Structural Remodeling In Atrial Fibrillation Research Articles

PDCD4 promotes inflammation/fibrosis by activating the PPAR‑γ/NF‑κB pathway in mouse atrial myocytes.

Fibrosis is the basis of structural remodeling in atrial fibrillation (AF), during which inflammation is crucial. Programmed cell death factor 4 (PDCD4) is a newly identified inflammatory gene, with unknown mechanisms of action in AF. The present study aimed to elucidate the effects of PDCD4 on the inflammation and structural remodeling of atrial myocytes. For this purpose, a PDCD4 overexpression plasmid (oePDCD4) and PDCD4 small interfering (si)RNA (siPDCD4) were used to modulate PDCD4 expression in mouse atrial myocytes (HL‑1 cells). The expression of PDCD4 was detected using reverse transcription‑quantitative PCR and western blot analysis. The optimal drug concentrations of peroxisome proliferator‑activated receptor γ (PPARγ) agonist (pioglitazone hydrochloride), NF‑κB inhibitor (CBL0137), PPARγ inhibitor (GW9962) and NF‑κB agonist (betulinic acid) were screened using a Cell Counting Kit‑8 assay. The levels of inflammatory factors were detected using enzyme‑linked immunosorbent assays, the expression levels of fibrosis‑related proteins and NF‑κB subunits were detected using western blot analysis, and the expression of phosphorylated (p‑)p65/p65 was detected using immunofluorescence staining. The results revealed that PDCD4 overexpression increased the levels of fibrotic factors (collagen I, collagen III, fibronectin, α‑smooth muscle actin and matrix metalloproteinase 2), pro‑inflammatory cytokines (IFN‑γ, IL‑6, IL‑17A and TNF‑α) and p‑p65, whereas it reduced the levels of anti‑inflammatory cytokines (IL‑4) in HL‑1 cells. Additionally, treatment with the PPARγ agonist and NF‑κB inhibitor reversed the levels of fibrotic‑, pro‑inflammatory and anti‑inflammatory factors in oePDCD4‑HL‑1 cells. By contrast, PDCD4 silencing exerted the opposite effects on fibrotic factors, pro‑inflammatory cytokines, anti‑inflammatory cytokines and p‑p65. In addition, treatment with the PPARγ inhibitor and NF‑κB agonist reversed the levels of fibrotic‑, pro‑inflammatory and anti‑inflammatory factors in siPDCD4‑HL‑1 cells. In conclusion, the present study demonstrated that PDCD4 may induce inflammation and fibrosis by activating the PPARγ/NF‑κB signaling pathway, thereby promoting the structural remodeling of atrial myocytes in AF.

MiR-135a Regulates Atrial Fibrillation by Targeting Smad3.

Atrial fibrillation (AF) is the most common arrhythmia in clinical. Atrial fibrosis is a hallmark feature of atrial structural remodeling in AF, which is regulated by the TGF-β1/Smad3 pathway. Recent studies have implicated that miRNAs are involved in the process of AF. However, the regulatory mechanisms of miRNAs remain largely unknown. This study is aimed at investigating the function and regulatory network of miR-135a in AF. In vivo, the plasma was collected from patients with AF and non-AF subjects. Adult SD rats were induced by acetylcholine (ACh) (66 μg/ml)-CaCl2 (10 mg/ml) to establish an AF rat model. In vitro, atrial fibroblasts (AFs), isolated from adult SD rats, were treated with high-frequency electrical stimulation (HES) (12 h) and hypoxia (24 h) to mimic the AF and atrial fibrosis, respectively. miR-135a expression was detected through quantitative real-time polymerase chain reaction (qRT-PCR). The association between miR-135a and Smad3 was speculated by the TargetScan database and confirmed by the luciferase reporter assay. Fibrosis-related genes, Smad3, and TRPM7 were all assessed. The expression of miR-135a was markedly decreased in the plasma of AF patients and AF rats, which was consistent with that in HES-treated and hypoxia-treated AFs. Smad3 was identified as a target of miR-135a. the downregulation of miR-135a was associated with the enhancement of Smad3/TRPM7 expressions in AFs. Additionally, the knockdown of Smad3 significantly reduced the expression of TRPM7 and further inhibited atrial fibrosis. Our study demonstrates that miR-135a regulates AF via Smad3/TRPM7, which is a potential therapeutic target for AF.

KCa3.1 Promotes Proinflammatory Exosome Secretion by Activating AKT/Rab27a in Atrial Myocytes during Rapid Pacing.

