium concentration of the mutant cardiomyocytes (CMs) becomes as similar as possible to their wild type counterparts after the drug has been applied. In order to demonstrate the utility of this method, we address the question of computing an optimal drug for the short QT syndrome type 1 (SQT1). For the SQT1 mutation N588K, there are available data sets that describe the effect of various drugs on the mutated K + channel. These published findings are the basis for our computational analysis which can identify optimal compounds in the sense that the AP of the mutant CMs resembles essential biomarkers of the wild type CMs. Using recently developed insights regarding electrophysiological properties among myocytes from different species, we compute optimal drug combinations for hiPSC-CMs, rabbit ventricular CMs and adult human ventricular CMs with the SQT1 mutation. Since the ‘composition’ of ion channels that form the AP is different for the three types of myocytes under consideration, so is the composition of the optimal drug.
Publisher: Wiley
Date: 27-10-2022
DOI: 10.1113/JP283363
Abstract: Intracellular calcium (Ca 2+ ) cycling is tightly regulated in the healthy heart ensuring effective contraction. This is achieved by transverse (t)‐tubule membrane invaginations that facilitate close coupling of key Ca 2+ ‐handling proteins such as the L‐type Ca 2+ channel and Na + ‐Ca 2+ exchanger (NCX) on the cell surface with ryanodine receptors (RyRs) on the intracellular Ca 2+ store. Although less abundant and regular than in the ventricle, t‐tubules also exist in atrial myocytes as a network of transverse invaginations with axial extensions known as the transverse‐axial tubule system (TATS). In heart failure and atrial fibrillation, there is TATS remodelling that is associated with aberrant Ca 2+ ‐handling and Ca 2+ ‐induced arrhythmic activity however, the mechanism underlying this is not fully understood. To address this, we developed a novel 3D human atrial myocyte model that couples electrophysiology and Ca 2+ ‐handling with variable TATS organization and density. We extensively parameterized and validated our model against experimental data to build a robust tool examining TATS regulation of subcellular Ca 2+ release. We found that varying TATS density and thus the localization of key Ca 2+ ‐handling proteins has profound effects on Ca 2+ handling. Following TATS loss, there is reduced NCX that results in increased cleft Ca 2+ concentration through decreased Ca 2+ extrusion. This elevated Ca 2+ increases RyR open probability causing spontaneous Ca 2+ releases and the promotion of arrhythmogenic waves (especially in the cell interior) leading to voltage instabilities through delayed afterdepolarizations. In summary, the present study demonstrates a mechanistic link between TATS remodelling and Ca 2+ ‐driven proarrhythmic behaviour that probably reflects the arrhythmogenic state observed in disease. image Transverse‐axial tubule systems (TATS) modulate Ca 2+ handling and excitation–contraction coupling in atrial myocytes, with TATS remodelling in heart failure and atrial fibrillation being associated with altered Ca 2+ cycling and subsequent arrhythmogenesis. To investigate the poorly understood mechanisms linking TATS variation and spontaneous Ca 2+ release, we built, parameterized and validated a 3D human atrial myocyte model coupling electrophysiology and spatially‐detailed subcellular Ca 2+ handling governed by the TATS. Simulated TATS loss causes diastolic Ca 2+ and voltage instabilities through reduced Na + ‐Ca 2+ exchanger‐mediated Ca 2+ removal, cleft Ca 2+ accumulation and increased ryanodine receptor open probability, resulting in spontaneous Ca 2+ release and promotion of arrhythmogenic waves and delayed afterdepolarizations. At fast electrical rates typical of atrial tachycardia/fibrillation, spontaneous Ca 2+ releases are larger and more frequent in the cell interior than at the periphery. Our work provides mechanistic insight into how atrial TATS remodelling can lead to Ca 2+ ‐driven instabilities that may ultimately contribute to the arrhythmogenic state in disease.
Publisher: Springer Science and Business Media LLC
Date: 27-04-2022
DOI: 10.1038/S41551-022-00884-4
Abstract: The immature physiology of cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) limits their utility for drug screening and disease modelling. Here we show that suitable combinations of mechanical stimuli and metabolic cues can enhance the maturation of hiPSC-derived cardiomyocytes, and that the maturation-inducing cues have phenotype-dependent effects on the cells' action-potential morphology and calcium handling. By using microfluidic chips that enhanced the alignment and extracellular-matrix production of cardiac microtissues derived from genetically distinct sources of hiPSC-derived cardiomyocytes, we identified fatty-acid-enriched maturation media that improved the cells' mitochondrial structure and calcium handling, and observed ergent cell-source-dependent effects on action-potential duration (APD). Specifically, in the presence of maturation media, tissues with abnormally prolonged APDs exhibited shorter APDs, and tissues with aberrantly short APDs displayed prolonged APDs. Regardless of cell source, tissue maturation reduced variabilities in spontaneous beat rate and in APD, and led to converging cell phenotypes (with APDs within the 300-450 ms range characteristic of human left ventricular cardiomyocytes) that improved the modelling of the effects of pro-arrhythmic drugs on cardiac tissue.
