Lone Atrial Fibrillation Patients Research Articles

Relationship between duration of atrial fibrillation and right heart structure remodeling as assessed by 3-dimensional transesophageal echocardiography

BackgroundTricuspid valve (TV) remodeling occurs in patients with atrial fibrillation (AF); however, the affecting factor related to TV remodeling in AF remains to be elucidated. We sought to explore whether the AF persistence itself affects right heart remodeling. MethodsA total of 372 lone AF patients (234 paroxysmal AF [paroxAF] and 138 persistent AF [persAF]) who underwent 3-dimensional transesophageal echocardiography (3D-TEE) was retrospectively reviewed. The duration from first-detected episode of AF to the TEE exam date was defined as AF duration. ResultsPersAF patients had a larger TV area index (625.4 vs 719.0 mm2/m2; P < 0.001) and a higher right atrium area-to-right ventricle end-systolic area ratio (RA/RVESA ratio, 1.7 vs 1.9; P = 0.005) than paroxAF patients. The prevalence of AF-tricuspid regurgitation was higher in persAF than in paroxAF patients (1.3% vs 12.3%; P < 0.001). In persAF patients, AF duration was moderately correlated with TV diameter and 3D-TEE-derived TV annular area but not in paroxAF. On multivariable analysis, AF duration was independently associated with TV annular dilatation even after adjustment for RA/RVESA ratio and tricuspid regurgitation severity (β 0.37 [95% CI: 0.77–1.81]; P < 0.001). Additionally, AF duration with cutoff values of 20 months for predicting TV annular dilatation and 37 months for predicting RA/RVESA ratio > 2.1 had both high diagnostic accuracies among persAF patients (both P < 0.01). ConclusionsAF duration itself is independently associated with right heart remodeling in persAF but not in paroxAF, such as TV annular dilatation and predominant RA remodeling which may lead to subsequent TR progression and adverse outcomes.

Two Novel Functional Mutations in Promoter Region of SCN3B Gene Associated with Atrial Fibrillation.

The sodium voltage-gated channel beta subunit 3 (SCN3B) plays a crucial role in electrically excitable cells and conduction tissue in the heart. Some previous studies have established that genetic modification in sodium voltage-channel genes encoding for the cardiac β-subunits, such as SCN1B, SCN2B, SCN3B and SCN4B, can result in atrial fibrillation (AF). In the current study, we identified two rare variants in 5'UTR (NM_018400.4: c.-324C&gt;A, rs976125894 and NM_018400.4: c.-303C&gt;T, rs1284768362) of SCN3B in two unrelated lone AF patients. Our further functional studies discovered that one of them, the A allele of c.-324C&gt;A (rs976125894), can improve transcriptional activity and may raise SCN3B expression levels. The A allele of c.-324C&gt;A (rs976125894) has higher transcriptional activity when it interacts with GATA4, as we confirmed transcription factor GATA4 is a regulator of SCN3B. To the best of our knowledge, the current study is the first to demonstrate that the gain-of-function mutation of SCN3B can produce AF and the first to link a mutation occurring in the non-coding 5'UTR region of SCN3B to lone AF. The work also offers empirical proof that GATA4 is a critical regulator of SCN3B gene regulation. Our findings may serve as an encyclopedia for AF susceptibility variants and can also provide insight into the investigation of the functional mechanisms behind AF variants discovered by genetic methods.

Genomic and Proteomic Study of the Inflammatory Pathway in Patients With Atrial Fibrillation and Cardiometabolic Syndrome.

Atrial fibrillation (AF) and cardiometabolic syndrome (CMS) have been linked to inflammation and fibrosis. However, it is still unknown which inflammatory cytokines contribute to the pathogenesis of AF. Furthermore, cardiometabolic syndrome (CMS) risk factors such as obesity, hypertension, insulin resistance/glucose intolerance are also associated with inflammation and increased level of cytokines and adipokines. We hypothesized that the inflammatory immune response is exacerbated in patients with both AF and CMS compared to either AF or CMS alone. We investigated inflammatory cytokines and fibrotic markers as well as cytokine genetic profiles in patients with lone AF and CMS. CMS, lone AF patients, patients with both lone AF and CMS, and control patients were recruited. Genetic polymorphisms in inflammatory and fibrotic markers were assessed. Serum levels of connective tissue growth factor (CTGF) were tested along with other inflammatory markers including platelet-to-lymphocyte ratio (PLR), monocyte-to-HDL ratio (MHR) in three groups of AF+CMS, AF, and CMS patients. There was a trend in the CTGF levels for statistical significance between the AF and AF+CMS group (P = 0.084). Genotyping showed high percentages of patients in all groups with high secretor genotypes of Interleukin-6 (IL-6) (P = 0.037). Genotyping of IFN-γ and IL-10 at high level showed an increase in expression in the AF + CMS group compared to AF and CMS alone suggesting an imbalance between the inflammatory and anti-inflammatory cytokines which is exacerbated by AF. Serum cytokine inflammatory cytokine levels showed that IL-4, IL-5, IL-10, IL-17F, and IL-22 were significant between the AF, AF+CMS, and CMS patients. Combination of both CMS and AF may be associated with a higher degree of inflammation than what is seen in either CMS or AF alone. Thus, the identification of a biomarker capable of identifying metabolic syndrome associated with disease will help in identification of a therapeutic target in treating this devastating disease.

