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Semiconductor nanowires are known for their unusual geometry, providing unique electronic and optical properties. Substrates with vertical nanowires have highly non-uniform surfaces, which are attractive in terms of the study of live cells that can interact and be labeled with the wires. Despite several previous works studying cells cultivated over nanowires, questions regarding cell rupture and interaction with the wires remain open. Here, we demonstrate that nanowires can not only penetrate the cell membrane, but even be broken by a cell and trapped inside it. Even after mechanical poration of the membrane manifested by the efficient transfection and delivery of a fluorescent protein encoding plasmid, the cells are found to be viable for 7 days of incubation. The endocytosed wires are then aligned along the nucleus periphery and ousted to pseudopodia with the formation of nanowire-rich fibrils as a result of complex intracellular processes. We demonstrate that endocytosis of the wires may lead to their chemical modification manifested by the red shift of the luminescence spectra. Analysis of the wires' breakdown reveals that the cells can generate forces as high as several hundreds of nN. Using this work, we demonstrate several phenomena with the potential to be used in intriguing methods for intracellular visualization and the development of biointerfaces.

The sinoatrial node (SAN), the primary pacemaker of the heart, is responsible for the initiation and robust regulation of sinus rhythm. 3D mapping studies of the ex-vivo human heart suggested that the robust regulation of sinus rhythm relies on specialized fibrotically-insulated pacemaker compartments (head, center and tail) with heterogeneous expressions of key ion channels and receptors. They also revealed up to five sinoatrial conduction pathways (SACPs), which electrically connect the SAN with neighboring right atrium (RA). To elucidate the role of these structural-molecular factors in the functional robustness of human SAN, we developed comprehensive biophysical computer models of the SAN based on 3D structural, functional and molecular mapping of ex-vivo human hearts. Our key finding is that the electrical insulation of the SAN except SACPs, the heterogeneous expression of If, INa currents and adenosine A1 receptors (A1R) across SAN pacemaker-conduction compartments are required to experimentally reproduce observed SAN activation patterns and important phenomena such as shifts of the leading pacemaker and preferential SACP. In particular, we found that the insulating border between the SAN and RA, is required for robust SAN function and protection from SAN arrest during adenosine challenge. The heterogeneity in the expression of A1R within the human SAN compartments underlies the direction of pacemaker shift and preferential SACPs in the presence of adenosine. Alterations of INa current and fibrotic remodelling in SACPs can significantly modulate SAN conduction and shift the preferential SACP/exit from SAN. Finally, we show that disease-induced fibrotic remodeling, INa suppression or increased adenosine make the human SAN vulnerable to pacing-induced exit blocks and reentrant arrhythmia. In summary, our computer model recapitulates the structural and functional features of the human SAN and can be a valuable tool for investigating mechanisms of SAN automaticity and conduction as well as SAN arrhythmia mechanisms under different pathophysiological conditions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Zhao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Persistent atrial fibrillation (AF) is not effectively treated due to a lack of adequate tools for identifying patient-specific AF substrates. Recent studies revealed that in 30-50% of patients, persistent AF is maintained by localized drivers not only in the left atrium (LA) but also in the right atrium (RA). The chamber-specific atrial wall thickness (AWT) features underlying AF remain elusive, though the important role of AWT in AF is widely acknowledged. We aimed to provide direct evidence of the existence of distinguished RA and LA AWT features underlying AF drivers by analysing functionally and structurally mapped human hearts ex vivo . Coronary-perfused intact human atria ( n = 7, 47 ± 14 y.o.; two female) were mapped using panoramic near-infrared optical mapping during pacing-induced AF. Then the hearts were imaged at approximately 170 µm 3 resolution by 9.4 T gadolinium-enhanced MRI. The heart was segmented, and 3D AWT throughout atrial chambers was estimated and analysed. Optical mapping identified six localized RA re-entrant drivers in four hearts and four LA drivers in three hearts. All RA AF drivers were anchored to the pectinate muscle junctions with the crista terminalis or atrial walls. The four LA AF drivers were in the posterior LA. RA ( n = 4) with AF drivers were thicker with greater AWT variation than RA ( n = 3) without drivers (5.4 ± 2.6 mm versus 5.0 ± 2.4 mm, T -test p < 0.05; F -test p < 0.05). Furthermore, AWT in RA driver regions was thicker and varied more than in RA non-driver regions (5.1 ± 2.5 mm versus 4.4 ± 2.2 mm, T -test p < 0.05; F -test p < 0.05). On the other hand, LA ( n = 3) with drivers was thinner than the LA ( n = 4) without drivers. In particular, LA driver regions were thinner than the rest of LA regions (3.4 ± 1.0 mm versus 4.2 ± 1.0 mm, T -test p < 0.05). This study demonstrates chamber-specific AWT features of AF drivers. In RA, driver regions are thicker and have more variable AWT than non-driver regions. By contrast, LA drivers are thinner than non-drivers. Robust evaluation of patient-specific AWT features should be considered for chamber-specific targeted ablation., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors.)

Emerging technologies for integrated optical circuits demand novel approaches and materials. This includes a search for nanoscale waveguides that should satisfy criteria of high optical density, small cross-section, technological feasibility and structural perfection. All these criteria are met with self-assembled gallium phosphide (GaP) epitaxial nanowires. In this work, the effects of the nanowire geometry on their waveguiding properties are studied both experimentally and numerically. Cut-off wavelength dependence on the nanowire diameter is analyzed to demonstrate the pathways for fabrication of low-loss and subwavelength cross-section waveguides for visible and near-infrared (IR) ranges. Probing the waveguides with a supercontinuum laser unveils the filtering properties of the nanowires due to their resonant action. The nanowires exhibit perfect elasticity allowing fabrication of curved waveguides. It is demonstrated that for the nanowire diameters exceeding the cut-off value, the bending does not sufficiently reduce the field confinement promoting applicability of the approach for the development of nanoscale waveguides with a preassigned geometry. Optical X-coupler made of two GaP nanowires allowing for spectral separation of the signal is fabricated. The results of this work open new ways for the utilization of GaP nanowires as elements of advanced photonic logic circuits and nanoscale interferometers., (© 2023 Wiley-VCH GmbH.)

Gallium nitride (GaN) is one of the most promising materials for high-frequency devices owing to its prominent material properties. We report on the fabrication and study of a series of Schottky diodes in the ground-signal-ground topology based on individual GaN nanowires. The electrical characterization of I - V curves demonstrated relatively high ideality factor value (about 6-9) in comparison to the planar Au/GaN diodes that can be attributed to the nanowire geometry. The effective barrier height in the studied structures was defined in the range of 0.25-0.4 eV. The small-signal frequency analysis was employed to study the dependency of the scattering parameters in the broad range from 0.1 to 40 GHz. The approximation fitting of the experimental data indicated the record high cutoff frequency of about 165.8 GHz., (© 2023 IOP Publishing Ltd.)

