Free thyroxine within the normal reference range predicts risk of atrial fibrillation.

INTRODUCTION: Hyperthyroidism is a known precipitating factor for atrial fibrillation (AF). However, recent reports have suggested an increased risk of AF with free thyroxine (fT4) levels even within the upper reference (normal) range. We sought to test whether higher fT4 levels within the reference range are associated with an increased risk of AF. METHODS AND RESULTS: All patients in the Intermountain Healthcare electronic medical record database with an fT4 level not on thyroid medication were included. The reference range of fT4 was divided into quartiles (Q), and associations with prevalent and incident AF were assessed by multivariable regression. Similar analyses were performed for thyroid stimulating hormone (TSH) and total and free T3. A total of 174 914 patients were included and followed for 7.0 ± 4.9 years. Of these, 7.4%, 88.4%, and 4.2% had fT4 levels below, within, and above the reference range. As expected, prevalent AF was greater with elevated fT4. However, gradients also were noted within the reference range, comparing Q4 to Q1, for prevalent AF (adjusted odds ratio 1.4, P < .0001) and incident AF (adjusted hazard ratio 1.16, P < .0001). In contrast, no relationship with AF prevalence and incidence was noted for total and free T3 within their reference ranges, and the pattern for TSH was uninformative. CONCLUSION: Higher fT4 levels within the reference range were associated with an increased prevalence and incidence of AF. These findings in a large dataset prospectively validate earlier reports and may have important implications, including a redefinition of the normal range and fT4 targets for replacement therapy.

Biomarkers in the risk assessment for stroke and dementia in atrial fibrillation.

PURPOSE OF REVIEW: Atrial fibrillation is one of the most common clinically encountered arrhythmias exhibiting a strong association with a spectrum of cerebral injuries from the occurrence of clinical stroke, subclinical stroke, dementia, and cognitive decline. Dynamic noninvasive specific and sensitive diagnostic tests may allow a personalized approach to the atrial fibrillation patient's treatment based upon quantitative parameters, aiming to prevent or delay stroke, dementia, progressive cognitive decline, or to assess responses to these therapies. This review will explore molecular markers that have been shown to have an association with atrial fibrillation, and have a potential to be predictive for the risk for stroke, cognitive dysfunction, and dementia in these patients. RECENT FINDINGS: Circulating biomarkers of vascular disease, fibrosis, thrombosis, and inflammation are associated with risk of stroke in patients with atrial fibrillation. These biomarkers are additive to the predictive utility of the CHADS2 and CHA2DS2-VASc scores, and in some cases allow for additional risk prognostication of the broad categories allocated by CHADS2 and CHA2DS2-VASc scores of low, medium, and high. SUMMARY: Across the spectrum of cerebral injuries in patients with atrial fibrillation, biomarkers hold the promise of personalized risk stratification and management to minimize risks of disease.

Augmented intelligence decision tool for stroke prediction combines factors from CHA2 DS2 -VASc and the intermountain risk score for patients with atrial fibrillation.

INTRODUCTION: CHA2 DS2 -VASc and CHADS2 are computationally simple risk prediction tools used to guide anticoagulation decisions for stroke prophylaxis, but they have modest risk discrimination ability and use static dichotomous variables. The Intermountain Mortality Risk Scores (IMRS) are dynamic decision tools using standard clinical laboratory tests. This study derived new stroke prediction scores using variables from both CHA2 DS2 -VASc and IMRS. METHODS AND RESULTS: In outpatients with first atrial fibrillation (AF) diagnosis at the Intermountain Healthcare (females, n = 26 063 males, n = 29 807), sex-specific "IMRS-VASc" scores were derived using variables from CHA2 DS2 -VASc, warfarin use, the complete blood count, and the comprehensive metabolic profile. Validation was performed in an independent Intermountain outpatient AF cohort (females, n = 11 021; males, n = 12 641). Stroke occurred among 3.1% and 3.1% of females and 2.3% and 2.5% of males in derivation and validation groups, respectively. IMRS-VASc stratified stroke with similar ability in derivation (c-statistics, females: c = 0.703, males: c = 0.697) and validation groups (females: c = 0.681, males: c = 0.685). CHA2 DS2 -VASc (females: c = 0.581 and c = 0.605; males: c = 0.616 and c = 0.613 in derivation and validation, respectively) and CHADS2 (females: c = 0.581 and c = 0.608; males: c = 0.620 and c = 0.621 in derivation and validation, respectively) were substantially weaker stroke predictors. IMRS was the strongest mortality predictor (females: c = 0.783 and c = 0.782; males: c = 0.796 and c = 0.794 in derivation and validation, respectively) and all scores were poor at predicting bleeding risk. CONCLUSIONS: A temporally dynamic risk score, IMRS-VASc was derived and validated as a predictor of stroke in outpatients with AF. IMRS-VASc requires further validation and the evaluation of its use in guiding care and treatment decisions for patients with AF.

