Rate-dependent propagation of cardiac action potentials in a one-dimensional fiber

Action potential duration (APD) restitution, which relates APD to the preceding diastolic interval (DI), is a useful tool for predicting the onset of abnormal cardiac rhythms. However, it is known that different pacing protocols lead to different APD restitution curves (RCs). This phenomenon, known as APD rate-dependence, is a consequence of memory in the tissue. In addition to APD restitution, conduction velocity restitution also plays an important role in the spatiotemporal dynamics of cardiac tissue. We present new results concerning rate-dependent restitution in the velocity of propagating action potentials in a one-dimensional fiber. Our numerical simulations show that, independent of the amount of memory in the tissue, waveback velocity exhibits pronounced rate-dependence and the wavefront velocity does not. Moreover, the discrepancy between waveback velocity RCs is most significant for small DI. We provide an analytical explanation of these results, using a system of coupled maps to relate the wavefront and waveback velocities. Our calculations show that waveback velocity rate-dependence is due to APD restitution, not memory.Comment: 17 pages, 7 figure

Polyunsaturated fatty acids inhibit k_v1.4 by interacting with positively charged extracellular pore residues

Polyunsaturated fatty acids (PUFAs) modulate voltage-gated K(+) channel inactivation by an unknown site and mechanism. The effects of ω-6 and ω-3 PUFAs were investigated on the heterologously expressed K(v)1.4 channel. PUFAs inhibited wild-type K(v)1.4 during repetitive pulsing as a result of slowing of recovery from inactivation. In a mutant K(v)1.4 channel lacking N-type inactivation, PUFAs reversibly enhanced C-type inactivation (K(d), 15–43 μM). C-type inactivation was affected by extracellular H(+) and K(+) as well as PUFAs and there was an interaction among the three: the effect of PUFAs was reversed during acidosis and abolished on raising K(+). Replacement of two positively charged residues in the extracellular pore (H508 and K532) abolished the effects of the PUFAs (and extracellular H(+) and K(+)) on C-type inactivation but had no effect on the lipoelectric modulation of voltage sensor activation, suggesting two separable interaction sites/mechanisms of action of PUFAs. Charge calculations suggest that the acidic head group of the PUFAs raises the pK(a) of H508 and this reduces the K(+) occupancy of the selectivity filter, stabilizing the C-type inactivated state

Comparison of formaldehyde and methanol fixatives used in the detection of ion channel proteins in isolated rat ventricular myocytes by immunofluorescence labelling and confocal microscopy

In this study, a fixation protocol using a 10% neutral buffered formalin (FA) solution and another protocol using a methanol (MeOH) solution were compared for detection of ion channels, Kv1.5, Kv4.2, Cav1.2, Kir6.2, Nav1.5 and Nav1.1 in rat myocytes by immunolabelling. Kv1.5 and Kv4.2 at intercalated discs and Cav1.2 at transverse tubules were not detected by FA but were detected by MeOH. Kir6.2 at transverse tubules and Nav1.5 at sarcolemma were detected by FA but not by MeOH. It is suggested that both FA and MeOH fixation protocols should be used for the detection of cardiac ion channels by immunolabellin

Arrhythmogenic gene remodelling in elderly patients with type 2 diabetes with aortic stenosis and normal left ventricular ejection fraction

