scholarly journals The Effects of Fibrotic Cell Type and Its Density on Atrial Fibrillation Dynamics: An In Silico Study

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2769
Author(s):  
Laura C. Palacio ◽  
Juan P. Ugarte ◽  
Javier Saiz ◽  
Catalina Tobón
Keyword(s):  
Atrial Fibrillation ◽  
Conduction Velocity ◽  
Structural Changes ◽  
Cell Types ◽  
Realistic Model ◽  
Dominant Frequency ◽  
Diffuse Fibrosis ◽  
Fibrotic Process ◽  
In Silico Study ◽  
Fibrillatory Conduction

Remodeling in atrial fibrillation (AF) underlines the electrical and structural changes in the atria, where fibrosis is a hallmark of arrhythmogenic structural alterations. Fibrosis is an important feature of the AF substrate and can lead to abnormal conduction and, consequently, mechanical dysfunction. The fibrotic process comprises the presence of fibrotic cells, including fibroblasts, myofibroblasts and fibrocytes, which play an important role during fibrillatory dynamics. This work assesses the effect of the diffuse fibrosis density and the intermingled presence of the three types of fibrotic cells on the dynamics of persistent AF. For this purpose, the three fibrotic cells were electrically coupled to cardiomyocytes in a 3D realistic model of human atria. Low (6.25%) and high (25%) fibrosis densities were implemented in the left atrium according to a diffuse fibrosis representation. We analyze the action potential duration, conduction velocity and fibrillatory conduction patterns. Additionally, frequency analysis was performed in 50 virtual electrograms. The tested fibrosis configurations generated a significant conduction velocity reduction, where the larger effect was observed at high fibrosis density (up to 82% reduction in the fibrocytes configuration). Increasing the fibrosis density intensifies the vulnerability to multiple re-entries, zigzag propagation, and chaotic activity in the fibrillatory conduction. The most complex propagation patterns were observed at high fibrosis densities and the fibrocytes are the cells with the largest proarrhythmic effect. Left-to-right dominant frequency gradients can be observed for all fibrosis configurations, where the fibrocytes configuration at high density generates the most significant gradients (up to 4.5 Hz). These results suggest the important role of different fibrotic cell types and their density in diffuse fibrosis on the chaotic propagation patterns during persistent AF.

scholarly journals In-silico study of the ionic current gradients determining left-to-right atrial frequencies during paroxysmal atrial fibrillation

SIMULATION ◽  
2019 ◽  
Vol 95 (12) ◽  
pp. 1129-1139
Author(s):  
Laura C Palacio ◽  
Juan P Ugarte ◽  
Catalina Tobón
Keyword(s):  
Atrial Fibrillation ◽  
Paroxysmal Atrial Fibrillation ◽  
Potassium Current ◽  
Ionic Current ◽  
Dominant Frequency ◽  
Right Atrial ◽  
Therapeutic Approaches ◽  
In Silico Study ◽  
Frequency Gradient

Atrial fibrillation is the most prevalent cardiac arrhythmia. Paroxysmal atrial fibrillation (pAF) may occur in episodes lasting from minutes to days. Recent studies suggest that some pAF episodes present a left-to-right dominant frequency gradient caused by ionic current gradients. However, how each ionic current gradient affects the left-to-right dominant frequency gradient during pAF has not been studied. In this work, we use a 3D model of human atria to study how the ionic current gradients affect the dominant frequency gradient during pAF induced by continuous ectopic activity. The role of the specific gradients of acetylcholine-activated potassium current ( IKACh) and inward-rectifier potassium current ( IK1) on determining the left-to-right dominant frequency gradient was assessed. The main outcome of this study is that either or both of the IKACh or IK1 gradients are necessary to induce a left-to-right dominant frequency gradient during pAF. However, both gradients are necessary to the left atrium maintaining, by itself, the pAF episode. These findings have potentially important implications for the development of atrial-selective therapeutic approaches.

Abstract 16685: Obstructive Fibrosis Related to Transverse Conduction Slowing in Chronic Atrial Fibrillation

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Nathan A Angel ◽  
Li Li ◽  
Rob S MacLeod ◽  
Nassir Marrouche ◽  
Ravi Ranjan ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Conduction Velocity ◽  
Longitudinal Direction ◽  
Chronic Atrial Fibrillation ◽  
Diffuse Fibrosis ◽  
Control Group ◽  
Total Density ◽  
Atrial Contraction ◽  
Premature Atrial Contraction ◽  
History Of

