Stroke Risk In Atrial Fibrillation Research Articles

Time-trends of sex differences in stroke risk in atrial fibrillation: Are female patients still at higher risk today? A nationwide cohort study

Abstract Background Female sex is associated with higher risk of stroke in patients with atrial fibrillation (AF), particularly in the presence of other stroke risk factors. This has implications for oral anticoagulant treatment (OAC) decision-making, based on points of the CHA2DS2-VASc score. However, stroke rates have declined over recent years, and management has evolved over time towards a holistic approach that may have diminished the sex differences in AF-related stroke. Purpose To examine the changes in stroke risk over time in relation to risk differences between males and females not treated with oral anticoagulants in a nationwide cohort study. Methods This was an observational cohort study including patients with a hospital diagnosis of AF between 2007 and 2021. Data were obtained from the Danish nationwide registries. We identified a cohort of adult patients who were not receiving OAC treatment for up to 30 days after their AF diagnosis. Patients were followed up for thromboembolic events within one year after the AF diagnosis. Survival analysis was applied to describe the yearly rate of events and to estimate the risk ratio for females vs males of thromboembolism according to baseline risk levels, i.e., the CHA2DS2-VA score level (leaving out the ‘Sc’ sex criterion). Results A total of 188,704 AF patients (median age 75 years (IQR: 64 to 84); 49.7% female) who did not receive OAC treatment were included. The risk of thromboembolism during the entire study period was overall higher in females (3.5% in males vs. 4.7% among females). The overall one-year thromboembolic risk declined over time from 4.9% between 1997-2000 to 3.3% between 2017-2020, with male-female risk differences less evident in recent years (Figure 1a). The relative risk of stroke diminished from 1.22 (95%CI 1.10-1.34) in years 1997-2000 to 1.02 (95%CI 0.85-1.19) in years 2017-2020 for patients with a CHA2DS2-VA score of ≥2 (Figure 1b). For patients with a score of <2, the relative risk was lowest between 2005-2008 (1.02 (95%CI 0.63-1.42)) and was 1.18 (95%CI 0.54-1.83) in the latest time period. Formal statistical test for time trends according to score level revealed non-significant results (p-value=0.10 for score 0-1; p-value=0.17 for score levels of ≥2). Conclusion The risk of stroke among patients with AF has been declining over the last two decades. The excess stroke risk observed among females relative to males has also diminished, most evident among AF patients with ≥2 prevalent stroke risk factors.

Female sex is not a component of stroke risk in atrial fibrillation

Female sex is not a component of stroke risk in atrial fibrillation

Abstract 54: Circulating Biomarkers and Anticoagulation Breakthrough Stroke Risk in Atrial Fibrillation: The REGARDS Study

Introduction: Anticoagulation reduces ischemic stroke risk in atrial fibrillation (AF), but “breakthrough” stroke occurs. Blood biomarkers might help identify patients at risk for anticoagulation breakthrough stroke, but existing studies are limited by examining few biomarkers in select populations. Hypotheses: Established biomarkers of ischemic stroke risk will also be associated with ischemic stroke risk in people with AF on anticoagulation sampled from the general population. Methods: REGARDS is a prospective cohort of 30,239 Black or White adults aged ≥45 on enrollment in 2003-7 monitored for stroke. Nine established blood biomarkers of ischemic stroke risk were measured at baseline in participants with AF and with no prior stroke who were taking oral anticoagulation at baseline. Hazard ratios of ischemic stroke were estimated by Cox models adjusted for demographics and stroke risk factors. Results: Among 713 participants with AF on anticoagulation (median age 76, 36% female, 17% Black, all taking vitamin K antagonists), 67 (9%) developed a first-time ischemic stroke over 12 years. In models adjusted for demographics, there were positive associations of all biomarkers with stroke risk except for galectin-3, lipoprotein(a), and cystatin C which had inverse or null associations (Figure). Adjustment for risk factors minimally impacted interpretation of results. The greatest associations were with higher N-terminal pro-B type natriuretic peptide, factor VIII, D-dimer, and growth differentiation factor 15; associations for D-dimer and growth differentiation factor 15 were not statistically significant. Hazards for galectin-3, gamma glutamyl transferase, interleukin 6, and lipoprotein (a) were modest and not statistically significant. Conclusion: Biomarkers of cardiac strain (specifically atriopathy), coagulation, and inflammation were associated with higher ischemic stroke risk in people with AF on anticoagulation at baseline. Findings highlight new avenues for reducing stroke risk in AF.