Five-year impact of catheter ablation for atrial fibrillation in patients with a prior history of stroke.

BACKGROUND: Catheter ablation of atrial fibrillation (AF) is an established therapeutic rhythm approach. Patients with a prior history of a stroke (CVA) represent a unique high-risk population for recurrent thromboembolic events. The role of antiarrhythmic treatment on the natural history of stroke recurrence in these patients is not fully understood. METHODS: Three patient groups with a prior CVA and 5 years of follow-up were matched 1:3:3 by propensity score (±0.01): AF ablation patients receiving their first ablation (n  =  139), AF patients that did not receive an ablation (n  =  416), and CVA patients without clinical AF (n  =  416). Prior CVA was determined by medical chart review. Patients were followed for outcomes of recurrent CVA, heart failure, and death. RESULTS: The average age of the population was 69 ± 11 years and 51% male. AF ablation patients had higher rates of hypertension and heart failure (P < 0.0001), but diabetes prevalence was similar between the groups (P  =  0.5). Note that 5-year risk of CVA (HR  =  2.26, P < 0.0001) and death (HR  =  2.43, P < 0.0001) were higher in the AF, no ablation group compared those that were ablated. When comparing AF, ablation to no AF patients, there was not a significant difference in 5-year risk of for CVA (HR  =  0.82, P  =  0.39) and death (HR  =  0.92, P  =  0.70); however, heart failure risk was increased (HR  =  3.08, P  =  0.001). CONCLUSION: In patients with AF and a prior CVA, patients undergoing ablation have lower rates of recurrent stroke compared to AF patients not ablated. Although the full mechanisms of benefit are unknown, as CVA rates are similar to patients without AF these data are suggestive of a potential altering of the natural history of disease progression.

Vagus nerve injury symptoms after catheter ablation for atrial fibrillation.

BACKGROUND: Vagus nerve injury during catheter ablation for atrial fibrillation can significantly impact quality of life and result in lingering gastrointestinal symptoms. This study was designed to define risk factors of vagus nerve injury, symptoms, prevalence, and temporal resolution. METHODS: A total of 100 patients undergoing radiofrequency catheter ablation (RFCA) were enrolled and consented to participate in the study. Patients completed a 22-item questionnaire that included questions specific to vagus nerve injury symptomatology during their baseline visit and at 1 and 3 months post-RFCA. RESULTS: The average age of the population was 63 ± 10.6 years and 68% were male. A total of 100 patients completed their baseline questionnaire (90 patients completed the 1-month questionnaires and 85 patients completed the 3-month questionnaires). Symptoms rated as moderate were prevalent at baseline (trouble swallowing 13%, bloating 26%, feeling full 20%), and increased in all categories analyzed at 1 month and with the exception of trouble swallowing returned to the preablation percentages at 3 months (heartburn 22.4%, trouble swallowing 18.8%, bloating 16.5%, nausea 8.2%, vomiting 3.5%, constipation 18.8%, diarrhea 16.4%, feeling full 15.3%). Severe rated symptoms of trouble swallowing (2-5.5%), bloating (5-7.6%), and early satiety (5-9.8%) increased at 1 month and bloating and early satiety percentages remained approximately two times higher at 3 months (trouble swallowing 2.4%, bloating 8.2%, early satiety 7.1%). CONCLUSION: The majority of symptoms were resolved by 3 months, although those patients who rate bloating and early satiety at a severe rating may have persistent symptoms.

Atrial fibrillation incrementally increases dementia risk across all CHADS2 and CHA2DS2VASc strata in patients receiving long-term warfarin.