Semiconductor nanowires are the perfect platform for nanophotonic applications owing to their resonant, waveguiding optical properties and technological capabilities providing control over their crystalline and chemical compositions. The vapor-liquid-solid growth mechanism allows the formation of hybrid metal-dielectric nanostructures promoting sub-wavelength light manipulation. In this work, we explore both experimentally and numerically the plasmonic effects promoted by a gallium (Ga) nanoparticle optical antenna decorating the facet of gallium phosphide (GaP) nanowires. Raman, photoluminescence and near-field mapping techniques are used to study the effects. We demonstrate several phenomena including field enhancement, antenna effect and increase in internal reflection. We show that the observed effects have to be considered when nanowires with a plasmonic particle are used in nanophotonic circuits and discuss the ways for utilization of these effects for efficient coupling of light into nanowire waveguide and field tailoring. The results open up promising pathways for the development of both passive and active nanophotonic elements, light harvesting and sensorics.

The sinoatrial node (SAN) is the primary pacemaker of the human heart. It is a single, elongated, 3-dimensional (3D) intramural fibrotic structure located at the junction of the superior vena cava intercaval region bordering the crista terminalis (CT). SAN activation originates in the intranodal pacemakers and is conducted to the atria through 1 or more discrete sinoatrial conduction pathways. The complexity of the 3D SAN pacemaker structure and intramural conduction are underappreciated during clinical multielectrode mapping and ablation procedures of SAN and atrial arrhythmias. In fact, defining and targeting SAN is extremely challenging because, even during sinus rhythm, surface-only multielectrode mapping may not define the leading pacemaker sites in intramural SAN but instead misinterpret them as epicardial or endocardial exit sites through sinoatrial conduction pathways. These SAN exit sites may be distributed up to 50 mm along the CT beyond the ∼20-mm-long anatomic SAN structure. Moreover, because SAN reentrant tachycardia beats may exit through the same sinoatrial conduction pathway as during sinus rhythm, many SAN arrhythmias are underdiagnosed. Misinterpretation of arrhythmia sources and/or mechanisms (eg, enhanced automaticity, intranodal vs CT reentry) limits diagnosis and success of catheter ablation treatments for poorly understood SAN arrhythmias. The aim of this review is to provide a state-of-the-art overview of the 3D structure and function of the human SAN complex, mechanisms of SAN arrhythmias and available approaches for electrophysiological mapping, 3D structural imaging, pharmacologic interventions, and ablation to improve diagnosis and mechanistic treatment of SAN and atrial arrhythmias., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

In this work we investigate the Raman response of extremely strained gallium phosphide nanowires. We analyze new strain-induced spectral phenomena such as 2-fold and 3-fold phonon peak splitting which arise due to nontrivial internal electric field distribution coupled with inhomogeneous strain. We show that high bending strain acts as a probe allowing us to define the electric field distribution with deep subwavelength resolution using the corresponding changes of the Raman spectra. We investigate the nature of the localization with respect to nanowire diameter, excitation spot position, and light polarization, supporting the experiment with 3D numerical modeling. Based on our findings we propose a research tool allowing to precisely localize the electric field in a certain subwavelength region of the nanophotonic resonator.

Semiconductor nanowires exhibit numerous capabilities to advance the development of future optoelectronic devices. Among the III-V material family, gallium phosphide (GaP) is an attractive platform with low optical absorption and high nonlinear susceptibility, making it especially promising for nanophotonic applications. However, investigation of single nanostructures and their waveguiding properties remains challenging owing to typically planar experimental arrangements. Here we study the linear and nonlinear waveguiding optical properties of a single GaP nanowire in a special experimental layout, where an optically trapped structure is aligned along its major axis. We demonstrate efficient second harmonic generation in individual nanowires and unravel phase matching conditions, linking between linear guiding properties of the structure and its nonlinear tensorial susceptibility. The capability to pick up single nanowires, sort them with the aid of optomechanical manipulation and accurately position pre-tested structures opens a new avenue for the generation of optoelectronic origami-type devices.

Tailorable synthesis of axially heterostructured epitaxial nanowires (NWs) with a proper choice of materials allows for the fabrication of novel photonic devices, such as a nanoemitter in the resonant cavity. An example of the structure is a GaP nanowire with ternary GaPAs insertions in the form of nano-sized discs studied in this work. With the use of the micro-photoluminescence technique and numerical calculations, we experimentally and theoretically study photoluminescence emission in individual heterostructured NWs. Due to the high refractive index and near-zero absorption through the emission band, the photoluminescence signal tends to couple into the nanowire cavity acting as a Fabry-Perot resonator, while weak radiation propagating perpendicular to the nanowire axis is registered in the vicinity of each nano-sized disc. Thus, within the heterostructured nanowire, both amplitude and spectrally anisotropic photoluminescent signals can be achieved. Numerical modeling of the nanowire with insertions emitting in infrared demonstrates a decay in the emission directivity and simultaneous rise of the emitters coupling with an increase in the wavelength. The emergence of modulated and non-modulated radiation is discussed, and possible nanophotonic applications are considered.

The architecture of transparent contacts is of utmost importance for creation of efficient flexible light-emitting devices (LEDs) and other deformable electronic devices. We successfully combined the newly synthesized transparent and durable silicone rubbers and the semiconductor materials with original fabrication methods to design LEDs and demonstrate their significant flexibility. We developed electrodes based on a composite GaP nanowire-phenylethyl-functionalized silicone rubber membrane, improved with single-walled carbon nanotube films for a hybrid poly(ethylene oxide)-metal-halide perovskite (CsPbBr 3 ) flexible green LED. The proposed approach provides a novel platform for fabrication of flexible hybrid optoelectronic devices.

Heart failure (HF) is frequently accompanied with the sinoatrial node (SAN) dysfunction, which causes tachy-brady arrhythmias and increased mortality. MicroRNA (miR) alterations are associated with HF progression. However, the transcriptome of HF human SAN, and its role in HF-associated remodeling of ion channels, transporters, and receptors responsible for SAN automaticity and conduction impairments is unknown. We conducted comprehensive high-throughput transcriptomic analysis of pure human SAN primary pacemaker tissue and neighboring right atrial tissue from human transplanted HF hearts (n = 10) and non-failing (nHF) donor hearts (n = 9), using next-generation sequencing. Overall, 47 miRs and 832 mRNAs related to multiple signaling pathways, including cardiac diseases, tachy-brady arrhythmias and fibrosis, were significantly altered in HF SAN. Of the altered miRs, 27 are predicted to regulate mRNAs of major ion channels and neurotransmitter receptors which are involved in SAN automaticity (e.g. HCN1, HCN4, SLC8A1) and intranodal conduction (e.g. SCN5A, SCN8A) or both (e.g. KCNJ3, KCNJ5). Luciferase reporter assays were used to validate interactions of miRs with predicted mRNA targets. In conclusion, our study provides a profile of altered miRs in HF human SAN, and a novel transcriptome blueprint to identify molecular targets for SAN dysfunction and arrhythmia treatments in HF., (© 2021. The Author(s).)

