scholarly journals Genetic Inhibition of Serum Glucocorticoid Kinase 1 Prevents Obesity-related Atrial Fibrillation

2021 ◽  
Author(s):  
Aneesh Bapat ◽  
Guoping Li ◽  
Ling Xiao ◽  
Maarten Hulsmans ◽  
Maximilian J Schloss ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Ventricular Remodeling ◽  
Optical Mapping ◽  
Therapeutic Potential ◽  
Dominant Negative ◽  
Diet Induced Obesity ◽  
Pediatric Populations ◽  
Mechanistic Basis ◽  
Biochemical Analyses ◽  
Electrophysiologic Studies

Rationale: Given its rising prevalence in both the adult and pediatric populations, obesity has become an increasingly important risk factor in the development of atrial fibrillation. However, a better mechanistic understanding of obesity-related atrial fibrillation is required. Serum glucocorticoid kinase 1 (SGK1) is a kinase positioned downstream of multiple obesity-related pathways, and prior work has shown a pathologic role for SGK1 signaling in ventricular remodeling and arrhythmias. Objective: To determine the mechanistic basis of obesity associated atrial fibrillation and explore the therapeutic potential of targeting SGK1 in this context. Methods and Results: We utilized a mouse model of diet induced obesity to determine the atrial electrophysiologic effects of obesity using electrophysiologic studies, optical mapping, and biochemical analyses. In C57BL/6J mice fed a high fat diet, there was upregulation of SGK1 signaling along with an increase in AF inducibility determined at electrophysiology (EP) study. These changes were associated with an increase in fibrotic and inflammatory signaling. Transgenic mice expressing a cardiac specific dominant negative SGK1 (SGK1 DN) were protected from obesity-related AF as well as the fibrotic and inflammatory consequences of AF. Finally, optical mapping demonstrated a shorter action potential duration and patch clamp revealed effects on INa, with a decreased peak current as well as a depolarizing shift in activation/inactivation properties in atrial myocytes. Conclusions: Diet induced obesity leads to increased cardiac SGK1 signaling as well as an increase in AF inducibility in obese mice. Genetic SGK1 inhibition reduced AF inducibility, and this effect may be mediated by effects on inflammation, fibrosis, and cellular electrophysiology. 

scholarly journals Mutant VAPB: Culprit or Innocent Bystander of Amyotrophic Lateral Sclerosis?

Contact ◽  
2021 ◽  
Vol 4 ◽  
pp. 251525642110225
Author(s):  
Nica Borgese ◽  
Francesca Navone ◽  
Nobuyuki Nukina ◽  
Tomoyuki Yamanaka
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Dominant Negative ◽  
Negative Effects ◽  
Membrane Contact Sites ◽  
Familial Form ◽  
Main Driver ◽  
Mechanistic Basis ◽  
Lateral Sclerosis

Nearly twenty years ago a mutation in the VAPB gene, resulting in a proline to serine substitution (p.P56S), was identified as the cause of a rare, slowly progressing, familial form of the motor neuron degenerative disease Amyotrophic Lateral Sclerosis (ALS). Since then, progress in unravelling the mechanistic basis of this mutation has proceeded in parallel with research on the VAP proteins and on their role in establishing membrane contact sites between the ER and other organelles. Analysis of the literature on cellular and animal models reviewed here supports the conclusion that P56S-VAPB, which is aggregation-prone, non-functional and unstable, is expressed at levels that are insufficient to support toxic gain-of-function or dominant negative effects within motor neurons. Instead, insufficient levels of the product of the single wild-type allele appear to be required for pathological effects, and may be the main driver of the disease. In light of the multiple interactions of the VAP proteins, we address the consequences of specific VAPB depletion and highlight various affected processes that could contribute to motor neuron degeneration. In the future, distinction of specific roles of each of the two VAP paralogues should help to further elucidate the basis of p.P56S familial ALS, as well as of other more common forms of the disease.

