Secretome of atrial epicardial adipose tissue facilitates reentrant arrhythmias by myocardial remodeling

Ernault, Auriane C.; Verkerk, Arie O.; Bayer, Jason D.; Aras, Kedar; Montañés-Agudo, Pablo; Mohan, Rajiv A; Veldkamp, Marieke W.; Rivaud, Mathilde R.; Winter, Rosan de; Kawasaki, Masanori; Amersfoorth, Shirley C.M. van; Meulendijks, Eva R.; Driessen, Antoine H.G.; Efimov, Igor R.; Groot, Joris R. de; Coronel, Ruben

doi:10.1016/j.hrthm.2022.05.011

Cited by 25 publications

(20 citation statements)

References 14 publications

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“…Other studies have also reached similar conclusions 123,124 . Based on CT measurements of EAT volume and cardiac electrophysiological mapping in patients, Nalliah et al 123 .…”

Section: Remodeled Eat Might Be a Cause Of Cvds: Preliminary Evidence...mentioning

confidence: 64%

“…Other studies have also reached similar conclusions. 123,124 Based on CT measurements of EAT volume and cardiac electrophysiological mapping in patients, Nalliah et al 123 found that the right atrial EAT volume is highly associated with atrial electrophysiological dysfunction and cardiac fibrosis, which are related to the mechanisms underlying AF. Further, they performed in vitro coculture experiments to investigate the paracrine effects of EAT on cardiomyocyte electrophysiology.…”

Section: Exploring the Causal Link Between Eat And Afmentioning

confidence: 99%

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Epicardial adipose tissue, metabolic disorders, and cardiovascular diseases: recent advances classified by research methodologies

Song,

Tan,

Deng

et al. 2023

MedComm

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Epicardial adipose tissue (EAT) is located between the myocardium and visceral pericardium. The unique anatomy and physiology of the EAT determines its great potential in locally influencing adjacent tissues such as the myocardium and coronary arteries. Classified by research methodologies, this study reviews the latest research progress on the role of EAT in cardiovascular diseases (CVDs), particularly in patients with metabolic disorders. Studies based on imaging techniques demonstrated that increased EAT amount in patients with metabolic disorders is associated with higher risk of CVDs and increased mortality. Then, in‐depth profiling studies indicate that remodeled EAT may serve as a local mediator of the deleterious effects of cardiometabolic conditions and plays a crucial role in CVDs. Further, in vitro coculture studies provided preliminary evidence that the paracrine effect of remodeled EAT on adjacent cardiomyocytes can promote the occurrence and progression of CVDs. Considering the important role of EAT in CVDs, targeting EAT might be a potential strategy to reduce cardiovascular risks. Several interventions have been proved effective in reducing EAT amount. Our review provides valuable insights of the relationship between EAT, metabolic disorders, and CVDs, as well as an overview of the methodological constructs of EAT‐related studies.

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“…Other studies have also reached similar conclusions 123,124 . Based on CT measurements of EAT volume and cardiac electrophysiological mapping in patients, Nalliah et al 123 .…”

Section: Remodeled Eat Might Be a Cause Of Cvds: Preliminary Evidence...mentioning

confidence: 64%

Section: Exploring the Causal Link Between Eat And Afmentioning

confidence: 99%

Epicardial adipose tissue, metabolic disorders, and cardiovascular diseases: recent advances classified by research methodologies

Song,

Tan,

Deng

et al. 2023

MedComm

View full text Add to dashboard Cite

show abstract

“…Fibrofatty infiltrates are associated with AF, potentially through conduction slowing or heterogeneity [ 12 , 17 ]. Besides myocardial infiltration, which potentially forms structural conduction barriers, we recently demonstrated a direct effect on conduction slowing and heterogeneity in cardiomyocyte cultures exposed to EAT secretome of patients with AF [ 13 ]. No conduction slowing was observed when cell cultures were exposed to subcutaneous AT secretome.…”

Section: Discussionmentioning

confidence: 99%

Atrial epicardial adipose tissue abundantly secretes myeloperoxidase and activates atrial fibroblasts in patients with atrial fibrillation