P1392Next generation sequencing in lone atrial fibrillation patients

Abstract Background. Minor part of atrial fibrillation (AF) patients develops the disease without any well-known risk factors, which is a particular form of the disease, known as a lone AF. Rare genetic variants were described as causative for lone AF. The aim of this study was to investigate occurrence of rare genetic variants in lone AF patients. Material and Methods. We performed Mendeliome sequencing for 21 lone AF patients. Lone AF was defined as AF in individuals younger than 65 years in the absence of cardiovascular or structural heart disease, endocrinologic or pulmonary disease, chronic kidney disease, obesity and excessive alcohol consumption. Data analysis was performed by current laboratory pipeline. We analyzed 453 cardiomyopathy, arrhythmias and sudden cardiac death related genes. Results. In eight out of 21 (38%) lone AF patients rare likely pathogenic variants were found (Table 1.). Seven rare truncating TTN variants and one LMNA missense variant were observed. Four unrelated patients were positive for the same TTN variant c.13696 C &amp;gt; T; p.(Gln4566Ter). The same variant was previously found in ARVC patient in our laboratory. Segregation analysis and phenotyping of relatives is ongoing. Conclusions. Rare genetic variants are common causes of the lone atrial fibrillation. TTN gene variant c.13696C &amp;gt; T; p.(Gln4566Ter) is a potential founder variant in the Baltic population. Table 1. Genetic variants in lone AF Gender Age of AF onset Genetic variant Family history Male 53 LMNA: p.(Ser326Thr) AF in mother Male 11 TTN: p.(Trp31854Ter) AF in father Male 30 TTN: p.(GLn4566Ter) AF in uncle Female 45 TTN: p.(GLn4566Ter) Negative Male 37 TTN: p.(GLn4566Ter) AF in father Male 25 TTN: p.(GLn4566Ter) AF in father, maternal and paternal grandmother Female 60 TTN: p.(Arg27414Ter) Sudden cardiac death at the age of 50 in grand father Female 52 TTN: p.(Arg1012Ter) AF in mother

Verification of threshold for image intensity ratio analyses of late gadolinium enhancement magnetic resonance imaging of left atrial fibrosis in 1.5T scans

The use of cardiovascular magnetic resonance imaging left atrial late gadolinium enhancement (LA LGE) is increasing for fibrosis evaluation though the use is still limited to specialized centres due to complex image acquisition and lack of consensus on image analyses. Analysis of LA LGE with image intensity ratio (IIR) (pixel intensity of atrial wall normalized by blood pool intensity) provides an objective method to obtain quantitative data on atrial fibrosis. A threshold between healthy myocardium and fibrosis of 1.2 has previously been established in 3T scans. The aim of the study was to reaffirm this threshold in 1.5T scans. LA LGE was performed using a 1.5T magnetic resonance scanner on: 11 lone-AF patients, 11 age-matched healthy volunteers (aged 27–44) and 11 elderly patients without known history of AF but varying degrees of comorbidities. Mean values of IIR for all healthy volunteers +2SD were set as upper limit of normality and was reproduced to 1.21 and the original IIR-threshold of 1.20 was maintained. The degree of fibrosis in lone-AF patients [median 9.0% (IQR 3.9–12.0)] was higher than in healthy volunteers [2.8% (1.3–8.3)] and even higher in elderly non-AF [20.1% (10.2–35.8), p = 0.001]. The previously established IIR-threshold of 1.2 was reaffirmed in 1.5T LA LGE scans. Patients with lone AF presented with increased degrees of atrial fibrosis compared to healthy volunteers in the same age-range. Elderly patients with no history of AF showed significantly higher degrees of fibrosis compared to both groups with younger individuals.