Temporal Trends in Hypertension-Related Ischemic Stroke Risk in Atrial Fibrillation from 2007 to 2018: A Nationwide Cohort Study.

Temporal Trends in Hypertension-Related Ischemic Stroke Risk in Atrial Fibrillation from 2007 to 2018: A Nationwide Cohort Study.

Abstract 11396: Circulating Biomarkers Improve ChA 2 DS 2 -VASC Risk Prediction in Atrial Fibrillation: The CHA 2 DS 2 -VASc-Biomarkers Model

Introduction: Anticoagulation reduces stroke risk in atrial fibrillation (AF) but increases bleeding. Risk calculators are used to inform decision making for anticoagulation in AF. Yet, existing tools have substantial limitations and improvement efforts failed to change practice. Hypotheses: Biomarkers of ischemic stroke risk for general populations are associated with stroke risk in AF and improve performance of a recommended risk score (CHA 2 DS 2 -VASc). Methods: REGARDS is a prospective cohort of 30,239 Black or White adults aged ≥45 monitored for stroke. Nine blood biomarkers were measured at baseline in participants with AF, no prior stroke, and not taking anticoagulation at baseline. Hazard ratios of ischemic stroke were estimated by Cox models adjusted for demographics and stroke risk factors. Models with CHA 2 DS 2 -VASc alone and with biomarkers (CHA 2 DS 2 -VASc-B) were compared using tests of fit (likelihood ratio test and Aikake information criterion [AIC]) and predictive ability (continuous net reclassification index [NRI]). Results: Among 2,411 participants with baseline AF (median age 69, 55% female, 36% Black), 163 (7%) developed stroke over 13 years. After adjustments, higher cystatin C, growth differentiation factor 15 (GDF-15), interleukin 6, lipoprotein (a), and N-terminal pro-B type natriuretic peptide (NTproBNP) were associated with higher stroke risk (Figure A). Including all biomarkers substantially improved CHA 2 DS 2 -VASc model fit (Figure B; p <0.001; ΔAIC -12.6; <-10 indicates marked improvement) and predictive ability (Figure C; 5-year NRI 0.42). Adding only GDF-15 and NTproBNP resulted in the best model fit and a similar NRI, compared to all biomarkers. Conclusions: Higher levels of five blood biomarkers were associated with ischemic stroke risk in a large general population cohort with AF. Moreover, the CHA 2 DS 2 -VASc-B model was superior to CHA 2 DS 2 -VASc. Findings suggest we can better tailor anticoagulation to reduce stroke in AF.

Abstract 13115: Association of Hospital Racial Composition and Anticoagulation for Atrial Fibrillation: A Nationwide Study

Introduction: Anticoagulation reduces stroke risk in atrial fibrillation (AF). Patient-level studies show significant Black-White disparities in any anticoagulant and direct oral anticoagulant (DOAC) prescribing. Little is known about whether such disparities exist at the hospital level, thus we examined the association of hospital racial composition and anticoagulant initiation. Hypothesis: Hospitals with higher rates of Black patients would have lower anticoagulation. Methods: We conducted a retrospective cohort study of patients with incident AF treated at a VA medical center (VAMC) from 2018-2021. Our independent variable was hospital racial composition, defined by the proportion of Black patients cared for at a VAMC, with Quartile 1 (Q1) being the lowest, and Quartile (Q4) being the highest. We used a multivariable logistic regression model, adjusting for clinical factors (e.g., stroke and bleeding risk), year of diagnosis, and region, to estimate the odds of any anticoagulant and/or DOAC initiation by hospital racial composition. Results: We identified 86,436 patients with incident AF at 140 VAMCs, 10.5% Black, 89.5% White, mean age 73 years. Patients in Q4 were younger with similar stroke and bleeding risk to those in Q1. Overall, any anticoagulant use was 73.4% in Q1 and 71.4% in Q4 and lower for Black vs. White patients in both quartiles (Q1: 68.9% vs. 73.5%; Q4: 69.1 vs. 72.0%). The odds of initiating any anticoagulant overall were lower in Q1 hospitals compared to Q4: adjusted odds ratio (aOR): 0.85; 95% CI 0.73-0.99; p=0.04. DOAC use was similar in Q1 and Q4 (67.6% vs. 67.2%) though lower for Black vs. White patients in both quartiles (Q1: 57.4% vs. 67.7%; Q4: 63.3 vs. 68.5%). There was no significant difference overall in the odds of initiating DOAC in Q1 hospitals compared to Q4, aOR: 0.96; 95% CI 0.83-1.12; p=0.61. Conclusions: In a national study of patients with AF in the VA, we observed a significant difference in any anticoagulant but not DOAC initiation by hospital racial composition. Racial differences in anticoagulant use existed across quartiles, as in prior work. These data suggest that racial disparities in anticoagulant use in the VA, a safety net health system, may require local rather than national-level solutions alone to eliminate them.

