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Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This study was supported by Netherlands Organization for Health Research and Development Background Myeloperoxidase (MPO), an enzyme most abundantly expressed by neutrophils, is increased in the atrial tissue of AF patients and is associated with treatment failure. Moreover, MPO increases fibrosis and AF susceptibility in mouse atria. However, how MPO promotes AF has yet to be fully established. Purpose To investigate the role of MPO in electrophysiological and structural remodelling. Methods We incubated cultured neonatal rat ventricular myocyte (NRVM) monolayers with 1 μg/mL MPO or vehicle for 24 hours. We then performed electrophysiological mapping using an 8x8 multielectrode array (MEA) setup with 100 μm-sized electrodes and 700 μm inter-electrode distance (n=8 MPO, n=7 control) and recorded action potentials (AP) using a microelectrode during pacing. Additionally, we quantified the number of fibroblasts using vimentin staining (n=5/group) and the expression of extracellular matrix (ECM) genes (COL1A1, COL8A2, FN1, CTGF, TNC, THBS2, MMP2, MMP12) using qPCR (n=4/group). Multielectrode data were analyzed with custom-made software in MATLAB. Statistical analysis was performed in R. Data presented as median [interquartile range]. Results NRVM monolayers incubated with MPO were unresponsive to pacing (5/8 vs 0/7 control) or had a higher pacing threshold (1300 [1000-2500] vs 500 [400-600] μA) (p=0.02). The percent of excitable tissue was lower in the MPO than in the control group, and the propagation of spontaneous activations was slower and more heterogeneous (index: 5 [3.6-9.5] vs 2 [1.5-3], p=0.004). More fractionated electrograms were present in MPO than in the control (29 [25-40] vs 11 [4-23] electrodes per grid, p=0.02). Re-entry was observed in 3/8 MPO-incubated monolayers vs 0/7 controls. Intracellular recordings revealed a less negative resting membrane potential (-50 [-24- -52] vs -69 [-56- -79] mV, p=0.04) and lower AP upstroke velocity (4 [2.5-14] vs 26 [22-28] V/s, p=0.01) in MPO-incubated cardiomyocytes than in the control. Moreover, relative to the control, MPO significantly increased the number of fibroblasts (126 [120-128] vs 87 [70-106] cells/0.26 mm^2, p=0.02) and the expression of MMP12 (1.17 (fold-change), p=0.04), whereas a trend toward increase was observed for other ECM genes, such as COL8A2 (1.5 (fold change), p=0.1). Conclusion Incubation of NVRM with MPO results in depolarization of cardiomyocytes and an increase in the number of fibroblasts and ECM gene expression. Thereby, MPO increases conduction heterogeneity and susceptibility to re-entry.

Background To which extent atrial remodeling occurs before atrial fibrillation (AF) is unknown. Objective The PREventive left atrial appenDage resection for the predICtion of fuTure Atrial Fibrillation (PREDICT-AF) study investigated such subclinical remodeling, which may be used for risk stratification and AF prevention. Methods Patients (N = 150) without a history of AF with a CHA2DS2-VASc score of ≥2 at an increased risk of developing AF were included. The left atrial appendage was excised and blood samples were collected during elective cardiothoracic surgery for biomarker discovery. Participants were followed for 2 years with Holter monitoring to determine any atrial tachyarrhythmia after a 50-day blanking period. Results Eighteen patients (12%) developed incident AF, which was associated with increased tissue gene expression of collagen I (COL1A1), collagen III (COL3A1), and collagen VIII (COL8A2), tenascin-C (TNC), thrombospondin-2 (THBS2), and biglycan (BGN). Furthermore, the fibroblast activating endothelin-1 (EDN1) and sodium voltage-gated channel β subunit 2 (SCN2B) were associated with incident AF whereas the Kir2.1 channel (KCNJ2) tended to downregulate. The plasma levels of COL8A2 and TNC correlated with tissue expression and predicted incident AF. A gene panel including tissue KCNJ2, COL1A1, COL8A2, and EDN1 outperformed clinical prediction models in discriminating incident AF. Conclusion The PREDICT-AF study demonstrates that atrial remodeling occurs long before incident AF and implies future potential for early patient identification and therapies to prevent AF ( ClinicalTrials.gov identifier NCT03130985 ).

