Stroke Risk In Atrial Fibrillation Research Articles

Trimetazidine reduces stroke risk in ischemic atrial fibrillation: a territory-wide, propensity-matched study

Abstract Introduction Trimetazidine ameliorates myocardial ischemia via potentiating glucose oxidation. Whether such metabolic reprogramming protects against stroke risk in atrial fibrillation (AF) with ischemic heart disease (IHD) was unknown. Purpose To investigate the therapeutic impact of trimetazidine dihydrochloride on ischemic stroke in AF associated with IHD. Methods We collected data from a territory-wide clinical data registry (January 1999 to December 2020) with a coverage of 7.5 million population. 200,563 patients with IHD were identified. Amongst them, 13,092 (6.5%) had baseline AF (mean [SD] age: 79.7 [10.3] years, 44.8% female), and were identified as trimetazidine users (n=1,488) versus non-users (long-acting nitrates as control, n=11,604). Propensity matching at 1:1 was performed. Multivariable Cox regression was used to derive hazard ratios (HRs) for new-onset ischemic stroke. Result Over mean follow-up over 53.5 +/- 50.4 months, trimetazidine use was associated with a lower incidence of ischemic stroke (3.4% vs 7.6%, P<.001). Kaplan-Meier analyses showed trimetazidine use was associated with increased stroke-free survival period (Mean survival: 227.9 [4.9] versus 217.5 [3.6] months, Chi-square=39.0 P<.001). After adjusting for confounding factors, trimetazidine use remained an independent predictor of reduced ischemic stroke risk (adjusted HRs, 0.54, 95% CI, 0.37-0.78, P<.001). Conclusion Trimetazidine may reduce the risk of ischemic stroke in ischemic AF. These findings will need to be confirmed by randomized controlled trials.

Comparison of left atrial and left atrial appendage mechanics in patients with ischaemic strokes of different aetiologies

Abstract Background Left atrial (LA) and left atrial appendage (LAA) mechanical dysfunction account for an increase in cardioembolic stroke risk in atrial fibrillation (AF), and more recently in individuals in sinus rhythm (SR). However, the exact contribution of LA and LAA to the pathogenesis of thromboembolic events is not fully understood. Here, we aimed to assess the alterations of LA and LAA mechanics in different stroke subtypes. Methods We recruited three groups of participants: patients with paroxysmal or persistent AF with a history of stroke (AF-stroke, n=69,respectively), individuals in SR with no history of AF but with acute ischaemic stroke(non-AF stroke,n=46); individuals with no history of AF or stroke(control group,n=17). Patients with AF were further categorized into sinus rhythm group (AF-stroke-SR,n=24) and AF rhythm group(AF-stroke-AF, n=45) according to the rhythm at the time of echocardiography. Using speckle-tracking echocardiography, global longitudinal strain (GLS) and mechanical dispersion (MD) of LA and LAA were measured in all patients. Mechanical dispersion was defined as the standard deviation of the time to peak of the regional strain corrected by R-R interval. Results Patients with AF-stroke demonstrated prominently impaired LA and LAA mechanics(LA GLS: 20±6%(AF-stroke-SR),11±4%(AF-stroke-AF); LA MD: 9±3%,11±3%; LAA GLS: 15±3%,11±4% ; LAA MD: 11±4%,12±3% ,respectively) compare with those with non-AF stroke and controls (LA GLS:35±8%, 41±11%;LA MD,6±2%, 4±2%; LAA GLS:21±5%, 23±7%; LAA MD:8±4%, 7±3%,respectively) (all p<0.01). Interestingly, LA and LAA mechanical function was not significantly different between patients with non-AF strokes and the control group. In multivariable analysis, only AF-strokes were independently associated with LA and LAA GLS after adjusting for age and comorbidities (both P<0.01). Conclusions Mechanical dysfunction of LA and LAA might play a greater role in pathogenesis of strokes related to AF rather than non-AF strokes.

Persistence and predictors for non-persistence to edoxaban therapy in patients with atrial fibrillation: 4-year follow-up data from the ETNA-AF-Europe study