New Findings What is the central question of this study? Type 2 diabetes is associated with a higher rate of ventricular arrhythmias compared with the non‐diabetic population, but the associated myocardial gene expression changes are unknown; furthermore, it is also unknown whether any changes are attributable to chronic hyperglycaemia or are a consequence of structural changes. What is the main finding and its importance? We found downregulation of left ventricular ERG gene expression and increased NCX1 gene expression in humans with type 2 diabetes compared with control patients with comparable left ventricular hypertrophy and possible myocardial fibrosis. This was associated with QT interval prolongation. Diabetes and associated chronic hyperglycaemia may therefore promote ventricular arrhythmogenesis independently of structural changes. Type 2 diabetes is associated with a higher rate of ventricular arrhythmias, and this is hypothesized to be independent of coronary artery disease or hypertension. To investigate further, we compared changes in left ventricular myocardial gene expression in type 2 diabetes patients with patients in a control group with left ventricular hypertrophy. Nine control patients and seven patients with type 2 diabetes with aortic stenosis undergoing aortic valve replacement had standard ECGs, signal‐averaged ECGs and echocardiograms before surgery. During surgery, a left ventricular biopsy was taken, and mRNA expressions for genes relevant to the cardiac action potential were estimated by RT‐PCR. Mathematical modelling of the action potential and calcium transient was undertaken using the O'Hara–Rudy model using scaled changes in gene expression. Echocardiography revealed similar values for left ventricular size, filling pressures and ejection fraction between groups. No difference was seen in positive signal‐averaged ECGs between groups, but the standard ECG demonstrated a prolonged QT interval in the diabetes group. Gene expression of KCNH2 and KCNJ3 were lower in the diabetes group, whereas KCNJ2 , KCNJ5 and SLC8A1 expression were higher. Modelling suggested that these changes would lead to prolongation of the action potential duration with generation of early after‐depolarizations secondary to a reduction in density of the rapid delayed rectifier K+ current and increased Na+–Ca2+ exchange current. These data suggest that diabetes leads to pro‐arrythmogenic changes in myocardial gene expression independently of left ventricular hypertrophy or fibrosis in an elderly population

Developing a novel comprehensive framework for the investigation of cellular and whole heart electrophysiology in the in situ human heart: Historical perspectives, current progress and future prospects

Understanding the mechanisms of fatal ventricular arrhythmias is of great importance. In view of the many electrophysiological differences that exist between animal species and humans, the acquisition of basic electrophysiological data in the intact human heart is essential to drive and complement experimental work in animal and in-silico models. Over the years techniques have been developed to obtain basic electrophysiological signals directly from the patients by incorporating these measurements into routine clinical procedures which access the heart such as cardiac catheterisation and cardiac surgery. Early recordings with monophasic action potentials provided valuable information including normal values for the in vivo human heart, cycle length dependent properties, the effect of ischaemia, autonomic nervous system activity, and mechano-electric interaction. Transmural recordings addressed the controversial issue of the mid myocardial “M” cell. More recently, the technique of multielectrode mapping (256 electrodes) developed in animal models has been extended to humans, enabling mapping of activation and repolarisation on the entire left and right ventricular epicardium in patients during cardiac surgery. Studies have examined the issue of whether ventricular fibrillation was driven by a “mother” rotor with inhomogeneous and fragmented conduction as in some animal models, or by multiple wavelets as in other animal studies; results showed that both mechanisms are operative in humans. The simpler spatial organisation of human VF has important implications for treatment and prevention. To link in-vivo human electrophysiological mapping with cellular biophysics, multielectrode mapping is now being combined with myocardial biopsies. This technique enables region-specific electrophysiology changes to be related to underlying cellular biology, for example: APD alternans, which is a precursor of VF and sudden death. The mechanism is incompletely understood but related to calcium cycling and APD restitution. Multielectrode sock mapping during incremental pacing enables epicardial sites to be identified which exhibit marked APD alternans and sites where APD alternans is absent. Whole heart electrophysiology is assessed by activation repolarisation mapping and analysis is performed immediately on-site in order to guide biopsies to specific myocardial sites. Samples are analysed for ion channel expression, Ca2+-handling proteins, gap junctions and extracellular matrix. This new comprehensive approach to bridge cellular and whole heart electrophysiology allowed to identify 20 significant changes in mRNA for ion channels Ca2+-handling proteins, a gap junction channel, a Na+–K+ pump subunit and receptors (particularly Kir 2.1) between the positive and negative alternans sites

Contrast Enhanced Micro-Computed Tomography Resolves the 3-Dimensional Morphology of the Cardiac Conduction System in Mammalian Hearts