The aim of this study was to investigate the role of the medium-conductance calcium-activated potassium channel (KCNN4, KCa3.1) in the secretion of proinflammatory exosomes by atrial myocytes. Eighteen beagles were randomly divided into the sham group (n = 6), pacing group (n = 6), and pacing+TRAM-34 group (n = 6). Electrophysiological data, such as the effective refractory period, atrial fibrillation (AF) induction, and AF duration, were collected by programmed stimulation. Atrial tissues were subjected to hematoxylin and eosin, Masson's trichrome, and immunofluorescence staining. The expression of KCa3.1 and Rab27a was assessed by immunohistochemistry and western blotting. The downstream signaling pathways involved in KCa3.1 were examined by rapid pacing or overexpressing KCNN4 in HL-1 cells. Atrial rapid pacing significantly induced electrical remodeling, inflammation, fibrosis, and exosome secretion in the canine atrium, while TRAM-34 (KCa3.1 blocker) inhibited these changes. Compared with those in control HL-1 cells, the levels of exosome markers and inflammatory factors were increased in pacing HL-1 cells. Furthermore, the levels of CD68 and iNOS in macrophages incubated with exosomes derived from HL-1 cells were higher in the pacing-exo group than in the control group. More importantly, KCa3.1 regulated exosome secretion through the AKT/Rab27a signaling pathway. Similarly, inhibiting the downstream signaling pathway of KCa3.1 significantly inhibited exosome secretion. KCa3.1 promotes proinflammatory exosome secretion through the AKT/Rab27a signaling pathway. Inhibiting the KCa3.1/AKT/Rab27a signaling pathway reduces myocardial tissue structural remodeling in AF.

Novel preventive effect of isorhamnetin on electrical and structural remodeling in atrial fibrillation.

Isorhamnetin, a natural flavonoid, has strong antioxidant and antifibrotic effects, and a regulatory effect against Ca2+-handling. Atrial remodeling due to fibrosis and abnormal intracellular Ca2+ activities contributes to initiation and persistence of atrial fibrillation (AF). The present study investigated the effect of isorhamnetin on angiotensin II (AngII)-induced AF in mice. Wild-type male mice (C57BL/6J, 8 weeks old) were assigned to three groups: (1) control group, (2) AngII-treated group, and (3) AngII- and isorhamnetin-treated group. AngII (1000 ng/kg/min) and isorhamnetin (5 mg/kg) were administered continuously via an implantable osmotic pump for two weeks and intraperitoneally one week before initiating AngII administration, respectively. AF induction and electrophysiological studies, Ca2+ imaging with isolated atrial myocytes and HL-1 cells, and action potential duration (APD) measurements using atrial tissue and HL-1 cells were performed. AF-related molecule expression was assessed and histopathological examination was performed. Isorhamnetin decreased AF inducibility compared with the AngII group and restored AngII-induced atrial effective refractory period prolongation. Isorhamnetin eliminated abnormal diastolic intracellular Ca2+ activities induced by AngII. Isorhamnetin also abrogated AngII-induced APD prolongation and abnormal Ca2+ loading in HL-1 cells. Furthermore, isorhamnetin strongly attenuated AngII-induced left atrial enlargement and atrial fibrosis. AngII-induced elevated expression of AF-associated molecules, such as ox-CaMKII, p-RyR2, p-JNK, p-ERK, and TRPC3/6, was improved by isorhamnetin treatment. The findings of the present study suggest that isorhamnetin prevents AngII-induced AF vulnerability and arrhythmogenic atrial remodeling, highlighting its therapeutic potential as an anti-arrhythmogenic pharmaceutical or dietary supplement.

Abstract 9449: Increased Neprilysin Expression Links Atrial Fibrotic Remodeling in Cardiovascular Surgery Patients

Introduction: Deposition of extracellular matrix (ECM) such as collagen leads to fibrosis, which plays essential roles in structural remodeling in atrial fibrillation (AF). Neprilysin (NEP) is an integral membrane-bound metallopeptidase with a wide spectrum of substrates and physiological functions. Hypothesis: We investigated the association of NEP and the atrial fibrosis-related genes in cardiovascular surgery patients including heart valve disease. Methods: Atrial mRNA expression including collagen and NEP were analyzed by real-time reverse transcription polymerase chain reaction (RT-PCR) in 59 cases (sinus rhythm (SR) 24 patients, AF 35 patients) in which LA tissues were removed from the appendage during surgery. NEP mRNA expression was also analyzed in adipose tissues (AT) obtained from both epicardial and subcutaneous adipose tissues. The NEP protein expression was measured by western blotting analysis and immunohistochemistry staining, and serum level of NEP was measured by ELISA. Results: The immunohistochemical staining showed the expression of NEP in both AT and LA. Higher expression of NEP mRNA and protein in adipose tissues was observed, compared with LA. Serum NEP concentration did not significantly correlate with NEP mRNA and protein expression of AT and LA. The significant correlations were observed among ECM (COL1A1, COL3A1, fibronectin) and the five selected fibrosis-related genes (TGFβ1, CTGF, miR21, NOX2 and BAX) attributed to the fibrosis of myocardium in LA. NEP mRNA expression of LA also positively correlated with the ECM and the fibrosis-related gene expression level. The multiple regression analysis revealed TGFβ1, NOX2, and NEP as independent predictors of atrial COL1A1 mRNA expression level. In addition, it revealed NEP as an independent predictor of COL1A1 mRNA expression level, even adjusted by age, sex, and BMI. Serum NEP concentration did not correlate with the ECM and the fibrosis-gene expression level. Patients with AF had higher atrial expression of NEP protein, compared to those with SR. Conclusions: Increased atrial expression of NEP links atrial fibrotic remodeling and developing AF in cardiovascular surgery patients. However, serum NEP did not reflect atrial NEP expression in LA.