Introduction: Patients with paroxysmal atrial fibrillation (AF) often transition between sinus rhythm and AF. For AF to initiate there must be both a trigger and a substrate that facilitates reentrant activity. This trigger is often caused by a premature atrial contraction or focal activations within the atrium. Hypothesis: We hypothesize long strands of continuous fibrosis act as a substrate that slows conduction, but only after a premature contraction. Methods: A high density electrode plaque was placed on 13 controls and 6 chronic AF goats (an average of 6 months of rapid pacing induced AF). Conduction slowing following a premature contraction was quantified. Atrial fibrosis was quantified into two groups, non-obstructive and obstructive fibrosis. Obstructive fibrosis was considered fibrosis that was at least the length of a myocyte (100 μm), thus potentially disrupting transverse cell to cell conduction. Non-obstructive fibrosis had a length less than 100 μm. Results: Conduction velocity of the AF goats was significantly slowed compared to the control goats in the transverse direction (0.40±0.03 m/s vs. 0.53±0.15 m/s, p<0.05) but not in the longitudinal direction (0.70±0.27 m/s vs. 0.76±0.18 m/s, p = N.S.) following a premature atrial contraction. The AF goats had more obstructive fibrosis than the controls (18±8 fibers/mm 2 vs. 9±3 fibers/mm 2 , p<0.05). The control group trended towards more non-obstructive, diffuse fibrosis than the AF animals (1109±309 fibers/mm 2 vs. 718±380 fibers/mm 2 , p = 0.07, N.S). Conclusions: Structural and electrophysiological remodeling in chronic AF leads conduction velocity slowing transverse to fiber orientation. Histology from goats with a history of chronic AF had more obstructive fibrosis, which may lead to the conduction slowing and alteration in conduction pathways to make the tissue more susceptible to AF. The amount of obstructive fibrosis may be more important to AF outcomes than the total density of fibrosis.

Neuronal mRNA Translation in Addiction

2018 ◽  
Author(s):  
Emma Puighermanal ◽  
Emmanuel Valjent
Keyword(s):  
Structural Changes ◽  
Drugs Of Abuse ◽  
Mrna Translation ◽  
Cell Types ◽  
Behavioral Changes ◽  
Translational Machinery ◽  
Addictive Drugs ◽  
Specific Mrnas ◽  
Cell Type Specific ◽  
Future Work

Addictive drugs trigger persistent synaptic and structural changes in the neuronal reward circuits that are thought to underlie the development of drug-adaptive behavior. While transcriptional and epigenetic modifications are known to contribute to these circuit changes, accumulating evidence indicates that altered mRNA translation is also a key molecular mechanism. This chapter reviews recent studies demonstrating how addictive drugs alter protein synthesis and/or the translational machinery and how this leads to neuronal circuit remodeling and behavioral changes. Future work will determine precisely which neuronal circuits and cell types participate in these changes. The chapter summarizes current methodologies for identifying cell type-specific mRNAs whose translation is affected by drugs of abuse and gives recent examples of the mechanistic insights into addiction they provide.

scholarly journals P1151Structural remodeling and conduction velocity dynamics in the human left atrium: relationship with reentrant mechanisms sustaining atrial tachycardia and atrial fibrillation

EP Europace ◽  
2018 ◽  
Vol 20 (suppl_1) ◽  
pp. i219-i219
Author(s):  
S Honarbakhsh ◽  
R J Schilling ◽  
M Orini ◽  
R Providencia ◽  
E Keating ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Left Atrium ◽  
Conduction Velocity ◽  
Atrial Tachycardia

scholarly journals Intercellular calcium signalling between chondrocytes and synovial cells in co-culture

1998 ◽  
Vol 329 (3) ◽  
pp. 681-687 ◽  
Author(s):  
Paola D'ANDREA ◽  
Alessandra CALABRESE ◽  
Micaela GRANDOLFO
Keyword(s):  
Gap Junctions ◽  
Intercellular Communication ◽  
Structural Changes ◽  
Articular Chondrocytes ◽  
Cell Metabolism ◽  
Second Messengers ◽  
Calcium Signalling ◽  
Cell Types ◽  
Synovial Cells ◽  
Cell Coupling

Intercellular communication allows the co-ordination of cell metabolism between tissues as well as sensitivity to extracellular stimuli. Paracrine stimulation and cell-to-cell coupling through gap junctions induce the formation of complex cellular networks that favour the intercellular exchange of nutrients and second messengers. Heterologous intercellular communication was studied in co-cultures of articular chondrocytes and HIG-82 synovial cells by measuring mechanically induced cytosolic changes in Ca2+ ion levels by digital fluorescence video imaging. In confluent co-cultures, mechanical stimulation induced intercellular Ca2+ waves that propagated to both cell types with similar kinetics. Intercellular wave spreading was inhibited by 18α-glycyrrhetinic acid and by treatments inhibiting the activation of purinoreceptors, suggesting that intercellular signalling between these two cell types occurs both through gap junctions and ATP-mediated paracrine stimulation. In rheumatoid arthritis the formation of the synovial pannus induces structural changes at the chondrosynovial junction, where chondrocyte and synovial cells come into close apposition: these results provide the first evidence for direct intercellular communication between these two cell types.