The general anatomy of the cardiac conduction system (CCS) has been known for 100 years, but its complex and irregular three-dimensional (3D) geometry is not so well understood. This is largely because the conducting tissue is not distinct from the surrounding tissue by dissection. The best descriptions of its anatomy come from studies based on serial sectioning of samples taken from the appropriate areas of the heart. Low X-ray attenuation has formerly ruled out micro-computed tomography (micro-CT) as a modality to resolve internal structures of soft tissue, but incorporation of iodine, which has a high molecular weight, into those tissues enhances the differential attenuation of X-rays and allows visualisation of fine detail in embryos and skeletal muscle. Here, with the use of a iodine based contrast agent (I2KI), we present contrast enhanced micro-CT images of cardiac tissue from rat and rabbit in which the three major subdivisions of the CCS can be differentiated from the surrounding contractile myocardium and visualised in 3D. Structures identified include the sinoatrial node (SAN) and the atrioventricular conduction axis: the penetrating bundle, His bundle, the bundle branches and the Purkinje network. Although the current findings are consistent with existing anatomical representations, the representations shown here offer superior resolution and are the first 3D representations of the CCS within a single intact mammalian heart

Remodelling of human atrial K+ currents but not ion channel expression by chronic β-blockade

Chronic β-adrenoceptor antagonist (β-blocker) treatment in patients is associated with a potentially anti-arrhythmic prolongation of the atrial action potential duration (APD), which may involve remodelling of repolarising K+ currents. The aim of this study was to investigate the effects of chronic β-blockade on transient outward, sustained and inward rectifier K+ currents (ITO, IKSUS and IK1) in human atrial myocytes and on the expression of underlying ion channel subunits. Ion currents were recorded from human right atrial isolated myocytes using the whole-cell-patch clamp technique. Tissue mRNA and protein levels were measured using real time RT-PCR and Western blotting. Chronic β-blockade was associated with a 41% reduction in ITO density: 9.3 ± 0.8 (30 myocytes, 15 patients) vs 15.7 ± 1.1 pA/pF (32, 14), p < 0.05; without affecting its voltage-, time- or rate dependence. IK1 was reduced by 34% at −120 mV (p < 0.05). Neither IKSUS, nor its increase by acute β-stimulation with isoprenaline, was affected by chronic β-blockade. Mathematical modelling suggested that the combination of ITO- and IK1-decrease could result in a 28% increase in APD90. Chronic β-blockade did not alter mRNA or protein expression of the ITO pore-forming subunit, Kv4.3, or mRNA expression of the accessory subunits KChIP2, KChAP, Kvβ1, Kvβ2 or frequenin. There was no reduction in mRNA expression of Kir2.1 or TWIK to account for the reduction in IK1. A reduction in atrial ITO and IK1 associated with chronic β-blocker treatment in patients may contribute to the associated action potential prolongation, and this cannot be explained by a reduction in expression of associated ion channel subunits

Low-mass bursty galaxies in JADES efficiently produce ionising photons and could represent the main drivers of reionisation