Clinical implication of disturbed left atrial phasic functions in the heterogeneous population associated with hypertension or atrial fibrillation

BackgroundTo evaluate left atrial (LA) phasic functions in patients with hypertension and/or paroxysmal atrial fibrillation (PAF) and its clinical significance.MethodsLA strain was studied in 77 patients (25 hypertension, 24 lone AF, and 28 with both hypertension and PAF) and 28 controls using two-dimensional speckle-tracking echocardiography (2D STE). The following indexes during atrial reservoir, conduit and pump phase were analyzed respectively: (1) peak atrial longitudinal strain (PALS) and strain rate (PALSR), (2) the standard deviation of time to PALS and PALSR of all LA segments (TpS-SD% and TpSR-SD%).ResultsCompared with controls, PALSres, PALScond and PALSRcond were significantly reduced in patients with isolated hypertension (all P < 0.01) but no significant differences were observed in PALSpump, PALSRpump and TpSpump-SD% between them (all P > 0.05). PALSpump, PALSRpump and PALSRres were significantly lower in patients with both hypertension and PAF than in those with isolated hypertension (all P < 0.05). PALS and PALSR were significantly decreased, and TpS-SD% was significantly increased during each phase in lone AF patients than in controls (all P < 0.05), and PALSRpump was further depressed in patients with both hypertension and PAF (P = 0.029). PALSRcond ≤ 1.475 s− 1 combined with TpSpump-SD% ≥ 3.25% (sensitivity, 85%; specificity, 71%; AUC = 0.845, P < 0.001) could distinguish lone AF from healthy subjects effectively, while in hypertensive patients, PALSpump ≤ 14.2% was found to be an independent differentiator for occurrence of AF or not with sensitivity of 81% and specificity of 84% (AUC = 0.838, P < 0.001). LAVI≥29.3 mL/m2 was an independent characteristic for reflecting different LA remodeling in lone AF or hypertension with AF.ConclusionsThe impairment of LA phasic functions was varied in patients with hypertension and/or AF. The disturbed LA phasic functions were proved to have independent abilities of differential diagnosis in this heterogeneous population associated with hypertension or AF.

RARE LOSS-OF-FUNCTION VARIANT ANALYSIS IN LONE ATRIAL FIBRILLATION

Atrial fibrillation (AF) is a complex heritable disorder that substantially increases the risk for stroke, sudden death and all-cause mortality. Lone AF is a subset defined by early diagnosis (less than 60 years) and with no evidence of cardiopulmonary disease. Genome-wide association studies have associated loci near genes for structural integrity and function of muscles with AF susceptibility. In addition, some studies have identified rare loss-of-function (LoF) variants in dilated cardiomyopathy (DCM) genes in lone AF. The increased burden of these variants in lone AF patients may indicate a shared predisposition between AF and DCM. We performed a retrospective study on 252 adult patients and a control group of 503 healthy European subjects. Exome sequencing and microarray assays were performed at the McGill Genome Center while exome data from the controls was retrieved from 1KG Consortium. Principal component analysis was performed to define a group with common ancestry using SVS software. Variants within candidate DCM genes were filtered by minor allele frequency of ≤0.1%, a Combined Annotation Dependent Depletion (CADD) Phred score of >20 and a LoF variant type (frameshift, splice acceptor, splice donor and stop gain). These factors were retrieved from public annotation databases and applied using VarSeq software for variant analysis. All variants were confirmed with Sanger sequencing. Cascade screening was attempted on all cases positive for variants. The AF cohort, an ethnically homogenous composite of 181 lone AF cases, had 6 heterozygous LoF variants, including 4 novel variants, in 6 individuals, while the controls had 4 in 503 individuals. Half of variants in the cases were in the TTN gene (3/6). The prevalence of rare LoF variants in the lone AF cohort was 3.3% while in the control cohort 0.79%, the odds ratio of rare LoF variants found in lone AF patients compared to controls is 4.28 (95%CI: 1.19-15.33, P-value: 2.5E-02). Cascade screening in one family demonstrated co-segregation of one of the rare TTN variants and AF. Patients with lone AF carry a significant burden of heterozygous LoF variants in DCM genes. Our results are in agreement with a previous study identifying TTN variants in lone AF patients. Further, we identified novel variants in different DCM genes and confirmed the co-segregation of a TTN variant and AF in one family. Our findings may indicate a common genetic predisposition between lone AF and DCM, which may help elucidate novel pathophysiologic mechanisms, and improve diagnosis and treatment.