Abstract 14839: High-resolution Spatiotemporal Changes in Dominant Frequency and Structural Organization During Persistent Atrial Fibrillation

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Terrence Pong ◽  
Joy Aparicio Valenzuela ◽  
Kevin J Cyr ◽  
Cody Carlton ◽  
Sasank Sakhamuri ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
High Resolution ◽  
Structural Organization ◽  
Porcine Model ◽  
Dominant Frequency ◽  
Patient Specific ◽  
Structural Remodeling ◽  
Atrial Activity ◽  
Spatiotemporal Changes ◽  
Mapping Arrays

Introduction: Spatiotemporal differences in atrial activity are thought to contribute to the maintenance of atrial fibrillation (AF). While recent evidence has identified changes in dominant frequency (DF) during the transition from paroxysmal to persistent AF, little is known about the frequency characteristics of the epicardium during this transition. The purpose of this study was to perform high-resolution mapping of the atrial epicardium and to characterize changes in frequency activity and structural organization during the transition from paroxysmal to persistent AF. Hypothesis: In a porcine model of persistent AF, we tested the hypothesis that the epicardium undergoes spatiotemporal changes in atrial activity and structural organization during persistent AF. Methods: Paroxysmal and persistent AF was induced in adult Yorkshire swine by atrial tachypacing. Atrial morphology was segmented from magnetic resonance imaging and high-resolution patient-specific flexible mapping arrays were 3D printed to match the epicardial contours of the atria. Epicardial activation and DF mapping was performed in four paroxysmal and four persistent AF animals using personalized mapping arrays. Histological analysis was performed to determine structural differences between paroxysmal and persistent AF. Results: The left atrial epicardium was associated with a significant increase in DF between paroxysmal and persistent AF (6.5 ± 0.2 vs. 7.4 ± 0.5 Hz, P = 0.03). High-resolution spatiotemporal mapping identified organized clusters of DF during paroxysmal AF which were lost during persistent AF. The development of persistent AF led to structural remodeling with increased atrial epicardial fibrosis. The organization index (OI) significantly decreased during persistent AF in both the left atria (0.3 ± 0.03 vs. 0.2 ± 0.03, P = 0.01) and right atria (0.33 ± 0.04 vs. 0.23 ± 0.02, P = 0.02). Conclusions: In the porcine model of persistent AF, the epicardium undergoes structural remodeling with increased epicardial fibrosis, reflected by changes in atrial organization index and dominant frequency.

Abstract 3863: Deletion Of Integrin Alpha7 Leads To Altered Cardiac Conduction And Sudden Death Associated With Connexin43 Downregulation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Raja Nadif ◽  
Michael Emerson ◽  
Ulrike Mayer ◽  
Ludwig Neyses ◽  
Elizabeth Cartwright
Keyword(s):  
Atrial Fibrillation ◽  
Extracellular Matrix ◽  
Ventricular Hypertrophy ◽  
Structural Changes ◽  
Cellular Adhesion ◽  
Left Ventricular ◽  
Cardiac Conduction ◽  
Cardiac Phenotype ◽  
One Year ◽  
Deficient Mice

Effective propagation of the electrical impulse throughout the myocardium is highly dependent on cell-to-cell and cell-to-extracellular matrix interactions. Increasing evidence indicates that dysregulation of cellular adhesion is a critical determinant in the genesis of arrhythmia. Null mutations in the integrin α7 gene, an essential mediator of cellular adhesion in cardiac and skeletal muscles, have been linked to myopathy in humans, however, the in vivo role of the integrin α7 subunit in the heart is undefined. The mouse model of integrin α7 deletion dies prematurely at one year of age. We therefore analysed the cardiac phenotype in integrin α7 deficient mice (α7 −/− ) to determine whether their premature death was associated with altered cardiac conduction. One year old integrin α7 −/− mice exhibited altered cardiac conduction characterised by spontaneous atrial fibrillation and prolonged QTc duration (α7 −/− : 25.7±0.74ms, α7 +/+ : 19.5±0.61ms; n=6; p<0.001, QTc=QT/(RR/100) 1/2 ). The abnormal cardiac conduction was associated with downregulation of connexin43. However, no significant changes were observed in the expression of ion chanels that have been linked to long QT syndrome or atrial fibrillation (kv1.1, kv1.5, kcne1, kcnq1, erg1, Cav1.2 and Cav1.3). In addition, α7 −/− mice displayed increased susceptibility to drug-induced arrhythmias: treatment with ouabain (2mg/kg BW) in combination with isoprenaline (2.5mg/kg BW) induced atrial fibrillation and ventricular tachycardia and eventually death in 6 month-old integrin α7 −/− mice, but not in α7 +/+ mice. Interestingly, α7 −/− also displayed concentric ventricular hypertrophy with increased septal wall thickness and reduced left ventricular end-diastolic diameter starting from 6 months of age. These structural changes were accompanied by an increase in myocyte size and increased ERK1/2 phosphorylation. In conclusion, deletion of the integrin α7 gene in mice leads to ventricular hypertrophy and to abnormal cardiac conduction. The integrin α7 deficient mice have a marked propensity to lethal arrhythmias through alterations in gap junctions but not ion channels. The integrin α7 knockout model provides new insight into the link between the extracellular matrix and cardiac conduction.

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