The association between eicosanoids and incident atrial fibrillation in the Framingham Heart Study.

Chronic inflammation is a continuous low-grade activation of the systemic immune response. Whereas downstream inflammatory markers are associated with atrial fibrillation (AF), upstream inflammatory effectors including eicosanoids are less studied. To examine the association between eicosanoids and incident AF. We used a liquid chromatography-mass spectrometry for the non-targeted measurement of 161 eicosanoids and eicosanoid-related metabolites in the Framingham Heart Study. The association of each eicosanoid and incident AF was assessed using Cox proportional hazards models and adjusted for AF risk factors, including age, sex, height, weight, systolic/diastolic blood pressure, current smoking, antihypertensive medication, diabetes, history of myocardial infarction and heart failure. False discovery rate (FDR) was used to adjust for multiple testing. Eicosanoids with FDR < 0.05 were considered significant. In total, 2676 AF-free individuals (mean age 66 ± 9 years, 56% females) were followed for mean 10.8 ± 3.4 years; 351 participants developed incident AF. Six eicosanoids were associated with incident AF after adjusting for multiple testing (FDR < 0.05). A joint score was built from the top eicosanoids weighted by their effect sizes, which was associated with incident AF (HR = 2.72, CI = 1.71-4.31, P = 2.1 × 10-5). In conclusion, six eicosanoids were associated with incident AF after adjusting for clinical risk factors for AF.

The association of education and household income with the lifetime risk of incident atrial fibrillation: The Framingham Heart study.

Background: Social determinants of health, in particular education and income, influence the incidence, management, and outcomes of cardiovascular diseases including atrial fibrillation (AF). Data are limited on the associations of socioeconomic status with lifetime risk of incident AF. Methods: We selected 2172 FHS participants (51% women) who were free of AF at the index age of 55 years. We assessed educational attainment (≥college) at the last exam prior to index age and household income ($40k/50k/≥55k depending on the FHS cohort). We estimated the lifetime risk of AF as the cumulative incidence of AF, accounting for the competing risk of death, at age 95 years. We analyzed strata defined by education and household income separately, and by combining education and household income. We adjusted analyses for sex, height, weight, systolic and diastolic blood pressure, current smoking, alcohol consumption, use of antihypertensive medication, diabetes, history of myocardial infarction, and history of heart failure. Results: Over a mean follow-up of 13 years, 265 participants developed incident AF. The lifetime risk of developing AF was 32.5% (95%CI, 26.5% to 38.5%) and 32.5% (95%CI, 28.7% to 38.3%) among participants with lower and higher education attainment (p=0.98). The lifetime risk of developing AF was 32.1% (95%CI, 26.7% to 37.5%) and 31.8% (95%CI, 26.6% to 36.9%) among participants with lower and higher household income (p=0.79). There was no evidence of interaction between education and income on lifetime risk of AF (p = 0.84). Results were similar in subgroups of women and men. Conclusion: In our community-based sample, there was no evidence of an association between education or household income and lifetime risk of AF.

Anti-inflammatory HDL effects are impaired in atrial fibrillation.