Exosomes in atrial fibrillation: therapeutic potential and role as clinical biomarkers

2021 ◽  
Author(s):  
Kun Xiang ◽  
Muhammad Akram ◽  
Walaa Fikry Elbossaty ◽  
Jinfu Yang ◽  
Chengming Fan
Keyword(s):  
Atrial Fibrillation ◽  
Therapeutic Potential ◽  
Clinical Biomarkers

scholarly journals Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload cardiac hypertrophy

2015 ◽  
Vol 1853 (11) ◽  
pp. 2870-2884 ◽  
Author(s):  
Manuel Ramos-Kuri ◽  
Kleopatra Rapti ◽  
Hind Mehel ◽  
Shihong Zhang ◽  
Perundurai S. Dhandapany ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Ventricular Remodeling ◽  
Pressure Overload ◽  
Dominant Negative

scholarly journals MAG-EPA reduces severity of DSS-induced colitis in rats

2016 ◽  
Vol 310 (10) ◽  
pp. G808-G821 ◽  
Author(s):  
Caroline Morin ◽  
Pierre U. Blier ◽  
Samuel Fortin
Keyword(s):  
Therapeutic Potential ◽  
Combined Treatment ◽  
Neutrophil Infiltration ◽  
Antagonistic Effect ◽  
Omega 3 ◽  
Strong Activity ◽  
Tnf Α ◽  
Biochemical Analyses ◽  
Relaxing Effect

Ulcerative colitis (UC) is a chronic disease characterized by diffuse inflammation of the intestinal mucosa of the large bowel. Omega-3 (ω3) fatty acid supplementation has been associated with a decreased production of inflammatory cytokines involved in UC pathogenesis. The aim of this study was to determine the preventive and therapeutic potential of eicosapentaenoic acid monoglyceride (MAG-EPA) in an in vivo rats model of UC induced by dextran sulfate sodium (DSS). DSS rats were untreated or treated per os with MAG-EPA. Morphological, histological, and biochemical analyses were performed following MAG-EPA administrations. Morphological and histological analyses revealed that MAG-EPA pretreatment (12 days pre-DSS) and treatment (6 days post-DSS) exhibited strong activity in reducing severity of disease in DSS rats. Following MAG-EPA administrations, tissue levels of the proinflammatory cytokines TNF-α, IL-1β, and IL-6 were markedly lower compared with rats treated only with DSS. MAG-EPA per os administration decrease neutrophil infiltration in colon tissues, as depicted by myelohyperoxidase activity. Results also revealed a reduced activation of NF-κB pathways correlated with a decreased expression of COX-2 in colon homogenates derived from MAG-EPA-pretreated and treated rats. Tension measurements performed on colon tissues revealed that contractile responses to methacholine and relaxing effect induced by sodium nitroprusside were largely increased following MAG-EPA treatment. The combined treatment of MAG-EPA and vitamin E displayed an antagonistic effect on anti-inflammatory properties of MAG-EPA in DSS rats.

scholarly journals Isolated superfused rats atrial model for the investigation of atrial fibrillation mechanisms and treatment

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
S Glatstein ◽  
M Ghiringhelli ◽  
L Maizels ◽  
E Heller ◽  
E Maor ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
High Resolution ◽  
Sinus Rhythm ◽  
Optical Mapping ◽  
Ex Vivo ◽  
Anatomical Landmarks ◽  
Ex Vivo Model ◽  
Electrophysiological Properties ◽  
Custom Made ◽  
Isolated Atria

Abstract Background One of the major barriers to an improved mechanistic understanding of atrial fibrillation (AF), and thus in the pipeline of drug development, has been a lack of appropriate tissue models, especially in small animals. Aim We propose an advanced anatomical ex-vivo model based on rat atria for acute assessment of AF susceptibility. This novel model could yield a better understanding of arrhythmia mechanisms as well as the development of potential therapeutic strategies for the prevention or termination of atrial arrhythmias. Methods Wistar rats atria (N=25) were isolated, flattened and pinned to a custom-made silicon plate. Atria were superfused with an oxygenized Tyrode's solution. Tissues were then loaded with a voltage-sensitive dye and mapped using a high-resolution optical mapping system. AF was induced with 1uM carbamylcholine (N=23) coupled with pacing maneuvers and treated with 30uM Vernakalant (N=10) or 10uM Flecainide (N=10). Finally, the feasibility of a new ablation technique (electroporation) was evaluated. Results Optical mapping results suggested that the superfusion procedure led to a fast atrial recovery. Sinus activity was conserved for all atria for a long period. All the anatomical landmarks were clearly visualized. The acquired optical signals were analyzed during sinus rhythm and pacing, which allowed the creation of detailed activation maps and measurements of action potential duration (APD) and conduction velocity (CV) at different pacing rates. The resulting APD restitution curves revealed electrical excitation at high pacing rates (cycle length between 50ms and 300ms) with a relatively flattened curve. AF was successfully induced and optically mapping confirmed the presence of reentrant activity. AF was successfully treated using Vernacalant and Flecainide. Finally, we demonstrated the feasibility of a new ablation approach (electroporation) for creation of a continuous linear lesion serving as a functional block. Conclusion The isolated superfused atria model, coupled with voltage-sensitive dyes, can be utilized for long-term high-resolution functional imaging of the atria during sinus rhythm, pacing and arrhythmogenic activity. This allows the study of the atrial electrophysiological properties, the mechanisms involved in AF initiation, perpetuation, and termination as well as the study of drug and new ablation modalities. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Research Council (ERC) Spontaneous activation of isolated atria