Abstract 18187: Scoring System to Predict Reduced Left Atrial Appendage Emptying Velocity

Introduction: Left atrial appendage emptying velocity (LAAev) as assessed on transesophageal echocardiography (TEE) is a surrogate for propensity for LAA thrombus and cardioembolic stroke. Identifying patients with decreased LAAev is important for risk stratification. CHA 2 DS 2 -VASc score is used to stratify stroke risk in atrial fibrillation (AF) but does not incorporate rhythm, type of atrial fibrillation or transthoracic echocardiography (TTE). Objective: To create a composite scoring system using clinical and TTE variables to predict reduced LAAev. Methods: We searched TEE reports of unique patients from 2016-2022 at the University of Kansas Medical Center. Additional information was extracted from review of TEE imaging, TTE reports and detailed medical chart review. Significant univariate predictors of reduced LAAev (<30 cm/s) were added to a stepwise selection multivariable logistic regression model with significance level for entry and stay 0.15. Based on their respective odds ratios, selected variables were assigned different point values to create a risk score. Results: We included 995 patients (women 38.1% men, age 71.3±12.7 yrs, white 89.3%, LAAev 41.6±21.0 cm/s). The derived score includes different points assigned for long-standing persistent/permanent AF, persistent AF, paroxysmal AF, current rhythm AF, coronary artery disease, congestive heart failure, female sex, age ≥70 yrs and negative points for >moderate mitral regurgitation; categorized into high, intermediate and low risk (see Figure). The rate of reduced LAAev <30 cm/s was respectively 55.7%, 35.2% and 9.0%. Conclusions: Our scoring system was able to stratify risk of reduced LAAev and needs to be validated in independent datasets.

PPP1R12C Promotes Atrial Hypocontractility in Atrial Fibrillation.

Atrial fibrillation (AF)-the most common sustained cardiac arrhythmia-increases thromboembolic stroke risk 5-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function remain unknown. We tested the hypothesis that increased expression of PPP1R12C (protein phosphatase 1 regulatory subunit 12C)-the PP1 (protein phosphatase 1) regulatory subunit targeting MLC2a (atrial myosin light chain 2)-causes hypophosphorylation of MLC2a and results in atrial hypocontractility. Right atrial appendage tissues were isolated from human patients with AF versus sinus rhythm controls. Western blots, coimmunoprecipitation, and phosphorylation studies were performed to examine how the PP1c (PP1 catalytic subunit)-PPP1R12C interaction causes MLC2a dephosphorylation. In vitro studies of pharmacological MRCK (myotonic dystrophy kinase-related Cdc42-binding kinase) inhibitor (BDP5290) in atrial HL-1 cells were performed to evaluate PP1 holoenzyme activity on MLC2a. Cardiac-specific lentiviral PPP1R12C overexpression was performed in mice to evaluate atrial remodeling with atrial cell shortening assays, echocardiography, and AF inducibility with electrophysiology studies. In human patients with AF, PPP1R12C expression was increased 2-fold versus sinus rhythm controls (P=2.0×10-2; n=12 and 12 in each group) with >40% reduction in MLC2a phosphorylation (P=1.4×10-6; n=12 and 12 in each group). PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF (P=2.9×10-2 and 6.7×10-3, respectively; n=8 and 8 in each group). In vitro studies utilizing drug BDP5290, which inhibits T560-PPP1R12C phosphorylation, demonstrated increased PPP1R12C binding with both PP1c and MLC2a and dephosphorylation of MLC2a. Mice treated with lentiviral PPP1R12C vector demonstrated a 150% increase in left atrial size versus controls (P=5.0×10-6; n=12, 8, and 12), with reduced atrial strain and atrial ejection fraction. Pacing-induced AF in mice treated with lentiviral PPP1R12C vector was significantly higher than in controls (P=1.8×10-2 and 4.1×10-2, respectively; n=6, 6, and 5). Patients with AF exhibit increased levels of PPP1R12C protein compared with controls. PPP1R12C overexpression in mice increases PP1c targeting to MLC2a and causes MLC2a dephosphorylation, which reduces atrial contractility and increases AF inducibility. These findings suggest that PP1 regulation of sarcomere function at MLC2a is a key determinant of atrial contractility in AF.