High-density lipoprotein (HDL), best known for cholesterol transport, also has anti-inflammatory effects. Previous studies suggest involvement of myeloperoxidase (MPO) in modification of HDL. HDL bound Sphingosine-1-phosphate (S1P) has been implied to be an essential protein regarding beneficial HDL effects. In this study, we analyzed anti-inflammatory HDL properties in patients with atrial fibrillation (AF), a disease involving atrial inflammation, compared to non-AF controls and whether anti-inflammatory properties improve upon catheter ablation. Additionally, association with serum concentrations of MPO and S1P were assessed. We isolated HDL from 25 AF patients, 13 non-AF individuals and 14 AF patients at follow-up (FU) after catheter ablation. S1P was measured in a cohort of 141 AF and 21 FU patients. Following preincubation with HDL from either group, bovine aortic endothelial cells were stimulated using tumor necrosis factor α and expression of pro-inflammatory genes intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), E-selectin (SELE) and P-selectin (SELP) was assessed using qPCR. Concentrations of circulating protein of these genes as well as MPO and S1P were measured in serum samples. Compared to non-AF individuals HDL from AF patients suppressed gene expression of the pro-inflammatory adhesion molecules ICAM1, VCAM1, SELE and SELP 27%, 18%, 21% and 57% less, respectively (p < 0.05 for all except SELE p = 0.06). In FU patients, the anti-inflammatory HDL activity was improved (suppression of ICAM1 + 22%, VCAM1 + 10%, SELE + 38% and SELP + 75%, p < 0.05 for all except VCAM1 p = 0.08). AF patients using angiotensin converting enzyme inhibitors or angiotensin receptor blockers had better anti-inflammatory HDL properties than non-users (gene expression suppression at least 28% more, p < 0.05 for all except ICAM1 p = 0.051). Circulating protein concentrations were not correlated with in vitro gene-expression, but circulating P-selectin was generally elevated in AF and FU patients compared to non-AF patients. MPO plasma concentration was positively associated with gene-expression of ICAM1, VCAM1 and SELP (r2 > 0.4, p < 0.05). Serum concentrations of S1P were increased in FU patients {1.201 µM [1.077-1.543]} compared to AF patients {0.953 µM [0.807-1.135], p < 0.01} but not correlated with ICAM1, VCAM1 and SELP gene expression. We conclude that the anti-inflammatory activity of HDL is impaired in AF patients, which might promote AF progression and AF-associated complications.

Epigenetic Age and the Risk of Incident Atrial Fibrillation.

BACKGROUND: The most prominent risk factor for atrial fibrillation (AF) is chronological age; however, underlying mechanisms are unexplained. Algorithms using epigenetic modifications to the human genome effectively predict chronological age. Chronological and epigenetic predicted ages may diverge in a phenomenon referred to as epigenetic age acceleration (EAA), which may reflect accelerated biological aging. We sought to evaluate for associations between epigenetic age measures and incident AF. METHODS: Measures for 4 epigenetic clocks (Horvath, Hannum, DNA methylation [DNAm] PhenoAge, and DNAm GrimAge) and an epigenetic predictor of PAI-1 (plasminogen activator inhibitor-1) levels (ie, DNAm PAI-1) were determined for study participants from 3 population-based cohort studies. Cox models evaluated for associations with incident AF and results were combined via random-effects meta-analyses. Two-sample summary-level Mendelian randomization analyses evaluated for associations between genetic instruments of the EAA measures and AF. RESULTS: Among 5600 participants (mean age, 65.5 years; female, 60.1%; Black, 50.7%), there were 905 incident AF cases during a mean follow-up of 12.9 years. Unadjusted analyses revealed all 4 epigenetic clocks and the DNAm PAI-1 predictor were associated with statistically significant higher hazards of incident AF, though the magnitudes of their point estimates were smaller relative to the associations observed for chronological age. The pooled EAA estimates for each epigenetic measure, with the exception of Horvath EAA, were associated with incident AF in models adjusted for chronological age, race, sex, and smoking variables. After multivariable adjustment for additional known AF risk factors that could also potentially function as mediators, pooled EAA measures for 2 clocks remained statistically significant. Five-year increases in EAA measures for DNAm GrimAge and DNAm PhenoAge were associated with 19% (adjusted hazard ratio [HR], 1.19 [95% CI, 1.09-1.31]; P<0.01) and 15% (adjusted HR, 1.15 [95% CI, 1.05-1.25]; P<0.01) higher hazards of incident AF, respectively. Mendelian randomization analyses for the 5 EAA measures did not reveal statistically significant associations with AF. CONCLUSIONS: Our study identified adjusted associations between EAA measures and incident AF, suggesting that biological aging plays an important role independent of chronological age, though a potential underlying causal relationship remains unclear. These aging processes may be modifiable and not constrained by the immutable factor of time.