Publisher: Frontiers Media SA
Date: 08-03-2022
DOI: 10.3389/FPHYS.2022.834211
Abstract: Complementary developments in microscopy and mathematical modeling have been critical to our understanding of cardiac excitation–contraction coupling. Historically, limitations imposed by the spatial or temporal resolution of imaging methods have been addressed through careful mathematical interrogation. Similarly, limitations imposed by computational power have been addressed by imaging macroscopic function in large subcellular domains or in whole myocytes. As both imaging resolution and computational tractability have improved, the two approaches have nearly merged in terms of the scales that they can each be used to interrogate. With this review we will provide an overview of these advances and their contribution to understanding ventricular myocyte function, including exciting developments over the last decade. We specifically focus on experimental methods that have pushed back limits of either spatial or temporal resolution of nanoscale imaging (e.g., DNA-PAINT), or have permitted high resolution imaging on large cellular volumes (e.g., serial scanning electron microscopy). We also review the progression of computational approaches used to integrate and interrogate these new experimental data sources, and comment on near-term advances that may unify understanding of the underlying biology. Finally, we comment on several outstanding questions in cardiac physiology that stand to benefit from a concerted and complementary application of these new experimental and computational methods.
Publisher: Wiley
Date: 09-08-2020
DOI: 10.1111/BPH.15198
Abstract: Pharmacotherapy of atrial fibrillation (AF), the most common cardiac arrhythmia, remains unsatisfactory due to low efficacy and safety concerns. New therapeutic strategies target atrial‐predominant ion‐channels and involve multichannel block (poly)therapy. As AF is characterized by rapid and irregular atrial activations, compounds displaying potent antiarrhythmic effects at fast and minimal effects at slow rates are desirable. We present a novel systems pharmacology framework to quantitatively evaluate synergistic anti‐AF effects of combined block of multiple atrial‐predominant K + currents (ultra‐rapid delayed rectifier K + current, I Kur , small conductance Ca 2+ ‐activated K + current, I KCa , K 2P 3.1 2‐pore‐domain K + current, I K2P ) in AF. We constructed experimentally calibrated populations of virtual atrial myocyte models in normal sinus rhythm and AF‐remodelled conditions using two distinct, well‐established atrial models. Sensitivity analyses on our atrial populations was used to investigate the rate dependence of action potential duration (APD) changes due to blocking I Kur , I K2P or I KCa and interactions caused by blocking of these currents in modulating APD. Block was simulated in both single myocytes and one‐dimensional tissue strands to confirm insights from the sensitivity analyses and examine anti‐arrhythmic effects of multi‐atrial‐predominant K + current block in single cells and coupled tissue. In both virtual atrial myocytes and tissues, multiple atrial‐predominant K + ‐current block promoted favourable positive rate‐dependent APD prolongation and displayed positive rate‐dependent synergy, that is, increasing synergistic antiarrhythmic effects at fast pacing versus slow rates. Simultaneous block of multiple atrial‐predominant K + currents may be a valuable antiarrhythmic pharmacotherapeutic strategy for AF.
Publisher: Elsevier BV
Date: 11-2014
Publisher: Frontiers Media SA
Date: 12-10-2021
DOI: 10.3389/FPHYS.2021.744730
Abstract: Dysfunctional sarcoplasmic reticulum Ca 2+ handling is commonly observed in heart failure, and thought to contribute to arrhythmogenesis through several mechanisms. Some time ago we developed a cardiomyocyte-specific inducible SERCA2 knockout mouse, which is remarkable in the degree to which major adaptations to sarcolemmal Ca 2+ entry and efflux overcome the deficit in SR reuptake to permit relatively normal contractile function. Conventionally, those adaptations would also be expected to dramatically increase arrhythmia susceptibility. However, that susceptibility has never been tested, and it is possible that the very rapid repolarization of the murine action potential (AP) allows for large changes in sarcolemmal Ca 2+ transport without substantially disrupting electrophysiologic stability. We investigated this hypothesis through telemetric ECG recording in the SERCA2-KO mouse, and patch-cl electrophysiology, Ca 2+ imaging, and mathematical modeling of isolated SERCA2-KO myocytes. While the SERCA2-KO animals exhibit major (and unique) electrophysiologic adaptations at both the organ and cell levels, they remain resistant to arrhythmia. A marked increase in peak L-type calcium ( I CaL ) current and slowed I CaL decay elicited pronounced prolongation of initial repolarization, but faster late repolarization normalizes overall AP duration. Early afterdepolarizations were seldom observed in KO animals, and those that were observed exhibited a mechanism intermediate between murine and large mammal dynamical properties. As expected, spontaneous SR Ca 2+ sparks and waves were virtually absent. Together these findings suggest that intact SR Ca 2+ handling is an absolute requirement for triggered arrhythmia in the mouse, and that in its absence, dramatic changes to the major inward currents can be resisted by the substantial K + current reserve, even at end-stage disease.
Publisher: Oxford University Press (OUP)
Date: 22-11-2019
Location: United States of America
Start Date: 2020
End Date: 2021
Funder: NIH Clinical Center
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