Abstract EC.02: Myosin Light Chain Dephosphorylation By Ppp1r12c Promotes Atria Hypocontractility In Atrial Fibrillation

Background: Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, increases thromboembolic stroke risk five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function remain unknown. We tested the hypothesis that increased expression of PPP1R12C, the PP1 regulatory subunit targeting atrial myosin light chain 2 (MLC2a), causes hypophosphorylation of MLC2a and results in atrial hypocontractility. Methods: Right atrial appendage tissues were isolated from human AF patients versus sinus rhythm (SR) controls. Western blots, co-immunoprecipitation, and phosphorylation studies were performed to examine how the PP1c-PPP1R12C interaction causes MLC2a de-phosphorylation. In vitro studies of pharmacologic MRCK inhibitor (BDP5290) in atrial HL-1 cells were performed to evaluate PP1 holoenzyme activity on MLC2a. Cardiac-specific lentiviral PPP1R12C overexpression was performed in mice to evaluate atrial remodeling with atrial cell shortening assays, echocardiography, and AF inducibility with EP studies. Results: In human patients with AF, PPP1R12C expression was increased two-fold versus SR controls with > 40% reduction in MLC2a phosphorylation. 12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF. In vitro studies utilizing drug BDP5290, which inhibits T560-PPP1R12C phosphorylation, demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Lenti-12C mice demonstrated a 150% increase in LA size versus controls, with reduced atrial strain and atrial ejection fraction. Pacing-induced AF in Lenti-12C mice was significantly higher than controls. Conclusions: AF patients exhibit increased levels of PPP1R12C protein compared to controls. PPP1R12C overexpression in mice increases PP1c targeting to MLC2a and causes MLC2a dephosphorylation, which reduces atrial contractility and increases AF inducibility. These findings suggest that PP1 regulation of sarcomere function at MLC2a is a key regulator of atrial contractility in AF.

Associations of Community and Individual Social Determinants of Health With Medication Adherence in Patients With Atrial Fibrillation: A Retrospective Cohort Study

Background Despite guideline-recommended use of oral anticoagulation (OAC) for stroke prevention in atrial fibrillation (AF), OAC medication adherence among patients with AF in the United States ranges from 47% to 82%. To characterize potential causes of nonadherence, we analyzed associations between community and individual social risk factors and OAC adherence for stroke prevention in AF. Methods and Results A retrospective cohort analysis of patients with AF was conducted using the IQVIA PharMetrics Plus claims data from January 2016 to June 2020, and 3-digit ZIP code-level social risk scores were calculated using American Community Survey and commercial data. Logistic regression models evaluated associations between community social determinants of health, community social risk scores for 5 domains (economic climate, food landscape, housing environment, transportation network, and health literacy), patient characteristics and comorbidities, and 2 adherence outcomes: persistence on OAC for 180 days and proportion of days covered ≥0.80 at 360 days. Of 28 779 patients with AF included in the study, 70.8% of patients were male, 94.6% were commercially insured, and the average patient age was 59.2 years. Multivariable regression found that greater health literacy risk was negatively associated with 180-day persistence (odds ratio [OR]=0.80 [95% CI, 0.76-0.83]) and 360-day proportion of days covered (OR, 0.81 [95% CI, 0.76-0.87]). Patient age and higher AF stroke risk score and AF bleeding risk scores were positively associated with both 180-day persistence and 360-day proportion of days covered. Conclusions Social risk domains, such as health literacy, may affect OAC adherence among patients with AF. Future studies should explore associations between social risk factors and nonadherence with greater geographic granularity.