P-wave signal-averaged electrocardiography: Reference values, clinical correlates, and heritability in the Framingham Heart Study.

BACKGROUND: P-wave signal-averaged electrocardiography (P-SAECG) quantifies atrial electrical activity. P-SAECG measures and their clinical correlates and heritability have had limited characterization in community-based cohorts. OBJECTIVE: The purpose of this study was to (1) establish reference values; (2) identify clinical risk factors associated with P-SAECG; and (3) estimate genetic heritability for P-SAECG traits. METHODS: We performed P-SAECG in 2 generations of Framingham Heart Study participants. We performed backward elimination regression models to assess associations of clinical factors with each SAECG trait (P-wave [PW] duration, root mean square voltage in terminal 40 ms [RMS40], terminal 30 ms RMS30, terminal 20 ms RMS20, RMS PW, and PW integral). We estimated the adjusted genetic heritability of P-SAECG measures using the Sequential Oligogenic Linkage Analysis Routines (SOLAR) program. RESULTS: We included 4307 participants (age 55 ± 14 years; 56% female). The reference values were derived from 1752 participants without cardiovascular risk factors. Median (2.5th percentile; 97.5th percentile) total PW duration was 118 ms (93; 146) in women and 128 ms (104; 158) in men in the reference sample, and 121 ms (94; 151) in women and 129 ms (103; 159) in the entire study cohort (broad sample). In the broad sample, after adjusting for age and sex, total PW duration was positively associated with height, weight, prevalent heart failure, history of atrial fibrillation (AF), and atrioventricular node blockers, and negatively associated with smoking, waist circumference, heart rate, and diabetes. The estimated heritability of P-SAECG traits was moderate, ranging from 11.9% for RMS30 to 24.9% for PW integral. CONCLUSION: P-SAECG traits are associated with multiple AF-related risk factors and are moderately heritable.

Impact of single versus double transseptal puncture on outcome and complications in pulmonary vein isolation procedures.

BACKGROUND: The aim of the current study was to analyze the impact of single versus double transseptal puncture (TSP) for atrial fibrillation (AF) ablation. METHODS: Consecutive patients undergoing AF ablation were prospectively included in the AF ablation registry and were analyzed according to single versus double TSP. RESULTS: A total of 478 patients (female 35%, persistent AF 67%) undergoing AF ablation between 01/2014 and 09/2014 were included. Single TSP was performed in 202 (42%) patients, double TSP in 276 (58%) patients. Age, gender, body mass index, CHA2DS2-VASc score, left ventricular ejection fraction and operator experience (experienced operator defined as ≥ 5 years of experience in invasive electrophysiology) were equally distributed between the two groups. Repeat procedures (re-dos) were more frequently performed using single TSP access (p < 0.001). Left atrial (LA) diameter was larger in patients with double TSP (p = 0.001). Procedure duration in single TSP was identical to double TSP procedures (p = 0.823). Radiation duration was similar between the two groups (p = 0.217). There were 49 (10%) patients with complications after catheter ablation. There were no differences between complication rates and TSP type (p = 0.555). Similarly, recurrence rates were comparable between both TSP groups (p = 0.788). CONCLUSIONS: There was no clear benefit of single or double TSP in AF ablation.

Association Between Frailty and Atrial Fibrillation in Older Adults: The Framingham Heart Study Offspring Cohort.

