scholarly journals Unmasking Arrhythmogenic Hubs of Reentry Driving Persistent Atrial Fibrillation for Patient‐Specific Treatment

2020 ◽  
Vol 9 (19) ◽  
Author(s):  
Brian J. Hansen ◽  
Jichao Zhao ◽  
Katelynn M. Helfrich ◽  
Ning Li ◽  
Alexander Iancau ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Near Infrared ◽  
Ex Vivo ◽  
Specific Treatment ◽  
Persistent Atrial Fibrillation ◽  
Patient Specific ◽  
Computational Simulations ◽  
3 Dimensional ◽  
Atrial Refractoriness

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.

scholarly journals Applications of Vibrational Spectroscopy for Analysis of Connective Tissues

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 922
Author(s):  
William Querido ◽  
Shital Kandel ◽  
Nancy Pleshko
Keyword(s):  
Raman Spectroscopy ◽  
Vibrational Spectroscopy ◽  
Near Infrared ◽  
Ex Vivo ◽  
Biological Tissues ◽  
Label Free ◽  
Connective Tissues ◽  
Bone Properties ◽  
Composition And Structure

Advances in vibrational spectroscopy have propelled new insights into the molecular composition and structure of biological tissues. In this review, we discuss common modalities and techniques of vibrational spectroscopy, and present key examples to illustrate how they have been applied to enrich the assessment of connective tissues. In particular, we focus on applications of Fourier transform infrared (FTIR), near infrared (NIR) and Raman spectroscopy to assess cartilage and bone properties. We present strengths and limitations of each approach and discuss how the combination of spectrometers with microscopes (hyperspectral imaging) and fiber optic probes have greatly advanced their biomedical applications. We show how these modalities may be used to evaluate virtually any type of sample (ex vivo, in situ or in vivo) and how “spectral fingerprints” can be interpreted to quantify outcomes related to tissue composition and quality. We highlight the unparalleled advantage of vibrational spectroscopy as a label-free and often nondestructive approach to assess properties of the extracellular matrix (ECM) associated with normal, developing, aging, pathological and treated tissues. We believe this review will assist readers not only in better understanding applications of FTIR, NIR and Raman spectroscopy, but also in implementing these approaches for their own research projects.

Abstract 13383: The Vascular Endothelial Barrier: A Novel Therapeutic Target for Preventing Atrial Fibrillation

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Louisa Mezache ◽  
Heather Struckman ◽  
Anna Phillips ◽  
Stephen Baine ◽  
Amara Greer-short ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Ex Vivo ◽  
Vascular Dysfunction ◽  
Super Resolution ◽  
Vascular Endothelial ◽  
Vascular Leak ◽  
Barrier Breakdown ◽  
Endothelial Growth Factor ◽  
Intercalated Disk

Atrial fibrillation (AF), the most common arrhythmia, is associated with inflammation and vascular dysfunction. AF patients have elevated levels of vascular endothelial growth factor (VEGF; 90-580 pg/ml), which promotes vascular leak and edema. We have previously identified edema-induced disruption of sodium channel (Na V 1.5) -rich intercalated disk (ID) nanodomains as a novel arrhythmia mechanism. We hypothesized that (i) elevated VEGF levels promote AF by disrupting ID nanodomains, and slowing atrial conduction, and (ii) protection of the vascular barrier can prevent these arrhythmias. Clinically-relevant VEGF levels (500 pg/ml, 60 minutes) increased FITC-dextran extravasation (99.3% vs. 24.3% in vehicle controls) in WT mouse hearts, consistent with increased vascular leak. Electron microscopy revealed ID nanodomain swelling, near both gap junctions (perinexi; 64±9nm vs 17±1nm) and mechanical junctions (63±4nm vs 27±2nm) in VEGF-treated hearts relative to controls. Super-resolution STORM microscopy revealed Na V 1.5 enrichment at perinexi (9±2 fold) and N-cadherin-rich sites (7±1 fold) relative to non-junctional ID sites in control hearts. VEGF reduced Na V 1.5 enrichment at both sites (6±1 and 4±1 fold, respectively), consistent with Na V 1.5 translocation from ID nanodomains. Atrial conduction, assessed by optical mapping, was slowed by VEGF (10±0.4 cm/s vs 21.3±1.3 cm/s at baseline). VEGF increased atrial arrhythmia burden both ex vivo (80% vs 0% in vehicle controls) and in vivo (70% vs 20% in vehicle controls). Next, we tested two strategies shown to prevent vascular barrier breakdown. Blocking connexin43 hemichannels (αCT11 peptide) decreased both incidence (40%) and duration (1.45±3.42s) of VEGF-induced arrhythmias. Likewise, blocking pannexin1 channels (Panx1-IL2 peptide) shortened VEGF-induced arrhythmias (2.48±0.83s). Mefloquine and spironolactone, which are small molecules that respectively inhibit Cx43 hemichannels and pannexin channels, were also found to effectively prevent VEGF-induced atrial arrhythmias. These results highlight VEGF-induced vascular leak as a novel mechanism for AF, and suggest vascular barrier protection as an anti-arrhythmic strategy.