Background Persistent atrial fibrillation (AF) is associated with higher stroke and mortality risk than paroxysmal AF (pAF). Outcomes of catheter or surgical ablation are worse in patients with persistent AF than in pAF, and the optimal invasive rhythm control strategy has not been established. Purpose We provide a contemporary systematic overview on efficacy and safety of catheter and minimally-invasive surgical ablation for persistent AF. Methods We systematically searched EMBASE, MEDLINE and CENTRAL from inception to July 2018 for randomized trials on surgical and catheter ablation, and included all study arms on persistent AF. Outcome was AF freedom after ≥12 months follow-up without AAD use. Random effects models were used to calculate proportions with 95%-confidence intervals. Safety consisted of adverse events during treatment and follow-up. Results We included 6 studies on minimally-invasive surgical ablation and 56 on catheter ablation, involving 7624 patients with persistent AF. AF Freedom at 12 months was 69% (95%CI 64–74%) after surgical and 51% (95%CI 46–56%) after catheter ablation. More severe procedural adverse events occurred with surgery than with catheter ablation. Conclusions In persistent AF patients, minimally-invasive surgical ablation is associated with more procedural complications, but higher AF freedom. As adverse events after surgical ablation appear more severe than in catheter ablation, a patient-tailored therapy choice is warranted.

Despite our expanding knowledge about the mechanism underlying atrial fibrillation (AF), the interplay between the biological events underlying AF remains incompletely understood. This study aimed to identify the functionally enriched gene-sets in AF and capture their interconnection via pivotal factors, that may drive or be driven by AF. Global abundance of the proteins in the left atrium of AF patients compared to control patients (n = 3/group), and the functionally enriched biological processes in AF were determined by mass-spectrometry and gene set enrichment analysis, respectively. The data were validated in an independent cohort (n = 19–20/group). In AF, the gene-sets of innate immune system, metabolic process, cellular component disassembly and ion homeostasis were up-regulated, while the gene-set of ciliogenesis was down-regulated. The innate immune system was over-represented by neutrophil degranulation, the components of which were extensively shared by other gene-sets altered in AF. In the independent cohort, an activated form of neutrophils was more present in the left atrium of AF patients with the increased gene expression of neutrophil granules. MYH10, required for ciliogenesis, was decreased in the atrial fibroblasts of AF patients. We report the increased neutrophil degranulation appears to play a pivotal role, and affects multiple biological processes altered in AF.

BACKGROUND: Monosodium glutamate (MSG), also referred to as Vetsin or E621, is a flavour enhancer frequently used in Asian cuisine and abundantly present in the famous Chinese dish Peking duck. MSG is notorious for triggering the onset of the so-called 'Chinese restaurant syndrome' (CRS), a complex of unpleasant symptoms, which might include flushing, sweating and the onset of atrial fibrillation (AF). This study aims to determine the effects of MSG on the occurrence of AF. METHODS: We conducted a placebo self-controlled single-arm study in the Academic Medical Centre in Amsterdam. We included paroxysmal AF patients who reported a consistent onset of AF upon MSG intake. During three admissions, participants were subsequently administered: placebo, 1.5 g and 3 g MSG. If AF was recorded after the dose of 1.5 g MSG, patients were given another placebo instead of 3 g MSG. The primary outcome was the onset of AF registered by 24-hour Holter monitoring. The secondary outcomes were any other arrhythmia and the onset of CRS defined as two or more symptoms of CRS after MSG intake. RESULTS: Six men participated in the study. Both 1.5 g and 3 g MSG were unrelated to CRS, arrhythmias or AF occurrence. CONCLUSION: Peking duck can be put on the Christmas menu without risking guests to be admitted to the emergency department with new episodes of AF.

Background Atrial fibrosis is a hallmark of atrial fibrillation (AF) and serves as an important arrhythmogenic substrate. It is formed by fibroblasts in response to tissue dyshomeostasis induced by multiple factors such as ageing, hypertension and inflammation. How fibroblasts phenotypically transform into an active form with enhanced profibrotic capacity in AF pathophysiology remains elusive. The primary cilium is an antenna-like small organelle, that function as a sensor to transduce external stimuli to intracellular signaling thereby potentially mediating the fibroblast's profibrotic capacity. Their involvement in AF pathophysiology is not known. Objective To explore the role of fibroblasts' primary cilium in the formation of the atrial fibrosis in AF. Methods Left atrial appendages (LAA) were obtained from persistent AF patients (AF: n=10) and patients without AF undergoing cardiac surgery (control: n=10). Primary cilia were immunostained with anti-acetylated a-tubulin in cryosections of the LAA. The loss of cilia in fibroblasts isolated from fresh LAA (AF: n=3, control: n=3) was induced by RNAi targeting IFT88, an essential factor for cilia formation. Gene expression and protein levels in LAA were quantified by qPCR and western blot, respectively (AF: n=20, control: n=20). Results The ratio of fibroblasts with primary cilium was significantly decreased in LAA of AF cohort (AF: 14.7%±4.6 vs control: 25.9%±3.6, p Primary cilium is disassembled along with degradation of acetylated a-tubulin by HDAC6. Indeed, a negative correlation between the protein levels of acetylated a-tubulin and HDAC6 were observed in the LAA of AF cohort (p Conclusion The formation of primary cilia in fibroblasts is actively suppressed in AF via HEF1/AURKA/HDAC6 cascade, which in turn enhances the profibrotic response of fibroblasts. This study provides an innovative paradigm for fibrosis formation in AF, and implicates that the primary cilium of fibroblasts potentially become a novel therapeutic target to treat the AF substrate.