BACKGROUND: Patients with atrial fibrillation (AF) are at higher risk for developing dementia. Warfarin is a common therapy for the prevention of thromboembolism in AF, valve replacement, and thrombosis patients. The extent to which AF itself increases dementia risk remains unknown. METHODS: A total 6030 patients with no history of dementia and chronically anticoagulated with warfarin were studied. Warfarin management was provided through a Clinical Pharmacy Anticoagulation Service. Patients were stratified by warfarin indication of AF (n=3015) and non-AF (n=3015) and matched by propensity score (±0.01). Patients were stratified by the congestive heart failure, hypertension, age >75 years, diabetes, stroke (CHADS2) score calculated at the time of warfarin initiation and followed for incident dementia. RESULTS: The average age of the AF cohort was 69.3±11.2 years, and 52.7% were male; average age of non-AF cohort was 69.3±10.9 years, and 51.5% were male. Increasing CHADS2 score was associated with increased dementia incidence, P trend=.004. When stratified by warfarin indication, AF patients had an increased risk of dementia incidence. After multivariable adjustment, AF patients continued to display a significantly increased risk of dementia when compared with non-AF patients across all CHADS2 scores strata. CONCLUSIONS: In patients receiving long-term warfarin therapy, dementia risk increased with increasing CHADS2 scores. However, the presence of AF was associated with higher rates of dementia across all CHADS2 score strata. These data suggest that AF contributes to the risk of dementia and that this risk is not solely attributable to anticoagulant use. Dementia may be an end manifestation of a systemic disease state, and AF likely contributes to its progression.

Long-term aspirin does not lower risk of stroke and increases bleeding risk in low-risk atrial fibrillation ablation patients.

BACKGROUND: Stroke risk is a significant concern in patients with atrial fibrillation (AF). Low stroke risk patients (CHADS2 VASc 0-2) are often treated long-term with aspirin after catheter ablation. Defining the long-term risks versus benefits of aspirin therapy, after an ablation, is essential to validate this common clinical approach. METHODS: A total of 4,124 AF ablation patients undergoing their index ablation were included in this retrospective observational study. We compared 1- and 3-year outcomes for cerebrovascular accident (CVA), transient ischemic attack (TIA), gastrointestinal (GI) bleeding, genitourinary (GU) bleeding, any bleeding, and AF recurrence among patients receiving: none, aspirin, or warfarin as long-term therapies. RESULTS: Patient distribution by CHADS2 VASc scores was as follows: 0: 1,143 (28%), 1: 1,588 (39%), and 2: 1,393 (34%). Significantly higher incidents of: female gender, hypertension, diabetes mellitus, heart failure, and vascular disease were seen with higher CHADS2 VASc scores (P < 0.0001 for all). At 3 years, 238 (5.9%) patients were on warfarin, 743 (18.6) on aspirin, and 3,013 (75.5%) on no therapy; with occurrences of CVA/TIA (1.4%, 3.0%, 3.9%, P < 0.0001, respectively), GI bleeding (0.8%, 1.9%, 1.1%, P = 0.06, respectively), and GU bleeding (1.7%, 2.8%, 2.1%, P = 0.008, respectively) that increased with advancing CHA2 DS2 VASc score. There was a significantly increased risk for both CVA/TIA with aspirin therapy, when compared to no therapy or warfarin therapy in general, and across all CHA2 DS2 VASc scores. CONCLUSIONS: After catheter ablation, low risk patients do not benefit from long-term aspirin therapy, but are at risk for higher rates of bleeding when compared to no therapy or warfarin.

The Impact of Age on 5-Year Outcomes After Atrial Fibrillation Catheter Ablation.