Progressive and Simultaneous Right and Left Atrial Remodeling Uncovered by a Comprehensive Magnetic Resonance Assessment in Atrial Fibrillation.

Background Left atrial structural remodeling contributes to the arrhythmogenic substrate of atrial fibrillation (AF), but the role of the right atrium (RA) remains unknown. Our aims were to comprehensively characterize right atrial structural remodeling in AF and identify right atrial parameters predicting recurrences after ablation. Methods and Results A 3.0 T late gadolinium enhanced-cardiac magnetic resonance was obtained in 109 individuals (9 healthy volunteers, 100 patients with AF undergoing ablation). Right and left atrial volume, surface, and sphericity were quantified. Right atrial global and regional fibrosis burden was assessed with validated thresholds. Patients with AF were systematically followed after ablation for recurrences. Progressive right atrial dilation and an increase in sphericity were observed from healthy volunteers to patients with paroxysmal and persistent AF; fibrosis was similar among the groups. The correlation between parameters recapitulating right atrial remodeling was mild. Subsequently, remodeling in both atria was compared. The RA was larger than the left atrium (LA) in all groups. Fibrosis burden was higher in the LA than in the RA of patients with AF, whereas sphericity was higher in the LA of patients with persistent AF only. Fibrosis, volume, and surface of the RA and LA, but not sphericity, were strongly correlated. Tricuspid regurgitation predicted right atrial volume and shape, whereas diabetes was associated with right atrial fibrosis burden; sex and persistent AF also predicted right atrial volume. Fibrosis in the RA was mostly located in the inferior vena cava-RA junction. Only right atrial sphericity is significantly associated with AF recurrences after ablation (hazard ratio, 1.12 [95% CI, 1.01-1.25]). Conclusions AF progression associates with right atrial remodeling in parallel with the LA. Right atrial sphericity yields prognostic significance after ablation.

Clinical outcomes and structural remodelling after ablation of atrial fibrillation in heart failure with mildly reduced or mid-range ejection fraction.

The efficacy of catheter ablation (CA) on clinical outcomes and cardiac structural remodelling in atrial fibrillation (AF) patients with HF with mildly reduced or mid-range ejection fraction (HFmrEF) remains unclear. We aimed to compare the efficacy of CA with medical therapy (MT) in AF patients with HFmrEF. We retrospectively screened a total of 36879 patients with AF between 2005 and 2020. Patients who were initially diagnosed with echocardiography-proved HFmrEF and had follow-up echocardiography were enrolled. After applying propensity score matching in a 1:1 ratio, 72 patients treated by CA (Group 1) and 72 patients receiving MT (Group 2) were taken into further analysis. The co-morbidities were similar between the two groups, except for hyperlipidaemia. After a mean follow-up duration of 58.9±42.6months, Group 1 had a lower HF hospitalization and all-cause mortality compared with Group 2 (hazard ratio (HR), 0.089 [95% confidence interval (CI), 0.011-0.747]; P=0.026 and HR, 0.121 [95% CI, 0.016-0.894]; P=0.038, respectively). As for cardiac structural remodelling, the Group 1 had a better improvement in left ventricular ejection fraction (LVEF) and a more decreased left atrium (LA) diameter than Group 2 (+25.0%±18.0% vs. +6.2%±21.6%, P=<0.0001 and -1.6±4.7mm vs. +1.5±8.2mm, P=0.008, respectively). In patients with HFmrEF and AF, CA of AF could reduce both HF hospitalization and all-cause mortality as compared with those with MT. A significant improvement in LVEF and decrease in LA diameter were also observed in the CA group. Early rhythm control with CA should be taken into consideration in patients with HFmrEF and AF.