scholarly journals Modeling glioblastoma invasion using human brain organoids and single-cell transcriptomics

2019 ◽  
Author(s):  
Teresa G Krieger ◽  
Stephan M Tirier ◽  
Jeongbin Park ◽  
Tanja Eisemann ◽  
Heike Peterziel ◽  
...  
Keyword(s):  
Single Cell ◽  
Specific Treatment ◽  
Cellular Heterogeneity ◽  
Patient Specific ◽  
Before And After ◽  
Invasive Capacity ◽  
Transcriptional Changes ◽  
Potential Interactions

AbstractGlioblastoma multiforme (GBM) are devastating neoplasms with high invasive capacity. GBM has been difficult to study in vitro. Therapeutic progress is also limited by cellular heterogeneity within and between tumors. To address these challenges, we present an experimental model using human cerebral organoids as a scaffold for patient-derived glioblastoma cell invasion. By tissue clearing and confocal microscopy, we show that tumor cells within organoids extend a network of long microtubes, recapitulating the in vivo behavior of GBM. Single-cell RNA-seq of GBM cells before and after co-culture with organoid cells reveals transcriptional changes implicated in the invasion process that are coherent across patient samples, indicating that GBM cells reactively upregulate genes required for their dispersion. Functional therapeutic targets are identified by an in silico receptor-ligand pairing screen detecting potential interactions between GBM and organoid cells. Taken together, our model has proven useful for studying GBM invasion and transcriptional heterogeneity in vitro, with applications for both pharmacological screens and patient-specific treatment selection at a time scale amenable to clinical practice.

scholarly journals Efficient Photoacoustic Imaging With Biomimetic Mesoporous Silica-Based Nanoparticles

2021 ◽  
Vol 9 ◽  
Author(s):  
Chuangjia Huang ◽  
Xiaoling Guan ◽  
Hui Lin ◽  
Lu Liang ◽  
Yingling Miao ◽  
...  
Keyword(s):  
Mesoporous Silica ◽  
Near Infrared ◽  
Ex Vivo ◽  
Photoacoustic Imaging ◽  
Mesoporous Silica Nanoparticles ◽  
Good Biocompatibility ◽  
Targeting Ability ◽  
Body Clearance

Indocyanine green (ICG), a near-infrared (NIR) fluorescent dye approved by the Food and Drug Administration (FDA), has been extensively used as a photoacoustic (PA) probe for PA imaging. However, its practical application is limited by poor photostability in water, rapid body clearance, and non-specificity. Herein, we fabricated a novel biomimetic nanoprobe by coating ICG-loaded mesoporous silica nanoparticles with the cancer cell membrane (namely, CMI) for PA imaging. This probe exhibited good dispersion, large loading efficiency, good biocompatibility, and homologous targeting ability to Hela cells in vitro. Furthermore, the in vivo and ex vivo PA imaging on Hela tumor-bearing nude mice demonstrated that CMI could accumulate in tumor tissue and display a superior PA imaging efficacy compared with free ICG. All these results demonstrated that CMI might be a promising contrast agent for PA imaging of cervical carcinoma.

scholarly journals Real-Time Optical Monitoring of Endotracheal Tube Displacement

Biosensors ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 174
Author(s):  
Ramzan Ullah ◽  
Karl Doerfer ◽  
Pawjai Khampang ◽  
Faraneh Fathi ◽  
Wenzhou Hong ◽  
...  
Keyword(s):  
Endotracheal Tube ◽  
Real Time ◽  
Near Infrared ◽  
Ex Vivo ◽  
Light Emitting Diode ◽  
Clinical Care ◽  
Cost Effective ◽  
Infrared Light ◽  
In Vivo Experiments

Proper ventilation of a patient with an endotracheal tube (ETT) requires proper placement of the ETT. We present a sensitive, noninvasive, operator-free, and cost-effective optical sensor, called Opt-ETT, for the real-time assessment of ETT placement and alerting of the clinical care team should the ETT become displaced. The Opt-ETT uses a side-firing optical fiber, a near-infrared light-emitting diode, two photodetectors with an integrated amplifier, an Arduino board, and a computer loaded with a custom LabVIEW program to monitor the position of the endotracheal tube inside the windpipe. The Opt-ETT generates a visual and audible warning if the tube moves over a distance set by the operator. Displacement prediction is made using a second-order polynomial fit to the voltages measured from each detector. The system is tested on ex vivo porcine tissues, and the accuracy is determined to be better than 1.0 mm. In vivo experiments with a pig are conducted to test the performance and usability of the system.