BACKGROUND: Catheter ablation of atrial fibrillation (AF) is an established therapeutic rhythm approach in symptomatic patients. Many studies have shown that age has little to no impact on outcomes during the first year after ablation. However, AF is a disease of aging and age-based substrate for arrhythmia is likely to progress. To this regard, we examined patients with 5-year outcome data following an index AF ablation procedure to define the impact of age on long-term outcomes. METHODS: A total of 923 patients that underwent their index AF ablation and had 5 years of follow-up were studied. Patients were followed up for atrial flutter/AF recurrence, heart failure, stroke, death, and cardiac function. Patients were separated and compared in 5 age-based groups (<50, 51-60, 61-70, 71-80, >80). RESULTS: The average age of the population was 66 ± 11 years and 59% were male. The AF was paroxysmal in 55%, persistent in 27%, and longstanding persistent in 18%. Older patients were more likely female and had higher rates of cardiovascular diseases. For every 10-year increase in age there was a higher multivariate-adjusted risk of atrial flutter/AF recurrence (HR: 1.13, P = 0.01), death (HR:1.91, P < 0.0001), and major adverse cardiac events (HR: 1.09, P = 0.07). Although atrial flutter/AF recurrence rates by age were similar at 1 year, at 5 years, younger patients had significantly lower rates of recurrences. CONCLUSION: Age significantly impacts outcomes after AF ablation when analyzed with long-term follow-up. These data highlight the progressive nature of AF and the need to consider interventions early.

Five-year outcomes of catheter ablation in patients with atrial fibrillation and left ventricular systolic dysfunction.

BACKGROUND: Catheter ablation of atrial fibrillation (AF) is an established therapy for symptomatic patients. The long-term efficacy and impact of catheter ablation among patients with severe systolic heart failure (SHF) requires additional study to understand if outcomes achieved at 1 year are maintained and mechanisms of AF recurrence. METHODS: Three groups with SHF and 5 years of follow-up were matched 1:4:4 by age (±5 years) and sex: AF ablation patients receiving their first ablation (n = 267), AF patients that did not receive an ablation (n = 1,068), and SHF patient without AF (n = 1,068). SHF was based upon clinical diagnosis and an ejection fraction (EF) ≤35%. Patients were followed for 5-year primary outcomes of AF recurrence, heart failure, stroke, death, and cardiac function. RESULTS: At 5 years, 60.7% of patients had clinical recurrence of AF. Diabetes and a prior heart attack were significant predictors of long-term risk of AF recurrence. Long-term mortality rates were 27%, 55%, 50%, in the AF ablation, AF, and no AF groups, respectively (P < 0.0001), with the lower rates attributed to lower cardiovascular mortality. At 5 years, there was no difference in EF, yet HF hospitalizations were lower following AF ablation compared to patients with AF and no ablation. Stroke rates at 5 years trended to be lower in the AF ablation group, but the difference was not statistically significant. CONCLUSION: Recurrence rates of AF in patients with SHF after ablation are common at 5 years with an anticipated ongoing increase. Long-term AF-related comorbidities tended to be less in the AF ablation group.

Percent Time With a Supratherapeutic INR in Atrial Fibrillation Patients Also Using an Antiplatelet Agent Is Associated With Long-Term Risk of Dementia.

BACKGROUND: Patients with atrial fibrillation (AF) are at higher risk of developing dementia. AF patients treated with warfarin with poor time in therapeutic ranges are significantly more likely to develop dementia. AF patients are also frequently treated with antiplatelet agents due to coexistent vascular disease. We hypothesize that AF patients with anticoagulation and antiplatelet therapies will be at higher risk of dementia, particularly with chronic exposure to over-anticoagulation. METHODS: Chronically anticoagulated patients receiving warfarin (target INR 2-3) for AF and managed by the Intermountain Healthcare Clinical Pharmacist Anticoagulation Service (CPAS) on concurrent antiplatelet agents with no history of dementia or stroke/TIA were included. The primary outcome was the presence of dementia defined by neurologist determined ICD-9 codes. Percent time with an INR>3.0 was determined and then compared by 3 strata <10% (n = 340), 10-24% (n = 417), ≥25% (n = 235). Multivariable Cox hazard regression was utilized to determine dementia incidence by percent time. RESULTS: A total of 992 patients were studied. Patients with an INR>3 more than 25% of the time were 2.40 times more likely to develop dementia (P = 0.04). A comparison between < 10% group and 10-24.9% group with INR>3 indicated no difference in risk for the development of dementia (P = 0.74). The risk was significantly increased in patients using triple antithrombotic therapy, although the number of patients within this group was small. CONCLUSION: In AF patients receiving antiplatelet and anticoagulant therapies, the percent of time exposed to over-anticoagulation increased dementia risk. These data support the possibility of chronic cerebral injury from microbleeds as a mechanism underlying the association of AF and dementia.