P6580Prevalence and clinical significance of latent Brugada syndrome in juvenile lone atrial fibrillation

Abstract Introduction Brugada syndrome (BrS) cause about 20% of sudden cardiac death (SCD) in young healthy adults. Nearly 20% of Brugada patients develop supraventricular arrhythmias, mostly atrial fibrillation (AF). But whether lone AF may be the first clinical manifestation in young patients with latent BrS remains unclear. Purpose To estimate the prevalence and clinical significance of latent Brugada ECG pattern in young population (age ≤45 years) with lone AF. Methods A total of 78 patients with lone atrial fibrillation (mean age 35±7) were selected from 111 young patients with juvenile atrial fibrillation (age ≤45 years) between January 2015 and November 2017. All patients were clinically evaluated. Moreover 12 lead-24H Holter ECG and pharmacological class 1C antiarrhythmic drug (AAD) test were done for high suspicious cases of Brugada ECG. The diagnosis of Brugada ECG pattern was established according to the second consensus report criteria 2005 and since 2013, according to HRS/EHRA/APHRS expert consensus statement. Results According to the study protocol, we considered two groups of patients, group 1: 13 patients (16.7%; mean age 37±8) were diagnosed with type 1 Brugada ECG pattern (3 during class 1C AADs therapy and 10 induced by class 1C AAD test), group 2: 65 patients (83%; mean age 35±7) diagnosed as lone AF without type 1 Brugada ECG. The clinical characteristics of the two groups are described in table 1. Regarding to group 1, two patients had positive electrophysiological study with subsequent ICD implantation and genetic test for SCN5A mutation was positive in 3 patients. Table 1. G1, G2 clinical characteristics Patients characteristics Group 1 (n=13) Group 2 (n=65) P value Mean age (years) 37±8 35±7 0.42 Gender (Male %) 7 (54%) 54 (83%) 0.02 Family history of BrS 2 (15%) 0 (0%) 0.03 Family history of SCD 1 (8%) 1 (1.5%) 0.20 Syncope 4 (31%) 5 (8%) 0.02 Sick Sinus Syndrome 1 (8%) 7 (11%) 0.70 Paroxysmal AF 12 (92%) 54 (83%) 0.40 Suspected basal ECG for BrS 13 (100%) 28 (43%) &lt;0.01 Statistical test is considered significant when p value &lt;0.05. Conclusions Up to our knowledge this study is the first one that estimate the prevalence of latent BrS in juvenile lone AF patients. Young patients with lone AF had a high prevalence of latent BrS. Syncope, family history of SCD and family history of BrS are significant indicators of the presence of latent BrS in young patients with lone atrial fibrillation.

P4797Genetic testing in 101 consecutive lone atrial fibrillation patients is able to identify a subgroup with increased severity

Abstract Introduction Atrial fibrillation (AF) is the most common arrhythmia and the cause of 15% of all strokes and up to 6% of medical admissions. It is estimated that currently about 2.0 million Brazilians, and 30 million individuals worldwide, are affected by the disease. It is a complex and multifactorial disease, and the mechanisms are still not well understood. Between 10–20% of AF patients do not have any known predisposing factors, a condition once called “lone AF”. The role of genetic testing still remains controversial in this clinical scenario. Purpose The aim of this study was to identify the occurrence of pathogenic genetic variants in patients with atrial fibrillation without known risk factors. Methods In a tertiary hospital, 101 young patients with apparent “lone AF” were screened with genetic testing by NGS using a custom genetic panel with 159 channelopathy and cardiomyopathy related genes. Variants found were classified according to the American College of Genetic and Genomic (ACMG) criteria. Subjects were evaluated with clinical and familial history, electrocardiogram, 24 hours Holter monitoring, echocardiogram, cardiac MRI and treatment response. Multivariate analyses were performed by logistic linear regression model. Results During an inclusion period of 4 years, 101 consecutive patients, with mean age of 38.6 years old, were classified as “lone AF” (78% male); 76% presented paroxysmal AF and 24% persistent/permanent AF. Family history of early sudden death (bellow 60 years old) was reported in 37% of cases (78% below 50 years old); 10% had family members with pacemakers; and 44% reported having family members with early AF onset. Genetic testing demonstrated that 14/101 (13.8%) of patients presented genetic variants classified as pathogenic or likely pathogenic (P/LP) according to ACMG criteria. The genes most frequently affected were LMNA (3/101), ANK2 (3/101) and truncating variants in TTN (3/101). Two variables were significantly associated with harboring a pathogenic mutation: family history of sudden death (OR: 5.58; 1,19–26,12 CI; p=0.029) and pacemaker reported in the family history (OR: 6.83; 1.11–42.04 CI; p=0.038). Conclusion Our data showed that approximately 15% of “lone AF” patients are carriers of known pathogenic mutations in genes associated with inherithed cardiomyopathy. In addition, we show that being a carrier is potentially associated with a more severe phenotype. These findings suggest that genetic testing in “lone AF” patients may be able to identify a subgroup with a more severe phenotype are for whom a different management strategy might be indicated. Acknowledgement/Funding National Council for Scientific and Technological Development (CNPq)

