Atrial Fibrillation: Mechanisms, Therapeutics, and Future Directions

Pellman, Jason; Sheikh, Farah

doi:10.1002/cphy.c140047

Cited by 118 publications

(99 citation statements)

References 279 publications

(306 reference statements)

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“…Atrial fibrillation (AF) is the most common cardiac arrhythmia reported in clinical practice (1). There are three predominant mechanisms underlying AF: Electrical remodeling, structural remodeling and autonomic nerve remodeling (2). It is generally recognized that autonomic nerve remodeling serves an important role in the induction and maintenance of atrial tachycardia and AF (3).…”

Section: Introductionmentioning

confidence: 99%

Connexin 43 reduces susceptibility to sympathetic atrial fibrillation

et al. 2018

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Atrial fibrillation (AF) is the most common arrhythmia reported in clinical practice. Connexin 43 (Cx43) is a member of the connexin protein family, which serves important roles in signal transduction in vivo. The aim of the present study was to investigate the role of Cx43 in the induction and maintenance of atrial fibrillation by using an animal model of sympathomimetic atrial fibrillation. Cx43 was successfully knocked down in the myocardium with gene‑specific small interfering (si)RNA via lentiviral infection. A total of 25 dogs were randomly and evenly divided into five groups: Normal (N), rapid atrial pacing (RAP), isoproterenol (ISO) + RAP, RAP + Cx43 siRNA and ISO + RAP + Cx43 siRNA. The mRNA and protein levels, as well as the distribution of Cx43 on the cell membrane, were gradually decreased in each group compared with the N group following treatment (P<0.05). The induction rate of the atrial effective refractory period was not significantly affected in the RAP and RAP + Cx43 siRNA groups, whereas it was significantly reduced in the ISO + RAP and ISO + RAP + Cx43 siRNA groups compared with the N group (P<0.05). The induction rate of AF was gradually increased in the RAP + Cx43 siRNA, ISO + RAP and ISO + RAP + Cx43 siRNA groups compared with the N group (P<0.05). The expression of nerve growth factor (NGF) and tyrosine hydroxylase (TH) was gradually increased in the ISO + RAP and ISO + RAP + Cx43 siRNA groups compared with their respective controls (RAP and RAP + Cx43 siRNA groups, respectively). However, no significant difference in the levels of NGF and TH was observed between the RAP, RAP + Cx43 siRNA, ISO + RAP and ISO + RAP + Cx43 siRNA groups. The mitochondrial morphology in each group was notably altered compared with the N group. The mitochondrial reactive oxygen species production and apoptotic index were gradually increased in each group compared with the N group (P<0.05). The results of the present study suggest that Cx43 reduces susceptibility to AF. Downregulation of Cx43 mediates the induction and maintenance of sympathetic AF.

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Section: Introductionmentioning

confidence: 99%

Connexin 43 reduces susceptibility to sympathetic atrial fibrillation

et al. 2018

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“…Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting 1 to 2% of the population, and about 8% of individuals over 80 years of age (1). It is characterised by rapid and disorganised heart beating, triggered by electrical impulses usually originating in the roots of the pulmonary veins in the left atrium (LA), and has been identified as the leading cause of thromboembolic events, such as stroke and vascular dementia (2).…”

Section: Introductionmentioning

confidence: 99%

Computational Fluid Dynamic Analysis of the Left Atrial Appendage to Predict Thrombosis Risk

Bosi

Cook

Rai

et al. 2018

Front. Cardiovasc. Med.