et al. 2023

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Background Epicardial adipose tissue (EAT) secretome induces fibrosis. Fibrosis, primarily extracellular matrix (ECM) produced by fibroblasts, creates a substrate for atrial fibrillation (AF). Whether the EAT secretome from patients with AF activates human atrial fibroblasts and through which components, remains unexplored. Research aims (a) To investigate if the EAT secretome from patients with versus without AF increases ECM production in atrial fibroblasts. (b) To identify profibrotic proteins and processes in the EAT secretome and EAT from patients with, who will develop (future onset), and without AF. Methods Atrial EAT was obtainded during thoracoscopic ablation (AF, n = 20), or open-heart surgery (future onset and non-AF, n = 35). ECM gene expression of human atrial fibroblasts exposed to the EAT secretome and the proteomes of EAT secretome and EAT were assessed in patients with and without AF. Myeloperoxidase and neutrophil extracellular traps (NETs) were assessed immunohistochemically in patients with paroxysmal, persistent, future onset, and those who remain free of AF (non-AF). Results The expression of COL1A1 and FN1 in fibroblasts exposed to secretome from patients with AF was 3.7 and 4.7 times higher than in patients without AF (p < 0.05). Myeloperoxidase was the most increased protein in the EAT secretome and EAT from patients with versus without AF (FC 18.07 and 21.57, p < 0.005), as was the gene-set neutrophil degranulation. Immunohistochemically, myeloperoxidase was highest in persistent (FC 13.3, p < 0.0001) and increased in future onset AF (FC 2.4, p = 0.02) versus non-AF. Myeloperoxidase aggregated subepicardially and around fibrofatty infiltrates. NETs were increased in patients with persistent versus non-AF (p = 0.03). Conclusion In AF, the EAT secretome induces ECM gene expression in atrial fibroblasts and contains abundant myeloperoxidase. EAT myeloperoxidase was increased prior to AF onset, and both myeloperoxidase and NETs were highest in persistent AF, highlighting the role of EAT neutrophils in the pathophysiology of AF.

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“…Electrical mapping was performed as previously described ( Ernault et al, 2022 ). Briefly, 10 min before measurements, CM-FB culture media were replaced by a modified Tyrode’s solution (36.5°C) containing (mM): NaCl 140, KCl 5.4, CaCl2 1.8, MgCl2 1.0, glucose 5.5, HEPES 5.0; pH 7.4.…”

Section: Methodsmentioning

confidence: 99%

Knockdown of Ift88 in fibroblasts causes extracellular matrix remodeling and decreases conduction velocity in cardiomyocyte monolayers

et al. 2022

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Background: Atrial fibrosis plays an important role in the development and persistence of atrial fibrillation by promoting reentry. Primary cilia have been identified as a regulator of fibroblasts (FB) activation and extracellular matrix (ECM) deposition. We hypothesized that selective reduction of primary cilia causes increased fibrosis and facilitates reentry.Aim: The aim of this study was to disrupt the formation of primary cilia in FB and examine its consequences on ECM and conduction in a co-culture system of cardiomyocytes (CM) and FB.Materials: Using short interfering RNA (siRNA), we removed primary cilia in neonatal rat ventricular FB by reducing the expression of Ift88 gene required for ciliary assembly. We co-cultured neonatal rat ventricular cardiomyocytes (CM) with FB previously transfected with Ift88 siRNA (siIft88) or negative control siRNA (siNC) for 48 h. We examined the consequences of ciliated fibroblasts reduction on conduction and tissue remodeling by performing electrical mapping, microelectrode, and gene expression measurements.Results: Transfection of FB with siIft88 resulted in a significant 60% and 30% reduction of relative Ift88 expression in FB and CM-FB co-cultures, respectively, compared to siNC. Knockdown of Ift88 significantly increased the expression of ECM genes Fn1, Col1a1 and Ctgf by 38%, 30% and 18%, respectively, in comparison to transfection with siNC. Conduction velocity (CV) was significantly decreased in the siIft88 group in comparison to siNC [11.12 ± 4.27 cm/s (n = 10) vs. 17.00 ± 6.20 (n = 10) respectively, p < 0.05]. The fraction of sites with interelectrode activation block was larger in the siIft88 group than in the siNC group (6.59 × 10−2 ± 8.01 × 10−2 vs. 1.18 × 10−2 ± 3.72 × 10−2 respectively, p < 0.05). We documented spontaneous reentrant arrhythmias in two cultures in the siIft88 group and in none of the siNC group. Action potentials were not significantly different between siNC and siIft88 groups.Conclusion: Disruption of cilia formation by siIft88 causes ECM remodeling and conduction abnormalities. Prevention of cilia loss could be a target for prevention of arrhythmias.

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Secretome of atrial epicardial adipose tissue facilitates reentrant arrhythmias by myocardial remodeling

Cited by 25 publications

References 14 publications

Epicardial adipose tissue, metabolic disorders, and cardiovascular diseases: recent advances classified by research methodologies

Epicardial adipose tissue, metabolic disorders, and cardiovascular diseases: recent advances classified by research methodologies

Atrial epicardial adipose tissue abundantly secretes myeloperoxidase and activates atrial fibroblasts in patients with atrial fibrillation

Knockdown of Ift88 in fibroblasts causes extracellular matrix remodeling and decreases conduction velocity in cardiomyocyte monolayers

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