Heart rate variability and stroke or systemic embolism in patients with atrial fibrillation.

BACKGROUND: Stroke remains one of the most serious complications in atrial fibrillation (AF) patients and has been linked to disturbances of the autonomic nervous system. OBJECTIVE: We hypothesized that impaired cardiac autonomic function might be associated with an enhanced stroke risk in AF patients. METHODS: We enrolled 1922 AF patients who were either in sinus rhythm (SR-group, n=1121) or AF (AF-group, n=801) on a 5-minute resting ECG recording. HRV triangular index (HRVI), standard deviation of normal-to-normal intervals, root mean square root of successive differences of normal-to-normal intervals, mean heart rate, 5-min total power and power in the high frequency, low frequency and very low frequency range were calculated. We constructed Cox regression models to examine the association of HRV parameters with the composite endpoint of stroke or systemic embolism. RESULTS: Mean age was 71±8 years in the SR group and 75±8 in the AF group. 37 patients in the SR group (3.4%) and 60 patients in the AF group (8.0%) experienced a stroke or systemic embolism during a follow-up time of 5 years. In patients with SR, HRVI <15 was the strongest HRV parameter to be associated with stroke or systemic embolism (hazard ratio 3.04; 95% confidence interval 1.3-7.0; p=0.009) after adjustment for multiple confounders. In the AF group, we found no HRV parameter to be associated with the composite endpoint. CONCLUSION: HRVI measured during SR on a single 5-minute ECG recording is independently associated with stroke or systemic embolism in AF patients. HRV analysis in SR may help to improve risk stratification in AF patients.

Sex-specific differences in physiological parameters related to SARS-CoV-2 infections among a national cohort (COVI-GAPP study).

Considering sex as a biological variable in modern digital health solutions, we investigated sex-specific differences in the trajectory of four physiological parameters across a COVID-19 infection. A wearable medical device measured breathing rate, heart rate, heart rate variability, and wrist skin temperature in 1163 participants (mean age = 44.1 years, standard deviation [SD] = 5.6; 667 [57%] females). Participants reported daily symptoms and confounders in a complementary app. A machine learning algorithm retrospectively ingested daily biophysical parameters to detect COVID-19 infections. COVID-19 serology samples were collected from all participants at baseline and follow-up. We analysed potential sex-specific differences in physiology and antibody titres using multilevel modelling and t-tests. Over 1.5 million hours of physiological data were recorded. During the symptomatic period of infection, men demonstrated larger increases in skin temperature, breathing rate, and heart rate as well as larger decreases in heart rate variability than women. The COVID-19 infection detection algorithm performed similarly well for men and women. Our study belongs to the first research to provide evidence for differential physiological responses to COVID-19 between females and males, highlighting the potential of wearable technology to inform future precision medicine approaches.

Patients on vitamin K treatment: is switching to direct-acting oral anticoagulation cost-effective? A target trial on a prospective cohort.

AIMS: Direct-acting oral anticoagulants (DOACs) have, to a substantial degree, replaced vitamin K antagonists (VKA) as treatments for stroke prevention in atrial fibrillation (AF) patients. However, evidence on the real-world causal effects of switching patients from VKA to DOAC is lacking. We aimed to assess the empirical incremental cost-effectiveness of switching patients to DOAC compared with maintaining VKA treatment. METHODS: The target trial approach was applied to the prospective observational Swiss-AF cohort, which enrolled 2415 AF patients from 2014 to 2017. Clinical data, healthcare resource utilisation and EQ-5D-based utilities representing quality of life were collected in yearly follow-ups. Health insurance claims were available for 1024 patients (42.4%). Overall survival, quality-of-life, costs from the Swiss statutory health insurance perspective and cost-effectiveness were estimated by emulating a target trial in which patients were randomly assigned to switch to DOAC or maintain VKA treatment. RESULTS: 228 patients switching from VKA to DOAC compared with 563 patients maintaining VKA treatment had no overall survival advantage over a 5-year observation period (HR 0.99, 95% CI 0.45, 1.55). The estimated gain in quality-adjusted life years (QALYs) was 0.003 over the 5-year period at an incremental costs of CHF 23 033 (€ 20 940). The estimated incremental cost-effectiveness ratio was CHF 425 852 (€ 387 138) per QALY gained. CONCLUSIONS: Applying a causal inference method to real-world data, we could not demonstrate switching to DOACs to be cost-effective for AF patients with at least 1 year of VKA treatment. Our estimates align with results from a previous randomised trial.

Omega-3 Fatty Acids and Markers of Thrombosis in Patients with Atrial Fibrillation.