Background Frailty is associated bidirectionally with cardiovascular disease. However, the relations between frailty and atrial fibrillation (AF) have not been fully elucidated. Methods and Results Using the FHS (Framingham Heart Study) Offspring cohort, we sought to examine both the association between frailty (2005-2008) and incident AF through 2016 and the association between prevalent AF and frailty status (2011-2014). Frailty was defined using the Fried phenotype. Models adjusted for age, sex, and smoking. Cox proportional hazards models, adjusted for competing risk of death, assessed the association between prevalent frailty and incident AF. Logistic regression models assessed the association between prevalent AF and new-onset frailty. For the incident AF analysis, we included 2053 participants (56% women; mean age, 69.7±6.9 years). By Fried criteria, 1018 (50%) were robust, 903 (44%) were prefrail, and 132 (6%) were frail. In total, 306 incident cases of AF occurred during an average 9.2 (SD, 3.1) follow-up years. After adjustment, there was no statistically significant association between prevalent frailty status and incident AF (prefrail versus robust: hazard ratio [HR], 1.22 [95% CI, 0.95-1.55]; frail versus robust: HR, 0.92 [95% CI, 0.57-1.47]). At follow-up, there were 111 new cases of frailty. After adjustment, there was no statistically significant association between prevalent AF and new-onset frailty (odds ratio, 0.48 [95% CI, 0.17-1.36]). Conclusions Although a bidirectional association between frailty and cardiovascular disease has been suggested, we did not find evidence of an association between frailty and AF. Our findings may be limited by sample size and should be further explored in other populations.

Relevance of esophageal position and temperature on thermal injuries and rhythm outcome in atrial fibrillation ablations.

BACKGROUND: Thermolesions are a dangerous complication of atrial fibrillation (AF) ablation. We aimed to assess the reasons for thermolesions and the effect of esophageal position on recurrences. METHODS: The study included consecutive patients undergoing AF catheter ablation at Heart Center Leipzig between January and September 2014. We collected data of esophagus localization, temperature, endoscopy, and follow-up. RESULTS: The study included 645 patients into analyses. A total of 626 (97.2%) received a temperature probe. Esophageal position was categorized: (A) behind left pulmonary veins, (B) left ostial, (C) in the middle of left atrium, (D) right ostial, and (E) behind right pulmonary veins. The most frequent esophageal position was B-C (n = 201, 32.1%), followed by B (n = 161, 25.7%), and C (n = 147, 23.5%). The temperature was highest in A-B positions (42.04°C) and in D-E positions (41.70°C). There was a significant correlation between the endoscopically detected esophageal lesions (EDEL) and the esophageal position (r² = -.115, P = .004) and the esophageal temperature (r² = .162, P = .000), but not with body mass index (BMI) (r² = -.016, P = .688). Additional substrate modification in the left atrium resulted in significantly higher esophageal temperatures (P < .001) and more frequent EDEL (P = .049). An EDEL was found in 15 patients (2.3% of all patients, 5.6% of patients receiving endoscopy). Of those, the median esophageal temperature was 41.8°C (interquartile range [IQR]: 41.2-42.4). Neither esophageal position nor temperature during ablation was associated with arrhythmia recurrences (both P > .400). CONCLUSIONS: EDEL depended on the esophageal position and temperature, but not on BMI. Esophageal position and intraluminal temperature during ablation had no effect on recurrences.

The APPLE score: a novel and simple score for the prediction of rhythm outcomes after catheter ablation of atrial fibrillation.

BACKGROUND: Recurrent atrial fibrillation (AF) occurs in up to 50 % of patients within 1 year after catheter ablation, and a clinical risk score to predict recurrence remains a critical unmet need. The aim of this study was to (1) develop a simple score for the prediction of rhythm outcome following catheter ablation; (2) compare it with the CHADS2 and CHA2DS2-VASc scores, and (3) validate it in an external cohort. METHODS: Rhythm outcome between 3 and 12 months after AF catheter ablation were documented. The APPLE score [one point for age >65 years, persistent AF, impaired eGFR (<60 ml/min/1.73 m(2)), LA diameter ≥43 mm, EF < 50 %] was associated with AF recurrence and was validated in an external cohort in 261 patients with comparable ablation and follow-up. RESULTS: In 1145 patients (60 ± 10 years, 65 % male, 62 % paroxysmal AF) the APPLE score showed better prediction of AF recurrences (AUC 0.634, 95 % CI 0.600-0.668, p < 0.001) than CHADS2 (AUC 0.538) and CHA2DS2-VASc (AUC 0.542). Compared to patients with an APPLE score of 0, the odds ratio for AF recurrences was 1.73, 2.79 and 4.70 for APPLE scores 1, 2, or ≥3, respectively (all p < 0.05). In the external validation cohort, the APPLE score showed similar results (AUC 0.624, 95 % CI 0.562-0.687, p < 0.001). CONCLUSIONS: The novel APPLE score is superior to the CHADS2 and CHA2DS2-VASc scores for prediction of rhythm outcome after catheter ablation. It holds promise as a useful tool to identify patients with low, intermediate, and high risk for AF recurrence.