Wurtzite GaP nanowires are interesting for the direct bandgap engineering and can be used as templates for further growth of hexagonal Si shells. Most wurtzite GaP nanowires have previously been obtained with Au catalysts. Here, we show that long (∼500 nm) wurtzite sections are formed in the top parts of self-catalyzed GaP nanowires grown by molecular beam epitaxy on Si(111) substrates in the droplet consumption stage, which is achieved by abruptly increasing the atomic V/III flux ratio from 2 to 3. We investigate the temperature dependence of the length of wurtzite sections and show that the longest sections are obtained at 610 °C. A supporting model explains the observed trends using a phase diagram of GaP nanowires, where the wurtzite phase is formed within a certain range of the droplet contact angles. The optimal growth temperature for growing wurtzite nanowires corresponds to the largest diffusion length of Ga adatoms, which helps to maintain the required contact angle for the longest time., (© 2021 IOP Publishing Ltd.)

Tailorable synthesis of III-V semiconductor heterostructures in nanowires (NWs) enables new approaches with respect to designing photonic and electronic devices at the nanoscale. We present a comprehensive study of highly controllable self-catalyzed growth of gallium phosphide (GaP) NWs on template-free silicon (111) substrates by molecular beam epitaxy. We report the approach to form the silicon oxide layer, which reproducibly provides a high yield of vertical GaP NWs and control over the NW surface density without a pre-patterned growth mask. Above that, we present the strategy for controlling both GaP NW length and diameter independently in single- or two-staged self-catalyzed growth. The proposed approach can be extended to other III-V NWs.

Background: Up to 50% of the adult human sinoatrial node (SAN) is composed of dense connective tissue. Cardiac diseases including heart failure (HF) may increase fibrosis within the SAN pacemaker complex, leading to impaired automaticity and conduction of electric activity to the atria. Unlike the role of cardiac fibroblasts in pathologic fibrotic remodeling and tissue repair, nothing is known about fibroblasts that maintain the inherently fibrotic SAN environment., Methods: Intact SAN pacemaker complex was dissected from cardioplegically arrested explanted nonfailing hearts (non-HF; n=22; 48.7±3.1 years of age) and human failing hearts (n=16; 54.9±2.6 years of age). Connective tissue content was quantified from Masson trichrome-stained head-center and center-tail SAN sections. Expression of extracellular matrix proteins, including collagens 1 and 3A1, CILP1 (cartilage intermediate layer protein 1), and POSTN (periostin), and fibroblast and myofibroblast numbers were quantified by in situ and in vitro immunolabeling. Fibroblasts from the central intramural SAN pacemaker compartment (≈10×5×2 mm 3 ) and right atria were isolated, cultured, passaged once, and treated ± transforming growth factor β1 and subjected to comprehensive high-throughput next-generation sequencing of whole transcriptome, microRNA, and proteomic analyses., Results: Intranodal fibrotic content was significantly higher in SAN pacemaker complex from HF versus non-HF hearts (57.7±2.6% versus 44.0±1.2%; P <0.0001). Proliferating phosphorylated histone 3 + /vimentin + /CD31 - (cluster of differentiation 31) fibroblasts were higher in HF SAN. Vimentin + /α-smooth muscle actin + /CD31 - myofibroblasts along with increased interstitial POSTN expression were found only in HF SAN. RNA sequencing and proteomic analyses identified unique differences in mRNA, long noncoding RNA, microRNA, and proteomic profiles between non-HF and HF SAN and right atria fibroblasts and transforming growth factor β1-induced myofibroblasts. Specifically, proteins and signaling pathways associated with extracellular matrix flexibility, stiffness, focal adhesion, and metabolism were altered in HF SAN fibroblasts compared with non-HF SAN., Conclusions: This study revealed increased SAN-specific fibrosis with presence of myofibroblasts, CILP1, and POSTN-positive interstitial fibrosis only in HF versus non-HF human hearts. Comprehensive proteotranscriptomic profiles of SAN fibroblasts identified upregulation of genes and proteins promoting stiffer SAN extracellular matrix in HF hearts. Fibroblast-specific profiles generated by our proteotranscriptomic analyses of the human SAN provide a comprehensive framework for future studies to investigate the role of SAN-specific fibrosis in cardiac rhythm regulation and arrhythmias.

Control and analysis of the crystal phase in semiconductor nanowires are of high importance due to the new possibilities for strain and band gap engineering for advanced nanoelectronic and nanophotonic devices. In this letter, we report the growth of the self-catalyzed GaP nanowires with a high concentration of wurtzite phase by molecular beam epitaxy on Si (111) and investigate their crystallinity. Varying the growth temperature and V/III flux ratio, we obtained wurtzite polytype segments with thicknesses in the range from several tens to 500 nm, which demonstrates the high potential of the phase bandgap engineering with highly crystalline self-catalyzed phosphide nanowires. The formation of rotational twins and wurtzite polymorph in vertical nanowires was observed through complex approach based on transmission electron microscopy, powder X-ray diffraction, and reciprocal space mapping. The phase composition, volume fraction of the crystalline phases, and wurtzite GaP lattice parameters were analyzed for the nanowires detached from the substrate. It is shown that the wurtzite phase formation occurs only in the vertically-oriented nanowires during vapor-liquid-solid growth, while the wurtzite phase is absent in GaP islands parasitically grown via the vapor-solid mechanism. The proposed approach can be used for the quantitative evaluation of the mean volume fraction of polytypic phase segments in heterostructured nanowires that are highly desirable for the optimization of growth technologies.

Atrial fibrillation (AF) occurrence and maintenance is associated with progressive remodeling of electrophysiological (repolarization and conduction) and 3D structural (fibrosis, fiber orientations, and wall thickness) features of the human atria. Significant diversity in AF etiology leads to heterogeneous arrhythmogenic electrophysiological and structural substrates within the 3D structure of the human atria. Since current clinical methods have yet to fully resolve the patient-specific arrhythmogenic substrates, mechanism-based AF treatments remain underdeveloped. Here, we review current knowledge from in-vivo, ex-vivo, and in-vitro human heart studies, and discuss how these studies may provide new insights on the synergy of atrial electrophysiological and 3D structural features in AF maintenance. In-vitro studies on surgically acquired human atrial samples provide a great opportunity to study a wide spectrum of AF pathology, including functional changes in single-cell action potentials, ion channels, and gene/protein expression. However, limited size of the samples prevents evaluation of heterogeneous AF substrates and reentrant mechanisms. In contrast, coronary-perfused ex-vivo human hearts can be studied with state-of-the-art functional and structural technologies, such as high-resolution near-infrared optical mapping and contrast-enhanced MRI. These imaging modalities can resolve atrial arrhythmogenic substrates and their role in reentrant mechanisms maintaining AF and validate clinical approaches. Nonetheless, longitudinal studies are not feasible in explanted human hearts. As no approach is perfect, we suggest that combining the strengths of direct human atrial studies with high fidelity approaches available in the laboratory and in realistic patient-specific computer models would elucidate deeper knowledge of AF mechanisms. We propose that a comprehensive translational pipeline from ex-vivo human heart studies to longitudinal clinically relevant AF animal studies and finally to clinical trials is necessary to identify patient-specific arrhythmogenic substrates and develop novel AF treatments., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The spontaneous activity of the sinoatrial node initiates the heartbeat. Sino-atrial node dysfunction (SND) and sick sinoatrial (sick sinus) syndrome are caused by the heart's inability to generate a normal sinoatrial node action potential. In clinical practice, SND is generally considered an age-related pathology, secondary to degenerative fibrosis of the heart pacemaker tissue. However, other forms of SND exist, including idiopathic primary SND, which is genetic, and forms that are secondary to cardiovascular or systemic disease. The incidence of SND in the general population is expected to increase over the next half century, boosting the need to implant electronic pacemakers. During the last two decades, our knowledge of sino-atrial node physiology and of the pathophysiological mechanisms underlying SND has advanced considerably. This review summarizes the current knowledge about SND mechanisms and discusses the possibility of introducing new pharmacologic therapies for treating SND.