Nonlinear dynamic approaches to identify atrial fibrillation progression based on topological methods

In recent years, atrial fibrillation (AF) development from paroxysmal to persistent or permanent forms has become an important issue in cardiovascular disorders. Information about AF pattern of presentation (paroxysmal, persistent, or permanent) was useful in the management of algorithms in each category. This management is aimed at reducing symptoms and stopping severe problems associated with AF. AF classification has been based on time duration and episodes until now. In particular, complexity changes in Heart Rate Variation (HRV) may contain clinically relevant signals of imminent systemic dysregulation. A number of nonlinear methods based on phase space and topological properties can give more insight into HRV abnormalities such as fibrillation. Aiming to provide a nonlinear tool to qualitatively classify AF stages, we proposed two geometrical indices (fractal dimension and persistent homology) based on HRV phase space, which can successfully replicate the changes in AF progression. The study population includes 38 lone AF patients and 20 normal subjects, which are collected from the Physio-Bank database. “Time of Life (TOL)” is proposed as a new feature based on the initial and final Čech radius in the persistent homology diagram. A neural network was implemented to prove the effectiveness of both TOL and fractal dimension as classification features. The accuracy of classification performance was 93%. The proposed indices provide a signal representation framework useful to understand the dynamic changes in AF cardiac patterns and to classify normal and pathological rhythms.

Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation

A family history of atrial fibrillation constitutes a substantial risk of developing the disease, however, the pathogenesis of this complex disease is poorly understood. We perform whole-exome sequencing on 24 families with at least three family members diagnosed with atrial fibrillation (AF) and find that titin-truncating variants (TTNtv) are significantly enriched in these patients (P = 1.76 × 10−6). This finding is replicated in an independent cohort of early-onset lone AF patients (n = 399; odds ratio = 36.8; P = 4.13 × 10−6). A CRISPR/Cas9 modified zebrafish carrying a truncating variant of titin is used to investigate TTNtv effect in atrial development. We observe compromised assembly of the sarcomere in both atria and ventricle, longer PR interval, and heterozygous adult zebrafish have a higher degree of fibrosis in the atria, indicating that TTNtv are important risk factors for AF. This aligns with the early onset of the disease and adds an important dimension to the understanding of the molecular predisposition for AF.

Deep sequencing of atrial fibrillation patients with mitral valve regurgitation shows no evidence of mosaicism but reveals novel rare germline variants

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Valvular heart disease is a strong predictor, yet the underlying molecular mechanisms are unknown. The purpose of this study was to investigate the prevalence of somatic variants in AF candidate genes in an AF patient population undergoing surgery for mitral valve regurgitation (MVR) to determine whether these patients are genetically predisposed to AF. DNA was extracted from blood and left atrial tissue from 44 AF patients with MVR. Using next-generation sequencing, we investigated 110 genes using the HaloPlex Target Enrichment System. MuTect software was used for identification of somatic point variants. We functionally characterized selected variants using electrophysiologic techniques. No somatic variants were identified in the cardiac tissue. Thirty-three patients (75%) had a rare germline variation in ≥1candidate genes. Fourteen variants were novel. Fifteen variants were predicted damaging or likely damaging in ≥6 in silico predictions. We identified rare variants in genes never directly associated with AF: KCNE4, SCN4B, NEURL1, and CAND2. Interestingly, 7 patients (16%) had variants in genes involved in cellular potassium handling. The variants KCNQ1 (p.G272S) and KCNH2 (p.A913V) resulted in gain of function due to faster activation (KCNQ1) and slowed deactivation kinetics (KCNQ1, KCNH2). We did not find any somatic variants in patients with AF and MVR. Surprisingly, we found that our cohort of non-lone AF patients might, like lone AF patients, be predisposed to AF by rare germline variants. Our findings emphasize the extent of still unknown factors in the pathogenesis of AF.