Abstract Background Non-persistence to non-vitamin K antagonist oral anticoagulants (NOACs) is associated with increased stroke risk in atrial fibrillation (AF) patients. To date, most NOAC persistence studies have been retrospective and often did not include patients receiving edoxaban. Identifying predictors for non-persistence may be useful when considering the design of future studies and help develop strategies to reduce non-persistence in clinical practice. Purpose To define and describe patients who did not reach the end of the study period and were non-persistent to edoxaban during the 4-year follow-up of ETNA-AF-Europe. Methods ETNA-AF-Europe was a prospective, observational study conducted in AF patients receiving edoxaban. In this subanalysis, patients not reaching the end of the study period and patients who were non-persistent (defined as permanent discontinuation of edoxaban) after 4 years of treatment were examined, including patients switching to other NOACs and reasons for discontinuation. Baseline predictors for not reaching the end of the study period and baseline predictors for non-persistence with edoxaban treatment during 4 years of follow-up were also examined. Persistent patients may have missed dose/interruption. Results Overall, 13,164 patients were included in the analysis. During the whole study period, 14.3% died. At the end of the study, 27.3% of patients prematurely terminated the study and 71.5% were classified as completing the study. Of patients who left the study (n=3598), 30.2% were lost-to-follow-up, 6.9% withdrew consent, and 5.9% transferred to another institution. Of patients who completed the study (n=9417), 87.4% were classified as persistent within the 4 years. Only 6.2% permanently discontinued edoxaban without switching to another NOAC (Table). Following backwards elimination, baseline characteristics associated with premature study termination (excluding death) were male sex, low body mass index, low renal function, chronic hepatic disease, long standing persistent/permanent AF, smoking, low compliance as judged by investigator, vitamin K antagonist-naïve, and no rate/rhythm control drug at baseline. Characteristics associated with non-persistence were increasing age, male sex, body weight extremes, low renal function, heart failure, vascular disease, chronic hepatic disease, alcohol use, perceived frailty, chronic obstructive pulmonary disease, smoking, current AF symptoms, and ablation (Figure). The criterion for backward elimination was p=0.05. Conclusions Most patients in ETNA-AF-Europe reached the end of the study. Less than a quarter were classified as non-persistent during the 4-year follow-up. The majority of patients who were non-persistent switched to another NOAC with a small number completely stopping anticoagulant therapy. Male sex, low renal function, chronic hepatic disease, and smoking were associated with both treatment discontinuation and non-persistence.Termination and persistence

Predictive value of neutrophil to lymphocyte ratio for clinical outcome in patients with atrial fibrillation: a systematic review and meta-analysis.

The association between the Neutrophil-to-Lymphocyte Ratio (NLR) and the prognosis of Atrial Fibrillation (AF) has been extensively studied, yet clinical outcomes have varied. Consequently, this analysis was undertaken to explore the link between NLR and the prognostic markers of AF. We conducted an exhaustive search across electronic databases, including PubMed, Embase, Web of Science, and the Cochrane Library, to investigate the correlation between the NLR and indicators of adverse clinical outcomes associated with AF from the database establishment date through March 31, 2024. In this study, the recurrence rate of AF was the primary outcome measure, while the secondary outcome measures were mortality, stroke, and left atrial thrombus. Odds ratio (OR), relative risk (RR), hazard ratio (HR) and standard mean difference (SMD) with a 95% confidence interval (CI) were integrated for assessment, and the stability of prognostic outcomes and publication bias were verified by sensitivity analysis and Egger's test, respectively. Subgroup analyses were performed to pinpoint the sources of heterogeneity. This analysis included 20 studies, encompassing a total of 59,256 patients. Our statistical analysis of both categorical and continuous variables revealed that an elevated NLR was significantly associated with increased risks in AF patients for recurrence (categorical variable: OR = 1.39, 95% CI = 1.21-1.60; continuous variable: SMD = 0.49, 95% CI = 0.24-0.74), mortality (categorical variable: OR = 1.87, 95% CI = 1.59-2.20), stroke (categorical variable: OR = 1.56, 95% CI = 1.13-2.17; continuous variable: SMD = 0.77, 95% CI = 0.63-0.91), and left atrial thrombus (categorical variable: OR = 1.87, 95% CI = 1.27-2.75; continuous variable: SMD = 0.59, 95% CI = 0.30-0.89). Subgroup analyses found that high NLR was significantly linked to AF recurrence when the NLR was >3. High NLR was significantly linked to the risk of stroke in AF when the NLR was ≤3. This study suggested that a high NLR is significantly linked to prognostic risk markers of AF, and NLR may be an effective biomarker for the prognosis of AF in clinical practice. PROSPERO (CRD42024530970).

Uncovering the Role of Direct Oral Anticoagulants in Stroke Prevention for Atrial Fibrillation: A Review of the Literature.

Atrial fibrillation (AF) is a predominant contributor to morbidity and mortality, and stroke prevention remains the mainstay for the management of AF. The precise mechanism involved in thrombus formation remains unknown. However, factors such as stretch-induced fibrosis, endothelial dysfunction, disordered atrial contractions, and pro-thrombotic states have been postulated for the development of AF. Various risk assessment strategies have been acknowledged for determining the risk of stroke in AF, of which the congestive heart failure, hypertension, age ≥75, diabetes, stroke, vascular disease, age between 65-74, and female sex (CHA2DS2-VASc) score remains the ultimate risk stratification tool. For the longest time, vitamin K antagonists (VKA) were the only oral anticoagulants available but were associated with an increased risk of bleeding. Recently, direct oral anticoagulants (DOACs) were approved and considered more efficient and safer than or as secure as warfarin in stroke prevention and lowering intra-cranial bleeding events. The pharmacodynamics and pharmacokinetics of DOACs were also clarified in this article. This review article compiles current evidence-based data on the role of DOACs, uncovering their underlying mechanisms, and comparing their efficacy with warfarin in stroke prevention in AF.