Flexible optoelectronic structures are required in a wide range of applications. Large scale modified silicone-embedded n-GaP nanowire arrays of a record 6 µm thin membranes were studied. A homogeneous silicone encapsulation was enabled by G-coating using a heavy-load centrifuge. The synthesized graft-copolymers of polydimethylsiloxane (PDMS) and polystyrene demonstrated two times lower adhesion to Si compared to standard PDMS, allowing 3 square inch area high quality silicone/nanowire membrane mechanical release, preserving the growth Si substrate for a further re-use after chemical cleaning. The 90% transparent single-walled carbon nanotubes electrical contacts to the embedded n-GaP nanowires demonstrated mechanical and electrical stability. The presented methods can be used for the fabrication of large scale flexible inorganic optoelectronic devices.

Controlled growth of heterostructured nanowires and mechanisms of their formation have been actively studied during the last decades due to perspectives of their implementation. Here, we report on the self-catalyzed growth of axially heterostructured GaPN/GaP nanowires on Si(111) by plasma-assisted molecular beam epitaxy. Nanowire composition and structural properties were examined by means of Raman microspectroscopy and transmission electron microscopy. To study the optical properties of the synthesized nanoheterostructures, the nanowire array was embedded into the silicone rubber membrane and further released from the growth substrate. The reported approach allows us to study the nanowire optical properties avoiding the response from the parasitically grown island layer. Photoluminescence and Raman studies reveal different nitrogen content in nanowires and parasitic island layer. The effect is discussed in terms of the difference in vapor solid and vapor liquid solid growth mechanisms. Photoluminescence studies at low temperature (5K) demonstrate the transition to the quasi-direct gap in the nanowires typical for diluted nitrides with low N-content. The bright room temperature photoluminescent response demonstrates the potential application of nanowire/polymer matrix in flexible optoelectronic devices., Competing Interests: The authors declare no conflict of interest.

Background Atrial fibrillation (AF) driver mechanisms are obscured to clinical multielectrode mapping approaches that provide partial, surface-only visualization of unstable 3-dimensional atrial conduction. We hypothesized that transient modulation of refractoriness by pharmacologic challenge during multielectrode mapping improves visualization of hidden paths of reentrant AF drivers for targeted ablation. Methods and Results Pharmacologic challenge with adenosine was tested in ex vivo human hearts with a history of AF and cardiac diseases by multielectrode and high-resolution subsurface near-infrared optical mapping, integrated with 3-dimensional structural imaging and heart-specific computational simulations. Adenosine challenge was also studied on acutely terminated AF drivers in 10 patients with persistent AF. Ex vivo, adenosine stabilized reentrant driver paths within arrhythmogenic fibrotic hubs and improved visualization of reentrant paths, previously seen as focal or unstable breakthrough activation pattern, for targeted AF ablation. Computational simulations suggested that shortening of atrial refractoriness by adenosine may (1) improve driver stability by annihilating spatially unstable functional blocks and tightening reentrant circuits around fibrotic substrates, thus unmasking the common reentrant path; and (2) destabilize already stable reentrant drivers along fibrotic substrates by accelerating competing fibrillatory wavelets or secondary drivers. In patients with persistent AF, adenosine challenge unmasked hidden common reentry paths (9/15 AF drivers, 41±26% to 68±25% visualization), but worsened visualization of previously visible reentry paths (6/15, 74±14% to 34±12%). AF driver ablation led to acute termination of AF. Conclusions Our ex vivo to in vivo human translational study suggests that transiently altering atrial refractoriness can stabilize reentrant paths and unmask arrhythmogenic hubs to guide targeted AF driver ablation treatment.

Background The sinus node (SN) is the primary pacemaker of the heart. SN myocytes possess distinctive action potential morphology with spontaneous diastolic depolarization because of a unique expression of ion channels and Ca 2+ -handling proteins. MicroRNAs (miRs) inhibit gene expression. The role of miRs in controlling the expression of genes responsible for human SN pacemaking and conduction has not been explored. The aim of this study was to determine miR expression profile of the human SN as compared with that of non-pacemaker atrial muscle. Methods and Results SN and atrial muscle biopsies were obtained from donor or post-mortem hearts (n=10), histology/immunolabeling were used to characterize the tissues, TaqMan Human MicroRNA Arrays were used to measure 754 miRs, Ingenuity Pathway Analysis was used to identify miRs controlling SN pacemaker gene expression. Eighteen miRs were significantly more and 48 significantly less abundant in the SN than atrial muscle. The most interesting miR was miR-486-3p predicted to inhibit expression of pacemaking channels: HCN1 (hyperpolarization-activated cyclic nucleotide-gated 1), HCN4, voltage-gated calcium channel (Ca v )1.3, and Ca v 3.1. A luciferase reporter gene assay confirmed that miR-486-3p can control HCN4 expression via its 3' untranslated region. In ex vivo SN preparations, transfection with miR-486-3p reduced the beating rate by ≈35±5% ( P <0.05) and HCN4 expression ( P <0.05). Conclusions The human SN possesses a unique pattern of expression of miRs predicted to target functionally important genes. miR-486-3p has an important role in SN pacemaker activity by targeting HCN4, making it a potential target for therapeutic treatment of SN disease such as sinus tachycardia.

Background: Atrial fibrillation (AF) can be maintained by localized intramural reentrant drivers. However, AF driver detection by clinical surface-only multielectrode mapping (MEM) has relied on subjective interpretation of activation maps. We hypothesized that application of machine learning to electrogram frequency spectra may accurately automate driver detection by MEM and add some objectivity to the interpretation of MEM findings., Methods: Temporally and spatially stable single AF drivers were mapped simultaneously in explanted human atria (n=11) by subsurface near-infrared optical mapping (NIOM; 0.3 mm 2 resolution) and 64-electrode MEM (higher density or lower density with 3 and 9 mm 2 resolution, respectively). Unipolar MEM and NIOM recordings were processed by Fourier transform analysis into 28 407 total Fourier spectra. Thirty-five features for machine learning were extracted from each Fourier spectrum., Results: Targeted driver ablation and NIOM activation maps efficiently defined the center and periphery of AF driver preferential tracks and provided validated annotations for driver versus nondriver electrodes in MEM arrays. Compared with analysis of single electrogram frequency features, averaging the features from each of the 8 neighboring electrodes, significantly improved classification of AF driver electrograms. The classification metrics increased when less strict annotation, including driver periphery electrodes, were added to driver center annotation. Notably, f1-score for the binary classification of higher-density catheter data set was significantly higher than that of lower-density catheter (0.81±0.02 versus 0.66±0.04, P <0.05). The trained algorithm correctly highlighted 86% of driver regions with higher density but only 80% with lower-density MEM arrays (81% for lower-density+higher-density arrays together)., Conclusions: The machine learning model pretrained on Fourier spectrum features allows efficient classification of electrograms recordings as AF driver or nondriver compared with the NIOM gold-standard. Future application of NIOM-validated machine learning approach may improve the accuracy of AF driver detection for targeted ablation treatment in patients.