Degree of Fibrosis in Human Atrial Tissue Is Not the Hallmark Driving AF

Background: The current paradigm is that fibrosis promotes electrophysiological disorders and drives atrial fibrillation (AF). In this current study, we investigated the relation between the degree of fibrosis in human atrial tissue samples of controls and patients in various stages of AF and the degree of electrophysiological abnormalities. Methods: The degree of fibrosis was measured in the atrial tissue and serum of patients in various stages of AF and the controls. Hereto, picrosirius and H&E staining were performed to quantify degree of total, endo-perimysial fibrosis, and cardiomyocyte diameter. Western blot quantified fibrosis markers: neural cell adhesion molecule, tissue inhibitor of metalloproteinase, lysyl oxidase, and α-smooth muscle actin. In serum, the ratio carboxyl-terminal telopeptide of collagen/matrix-metalloproteinase1 was determined. High-resolution epicardial mapping evaluated low-voltage areas and conduction abnormalities. Results: No significant differences were observed in the degree of fibrosis between the groups. Finally, no significant correlation—absolute nor spatial—was observed between all electrophysiological parameters and histological fibrosis markers. Conclusions: No differences in the degree of fibrosis were observed in patients from various stages of AF compared to the controls. Moreover, electrophysiological abnormalities did not correlate with any of the fibrosis markers. The findings indicate that fibrosis is not the hallmark of structural remodeling in AF.

Serum interleukin-17A/interferon-gamma ratio as a predictor for the severity of atrial low voltage in atrial fibrillation: from FIB-MARK study

Abstract Background Atrial fibrosis is hallmark of structural remodeling in atrial fibrillation (AF), but the inflammatory mechanism remains unclear. The purpose of the present study was to identify the specific inflammatory biomarkers to atrial fibrosis evaluated by atrial low voltage (LV) in AF patients for clarification of the mechanism. Methods Forty inflammatory biomarkers were quantified in 16 consecutive AF patients measured left atrial low voltage during catheter ablation. Results Median %LV area was 17%. In Pearson's correlation analysis, interleukin (IL)-17A and interferon (IFN)-γ was the most significant positive and negative correlation with %LV (R=0.35 and 0.43, P&amp;lt;0.001). Furthermore, there was a significant correlation between IL-17A/IFN-γ ratio and %LV (R=0.65, P=0.007). The area under the receiver operator characteristics curve of IL-17A/IFN-γ ratio for significant LV (%LV &amp;gt;10% as a reference standard) was 0.88. IL-17A/IFN-γ ratio was significantly higher in patients with significant LV than those without (1.41 versus 0.97, P=0.01), Furthermore, the sensitivity, specificity, and accuracy for detecting significant LV were 60%, 100%, and 75.0% at the cutoff value of 1.3. The event free survival from recurrent atrial tachyarrhythmias was not significantly different between patients with and without IL-17A/IFN-γ ratio &amp;gt;1.3 (83.3% versus 80.0% at 1-year, P=0.81). Conclusions Among inflammatory biomarkers, IL-17A/IFN-γ ratio was a significant predictor for the severity of left atrial low voltage n AF patients. Further study is needed to reveal the association between IL-17A and IFN-γ for development of fibrosis in AF. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): JSPS KAKENHI GrantNumber JP19K17594

Enhanced monocyte migratory activity in the pathogenesis of structural remodeling in atrial fibrillation.

Pathophysiological roles of monocytes in atrial fibrillation (AF), particularly for the progression of structural remodeling of the left atrium (LA), remain elusive. This study examined the association between the characteristics of circulating and local monocytes and extent of structural remodeling in LA, gauged by LA size, in AF patients. First, 161 AF patients who were referred for catheter ablation were enrolled and divided into two groups according to the median of LA diameter (≤39 mm: normal LA group, >39 mm: enlarged LA group). As a control group, 22 patients underwent catheter ablation for paroxysmal supraventricular tachycardia (PSVT) without history of AF were analyzed. Blood samples were collected for flow cytometric analyses to evaluate monocyte subsets based on the levels of CD14 and CD16. Moreover, monocytes were isolated from blood to measure CC chemokine receptor 2 (CCR2) transcripts and protein levels, and migratory activity toward monocyte chemoattractant protein 1 (MCP-1). Second, to characterize the local monocytes in the atrial wall in AF, the resected left atrial appendages (LAA) in AF patients underwent cardiac surgery were histologically evaluated (n = 20). The proportions of monocyte subsets based on CD14 and CD16 expressions were not significantly different between the normal and enlarged LA group. Both transcripts and total protein levels of CCR2 in monocytes were higher in the enlarged LA group compared to those in the normal LA group. In the enlarged LA group, monocytes exhibited more enhanced migratory activity than the normal LA group. Moreover, we found a significantly higher number of CCR2-positive monocytes/macrophages in the LAA in the enlarged LA group. Enhanced migratory activity in circulating and local monocytes may play a pivotal role in the pathogenesis of progression in atrial remodeling in AF patients.