Background Severely enlarged left atrial (LA) volume is associated with a considerable ineffective outcome of ablation for atrial fibrillation (AF). Therefore, in patients with AF and a giant atrial volume catheter ablation is not recommended. However, thoracoscopic AF ablation is being performed in patients with AF and giant LA, but with unknown efficacy. Purpose To determine efficacy of thoracoscopic AF ablation in patients with AF and a giant LA. Methods Patients underwent thoracoscopic AF ablation (paroxysmal AF) plus additional left atrial ablations (persistent AF) and were prospectively followed. Giant LA was defined as left atrial volume index (LAVI)≥50 ml/m2, outcome was also assessed for LAVI≥55 ml/m2. Follow-up was performed with ECGs and 24-hour Holters every three months. After a 3-month blanking period, all AADs were discontinued. Primary outcome was recurrence of any atrial tachycardia ≥30 sec during one year of follow-up. Results Between 2008–2017, 357 patients underwent thoracoscopic AF ablation. At baseline, giant LA was diagnosed in 72 (20.2%) patients (mean LAVI: 59.5±9.6 ml/m2), while 285 (79.8%) had a smaller left atrium (mean LAVI: 36.3±7.8 ml/m2), p Kaplan-Meier analysis of AF recurrence i Conclusion Thoracoscopic AF ablation is an effective therapy in patients with a giant LA. Thoracoscopic AF ablation may therefore be a feasible treatment for patients with a giant LA.

Purpose To evaluate the proportion of patients in whom parameters that define the diagnosis of HFpEF and HFmrEF persist versus normalize upon elimination of AF. Background Atrial fibrillation (AF) and heart failure with preserved or mid-range ejection fraction (HFpEF or HFmrEF) concur in many patients. Distinction between these two diagnoses remains challenging as one can cause or exacerbate the other. Adequate patient selection for invasive AF treatment is crucial to improve rhythm outcome. Methods Patients underwent thoracoscopic ablation, consisting of pulmonary vein isolation (PVI) alone or PVI with additional lines in the case of persistent AF. Patients were prospectively followed-up. HFmrEF or HFpEF was defined as left ventricular ejection fraction (LVEF) ≥40% or ≥50% respectively and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels >125 pg/ml. Patients who remained free from AF, or any atrial tachycardia of more than 30 seconds, at 6 months postoperatively, were included in this study. Patients with AF recurrences during this period were excluded. The primary outcome was the change of NT-proBNP at 6 month follow-up. Results From 2008 to 2017, 92 patients undergoing thoracoscopic AF ablation fulfilled the aforementioned criteria and were included. Of these patients, mean age was 61±8 years and 66 (72%) were male. Median NT-proBNP was 366 pg/ml (128–2916) and mean LVEF was 53±7%. Thirty (35%) patients had a LVEF of 40–49%. Six months after elimination of AF, NT-proBNP was Figure 1. NT-proBNP alterations after thoracoscopic AF ablation from baseline to 6 month follow-up. A. Patients with normalization of NT-proBNP. B. Patients with unchanged high levels of NT-proBNP. Conclusion In 28% of patients the diagnostic criteria of HFpEF/HFmrEF are caused by AF and normalize upon elimination of AF with thoracoscopic ablation.