Associations of big endothelin-1 and C-reactive protein in atrial fibrillation.

BackgroundAtrial fibrillation (AF) is associated with inflammation and endothelial dysfunction. However, the association between inflammation (as indexed by high-sensitivity C-reactive protein, hs-CRP) and endothelial function [as indexed by big endothelin-1 (ET-1)] in AF patients remains unclear.MethodsWe enrolled 128 patients with lone AF, among which 83 had paroxysmal AF, and 45 had persistent AF. Eighty-two age- and gender-matched controls of paroxysmal supraventricular tachycardia without AF history were evaluated. Plasma hs-CRP, big ET-1 levels and other clinical characteristics were compared among the groups.ResultsPatients with persistent AF had higher hs-CRP concentrations than those with paroxysmal AF (P < 0.05), both groups had higher hs-CRP level than controls (P < 0.05). Patients with persistent AF had higher big ET-1 level than those with paroxysmal AF, although the difference did not reach the statistical significance (P > 0.05), and both groups had higher big ET-1 levels than controls (P < 0.05). Multiple regression analyses revealed hs-CRP as an independent determinant of AF (P < 0.001). Further adjusted for big ET-1, both big ET-1 and hs-CRP were independent predictors for AF (P < 0.001), but the odds ratio for hs-CRP in predicting AF attenuated from 8.043 to 3.241. There was a positive relation between hs-CRP level and big ET-1 level in paroxysmal AF patients (r = 0.563, P < 0.05), however, the relationship in persistent AF patients was poor (r = 0.094, P < 0.05).ConclusionsBoth plasma hs-CRP and big ET-1 levels are elevated in lone AF patients, and are associated with AF. In paroxysmal lone AF patients, there were significant positive correlations between plasma hs-CRP level and big ET-1 level.

Second-Generation Cryoballoon Ablation in the Setting of Lone Paroxysmal Atrial Fibrillation: Single Procedural Outcome at 12 Months.

Lone atrial fibrillation (LAF) develops in younger individuals without cardiovascular or pulmonary disease. As pulmonary vein isolation has been recognized as an optimal treatment for drug-resistant atrial fibrillation, cryoballoon ablation with second-generation balloon (CB-A) may be an ideal solution for LAF patients. The aim of this study was to investigate acute success, periprocedural complications and outcome over a 12-month follow-up period in a cohort of patients having undergone PV isolation (PVI) for LAF using CB-A technology. A total of 75 consecutive patients (50 male, mean age 47 ± 12 years) with a diagnosis of lone paroxysmal atrial fibrillation who underwent pulmonary vein isolation (PVI) by CB-A from June 2012 were included. All patients underwent this procedure with the 28 mm CB-A. A total of 299 PVs (100%) could be isolated with CB-A alone. The freedom from AF recurrence after a single procedure was 92% of patients during the entire 13-month follow-up. When considering a blanking period (BP) of 3 months, success rate was 93.3%. Transient phrenic nerve palsy (PNP) was the most frequent complication, occurring in 5.3% of individuals (4 patients); complete recovery was documented for all of these patients prior to hospital discharge. CB-A is extremely effective in achieving PVI and affords freedom from AF at 13-month follow-up in 93% of young patients affected by drug-resistant LPAF following a 3-month BP. The most frequent complication observed was PNP, which reverted prior to discharge in all patients.

Abstract 17987: Structural and Senescence Changes in the Atria of Lone Atrial Fibrillation Patients

Introduction: Hypertension and structural heart disease (SHD) are the most frequent causes of Atrial Fibrillation (AF). Hemodynamic overload and inflammation are key mediators of the arrhythmogenic substrate, at least partly by triggering accelerated senescence. Remarkably, up to one third of AF patients have no associated SHD (lone AF), and their arrhythmogenic substrate is largely unknown. We sought to compare structural and senescence changes in AF patients with or without SHD. Methods: Atrial appendage samples from four groups of patients were analyzed; patients with no SHD (AF_lone, n=10), AF patients with SHD (AF_Card, n=14), controls with no AF but with other cardiovascular diseases (CVD) (C_CVD, n=18) and controls with no CVD (C_Healthy, n=5). The percentage of intramyocardial collagen deposition was quantified by sirius red staining and morphometric analysis, and connexin-43 was analyzed by immunohistochemistry. Tissue senescence was evaluated with telomere length quantification and mRNA levels of a family of proteins involved in cellular senescence (Sirtuin-1, -2, -3 and -6). Results: There were no differences in age (overall mean 60 ± 2 years) and the percentage of male gender (overall 67%) between groups of patients. AF patients had a marked increase in atrial fibrosis, with no differences between AF_lone and AF_Card (Figure A). Connexin-43 quantification and distribution was similar in AF patients with or without SHD. Nevertheless, telomeres were longer in AF_lone than in AF_Card patients (Figure B). Also, AF_lone samples had higher mRNA levels of sirtuin-2 and -3 compared to AF_Card samples with no changes in sirtuin-1 and -6. Conclusions: Even though a similar degree of structural remodelling was found, AF_Card patients presented an accelerated atrial senescence when compared to AF_lone patients. These results could have important implications in the prognosis and therapeutic options of AF_lone patients.