Engineering of nonlinear optical response in nanostructures is one of the key topics in nanophotonics, as it allows for broad frequency conversion at the nanoscale. Nevertheless, the application of the developed designs is limited by either high cost of their manufacturing or low conversion efficiencies. This paper reports on the efficient second-harmonic generation in a free-standing GaP nanowire array encapsulated in a polymer membrane. Light coupling with optical resonances and field confinement in the nanowires together with high nonlinearity of GaP material yield a strong second-harmonic signal and efficient near-infrared (800-1200 nm) to visible upconversion. The fabricated nanowire-based membranes demonstrate high flexibility and semitransparency for the incident infrared radiation, allowing utilizing them for infrared imaging, which can be easily integrated into different optical schemes without disturbing the visualized beam.

Reduction of the wavelength in on-chip light circuitry is critically important not only for the sake of keeping up with Moore's law for photonics but also for reaching toward the spectral ranges of operation of emerging materials, such as atomically thin semiconductors, vacancy-based single-photon emitters, and quantum dots. This requires efficient and tunable light sources as well as compatible waveguide networks. For the first challenge, halide perovskites are prospective materials that enable cost-efficient fabrication of micro- and nanolasers. On the other hand, III-V semiconductor nanowires are optimal for guiding of visible light as they exhibit a high refractive index as well as excellent shape and crystalline quality beneficial for strong light confinement and long-range waveguiding. Here, we develop an integrated platform for visible light that comprises gallium phosphide (GaP) nanowires directly embedded into compact CsPbBr 3 -based light sources. In our devices, perovskite microcrystals support stable room-temperature lasing and broadband chemical tuning of the emission wavelength in the range of 530-680 nm, whereas GaP nanowaveguides support efficient outcoupling of light, its subwavelength (<200 nm) confinement, and long-range guiding over distances more than 20 μm. As a highlight of our approach, we demonstrate sequential transfer and conversion of light using an intermediate perovskite nanoparticle in a chain of GaP nanowaveguides.

Bradyarrhythmias are an important cause of mortality in heart failure and previous studies indicate a mechanistic role for electrical remodelling of the key pacemaking ion channel HCN4 in this process. Here we show that, in a mouse model of heart failure in which there is sinus bradycardia, there is upregulation of a microRNA (miR-370-3p), downregulation of the pacemaker ion channel, HCN4, and downregulation of the corresponding ionic current, I f , in the sinus node. In vitro, exogenous miR-370-3p inhibits HCN4 mRNA and causes downregulation of HCN4 protein, downregulation of I f , and bradycardia in the isolated sinus node. In vivo, intraperitoneal injection of an antimiR to miR-370-3p into heart failure mice silences miR-370-3p and restores HCN4 mRNA and protein and I f in the sinus node and blunts the sinus bradycardia. In addition, it partially restores ventricular function and reduces mortality. This represents a novel approach to heart failure treatment.

Delayed afterdepolarizations (DADs) and spontaneous depolarizations (SDs) are typically triggered by spontaneous diastolic Ca 2+ release from the sarcoplasmic reticulum (SR) which is caused by an elevated SR Ca 2+ -ATPase (SERCA) uptake and dysfunctional ryanodine receptors. However, recent studies on the T-box transcription factor gene (TBX5) demonstrated that abnormal depolarizations could occur despite a reduced SERCA uptake. Similar findings have also been reported in experimental or clinical studies of diabetes and heart failure. To investigate the sensitivity of SERCA in the genesis of DADs/SDs as well as its dependence on other Ca 2+ handling channels, we performed systematic analyses using the Maleckar et al . model. Results showed that the modulation of SERCA alone cannot trigger abnormal depolarizations, but can instead affect the interdependency of other Ca 2+ handling channels in triggering DADs/SDs. Furthermore, we discovered the existence of a threshold value for the intracellular concentration of Ca 2+ ([Ca 2+ ] i ) for abnormal depolarizations, which is modulated by the maximum SERCA uptake and the concentration of Ca 2+ in the uptake and release compartments in the SR ([Ca 2+ ] up and [Ca 2+ ] rel ). For the first time, our modelling study reconciles different mechanisms of abnormal depolarizations in the setting of 'lone' AF, reduced TBX5, diabetes and heart failure, and may lead to more targeted treatment for these patients. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.

The influence of hydrogen plasma treatment on the electrical and optical properties of vertical GaN nanowire (NW)/Si heterostructures synthesized via plasma assisted molecular beam epitaxy is studied. The effect of the treatment is thoroughly studied via variation of the passivation duration. Photoluminescence investigation demonstrates that the passivation affects the doping of the GaN NWs. The samples were processed as photodiodes with a top transparent electrode to obtain detailed information about the n-GaN NWs/p-Si heterointerface under illumination. The electron beam induced current measurements demonstrated the absence of potential barriers between the active parts of the diode and the contacts, indicating ohmic behavior of the latter. I-V characteristics obtained in the dark and under illumination show that hydrogen can effectively passivate the recombination centers at the GaN NWs/Si heterointerface. The optimum passivation duration, providing improved electrical properties, is found to be 10 min within the studied passivation regimes. It is demonstrated that longer treatment causes degradation of the electrical properties. The discovered phenomenon is discussed in detail.