111

114

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During Atrial Fibrillation (AF) more than 90% of the left atrial thrombi responsible for thromboembolic events originate in the left atrial appendage (LAA), a complex small sac protruding from the left atrium (LA). Current available treatments to prevent thromboembolic events are oral anticoagulation, surgical LAA exclusion, or percutaneous LAA occlusion. However, the mechanism behind thrombus formation in the LAA is poorly understood. The aim of this work is to analyse the hemodynamic behaviour in four typical LAA morphologies - “Chicken wing”, “Cactus”, “Windsock” and “Cauliflower” - to identify potential relationships between the different shapes and the risk of thrombotic events. Computerised tomography (CT) images from four patients with no LA pathology were segmented to derive the 3D anatomical shape of LAA and LA. Computational Fluid Dynamic (CFD) analyses based on the patient-specific anatomies were carried out imposing both healthy and AF flow conditions. Velocity and shear strain rate (SSR) were analysed for all cases. Residence time in the different LAA regions was estimated with a virtual contrast agent washing out. CFD results indicate that both velocity and SSR decrease along the LAA, from the ostium to the tip, at each instant in the cardiac cycle, thus making the LAA tip more prone to fluid stagnation, and therefore to thrombus formation. Velocity and SSR also decrease from normal to AF conditions. After four cardiac cycles, the lowest washout of contrast agent was observed for the Cauliflower morphology (3.27% of residual contrast in AF), and the highest for the Windsock (0.56% of residual contrast in AF). This suggests that the former is expected to be associated with a higher risk of thrombosis, in agreement with clinical reports in the literature. The presented computational models highlight the major role played by the LAA morphology on the hemodynamics, both in normal and AF conditions, revealing the potential support that numerical analyses can provide in the stratification of patients under risk of thrombus formation, towards personalised patient care.

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“…Regarding atrial extracellular matrix gene expression, TGF-β1 was similar between groups. TGFβ1 is an established positive regulator of cardiac brosis [27], is upregulated in AF patients with mitral valve disease submitted to valve replacement, and [28] postoperative AF in patients submitted to myocardial revascularization [29]. Nevertheless, studies on aortic stenosis are scarce.…”

Section: Discussionmentioning

confidence: 99%

Atrial Matrix Remodeling in Atrial Fibrillation Patients With Aortic Stenosis

Fragão-Marques¹,

Miranda²,

Martins

et al. 2020

Preprint

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Background: This study aimed to evaluate atrium extracellular matrix remodeling in Atrial fibrillation (AF) patients with severe aortic stenosis, through histological fibrosis quantification and extracellular matrix gene expression analysis, as well as serum quantification of selected protein targets. Methods: A posthoc analysis of a prospective study was performed in a cohort of aortic stenosis patients. Between 2014 and 2019, 56 patients with severe aortic stenosis submitted to Aortic valve replacement (AVR) surgery in a tertiary hospital were selected. Results: Fibrosis was significantly increased in the AF group when compared to Sinus Rhythm (SR) patients (p=0.024). Moreover, cardiomyocyte area was significantly higher in AF patients vs SR patients (p=0.008). Conversely, collagen III gene expression was increased in AF patients (p=0.038). TIMP1 was less expressed in the atria of AF patients. MMP16/TIMP4 ratio was significantly decreased in AF patients (p=0.006). TIMP1 (p=0.004) and TIMP2 (p=0.012) were significantly increased in the serum of AF patients. Aortic valve maximum (p=0.0159) and mean (p=0.031) gradients demonstrated a negative association with serum TIMP1. Conclusion: Atrial fibrillation patients with severe aortic stenosis present increased atrial fibrosis and collagen type III synthesis, with extracellular matrix remodelling demonstrated by a decrease in the MMP16/TIMP4 ratio, along with an increased serum TIMP1 and TIMP2 proteins.

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Atrial Fibrillation: Mechanisms, Therapeutics, and Future Directions

Cited by 118 publications

References 279 publications

Connexin 43 reduces susceptibility to sympathetic atrial fibrillation

Connexin 43 reduces susceptibility to sympathetic atrial fibrillation

Computational Fluid Dynamic Analysis of the Left Atrial Appendage to Predict Thrombosis Risk

Atrial Matrix Remodeling in Atrial Fibrillation Patients With Aortic Stenosis

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