S-10-5: OPTIMAL BLOOD PRESSURE AND CARDIOVASCULAR RISK MANAGEMENT IN PATIENTS WITH ATRIAL FIBRILLATION

Hypertension is one of the most common cardiovascular disorders. On a population basis, and high blood pressure (BP) is a major independent risk factor for incident atrial fibrillation (AF) and AF-related complications. Given the high prevalence and both disorders being commonly asymptomatic, opportunistic arrhythmia screening in hypertensive patients is needed. In terms of management, AF could be regarded as a manifestation of hypertensive target organ damage, and optimal BP control is recommended, ideally aiming for a target systolic BP of 120–129mmHg, and diastolic BP of < 80mmHg. There is a close link between hypertension and the risk of stroke in AF, as well as the risk of serious bleeds in anticoagulated AF patients. Also, hypertension burden can be related to other AF-related complications, such as dementia and end renal disease. BP control should also be complementary to lifestyle factors, such as weight reduction, smoking cessation, alcohol reduction and regular exercise, given the close association with incident AF and AF-related complications such as stroke, major adverse cardiac events (MACE) and heart failure. Contemporary management of AF has moved towards a more holistic or integrated care approach to AF management, summed up as the ABC (Atrial fibrillation Better Care) pathway: A/Avoid stroke with Anticoagulation; B/ Better symptom control with patient-centred symptom-directed decisions on rate or rhythm control; and C/Cardiovascular risk and comorbidity management, including lifestyle changes. Adherence to the ABC pathway is associated with a profound reduction in death, hospitalisation, stroke and bleeding in AF patents [Fgure]. In summary, increased awareness, diagnosis and proactive management of detected hypertension is crucial in patients with AF. Optimised blood pressure control is an essential component of such a holistic approach to AF care.

712 INFLAMMATION, HAEMOSTASIS AND EXTRACELLULAR MATRIX IN THE STRATIFICATION OF BLEEDING AND THROMBOTIC RISK OF ATRIAL FIBRILLATION ON ORAL ANTICOAGULANT THERAPY: INSIGHTS FROM STRAT-AF STUDY

Abstract Background In anticoagulated atrial fibrillation patients, the validity of models recommended for the stratification of the risk ratio between benefits and hemorrhage risk is limited. We hypothesize that biological markers – both circulating and neuroimaging-based – and their possible interaction, might improve the prediction of bleeding risk in atrial fibrillation patients under treatment with any type of oral anticoagulant. Methods The Strat-AF study is an observational, prospective, single-center hospital-based study enrolling patients with atrial fibrillation, aged 65 years or older, and with no contraindications to undergo magnetic resonance imaging. Recruited patients are evaluated by means of a comprehensive protocol, with clinical, cerebral magnetic resonance imaging and circulating biomarkers assessment. The main outcomes are the evaluation of cerebral microangiopathy using MRI (lacunar infarcts, non-lacunar infarcts, microbleeds, hyperintensity of the white matter, SVDs [small vessel disease score]) and the onset of ischemic or hemorrhagic stroke related to the levels of circulating biomarkers of inflammation (IL-6, IL-8, TNFα, IL-4, IL-10, CCL2, CXCL10, ICAM-1, VCAM-1, VEGF), haemostasis (PAI-1, CLT, vWF) and extracellular matrix remodeling (MMP-2,-7,-8,-9,-12, TIMP-1,-2,-3,-4). Starting from September 2017, 191 patients (mean age 78.1±6.7, range 65-97; 65.3% males) were enrolled. 56 patients (29.3%) were on vitamin K antagonists, and 135 (70.7%) were on direct oral anticoagulants. Follow-up clinical evaluation and brain MRI were performed at 18 months. Results At multivariate analysis, adjusted for age, sex, CHA2DS2-VASc, HAS-BLED and type of anticoagulant, independent predictors were: low levels of vWF and elevated levels of TIMP-2 for microbleeds [OR:0.62 95%CI(0.42-0.89), p=0.011and OR:1.25 (1.01-1.77), p=0.049 respectively]; elevated levels of IL-6 and TIMP-4 for hyperintensity of white matter [OR: 1.55 (1.01-2.58), p=0.049 and OR: 1.44 (1.01-2.07), p=0.047 respectively]; elevated levels of MMP-2 and of TIMP-1 and TIMP-2 for lacunar infarcts [OR: 1.33 (1.01-1.89), p=0.049, OR: 1.48(1.01-2.18), p=0.048 and 1.50 (1.05-2.16), p=0.028 respectively]; elevated levels of TIMP-1, TIMP-2, TIMP-3 for the appearance of at least 1 new lesion according to the SVD score [OR: 1.48 (1.01-2.19), p=0.046, OR:1.53 (1.05-2.23), p=0.028 and OR: 1.58 (1.09-2.31), p=0.016 respectively]. Conclusions The Strat-AF study may be an essential step towards the exploration of the role of a combined clinical biomarker or multiple biomarker models in predicting stroke risk in atrial fibrillation and might sustain the incorporation of such new markers in the existing stroke prediction schemes by the demonstration of a greater incremental value in predicting stroke risk and improvement in clinical outcomes in a cost-effective fashion.