Background: Atrial fibrillation (AF) is the most common type of arrhythmia. Abnormal atrial myocyte Ca 2+ handling promotes aberrant membrane excitability and remodeling that are important for atrial arrhythmogenesis. The sequence of molecular events leading to loss of normal atrial myocyte Ca 2+ homeostasis is not established. Late Na + current (I Na,L ) is increased in atrial myocytes from AF patients together with an increase in activity of Ca 2+ /calmodulin-dependent kinase II (CaMKII)., Objective: The purpose of this study was to determine whether CaMKII-dependent phosphorylation at Ser571 on Na V 1.5 increases atrial I Na,L , leading to aberrant atrial Ca 2+ cycling, altered electrophysiology, and increased AF risk., Methods: Atrial myocyte electrophysiology, Ca 2+ handling, and arrhythmia susceptibility were studied in wild-type and Scn5a knock-in mice expressing phosphomimetic (S571E) or phosphoresistant (S571A) Na V 1.5 at Ser571., Results: Atrial myocytes from S571E but not S571A mice displayed an increase in I Na,L and action potential duration, and with adrenergic stress have increased delayed afterdepolarizations. Frequency of Ca 2+ sparks and waves was increased in S571E atrial myocytes compared to wild type. S571E mice showed an increase in atrial events induced by adrenergic stress and AF inducibility in vivo. Isolated S571E atria were more susceptible to spontaneous atrial events, which were abrogated by inhibiting sarcoplasmic reticulum Ca 2+ release, CaMKII, or the Na + /Ca 2+ exchanger. Expression of phospho-Na V 1.5 at Ser571 and autophosphorylated CaMKII were increased in atrial samples from human AF patients., Conclusion: This study identified CaMKII-dependent regulation of Na V 1.5 as an important upstream event in Ca 2+ handling defects and abnormal impulse generation in the setting of AF., (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is a major cause of stroke and morbidity. Recent genome-wide association studies have shown that paired-like homeodomain transcription factor 2 (Pitx2) to be strongly associated with AF. However, the mechanisms underlying Pitx2 modulated arrhythmogenesis and variable effectiveness of antiarrhythmic drugs (AADs) in patients in the presence or absence of impaired Pitx2 expression remain unclear. We have developed multi-scale computer models, ranging from a single cell to tissue level, to mimic control and Pitx2-knockout atria by incorporating recent experimental data on Pitx2-induced electrical and structural remodeling in humans, as well as the effects of AADs. The key findings of this study are twofold. We have demonstrated that shortened action potential duration, slow conduction and triggered activity occur due to electrical and structural remodelling under Pitx2 deficiency conditions. Notably, the elevated function of calcium transport ATPase increases sarcoplasmic reticulum Ca2+ concentration, thereby enhancing susceptibility to triggered activity. Furthermore, heterogeneity is further elevated due to Pitx2 deficiency: 1) Electrical heterogeneity between left and right atria increases; and 2) Increased fibrosis and decreased cell-cell coupling due to structural remodelling slow electrical propagation and provide obstacles to attract re-entry, facilitating the initiation of re-entrant circuits. Secondly, our study suggests that flecainide has antiarrhythmic effects on AF due to impaired Pitx2 by preventing spontaneous calcium release and increasing wavelength. Furthermore, our study suggests that Na+ channel effects alone are insufficient to explain the efficacy of flecainide. Our study may provide the mechanisms underlying Pitx2-induced AF and possible explanation behind the AAD effects of flecainide in patients with Pitx2 deficiency., Competing Interests: The authors have declared that no competing interests exist.

Mechanisms for human sinoatrial node (SAN) dysfunction are poorly understood and whether human SAN excitability requires voltage-gated sodium channels (Nav) remains controversial. Here, we report that neuronal (n)Nav blockade and selective nNav1.6 blockade during high-resolution optical mapping in explanted human hearts depress intranodal SAN conduction, which worsens during autonomic stimulation and overdrive suppression to conduction failure. Partial cardiac (c)Nav blockade further impairs automaticity and intranodal conduction, leading to beat-to-beat variability and reentry. Multiple nNav transcripts are higher in SAN vs atria; heterogeneous alterations of several isoforms, specifically nNav1.6, are associated with heart failure and chronic alcohol consumption. In silico simulations of Nav distributions suggest that I Na is essential for SAN conduction, especially in fibrotic failing hearts. Our results reveal that not only cNav but nNav are also integral for preventing disease-induced failure in human SAN intranodal conduction. Disease-impaired nNav may underlie patient-specific SAN dysfunctions and should be considered to treat arrhythmias.

Aims: Bradycardia contributes to tachy-brady arrhythmias or sinus arrest during heart failure (HF). Sinoatrial node (SAN) adenosine A1 receptors (ADO A1Rs) are upregulated in HF, and adenosine is known to exert negative chronotropic effects on the SAN. Here, we investigated the role of A1R signaling at physiologically relevant ADO concentrations on HF SAN pacemaker cells., Main Methods: Dogs with tachypacing-induced chronic HF and normal controls (CTL) were studied. SAN tissue was collected for A1R and GIRK mRNA quantification. SAN cells were isolated for perforated patch clamp recordings and firing rate (bpm), slope of slow diastolic depolarization (SDD), and maximum diastolic potential (MDP) were measured. Action potentials (APs) and currents were recorded before and after addition of 1 and 10 μM ADO. To assess contributions of A1R and G protein-coupled Inward Rectifier Potassium Current (GIRK) to ADO effects, APs were measured after the addition of DPCPX (selective A1R antagonist) or TPQ (selective GIRK blocker)., Key Findings: A1R and GIRK mRNA expression were significantly increased in HF. In addition, ADO induced greater rate slowing and membrane hyperpolarization in HF vs CTL (p < 0.05). DPCPX prevented ADO-induced rate slowing in CTL and HF cells. The ADO-induced inward rectifying current, I Kado , was observed significantly more frequently in HF than in CTL. TPQ prevented ADO-induced rate slowing in HF., Significance: An increase in A1R and GIRK expression enhances I KAdo , causing hyperpolarization, and subsequent negative chronotropic effects in canine chronic HF at relevant [ADO]. GIRK blockade may be a useful strategy to mitigate bradycardia in HF., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Atrial fibrillation (AF) is the most prevalent form of cardiac arrhythmia. The atrial wall thickness (AWT) can potentially improve our understanding of the mechanism underlying atrial structure that drives AF and provides important clinical information. However, most existing studies for estimating AWT rely on ruler-based measurements performed on only a few selected locations in 2D or 3D using digital calipers. Only a few studies have developed automatic approaches to estimate the AWT in the left atrium, and there are currently no methods to robustly estimate the AWT of both atrial chambers. Therefore, we have developed a computational pipeline to automatically calculate the 3D AWT across bi-atrial chambers and extensively validated our pipeline on both ex vivo and in vivo human atria data. The atrial geometry was first obtained by segmenting the atrial wall from the MRIs using a novel machine learning approach. The epicardial and endocardial surfaces were then separated using a multi-planar convex hull approach to define boundary conditions, from which, a Laplace equation was solved numerically to automatically separate bi-atrial chambers. To robustly estimate the AWT in each atrial chamber, coupled partial differential equations by coupling the Laplace solution with two surface trajectory functions were formulated and solved. Our pipeline enabled the reconstruction and visualization of the 3D AWT for bi-atrial chambers with a relative error of 8% and outperformed existing algorithms by >7%. Our approach can potentially lead to improved clinical diagnosis, patient stratification, and clinical guidance during ablation treatment for patients with AF., (Copyright © 2019. Published by Elsevier Ltd.)