P333Left atrial function by echocardiography is independent of degree of left atrial electrical scar

Abstract Introduction Assessment of left atrial function via transthoracic echocardiography (TTE) is performed most commonly by measuring the transmitral A wave in sinus rhythm. Left atrial (LA) fibrosis plays an important role in the pathogenesis and perpetuation of Atrial Fibrillation (AF). It may be identified by bipolar voltage (BiV) mapping, which can easily be performed at the beginning of a Pulmonary Vein Isolation (PVI) procedure. The relationship between the degree of LA fibrosis, characterised with mapping, and LA function, determined by echocardiography, has not previously been elucidated. Methods Patients were enrolled in a project to evaluate the degree of fibrosis during PVI procedures. Pre-procedure TTEs of those presenting in sinus rhythm were assessed and the transmitral A wave was measured and compared to the degree of scarring seen. The high density electroanatomic maps (HD-EAMs) created during the PVIs were analysed using a novel VHA algorithm after the procedure. All points with voltages &amp;lt; 0.5mV were defined to have electrical scar. Patients were classified into 4 quartiles based on the levels of scar seen (Figure 1). Results 39 patients were included in the evaluation. Average age was 60.6 +/- 13.2 years. 32 (82.0%) of the patients were male. Mean CHADS2VASc score was 1.5. The mean percentage of scar was calculated as 19.6 +/- 15.9%. The average A wave was 0.62 +/- 0.18 ms-1. Pearson’s correlation coefficient showed no relationship between LA scar and either A wave velocities (r = 0.26, p = 0.11) or E:A ratio (r=-0.02, p = 0.91). A significant correlation between A wave velocity and CHADS2VASc was observed (r = 0.49, p = 0.001). Conclusion Our study demonstrates no relationship between degree of LA scarring and reduced LA function on TTE as assessed by the A wave. It has been established that structural remodelling in AF (such as atrial dilatation) may occur independently of the electrical remodelling. A potential explanation for our findings is that the electrical scarring in AF, which results in alterations in refractory periods, precedes the negative remodelling which ultimately results in reduced atrial function. This hypothesis would need to be further evaluated in larger studies. Abstract Figure 1

Omentin-1 is associated with atrial fibrillation in patients with cardiac valve disease

BackgroundEpicardial adipose tissue (EAT) remodeling and adipocytokines are associated with structural remodeling in atrial fibrillation (AF). However, the role of omentin-1, a novel adipocytokine, in structural remodeling remains unknown.MethodsHematoxylin and eosin (H&E) and Masson’s trichrome stains were used to investigate the histology of EAT and right atrial appendages. The expression levels of adipocytokines in these human samples were determined by immunohistochemical assay and western blotting. Models of transforming growth factor (TGF)-β1-induced activation of cardiac fibroblasts (CFs) and TGF-β1-induced endothelial-mesenchymal transition (EndMT) of human umbilical vein endothelial cell (HUVEC) were established to explore roles of omentin-1 in these processes. To determine changes in adipocytokines secretion under hypoxia conditions, adipocytes were treated with 5% O2 and 95% N2, and then CFs and HUVECs were co-cultured with the conditioned medium of adipocytes to determine the effects of hypoxia-treated adipocytes on these cells.ResultsExpression of omentin-1 was downregulated in the EAT and right atrial appendages from patients with AF compared to samples from patients without AF, while the TGF-β1 level was upregulated in EAT from patients with AF. EAT from patients with AF exhibited adipocyte hypertrophy and severe interstitial fibrosis. Omentin-1 inhibited TGF-β1-induced CF activation and reversed TGF-β1-induced HUVEC EndMT. Adipocytes treated with hypoxia exhibited downregulation of omentin-1 and partly activated CFs.ConclusionsThis study demonstrated that omentin-1 was an antifibrotic adipocytokine and was downregulated in patients with AF, which was partly mediated by hypoxia.

Sacubitril/valsartan attenuates atrial electrical and structural remodelling in a rabbit model of atrial fibrillation

Atrial structural and electrical remodelling play important roles in atrial fibrillation (AF). Sacubitril/valsartan attenuates cardiac remodelling in heart failure. However, the effect of sacubitril/valsartan on AF is unclear. The aim of this study was to evaluate the effect of sacubitril/valsartan on atrial electrical and structural remodelling in AF and investigate the underlying mechanism of action.Thirty-three rabbits were randomized into sham, RAP, and sac/val groups. HL-1 cells were subjected to control treatment or rapid pacing with or without LBQ657 and valsartan. Echocardiography, atrial electrophysiology, and histological examination were performed. The concentration of Ca2+ and expression levels of calcineurin, NFAT, p-NFAT, Cav1.2, collagen Ⅰ and Ⅲ, ANP, BNP, CNP, NT-proBNP, and ST2 in HL-1 cells, and IcaL in left atrial cells, were determined.We observed that compared to that in the sham group, the atrium and right ventricle were enlarged, myocardial fibrosis was markedly higher, AF inducibility was significantly elevated, and atrial effective refractory periods were shortened in the RAP group. These effects were significantly reversed by sacubitril/valsartan. Compared to that in the sham group, collagen Ⅰ and Ⅲ, NT-proBNP, ST2, calcineurin, and NFAT were significantly up-regulated, while p-NFAT and Cav1.2 were down-regulated in the RAP group, and sacubitril/valsartan inhibited these changes. Ca2+ concentration increased and ICaL density decreased in in vivo and in vitro AF models, reversed by sacubitril/valsartan.Sacubitril/valsartan attenuates atrial electrical remodelling and ameliorates structure remodelling in AF. This study paves the way for the possibility of clinical use of sacubitril/valsartan in AF patients.