Contemporary management of atrial fibrillation and the predicted vs. absolute risk of ischaemic stroke despite treatment: a report from ESC-EHRA EORP-AF Long-Term General Registry.

Risk stratification in patients with atrial fibrillation (AF) is important to facilitate guideline-directed therapies. The Calculator of Absolute Stroke Risk (CARS) scheme enables an individualized estimation of 1-year absolute risk of stroke in AF. We aimed to investigate the predicted and absolute risks of ischaemic stroke, and evaluate whether CARS (and CHA2DS2-VASc score) may be useful for identifying high risk patients with AF despite contemporary treatment. We utilized the EORP-AF General Long-Term Registry which prospectively enrolled patients with AF from 250 centres across 27 participating European countries. Patients with sufficient data to determine CARS and CHA2DS2-VASc score, and reported outcomes of ischaemic stroke were included in this analysis. The primary outcome of ischaemic stroke was recorded over a 2-year follow-up period. A total of 9444 patients were included (mean age 69.1 [±11.4] years; 3776 [40.0%] females). There was a high uptake (87.9%) of anticoagulation therapy, predominantly with vitamin K antagonist (50.0%). Over a mean follow-up period of 24 months, there were a total of 101 (1.1%) ischaemic stroke events. In the entire cohort, the median CARS and absolute annual risks of ischaemic stroke were 2.60 (IQR 1.60-4.00) and 0.53% (95%CI 0.43-0.64%), respectively. There was no statistical difference between the predictive performance of CARS and CHA2DS2-VASc score (0.621 [95%CI 0.563-0.678] vs. 0.626 [95%CI 0.573-0.680], P = 0.725). Contemporary management of AF was associated with a low risk of ischaemic stroke. CARS and CHA2DS2-VASc score may be useful to identify high risk patients despite treatment who may benefit from more aggressive treatment and follow-up.

Bone morphogenetic protein 10: a novel risk marker of ischaemic stroke in patients with atrial fibrillation.

Biomarkers specifically related to atrial tissue may increase the understanding of the pathophysiology of atrial fibrillation (AF) and further improve risk prediction in this setting. Bone morphogenetic protein 10 (BMP10) is a protein expressed in the atrial myocardium. We evaluated the association between BMP10 and the risk of ischaemic stroke and other cardiovascular events in large cohorts of patients with AF, treated with and without oral anticoagulation (OAC). BMP10 was measured in plasma samples collected at randomisation in patients with AF without OAC in the ACTIVE A and AVERROES trials (n = 2974), and with OAC in the ARISTOTLE trial (n = 13 079). BMP10 was analysed with a prototype Elecsys immunoassay. Associations with outcomes were evaluated by Cox-regression models adjusted for clinical characteristics, kidney function, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Median concentrations of BMP10 were 2.47 and 2.44 ng/mL, in the non-OAC and OAC cohort, respectively. Increasing BMP10 was associated with lower body mass index, older age, female sex, kidney dysfunction, and AF rhythm. BMP10 was consistently associated with ischaemic stroke. In the non-OAC cohort, BMP10 increased the concordance index of the multivariable model from 0.713 to 0.733 (P = 0.004) and in the OAC cohort from 0.673 to 0.694 (P < 0.001). Additionally, BMP10 maintained a significant prognostic value after additionally adjusting for NT-proBNP. BMP10 was not independently associated with bleeding or with death. The novel atrial biomarker BMP10 was independently associated with ischaemic stroke in patients with AF irrespective of OAC treatment. BMP10 seems to be more specifically related to the risk of ischaemic stroke in AF. In this study, BMP10 may be a novel specific biomarker of ischaemic stroke in patients with atrial fibrillation, irrespective of oral anticoagulation.