Increased fibrosis is a characteristic remodeling response to biomechanical and neurohumoral stress and a determinant of cardiac mechanical and electrical dysfunction in disease. Stress-induced activation of cardiac fibroblasts (CFs) is a critical step in the fibrotic response, although the precise sequence of events underlying activation of these critical cells in vivo remain unclear. Here, we tested the hypothesis that a βIV-spectrin/STAT3 complex is essential for maintenance of a quiescent phenotype (basal nonactivated state) in CFs. We reported increased fibrosis, decreased cardiac function, and electrical impulse conduction defects in genetic and acquired mouse models of βIV-spectrin deficiency. Loss of βIV-spectrin function promoted STAT3 nuclear accumulation and transcriptional activity, and it altered gene expression and CF activation. Furthermore, we demonstrate that a quiescent phenotype may be restored in βIV-spectrin-deficient fibroblasts by expressing a βIV-spectrin fragment including the STAT3-binding domain or through pharmacological STAT3 inhibition. We found that in vivo STAT3 inhibition abrogates fibrosis and cardiac dysfunction in the setting of global βIV-spectrin deficiency. Finally, we demonstrate that fibroblast-specific deletion of βIV-spectrin is sufficient to induce fibrosis and decreased cardiac function. We propose that the βIV-spectrin/STAT3 complex is a determinant of fibroblast phenotype and fibrosis, with implications for remodeling response in cardiovascular disease (CVD).

The role of Si (111) substrate surface preparation and buffer layer composition in the growth, electronic and optical properties of the GaN nanowires (NWs) synthesized via plasma-assisted molecular beam epitaxy is studied. A comparison study of GaN NWs growth on the bare Si (111) substrate, silicon nitride interlayer, predeposited AlN and GaO x buffer layers, monolayer thick Ga wetting layer and GaN seeding layer prepared by the droplet epitaxy is performed. It is demonstrated that the homogeneity and the morphology of the NW arrays drastically depend on the chosen buffer layer and surface preparation technique. An effect of the buffer and seeding layers on the nucleation and desorption is also discussed. The lowest NWs surface density of 14 μm -2 is obtained on AlN buffer layer and the highest density exceeding the latter value by more than an order of magnitude corresponds to the growth on the 0.3 ML thick Ga wetting layer. It is shown, that the highest NWs mean elongation rate is obtained with AlN buffer layer, while the lowest elongation rate corresponds to the bare Si (111) surface and it is twice as lower as the first case. It is found, that use of AlN buffer layer corresponds to the most homogeneous NWs array with the smallest length dispersion while the least homogeneous array corresponds to the bare Si substrate. Vertically aligned GaN NWs array on the wide bandgap GaO x semiconductor buffer layer grown by plasma-enhanced chemical vapor deposition demonstrates its potential for electronic applications. Photoluminescence (PL) study of the synthesized samples is characterized by an intense optical response related to the excitons bound to neutral donors. The highest PL intensity is obtained in the sample with AlN buffer layer.

The sinoatrial node (SAN) is the primary pacemaker in canine and human hearts. The SAN in both species has a unique three-dimensional heterogeneous structure characterized by small pacemaker myocytes enmeshed within fibrotic strands, which partially insulate the cells from aberrant atrial activation. The SAN pacemaker tissue expresses a unique signature of proteins and receptors that mediate SAN automaticity, ion channel currents, and cell-to-cell communication, which are predominantly similar in both species. Recent intramural optical mapping, integrated with structural and molecular studies, has revealed the existence of up to five specialized SAN conduction pathways that preferentially conduct electrical activation to atrial tissues. The intrinsic heart rate, intranodal leading pacemaker shifts, and changes in conduction in response to physiological and pathophysiological stimuli are similar. Structural and/or functional impairments due to cardiac diseases including heart failure cause SAN dysfunctions (SNDs) in both species. These dysfunctions are usually manifested as severe bradycardia, tachy-brady arrhythmias, and conduction abnormalities including exit block and SAN reentry, which could lead to atrial tachycardia and fibrillation, cardiac arrest, and heart failure. Pharmaceutical drugs and implantable pacemakers are only partially successful in managing SNDs, emphasizing a critical need to develop targeted mechanism-based therapies to treat SNDs. Because several structural and functional characteristics are similar between the canine and human SAN, research in these species may be mutually beneficial for developing novel treatment approaches. This review describes structural, functional, and molecular similarities and differences between the canine and human SAN, with special emphasis on arrhythmias and unique causal mechanisms of SND in diseased hearts., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Atrial fibrillation (AF) is the most prevalent form of cardiac arrhythmia. Current treatments for AF remain suboptimal due to a lack of understanding of the underlying atrial structures that directly sustain AF. Existing approaches for analyzing atrial structures in 3-D, especially from late gadolinium-enhanced (LGE) magnetic resonance imaging, rely heavily on manual segmentation methods that are extremely labor-intensive and prone to errors. As a result, a robust and automated method for analyzing atrial structures in 3-D is of high interest. We have, therefore, developed AtriaNet, a 16-layer convolutional neural network (CNN), on 154 3-D LGE-MRIs with a spatial resolution of 0.625 mm ×0.625 mm ×1.25 mm from patients with AF, to automatically segment the left atrial (LA) epicardium and endocardium. AtriaNet consists of a multi-scaled, dual-pathway architecture that captures both the local atrial tissue geometry and the global positional information of LA using 13 successive convolutions and three further convolutions for merging. By utilizing computationally efficient batch prediction, AtriaNet was able to successfully process each 3-D LGE-MRI within 1 min. Furthermore, benchmarking experiments have shown that AtriaNet has outperformed the state-of-the-art CNNs, with a DICE score of 0.940 and 0.942 for the LA epicardium and endocardium, respectively, and an inter-patient variance of <0.001. The estimated LA diameter and volume computed from the automatic segmentations were accurate to within 1.59 mm and 4.01 cm 3 of the ground truths. Our proposed CNN was tested on the largest known data set for LA segmentation, and to the best of our knowledge, it is the most robust approach that has ever been developed for segmenting LGE-MRIs. The increased accuracy of atrial reconstruction and analysis could potentially improve the understanding and treatment of AF.