Downregulation of miR-96 suppresses the profibrogenic functions of cardiac fibroblasts induced by angiotensin II and attenuates atrial fibrosis by upregulating KLF13.

Atrial fibrosis is a hallmark of structural remodeling in atrial fibrillation (AF). MicroRNA-96 (miR-96) has been reported to be associated with pulmonary fibrosis and hepatic fibrosis. Nevertheless, the role of miR-96 in atrial fibrosis is still unclear. In our study, we showed that miR-96 is upregulated in human atrial tissues from AF patients and positively correlates with collagen I and collagen III levels. Knockdown of miR-96 reduced angiotensin II (Ang-II)-induced cardiac-fibroblast proliferation, migration, and collagen production, whereas ectopic expression of miR-96 yielded opposite results. Furthermore, we demonstrated that miR-96 represses KLF13 expression, subsequently promoting Ang-II-induced proliferation, migration, and collagen production in murine cardiac fibroblasts. Moreover, we observed that the knockdown of miR-96 attenuated the Ang-II-induced atrial fibrosis in a mouse model of AF. All the findings point to a potential target for the prevention or treatment of atrial fibrosis.

Correlation between serum homocysteine, Galectin-3 concentration and atrial structural remodeling in atrial fibrillation patients

Abstract Objective To investigate the correlation between serum homocysteine (Hcy), Galectin-3 concentration and atrial structural remodeling in atrial fibrillation (AF) patients. Methods Twenty-five patients with persistent atrial fibrillation (PeAF), 24 patients with paroxysmal atrial fibrillation (PaAF) and 23 healthy controls were included in the present work. All subjects received an echocardiography examination. Serum concentration of Hcy and Galectin-3 were also examined by Enzyme Linked Immunosorbent Assay (ELISA). Results Echocardiography examination demonstrated that there were significant differences for LAD (p=0.002), LVEF (p=0.005) and LVAI (p=0.0001) between the control, PaAF and PeAF groups. However, LVSD and LVDD were not significantly different between the three groups (pall&gt;0.05). There was a significant positive correlation between LAVI and serum Hcy level in both PaAF (rpearson=0.49, p=0.016) and PeAF (rpearson=0.51, p=0.009) groups. The correlation between LAVI and serum Galectin-3 concentration was also statistically significant for PaAF (rpearson=0.54, p=0.006) and PeAF (rpearson=0.60, p=0.001) groups. Using serum Hcy as reference, diagnostic sensitivity and specificity were calculated as 72.00 (95%CI: 50.61-87.93) and 62.50 (95%CI: 40.59-81.20), respectively, with an AUC of 0.68 for PaAF and PeAF. For serum Galectin-3, the sensitivity and specificity values were 64.00 (95%CI:42.52-82.03) and 66.67 (95%CI:44.68-84.37), respectively, with an AUC of 0.68. Conclusion: Serum Hcy and Galectin-3 were elevated in AF patients and thus may be potential markers of atrial structural remodeling. However, the diagnostic efficacy of PeAF from PaAF was limited by low AUC values.

Serum tenascin-C levels in atrium predict atrial structural remodeling processes in patients with atrial fibrillation.

Fibro-inflammatory processes in the extracellular matrix are closely associated with progressive structural remodeling in atrial fibrillation (AF). Serum concentrations of tenascin-C (TNC), an extracellular matrix glycoprotein, and of high-sensitivity C-reactive protein (CRP) might serve as a marker of remodeling and progressive inflammation of the aorta and in myocardial diseases. This study aimed to clarify relationships between TNC and CRP in patients with AF. This study included 38 patients with AF and five controls without left ventricular dysfunction who underwent catheter ablation. Blood was collected immediately before ablation from the left atrium (LA), right atrium (RA), and femoral artery (FA), and left and right atrial pressure was measured. Levels of TNC in the LA (TNC-LA), RA (TNC-RA), and FA (TNC-FA) and high-sensitivity C-reactive protein (CRP) were measured. Atrial size was also determined by echocardiography. Levels of TNC corrected by atrial size were maximal in the LA, followed by the RA (3.69 ± 0.32 and 2.87 ± 0.38ng/mL/cm, respectively). Mean transverse diameter corrected by body surface area was larger and mean atrial pressure was greater in the LA than the RA. A relationship was found between CRP from the femoral vein and TNC-LA and TNC-RA, but not TNC-FA. None of TNC-LA, TNC-RA, or TNC-FA correlated with ANP or BNP in the femoral vein. Intracardiac (atrial) TNC expression plays an important role in the development of remodeling processes in the atrium with AF. Tenascin-C from the LA and RA (but not TNC, ANP, and BNPfrom FA) might serve as novel markers of these processes.