Abstract 13457: Ability of CHARGE-AF and CHA 2 DS 2 -VASc Scores to Predict Prevalent Atrial Fibrillation in a High-Risk Population

Introduction: The CHARGE-AF score estimates 5-year risk of developing atrial fibrillation (AF) using information on age, race, weight, height, systolic and diastolic blood pressure, diabetes, smoking, use of antihypertensive medication, and prevalence of heart failure and myocardial infarction. Similarly, the CHA 2 DS 2 -VASc score for estimation of stroke risk in AF has been proposed as a useful tool for incident AF prediction. It is unclear whether these scores can predict AF in a high-risk population. We evaluated whether the CHARGE-AF and CHA 2 DS 2 -VASc scores predict the prevalence of AF in the Emory Cardiovascular Biobank cohort (EmCAB) that recruited patients undergoing cardiac catheterization with suspected or confirmed coronary artery disease. Methods: In 6951 EmCAB participants, logistic regression was used to determine the association between baseline characteristics, CHARGE-AF and CHA 2 DS 2 -VASc scores and the presence of prevalent AF. To assess the discrimination of the CHARGE-AF and CHA 2 DS 2 -VASc models, we estimated the C-statistic. Internal calibration was determined with the Hosmer-Lemeshow test. Results: Mean age of patients was 62 (SD=13), 64% male, 76% White. Median 5-year risk of AF using the CHARGE-AF score was significantly higher in those with compared to those without prevalent AF (11% vs. 4%, p=&lt;0.001). However, the median CHA 2 DS 2 -VASc scores were similar in both groups (3.0). The C-statistic for predicting prevalent AF was better with the CHARGE-AF compared to the CHA 2 DS 2 -VASc score (0.662 vs. 0.606). The strongest risk predictor of prevalent AF was heart failure (OR 2.52, 95%CI 2.13-2.98). Conclusion: In a high risk cohort of patients with CAD, the CHARGE-AF score had a moderate discrimination ability to predict AF and showed better performance than the CHA 2 DS 2 -VASc score. Whether the CHARGE-AF score is useful in predicting incident AF in high risk patients needs to be further investigated.

Abstract 13258: Myosin Light Chain Dephosphorylation by Ppp1r12c Promotes Atrial Hypocontractility in Atrial Fibrillation

Introduction: Atrial fibrillation (AF) is the most common sustained arrhythmia, with an estimated prevalence in the U.S. of 6.1 million . AF increases the risk of a thromboembolic stroke in five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function in AF remains unknown. We have recently identified protein phosphatase 1 subunit 12c (PPP1R12C) as a key molecule targeting myosin light chain phosphorylation in AF. Objective We hypothesize that the overexpression of PPP1R12C causes hypophosphorylation of atrial myosin light chain 2 (MLC2a), thereby decreasing atrial contractility in AF. Methods and Results Left and right atrial appendage tissues were isolated from AF patients versus sinus rhythm (SR). To evaluate the role of the PP1c-PPP1R12C interaction in MLC2a de-phosphorylation, we utilized Western blots, co-immunoprecipitation, and phosphorylation assays. In patients with AF, PPP1R12C expression was increased 3.5-fold versus SR controls with an 88% reduction in MLC2a phosphorylation. PPP1R12CPP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF. In vitro studies of either pharmacologic (BDP5290) or genetic (T560A) PPP1R12C activation demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Additionally, to evaluate the role of PPP1R12C expression in cardiac function, mice with lentiviral cardiac-specific overexpression of PPP1R12C (Lenti-12C) were evaluated for atrial contractility using echocardiography, versus wild-type and Lenti-controls. Lenti-12C mice demonstrated a 150% increase in left atrium size versus controls, with reduced atrial strain and atrial ejection fraction. Also, programmed electrical stimulation was performed to evaluate AF inducibility in vivo. Pacing-induced AF in Lenti-12C mice was significantly higher than controls. Conclusion The overexpression of PPP1R12C increases PP1c targeting to MLC2a and provokes dephosphorylation, associated with a reduction in atrial contractility and increase in AF inducibility. All these discoveries suggest that PP1 regulation of sarcomere function at MLC2a is a main regulator of atrial contractility in AF.

Rule-based definition of muscle bundles in patient-specific models of the left atrium.