Omega-3 fatty acids (n-3 FAs) are associated with a lower risk of ischemic stroke in patients with atrial fibrillation (AF). Antithrombotic mechanisms may in part explain this observation. Therefore, we examined the association of n-3 FAs with D-dimer and beta-thromboglobulin (BTG), markers for activated coagulation and platelets, respectively. The n-3 FAs eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) and alpha-linolenic acid (ALA) were determined via gas chromatography in the whole blood of 2373 patients with AF from the Swiss Atrial Fibrillation cohort study (ClinicalTrials.gov Identifier: NCT02105844). In a cross-sectional analysis, we examined the association of total n-3 FAs (EPA + DHA + DPA + ALA) and the association of individual fatty acids with D-dimer in patients with detectable D-dimer values (n = 1096) as well as with BTG (n = 2371) using multiple linear regression models adjusted for confounders. Median D-dimer and BTG levels were 0.340 ug/mL and 448 ng/mL, respectively. Higher total n-3 FAs correlated with lower D-dimer levels (coefficient 0.94, 95% confidence interval (Cl) 0.90-0.98, p = 0.004) and lower BTG levels (coefficient 0.97, Cl 0.95-0.99, p = 0.003). Likewise, the individual n-3 FAs EPA, DHA, DPA and ALA showed an inverse association with D-dimer. Higher levels of DHA, DPA and ALA correlated with lower BTG levels, whereas EPA showed a positive association with BTG. In patients with AF, higher levels of n-3 FAs were associated with lower levels of D-dimer and BTG, markers for activated coagulation and platelets, respectively. These findings suggest that n-3 FAs may exert antithrombotic properties in patients with AF.

Longitudinal Changes in Health-Related Quality of Life in Patients With Atrial Fibrillation.

Background Optimizing health-related quality of life (HRQoL) is an important aim of atrial fibrillation (AF) treatment. Little is known about patients' long-term HRQoL trajectories and the impact of patient and disease characteristics. The aim of this study was to describe HRQoL trajectories in an observational AF study population and in clusters of patients with similar patient and disease characteristics. Methods and Results We used 5-year follow-up data from the Swiss-Atrial Fibrillation prospective cohort, which enrolled 2415 patients with prevalent AF from 2014 to 2017. HRQoL data, collected yearly, comprised EuroQoL-5 dimension utilities and EuroQoL visual analog scale scores. Patient clusters with similar characteristics at enrollment were identified using hierarchical clustering. HRQoL trajectories were analyzed descriptively and with inverse probability-weighted regressions. Effects of postbaseline clinical events were additionally assessed using time-shifted event variables. Among 2412 (99.9%) patients with available baseline HRQoL, 3 clusters of patients with AF were identified, which we characterized as follows: "cardiovascular dominated," "isolated symptomatic," and "severely morbid without cardiovascular disease." Utilities and EuroQoL visual analog scale scores remained stable over time for the full population and the clusters; isolated symptomatic patients showed higher levels of HRQoL. Utilities were reduced after occurrences of stroke, hospitalization for heart failure, and bleeding, by -0.12 (95% CI, -0.18 to -0.06), -0.10 (95% CI, -0.13 to -0.08), and -0.06 (95% CI, -0.08 to -0.04), respectively, on a 0 to 1 utility scale. Utility of surviving patients returned to preevent levels 4 years after heart failure hospitalization; 3 years after bleeding; and 1 year after stroke. Conclusions In patients with prevalent AF, HRQoL was stable over time, irrespective of baseline patient characteristics. Clinical events of hospitalization for heart failure, stroke, and bleeding had only a temporary effect on HRQoL.

The Association of suPAR with Cardiovascular Risk Factors in Young and Healthy Adults.