scholarly journals Atrial fibrillation associated common risk variants in SYNE2 lead to lower expression of nesprin-2α1 and increased nuclear stiffness

2019 ◽  
Author(s):  
Nana Liu ◽  
Jeffrey Hsu ◽  
Gautam Mahajan ◽  
Han Sun ◽  
John Barnard ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Association Studies ◽  
Dominant Negative ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Gene Encoding ◽  
Enhancer Activity ◽  
Risk Alleles ◽  
Risk Variants ◽  
Lower Expression

ABSTRACTRationaleAtrial fibrillation (AF) genome-wide association studies (GWAS) identified significant associations for rs1152591 and linked variants in the SYNE2 gene encoding the nesprin-2 protein that connects the nuclear membrane with the cytoskeletonObjectiveDetermine the effects of the AF-associated rs1152591 and rs1152595, two linked intronic single nucleotide polymorphisms (SNPs), on SYNE2 expression and investigate the mechanisms for their association with AF.Methods and ResultsRNA sequencing of human left atrial appendage (LAA) tissues indicated that rs1152591 and rs1152595 were significantly associated with the expressions of SYNE2α1, a short mRNA isoform, without an effect on the expression of the full-length SYNE2 mRNA. SYNE2α1 mRNA uses an alternative transcription start site and encodes an N-terminal deleted 62 kDa nesprin-2α1 isoform, which can act as a dominant-negative on nuclear-cytoskeleton connectivity. Western blot and qPCR assays confirmed that AF risk alleles of both SNPs were associated with lower expression of nesprin-2α1 in human LAA tissues. Reporter gene transfections demonstrated that the risk vs. reference alleles of rs1152591 and rs1152595 had decreased enhancer activity. SYNE2 siRNA knockdown (KD) or nesprin-2α1 overexpression studies in human stem cell-derived induced cardiomyocytes (iCMs) resulted in ~12.5 % increases in the nuclear area compared to controls (p<0.001). Atomic force microscopy demonstrated that SYNE2 KD or nesprin-2α1 overexpression led to 57.5% or 33.2% decreases, respectively, in nuclear stiffness compared to controls (p< 0.0001).ConclusionsAF-associated SNPs rs1152591 and rs1152595 downregulate the expression of SYNE2α1, increasing nuclear-cytoskeletal connectivity and nuclear stiffness. The resulting increase in mechanical stress may play a role in the development of AF.

Termination of equine atrial fibrillation by quinidine: An optical mapping study

2008 ◽  
Vol 10 (2) ◽  
pp. 87-103 ◽  
Author(s):  
Flavio H. Fenton ◽  
Elizabeth M. Cherry ◽  
Bruce G. Kornreich
Keyword(s):  
Atrial Fibrillation ◽  
Optical Mapping ◽  
Mapping Study

scholarly journals Optical Mapping-Validated Machine Learning Improves Atrial Fibrillation Driver Detection by Multi-Electrode Mapping

2020 ◽  
Vol 13 (10) ◽  
Author(s):  
Alexander M. Zolotarev ◽  
Brian J. Hansen ◽  
Ekaterina A. Ivanova ◽  
Katelynn M. Helfrich ◽  
Ning Li ◽  
...  
Keyword(s):  
Machine Learning ◽  
Atrial Fibrillation ◽  
Near Infrared ◽  
Fourier Spectrum ◽  
Optical Mapping ◽  
Binary Classification ◽  
Future Application ◽  
Data Set ◽  
Frequency Spectra

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.

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