Objectives: This study sought to improve atrial fibrillation (AF) driver identification by integrating clinical multielectrode mapping with driver fingerprints defined by high-resolution ex vivo 3-dimensional (3D) functional and structural imaging., Background: Clinical multielectrode mapping of AF drivers suffers from variable contact, signal processing, and structural complexity within the 3D human atrial wall, raising questions on the validity of such drivers., Methods: Sustained AF was mapped in coronary-perfused explanted human hearts (n = 11) with transmural near-infrared optical mapping (∼0.3 mm 2 resolution). Simultaneously, custom FIRMap catheters (∼9 × 9 mm 2 resolution) mapped endocardial and epicardial surfaces, which were analyzed by Focal Impulse and Rotor Mapping activation and Rotational Activity Profile (Abbott Labs, Chicago, Illinois). Functional maps were integrated with contrast-enhanced cardiac magnetic resonance imaging (∼0.1 mm 3 resolution) analysis of 3D fibrosis architecture., Results: During sustained AF, near-infrared optical mapping identified 1 to 2 intramural, spatially stable re-entrant AF drivers per heart. Driver targeted ablation affecting 2.2 ± 1.1% of the atrial surface terminated and prevented AF. Driver regions had significantly higher phase singularity density and dominant frequency than neighboring nondriver regions. Focal Impulse and Rotor Mapping had 80% sensitivity to near-infrared optical mapping-defined driver locations (16 of 20), and matched 14 of 20 driver visualizations: 10 of 14 re-entries seen with Rotational Activity Profile; and 4 of 6 breakthrough/focal patterns. Focal Impulse and Rotor Mapping detected 1.1 ± 0.9 false-positive rotational activity profiles per recording, but these regions had lower intramural contrast-enhanced cardiac magnetic resonance imaging fibrosis than did driver regions (14.9 ± 7.9% vs. 23.2 ± 10.5%; p < 0.005)., Conclusions: The study revealed that both re-entrant and breakthrough/focal AF driver patterns visualized by surface-only clinical multielectrodes can represent projections of 3D intramural microanatomic re-entries. Integration of multielectrode mapping and 3D fibrosis analysis may enhance AF driver detection, thereby improving the efficacy of driver-targeted ablation., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Transcription factors TBX5 and PITX2 involve in the regulation of gene expression of ion channels and are closely associated with atrial fibrillation (AF), the most common cardiac arrhythmia in developed countries. The exact cellular and molecular mechanisms underlying the increased susceptibility to AF in patients with TBX5/PITX2 insufficiency remain unclear. In this study, we have developed and validated a novel human left atrial cellular model (TPA) based on the ten Tusscher-Panfilov ventricular cell model to systematically investigate how electrical remodeling induced by TBX5/PITX2 insufficiency leads to AF. Using our TPA model, we have demonstrated that spontaneous diastolic depolarization observed in atrial myocytes with TBX5-deletion can be explained by altered intracellular calcium handling and suppression of inward-rectifier potassium current (I K1 ). Additionally, our computer simulation results shed new light on the novel cellular mechanism underlying AF by indicating that the imbalance between suppressed outward current I K1 and increased inward sodium-calcium exchanger current (I NCX ) resulted from SR calcium leak leads to spontaneous depolarizations. Furthermore, our simulation results suggest that these arrhythmogenic triggers can be potentially suppressed by inhibiting sarcoplasmic reticulum (SR) calcium leak and reversing remodeled I K1 . More importantly, this study has clinically significant implications on the drugs used for maintaining SR calcium homeostasis, whereby drugs such as dantrolene may confer significant improvement for the treatment of AF patients with TBX5/PITX2 insufficiency.

Objective: The electrocardiogram (ECG) provides an effective, non-invasive approach for clinical diagnosis in patients with cardiac diseases such as atrial fibrillation (AF). AF is the most common cardiac rhythm disturbance and affects ~2% of the general population in industrialized countries. Automatic AF detection in clinics remains a challenging task due to the high inter-patient variability of ECGs, and unsatisfactory existing approaches for AF diagnosis (e.g. atrial or ventricular activity-based analyses)., Approach: We have developed RhythmNet, a 21-layer 1D convolutional recurrent neural network, trained using 8528 single-lead ECG recordings from the 2017 PhysioNet/Computing in Cardiology (CinC) Challenge, to classify ECGs of different rhythms including AF automatically. Our RhythmNet architecture contained 16 convolutions to extract features directly from raw ECG waveforms, followed by three recurrent layers to process ECGs of varying lengths and to detect arrhythmia events in long recordings. Large 15  ×  1 convolutional filters were used to effectively learn the detailed variations of the signal within small time-frames such as the P-waves and QRS complexes. We employed residual connections throughout RhythmNet, along with batch-normalization and rectified linear activation units to improve convergence during training., Main Results: We evaluated our algorithm on 3658 testing data and obtained an F 1 accuracy of 82% for classifying sinus rhythm, AF, and other arrhythmias. RhythmNet was also ranked 5th in the 2017 CinC Challenge., Significance: Potentially, our approach could aid AF diagnosis in clinics and be used for patient self-monitoring to improve the early detection and effective treatment of AF.

Background: In patients with end-stage heart failure, the primary etiology often originates in the left ventricle, and eventually the contractile function of the right ventricle (RV) also becomes compromised. RV tissue-level deficits in contractile force and/or kinetics need quantification to understand involvement in ischemic and non-ischemic failing human myocardium., Methods and Results: The human population suffering from heart failure is diverse, requiring many subjects to be studied in order to perform an adequately powered statistical analysis. From 2009-present we assessed live tissue-level contractile force and kinetics in isolated myocardial RV trabeculae from 44 non-failing and 41 failing human hearts. At 1 Hz stimulation rate (in vivo resting state) the developed active force was not different in non-failing compared to failing ischemic nor non-ischemic failing trabeculae. In sharp contrast, the kinetics of relaxation were significantly impacted by disease, with 50% relaxation time being significantly shorter in non-failing vs. non-ischemic failing, while the latter was still significantly shorter than ischemic failing. Gender did not significantly impact kinetics. Length-dependent activation was not impacted. Although baseline force was not impacted, contractile reserve was critically blunted. The force-frequency relation was positive in non-failing myocardium, but negative in both ischemic and non-ischemic myocardium, while the β-adrenergic response to isoproterenol was depressed in both pathologies., Conclusions: Force development at resting heart rate is not impacted by cardiac pathology, but kinetics are impaired and the magnitude of the impairment depends on the underlying etiology. Focusing on restoration of myocardial kinetics will likely have greater therapeutic potential than targeting force of contraction., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Genetic variants at the SCN5A / SCN10A locus are strongly associated with electrocardiographic PR and QRS intervals. While SCN5A is the canonical cardiac sodium channel gene, the role of SCN10A in cardiac conduction is less well characterized., Methods: We sequenced the SCN10A locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue. We explored the biophysical effect of variation on channel function using cellular electrophysiology., Results: We identified 2 intronic single nucleotide polymorphisms in high linkage disequilibrium ( r   2 =0.86) with each other to be the strongest signals for PR (rs10428132, β=-4.74, P =1.52×10 -14 ) and QRS intervals (rs6599251, QRS β=-0.73; P =1.2×10 -4 ), respectively. Although these variants were not associated with SCN5A or SCN10A expression in human atrial tissue (n=490), they were in high linkage disequilibrium ( r   2 ≥0.72) with a common SCN10A missense variant, rs6795970 (V1073A). In total, we identified 7 missense variants, 4 of which (I962V, P1045T, V1073A, and L1092P) were associated with cardiac conduction. These 4 missense variants cluster in the cytoplasmic linker of the second and third domains of the SCN10A protein and together form 6 common haplotypes. Using cellular electrophysiology, we found that haplotypes associated with shorter PR intervals had a significantly larger percentage of late current compared with wild-type (I962V+V1073A+L1092P, 20.2±3.3%, P =0.03, and I962V+V1073A, 22.4±0.8%, P =0.0004 versus wild-type 11.7±1.6%), and the haplotype associated with the longest PR interval had a significantly smaller late current percentage (P1045T, 6.4±1.2%, P =0.03)., Conclusions: Our findings suggest an association between genetic variation in SCN10A , the late sodium current, and alterations in cardiac conduction., (© 2018 American Heart Association, Inc.)