The soluble urokinase plasminogen activator receptor (suPAR), as a correlate of chronic low-grade inflammation, may be used to predict individual cardiovascular risk. Since chronic low-grade inflammation is thought to be associated with the development of cardiovascular disease, this study aimed to evaluate if suPAR plasma levels are correlated with cardiovascular risk factors in young and healthy adults (aged 25-41 years). Consequently, data from the GAPP (genetic and phenotypic determinants of blood pressure and other cardiovascular risk factors) study were used to investigate suPAR plasma levels in relation to the following cardiovascular risk factors and laboratory parameters: BMI, physical activity, alcohol consumption, smoking status, blood pressure parameters, glucose status, and lipid levels. Additionally, suPAR was compared to the healthy lifestyle score and the Framingham score representing the overall cardiovascular risk profile. These associations were assessed using two different statistical approaches. Firstly, all cardiovascular risk factors and scores were compared amongst sex-specific suPAR plasma levels with ANOVA analysis. Secondly, sex-specific multivariable linear regressions were performed. Female participants had higher plasma suPAR levels than male participants (1.73 ng/mL versus 1.50 ng/mL; p < 0.001). A significant inverse correlation between suPAR plasma levels and HDL cholesterol was found in men (p = 0.001) and women (p < 0.001). Furthermore, male (p < 0.001) and female participants (p < 0.001) who smoked showed significantly higher plasma levels of suPAR (p < 0.001). For male participants, an inverse correlation of the healthy lifestyle score with suPAR plasma levels (p = 0.001) and a positive correlation of the Framingham score with suPAR plasma levels (p < 0.001) were detected. In women, no such correlation was found. The cholesterol levels (p = 0.001) and HbA1c (p = 0.008) correlated significantly with plasma suPAR levels in female participants. suPAR plasma levels were found to be strongly associated with certain cardiovascular risk factors; however, sex-specific differences were found. These sex-specific differences might be explained by the higher prevalence of cardiovascular risk factors in men resulting in a stronger correlation of suPAR as a marker of low-grade inflammation, since the existence of the risk factors already led to subclinical damage in men. Further research on suPAR levels in an older study population is needed.

Estimating the cost impact of atrial fibrillation using a prospective cohort study and population-based controls.

AIMS: Atrial fibrillation (AF) costs are expected to be substantial, but cost comparisons with the general population are scarce. Using data from the prospective Swiss-AF cohort study and population-based controls, we estimated the impact of AF on direct healthcare costs from the Swiss statutory health insurance perspective. METHODS: Swiss-AF patients, enrolled from 2014 to 2017, had documented, prevalent AF. We analysed 5 years of follow-up, where clinical data, and health insurance claims in 42% of the patients were collected on a yearly basis. Controls from a health insurance claims database were matched for demographics and region. The cost impact of AF was estimated using five different methods: (1) ordinary least square regression (OLS), (2) OLS-based two-part modelling, (3) generalised linear model-based two-part modelling, (4) 1:1 nearest neighbour propensity score matching and (5) a cost adjudication algorithm using Swiss-AF data non-comparatively and considering clinical data. Cost of illness at the Swiss national level was modelled using obtained cost estimates, prevalence from the Global Burden of Disease Project, and Swiss population data. RESULTS: The 1024 Swiss-AF patients with available claims data were compared with 16 556 controls without known AF. AF patients accrued CHF5600 (EUR5091) of AF-related direct healthcare costs per year, in addition to non-AF-related healthcare costs of CHF11100 (EUR10 091) per year accrued by AF patients and controls. All five methods yielded comparable results. AF-related costs at the national level were estimated to amount to 1% of Swiss healthcare expenditure. CONCLUSIONS: We robustly found direct medical costs of AF patients were 50% higher than those of population-based controls. Such information on the incremental cost burden of AF may support healthcare capacity planning.

Real-World Cost-Effectiveness of Pulmonary Vein Isolation for Atrial Fibrillation: A Target Trial Approach.

OBJECTIVES: Randomized controlled trials of pulmonary vein isolation (PVI) for treating atrial fibrillation (AF) have proven the procedure's efficacy. Studies assessing its empirical cost-effectiveness outside randomized trial settings are lacking. We aimed to evaluate the effectiveness and cost-effectiveness of PVI versus medical therapy for AF. METHODS: We followed a target trial approach using the Swiss-AF cohort, a prospective observational cohort study that enrolled patients with AF between 2014 and 2017. Resource utilization and cost information were collected through claims data. Quality of life was measured with EQ-5D-3L utilities. We estimated incremental cost-effectiveness ratios (ICERs) from the perspective of the Swiss statutory health insurance system. RESULTS: Patients undergoing PVI compared with medical therapy had a 5-year overall survival advantage with a hazard ratio of 0.75 (95% CI 0.46-1.21; P = .69) and a 19.8% SD improvement in quality of life (95% CI 15.5-22.9; P < .001), at an incremental cost of 29 604 Swiss francs (CHF) (95% CI 16 354-42 855; P < .001). The estimated ICER was CHF 158 612 per quality-adjusted life-year (QALY) gained within a 5-year time horizon. Assuming similar health effects and costs over 5 additional years changed the ICER to CHF 82 195 per QALY gained. Results were robust to the sensitivity analyses performed. CONCLUSIONS: Our results show that PVI might be a cost-effective intervention within the Swiss healthcare context in a 10-year time horizon, but unlikely to be so at 5 years, if a willingness-to-pay threshold of CHF 100 000 per QALY gained is assumed. Given data availability, we find target trial designs are a valuable tool for assessing the cost-effectiveness of healthcare interventions outside of randomized controlled trial settings.