The predictive value of CHA2DS2-VASc score on the prognosis of patients with atrial fibrillation based on a prospective cohort study.

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia encountered in clinical practice, and it is associated with an increased risk of mortality, stroke, and peripheral embolism. The risk of stroke in AF is heterogeneous and dependent on underlying clinical conditions included in current risk stratification schemes. Recently, the CHA2DS2-VASc score has been incorporated into guidelines to encompass common stroke risk factors observed in routine clinical practice. The aim of this study was to study the predictive value of CHA2DS2-VASc score on the prognosis of patients with AF to determine the correlation of major complications including cerebral infarction and intracranial hemorrhage in patients with AF with oral anticoagulant and antiplatelet aggregation drugs and to identify the risk factors for all-cause mortality. A prospective study was conducted on 181 patients with AF who underwent physical examinations at Hai'an Qutang Central Hospital from January 2020 to December 2020. The patient's general condition, chronic disease history, CHA2DS2-VASc [congestive heart failure, hypertension, age ≥75 years (doubled), diabetes, stroke (doubled), vascular disease, age 65 to 74 years, and sex category (female)] score, left ventricular ejection fraction (LVEF), lipid metabolism, and oral anticoagulant and antiplatelet aggregation medication during physical examination were recorded. By using telephone meetings to complete the follow-up, we tracked the patient's cerebral infarction, intracranial hemorrhage, and survival status within 2 years of follow-up, statistically analyzed the relationship between AF complications and medication, and grouped patients with AF based on the CHA2DS2-VASc score to evaluate its predictive ability for mortality outcomes in these patients. The patients were divided into four groups according to the medication situation, and the incidence of cerebral infarction in the combination group was significantly lower than that in the non-medication group (0.0% vs. 19.2%; P<0.01). The incidence of intracranial hemorrhage in the combination group was significantly higher than that in the non-drug group (13.8% vs. 0.0%; P<0.01). The logistic regression model indicated that patients with a history of cerebral infarction had an increased risk of death compared to those without a history of cerebral infarction [odds ratio (OR) =7.404; 95% confidence interval (CI): 2.255-24.309]. After grouping according to the CHA2DS2-VASc score, we found that there was a significant difference in the 2-year survival rate between patients with CHA2DS2-VASc score <5 and those with a score ≥5 (P<0.01). The characteristic curve analysis of the participants showed that the CHA2DS2-VASc score had good predictive ability for all-cause mortality in patients with AF (area under the curve =0.754), with a cutoff value of 4, a sensitivity of 62.50%, a specificity of 86.06%, and a 95% CI of 0.684-0.815. The CHA2DS2-VASc score demonstrated high predictive value for all-cause mortality in patients with AF.

Prothrombotic plasma fibrin clot phenotype is associated with spontaneous echo contrast in atrial fibrillation: The role of protein carbonylation

IntroductionSpontaneous echo contrast (SEC) and left atrial appendage thrombus (LAAT) increase the risk of stroke and its severity in patients with atrial fibrillation (AF). Formation of denser fibrin networks and impaired fibrinolysis are associated with stroke risk in AF. This study investigated whether the prothrombotic fibrin clot phenotype characterizes patients with SEC/LAAT. MethodsWe studied 139 anticoagulated patients with AF (median age, 70 years), who underwent transesophageal echocardiography (TEE). SEC and LAAT were recorded. We assessed plasma fibrin clot properties, i.e. permeability (Ks) and clot lysis time (CLT), von Willebrand Factor (vWF) antigen, endogenous thrombin potential (ETP), proteins involved in thrombosis and fibrinolysis, as well as plasma carbonylated protein content (PC). ResultsSEC/LAAT was identified in 36 subjects (25.9 %) and was associated with heart failure (HF), AF duration, higher CHA2DS2VASc score, N-terminal prohormone of brain natriuretic peptide, and growth differentiation factor 15. Patients with SEC/LAAT had lower Ks (−15 %) and prolonged CLT (+19 %), along with higher fibrinogen (+24 %), ETP (+3 %), and plasminogen activator inhibitor-1 antigen (+16 %) compared with the remainder. Thrombin-activatable fibrinolysis inhibitor antigen, plasminogen, α2 − antiplasmin, and tissue plasminogen activator antigen were similar between the two groups. PC content was 50 % higher in SEC/LAAT and correlated with Ks (r = −0.47, p < 0.001) and CLT (r = 0.40, p < 0.001). On multivariate analysis, Ks, CLT, and PC levels, along with HF, remained independently associated with SEC/LAAT. ConclusionsWe demonstrated a formation of denser and poorly lysable fibrin networks in AF patients with SEC/LAAT despite anticoagulation. We suggest that this phenomenon is in part related to enhanced oxidative stress.

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 &amp;lt;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 &lt;0.001; ΔAIC -12.6; &lt;-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 (&lt;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 &gt;moderate mitral regurgitation; categorized into high, intermediate and low risk (see Figure). The rate of reduced LAAev &lt;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 &gt; 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 &lt; 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.