Spatial multi-omics reveal intratumoral humoral immunity niches associated with tertiary lymphoid structures in pancreatic cancer immunotherapy pathologic responders.

Pancreatic adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. We generated a spatial multi-omics atlas encompassing 26 PDAC tumors from patients treated with combination immunotherapies. Using machine learning-enabled H&E image classification models and unsupervised gene expression matrix factorization methods for spatial transcriptomics, we characterized cellular states within TLS niches spanning across distinct morphologies and immunotherapies. Unsupervised learning generated a TLS-specific spatial gene expression signature that significantly associates with improved survival in PDAC patients. These analyses demonstrate TLS-associated intratumoral B cell maturation in pathological responders, confirmed with spatial proteomics and BCR profiling. Our study also identifies spatial features of pathologic immune responses, revealing TLS maturation colocalizing with IgG/IgA distribution and extracellular matrix remodeling. HIGHLIGHTS: Integrated multi-modal spatial profiling of human PDAC tumors from neoadjuvant immunotherapy clinical trials reveal diverse spatial niches enriched in TLS.TLS maturity is influenced by tumor location and the cellular neighborhoods in which TLS immune cells are recruited.Unsupervised machine learning of genome-wide signatures on spatial transcriptomics data characterizes the TLS-enriched TME and associates TLS transcriptomes with survival outcomes in PDAC.Interactions of spatially variable gene expression patterns showed TLS maturation is coupled with immunoglobulin distribution and ECM remodeling in pathologic responders.Intratumoral plasma cell and immunoglobin gene expression spatial dynamics demonstrate trafficking of TLS-driven humoral immunity in the PDAC TME. Significance: We report a spatial multi-omics atlas of PDAC tumors from a series of immunotherapy neoadjuvant clinical trials. Intratumorally, pathologic responders exhibit mature TLS that propagate plasma cells into malignant niches. Our findings offer insights on the role of TLS-associated humoral immunity and stromal remodeling during immunotherapy treatment.

Impact of anticoagulation therapy on the cognitive decline and dementia in patients with non-valvular atrial fibrillation (cognitive decline and dementia in patients with non-valvular atrial fibrillation [CAF] trial).

Background: Atrial fibrillation (AF) is associated with a risk for cognitive impairment and dementia, which is more pronounced in patients with a history of clinical stroke. Anticoagulation use and efficacy impact long-term risk of dementia in AF patients in observational trials. Methods: The cognitive decline and dementia in patients with non-valvular atrial fibrillation (CAF) Trial was a randomized, prospective, open-label vanguard clinical study with blinded endpoint assessment involving patients with moderate- to high-risk (CHADS2 or CHA2DS2-Vasc scores of ≥2) non-valvular AF assigned to dabigatran etexilate or warfarin. The primary endpoint was incident dementia or moderate cognitive decline at 24 months. Results: A total of 101 patients were enrolled [mean age:73.7 ± 6.0 years, male: 54(53.5%)]. Prior stroke and stroke risk factors were similar between groups. Average INR over the study was 2.41 ± 0.68 in the warfarin group. No patient experienced a stroke or developed dementia. Mini-Mental Status Evaluation, Hachinski Ischemic scale, cognitive subscale of the Alzheimer's Disease Assessment Scale, Disability Assessment for Dementia, Quality of Life Improvement as assessed by Minnesota Living with Heart Failure Scale and the Anti-Clot Treatment Scale Quality of Life Survey scores did not vary at baseline or change over 2 years. Biomarker analysis indicated a similar efficacy of anticoagulation strategies. Conclusion: Use of dabigatran and well-managed warfarin therapy were associated with similar risks of stroke, cognitive decline, and dementia at 2 years, suggestive that either strategy is acceptable. The results of this Vanguard study did not support the pursuit of a larger formally powered study.

Stroke and dementia risk in patients with and without atrial fibrillation and carotid arterial disease.