Association of chocolate consumption with neurological and cardiovascular outcomes in atrial fibrillation: data from two Swiss atrial fibrillation cohort studies (Swiss-AF and BEAT-AF).

AIM: To assess the associations of chocolate consumption with neurocognitive function, brain lesions on magnetic resonance imaging (MRI), and cardiovascular outcome in patients with atrial fibrillation (AF). METHODS: We analysed data from patients of two prospective multicentre Swiss atrial fibrillation cohort studies (Swiss-AF) and (BEAT-AF). Assessments of MRI findings and neurocognitive function were performed only in the Swiss-AF population (in 1727 of 2415 patients [71.5%] with a complete data set), as patients enrolled in BEAT-AF were not systematically evaluated for these outcomes. Otherwise, the two cohorts had an equivalent set of clinical assessments. Clinical outcome analysis was performed in 3931 patients of both cohorts. Chocolate consumption was assessed by questionnaire. Patients were categorised as no/low chocolate consumption (No/Low-Ch) ≤1 servings/week, moderate chocolate consumption (Mod-Ch) >1-6 servings/week, and high chocolate consumption (High-Ch) >6 servings/week, respectively. Brain lesions were evaluated by MRI. Assessment of cognitive function was performed by neurocognitive functional testing and included global cognition measurement with a cognitive construct score. Cerebral MRI and cognition were evaluated at baseline. Cross-sectional associations between chocolate consumption and MRI findings were analysed by multivariate logistic regression models and associations with neurocognitive function by multivariate linear regression models. Clinical outcome events during follow-up were recorded and assessed by a clinical event committee. The associations between chocolate consumption and clinical outcomes were evaluated by Cox regression models. The median follow-up time was 6 years. RESULTS: Chocolate consumption was not associated with prevalence or volume of vascular brain lesions on MRI, nor major adverse cardiac events (ischaemic stroke, myocardial infarction, cardiovascular death). However, No/Low-Ch was independently associated with a lower cognitive construct score compared to Mod-Ch (No/Low-Ch vs. Mod-Ch: coeff. -0.05, 95% CI -0.10-0), whereas other neurocognitive function tests were not independently associated with chocolate consumption categories. In addition, there was a higher risk of heart failure hospitalisation (No/Low-Ch vs. Mod-Ch: HR 1.24, 95% CI 1.01-1.52) and of all-cause mortality (No/Low-Ch vs. Mod-Ch: HR 1.29, 95% CI 1.06-1.58) in No/Low-Ch compared to Mod-Ch. No significant associations with the evaluated outcomes were observed when High-Ch was compared to Mod-Ch. CONCLUSION: While chocolate consumption was not associated with MRI findings and major adverse cardiac events in an atrial fibrillation population, No/Low-Ch was associated with a lower cognitive construct score, higher risk of heart failure hospitalisation and increased all-cause mortality compared to Mod-Ch. CLINICALTRIALS: gov Identifier: NCT02105844.

Biomarker, Imaging, and Clinical Factors Associated With Overt and Covert Stroke in Patients With Atrial Fibrillation.

BACKGROUND: Atrial fibrillation is a major risk factor for stroke and silent brain infarcts. We studied whether a multimodal approach offers additional insights to the CHA2DS2-VASc score in predicting stroke or new brain infarcts on magnetic resonance imaging (MRI) over a 2-year follow-up. METHODS: Swiss-AF is a prospective, multicenter cohort study of patients with known atrial fibrillation. We included patients with available brain MRI both at enrollment and 2 years later. The dates of the baseline and follow-up visits ranged from March 2014 to November 2020. The primary outcome was assessed 2 years after baseline and was defined as a composite of clinically identified stroke or any new brain infarct on the 2-year MRI. We compared a multivariable logistic regression model including prespecified clinical, biomarker, and baseline MRI variables to the CHA2DS2-VASc score. RESULTS: We included 1232 patients, 89.8% of them taking oral anticoagulants. The primary outcome occurred in 78 patients (6.3%). The following baseline variables were included in the final multivariate model and were significantly associated with the primary outcome: white matter lesion volume in milliliters (adjusted odds ratio [aOR], 1.91 [95% CI, 1.45-2.56]), NT-proBNP (N-terminal pro-B-type natriuretic peptide; aOR, 1.75 [95% CI, 1.20-2.63]), GDF-15 (growth differentiation factor-15; aOR, 1.68 [95% CI, 1.11-2.53]), serum creatinine (aOR, 1.50 [95% CI, 1.02-2.22]), IL (interleukin)-6 (aOR, 1.37 [95% CI, 1.00-1.86]), and hFABP (heart-type fatty acid-binding protein; aOR, 0.48 [95% CI, 0.31-0.73]). Overall performance and discrimination of the new model was superior to that of the CHA2DS2-VASc score (C statistic, 0.82 [95% CI, 0.77-0.87] versus 0.64 [95% CI, 0.58-0.70]). CONCLUSIONS: In patients with atrial fibrillation, a model incorporating white matter lesion volume on baseline MRI and selected blood markers yielded new insights on residual stroke risk despite a high proportion of patients on oral anticoagulants. This may be relevant to develop further preventive measures.