P3767Progressive left atrial remodeling associates with cholesterol efflux capacity of HDL in atrial fibrillation patients

Abstract Background The clinical significance of high-density lipoprotein (HDL) function, represented by cholesterol efflux capacity (CEC), in addition to serum HDL cholesterol (HDL-C) levels, has been recognized in the pathogenesis and prognosis in patients with atherosclerotic cardiovascular diseases. However, the roles of HDL in the development and the progression of atrial fibrillation (AF), has been rarely evaluated. In this study, we thus hypothesized that the compromised HDL function may be associated with the progression of pathological structural remodeling in left atrium (LA). Objective We explored the association between CEC of HDL and the left atrial dimension (LAD), a maker of structural remodeling in the LA, in patients with AF and control. Methods This is a single center case-control study including consecutive 260 AF patients (AF group) and 34 paroxysmal supraventricular tachycardia (PSVT) patients (PSVT group, served as a control group), who underwent catheter ablation from July 2017 to December 2018. Blood samples were collected before catheter ablation procedure. CEC of HDL was measured by using ex vivo radiotracer system that involved incubation of [3H] cholesterol-loaded J774.1 murine macrophage-like cells with apoB-depleted serum. Results Serum HDL-C level was lower in AF group compared to those of PSVT group (55.3±15.3mg/dl vs 61.7±13.3mg/dl: p=0.024). As a marker of HDL function, CEC of HDL was significantly lower in patients with AF group compared to those in PSVT patients (4.74±0.84% vs 5.20±0.99%: p=0.005, Fig 1). In all patients including both groups, CEC of HDL was inversely correlated with LAD (r=−0.25; p&lt;0.001, Fig 2), indicating the inverse association between HDL function and the progression of structural remodeling in AF. Moreover, multivariate logistic regression analysis adjusted by age, gender, body mass index, ejection fraction, and HDL-C demonstrated that increase in CEC of HDL was associated with the lower risk to be highest quartiles of LAD (&gt;42mm), even adjusted by serum HDL-C levels (odds ratio of 1-SD elevation in CEC of HDL for LAD&gt;42mm: 0.63; 95% confidence interval: 0.40–0.97, p=0.037), which implicated the link between HDL function and progression of left atrial structural remodeling. Conclusion Findings in this study may suggest that compromised HDL functionality is associated with the pathogenesis of left atrial structural remodeling in AF patients.

3057Relation of atrial remodeling to circulating biomarkers of myocardial fibrosis and apoptotic microparticles in patients with atrial fibrillation and heart failure with preserved ejection fraction