BACKGROUND: Patients with carotid arterial disease (CD) with and without atrial fibrillation (AF) are at risk of stroke. Patients with AF are at a higher risk of stroke and dementia. OBJECTIVES: We sought to understand the risks of stroke, transient ischemic attack (TIA), and dementia in patients with and without AF and CD or a combination of both as well as to determine whether therapies for each disease may influence risks. METHODS: A total of 11,572 patients were included in 4 groups, with 2893 patients populating each group (1: no AF or CD; 2: AF, no CD; 3: CD and no AF; 4: AF and CD) and matched for age, sex, and comorbidities. Long-term outcomes of stroke/TIA and dementia were assessed. Subset analyses of these outcomes were performed in patients with CD treated with revascularization and in patients with AF treated with ablation. RESULTS: CD increased the risk of stroke/TIA (hazard ratio [HR] 2.74; P < .0001) and dementia (HR 1.44; P < .0001). Similarly, AF increased the risk of stroke/TIA (HR 2.08; P < .0001) and dementia (HR 1.30; P = .004). The coexistence of AF and CD further augmented the risk of both end points. CD revascularization was associated with a decreased risk of dementia (HR 0.47; P < .0001) but not stroke. Ablation of AF improved outcomes of stroke/TIA (HR 0.55; P = .002), particularly in those with CD (HR 0.36; P < .0001), and was associated with a reduced risk of dementia (HR 0.51; P = .04). CONCLUSION: CD and AF augment risk of stroke/TIA and dementia in the general population, and the coexistence of both diseases is additive in risk. Ablation of AF was associated with lower risk, the magnitude of which was greater in those with CD.

Discovery of TITIN Gene Truncating Variant Mutations and 5-Year Outcomes in Patients With Nonischemic Dilated Cardiomyopathy.

Genetic factors play an important role in nonischemic dilated cardiomyopathy (NIDC). However, prime opportunities remain for genetic discovery and prognostic understanding. TITIN gene truncating variant mutations (TTNtv) are of interest because of their frequent appearance in NIDC series. We sought to discover known and novel TTNtv mutations in a NIDC cohort and assess 5-year outcomes. Patients with NIDC entered into the INSPIRE Registry with ≥3 years of follow-up were studied. Whole exome sequencing (WES) was performed using an Illumina Novaseq platform. Genetic analysis used Sentieon software and the GRCh38 human reference genome. Variant calls were annotated with ClinVar. Five-year outcomes were determined by functional assessment and ejection fraction (EF) as recovered (EF ≥50%), persistent (EF 21% to 49%), or progressive (left ventricular assist device, transplant, heart failure [HF] or arrhythmic death, or EF ≤20%). The study comprised 229 NIDC patients (age = 50 ± 15 years, 58% men). TTNtv's were discovered in 27 patients with 22 unique mutations; (7 known, 15 novel). TTNtv+ patients more frequently presented with severe NIDC (EF ≤20%) (p = 0.032). By 5-year, outcomes were worse in TTNtv+ patients (p = 0.027), and patients less often recovered (11% vs. 30%). Prognosis was similar with known and novel mutations. Nongenetic (e.g., environmental) cocausal risk factors for HF were frequently present, and these factors frequently appeared to act in concert with genetic variants to precipitate clinical HF. In conclusion, our study expands the library of likely pathogenic TTN mutations and increases our understanding of their clinical impact in association with other HF risk factors.

Genetic Susceptibility for Atrial Fibrillation in Patients Undergoing Atrial Fibrillation Ablation.