Concentrations of Serum Brain Injury Biomarkers Following SARS-CoV-2 Infection in Individuals with and without Long-COVID-Results from the Prospective Population-Based COVI-GAPP Study.

It is unknown whether neurological symptoms are associated with brain injury after SARS-CoV-2 infections and whether brain injury and related symptoms also emerge in Long-COVID patients. Biomarkers such as serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) can be used to elucidate neuro-axonal and astroglial injuries. We investigated whether these biomarkers are associated with COVID-19 infection status, associated symptoms and Long-COVID. From 146 individuals of the general population with a post-acute, mild-to-moderate SARS-CoV-2 infection, sNfL and sGFAP were measured before, during and after (five and ten months) the infection. Individual symptoms and Long-COVID status were assessed using questionnaires. Neurological associated symptoms were described for individuals after a mild and moderate COVID-19 infection; however, sNfL (p = 0.74) and sGFAP (p = 0.24) did not change and were not associated with headache (p = 0.51), fatigue (p = 0.93), anosmia (p = 0.77) or ageusia (p = 0.47). In Long-COVID patients, sGFAP (p = 0.038), but not sNfL (p = 0.58), significantly increased but was not associated with neurological associated symptoms. Long-COVID status, but not post-acute SARS-CoV-2 infections, may be associated with astroglial injury/activation, even if neurological associated symptoms were not correlated.

Omega-3 Fatty Acids and Heart Rhythm, Rate, and Variability in Atrial Fibrillation.

Background Previous randomized control trials showed mixed results concerning the effect of omega-3 fatty acids (n-3 FAs) on atrial fibrillation (AF). The associations of n-3 FA blood levels with heart rhythm in patients with established AF are unknown. The goal of this study was to assess the associations of total and individual n-3 FA blood levels with AF type (paroxysmal versus nonparoxysmal), heart rate (HR), and HR variability in patients with AF. Methods and Results Total n-3 FAs, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, and alpha-linolenic acid blood levels were determined in 1969 patients with known AF from the SWISS-AF (Swiss Atrial Fibrillation cohort). Individual and total n-3 FAs were correlated with type of AF, HR, and HR variability using standard logistic and linear regression, adjusted for potential confounders. Only a mild association with nonparoxysmal AF was found with total n-3 FA (odds ratio [OR], 0.97 [95% CI, 0.89-1.05]) and docosahexaenoic acid (OR, 0.93 [95% CI, 0.82-1.06]), whereas other individual n-3 FAs showed no association with nonparoxysmal AF. Higher total n-3 FAs (estimate 0.99 [95% CI, 0.98-1.00]) and higher docosahexaenoic acid (0.99 [95% CI, 0.97-1.00]) tended to be associated with slower HR in multivariate analysis. Docosapentaenoic acid was associated with a lower HR variability triangular index (0.94 [95% CI, 0.89-0.99]). Conclusions We found no strong evidence for an association of n-3 FA blood levels with AF type, but higher total n-3 FA levels and docosahexaenoic acid might correlate with lower HR, and docosapentaenoic acid with a lower HR variability triangular index.

Association of bone morphogenetic protein 10 and recurrent atrial fibrillation after catheter ablation.

