Extracellular Vesicles From Epicardial Fat Facilitate Atrial Fibrillation

Shaihov-Teper, Olga; Ram, Eilon; Ballan, Nimer; Brzezinski, Rafael Y.; Naftali‐Shani, Nili; Masoud, Rula; Ziv, Tamar; Lewis, Nir; Schary, Yeshai; Levin-Kotler, La-Paz; Volvovitch, David; Zuroff, Elchanan; Amunts, Sergei; Regev‐Rudzki, Neta; Sternik, Leonid; Raanani, Ehud; Gepstein, Lior; Leor, Jonathan

doi:10.1161/circulationaha.120.052009

Cited by 124 publications

(124 citation statements)

References 70 publications

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“…Bioinformatics analysis showed that these miRNAs and their targets possibly contribute to atrial fibrosis (11). Moreover, it has been demonstrated that, compared with the control group, the epicardial adipose tissue of patients with AF secretes more exosomes, and the expression of pro-inflammatory and pro-fibrotic factors is higher in exosomes (12). In addition, a recent study reported that myofibroblast-derived exosomes reduced the expression of voltage-gated L-type calcium channel subunit α1c (Ca v 1.2) and increased the vulnerability to AF (13).…”

Section: Introductionmentioning

confidence: 99%

Blockade of Exosome Release Suppresses Atrial Fibrillation by Alleviating Atrial Fibrosis in Canines With Prolonged Atrial Pacing

Yao

Wang

et al. 2021

Front. Cardiovasc. Med.

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Background: Clinical studies have shown that exosomes are associated with atrial fibrillation (AF). However, the roles and underlying mechanisms remain unclear. Hence, this study aimed to investigate the function of exosomes in AF development.Methods: Twenty beagles were randomly divided into the sham group (n = 6), the pacing group (n = 7), and the pacing + GW4869 group (n = 7). The pacing and GW4869 groups underwent rapid atrial pacing (450 beats/min) for 7 days. The GW4869 group received intravenous GW4869 injection (an inhibitor of exosome biogenesis/release, 0.3 mg/kg, once a day) during pacing. Electrophysiological measurements, transmission electron microscopy, nanoparticle tracking analysis, western blotting, RT-PCR, Masson's staining, and immunohistochemistry were performed in this study.Results: Rapid atrial pacing increased the release of plasma and atrial exosomes. GW4869 treatment markedly suppressed AF inducibility and reduced the release of exosomes. After 7 days of pacing, the expression of transforming growth factor-β1 (TGF-β1), collagen I/III, and matrix metalloproteinases was enhanced in the atrium, and the levels of microRNA-21-5p (miR-21-5p) were upregulated in both plasma exosomes and the atrium, while the tissue inhibitor of metalloproteinase 3 (TIMP3), a target of miR-21-5p, showed a lower expression in the atrium. The administration of GW4869 abolished these effects.Conclusions: The blockade of exosome release with GW4869 suppressed AF by alleviating atrial fibrosis in a canine model, which was probably related to profibrotic miR-21-5p enriched in exosomes and its downstream TIMP3/TGF-β1 pathway.

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Section: Introductionmentioning

confidence: 99%

Blockade of Exosome Release Suppresses Atrial Fibrillation by Alleviating Atrial Fibrosis in Canines With Prolonged Atrial Pacing

Yao

Wang

et al. 2021

Front. Cardiovasc. Med.

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“…Interestingly, a unique molecular footprint has recently been shown in EAT from AF subjects. In particular, EAT derived extracellular vesicles (EVs) exert profibrotic/proinflammatory effects on the neighboring atrial tissue, promoting arrhythmogenesis [ 71 ]. In addition, EAT expansion seems to be positively regulated through increased atrial natriuretic peptide (ANP) levels [ 72 ].…”