Relation of Biomarkers of Inflammation and Oxidative Stress with Hypertension Occurrence in Lone Atrial Fibrillation.

We compared plasma levels of biomarkers of inflammation (CRP) and oxidation (oxLDL), determined at study inclusion in lone atrial fibrillation (LAF) patients (48.6 ± 11.5 years; 74.0% men) and sinus rhythm controls (49.7 ± 9.3 years; 72.7% men, P > 0.05), and investigated the association of baseline CRP and oxLDL levels with the risk for vascular disease (VD) development (hypertension, cerebrovascular disease, coronary/peripheral artery disease, and pulmonary embolism) during prospective follow-up. Baseline CRP (1.2 [0.7–1.9] mg/L versus 1.1 [0.7–1.6] mg/L) and oxLDL levels (66.3 ± 21.2 U/L versus 57.1 ± 14.6 U/L) were higher in LAF patients (both P < 0.05). Following a median of 36 months, incident VD occurred in 14 (28.0%) LAF patients, all of whom developed arterial hypertension, and in 5 (11.4%) controls (hypertension, n = 4; coronary artery disease, n = 1), P < 0.05. LAF patients developed VD more frequently and at a younger age. Both CRP (HR, 2.54; 95% CI, 1.26–5.12; P = 0.009) and oxLDL (HR, 2.24; 95% CI, 1.14–4.40; P = 0.019) were multivariate predictors of incident hypertension in LAF patients, but not in the controls. Further research should clarify clinical relevance of investigated biomarkers for risk stratification and treatment of LAF patients.

Association of plasma fibronectin level with left atrial electrical and structural remodelling in lone paroxysmal atrial fibrillation: a cross-sectional study

Atrial fibrosis is one of the main components of atrial fibrillation (AF) pathophysiology and culminates in structural, electrical and contractile remodelling. Fibronectin is one of the well-known mediators of fibrogenesis. However, the association of plasma fibronectin with atrial remodelling has not been studied previously. Therefore, the aim of this study was to assess the relationship between plasma fibronectin level and atrial electrical and structural remodelling in patients with lone paroxysmal AF. A total of 51 lone paroxysmal AF patients and 40 age-, gender- and body mass index-matched healthy control subjects were enrolled. Plasma levels of fibronectin and high sensitive C-reactive protein (hs-CRP) were measured and transthoracic echocardiography for assessment of total atrial conduction time (TACT) and left atrial (LA) volume index was performed on all study participants. Plasma fibronectin, hs-CRP, TACT, LA diameter and LA volume index were significantly higher in lone paroxysmal AF group compared to healthy controls (p<0.05). Also, there was a positive correlation between plasma fibronectin level and TACT (r=0.362, p<0.001) and LA volume index (r=0.371, p<0.001). In multivariate logistic regression analysis, age, plasma fibronectin level (Odds ratio - OR: 1.003, 95% CI: 1.001-1.005, p=0.026) and hs-CRP (OR: 2.312, 95% CI: 1.503-6.459, p=0.017) were found to be the predictors of LA structural remodelling; however, only plasma fibronectin level (OR: 1.003, 95% CI: 1.001-1.005, p=0.032) and hs-CRP (OR: 3.212, 95% CI: 1.214-5.752, p=0.033) were found as the predictors of LA electrical remodelling. Our study results showed that profibrotic and proinflammatory biomarkers were associated with left atrial structural and electrical remodelling in lone paroxysmal AF patients.

Best practice for atrial fibrillation patient education.