Effects of radiofrequency catheter ablation of atrial fibrillation on soluble P-selectin, von Willebrand factor and IL-6 in the peripheral and cardiac circulation.

BACKGROUND: Catheter ablation (CA) of atrial fibrillation (AF) is associated with inflammatory response, endothelial damage and with increased risk of thrombosis. However, whether these processes differ in peripheral and cardiac circulation is unknown. METHODS: Plasma markers (von Willebrand factor (vWf), soluble P-selectin (sPsel) and interleukin-6 (IL-6)) were measured by ELISA at three time points in 80 patients (62±10 years, 63% males, 41% paroxysmal AF) undergoing CA. These were at baseline--from femoral vein (FV) and left atrium (LA) before ablation; directly after ablation--from the pulmonary vein (PV), LA and FV; and 24 hours after procedure--from a cubital vein (CV). RESULTS: The levels of vWF and IL6--but not sP-sel--increased significantly 24 h after procedure (p<0.001). Baseline vWF was significantly associated with persistent AF (Beta = .303, p = 0.006 and Beta = .300, p = 0.006 for peripheral and cardiac levels, respectively), while persistent AF (Beta = .250, p = 0.031) and LAA flow pattern (Beta = .386, p<0.001) remained associated with vWF in cardiac blood after ablation. Advanced age was significantly associated with IL6 levels at baseline and after ablation in peripheral and cardiac blood. There were no clinical, procedural or anti-coagulation characteristics associated with sP-sel levels in cardiac blood, while peripheral sP-sel levels were associated with hypertension before (Beta = -.307, p = 0.007) and with persistent AF after ablation (Beta = -.262, p = 0.020). CONCLUSIONS: vWF levels are higher in persistent AF and are associated with LAA rheological pattern after AF ablation. Increase of peripheral vWF and IL6 levels after procedure supports current AF ablation management with careful control of post-procedural anticoagulation to avoid ablation-related thromboembolism.

Anticoagulation management in nonvalvular atrial fibrillation: current and future directions.

Oral anticoagulant therapy, either with vitamin K antagonists (VKAs) or with novel oral anticoagulants such as dabigatran, rivaroxaban, and apixaban, is the mainstay for thromboprophylaxis in patients with atrial fibrillation (AF). Thromboembolic risk factors associated with AF and risk factors for bleeding associated with oral anticoagulant therapy are largely the same, and bleeding risk very rarely outweighs individual benefit of thrombosis prevention, thus resulting in positive net clinical benefit of oral anticoagulant therapy in almost all AF patients. Prevention of AF­related thromboembolic events most commonly requires long­term oral anticoagulant therapy. Over time, various clinical situations may occur in a given patient (e.g., a need for an urgent surgery or invasive intervention, acute stroke, etc.), which may require a temporary or permanent modification of anticoagulant therapy regardless of which anticoagulant drug has been used. This may be particularly challenging for physicians because many issues regarding optimal use of oral anticoagulant drugs in specific clinical situations still remain to be solved. In this review article, we discuss the periprocedural management of oral anticoagulant therapy, bridging, transition to another oral anticoagulant, the occurrence of acute stroke in a patient already taking an oral anticoagulant, and decision when it is safe to resume oral anticoagulation therapy after stroke. We summarize the available evidence and current (and future) approaches to oral anticoagulation management in such clinical situations.