Section: Atrial Fibrillation Pathogenesismentioning

confidence: 99%

Molecular Insights in Atrial Fibrillation Pathogenesis and Therapeutics: A Narrative Review

et al. 2021

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The prevalence of atrial fibrillation (AF) is bound to increase globally in the following years, affecting the quality of life of millions of people, increasing mortality and morbidity, and beleaguering health care systems. Increasingly effective therapeutic options against AF are the constantly evolving electroanatomic substrate mapping systems of the left atrium (LA) and ablation catheter technologies. Yet, a prerequisite for better long-term success rates is the understanding of AF pathogenesis and maintenance. LA electrical and anatomical remodeling remains in the epicenter of current research for novel diagnostic and treatment modalities. On a molecular level, electrical remodeling lies on impaired calcium handling, enhanced inwardly rectifying potassium currents, and gap junction perturbations. In addition, a wide array of profibrotic stimuli activates fibroblast to an increased extracellular matrix turnover via various intermediaries. Concomitant dysregulation of the autonomic nervous system and the humoral function of increased epicardial adipose tissue (EAT) are established mediators in the pathophysiology of AF. Local atrial lymphomononuclear cells infiltrate and increased inflammasome activity accelerate and perpetuate arrhythmia substrate. Finally, impaired intracellular protein metabolism, excessive oxidative stress, and mitochondrial dysfunction deplete atrial cardiomyocyte ATP and promote arrhythmogenesis. These overlapping cellular and molecular alterations hinder us from distinguishing the cause from the effect in AF pathogenesis. Yet, a plethora of therapeutic modalities target these molecular perturbations and hold promise in combating the AF burden. Namely, atrial selective ion channel inhibitors, AF gene therapy, anti-fibrotic agents, AF drug repurposing, immunomodulators, and indirect cardiac neuromodulation are discussed here.

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“…Subsequently, we discussed the pros and cons of the use of exosomes. The application of exosomes has many advantages (32,193,230): (1) Alterations in exo-cargoes profile secreted by cardiac cells during AF would reflect the parental cells pathophysiological state with extreme specificity and sensitivity, and therefore they may appear as "fingerprint" of the AF pathogenetic processes; (2) Exosomes can be isolated from nearly all obtainable biofluids such as blood and urine; (3) Exosomes serve as a vehicle that protects cargoes from degradation and targets the cargoes to the recipient cells, with the less traumatic and abnormal modifications. (4) Welldesigned engineered exosomes may enhance their therapeutic effects, making them promising tools for clinical application.…”

Section: Advantages and Disadvantages Of Exosome For Afmentioning

confidence: 99%

Exosomes and Exosomal Non-coding RNAs Are Novel Promises for the Mechanism-Based Diagnosis and Treatments of Atrial Fibrillation

Chen

Cheng

et al. 2021

Front. Cardiovasc. Med.

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Atrial fibrillation (AF) is the most common arrhythmia worldwide and has a significant impact on human health and substantial costs. Currently, there is a lack of accurate biomarkers for the diagnosis and prognosis of AF. Moreover, the long-term efficacy of the catheter ablation in the AF is unsatisfactory. Therefore, it is necessary to explore new biomarkers and treatment strategies for the mechanism-based AF. Exosomes are nano-sized biovesicles released by nearly all types of cells. Since the AF would be linked to the changes of the atrial cells and their microenvironment, and the AF would strictly influence the exosomal non-coding RNAs (exo-ncRNAs) expression, which makes them as attractive diagnostic and prognostic biomarkers for the AF. Simultaneously, the exo-ncRNAs have been found to play an important role in the mechanisms of the AF and have potential therapeutic prospects. Although the role of the exo-ncRNAs in the AF is being actively investigated, the evidence is still limited. Furthermore, there is a lack of consensus regarding the most appropriate approach for exosome isolation and characterization. In this article, we reviewed the new methodologies available for exosomes biogenesis, isolation, and characterization, and then discussed the mechanism of the AF and various levels and types of exosomes relevant to the AF, with the special emphasis on the exo-ncRNAs in the diagnosis, prognosis, and treatment of the mechanism-based AF.

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Extracellular Vesicles From Epicardial Fat Facilitate Atrial Fibrillation

Cited by 124 publications

References 70 publications

Blockade of Exosome Release Suppresses Atrial Fibrillation by Alleviating Atrial Fibrosis in Canines With Prolonged Atrial Pacing

Blockade of Exosome Release Suppresses Atrial Fibrillation by Alleviating Atrial Fibrosis in Canines With Prolonged Atrial Pacing

Molecular Insights in Atrial Fibrillation Pathogenesis and Therapeutics: A Narrative Review

Exosomes and Exosomal Non-coding RNAs Are Novel Promises for the Mechanism-Based Diagnosis and Treatments of Atrial Fibrillation

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