A new implantable tool for repeated assessment of supraventricular electrophysiology and atrial fibrillation susceptibility in freely moving rats

2020 ◽  
Author(s):  
Michael Murninkas ◽  
Roni Gillis ◽  
Danielle I Lee ◽  
Sigal Elyagon ◽  
Nikhil Suresh Bhandarkar ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Ex Vivo ◽  
Adult Rats ◽  
Electrophysiological Properties ◽  
Multiple Risk Factors ◽  
Electrophysiological Studies ◽  
Cycle Lengths ◽  
Major Factors

The complex pathophysiology of atrial fibrillation (AF) is governed by multiple risk factors in ways that are still elusive. Basic electrophysiological properties including atrial effective refractory period (AERP) and conduction velocity are major factors determining the susceptibility of the atrial myocardium to AF. Although there is a great need for affordable animal models in this field of research, in-vivo rodent studies are limited by technical challenges. Recently, we introduced an implantable system for long-term assessment of AF susceptibility in ambulatory rats. However, technical considerations did not allow us to perform concomitant supraventricular electrophysiology measurements. Here, we designed a novel quadripolar-electrode specifically adapted for comprehensive atrial studies in ambulatory rats. Electrodes were fabricated from medical-grade silicone, four platinum-iridium poles and stainless steel fixating pins. Initial quality validation was performed ex-vivo, followed by implantation in adult rats and repeated electrophysiological studies 1, 4 and 8 weeks post implantation. Capture threshold was stable. Baseline AERP values (38.1±2.3 and 39.5±2.0 using 70ms and 120ms S1-S1 cycle lengths, respectively) confirmed the expected absence of rate-adaptation in the unanesthetized state and validated our prediction that markedly higher values reported under anesthesia are non-physiological. Evaluation of AF substrate in parallel with electrophysiological parameters validated our recent finding of a gradual increase in AF susceptibility over-time and demonstrated that this phenomenon is associated with an electrical remodeling process characterized by AERP shortening. Our findings indicate that the miniature quadripolar-electrode is a potent new tool, which opens a window of opportunities for better utilization of rats in AF research.

In-vivo near-infrared optical imaging of growing osteosarcoma cell lesions xenografted in mice: dual-channel quantitative evaluation of volume and mineralization

2011 ◽  
Vol 52 (9) ◽  
pp. 978-988 ◽  
Author(s):  
Hitoshi Nakayama ◽  
Tomoyuki Kawase ◽  
Kazuhiro Okuda ◽  
Larry F Wolff ◽  
Hiromasa Yoshie
Keyword(s):  
Optical Imaging ◽  
Near Infrared ◽  
Imaging Technique ◽  
Ex Vivo ◽  
Acquisition Time ◽  
Osteosarcoma Cell ◽  
Dual Channel ◽  
Nir Imaging ◽  
Ex Vivo Imaging

Background In a previous study using a rodent osteosarcoma-grafted rat model, in which cell-dependent mineralization was previously demonstrated to proportionally increase with growth, we performed a quantitative analysis of mineral deposit formation using 99mTc-HMDP and found some weaknesses, such as longer acquisition time and narrower dynamic ranges (i.e. images easily saturated). The recently developed near-infrared (NIR) optical imaging technique is expected to non-invasively evaluate changes in living small animals in a quantitative manner. Purpose To test the feasibility of NIR imaging with a dual-channel system as a better alternative for bone scintigraphy by quantitatively evaluating mineralization along with the growth of osteosarcoma lesions in a mouse-xenograft model. Material and Methods The gross volume and mineralization of osteosarcoma lesions were evaluated in living mice simultaneously with dual-channels by NIR dye-labeled probes, 2-deoxyglucose (DG) and pamidronate (OS), respectively. To verify these quantitative data, retrieved osteosarcoma lesions were then subjected to ex-vivo imaging, weighing under wet conditions, microfocus-computed tomography (μCT) analysis, and histopathological examination. Results Because of less scattering and no anatomical overlapping, as generally shown, specific fluorescence signals targeted to the osteosarcoma lesions could be determined clearly by ex-vivo imaging. These data were well positively correlated with the in-vivo imaging data ( r > 0.8, P < 0.02). Other good to excellent correlations ( r > 0.8, P < 0.02) were observed between DG accumulation and tumor gross volume and between OS accumulation and mineralization volume. Conclusion This in-vivo NIR imaging technique using DG and OS is sensitive to the level to simultaneously detect and quantitatively evaluate the growth and mineralization occuring in this type of osteosarcoma lesions of living mice without either invasion or sacrifice. By possible mutual complementation, this dual imaging system might be useful for accurate diagnosis even in the presence of overlapping tissues.

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