Abstract Introduction Left atrial (LA) remodeling is a mainstay for atrial fibrillation (AF) occurrence. AF further promotes structural changes in LA, as fibrosis and stretching, followed by AF progression to its permanent form. Many profibrotic pathways have been studied, and circulating microparticles (MPs) may have a role. MPs are extracellular submicron anucleoid phospholipid vesicles released from different cells. Annexin V-binding (AnV+) MPs were suggested as a marker of apoptosis. Purpose To evaluate association of circulating biomarkers of myocardial fibrosis and MPs subsets with LA remodeling in patients with AF and heart failure with preserved ejection fraction. Methods We studied 274 patients (median age 62 years, 37% females). Paroxysmal AF was diagnosed in 150 patients (55%) and non-paroxysmal AF (persistent or permanent) in 124 (45%). Median CHA2DS2-VASc score was 3 in males and 4 in females. Patients with valvular AF, recent (&lt;6 months) thromboembolic or hemorrhagic event, advanced chronic kidney or hepatic dysfunction, malignancy or active inflammatory disorders were excluded. Transthoracic echocardiography was performed. LA maximum volume index (LAVi) was measured as an index of LA structural remodeling in AF. Average values from ten consecutive cardiac cycles were calculated. Blood levels of galectin 3, interleukin-1 receptor-like 1 (ST2), transforming growth factor beta 1 (TGF-β1), procollagen type III aminoterminal propeptide (PIIINP), matrix metalloproteinase 9 (MMP-9), tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), angiotensin II and aldosterone were assayed as surrogate biomarkers of myocardial fibrosis with ELISA. Using microflow cytometry (Figure), numbers of platelet-derived (CD42b+), monocyte-derived (CD14+), endothelial (CD144+), and apoptotic MPs (AnV+) were quantified in plasma samples. Linear regression was used to reveal parameters associated with LAVi. Raw data were normalized with Box-Cox transformation. Results Median LAVi in studied patients was 48 (39–59) ml/m2 and increased from patients with paroxysmal AF (42 [35–51] ml/m2) to persistent AF (53 [43–62] ml/m2) and permanent AF (57 [46–69] ml/m2), p&lt;0.001. On univariate analysis male gender (β=0.11, p=0.04); history of hypertension (β=0.18, p=0.03); AF type, i.e. progression from paroxysmal to permanent (β=0.38, p&lt;0.001); AnV+ MPs (β=0.19, p=0.005); ST2 (β=0.15, p=0.02); and early mitral inflow velocity (E)/early mitral annular diastolic velocity (E/E') averaged for LV septal and lateral basal regions (β=0.18, p=0.005) were associated with LAVi. Using stepwise multivariate regression AnV+ MPs (β=0.14, p=0.03); AF type (β=0.35, p&lt;0.001); and E/E' ratio (β=0.11, p=0.04) remained significant predictors of LAVi (adjusted for age and gender). Apoptotic MPs detection with microFCM Conclusion Level of circulating apoptotic MPs is associated with LAVi in AF patients with HFpEF, and may be involved in remodeling process or could represent surrogate markers of myocardial damage in AF. Acknowledgement/Funding ESC Research Grant, EHRA Academic Research Fellowship Programme

Effects of febuxostat on atrial remodeling in a rabbit model of atrial fibrillation induced by rapid atrial pacing.

BackgroundFebuxostat, a novel nonpurine selective inhibitor of xanthine oxidase (XO), may be used in the prevention and management of atrial fibrillation (AF). The purpose of this study was to evaluate the effects of febuxostat on atrial remodeling in a rabbit model of AF induced by rapid atrial pacing (RAP) and the mechanisms by which it acts.MethodsTwenty-four rabbits were randomly divided into four groups: sham-operated group (Group S), RAP group (Group P), RAP with 5 mg/kg per day febuxostat group (Group LFP), and RAP with 10 mg/kg per day febuxostat group (Group HFP). All rabbits except those in Group S were subjected to RAP at 600 beats/min for four weeks. The effects of febuxostat on atrial electrical and structural remodeling, markers of inflammation and oxidative stress, and signaling pathways involved in the left atrium were examined.ResultsShortened atrial effective refractory period (AERP), increased AF inducibility, decreased mRNA levels of Cav1.2 and Kv4.3, and left atrial enlargement and dysfunction were observed in Group P, and these changes were suppressed in the groups treated with febuxostat. Prominent atrial fibrosis was observed in Group P, as were increased levels of TGF-β1, Collagen I, and α-SMA and decreased levels of Smad7 and eNOS. Treatment with febuxostat attenuated these differences. Changes in inflammatory and oxidative stress markers induced by RAP were consistent with the protective effects of febuxostat.ConclusionsThis study is the first to find that febuxostat can inhibit atrial electrical and structural remodeling of AF by suppressing XO and inhibiting the TGF-β1/Smad signaling pathway.

Circulating primary bile acid is correlated with structural remodeling in atrial fibrillation.

Circulating primary bile acid was involved in the regulation of cardiac ionic channel currents and ventricular myocyte apoptosis, but it was unknown whether or not it played a role in structural remodeling of AF. This study was aimed to testify the hypothesis that elevated chenodeoxycholic acid (CDCA) concentration correlated with left atrial low voltage area (LVA) and could induce apoptosis of atrial myocytes in AF. Serum concentrations of 12 types of bile acids were determined in patients with paroxysmal (n = 21), persistent AF (n = 20), and type A pre-excitation and paroxysmal supraventricular tachycardia (PSVT) (n = 19) and were correlated with LVA in AF, which was obtained by electroanatomical mapping during ablation. Additionally, the impact of CDCA incubation on apoptosis of mouse atrial myocytes was evaluated. Serum levels of CDCA and cholic acid were significantly higher in AF than in PSVT. CDCA serum concentration was significantly higher in persistent AF than in paroxysmal AF. CDCA serum level was positively correlated with the size (r = 0.78, P < 0.05) and proportion of LVA (r = 0.89, P < 0.05) in AF patients. CDCA (75μM, 100μM) promoted atrial myocyte apoptosis in a concentration-dependent manner. The higher circulating level of CDCA in AF than in PSVT, positive correlation of CDCA with LVA in AF, and incubation dose-dependent increase of mouse atrial myocyte apoptosis indicated that CDCA might play a significant role in the progress of structural remodeling of AF.