Atrial fibrillation (AF) is the most common arrhythmia encountered clinically, and as the population ages, its prevalence is increasing. Although the CHA2DS2− VASc score is the most used risk-stratification system for stroke risk in AF, it lacks personalization. Patient-specific computer models of the atria can facilitate personalized risk assessment and treatment planning. However, a challenge faced in creating such models is the complexity of the atrial muscle arrangement and its influence on the atrial fiber architecture. This work proposes a semi-automated rule-based algorithm to generate the local fiber orientation in the left atrium (LA). We use the solutions of several harmonic equations to decompose the LA anatomy into subregions. Solution gradients define a two-layer fiber field in each subregion. The robustness of our approach is demonstrated by recreating the fiber orientation on nine models of the LA obtained from AF patients who underwent WATCHMAN device implantation. This cohort of patients encompasses a variety of morphology variants of the left atrium, both in terms of the left atrial appendages (LAAs) and the number of pulmonary veins (PVs). We test the fiber construction algorithm by performing electrophysiology (EP) simulations. Furthermore, this study is the first to compare its results with other rule-based algorithms for the LA fiber architecture definition available in the literature. This analysis suggests that a multi-layer fiber architecture is important to capture complex electrical activation patterns. A notable advantage of our approach is the ability to reconstruct the main LA fiber bundles in a variety of morphologies while solving for a small number of harmonic fields, leading to a comparatively straightforward and reproducible approach.

Long-term outcome and risk factors associated with events in patients with atrial fibrillation treated with oral anticoagulants: The ASSAF-K registry

BackgroundOral anticoagulant therapy for atrial fibrillation (AF) has changed dramatically. Direct oral anticoagulant (DOAC) therapy is administered by general practitioners and specialists. However, the beneficial long-term effects and safety of DOACs have not been well investigated in real-world clinical practice. MethodsThe ASSAF-K (a study of the safety and efficacy of OAC therapy in the treatment of AF in Kanagawa), a prospective, multi-center, observational study, was conducted to clarify patient characteristics, status of OAC treatment, long-term outcomes, and adverse events, including cerebrovascular disease, bleeding, and death. ResultsA total of 4014 patients were enrolled (hospital: 2500 cases; clinic: 1514 cases). The number of patients in the final dataset was 3367 (mean age, 72.6 ± 10.0 years; males, 66.3 %). CHA2DS2-VASc and HAS-BLED scores were 3.0 ± 1.6 and 2.2 ± 1.0, respectively. The risk factors of the primary composite outcome (all-cause death, serious bleeding events, cerebral hemorrhage, and stroke) were higher age, lower body mass index, lower diastolic blood pressure, lower creatine clearance, history of heart failure, history of stroke, and medication of anti-platelet agents. The event-free rates of the primary composite outcome with DOACs, warfarin, and without OACs were 92.7 %, 88.0 %, and 87.4 %, respectively. The event rate of DOACs was significantly lower than that of warfarin [HR 0.63 (95 % CI 0.48–0.81)], and similar results were observed after adjustment for AF stroke risk score [HR 0.70 (95 % CI 0.54–0.90)]. Serious bleeding events tended to occur less frequently with DOACs compared with warfarin [unadjusted HR 0.53 (95 % CI 0.31–0.91), adjusted HR 0.61 (95 % CI 0.33–1.11)]. ConclusionsThis multi-center registry demonstrated the long-term outcome in patients with AF treated with and without OACs and suggests that DOAC therapy is safe and beneficial in hospitals and clinics.

Assessment of Left Atrial Structure and Function by Echocardiography in Atrial Fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia with significant morbidity and mortality. Exacerbated by the aging population, the prevalence of AF is gradually increasing. Accurate evaluation of structure and function of left atrium (LA) has important prognostic significance in patients with AF. Echocardiography is the imaging technique of first choice to assess LA structure and function due to its better availability, accessibility and safety over cardiac computed tomography and cardiac magnetic resonance. Therefore, the aim of this review is to summarize the recent research progress of evaluating LA size by three-dimensional echocardiography and LA function by speckle tracking echocardiography (STE) in predicting the occurrence and recurrence of AF and determining the risk of stroke in AF. In addition, we summarized the role of traditional echocardiography in detecting AF patients that are at high risk of heart failure or cardiovascular death.

PO-684-05 A CHA₂DS₂-VASC SCORE OF 2 AND ABOVE PREDICTS STROKE RISK IN ATRIAL FLUTTER-A RETROSPECTIVE STUDY FROM THE NATIONAL INPATIENT SAMPLE

The CHA₂DS₂-VASc score is widely used to determine the stroke risk in atrial fibrillation (AF) patients. Although clinicians use the CHA₂DS₂-VASc score to determine the stroke risk in atrial flutter (AFL) patients, the use of the CHA₂DS₂-VASc score in AFL has not been well studied.