Patients' beliefs about their health (and illness), medications and healthcare they receive are important determinants of whether or not they accept recommended treatments; influence their coping responses in relation to their illness; make them adhere to recommended therapy and ultimately affect health outcomes. Incorporation of patients' preferences for therapy should now be considered an integral part of the decision-making process. This gradual shift in health-care practice from paternalistic to shared-decision making, whereby there is a two-way exchange of information between the patient and healthcare provider and both are involved in the treatment decision, requires a reasonable level of understanding and knowledge of the condition and its treatment by the patient. However, patients with atrial fibrillation (AF) often have poor knowledge about their condition and the benefits and risks of AF and AF treatments. Physicians and other healthcare providers may have doubts over a patient's ability to adhere to certain treatment regimens, particularly oral anticoagulation, due in part to the lack of patient knowledge, and this may be an important determinant of whether such treatments are even considered as therapeutic options. Further, patients often hold misconceptions about AF and treatment options, which may act as barriers to their acceptance of the condition and adherence to therapy. This review will summarise the literature on the knowledge of patients about AF and its management, how patients' values and preferences can impact on their treatment choices, the ideal components of patient education, the impact of educational interventions on patients' knowledge and perceptions of AF, and where appropriate highlight specific issues facing lone AF patients.

A prospective DE-MRI study evaluating the role of TGF-β1 in left atrial fibrosis and implications for outcomes of cryoballoon-based catheter ablation: new insights into primary fibrotic atriocardiomyopathy.

Transforming growth factor (TGF)-β1 mediated atrial fibrosis plays a major role in the development of vulnerable atrial substrate for atrial fibrillation (AF). Although cryoablation effectively eliminates the triggers for AF, the impact of atrial substrate on the success of cryoablation remains unclear. We aimed to investigate the association of plasma TGF-β1 level with extent of left atrium (LA) fibrosis using delayed-enhanced magnetic resonance imaging (DE-MRI) and also effects of LA fibrosis on the success of cryoablation. A total of 41 symptomatic lone paroxysmal AF patients (58.5% male; age: 49.2 ± 7.6 years) underwent initial cryoablation. Cardiac DE-MRI at 1.5-Tesla scanner to quantify atrial fibrosis, plasma TGF-β1, clinical and echocardiographic data were collected before cryoablation. Postablation blanking period was observed for 3 months. DE-MRI revealed LA fibrosis in 27 (65.9%) patients with a median enhancement of 5% of the LA surface area. A total of 179 pulmonary veins (PV) were successfully isolated without any major complication. At median 18 months follow-up, 32 patients (78.1%) remained free of AF recurrence. Only plasma TGF-β1 level (P = 0.001) was found to be the predictor of the extent of LA fibrosis. Multivariate Cox regression analysis pointed out that the extent of LA fibrosis (HR: 1.127, P = 0.007) and early AF recurrence (HR: 1.442, P = 0.011) were the independent predictors of AF recurrence in late follow-up. Higher levels of TGF-β1 are associated with more extensive LA fibrosis and extent of LA fibrosis predict recurrences in patients undergoing cryoablation for lone AF.

Abstract 15523: Absence of Chordae Tendineae near Valve Coaptation Leads to Mitral Regurgitation in Lone Atrial Fibrillation

Introduction: Mitral annuloplasty is performed to treat mitral valve regurgitation (MR) in lone atrial fibrillation (AF) patients. The mechanisms of the significant MR in lone AF patients are not known well. We assessed the hypothesis that absence of chordae tendineae near the mitral valve (MV) coaptation could lead to the significant functional MR in the lone AF patients. Methods: We analyzed 64 patients with a history of AF with greater than 50 % of the left ventricular (LV) ejection fraction, and no organic abnormality of MV. Of these 31 has mild or lesser MR (AF Groups) and 33 has moderate or severe MR (AFMR Group). We also analyzed 33 sinus rhythm patients with normal echocardiographic findings (Sinus Group). Parameters concerning to MV morphology were measured with commercial software. Chordae attaching points (CAPs) nearest from the coaptation line were detected on the anterior mitral leaflet (Figure). Ratio of the length from CAP to coaptation line against that from anterior annulus to coaptation line was calculated as CAP-C/An-C ratio. Results: Mitral annular area (P &lt; 0.05), leaflets surface area (P &lt; 0.05), and CAP-C/An-C ratio (P &lt; 0.05) were larger in the AFMR Group as compared with the AF Group (Table). With multivariate analysis, the correlation factor of significant MR in AF patients was increase in the CAP-C/An-C ratio (Odds ratio (per 1 % increase) = 1.70; p &lt;0.05). Conclusion: The absence of chordae tendineae near the coaptation line represented by larger CAP-C/An-C ratio is related to the functional MR in AF patients with normal LV function.