AIMS: Atrial remodelling, defined as a change in atrial structure, promotes atrial fibrillation (AF). Bone morphogenetic protein 10 (BMP10) is an atrial-specific biomarker released to blood during atrial development and structural changes. We aimed to validate whether BMP10 is associated with AF recurrence after catheter ablation (CA) in a large cohort of patients. METHODS AND RESULTS: We measured baseline BMP10 plasma concentrations in AF patients who underwent a first elective CA in the prospective Swiss-AF-PVI cohort study. The primary outcome was AF recurrence lasting longer than 30 s during a follow-up of 12 months. We constructed multivariable Cox proportional hazard models to determine the association of BMP10 and AF recurrence. A total of 1112 patients with AF (age 61 ± 10 years, 74% male, 60% paroxysmal AF) was included in our analysis. During 12 months of follow-up, 374 patients (34%) experienced AF recurrence. The probability for AF recurrence increased with increasing BMP10 concentration. In an unadjusted Cox proportional hazard model, a per-unit increase in log-transformed BMP10 was associated with a hazard ratio (HR) of 2.28 (95% CI 1.43; 3.62, P < 0.001) for AF recurrence. After multivariable adjustment, the HR of BMP10 for AF recurrence was 1.98 (95% CI 1.14; 3.42, P = 0.01), and there was a linear trend across BMP10 quartiles (P = 0.02 for linear trend). CONCLUSION: The novel atrial-specific biomarker BMP10 was strongly associated with AF recurrence in patients undergoing CA for AF. CLINICALTRIALS.GOV IDENTIFIER: NCT03718364; https://clinicaltrials.gov/ct2/show/NCT03718364.

Right Heart Structure and Function after Electrical Cardioversion for Atrial Fibrillation.

INTRODUCTION: Atrial fibrillation (AF) adversely impacts right ventricular (RV) and right atrial (RA) structure and function. There are limited data on these changes after electrical cardioversion (ECV) and the relative contribution of heart rate to evaluate the immediate (1-2 h) and short-term (4-6 weeks) changes in right cardiac chamber dimensions and RV function after ECV in patients with persistent AF. METHODS: Right cardiac chamber dimensions and RV function were measured in 64 patients using transthoracic echocardiography 1-2 h before, immediately after, and 4-6 weeks after ECV. Associations between changes in right-heart measures and rhythm status at follow-up were assessed using linear regression models. RESULTS: For patients who remained in sinus rhythm 4-6 weeks after ECV (n = 48), median fractional area change (FAC) at baseline, immediately after ECV, and 4-6 weeks after ECV were 39 (Q1:35, Q3:42) %, 42 (Q1:39, Q3:46) %, 46 (Q1:43, Q3:49) % (p < 0.01); median tricuspid annular plane systolic excursion (TAPSE) values at the same time points were 18 (Q1:17, Q3:20) mm, 20 (Q1:18, Q3:23) mm, and 24 (Q1:22, Q3:26) mm (p < 0.01), respectively. There was no significant difference in RV end systolic area and RA volume index before and after ECV. However, RV end systolic area and RA volume index decreased significantly after 4-6 weeks from a median of 10 (Q1:8, Q3:13) cm2 to 8 (Q1:7, Q3:10) cm2 (p < 0.01), and from a median of 30 (Q1:24, Q3:36) mL/m2 to 24 (Q1:20, Q3:27) mL/m2 (p < 0.01). Changes in TAPSE were significantly associated with sinus rhythm at follow-up (p = 0.027), changes in FAC showed a strong trend to association with sinus rhythm (p = 0.053), and this was not true for RA measures (p = 0.64). CONCLUSIONS: Among AF patients who remained in sinus rhythm after ECV, RV function improved immediately after ECV with further improvement at 4-6 weeks following sinus rhythm restoration.

Association of statin use and lipid levels with cerebral microbleeds and intracranial hemorrhage in patients with atrial fibrillation: A prospective cohort study.