© 2023 The Author(s). Published by Oxford University Press on behalf of Royal Astronomical Society. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/We study galaxies in JADES Deep to study the evolution of the ionising photon production efficiency, $\xi_{\rm{ion}}$, observed to increase with redshift. We estimate $\xi_{\rm{ion}}$ for a sample of 677 galaxies at $z \sim 4 - 9$ using NIRCam photometry. Specifically, combinations of the medium and wide bands F335M-F356W and F410M-F444W to constrain emission lines that trace $\xi_{\rm{ion}}$: H$\alpha$ and [OIII]. Additionally, we use the spectral energy distribution fitting code \texttt{Prospector} to fit all available photometry and infer galaxy properties. The flux measurements obtained via photometry are consistent with FRESCO and NIRSpec-derived fluxes. Moreover, the emission-line-inferred measurements are in tight agreement with the \texttt{Prospector} estimates. We also confirm the observed $\xi_{\rm{ion}}$ trend with redshift and M$_{\rm{UV}}$, and find: $\log \xi_{\rm{ion}} (z,\text{M}_{\rm{UV}}) = (0.05 \pm 0.02)z + (0.11 \pm 0.02) \text{M}_{\rm{UV}} + (27.33 \pm 0.37)$. We use \texttt{Prospector} to investigate correlations of $\xi_{\rm{ion}}$ with other galaxy properties. We see a clear correlation between $\xi_{\rm{ion}}$ and burstiness in the star formation history of galaxies, given by the ratio of recent to older star formation, where burstiness is more prevalent at lower stellar masses. We also convolve our $\xi_{\rm{ion}}$ relations with luminosity functions from the literature, and constant escape fractions of 10 and 20\%, to place constraints on the cosmic ionising photon budget. By combining our results, we find that if our sample is representative of the faint low-mass galaxy population, galaxies with bursty star formation are efficient enough in producing ionising photons and could be responsible for the reionisation of the Universe.Peer reviewe

Morpheus Reveals Distant Disk Galaxy Morphologies with JWST: The First AI/ML Analysis of JWST Images

The dramatic first images with JWST demonstrated its power to provide unprecedented spatial detail for galaxies in the high-redshift universe. Here, we leverage the resolution and depth of the JWST Cosmic Evolution Early Release Science Survey data in the Extended Groth Strip to perform pixel-level morphological classifications of galaxies in JWST F150W imaging using the Morpheus deep-learning framework for astronomical image analysis. By cross-referencing with existing photometric redshift catalogs from the Hubble Space Telescope (HST) CANDELS survey, we show that JWST images indicate the emergence of disk morphologies before z ∼ 2 and with candidates appearing as early as z ∼ 5. By modeling the light profile of each object and accounting for the JWST point-spread function, we find the high-redshift disk candidates have exponential surface brightness profiles with an average Sérsic index 〈n〉 = 1.04 and >90% displaying “disky” profiles (n < 2). Comparing with prior Morpheus classifications in CANDELS we find that a plurality of JWST disk galaxy candidates were previously classified as compact based on the shallower HST imagery, indicating that the improved optical quality and depth of the JWST helps to reveal disk morphologies that were hiding in the noise. We discuss the implications of these early disk candidates on theories for cosmological disk galaxy formation

Closing in on the sources of cosmic reionization: first results from the GLASS-JWST program

The escape fraction of Lyman-continuum (LyC) photons ($f_{esc}$) is a key parameter for determining the sources of cosmic reionization at $z\geq 6$. At these redshifts, owing to the opacity of the intergalactic medium, the LyC emission cannot be measured directly. However, LyC leakers during the epoch of reionization could be identified using indirect indicators that have been extensively tested at low and intermediate redshifts. These include a high [OIII]/[OII] flux ratio, high star-formation surface density, and compact sizes. In this work, we present observations of 29 $4.5 \leq z \leq 8$ gravitationally lensed galaxies in the Abell 2744 cluster field. From a combined analysis of JWST-NIRSpec and NIRCam data, we accurately derived their physical and spectroscopic properties: our galaxies have low masses $(\log(M_\star)\sim 8.5)$, blue UV spectral slopes ($\beta \sim -2.1$), compact sizes ($r_e \sim 0.3-0.5$ kpc), and high [OIII]/[OII] flux ratios. We confirm that these properties are similar to those characterizing low-redshift LyC leakers. Indirectly inferring the fraction of escaping ionizing photons, we find that more than 80% of our galaxies have predicted $f_{esc}$ values larger than 0.05, indicating that they would be considered leakers. The average predicted $f_{esc}$ value of our sample is 0.12, suggesting that similar galaxies at $z\geq 6$ have provided a substantial contribution to cosmic reionization.Comment: Accepted for publication in the 4. Extragalactic astronomy section of A&A, 12 pages, 8 figure