BACKGROUND: Ablation is a widely used therapy for atrial fibrillation (AF); however, arrhythmia recurrence and repeat procedures are common. Studies examining surrogate markers of genetic susceptibility to AF, such as family history and individual AF susceptibility alleles, suggest these may be associated with recurrence outcomes. Accordingly, the aim of this study was to test the association between AF genetic susceptibility and recurrence after ablation using a comprehensive polygenic risk score for AF. METHODS: Ten centers from the AF Genetics Consortium identified patients who had undergone de novo AF ablation. AF genetic susceptibility was measured using a previously described polygenic risk score (N=929 single-nucleotide polymorphisms) and tested for an association with clinical characteristics and time-to-recurrence with a 3 month blanking period. Recurrence was defined as >30 seconds of AF, atrial flutter, or atrial tachycardia. Multivariable analysis adjusted for age, sex, height, body mass index, persistent AF, hypertension, coronary disease, left atrial size, left ventricular ejection fraction, and year of ablation. RESULTS: Four thousand two hundred seventy-six patients were eligible for analysis of baseline characteristics and 3259 for recurrence outcomes. The overall arrhythmia recurrence rate between 3 and 12 months was 44% (1443/3259). Patients with higher AF genetic susceptibility were younger (P<0.001) and had fewer clinical risk factors for AF (P=0.001). Persistent AF (hazard ratio [HR], 1.39 [95% CI, 1.22-1.58]; P<0.001), left atrial size (per cm: HR, 1.32 [95% CI, 1.19-1.46]; P<0.001), and left ventricular ejection fraction (per 10%: HR, 0.88 [95% CI, 0.80-0.97]; P=0.008) were associated with increased risk of recurrence. In univariate analysis, higher AF genetic susceptibility trended towards a higher risk of recurrence (HR, 1.08 [95% CI, 0.99-1.18]; P=0.07), which became less significant in multivariable analysis (HR, 1.06 [95% CI, 0.98-1.15]; P=0.13). CONCLUSIONS: Higher AF genetic susceptibility was associated with younger age and fewer clinical risk factors but not recurrence. Arrhythmia recurrence after AF ablation may represent a genetically different phenotype compared to AF susceptibility.

Atrial Fibrillation and Dementia: Exploring the Association, Defining Risks and Improving Outcomes.

AF is strongly associated with a spectrum of cranial injuries including stroke and dementia. Dementia risk is seen in patients with and without a prior stroke and includes idiopathic forms of dementia, such as Alzheimer's disease. The initiation, use and efficacy of anticoagulation have been shown in multiple observational trials to have an impact on dementia risk. Cerebral hypoperfusion during AF can result in cognitive decline and patients with cranial atherosclerosis may have unique susceptibility. Therapies to carefully control the ventricular rate and catheter ablation have been shown in observational trials to lower dementia risk. There is a need for further research in multiple areas and the observational trials will require prospective trials confirmation. Recent guidelines for AF have advocated the initiation of effective anticoagulation, the treatment of associated disease conditions that may influence the progression of AF and catheter ablation, with long-term management of risk factors to lower risk of dementia.

Stroke-independent contribution of atrial fibrillation to dementia: a meta-analysis.

Background: Atrial fibrillation (AF) is associated with an increased risk of dementia. It is presently unknown to what extent AF contributes to dementia onset independently from prevalent and incident cerebrovascular accidents (CVAs)/transient ischaemic attacks (TIAs). Methods: MEDLINE/PubMed and Embase databases were searched for prospective observational results, which produced risk estimates for dementia in AF patients, adjusted for prevalent and incident CVAs/TIAs. Results: Five prospective observational studies were included, comprising 61 008 patients, having a median follow-up of 12.5 years. Meta-analysis of observational results indicates an increased risk of dementia in AF, adjusted for cerebrovascular clinical events (HR 1.28, 95% CI 1.17 to 1.41, I2=0%). Funnel plot analysis did not reveal a statistically significant asymmetry. Meta-regression analysis did not indicate statistically significant associations between baseline study-level covariates and risk estimates. Conclusion: AF confers a nearly 30% increased risk of dementia, independently from CVAs/TIAs. Screening for AF and subsequent optimised management to lower risk of cranial injury could help in preventing dementia, a condition characterised by high social and healthcare costs.

Rationale and design of the impact of anticoagulation therapy on the Cognitive Decline and Dementia in Patients with Nonvalvular Atrial Fibrillation (CAF) Trial: A Vanguard study.

Atrial fibrillation (AF) is associated with a risk for cognitive impairment and dementia, which is more pronounced in patients with a history of clinical stroke. Observational trials suggest that the implementation and quality of long-term anticoagulation impact dementia risk. Emerging evidence suggests that direct oral anticoagulants may improve long-term risk of dementia in AF patients. This manuscript describes the rational and trial design of the the Cognitive Decline and Dementia in Atrial Fibrillation Patients (CAF) Trial. CAF investigates if AF patients randomized to dabigatran etexilate will have long-term higher cognition scores and lower rates of dementia compared in the long term to dose-adjusted warfarin (International Normalized Ratio [INR]: 2.0-3.0). As of 27 February 2019, a total of 120 subjects will be enrolled at one investigational site in the United States and will be followed for 2 years after study enrollment. To date, 97 have been enrolled. The average age is 74.2 years, 53% are male, and 9% had a prior stroke. In this Vanguard study, patients will be followed for 2 years after study enrollment. These prospective, randomized data will inform the understanding of two anticoagulants in AF patients as it relates to risk of cognitive decline and dementia. Cranial imaging and biomarkers collected will assist in understanding mechanisms of brain injury.