BACKGROUND: An increased risk of intracranial hemorrhage (ICH) associated with statins has been reported, but data on the relationship between statin use and cerebral microbleeds (CMBs) in patients with atrial fibrillation (AF), a population at high bleeding and cardiovascular risk, are lacking. AIMS: To explore the association between statin use and blood lipid levels with the prevalence and progression of CMBs in patients with AF with a particular focus on anticoagulated patients. METHODS: Data of Swiss-AF, a prospective cohort of patients with established AF, were analyzed. Statin use was assessed during baseline and throughout follow-up. Lipid values were measured at baseline. CMBs were assessed using magnetic resonance imagining (MRI) at baseline and at 2 years follow-up. Imaging data were centrally assessed by blinded investigators. Associations of statin use and low-density lipoprotein (LDL) levels with CMB prevalence at baseline or CMB progression (at least one additional or new CMB on follow-up MRI at 2 years compared with baseline) were assessed using logistic regression models; the association with ICH was assessed using flexible parametric survival models. Models were adjusted for hypertension, smoking, body mass index, diabetes, stroke/transient ischemic attack, coronary heart disease, antiplatelet use, anticoagulant use, and education. RESULTS: Of the 1693 patients with CMB data at baseline MRI (mean ± SD age 72.5 ± 8.4 years, 27.6% women, 90.1% on oral anticoagulants), 802 patients (47.4%) were statin users. The multivariable adjusted odds ratio (adjOR) for CMBs prevalence at baseline for statin users was 1.10 (95% CI = 0.83-1.45). AdjOR for 1 unit increase in LDL levels was 0.95 (95% CI = 0.82-1.10). At 2 years, 1188 patients had follow-up MRI. CMBs progression was observed in 44 (8.0%) statin users and 47 (7.4%) non-statin users. Of these patients, 64 (70.3%) developed a single new CMB, 14 (15.4%) developed 2 CMBs, and 13 developed more than 3 CMBs. The multivariable adjOR for statin users was 1.09 (95% CI = 0.66-1.80). There was no association between LDL levels and CMB progression (adjOR 1.02, 95% CI = 0.79-1.32). At follow-up 14 (1.2%) statin users had ICH versus 16 (1.3%) non-users. The age and sex adjusted hazard ratio (adjHR) was 0.75 (95% CI = 0.36-1.55). The results remained robust in sensitivity analyses excluding participants without anticoagulants. CONCLUSIONS: In this prospective cohort of patients with AF, a population at increased hemorrhagic risk due to anticoagulation, the use of statins was not associated with an increased risk of CMBs.

Assessment of the atrial fibrillation burden in Holter electrocardiogram recordings using artificial intelligence.

Background: Emerging evidence indicates that a high atrial fibrillation (AF) burden is associated with adverse outcome. However, AF burden is not routinely measured in clinical practice. An artificial intelligence (AI)-based tool could facilitate the assessment of AF burden. Objective: We aimed to compare the assessment of AF burden performed manually by physicians with that measured by an AI-based tool. Methods: We analyzed 7-day Holter electrocardiogram (ECG) recordings of AF patients included in the prospective, multicenter Swiss-AF Burden cohort study. AF burden was defined as percentage of time in AF, and was assessed manually by physicians and by an AI-based tool (Cardiomatics, Cracow, Poland). We evaluated the agreement between both techniques by means of Pearson correlation coefficient, linear regression model, and Bland-Altman plot. Results: We assessed the AF burden in 100 Holter ECG recordings of 82 patients. We identified 53 Holter ECGs with 0% or 100% AF burden, where we found a 100% correlation. For the remaining 47 Holter ECGs with an AF burden between 0.01% and 81.53%, Pearson correlation coefficient was 0.998. The calibration intercept was -0.001 (95% CI -0.008; 0.006), and the calibration slope was 0.975 (95% CI 0.954; 0.995; multiple R2 0.995, residual standard error 0.017). Bland-Altman analysis resulted in a bias of -0.006 (95% limits of agreement -0.042 to 0.030). Conclusion: The assessment of AF burden with an AI-based tool provided very similar results compared to manual assessment. An AI-based tool may therefore be an accurate and efficient option for the assessment of AF burden.

Bone Morphogenetic Protein 10-A Novel Biomarker to Predict Adverse Outcomes in Patients With Atrial Fibrillation.

Background Patients with atrial fibrillation (AF) face an increased risk of death and major adverse cardiovascular events (MACE). We aimed to assess the predictive value of the novel atrial-specific biomarker BMP10 (bone morphogenetic protein 10) for death and MACE in patients with AF in comparison with NT-proBNP (N-terminal prohormone of B-type natriuretic peptide). Methods and Results BMP10 and NT-proBNP were measured in patients with AF enrolled in Swiss-AF (Swiss Atrial Fibrillation Study), a prospective multicenter cohort study. A total of 2219 patients were included (median follow-up 4.3 years [interquartile range 3.9, 5.1], mean age 73±9 years, 73% male). In multivariable Cox proportional hazard models, the adjusted hazard ratio (aHR) associated with 1 ng/mL increase of BMP10 was 1.60 (95% CI, 1.37-1.87) for all-cause death, and 1.54 (95% CI, 1.35-1.76) for MACE. For all-cause death, the concordance index was 0.783 (95% CI, 0.763-0.809) for BMP10, 0.784 (95% CI, 0.765-0.810) for NT-proBNP, and 0.789 (95% CI, 0.771-0.815) for both biomarkers combined. For MACE, the concordance index was 0.732 (95% CI, 0.715-0.754) for BMP10, 0.747 (95% CI, 0.731-0.768) for NT-proBNP, and 0.750 (95% CI, 0.734-0.771) for both biomarkers combined. When grouping patients according to NT-proBNP categories (<300, 300-900, >900 ng/L), higher aHRs were observed in patients with high BMP10 in the categories of low NT-proBNP (all-cause death aHR, 2.28 [95% CI, 1.15-4.52], MACE aHR, 1.88 [95% CI, 1.07-3.28]) and high NT-proBNP (all-cause death aHR, 1.61 [95% CI, 1.14-2.26], MACE aHR, 1.38 [95% CI, 1.07-1.80]). Conclusions BMP10 strongly predicted all-cause death and MACE in patients with AF. BMP10 provided additional prognostic information in low- and high-risk patients according to NT-proBNP stratification. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02105844.

Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease.

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.

Trimethylamine-N-oxide is associated with cardiovascular mortality and vascular brain lesions in patients with atrial fibrillation.

OBJECTIVE: Trimethylamine-N-oxide (TMAO) is a metabolite derived from the microbial processing of dietary phosphatidylcholine and carnitine and the subsequent hepatic oxidation. Due to its prothrombotic and inflammatory mechanisms, we aimed to assess its role in the prediction of adverse events in a susceptible population, namely patients with atrial fibrillation. METHODS: Baseline TMAO plasma levels were measured by liquid chromatography-tandem mass spectrometry in 2379 subjects from the ongoing Swiss Atrial Fibrillation cohort. 1722 underwent brain MRI at baseline. Participants were prospectively followed for 4 years (Q1-Q3: 3.0-5.0) and stratified into baseline TMAO tertiles. Cox proportional hazards and linear and logistic mixed effect models were employed adjusting for risk factors. RESULTS: Subjects in the highest TMAO tertile were older (75.4±8.1 vs 70.6±8.5 years, p<0.01), had poorer renal function (median glomerular filtration rate: 49.0 mL/min/1.73 m2 (35.6-62.5) vs 67.3 mL/min/1.73 m2 (57.8-78.9), p<0.01), were more likely to have diabetes (26.9% vs 9.1%, p<0.01) and had a higher prevalence of heart failure (37.9% vs 15.8%, p<0.01) compared with patients in the lowest tertile. Oral anticoagulants were taken by 89.1%, 94.0% and 88.2% of participants, respectively (from high to low tertiles). Cox models, adjusting for baseline covariates, showed increased total mortality (HR 1.65, 95% CI 1.17 to 2.32, p<0.01) as well as cardiovascular mortality (HR 1.86, 95% CI 1.21 to 2.88, p<0.01) in the highest compared with the lowest tertile. When present, subjects in the highest tertile had more voluminous, large, non-cortical and cortical infarcts on MRI (log-transformed volumes; exponentiated estimate 1.89, 95% CI 1.11 to 3.21, p=0.02) and a higher chance of small non-cortical infarcts (OR 1.61, 95% CI 1.16 to 2.22, p<0.01). CONCLUSIONS: High levels of TMAO are associated with increased risk of cardiovascular mortality and cerebral infarction in patients with atrial fibrillation. TRIAL REGISTRATION NUMBER: NCT02105844.

Patient clusters and cost trajectories in the Swiss Atrial Fibrillation cohort.

OBJECTIVE: Evidence on long-term costs of atrial fibrillation (AF) and associated factors is scarce. As part of the Swiss-AF prospective cohort study, we aimed to characterise AF costs and their development over time, and to assess specific patient clusters and their cost trajectories. METHODS: Swiss-AF enrolled 2415 patients with variable duration of AF between 2014 and 2017. Patient clusters were identified using hierarchical cluster analysis of baseline characteristics. Ongoing yearly follow-ups include health insurance clinical and claims data. An algorithm was developed to adjudicate costs to AF and related complications. RESULTS: A subpopulation of 1024 Swiss-AF patients with available claims data was followed up for a median (IQR) of 3.24 (1.09) years. Average yearly AF-adjudicated costs amounted to SFr5679 (€5163), remaining stable across the observation period. AF-adjudicated costs consisted mainly of inpatient and outpatient AF treatment costs (SFr4078; €3707), followed by costs of bleeding (SFr696; €633) and heart failure (SFr494; €449). Hierarchical analysis identified three patient clusters: cardiovascular (CV; N=253 with claims), isolated-symptomatic (IS; N=586) and severely morbid without cardiovascular disease (SM; N=185). The CV cluster and SM cluster depicted similarly high costs across all cost outcomes; IS patients accrued the lowest costs. CONCLUSION: Our results highlight three well-defined patient clusters with specific costs that could be used for stratification in both clinical and economic studies. Patient characteristics associated with adjudicated costs as well as cost trajectories may enable an early understanding of the magnitude of upcoming AF-related healthcare costs.