Background Left atrial (LA) strain has a prognostic value for atrial fibrillation (AF) recurrence after AF ablation. The value of LA strain as a predictor of AF recurrence after thoracoscopic AF surgery in patients in sinus rhythm (SR) or AF during echocardiography is unknown. Purpose To assess the association between LA strain and AF recurrence after thoracoscopic surgery for AF in both patients in SR and AF during baseline echocardiography. Methods Patients participating in the AFACT trial (n=240) with baseline transthoracic echocardiography (TTE) suitable for LA strain analysis were included in this subanalyses. All patients underwent thoracoscopic pulmonary vein isolation (PVI) with left atrial appendage (LAA) exclusion, and were randomized to ganglion plexus (GP) or no GP ablation. LA strain and mechanical dispersion (MD) of the LA reservoir, conduit and contraction phase were determined retrospectively from TTE images of both patients in AF and SR before thoracoscopic AF surgery. AF recurrence was defined as any recorded atrial tachyarrhythmia lasting >30 sec during a one year FU period. Results A total of 204 patients (58.6±7.8 years, 73% male, 57% persistent AF) were included. Of the 204 patients 121 (59%) were in SR and 83 (41%) were in AF during baseline TTE. Patients in SR during TTE had higher LA strain values and lower MD compared to patients in AF. Of all patients, those with AF recurrence had lower LA strain of the reservoir phase (13.0% vs. 16.6%; p=0.003) and contraction phase (7.4% vs. 11.5%; p=0.012). MD of the contraction phase was increased in patients with AF recurrence (65.1msec vs. 19.2 msec; p=0.003). Multivariable cox regression analysis showed an association between LA strain, MD and AF recurrence (figure). Conclusions Left atrial strain and mechanical dispersion prior to thoracoscopic AF surgery are associated with recurrence of AF. LA strain showed to be a valuable tool to add in the decision making for thoracoscopic AF surgery regardless rhythm during baseline echocardiography.

BACKGROUND AND AIM: Obesity is a recognized risk factor for new-onset atrial fibrillation (AF). The association between body fat distribution, which is measured by body mass index (BMI) and waist-hip ratio (WHR), its changes, and new-onset AF is conflicting. METHODS AND RESULTS: Participants of the European Prospective Investigation into Cancer and Nutrition in Norfolk cohort study were included, with exclusion criteria of prevalent AF, rheumatic heart disease, and cancer. AF was confirmed by the International Classification of Diseases-10 hospital discharge code I48. Adjusted sex-specific Cox proportional hazards models were used to quantify the AF risk per 1 standard deviation increase and for quintiles of adiposity indices. A total of 10,885 men and 12,857 women were followed up for a median of 19 years, yielding 451,098 person-years. New-onset AF was diagnosed in 1408 (12.9%) men and 1102 (8.6%) women. Multivariable analyses showed that BMI predicted new-onset AF in all, while WHR predicted only in men. New-onset AF risk gradually increased across the range of adiposity indices: for men in the highest BMI quintile, HR: 1.59 (CI 1.32-1.91, p for trend

Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with pronounced morbidity and mortality. Its prevalence, expected to further increase for the forthcoming years, and associated frequent hospitalizations turn AF into a major health problem. Structural and electrical atrial remodelling underlie the substrate for AF, but the exact mechanisms driving this remodelling remain incompletely understood. Recent studies have shown that microRNAs (miRNA), short non-coding RNAs that regulate gene expression, may be involved in the pathophysiology of AF. MiRNAs have been implicated in AF-induced ion channel remodelling and fibrosis. MiRNAs could therefore provide insight into AF pathophysiology or become novel targets for therapy with miRNA mimics or anti-miRNAs. Moreover, circulating miRNAs have been suggested as a new class of diagnostic and prognostic biomarkers of AF. However, the origin and function of miRNAs in tissue and plasma frequently remain unknown and studies investigating the role of miRNAs in AF vary in design and focus and even present contradicting results. Here, we provide a systematic review of the available clinical and functional studies investigating the tissue and plasma miRNAs in AF and will thereafter discuss the potential of miRNAs as biomarkers or novel therapeutic targets in AF. Electronic supplementary material The online version of this article (doi:10.1007/s10557-017-6736-z) contains supplementary material, which is available to authorized users.

IMPORTANCE Obesity is a risk factor for deep vein thrombosis of the leg and pulmonary embolism. To date, however, whether obesity is associated with adult cerebral venous thrombosis (CVT) has not been assessed. OBJECTIVE To assess whether obesity is a risk factor for CVT. DESIGN, SETTING, AND PARTICIPANTS A case-control study was performed in consecutive adult patients with CVT admitted from July 1, 2006 (Amsterdam), and October 1, 2009 (Berne), through December 31, 2014, to the Academic Medical Center in Amsterdam, the Netherlands, or Inselspital University Hospital in Berne, Switzerland. The control group was composed of individuals from the control population of the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis study, which was a large Dutch case-control study performed from March 1, 1999, to September 31, 2004, and in which risk factors for deep vein thrombosis and pulmonary embolism were assessed. Data analysis was performed from January 2 to July 12, 2015. MAIN OUTCOMES AND MEASURES Obesity was determined by body mass index (BMI). A BMI of 30 or greater was considered to indicate obesity, and a BMI of 25 to 29.99 was considered to indicate overweight. A multiple imputation procedure was used for missing data. We adjusted for sex, age, history of cancer, ethnicity, smoking status, and oral contraceptive use. Individuals with normal weight (BMI