The role of microRNAs in the development, regulation, and treatment of atrial fibrillation.

BACKGROUND: MicroRNAs (miRNA)s regulate expression of genes involved in various processes including cardiac automaticity, conduction, excitability, and fibrosis and therefore may provide a diagnostic utility to identify high-risk patients for atrial fibrillation (AF). In this study, we tested the hypothesis that specific profiles of circulating miRNAs can identify patients with AF and can also help to identify patients at high risk of AF recurrence after ablation. METHODS: Two patient populations were studied: 140 AF cases (93 paroxysmal and 47 persistent) and 50 healthy controls, and 141 AF ablation cases with (n = 86) and without (n = 55) 1-year recurrence. Assessment of several previously identified AF-associated plasma miRNAs (21, 29a, 133a, 133b, 150, 328) was performed with TaqMan assays, using synthetic miRNAs as standards. RESULTS: The AF cases compared to the healthy controls were older and were more often male and hypertensive. After multivariate adjustment, higher miRNA-21 levels significantly decreased the risk of AF (OR = 0.93 per fmol/µl (95% CI = 0.89-0.98, p = 0.007)). There were no significant differences in circulating miRNAs between the AF subtypes of persistent and paroxysmal. Among the AF ablation cases, miRNA-150 was lower for those with AF recurrences at 1 year (adjusted OR = 0.98 per 500,000 fmol/µl; 95% CI = 0.965, 0.998; p = 0.039). CONCLUSIONS: Decreased circulating miRNA-21 is associated with AF, but not with AF subtypes, suggestive that molecular mechanisms responsible for the onset and progression of the AF may be different. Circulating miRNA-150 was significantly associated with a reduction in 1-year AF recurrence post ablation suggestive of adverse structural and electrical remodeling as recurrence mechanisms.

CHA2DS2-VASc scores and Intermountain Mortality Risk Scores for the joint risk stratification of dementia among patients with atrial fibrillation.

BACKGROUND: High CHA2DS2-VASc scores in atrial fibrillation (AF) patients are generally associated with increased risks of stroke and dementia. At lower CHA2DS2-VASc scores, there remains an unquantifiable cranial injury risk, necessitating an improved risk assessment method within these lower-risk groups. OBJECTIVE: The purpose of this study was to determine whether sex-specific Intermountain Mortality Risk Scores (IMRS), a dynamic measures of systemic health that comprises commonly performed blood tests, can stratify dementia risk overall and among CHA2DS2-VASc score strata in AF patients. METHODS: Female (n = 34,083) and male (n = 39,998) AF patients with no history of dementia were studied. CHA2DS2-VASc scores were assessed at the time of AF diagnosis and were stratified into scores of 0-1, 2, and ≥3. Within each CHA2DS2-VASc score stratum, patients were further stratified by IMRS categories of low, moderate, and high. Multivariable Cox hazard regression was used to determine dementia risk. RESULTS: High-risk IMRS patients were generally older and had higher rates of hypertension, diabetes, heart failure, and prior stroke. Higher CHA2DS2-VASc score strata (≥3 vs ≤1: women, hazard ratio [HR] 7.77, 95% confidence interval [CI] 5.94-10.17, P < .001; men: HR 4.75, 95% CI 4.15-5.44, P < .001) and IMRS categories (high vs low: women, HR 3.09, 95% CI 2.71-3.51, P < .001; men, HR 2.70, 95% CI 2.39-3.06, P < .001) were predictive of dementia. When stratified by CHA2DS2-VASc scores, IMRS further identified risk in each stratum. CONCLUSION: Both CHA2DS2-VASc scores and IMRS were independently associated with dementia incidence among AF patients. IMRS further stratified dementia risk among CHA2DS2-VASc score strata, particularly among those with lower CHA2DS2-VASc scores.